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Medicare Modifications
Physicians who count Medicare among their payers already know the government green-lighted a 1.1% increase in Medicare Part B payments to physicians last summer. The increase was made official by the Centers for Medicare and Medicaid Services (CMS) on Oct. 30, with the release of the Medicare Physician Fee Schedule Final Rule for fiscal year 2009. The Final Rule governs what services are reimbursed by Medicare, the reimbursement levels for those services, and other rules pertaining to Medicare. Many of these changes, additions, and deletions were dictated by the Medicare Improvements for Patients and Providers Act, or MIPPA. (See “MIPPA Matters,” December 2008, p. 18.)
The 2009 Final Rule not only makes official the short-term, 1.1% payment increase, it also marks significant increases in payments for inpatient evaluation and management services, higher bonuses for participation in the Physician Quality Reporting Initiative (PQRI), and new policies to help direct the future of healthcare.
Here is a look at a few of the key aspects of the Final Rule, of which you may not be aware:
Transparent Physicians
In a continued effort to make healthcare transparent, CMS will begin posting the names of physicians who successfully report through the 2009 PQRI on a physician compare Web site in 2010. (2007 and 2008 PQRI participants will not be included.) Just as the Hospital Compare site enables consumers to view data on facilities, this site will allow consumers to view data reported by individual doctors.
Although consumers may be interested in checking for information on their primary care physician, it is unlikely inpatients will check the site before agreeing to see a specific hospitalist. However, the Physician Compare site will have some impact on hospital medicine. “I think this is the beginning of physicians’ commitment to greater transparency,” says Eric Siegal, MD, chair of SHM’s Public Policy Committee. “In a very broad sense, physicians who agree to be listed on the Physician Compare site very clearly value transparency and quality of care. Their inclusion could be seen as a differentiator, though a small one.”
Another factor to consider regarding transparency: “Physician Compare is not just about patients,” Dr. Siegal points out. “Third-party payers will look at this, as well. If they’re looking for someone to help take care of their patients, this data might sway them in their decision.”
Telehealth and Inpatients
Medicare already reimburses for certain exchanges of medical information from off-site physicians or vendors via interactive electronic communications, also known as telehealth or telemedicine services. Under the 2009 Final Rule, CMS will create a new series of Healthcare Common Procedure Coding System (HCPCS) codes for follow-up inpatient telehealth consultations, allowing practitioners to bill for follow-up inpatient consultations delivered via telehealth.
These codes are intended for use by physicians or non-physician providers when an inpatient consultation is requested from an appropriate source, such as the patient’s attending physician. CMS emphasizes the codes are not intended for use in billing for the ongoing evaluation and management of a hospital inpatient.
E-prescribe Out of Reach
Much attention has been given to a new Medicare program, which promotes the widespread adoption of electronic prescribing (e-prescribing). Physicians who successfully participate in CMS’ Electronic Prescribing Incentive Program will earn an extra bonus; however, the program was designed for primary care programs and hospitalists are unlikely to be able to take advantage of this.
“We don’t even know if hospitalists will be able to participate,” Dr. Siegal explains. The only way a hospitalist can take part in the e-prescribing initiative is if the hospital already has an acceptable system. However, Dr. Siegal warns, “If you create a mandate requiring a system for medication reconciliation at discharge, and then require another, separate system for e-prescribing, you’ve got problems. The primary driver should be that the hospital’s system supports both. And as far as we can tell, most hospital systems don’t do this.”
In August, SHM and the American College of Emergency Physicians conducted a teleconference with CMS to voice concerns with the e-prescribe initiative. “What we wanted was an exception,” Dr. Siegal says. SHM’s concern: When CMS stops rewarding physicians for e-prescribing and begins to penalize those who don’t—currently scheduled for 2013—hospitalists who can’t participate will be penalized through their Medicare payments. The outcome of the meeting, Dr. Siegal says, is “CMS turned around and said ‘either you can participate or you can’t.’ But at least they are considering our points; they seem to understand them.”
The good news is there is time to work the problem out, “At the moment, while e-prescribing is all bonus and no penalty, there’s no urgency to address it,” Dr. Siegal says.
Patient Safety
The Final Rule also includes improvements to PQRI, which allows eligible professionals to report on 153 quality measures. Physicians who successfully report on cases during 2009 will be able to earn an incentive payment, which has been increased to 2% (up from 1.5% in 2008), of their total allowed charges for covered professional services.
“I hope that more hospitalists will get on board with this,” Dr. Siegal says. He believes PQRI will be around for a while, and any hospital medicine group waiting to see if it is worth investing in the program can safely do so. “My feeling is that there’s growing bi-partisan support for something like this. I think it’s here to stay,” Dr. Siegal says.
SHM’s Opinion Counts
One reason the Final Rule is especially hospitalist-friendly is because SHM submitted extensive comment on CMS’s proposals in August. “SHM had a fair amount to say, and there are things in the rule that dovetail with our comments,” Dr. Siegal explains. “Part of the challenge is picking which battles to fight; there is a lot covered in this rule. We ended up focusing on areas that were really important to us, and on items where we thought we had a unique voice where nobody else was going to articulate.”
The Final Rule is available at www.cms.hhs.gov/center/physician.asp under “CMS-1403-FC.” Fact sheets covering major provisions of the Final Rule are available at www.cms.hhs.gov/apps/media/ fact_sheets.asp. TH
Jane Jerrard is a medical writer based in Chicago.
Physicians who count Medicare among their payers already know the government green-lighted a 1.1% increase in Medicare Part B payments to physicians last summer. The increase was made official by the Centers for Medicare and Medicaid Services (CMS) on Oct. 30, with the release of the Medicare Physician Fee Schedule Final Rule for fiscal year 2009. The Final Rule governs what services are reimbursed by Medicare, the reimbursement levels for those services, and other rules pertaining to Medicare. Many of these changes, additions, and deletions were dictated by the Medicare Improvements for Patients and Providers Act, or MIPPA. (See “MIPPA Matters,” December 2008, p. 18.)
The 2009 Final Rule not only makes official the short-term, 1.1% payment increase, it also marks significant increases in payments for inpatient evaluation and management services, higher bonuses for participation in the Physician Quality Reporting Initiative (PQRI), and new policies to help direct the future of healthcare.
Here is a look at a few of the key aspects of the Final Rule, of which you may not be aware:
Transparent Physicians
In a continued effort to make healthcare transparent, CMS will begin posting the names of physicians who successfully report through the 2009 PQRI on a physician compare Web site in 2010. (2007 and 2008 PQRI participants will not be included.) Just as the Hospital Compare site enables consumers to view data on facilities, this site will allow consumers to view data reported by individual doctors.
Although consumers may be interested in checking for information on their primary care physician, it is unlikely inpatients will check the site before agreeing to see a specific hospitalist. However, the Physician Compare site will have some impact on hospital medicine. “I think this is the beginning of physicians’ commitment to greater transparency,” says Eric Siegal, MD, chair of SHM’s Public Policy Committee. “In a very broad sense, physicians who agree to be listed on the Physician Compare site very clearly value transparency and quality of care. Their inclusion could be seen as a differentiator, though a small one.”
Another factor to consider regarding transparency: “Physician Compare is not just about patients,” Dr. Siegal points out. “Third-party payers will look at this, as well. If they’re looking for someone to help take care of their patients, this data might sway them in their decision.”
Telehealth and Inpatients
Medicare already reimburses for certain exchanges of medical information from off-site physicians or vendors via interactive electronic communications, also known as telehealth or telemedicine services. Under the 2009 Final Rule, CMS will create a new series of Healthcare Common Procedure Coding System (HCPCS) codes for follow-up inpatient telehealth consultations, allowing practitioners to bill for follow-up inpatient consultations delivered via telehealth.
These codes are intended for use by physicians or non-physician providers when an inpatient consultation is requested from an appropriate source, such as the patient’s attending physician. CMS emphasizes the codes are not intended for use in billing for the ongoing evaluation and management of a hospital inpatient.
E-prescribe Out of Reach
Much attention has been given to a new Medicare program, which promotes the widespread adoption of electronic prescribing (e-prescribing). Physicians who successfully participate in CMS’ Electronic Prescribing Incentive Program will earn an extra bonus; however, the program was designed for primary care programs and hospitalists are unlikely to be able to take advantage of this.
“We don’t even know if hospitalists will be able to participate,” Dr. Siegal explains. The only way a hospitalist can take part in the e-prescribing initiative is if the hospital already has an acceptable system. However, Dr. Siegal warns, “If you create a mandate requiring a system for medication reconciliation at discharge, and then require another, separate system for e-prescribing, you’ve got problems. The primary driver should be that the hospital’s system supports both. And as far as we can tell, most hospital systems don’t do this.”
In August, SHM and the American College of Emergency Physicians conducted a teleconference with CMS to voice concerns with the e-prescribe initiative. “What we wanted was an exception,” Dr. Siegal says. SHM’s concern: When CMS stops rewarding physicians for e-prescribing and begins to penalize those who don’t—currently scheduled for 2013—hospitalists who can’t participate will be penalized through their Medicare payments. The outcome of the meeting, Dr. Siegal says, is “CMS turned around and said ‘either you can participate or you can’t.’ But at least they are considering our points; they seem to understand them.”
The good news is there is time to work the problem out, “At the moment, while e-prescribing is all bonus and no penalty, there’s no urgency to address it,” Dr. Siegal says.
Patient Safety
The Final Rule also includes improvements to PQRI, which allows eligible professionals to report on 153 quality measures. Physicians who successfully report on cases during 2009 will be able to earn an incentive payment, which has been increased to 2% (up from 1.5% in 2008), of their total allowed charges for covered professional services.
“I hope that more hospitalists will get on board with this,” Dr. Siegal says. He believes PQRI will be around for a while, and any hospital medicine group waiting to see if it is worth investing in the program can safely do so. “My feeling is that there’s growing bi-partisan support for something like this. I think it’s here to stay,” Dr. Siegal says.
SHM’s Opinion Counts
One reason the Final Rule is especially hospitalist-friendly is because SHM submitted extensive comment on CMS’s proposals in August. “SHM had a fair amount to say, and there are things in the rule that dovetail with our comments,” Dr. Siegal explains. “Part of the challenge is picking which battles to fight; there is a lot covered in this rule. We ended up focusing on areas that were really important to us, and on items where we thought we had a unique voice where nobody else was going to articulate.”
The Final Rule is available at www.cms.hhs.gov/center/physician.asp under “CMS-1403-FC.” Fact sheets covering major provisions of the Final Rule are available at www.cms.hhs.gov/apps/media/ fact_sheets.asp. TH
Jane Jerrard is a medical writer based in Chicago.
Physicians who count Medicare among their payers already know the government green-lighted a 1.1% increase in Medicare Part B payments to physicians last summer. The increase was made official by the Centers for Medicare and Medicaid Services (CMS) on Oct. 30, with the release of the Medicare Physician Fee Schedule Final Rule for fiscal year 2009. The Final Rule governs what services are reimbursed by Medicare, the reimbursement levels for those services, and other rules pertaining to Medicare. Many of these changes, additions, and deletions were dictated by the Medicare Improvements for Patients and Providers Act, or MIPPA. (See “MIPPA Matters,” December 2008, p. 18.)
The 2009 Final Rule not only makes official the short-term, 1.1% payment increase, it also marks significant increases in payments for inpatient evaluation and management services, higher bonuses for participation in the Physician Quality Reporting Initiative (PQRI), and new policies to help direct the future of healthcare.
Here is a look at a few of the key aspects of the Final Rule, of which you may not be aware:
Transparent Physicians
In a continued effort to make healthcare transparent, CMS will begin posting the names of physicians who successfully report through the 2009 PQRI on a physician compare Web site in 2010. (2007 and 2008 PQRI participants will not be included.) Just as the Hospital Compare site enables consumers to view data on facilities, this site will allow consumers to view data reported by individual doctors.
Although consumers may be interested in checking for information on their primary care physician, it is unlikely inpatients will check the site before agreeing to see a specific hospitalist. However, the Physician Compare site will have some impact on hospital medicine. “I think this is the beginning of physicians’ commitment to greater transparency,” says Eric Siegal, MD, chair of SHM’s Public Policy Committee. “In a very broad sense, physicians who agree to be listed on the Physician Compare site very clearly value transparency and quality of care. Their inclusion could be seen as a differentiator, though a small one.”
Another factor to consider regarding transparency: “Physician Compare is not just about patients,” Dr. Siegal points out. “Third-party payers will look at this, as well. If they’re looking for someone to help take care of their patients, this data might sway them in their decision.”
Telehealth and Inpatients
Medicare already reimburses for certain exchanges of medical information from off-site physicians or vendors via interactive electronic communications, also known as telehealth or telemedicine services. Under the 2009 Final Rule, CMS will create a new series of Healthcare Common Procedure Coding System (HCPCS) codes for follow-up inpatient telehealth consultations, allowing practitioners to bill for follow-up inpatient consultations delivered via telehealth.
These codes are intended for use by physicians or non-physician providers when an inpatient consultation is requested from an appropriate source, such as the patient’s attending physician. CMS emphasizes the codes are not intended for use in billing for the ongoing evaluation and management of a hospital inpatient.
E-prescribe Out of Reach
Much attention has been given to a new Medicare program, which promotes the widespread adoption of electronic prescribing (e-prescribing). Physicians who successfully participate in CMS’ Electronic Prescribing Incentive Program will earn an extra bonus; however, the program was designed for primary care programs and hospitalists are unlikely to be able to take advantage of this.
“We don’t even know if hospitalists will be able to participate,” Dr. Siegal explains. The only way a hospitalist can take part in the e-prescribing initiative is if the hospital already has an acceptable system. However, Dr. Siegal warns, “If you create a mandate requiring a system for medication reconciliation at discharge, and then require another, separate system for e-prescribing, you’ve got problems. The primary driver should be that the hospital’s system supports both. And as far as we can tell, most hospital systems don’t do this.”
In August, SHM and the American College of Emergency Physicians conducted a teleconference with CMS to voice concerns with the e-prescribe initiative. “What we wanted was an exception,” Dr. Siegal says. SHM’s concern: When CMS stops rewarding physicians for e-prescribing and begins to penalize those who don’t—currently scheduled for 2013—hospitalists who can’t participate will be penalized through their Medicare payments. The outcome of the meeting, Dr. Siegal says, is “CMS turned around and said ‘either you can participate or you can’t.’ But at least they are considering our points; they seem to understand them.”
The good news is there is time to work the problem out, “At the moment, while e-prescribing is all bonus and no penalty, there’s no urgency to address it,” Dr. Siegal says.
Patient Safety
The Final Rule also includes improvements to PQRI, which allows eligible professionals to report on 153 quality measures. Physicians who successfully report on cases during 2009 will be able to earn an incentive payment, which has been increased to 2% (up from 1.5% in 2008), of their total allowed charges for covered professional services.
“I hope that more hospitalists will get on board with this,” Dr. Siegal says. He believes PQRI will be around for a while, and any hospital medicine group waiting to see if it is worth investing in the program can safely do so. “My feeling is that there’s growing bi-partisan support for something like this. I think it’s here to stay,” Dr. Siegal says.
SHM’s Opinion Counts
One reason the Final Rule is especially hospitalist-friendly is because SHM submitted extensive comment on CMS’s proposals in August. “SHM had a fair amount to say, and there are things in the rule that dovetail with our comments,” Dr. Siegal explains. “Part of the challenge is picking which battles to fight; there is a lot covered in this rule. We ended up focusing on areas that were really important to us, and on items where we thought we had a unique voice where nobody else was going to articulate.”
The Final Rule is available at www.cms.hhs.gov/center/physician.asp under “CMS-1403-FC.” Fact sheets covering major provisions of the Final Rule are available at www.cms.hhs.gov/apps/media/ fact_sheets.asp. TH
Jane Jerrard is a medical writer based in Chicago.
Beware Office Politics
Hospitalists routinely confront clinical, administrative, and ethical issues. Sometimes they face less-identifiable issues, such as office politics. Webster’s Dictionary defines office politics as “factional scheming for power and status within a group.” Wikipedia describes office politics as “the use of one’s individual or assigned power within an employing organization for the purpose of obtaining advantages beyond one’s legitimate authority.”
How much does office politics affect hospital medicine?
“Of course there is office politics in any work environment,” says Heather A. Harris, MD, former director of Eden Inpatient Services in Castro Valley, Calif., and currently splitting time as a hospitalist at the University of California San Francisco and the Palo Alto Medical Foundation. Dr. Harris, however, believes office politics is rare within hospital medicine because, “It is a young field and a growing field; everyone is growing together, so things tend to be pretty democratic. This is especially true of newer groups.”
Then again, there are times hospitalists find themselves embroiled in office politics. When this happens, what should you do?
Take the High Ground
Although she’s encountered few cases of office politics in her career, Dr. Harris’ general advice for hospitalists is, “First, recognize it, and then try to be a good team player.” Stay above the fray and try to tread carefully around political situations, especially if you’re a manager or informal leader.
Mary Jo Gorman, MD, MBA, CEO of Advanced ICU Care in St. Louis, and former SHM president, advises hospitalists and group directors to “take the high ground, no matter how frustrated you become.” She stresses discretion: “You can talk about it to your spouse, but if you’re a leader, you can’t even [comment on someone’s behavior] in front of your group. You never know, especially if you’re in a relatively small community, when you’re going to need someone’s support. You need to stay on good terms with people.” Dr. Gorman’s advice for leaders holds true for individuals hospitalists caught up in office politics.
Power Struggles
The role hospital medicine groups play as change agents probably is the main reason office politics may develop. “Any time you’re introducing a new concept that somebody feels threatened by, you’re going to incur some defensive maneuvers,” Dr. Gorman warns. “Whether you’re introducing a new hospital medicine group, or trying to change something, like the admissions process in the emergency room, you’re going to disrupt someone’s actions. Then you’ll find a whole broad range of reactions. And the more a person feels threatened, the more aggressive they’ll become.”
Based on her experiences establishing Eden Inpatient Services in 2003, Dr. Harris knows bringing a hospital medicine group into a hospital for the first time can be “a very political situation.” You can be stepping on personal, professional, and financial toes. “When you’re part of a new hospital medicine group … you’re potentially poised to take a lot of business away from people,” Dr. Harris explains. “It’s difficult to navigate those waters and build relationships” with physicians you’re consulting with and with primary care physicians. “In a way, this even extends to nurses,” she says. “You’re suddenly going to be working with them on patient care, and changing the way they work.” Dr. Harris encourages hospitalists to be aware of touchy situations, so as not to inadvertently fuel the fire of office politics. “Especially for young physicians just starting out, there can be a lack of recognition of other people’s feelings and turfs,” she cautions.
Hospitalists faced with an office issue should combine the cautionary approach with a willingness to work with people, even those who are engaging in office politics. “When you’re implementing a change, regardless of what it is, you need to identify who will think it’s a good thing and who will not,” Dr. Gorman advises. “You need to speak with individuals in the latter group, or choose others to speak to them, to garner their support.”
Take, for example, proposing a new project for your hospital’s Quality Improvement committee. A cautionary approach and team building will go a long way. “You’ve got to get to the people on the committee ahead of time, explain what you want to do, and get their feedback and support,” Dr. Gorman says. “If you find someone who opposes it, make sure you have enough support to override them. Or, better yet, find someone who can approach them on the topic, maybe their partner or another member of their group. This is a very practical approach.”
Identify Informal Leadership
When considering this inclusive approach, don’t forget the indirect leadership. “You may have a member of the medical staff who has some informal authority or power, maybe they have the most years of experience, or bring a lot of patients to the hospital, or maybe they are a member of the same group as someone in power,” Dr. Gorman says. “These informal leaders can create a lot of disturbance.”
To avoid problems, either direct or indirect, with these types of people, identify them early and make it a point to include them in the plan. “Usually, you know who holds informal power within your organization or the hospital,” Dr. Gorman says. “All you have to do is talk to them and explain what you’re doing. No one likes to be surprised. You might have to make some changes to accommodate their concerns.”
If this tactic fails and you still face opposition, you might have to weigh how important the opposition is. “You may decide to move ahead, even if you have to make changes and the project takes more time,” she says. “For physicians working in hospitals, we’re all used to instant results. You have to understand that process change takes time and you may have to take something bit by bit, and not get immediate results or responses.”
Be tactful about other professionals’ territories and feelings. Keep communication open and avoid springing surprises on stakeholders. Most importantly, stick to the high ground. These simple steps can help you stay far from the minefield known as office politics. TH
Jane Jerrard is a medical writer based in Chicago. She also writes “Public Policy” for The Hospitalist.
Hospitalists routinely confront clinical, administrative, and ethical issues. Sometimes they face less-identifiable issues, such as office politics. Webster’s Dictionary defines office politics as “factional scheming for power and status within a group.” Wikipedia describes office politics as “the use of one’s individual or assigned power within an employing organization for the purpose of obtaining advantages beyond one’s legitimate authority.”
How much does office politics affect hospital medicine?
“Of course there is office politics in any work environment,” says Heather A. Harris, MD, former director of Eden Inpatient Services in Castro Valley, Calif., and currently splitting time as a hospitalist at the University of California San Francisco and the Palo Alto Medical Foundation. Dr. Harris, however, believes office politics is rare within hospital medicine because, “It is a young field and a growing field; everyone is growing together, so things tend to be pretty democratic. This is especially true of newer groups.”
Then again, there are times hospitalists find themselves embroiled in office politics. When this happens, what should you do?
Take the High Ground
Although she’s encountered few cases of office politics in her career, Dr. Harris’ general advice for hospitalists is, “First, recognize it, and then try to be a good team player.” Stay above the fray and try to tread carefully around political situations, especially if you’re a manager or informal leader.
Mary Jo Gorman, MD, MBA, CEO of Advanced ICU Care in St. Louis, and former SHM president, advises hospitalists and group directors to “take the high ground, no matter how frustrated you become.” She stresses discretion: “You can talk about it to your spouse, but if you’re a leader, you can’t even [comment on someone’s behavior] in front of your group. You never know, especially if you’re in a relatively small community, when you’re going to need someone’s support. You need to stay on good terms with people.” Dr. Gorman’s advice for leaders holds true for individuals hospitalists caught up in office politics.
Power Struggles
The role hospital medicine groups play as change agents probably is the main reason office politics may develop. “Any time you’re introducing a new concept that somebody feels threatened by, you’re going to incur some defensive maneuvers,” Dr. Gorman warns. “Whether you’re introducing a new hospital medicine group, or trying to change something, like the admissions process in the emergency room, you’re going to disrupt someone’s actions. Then you’ll find a whole broad range of reactions. And the more a person feels threatened, the more aggressive they’ll become.”
Based on her experiences establishing Eden Inpatient Services in 2003, Dr. Harris knows bringing a hospital medicine group into a hospital for the first time can be “a very political situation.” You can be stepping on personal, professional, and financial toes. “When you’re part of a new hospital medicine group … you’re potentially poised to take a lot of business away from people,” Dr. Harris explains. “It’s difficult to navigate those waters and build relationships” with physicians you’re consulting with and with primary care physicians. “In a way, this even extends to nurses,” she says. “You’re suddenly going to be working with them on patient care, and changing the way they work.” Dr. Harris encourages hospitalists to be aware of touchy situations, so as not to inadvertently fuel the fire of office politics. “Especially for young physicians just starting out, there can be a lack of recognition of other people’s feelings and turfs,” she cautions.
Hospitalists faced with an office issue should combine the cautionary approach with a willingness to work with people, even those who are engaging in office politics. “When you’re implementing a change, regardless of what it is, you need to identify who will think it’s a good thing and who will not,” Dr. Gorman advises. “You need to speak with individuals in the latter group, or choose others to speak to them, to garner their support.”
Take, for example, proposing a new project for your hospital’s Quality Improvement committee. A cautionary approach and team building will go a long way. “You’ve got to get to the people on the committee ahead of time, explain what you want to do, and get their feedback and support,” Dr. Gorman says. “If you find someone who opposes it, make sure you have enough support to override them. Or, better yet, find someone who can approach them on the topic, maybe their partner or another member of their group. This is a very practical approach.”
Identify Informal Leadership
When considering this inclusive approach, don’t forget the indirect leadership. “You may have a member of the medical staff who has some informal authority or power, maybe they have the most years of experience, or bring a lot of patients to the hospital, or maybe they are a member of the same group as someone in power,” Dr. Gorman says. “These informal leaders can create a lot of disturbance.”
To avoid problems, either direct or indirect, with these types of people, identify them early and make it a point to include them in the plan. “Usually, you know who holds informal power within your organization or the hospital,” Dr. Gorman says. “All you have to do is talk to them and explain what you’re doing. No one likes to be surprised. You might have to make some changes to accommodate their concerns.”
If this tactic fails and you still face opposition, you might have to weigh how important the opposition is. “You may decide to move ahead, even if you have to make changes and the project takes more time,” she says. “For physicians working in hospitals, we’re all used to instant results. You have to understand that process change takes time and you may have to take something bit by bit, and not get immediate results or responses.”
Be tactful about other professionals’ territories and feelings. Keep communication open and avoid springing surprises on stakeholders. Most importantly, stick to the high ground. These simple steps can help you stay far from the minefield known as office politics. TH
Jane Jerrard is a medical writer based in Chicago. She also writes “Public Policy” for The Hospitalist.
Hospitalists routinely confront clinical, administrative, and ethical issues. Sometimes they face less-identifiable issues, such as office politics. Webster’s Dictionary defines office politics as “factional scheming for power and status within a group.” Wikipedia describes office politics as “the use of one’s individual or assigned power within an employing organization for the purpose of obtaining advantages beyond one’s legitimate authority.”
How much does office politics affect hospital medicine?
“Of course there is office politics in any work environment,” says Heather A. Harris, MD, former director of Eden Inpatient Services in Castro Valley, Calif., and currently splitting time as a hospitalist at the University of California San Francisco and the Palo Alto Medical Foundation. Dr. Harris, however, believes office politics is rare within hospital medicine because, “It is a young field and a growing field; everyone is growing together, so things tend to be pretty democratic. This is especially true of newer groups.”
Then again, there are times hospitalists find themselves embroiled in office politics. When this happens, what should you do?
Take the High Ground
Although she’s encountered few cases of office politics in her career, Dr. Harris’ general advice for hospitalists is, “First, recognize it, and then try to be a good team player.” Stay above the fray and try to tread carefully around political situations, especially if you’re a manager or informal leader.
Mary Jo Gorman, MD, MBA, CEO of Advanced ICU Care in St. Louis, and former SHM president, advises hospitalists and group directors to “take the high ground, no matter how frustrated you become.” She stresses discretion: “You can talk about it to your spouse, but if you’re a leader, you can’t even [comment on someone’s behavior] in front of your group. You never know, especially if you’re in a relatively small community, when you’re going to need someone’s support. You need to stay on good terms with people.” Dr. Gorman’s advice for leaders holds true for individuals hospitalists caught up in office politics.
Power Struggles
The role hospital medicine groups play as change agents probably is the main reason office politics may develop. “Any time you’re introducing a new concept that somebody feels threatened by, you’re going to incur some defensive maneuvers,” Dr. Gorman warns. “Whether you’re introducing a new hospital medicine group, or trying to change something, like the admissions process in the emergency room, you’re going to disrupt someone’s actions. Then you’ll find a whole broad range of reactions. And the more a person feels threatened, the more aggressive they’ll become.”
Based on her experiences establishing Eden Inpatient Services in 2003, Dr. Harris knows bringing a hospital medicine group into a hospital for the first time can be “a very political situation.” You can be stepping on personal, professional, and financial toes. “When you’re part of a new hospital medicine group … you’re potentially poised to take a lot of business away from people,” Dr. Harris explains. “It’s difficult to navigate those waters and build relationships” with physicians you’re consulting with and with primary care physicians. “In a way, this even extends to nurses,” she says. “You’re suddenly going to be working with them on patient care, and changing the way they work.” Dr. Harris encourages hospitalists to be aware of touchy situations, so as not to inadvertently fuel the fire of office politics. “Especially for young physicians just starting out, there can be a lack of recognition of other people’s feelings and turfs,” she cautions.
Hospitalists faced with an office issue should combine the cautionary approach with a willingness to work with people, even those who are engaging in office politics. “When you’re implementing a change, regardless of what it is, you need to identify who will think it’s a good thing and who will not,” Dr. Gorman advises. “You need to speak with individuals in the latter group, or choose others to speak to them, to garner their support.”
Take, for example, proposing a new project for your hospital’s Quality Improvement committee. A cautionary approach and team building will go a long way. “You’ve got to get to the people on the committee ahead of time, explain what you want to do, and get their feedback and support,” Dr. Gorman says. “If you find someone who opposes it, make sure you have enough support to override them. Or, better yet, find someone who can approach them on the topic, maybe their partner or another member of their group. This is a very practical approach.”
Identify Informal Leadership
When considering this inclusive approach, don’t forget the indirect leadership. “You may have a member of the medical staff who has some informal authority or power, maybe they have the most years of experience, or bring a lot of patients to the hospital, or maybe they are a member of the same group as someone in power,” Dr. Gorman says. “These informal leaders can create a lot of disturbance.”
To avoid problems, either direct or indirect, with these types of people, identify them early and make it a point to include them in the plan. “Usually, you know who holds informal power within your organization or the hospital,” Dr. Gorman says. “All you have to do is talk to them and explain what you’re doing. No one likes to be surprised. You might have to make some changes to accommodate their concerns.”
If this tactic fails and you still face opposition, you might have to weigh how important the opposition is. “You may decide to move ahead, even if you have to make changes and the project takes more time,” she says. “For physicians working in hospitals, we’re all used to instant results. You have to understand that process change takes time and you may have to take something bit by bit, and not get immediate results or responses.”
Be tactful about other professionals’ territories and feelings. Keep communication open and avoid springing surprises on stakeholders. Most importantly, stick to the high ground. These simple steps can help you stay far from the minefield known as office politics. TH
Jane Jerrard is a medical writer based in Chicago. She also writes “Public Policy” for The Hospitalist.
The latest research you need to know
In This Edition
- Aspirin plus extended-release dipyridamole and clopidogrel provide similar outcomes in stroke.
- Traditional readings of bedside chest radiographs are insensitive in detecting intraatrial central venous catheter placement.
- Improved outcomes with bortezomib in myeloma treatment.
- ICD firings in cardiomyopathy patients are associated with worse outcomes.
- The clinical dehydration scale rapidly assesses the severity of dehydration in children.
- Liberal red blood cell transfusions may be harming patients.
- Five-year risk of colorectal neoplasia is low in patients with negative screening colonoscopy.
- Vital sign instability and oxygenation predict prognosis following hospitalization for community acquired pneumonia.
Is aspirin plus extended release dipyridamole more efficacious and safer than clopidogrel in preventing recurrent stroke?
Background: Recurrent stroke is a frequent (7% to 8% thrombotic stroke recurrence in first year) and disabling event after ischemic stroke. Multiple randomized trials demonstrate efficacy of anti-platelet agents for the prevention of recurrent stroke after non-cardioembolic stroke. However, direct comparisons and relative benefits of various antiplatelet agents are not well defined.
Study design: Randomized, double-blinded, two-by-two factorial design with intention-to-treat analysis.
Setting: A total of 20,333 patients from 695 centers in 35 countries, including the U.S.
Synopsis: This study directly compared aspirin plus extended-release dipyridamole to clopidogrel within the PRoFESS trial. A total of 20,333 patients were enrolled and followed up for a mean duration of 2.5 years. Eligible patients randomly were assigned to receive either 25 mg aspirin plus 200 mg extended-release twice a day, or clopidogrel 75 mg a day; and either telmisartan 80 mg once a day or placebo. Groups were similar at baseline.
The primary outcome of recurrent stroke was similar in both the aspirin plus extended-release dipyrimadole group and the clopidogrel group (9.0% vs. 8.8%). The composite secondary outcome of stroke, myocardial infarction or vascular death, and tertiary outcomes were similar in both groups. The trial showed statistical equivalence in the rates of recurrent stroke in the two groups.
Despite more frequent hemorrhagic strokes in the group receiving aspirin plus extended-release dipyridamole (4.1% vs. 3.6%), there was no significant difference in the risk of fatal or disabling stroke between both the groups.
Bottom line: Aspirin plus extended-release dipyridamole is equivalent to clopidogrel in the prevention of recurrent stroke, in terms of relevant efficacy and safety parameters.
Citation: Sacco RL, Diener H, Yusuf S, et.al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008:359:1238-1251.
Is there a better method to judge the placement of central venous catheters?
Background: Placement of central venous catheters is common, particularly in critical care settings. Correct placement is usually confirmed by bedside chest radiography. The recommended location of the distal catheter tip is superior to the superior vena cava and right atria junction. However, determining this landmark on traditional bedside chest radiographs is frequently inaccurate.
Study design: Prospective, blinded study.
Setting: University hospital in Germany.
Synopsis: The researchers enrolled 212 patients scheduled for elective cardiac surgery. Either left or right internal jugular vein central lines were placed via EKG guidance, and more precisely evaluated by transesophageal echocardiography. Bedside chest radiographs were performed within three hours of admission to the ICU.
The radiologists were able to detect between 40% and 60% of incorrect central venous catheter placements when compared to transesophageal echocardiography. The researchers concluded TC-distance (tip of catheter to carina) of greater than 55 mm on chest X-ray performed better (98% accurate) in the detection of intra-atrial catheter placement, compared to conventional judgment by attending (93% accurate) or resident (53% accurate) radiologists. Limitations of the study include the use of only one attending radiologist. Secondly, the chest radiographs and echocardiograms were not done simultaneously, allowing for possible movement of the catheters between studies.
Bottom line: A TC distance of greater than 55 mm on chest X-ray should be further investigated as an accurate method to detect intra-atrial central venous catheters.
Citation: Wirsing M, Schummer C, Neumann R, et al. Is traditional reading of the bedside chest radiograph appropriate to detect intra-atrial central venous catheter position? Chest. 2008;134:527-533.
Does adding bortezomib to melphalan and prednisone improve outcomes in newly diagnosed myeloma?
Background: More than 50% of newly diagnosed myeloma patients are older than 65 and cannot receive optimal treatment with high-dose chemotherapy and stem-cell transplant. Previous trials have demonstrated patients with relapsed or refractory myeloma benefit from the administration of bortezomib, which sensitizes the myeloma cell lines to melphalan.
Study design: Randomized, open-label (unblinded) phase 3 study.
Setting: 151 centers, 22 countries in Asia, Europe, South and North America.
Synopsis: 682 patients with untreated multiple myeloma, who were ineligible for high-dose chemotherapy and stem cell transplant, were treated with bortezomib in combination with standard melphalan and prednisone, or melphalan and prednisone alone. The bortezomib group had improved partial or complete response (71% vs. 35%; NNT=3; p<0.001), increased median time to progression of disease (19.9 months vs. 13.1 months), and improved overall survival (87% vs. 78% over a 16-month median follow up; NNT=11; p=0.008). There were increased grade 3 adverse effects with the intervention, but no increase in grade 4 events or treatment related deaths compared to control. Limitations of the study include lack of blinding and involvement of the pharmaceutical company in data collection analysis, writing and editing of the manuscript.
Bottom line: Bortezomib is a valuable adjunct to standard treatment of multiple myeloma in patients over the age of 65 who may be ineligible for high-dose chemotherapy and stem cell transplant.
Citation: San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for the initial treatment of multiple myeloma. NEJM. 2008;359:906-917.
Does the occurrence of a shock increase the risk of death in cardiomyopathy patients with defibrillators?
Background: The SCD-HeFT trial, originally published in 2005, was instrumental in demonstrating the utility of defibrillators in the primary prevention of sudden cardiac deaths in patients with either ischemic or non-ischemic cardiomyopathy, NYHA class II or III, ejection fraction <35%, and no history of sustained ventricular tachycardia or fibrillation. This study re-examined the data derived from the SCD-HeFT trial to better understand the long-term prognosis of these patients with defibrillators who receive either appropriate shocks (ventricular fibrillation, sustained ventricular tachycardia), inappropriate shocks, or no shocks. Inappropriate shocks were defined as defibrillations due to supraventricular tachycardia, oversensing P or T waves as R waves, double counting of R waves, and artifact.
Study design: Retrospective cohort (analysis of patients randomized to implantable cardioverter-defibrillator (ICD) group in SCD-HeFT).
Setting: Multicenter trial.
Synopsis: The analysis demonstrated patients who received shocks were 11 times more likely to die compared with those who had no defibrillations (Hazard Ratio [HR]=11.3, p<0.001). These shocked patients were at more risk (HR=5.7, p<0.001) than those with inappropriate shocks (HR=2.0, p=0.002). Therefore, even inappropriate shocks themselves doubled the risk of death. Patients who received more than one shock, either appropriate or not, were at even higher odds of death (HR=8.3, p<0.001). The results highlight the higher mortality risk when patients with ICDs have received a shock (appropriate or inappropriate) and the need for further therapies to modify outcome in these patients.
Bottom Line: Appropriate or inappropriate defibrillations are associated with a poorer prognosis in patients with cardiomyopathy.
Citation: Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008(359):1009-1017.
Can a simple physical exam tool assess the degree of dehydration in children?
Background: Despite the frequency and the associated cost of acute gastroenteritis (AGE) in the pediatric population, there is no unified scale to assess the severity of dehydration. The authors of this paper previously reported a clinical dehydration scale (CDS) and applied it prospectively in a new cohort of patients ages 1 month to 5 years.
Study design: Prospective, observational study.
Setting: Single, tertiary care emergency department (ED) in Canada.
Synopsis: The CDS score is based purely on the physical findings of the child, including a) general appearance, b) eyes, c) mucous membranes, and d) amount of tears. On a point system, the patient is placed in one of three categories: no dehydration, some dehydration, moderate/severe dehydration. The trial enrolled 205 children and the CDS was applied by the triaging nurse. The attending ED pediatricians were blinded from this assessment. The CDS was able to predict the length of stay (mean + SD: no dehyrdation 245 + 181 mins; some dehydration, 397 + 302 mins; mod/severe dehydration, 501 + 389 mins), need for intravenous rehydration (none, 15%; some, 49%; mod/severe, 80%), and frequency of emesis/diarrhea as reported by the parents (none, 8.4 + 7.7; some, 13 + 10.7; mod/severe, 30.2 + 14.8). Only five children were categorized in the moderate/severe dehydration category, which may limit the ability to generalize the scoring system to that group of patients.
Bottom line: The CDS is an easy to use and promising tool to assess the severity of illness, expected ED length of stay, and need for intravenous rehydration in children with acute gastroenteritis.
Citation: Goldman RD, Friedman JN, Parkin PC. Validation of the clinical dehydration scale for children with acute gastroenteritis. Pediatrics. 2008;122(3):545-549.
Does maintaining a higher hemoglobin level benefit critical care patients?
Background: Historically, medical and surgical critical care patients liberally were transfused with little prospective evidence to support this approach. However, recent evidence has led to the use of a more-restricted transfusion threshold.
Study design: Systematic review and meta-analysis of cohort studies evaluating the effect of red blood cell (RBC) transfusion on patient outcomes.
Setting: Data sources include MEDLINE, Embase, and Cochrane databases.
Synopsis: The 45 cohort studies, including more than 272,000 patients, were selected due to focus on outcome measures, such as mortality, multiorgan dysfunction, acute respiratory distress syndrome, and infections. Primary studies were then placed into one of three categories: benefits outweigh the risk, neutral, or risks outweigh the benefit. Forty-two of these studies found the risks outweigh the benefits; two were neutral; and only one sub-study (in elderly patients with acute myocardial infarctions) suggested benefit outweighs the risk.
Although a systematic review of cohort studies has inherent limitations, the overwhelming direction of the results suggests statistically significant harm due to liberal transfusion practices (Summary Odd Ratios [OR] for a) death, OR = 1.69; b) infection, OR = 1.88; and c) Acute Respiratory Distress Syndrome, OR = 2.5). Due to the observational nature of the cohort studies, one might suspect RBC transfusions could simply reflect patient severity of illness. Thus, the harm suggested by the more liberal transfusion standards could just reflect the fact these patients carried a worse prognosis due to their respective illnesses.
Bottom Line: The preponderance of evidence suggests liberal transfusion practice is associated with increased morbidity and mortality of ICU patients. When considering RBC transfusions, the risks and benefits to each individual patient should be considered carefully.
Citation: Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008; 36(9);2667-2674.
What is the appropriate frequency of rescreening for patients with initial screening colonoscopies negative for adenomas?
Background: Colonoscopy is the preferred primary screening method for the detection of colorectal cancer and precancerous polyps. Data suggest colonoscopy may be performed too frequently and for inappropriate indications.
Study design: Retrospective cohort study.
Setting: Seven sites in central Indiana.
Synopsis: In this study of 2,436 persons with no adenomas on baseline screening colonoscopies, 1,256 of them (51.6%) were rescreened a mean of 5.34 + 1.34 years later. No cancers were found on rescreening. One or more adenomas were found in 201 persons (16.0%). Nineteen advanced adenomas were found in 16 persons (1.3%). Patients in this study were relatively young (mean age at baseline was 56.7 years). Men were more likely than women to have adenomas (RR 1.88; 95% CI 1.42-2.51) and to have advanced adenomas (RR 3.31; 95% CI 1.02-10.8).
Limitations included a small cohort sample size, as well as incomplete information on persons who did not follow up with the five-year examination. Also, there is uncertainty about the clinical significance of advanced adenomas.
Bottom Line: Among persons previously screened with colonoscopy who have no colorectal adenomas, the five-year risk of detecting an advanced adenoma is extremely low (1.3%), supporting a rescreening interval of more than five years after a normal colonoscopy. Men have greater risk, and may deserve a shorter interval screening.
Citation: Imperiale TF, Glowinski EA, Lin-Cooper C, et al. Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med. 2008;359:1218-1224.
Can validated discharge instability criteria predict mortality or readmission within 30 days of hospital discharge for community acquired pneumonia (CAP)?
Background: Prior prospective cohort data have delineated instability criteria utilizing vital sign criteria at hospital discharge for CAP. However, guidelines for determining patient readiness for discharge remain largely unstudied.
Study design: Prospective, observational cohort study.
Setting: A single, non-urban teaching hospital in Spain.
Synopsis: In this study, 870 adults with CAP were evaluated following discharge. Abnormal oxygenation and vital signs were utilized to calculate an instability score. Criteria for instability were defined as temperature >37.5° C, heart rate <100, respiratory rate >24, systolic blood pressure (SBP) <90 (or diastolic blood pressure, DBP <60), and oxygen saturation <90% (or PaO2 <60).
Of all the instability criteria, only low oxygenation predicted readmission at 30 days (Hazard Ratio [HR] 1.4, p=0.03). However, mortality was significantly increased when instability criteria of temperature (HR 4.5, p=0.04), blood pressure (HR 2.6, p=0.02), respiratory rate (HR 2.4, p=0.03), or oxygenation (HR 2.4, p=0.03) were met. Elevated heart rate was not found to predict death.
The authors assigned each of the significant instability criteria a score of one or two (based on the weight of its hazard ratio), with respiratory rate, low blood pressure, and low oxygenation each assigned one point, and temperature assigned two points. Patients with an instability score of two or more had a six-fold increased risk of death (HR 5.8; 95%, p=0.0001). The negative predictive value (NPV) of an instability score less than two was very helpful (NPV=98%) in identifying patients with low mortality risk; however, the positive predictive value (PPV) of an instability score >2 is not necessarily helpful (PPV=13%) clinically.
Bottom line: Patients with a temperature >37.5° C or any combination of RR >24, SBP <90 (or DBP <60), and SpO2 <90% (or Pa02 <60) are at increased risk of death. Identifying a low instability score is most helpful in clinical practice.
Citation: Capelastegui A, Espana P, Bilbao A, et al. Pneumonia: criteria for patient instability on hospital discharge. Chest. 2008;34:595-600.
In This Edition
- Aspirin plus extended-release dipyridamole and clopidogrel provide similar outcomes in stroke.
- Traditional readings of bedside chest radiographs are insensitive in detecting intraatrial central venous catheter placement.
- Improved outcomes with bortezomib in myeloma treatment.
- ICD firings in cardiomyopathy patients are associated with worse outcomes.
- The clinical dehydration scale rapidly assesses the severity of dehydration in children.
- Liberal red blood cell transfusions may be harming patients.
- Five-year risk of colorectal neoplasia is low in patients with negative screening colonoscopy.
- Vital sign instability and oxygenation predict prognosis following hospitalization for community acquired pneumonia.
Is aspirin plus extended release dipyridamole more efficacious and safer than clopidogrel in preventing recurrent stroke?
Background: Recurrent stroke is a frequent (7% to 8% thrombotic stroke recurrence in first year) and disabling event after ischemic stroke. Multiple randomized trials demonstrate efficacy of anti-platelet agents for the prevention of recurrent stroke after non-cardioembolic stroke. However, direct comparisons and relative benefits of various antiplatelet agents are not well defined.
Study design: Randomized, double-blinded, two-by-two factorial design with intention-to-treat analysis.
Setting: A total of 20,333 patients from 695 centers in 35 countries, including the U.S.
Synopsis: This study directly compared aspirin plus extended-release dipyridamole to clopidogrel within the PRoFESS trial. A total of 20,333 patients were enrolled and followed up for a mean duration of 2.5 years. Eligible patients randomly were assigned to receive either 25 mg aspirin plus 200 mg extended-release twice a day, or clopidogrel 75 mg a day; and either telmisartan 80 mg once a day or placebo. Groups were similar at baseline.
The primary outcome of recurrent stroke was similar in both the aspirin plus extended-release dipyrimadole group and the clopidogrel group (9.0% vs. 8.8%). The composite secondary outcome of stroke, myocardial infarction or vascular death, and tertiary outcomes were similar in both groups. The trial showed statistical equivalence in the rates of recurrent stroke in the two groups.
Despite more frequent hemorrhagic strokes in the group receiving aspirin plus extended-release dipyridamole (4.1% vs. 3.6%), there was no significant difference in the risk of fatal or disabling stroke between both the groups.
Bottom line: Aspirin plus extended-release dipyridamole is equivalent to clopidogrel in the prevention of recurrent stroke, in terms of relevant efficacy and safety parameters.
Citation: Sacco RL, Diener H, Yusuf S, et.al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008:359:1238-1251.
Is there a better method to judge the placement of central venous catheters?
Background: Placement of central venous catheters is common, particularly in critical care settings. Correct placement is usually confirmed by bedside chest radiography. The recommended location of the distal catheter tip is superior to the superior vena cava and right atria junction. However, determining this landmark on traditional bedside chest radiographs is frequently inaccurate.
Study design: Prospective, blinded study.
Setting: University hospital in Germany.
Synopsis: The researchers enrolled 212 patients scheduled for elective cardiac surgery. Either left or right internal jugular vein central lines were placed via EKG guidance, and more precisely evaluated by transesophageal echocardiography. Bedside chest radiographs were performed within three hours of admission to the ICU.
The radiologists were able to detect between 40% and 60% of incorrect central venous catheter placements when compared to transesophageal echocardiography. The researchers concluded TC-distance (tip of catheter to carina) of greater than 55 mm on chest X-ray performed better (98% accurate) in the detection of intra-atrial catheter placement, compared to conventional judgment by attending (93% accurate) or resident (53% accurate) radiologists. Limitations of the study include the use of only one attending radiologist. Secondly, the chest radiographs and echocardiograms were not done simultaneously, allowing for possible movement of the catheters between studies.
Bottom line: A TC distance of greater than 55 mm on chest X-ray should be further investigated as an accurate method to detect intra-atrial central venous catheters.
Citation: Wirsing M, Schummer C, Neumann R, et al. Is traditional reading of the bedside chest radiograph appropriate to detect intra-atrial central venous catheter position? Chest. 2008;134:527-533.
Does adding bortezomib to melphalan and prednisone improve outcomes in newly diagnosed myeloma?
Background: More than 50% of newly diagnosed myeloma patients are older than 65 and cannot receive optimal treatment with high-dose chemotherapy and stem-cell transplant. Previous trials have demonstrated patients with relapsed or refractory myeloma benefit from the administration of bortezomib, which sensitizes the myeloma cell lines to melphalan.
Study design: Randomized, open-label (unblinded) phase 3 study.
Setting: 151 centers, 22 countries in Asia, Europe, South and North America.
Synopsis: 682 patients with untreated multiple myeloma, who were ineligible for high-dose chemotherapy and stem cell transplant, were treated with bortezomib in combination with standard melphalan and prednisone, or melphalan and prednisone alone. The bortezomib group had improved partial or complete response (71% vs. 35%; NNT=3; p<0.001), increased median time to progression of disease (19.9 months vs. 13.1 months), and improved overall survival (87% vs. 78% over a 16-month median follow up; NNT=11; p=0.008). There were increased grade 3 adverse effects with the intervention, but no increase in grade 4 events or treatment related deaths compared to control. Limitations of the study include lack of blinding and involvement of the pharmaceutical company in data collection analysis, writing and editing of the manuscript.
Bottom line: Bortezomib is a valuable adjunct to standard treatment of multiple myeloma in patients over the age of 65 who may be ineligible for high-dose chemotherapy and stem cell transplant.
Citation: San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for the initial treatment of multiple myeloma. NEJM. 2008;359:906-917.
Does the occurrence of a shock increase the risk of death in cardiomyopathy patients with defibrillators?
Background: The SCD-HeFT trial, originally published in 2005, was instrumental in demonstrating the utility of defibrillators in the primary prevention of sudden cardiac deaths in patients with either ischemic or non-ischemic cardiomyopathy, NYHA class II or III, ejection fraction <35%, and no history of sustained ventricular tachycardia or fibrillation. This study re-examined the data derived from the SCD-HeFT trial to better understand the long-term prognosis of these patients with defibrillators who receive either appropriate shocks (ventricular fibrillation, sustained ventricular tachycardia), inappropriate shocks, or no shocks. Inappropriate shocks were defined as defibrillations due to supraventricular tachycardia, oversensing P or T waves as R waves, double counting of R waves, and artifact.
Study design: Retrospective cohort (analysis of patients randomized to implantable cardioverter-defibrillator (ICD) group in SCD-HeFT).
Setting: Multicenter trial.
Synopsis: The analysis demonstrated patients who received shocks were 11 times more likely to die compared with those who had no defibrillations (Hazard Ratio [HR]=11.3, p<0.001). These shocked patients were at more risk (HR=5.7, p<0.001) than those with inappropriate shocks (HR=2.0, p=0.002). Therefore, even inappropriate shocks themselves doubled the risk of death. Patients who received more than one shock, either appropriate or not, were at even higher odds of death (HR=8.3, p<0.001). The results highlight the higher mortality risk when patients with ICDs have received a shock (appropriate or inappropriate) and the need for further therapies to modify outcome in these patients.
Bottom Line: Appropriate or inappropriate defibrillations are associated with a poorer prognosis in patients with cardiomyopathy.
Citation: Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008(359):1009-1017.
Can a simple physical exam tool assess the degree of dehydration in children?
Background: Despite the frequency and the associated cost of acute gastroenteritis (AGE) in the pediatric population, there is no unified scale to assess the severity of dehydration. The authors of this paper previously reported a clinical dehydration scale (CDS) and applied it prospectively in a new cohort of patients ages 1 month to 5 years.
Study design: Prospective, observational study.
Setting: Single, tertiary care emergency department (ED) in Canada.
Synopsis: The CDS score is based purely on the physical findings of the child, including a) general appearance, b) eyes, c) mucous membranes, and d) amount of tears. On a point system, the patient is placed in one of three categories: no dehydration, some dehydration, moderate/severe dehydration. The trial enrolled 205 children and the CDS was applied by the triaging nurse. The attending ED pediatricians were blinded from this assessment. The CDS was able to predict the length of stay (mean + SD: no dehyrdation 245 + 181 mins; some dehydration, 397 + 302 mins; mod/severe dehydration, 501 + 389 mins), need for intravenous rehydration (none, 15%; some, 49%; mod/severe, 80%), and frequency of emesis/diarrhea as reported by the parents (none, 8.4 + 7.7; some, 13 + 10.7; mod/severe, 30.2 + 14.8). Only five children were categorized in the moderate/severe dehydration category, which may limit the ability to generalize the scoring system to that group of patients.
Bottom line: The CDS is an easy to use and promising tool to assess the severity of illness, expected ED length of stay, and need for intravenous rehydration in children with acute gastroenteritis.
Citation: Goldman RD, Friedman JN, Parkin PC. Validation of the clinical dehydration scale for children with acute gastroenteritis. Pediatrics. 2008;122(3):545-549.
Does maintaining a higher hemoglobin level benefit critical care patients?
Background: Historically, medical and surgical critical care patients liberally were transfused with little prospective evidence to support this approach. However, recent evidence has led to the use of a more-restricted transfusion threshold.
Study design: Systematic review and meta-analysis of cohort studies evaluating the effect of red blood cell (RBC) transfusion on patient outcomes.
Setting: Data sources include MEDLINE, Embase, and Cochrane databases.
Synopsis: The 45 cohort studies, including more than 272,000 patients, were selected due to focus on outcome measures, such as mortality, multiorgan dysfunction, acute respiratory distress syndrome, and infections. Primary studies were then placed into one of three categories: benefits outweigh the risk, neutral, or risks outweigh the benefit. Forty-two of these studies found the risks outweigh the benefits; two were neutral; and only one sub-study (in elderly patients with acute myocardial infarctions) suggested benefit outweighs the risk.
Although a systematic review of cohort studies has inherent limitations, the overwhelming direction of the results suggests statistically significant harm due to liberal transfusion practices (Summary Odd Ratios [OR] for a) death, OR = 1.69; b) infection, OR = 1.88; and c) Acute Respiratory Distress Syndrome, OR = 2.5). Due to the observational nature of the cohort studies, one might suspect RBC transfusions could simply reflect patient severity of illness. Thus, the harm suggested by the more liberal transfusion standards could just reflect the fact these patients carried a worse prognosis due to their respective illnesses.
Bottom Line: The preponderance of evidence suggests liberal transfusion practice is associated with increased morbidity and mortality of ICU patients. When considering RBC transfusions, the risks and benefits to each individual patient should be considered carefully.
Citation: Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008; 36(9);2667-2674.
What is the appropriate frequency of rescreening for patients with initial screening colonoscopies negative for adenomas?
Background: Colonoscopy is the preferred primary screening method for the detection of colorectal cancer and precancerous polyps. Data suggest colonoscopy may be performed too frequently and for inappropriate indications.
Study design: Retrospective cohort study.
Setting: Seven sites in central Indiana.
Synopsis: In this study of 2,436 persons with no adenomas on baseline screening colonoscopies, 1,256 of them (51.6%) were rescreened a mean of 5.34 + 1.34 years later. No cancers were found on rescreening. One or more adenomas were found in 201 persons (16.0%). Nineteen advanced adenomas were found in 16 persons (1.3%). Patients in this study were relatively young (mean age at baseline was 56.7 years). Men were more likely than women to have adenomas (RR 1.88; 95% CI 1.42-2.51) and to have advanced adenomas (RR 3.31; 95% CI 1.02-10.8).
Limitations included a small cohort sample size, as well as incomplete information on persons who did not follow up with the five-year examination. Also, there is uncertainty about the clinical significance of advanced adenomas.
Bottom Line: Among persons previously screened with colonoscopy who have no colorectal adenomas, the five-year risk of detecting an advanced adenoma is extremely low (1.3%), supporting a rescreening interval of more than five years after a normal colonoscopy. Men have greater risk, and may deserve a shorter interval screening.
Citation: Imperiale TF, Glowinski EA, Lin-Cooper C, et al. Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med. 2008;359:1218-1224.
Can validated discharge instability criteria predict mortality or readmission within 30 days of hospital discharge for community acquired pneumonia (CAP)?
Background: Prior prospective cohort data have delineated instability criteria utilizing vital sign criteria at hospital discharge for CAP. However, guidelines for determining patient readiness for discharge remain largely unstudied.
Study design: Prospective, observational cohort study.
Setting: A single, non-urban teaching hospital in Spain.
Synopsis: In this study, 870 adults with CAP were evaluated following discharge. Abnormal oxygenation and vital signs were utilized to calculate an instability score. Criteria for instability were defined as temperature >37.5° C, heart rate <100, respiratory rate >24, systolic blood pressure (SBP) <90 (or diastolic blood pressure, DBP <60), and oxygen saturation <90% (or PaO2 <60).
Of all the instability criteria, only low oxygenation predicted readmission at 30 days (Hazard Ratio [HR] 1.4, p=0.03). However, mortality was significantly increased when instability criteria of temperature (HR 4.5, p=0.04), blood pressure (HR 2.6, p=0.02), respiratory rate (HR 2.4, p=0.03), or oxygenation (HR 2.4, p=0.03) were met. Elevated heart rate was not found to predict death.
The authors assigned each of the significant instability criteria a score of one or two (based on the weight of its hazard ratio), with respiratory rate, low blood pressure, and low oxygenation each assigned one point, and temperature assigned two points. Patients with an instability score of two or more had a six-fold increased risk of death (HR 5.8; 95%, p=0.0001). The negative predictive value (NPV) of an instability score less than two was very helpful (NPV=98%) in identifying patients with low mortality risk; however, the positive predictive value (PPV) of an instability score >2 is not necessarily helpful (PPV=13%) clinically.
Bottom line: Patients with a temperature >37.5° C or any combination of RR >24, SBP <90 (or DBP <60), and SpO2 <90% (or Pa02 <60) are at increased risk of death. Identifying a low instability score is most helpful in clinical practice.
Citation: Capelastegui A, Espana P, Bilbao A, et al. Pneumonia: criteria for patient instability on hospital discharge. Chest. 2008;34:595-600.
In This Edition
- Aspirin plus extended-release dipyridamole and clopidogrel provide similar outcomes in stroke.
- Traditional readings of bedside chest radiographs are insensitive in detecting intraatrial central venous catheter placement.
- Improved outcomes with bortezomib in myeloma treatment.
- ICD firings in cardiomyopathy patients are associated with worse outcomes.
- The clinical dehydration scale rapidly assesses the severity of dehydration in children.
- Liberal red blood cell transfusions may be harming patients.
- Five-year risk of colorectal neoplasia is low in patients with negative screening colonoscopy.
- Vital sign instability and oxygenation predict prognosis following hospitalization for community acquired pneumonia.
Is aspirin plus extended release dipyridamole more efficacious and safer than clopidogrel in preventing recurrent stroke?
Background: Recurrent stroke is a frequent (7% to 8% thrombotic stroke recurrence in first year) and disabling event after ischemic stroke. Multiple randomized trials demonstrate efficacy of anti-platelet agents for the prevention of recurrent stroke after non-cardioembolic stroke. However, direct comparisons and relative benefits of various antiplatelet agents are not well defined.
Study design: Randomized, double-blinded, two-by-two factorial design with intention-to-treat analysis.
Setting: A total of 20,333 patients from 695 centers in 35 countries, including the U.S.
Synopsis: This study directly compared aspirin plus extended-release dipyridamole to clopidogrel within the PRoFESS trial. A total of 20,333 patients were enrolled and followed up for a mean duration of 2.5 years. Eligible patients randomly were assigned to receive either 25 mg aspirin plus 200 mg extended-release twice a day, or clopidogrel 75 mg a day; and either telmisartan 80 mg once a day or placebo. Groups were similar at baseline.
The primary outcome of recurrent stroke was similar in both the aspirin plus extended-release dipyrimadole group and the clopidogrel group (9.0% vs. 8.8%). The composite secondary outcome of stroke, myocardial infarction or vascular death, and tertiary outcomes were similar in both groups. The trial showed statistical equivalence in the rates of recurrent stroke in the two groups.
Despite more frequent hemorrhagic strokes in the group receiving aspirin plus extended-release dipyridamole (4.1% vs. 3.6%), there was no significant difference in the risk of fatal or disabling stroke between both the groups.
Bottom line: Aspirin plus extended-release dipyridamole is equivalent to clopidogrel in the prevention of recurrent stroke, in terms of relevant efficacy and safety parameters.
Citation: Sacco RL, Diener H, Yusuf S, et.al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008:359:1238-1251.
Is there a better method to judge the placement of central venous catheters?
Background: Placement of central venous catheters is common, particularly in critical care settings. Correct placement is usually confirmed by bedside chest radiography. The recommended location of the distal catheter tip is superior to the superior vena cava and right atria junction. However, determining this landmark on traditional bedside chest radiographs is frequently inaccurate.
Study design: Prospective, blinded study.
Setting: University hospital in Germany.
Synopsis: The researchers enrolled 212 patients scheduled for elective cardiac surgery. Either left or right internal jugular vein central lines were placed via EKG guidance, and more precisely evaluated by transesophageal echocardiography. Bedside chest radiographs were performed within three hours of admission to the ICU.
The radiologists were able to detect between 40% and 60% of incorrect central venous catheter placements when compared to transesophageal echocardiography. The researchers concluded TC-distance (tip of catheter to carina) of greater than 55 mm on chest X-ray performed better (98% accurate) in the detection of intra-atrial catheter placement, compared to conventional judgment by attending (93% accurate) or resident (53% accurate) radiologists. Limitations of the study include the use of only one attending radiologist. Secondly, the chest radiographs and echocardiograms were not done simultaneously, allowing for possible movement of the catheters between studies.
Bottom line: A TC distance of greater than 55 mm on chest X-ray should be further investigated as an accurate method to detect intra-atrial central venous catheters.
Citation: Wirsing M, Schummer C, Neumann R, et al. Is traditional reading of the bedside chest radiograph appropriate to detect intra-atrial central venous catheter position? Chest. 2008;134:527-533.
Does adding bortezomib to melphalan and prednisone improve outcomes in newly diagnosed myeloma?
Background: More than 50% of newly diagnosed myeloma patients are older than 65 and cannot receive optimal treatment with high-dose chemotherapy and stem-cell transplant. Previous trials have demonstrated patients with relapsed or refractory myeloma benefit from the administration of bortezomib, which sensitizes the myeloma cell lines to melphalan.
Study design: Randomized, open-label (unblinded) phase 3 study.
Setting: 151 centers, 22 countries in Asia, Europe, South and North America.
Synopsis: 682 patients with untreated multiple myeloma, who were ineligible for high-dose chemotherapy and stem cell transplant, were treated with bortezomib in combination with standard melphalan and prednisone, or melphalan and prednisone alone. The bortezomib group had improved partial or complete response (71% vs. 35%; NNT=3; p<0.001), increased median time to progression of disease (19.9 months vs. 13.1 months), and improved overall survival (87% vs. 78% over a 16-month median follow up; NNT=11; p=0.008). There were increased grade 3 adverse effects with the intervention, but no increase in grade 4 events or treatment related deaths compared to control. Limitations of the study include lack of blinding and involvement of the pharmaceutical company in data collection analysis, writing and editing of the manuscript.
Bottom line: Bortezomib is a valuable adjunct to standard treatment of multiple myeloma in patients over the age of 65 who may be ineligible for high-dose chemotherapy and stem cell transplant.
Citation: San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for the initial treatment of multiple myeloma. NEJM. 2008;359:906-917.
Does the occurrence of a shock increase the risk of death in cardiomyopathy patients with defibrillators?
Background: The SCD-HeFT trial, originally published in 2005, was instrumental in demonstrating the utility of defibrillators in the primary prevention of sudden cardiac deaths in patients with either ischemic or non-ischemic cardiomyopathy, NYHA class II or III, ejection fraction <35%, and no history of sustained ventricular tachycardia or fibrillation. This study re-examined the data derived from the SCD-HeFT trial to better understand the long-term prognosis of these patients with defibrillators who receive either appropriate shocks (ventricular fibrillation, sustained ventricular tachycardia), inappropriate shocks, or no shocks. Inappropriate shocks were defined as defibrillations due to supraventricular tachycardia, oversensing P or T waves as R waves, double counting of R waves, and artifact.
Study design: Retrospective cohort (analysis of patients randomized to implantable cardioverter-defibrillator (ICD) group in SCD-HeFT).
Setting: Multicenter trial.
Synopsis: The analysis demonstrated patients who received shocks were 11 times more likely to die compared with those who had no defibrillations (Hazard Ratio [HR]=11.3, p<0.001). These shocked patients were at more risk (HR=5.7, p<0.001) than those with inappropriate shocks (HR=2.0, p=0.002). Therefore, even inappropriate shocks themselves doubled the risk of death. Patients who received more than one shock, either appropriate or not, were at even higher odds of death (HR=8.3, p<0.001). The results highlight the higher mortality risk when patients with ICDs have received a shock (appropriate or inappropriate) and the need for further therapies to modify outcome in these patients.
Bottom Line: Appropriate or inappropriate defibrillations are associated with a poorer prognosis in patients with cardiomyopathy.
Citation: Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008(359):1009-1017.
Can a simple physical exam tool assess the degree of dehydration in children?
Background: Despite the frequency and the associated cost of acute gastroenteritis (AGE) in the pediatric population, there is no unified scale to assess the severity of dehydration. The authors of this paper previously reported a clinical dehydration scale (CDS) and applied it prospectively in a new cohort of patients ages 1 month to 5 years.
Study design: Prospective, observational study.
Setting: Single, tertiary care emergency department (ED) in Canada.
Synopsis: The CDS score is based purely on the physical findings of the child, including a) general appearance, b) eyes, c) mucous membranes, and d) amount of tears. On a point system, the patient is placed in one of three categories: no dehydration, some dehydration, moderate/severe dehydration. The trial enrolled 205 children and the CDS was applied by the triaging nurse. The attending ED pediatricians were blinded from this assessment. The CDS was able to predict the length of stay (mean + SD: no dehyrdation 245 + 181 mins; some dehydration, 397 + 302 mins; mod/severe dehydration, 501 + 389 mins), need for intravenous rehydration (none, 15%; some, 49%; mod/severe, 80%), and frequency of emesis/diarrhea as reported by the parents (none, 8.4 + 7.7; some, 13 + 10.7; mod/severe, 30.2 + 14.8). Only five children were categorized in the moderate/severe dehydration category, which may limit the ability to generalize the scoring system to that group of patients.
Bottom line: The CDS is an easy to use and promising tool to assess the severity of illness, expected ED length of stay, and need for intravenous rehydration in children with acute gastroenteritis.
Citation: Goldman RD, Friedman JN, Parkin PC. Validation of the clinical dehydration scale for children with acute gastroenteritis. Pediatrics. 2008;122(3):545-549.
Does maintaining a higher hemoglobin level benefit critical care patients?
Background: Historically, medical and surgical critical care patients liberally were transfused with little prospective evidence to support this approach. However, recent evidence has led to the use of a more-restricted transfusion threshold.
Study design: Systematic review and meta-analysis of cohort studies evaluating the effect of red blood cell (RBC) transfusion on patient outcomes.
Setting: Data sources include MEDLINE, Embase, and Cochrane databases.
Synopsis: The 45 cohort studies, including more than 272,000 patients, were selected due to focus on outcome measures, such as mortality, multiorgan dysfunction, acute respiratory distress syndrome, and infections. Primary studies were then placed into one of three categories: benefits outweigh the risk, neutral, or risks outweigh the benefit. Forty-two of these studies found the risks outweigh the benefits; two were neutral; and only one sub-study (in elderly patients with acute myocardial infarctions) suggested benefit outweighs the risk.
Although a systematic review of cohort studies has inherent limitations, the overwhelming direction of the results suggests statistically significant harm due to liberal transfusion practices (Summary Odd Ratios [OR] for a) death, OR = 1.69; b) infection, OR = 1.88; and c) Acute Respiratory Distress Syndrome, OR = 2.5). Due to the observational nature of the cohort studies, one might suspect RBC transfusions could simply reflect patient severity of illness. Thus, the harm suggested by the more liberal transfusion standards could just reflect the fact these patients carried a worse prognosis due to their respective illnesses.
Bottom Line: The preponderance of evidence suggests liberal transfusion practice is associated with increased morbidity and mortality of ICU patients. When considering RBC transfusions, the risks and benefits to each individual patient should be considered carefully.
Citation: Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008; 36(9);2667-2674.
What is the appropriate frequency of rescreening for patients with initial screening colonoscopies negative for adenomas?
Background: Colonoscopy is the preferred primary screening method for the detection of colorectal cancer and precancerous polyps. Data suggest colonoscopy may be performed too frequently and for inappropriate indications.
Study design: Retrospective cohort study.
Setting: Seven sites in central Indiana.
Synopsis: In this study of 2,436 persons with no adenomas on baseline screening colonoscopies, 1,256 of them (51.6%) were rescreened a mean of 5.34 + 1.34 years later. No cancers were found on rescreening. One or more adenomas were found in 201 persons (16.0%). Nineteen advanced adenomas were found in 16 persons (1.3%). Patients in this study were relatively young (mean age at baseline was 56.7 years). Men were more likely than women to have adenomas (RR 1.88; 95% CI 1.42-2.51) and to have advanced adenomas (RR 3.31; 95% CI 1.02-10.8).
Limitations included a small cohort sample size, as well as incomplete information on persons who did not follow up with the five-year examination. Also, there is uncertainty about the clinical significance of advanced adenomas.
Bottom Line: Among persons previously screened with colonoscopy who have no colorectal adenomas, the five-year risk of detecting an advanced adenoma is extremely low (1.3%), supporting a rescreening interval of more than five years after a normal colonoscopy. Men have greater risk, and may deserve a shorter interval screening.
Citation: Imperiale TF, Glowinski EA, Lin-Cooper C, et al. Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med. 2008;359:1218-1224.
Can validated discharge instability criteria predict mortality or readmission within 30 days of hospital discharge for community acquired pneumonia (CAP)?
Background: Prior prospective cohort data have delineated instability criteria utilizing vital sign criteria at hospital discharge for CAP. However, guidelines for determining patient readiness for discharge remain largely unstudied.
Study design: Prospective, observational cohort study.
Setting: A single, non-urban teaching hospital in Spain.
Synopsis: In this study, 870 adults with CAP were evaluated following discharge. Abnormal oxygenation and vital signs were utilized to calculate an instability score. Criteria for instability were defined as temperature >37.5° C, heart rate <100, respiratory rate >24, systolic blood pressure (SBP) <90 (or diastolic blood pressure, DBP <60), and oxygen saturation <90% (or PaO2 <60).
Of all the instability criteria, only low oxygenation predicted readmission at 30 days (Hazard Ratio [HR] 1.4, p=0.03). However, mortality was significantly increased when instability criteria of temperature (HR 4.5, p=0.04), blood pressure (HR 2.6, p=0.02), respiratory rate (HR 2.4, p=0.03), or oxygenation (HR 2.4, p=0.03) were met. Elevated heart rate was not found to predict death.
The authors assigned each of the significant instability criteria a score of one or two (based on the weight of its hazard ratio), with respiratory rate, low blood pressure, and low oxygenation each assigned one point, and temperature assigned two points. Patients with an instability score of two or more had a six-fold increased risk of death (HR 5.8; 95%, p=0.0001). The negative predictive value (NPV) of an instability score less than two was very helpful (NPV=98%) in identifying patients with low mortality risk; however, the positive predictive value (PPV) of an instability score >2 is not necessarily helpful (PPV=13%) clinically.
Bottom line: Patients with a temperature >37.5° C or any combination of RR >24, SBP <90 (or DBP <60), and SpO2 <90% (or Pa02 <60) are at increased risk of death. Identifying a low instability score is most helpful in clinical practice.
Citation: Capelastegui A, Espana P, Bilbao A, et al. Pneumonia: criteria for patient instability on hospital discharge. Chest. 2008;34:595-600.
Inhaled Insulin: Troubled Drug Rises from the Ashes
Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2
Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5
So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6
More Drugs Via the Pulmonary Route
Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7
Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.
New Delivery Systems: Will They Pan Out?
Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.
Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.
Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH
Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.
References
1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.
2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.
3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.
4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.
5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.
6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.
7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.
8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.
9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.
10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.
11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.
12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.
13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.
Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2
Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5
So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6
More Drugs Via the Pulmonary Route
Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7
Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.
New Delivery Systems: Will They Pan Out?
Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.
Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.
Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH
Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.
References
1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.
2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.
3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.
4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.
5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.
6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.
7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.
8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.
9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.
10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.
11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.
12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.
13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.
Remember all the hype leading up to the approval of the dry-powder formulation of human insulin, produced by means of recombinant DNA technology, a.k.a. inhaled insulin (Exubera)? That was three years ago (January 2006). Remember all the press releases regarding the removal of inhaled insulin from the market? That was October 2007.1,2
Almost immediately after Pfizer “pulled the plug” on inhaled insulin, cases of lung cancer started being reported—albeit it had occurred in Exubera-treated patients that had a history of smoking cigarettes—a contraindication within the drug’s approved label. Some clinicians questioned whether it was due to insulin being a weak growth factor when binding to the type 1 insulin-like growth factor receptor; others wondered if it was related to smoking history.3,4 Three other collaboration efforts for inhaled insulin—NovoNordisk/Aradigm, MannKind, and Alkermes/Eli Lilly AIR insulin— were in the pipeline when Pfizer bowed out of the market. MannKind’s Technosphere insulin and Alkermes/Eli Lilly AIR insulin are still being investigated. Both are in phase 3 clinical trials.5
So, contrary to popular belief, inhaled insulin is not dead, yet. These other companies are looking to improve upon what Pfizer lost out on. The AIR system uses a smaller, breathable inhaler, which would fit into a patient’s hand. The inhaled powder has a smaller particle size and a larger surface area, which provides deeper lung penetration of drug.6
More Drugs Via the Pulmonary Route
Aside from asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, where a hospitalist could expect to use pulmonary delivered drugs, other medicines are being investigated for administration via this route. The pulmonary route may be used for tuberculosis (TB), where lower doses can be given since high doses of systemic therapy lead to significant drug toxicity.7
Inhaled vaccines are being developed, including Bacillus Calmette-Guérin (BCG) TB and respiratory syncytial virus (RSV). Parathyroid hormone for osteoporosis, human factor IX for hemophilia, and interferon α-2b for hepatitis B virus, are potential and current inhaled treatments.
New Delivery Systems: Will They Pan Out?
Knowing the lung absorbs biologic drugs with a wide range of molecular weights, solubility, and charges, is a plus for pulmonary delivery. However, pulmonary drug delivery also presents challenges. These include local toxic effects, such as cell injury, edema, and altered tissue defenses. Drug carriers, preservatives, and propellants, such as sulfites, might harm pulmonary tissue or the body.
Safety is one of the biggest concerns when companies develop new drug delivery systems. These inhaled products and methods of delivering inhaled insulin are quickly moving through clinical trials.
Only time will tell when approvals will take place, but it looks as though there will be some innovative insulin products in the near future. TH
Michele B Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.
References
1. Alvey L. U.S. Food and Drug Administration. FDA ap-proves first ever inhaled insulin combination product for treatment of diabetes. www.fda.gov/bbs/topics/ news/2006/NEW01304.html. Published Jan. 27, 2006. Accessed Dec. 1, 2008.
2. U.S. Food and Drug Administration. Drug discontinuations. www.fda.gov/cder/drug/shortages/#disc. Published Oct. 19, 2007. Accessed Dec. 1, 2008.
3. von Kriegstein E, von Kriegstein K. Inhaled insulin for diabetes. N Engl J Med. 2007;356:2106-2108.
4. McMahon GT, Arky RA. Inhaled insulin for diabetes. N Engl J Med. 2007;356:497-502.
5. Opar A. Another blow for inhaled protein therapeutics. Nat Rev Drug Discov. 2008;7:189-190.
6. Dubin CH. The state of systemic pulmonary delivery: one year after Exubera’s approval. Nat Rev Drug Discov. 2007;7(4):61-67.
7. Greb E. Inhalable drugs in the launch pad: will they take off? Pharm Tech. 2008;4:48-55.
8. Riley K, Long P. FDA approves treatment for rare neurologic disease. www.fda.gov/bbs/topics/ NEWS/2008/NEW01884.html. Published Sept. 12, 2008. Accessed Dec. 1, 2008.
9. Keppra XR approved in the U.S. hugin.info/133973/ R/1251192/271964.pdf. Published Sept. 15, 2008. Accessed Sept. 15, 2008.
10. U.S. Food and Drug Administration. 2008 safety alerts for human medical products (drugs, biologics, medical devices, special nutritionals, and cosmetics). www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf Published Sept. 2008. Accessed Sept. 15, 2008.
11. U.S. Food and Drug Administration. Pregnacy and lactation labeling. www.fda.gov/cder/regulatory/ pregnancy_labeling/default.htm Published June 11, 2008. Accessed Sept. 15, 2008.
12. Cruzan S. U.S. Food and Drug Administration. FDA proposes new rule to provide updated information on the use of prescription drugs and biological products during pregnancy and breast-feeding. www. fda.gov/bbs/topics/NEWS/2008/NEW018 41.html. Published May 28, 2008. Accessed Sept. 15, 2008.
13. Peggy P. FDA to take A, B, and C out of pregnancy labeling. www.medpagetoday.com/OBGYN/Pregnancy/ tb/9626. Published May 28, 2008. Accessed Sept. 15, 2008.
JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?
The medical community has struggled with two important questions for the past 10 years: When it comes to the low-density lipoprotein cholesterol (LDL-C) level, how low should one go and at what cost? And are there other markers of risk that can identify a higher-risk subpopulation in relatively healthy people? The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) provided partial answers for these questions by finding that a highly potent statin lowered the risk of cardiovascular events in patients with “normal” LDL-C but elevated levels of high-sensitivity C-reactive protein (hs-CRP).1
In this article, we will critically evaluate the methods, results, and conclusions of the JUPITER trial. Additionally, we will discuss its limitations and areas of uncertainty.
BEFORE JUPITER
The LDL-C-lowering drugs called statins have revolutionized cardiovascular medicine.2 They are beneficial in both the primary prevention setting and in acute coronary syndromes, stable angina, and unstable angina and can halt the progression of coronary artery disease—in some cases even resulting in modest regression of plaque.3–6
Many experts have credited the reduction in LDL-C as being the sole factor responsible for the decrease in major adverse events seen with statin therapy.7 However, statins have other, non-lipid-lowering properties, including anti-inflammatory and antioxidant effects, that may also contribute to their benefits.8–15
One of the anti-inflammatory actions of statins is evidenced by lower levels of the acute-phase reactant CRP.10,11,15,16 Measuring systemic CRP levels with a highly sensitive assay (yielding the so-called high-sensitivity or hs-CRP level) provides significant clinical prognostic value across a spectrum of clinical situations, ranging from risk screening in apparently healthy people to stable and unstable angina.17–22 People with higher hs-CRP levels are, on average, at higher risk of adverse cardiovascular events. However, controversy remains as to whether hs-CRP plays a mechanistic role in plaque formation and acute complications. Indeed, recent genetic studies argue strongly that hs-CRP lies outside the mechanistic path of atherosclerosis.23 Nonetheless, an overwhelming amount of data indicates that hs-CRP serves as a marker of disease.17–21
Nissen et al10 showed that the rate of progression of atherosclerosis is lower when the levels of atherogenic lipoproteins and hs-CRP are both lowered with statin therapy. Simultaneously, Ridker et al11 showed that patients who have lower hs-CRP levels after statin therapy have better clinical outcomes than those with higher hs-CRP levels, regardless of their achieved level of LDL-C.
Collectively, these studies and others have led some to believe that, in people with relatively low LDL-C but persistently elevated hs-CRP, statin therapy may reduce the rate of events.15,24 The JUPITER trial was undertaken to test this hypothesis.
JUPITER STUDY DESIGN
JUPITER was designed to see whether highly potent statin therapy is beneficial in people with elevated hs-CRP who otherwise do not meet the criteria for lipid-lowering therapy. The study was conducted at 1,315 sites in 26 countries. It was sponsored by AstraZeneca, the maker of rosuvastatin (Crestor).
Inclusion and exclusion criteria
All participants had to be free of known cardiovascular disease, have an LDL-C level lower than 130 mg/dL, and have an hs-CRP level of 2.0 mg/L or greater. Patients were excluded if they were previous or current users of lipid-lowering drugs; had severe arthritis, lupus, or inflammatory bowel disease; or were taking immune-modulating drugs such as cyclosporine (Sandimmune, others), tacrolimus (Prograf), azathioprine (Azasan, Imuran), or long-term oral corticosteroids.
Rosuvastatin therapy
Participants were randomly assigned in a 1:1 ratio to receive rosuvastatin 20 mg daily or a matching placebo in a double-blind fashion.
End points
The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. Secondary end points were the individual components of the primary end point.
Statistical analysis
The study was powered to detect a 25% reduction in the primary end point among those treated with rosuvastatin. The trial was designed to run until 520 end point events had occurred. However, on March 29, 2008, after the first prespecified interim analysis, the Data and Safety Monitoring Board stopped the trial due to a significant reduction in the primary end point in the rosuvastatin group. As in most randomized clinical trials, all analyses were done on an intention-to-treat basis. Prespecified subgroup analyses were also performed.
STUDY RESULTS
Patient recruitment and eligibility
Between February 4, 2003, and December 15, 2006, a total of 89,890 people were screened. Of these, 17,802 met the inclusion and exclusion criteria and were included in the study. Of the 72,088 people who were excluded, 25,993 (36.1%) had an hs-CRP level below 2 mg/L and 37,611 (52.2%) had an LDL-C level of 130 mg/dL or higher.
A not-so-healthy population
The aim of the investigators was to include relatively healthy people. The median age was 66 years, about 16% of participants were current smokers, about 11% had a family history of heart disease, and about 41% met the criteria for metabolic syndrome, all conditions that are associated with elevated hs-CRP.25 Of note, the median hs-CRP level was 4.2 mg/L, a level indicating higher global risk according to the American College of Cardiology/American Heart Association consensus statement.26
Reduction in lipid levels and hs-CRP
By 12 months, in the rosuvastatin group, the median LDL-C level had fallen by 50% (from 108 to 55 mg/dL), and the median hs-CRP level had fallen by 37% (from 4.2 to 2.2 mg/L). Additionally, the triglyceride level had fallen by 17%. The high-density lipoprotein cholesterol levels did not change significantly.
Impact on end points
Adverse events
WHAT DOES THIS MEAN?
Is lower LDL-C better?
The JUPITER trial is the latest of several statin trials that have shown significant reductions in major adverse cardiovascular events when LDL-C was lowered below what has been recommended by the current guidelines.27,28
In 2002, the Heart Protection Study29 showed a significant reduction in major adverse cardiovascular events in patients at high risk of coronary artery disease if they received simvastatin (Zocor), even if they had LDL-C levels lower than 100 mg/dL at baseline. Similarly, the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial30 showed a 16% relative risk reduction in a composite end point in patients presenting with acute coronary syndrome if they received intensive statin therapy.
These two studies led to an update by the National Cholesterol Education Program (Adult Treatment Panel III), suggesting an optimal LDL-C goal of less than 70 mg/dL in those with coronary artery disease or its risk equivalent (ie, diabetes mellitus, peripheral vascular disease). Furthermore, in support of the “lower is better” theory, a number of studies that used intravascular ultrasonography have shown regression of coronary plaque with aggressive LDL-C lowering. Notably, in a Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (the ASTEROID trial),5 rosuvastatin 40 mg daily caused significant plaque regression while lowering LDL-C to 61 mg/dL over a 24-month period.
A number of high-dose statin trials have shown that lowering LDL-C to less than 70 mg/dL significantly reduces major adverse cardiovascular events.31–39 The JUPITER trial was unique in that it extended these findings to people without known coronary disease (ie, primary prevention) or elevated cholesterol but with elevated levels of a marker of inflammation—hs-CRP. In view of the JUPITER results and of studies using intravascular ultrasonography in the primary prevention setting, it seems clear that lowering LDL-C to levels less than 70 mg/dL also reduces both atherosclerotic plaque progression and the rate of first major adverse cardiovascular events in primary prevention in patients at higher global risk.
Did the study prove that reducing hs-CRP lowers risk?
Measuring hs-CRP levels has been extensively studied in apparently healthy populations, stable angina, unstable angina, and other cardiovascular settings.18,21,40–43 It has been shown to have significant prognostic implications in a number of primary and secondary trials.44 Additionally, those with elevated LDL-C and hs-CRP levels benefit the most from statin therapy.16,45,46 Animal studies have also provided some evidence that CRP may play a role in atherogenesis.47,48 However, recent clinical and genetic studies have raised doubt about the direct causal relationship between CRP and coronary artery disease,23,49,50 and epidemiologic studies have questioned its usefulness as a marker of risk.51,52
The JUPITER study adds little to clear up the controversy about whether hs-CRP is a mechanistic participant in atherosclerotic disease. However, it also shows that this issue is somewhat irrelevant, in that selection of patients for high-potency statin therapy solely on the basis of high hs-CRP without other indications for lipid-lowering therapy clearly reduces risk and improves survival.
JUPITER did not examine whether people with higher hs-CRP levels benefited more from statin therapy than those with lower levels. The hypothesis-generating data for JUPITER came from an analysis of changes in hs-CRP and LDL-C in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).16 Thus, JUPITER did not include people with both low LDL-C and low hs-CRP because, in the AFCAPS/TexCAPS analysis, those with low LDL-C and low hs-CRP had extremely low event rates and no clinical efficacy of statin therapy, despite good LDL-C reduction. In marked contrast, those with low LDL-C but elevated hs-CRP had high event rates and large relative risk reductions— hence the need for JUPITER to prospectively test this hypothesis. Nevertheless, the initial results of JUPITER as presented do not yet make it clear that there is a dose-response relationship between higher levels of hs-CRP and a greater reduction in events, even in a cohort with elevated hs-CRP at baseline. This analysis will no doubt be forthcoming in another manuscript from Ridker and colleagues. Specifically, it will be of interest to examine whether those with the highest hs-CRP levels benefited the most from rosuvastatin on both an absolute and relative scale, and whether those with the greatest hs-CRP reduction also benefited more. With the present data available from JUPITER, a reasonable interpretation is that an elevated hs-CRP simply widens the inclusion criterion for those for whom high-potency statin therapy improves clinical outcomes.53
Better markers are needed
Even with a nonspecific marker such as hs-CRP, patients at higher global risk and with LDL-C below the recommended levels could be identified and treated aggressively. This benefit, however, required that approximately 100 people be treated with rosuvastatin for 2 years to prevent one event. Additionally, only 20% of all patients screened were eligible for the trial. Therefore, one could argue that its generalizability is limited.
Markers of risk that are more specific and sensitive are needed to identify people at higher global risk who would otherwise be considered to be at low risk with the current risk assessment tools. A number of such inflammatory and oxidative markers are under development.54–60
Absolute vs relative risk reduction and the public health burden
The 44% reduction in the number of primary end point events in the rosuvastatin group was considerable in relative terms. However, in absolute terms, 95 people had to be treated for up to 2 years in order to prevent one event.53 In making recommendations, the United States Department of Health and Human Services has to consider the clinical benefit of a test or a drug in light of its cost. With health care costs increasing, many agencies are refusing to pay for therapies on the basis of cost or small absolute benefit.
While we do not have the answer as to whether treating 95 people for 2 years to see one benefit is cost-effective, one thing is clear: the field of medicine is in desperate need of a better way to identify individuals who may benefit from a test or therapy.61 Additionally, we think it is important to note that the “numbers-needed-to-treat” (95 at 2 years and 25 at 5 years) derived from JUPITER are actually smaller than the values observed in the AFCAPS/TexCAPS and the West of Scotland Coronary Prevention Study.62,63 This suggests that statin therapy is at least as cost-effective in those with elevated hs-CRP as in those with elevated LDL-C. Even our most robust therapies are effective in only a minority of patients treated.61
Should ‘healthy’ people be tested for hs-CRP?
In 2003, we wrote in this journal21 that measuring hs-CRP may add to the current risk-prediction models by identifying people at increased risk who would otherwise not be considered as such by current risk models. The US Centers for Disease Control and Prevention and the American Heart Association have also stated that measuring hs-CRP in those at intermediate risk may be reasonable.26
The JUPITER investigators intended to study a relatively healthy population, but, as we mentioned, a close look at the cohort’s baseline characteristics indicates a substantial proportion met the criteria for metabolic syndrome. Therefore, one could challenge whether we really need hs-CRP in such a population to identify who will benefit from statin therapy.
We agree with the recommendation from the Centers for Disease Control and Prevention and the American Heart Association that measuring hs-CRP in people at intermediate risk is a reasonable option.26 We also believe that hs-CRP should be tested as a secondary risk factor, in combination with blood pressure, lipids, diabetes, smoking, serum creatinine, and fasting blood glucose. Factors such as obesity, sedentary lifestyle, family history of heart disease, and emotional and physical stress should also be considered.
Safety of high-dose statin therapy
High-dose statin therapy has been well tolerated in clinical trials, but rates of discontinuation have been higher (7%–10%) than with moderate-dose therapy (4%–5%).64 Fortunately, the rates of serious adverse events have in general been low. For example, with simvastatin 80 mg, the rates of myopathy and rhabdomyolysis were quite low.31
Rates of elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with high-dose statin therapy have been reported to be below 1.3%. Studies have shown that reducing LDL-C to below 100 mg/dL is associated with a higher incidence of ALT and AST elevations. However, these elevations have usually been benign and often return to normal when the drug is reduced in dose or withdrawn.
In previous studies of rosuvastatin,65 the incidence of myopathy and liver function abnormalities was less than 0.1%. Rates of proteinuria were similarly low, and in many patients renal function actually improved on rosuvastatin.66,67 Furthermore, rosuvastatin may have different pharmacokinetic properties than atorvastatin (Lipitor) and simvastatin, which may result in a lower incidence of musculoskeletal toxicity.68,69
In general, the incidence of cancer has been similar in those treated with high-dose statins and those treated with placebo. The Treating to New Targets trial70 suggested that the incidence of cancer was higher with atorvastatin 80 mg daily than with 20 mg daily. However, a meta-analysis of 14 trials of moderate-dose statin therapy did not show any evidence of increased cancer rates with these agents.70 Indeed, in JUPITER, there was a reduction in cancer-related mortality rates, which could have been due to chance.
The JUPITER trial also showed an increase in the physician-reported incidence of diabetes mellitus with rosuvastatin. This is an important finding, and it may be a class effect because modest increases have similarly been reported with other statins in other major trials, eg, with pravastatin (Pravachol) in PROSPER, simvastatin in the Heart Protection Study, and atorvastatin in PROVE-IT. However, even in those with diabetes or impaired fasting glucose, the reduction in the rate of major adverse events is significant. For example, in JUPITER, almost all of the cases of “incident diabetes” were in those with impaired fasting glucose at baseline, and this group had nearly a 50% reduction in rates of myocardial infarction, stroke, and cardiovascular death. Therefore, on balance, the modest risk of earlier diagnosis of diabetes with statin therapy seems substantially offset by the marked reduction in rates of major adverse cardiovascular events in people with diabetes and impaired fasting glucose on statin therapy.
TAKE-HOME POINTS
The JUPITER trial, like previous high-dose statin trials, calls into question whether current LDL-C guidelines are appropriate for people at higher global risk with otherwise “normal” LDL-C levels.27,28 This trial heralds a new era in preventive therapy because it extends beyond LDL-C as an indication for statin therapy within the primary prevention setting. Statins have revolutionized the therapy of cardiovascular disease, and they continue to show benefit even in the “healthy.”
Clearly, hs-CRP serves as a nonlipid marker to identify those who may benefit from statin therapy. Nonetheless, more specific and sensitive markers (or panels) of cardiovascular risk are necessary. In the future, we will need markers that not only identify people at higher global risk, but that also tell us who would benefit from certain medical or surgical therapies. Elevated hs-CRP in a patient who otherwise would not be a candidate for statin therapy should trigger a reassessment of the risks vs benefits of statin therapy—JUPITER teaches us that statin therapy will benefit these patients.
Aggressive lifestyle modification that encompasses a balanced diet, routine exercise, and smoking cessation should be applied in both primary and secondary prevention. Additionally, risk factors such as elevated blood pressure and hyperlipidemia should be aggressively treated with appropriate medications.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207.
- Topol EJ. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 2004; 350:1562–1564.
- Cannon CP, Murphy SA, Braunwald E. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353:93–96.
- Cohen DJ, Carrozza JP, Baim DS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341:1853–1854.
- Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556–1565.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071–1080.
- Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46:1855–1862.
- Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103:276–283.
- Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005; 96:24F–33F.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352:29–38.
- Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352:20–28.
- Shishehbor MH, Aviles RJ, Brennan ML, et al. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003; 289:1675–1680.
- Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108:426–431.
- Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21:1712–1719.
- Shishehbor MH, Patel T, Bhatt DL. Using statins to treat inflammation in acute coronary syndromes: Are we there yet? Cleve Clin J Med 2006; 73:760–766.
- Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959–1965.
- Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98:731–733.
- Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836–843.
- Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285:2481–2485.
- Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 2001; 47:403–411.
- Shishehbor MH, Bhatt DL, Topol EJ. Using C-reactive protein to assess cardiovascular disease risk. Cleve Clin J Med 2003; 70:634–640.
- Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979.
- Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359:1897–1908.
- Ridker PM. Are statins anti-inflammatory? Issues in the design and conduct of the pravastatin inflammation C-reactive protein evaluation. Curr Cardiol Rep 2000; 2:269–273.
- Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107:391–397.
- Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511.
- Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497.
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227–239.
- Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract 2002; 56:53–56.
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504.
- de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292:1307–1316.
- LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425–1435.
- Liem AH, van Boven AJ, Veeger NJ, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J 2002; 23:1931–1937.
- Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437–2445.
- Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999; 341:70–76.
- Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of highdose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46:1405–1410.
- Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285:1711–1718.
- Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287:3215–3222.
- Patel TN, Shishehbor MH, Bhatt DL. A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J 2007; 28:664–672.
- Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med 2000; 45:391–418.
- Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813–1818.
- Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–2011.
- Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005; 112:25–31.
- Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49:2129–2138.
- Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64–70.
- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100:230–235.
- Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 2005; 96:714–716.
- Schwedler SB, Amann K, Wernicke K, et al. Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation 2005; 112:1016–1023.
- Pfister R, Hellmich M. Multiple biomarkers and cardiovascular risk. N Engl J Med 2008; 359:760.
- Schunkert H, Samani NJ. Elevated C-reactive protein in atherosclerosis— chicken or egg? N Engl J Med 2008; 359:1953–1955.
- Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387–1397.
- Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? Arch Intern Med 2002; 162:867–869.
- Hlatky MA. Expanding the orbit of primary prevention—moving beyond JUPITER. N Engl J Med 2008; 359:2280–2282.
- Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep 2004; 6:243–250.
- Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25:1102–1111.
- Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 2008; 299:1265–1276.
- Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 2008; 52:24–32.
- Hakonarson H, Thorvaldsson S, Helgadottir A, et al. Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 2005; 293:2245–2256.
- Ky B, Burke A, Tsimikas S, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008; 51:1653–1662.
- Levy AP, Levy JE, Kalet-Litman S, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 2007; 27:134–140.
- Mukherjee D, Topol EJ. Pharmacogenomics in cardiovascular diseases. Curr Probl Cardiol 2003; 28:317–347
- West of Scotland Coronary Prevention Study: identification of highrisk groups and comparison with other cardiovascular intervention trials. Lancet 1996; 348:1339–1342.
- Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–1622.
- Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49:1753–1762.
- Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf 2004; 3:547–557.
- Kasiske BL, Wanner C, O’Neill WC. An assessment of statin safety by nephrologists. Am J Cardiol 2006; 97:82C–85C.
- McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87:28B–32B.
- Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006; 97:44C–51C.
- Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94:1140–1146.
- Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–1278.
The medical community has struggled with two important questions for the past 10 years: When it comes to the low-density lipoprotein cholesterol (LDL-C) level, how low should one go and at what cost? And are there other markers of risk that can identify a higher-risk subpopulation in relatively healthy people? The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) provided partial answers for these questions by finding that a highly potent statin lowered the risk of cardiovascular events in patients with “normal” LDL-C but elevated levels of high-sensitivity C-reactive protein (hs-CRP).1
In this article, we will critically evaluate the methods, results, and conclusions of the JUPITER trial. Additionally, we will discuss its limitations and areas of uncertainty.
BEFORE JUPITER
The LDL-C-lowering drugs called statins have revolutionized cardiovascular medicine.2 They are beneficial in both the primary prevention setting and in acute coronary syndromes, stable angina, and unstable angina and can halt the progression of coronary artery disease—in some cases even resulting in modest regression of plaque.3–6
Many experts have credited the reduction in LDL-C as being the sole factor responsible for the decrease in major adverse events seen with statin therapy.7 However, statins have other, non-lipid-lowering properties, including anti-inflammatory and antioxidant effects, that may also contribute to their benefits.8–15
One of the anti-inflammatory actions of statins is evidenced by lower levels of the acute-phase reactant CRP.10,11,15,16 Measuring systemic CRP levels with a highly sensitive assay (yielding the so-called high-sensitivity or hs-CRP level) provides significant clinical prognostic value across a spectrum of clinical situations, ranging from risk screening in apparently healthy people to stable and unstable angina.17–22 People with higher hs-CRP levels are, on average, at higher risk of adverse cardiovascular events. However, controversy remains as to whether hs-CRP plays a mechanistic role in plaque formation and acute complications. Indeed, recent genetic studies argue strongly that hs-CRP lies outside the mechanistic path of atherosclerosis.23 Nonetheless, an overwhelming amount of data indicates that hs-CRP serves as a marker of disease.17–21
Nissen et al10 showed that the rate of progression of atherosclerosis is lower when the levels of atherogenic lipoproteins and hs-CRP are both lowered with statin therapy. Simultaneously, Ridker et al11 showed that patients who have lower hs-CRP levels after statin therapy have better clinical outcomes than those with higher hs-CRP levels, regardless of their achieved level of LDL-C.
Collectively, these studies and others have led some to believe that, in people with relatively low LDL-C but persistently elevated hs-CRP, statin therapy may reduce the rate of events.15,24 The JUPITER trial was undertaken to test this hypothesis.
JUPITER STUDY DESIGN
JUPITER was designed to see whether highly potent statin therapy is beneficial in people with elevated hs-CRP who otherwise do not meet the criteria for lipid-lowering therapy. The study was conducted at 1,315 sites in 26 countries. It was sponsored by AstraZeneca, the maker of rosuvastatin (Crestor).
Inclusion and exclusion criteria
All participants had to be free of known cardiovascular disease, have an LDL-C level lower than 130 mg/dL, and have an hs-CRP level of 2.0 mg/L or greater. Patients were excluded if they were previous or current users of lipid-lowering drugs; had severe arthritis, lupus, or inflammatory bowel disease; or were taking immune-modulating drugs such as cyclosporine (Sandimmune, others), tacrolimus (Prograf), azathioprine (Azasan, Imuran), or long-term oral corticosteroids.
Rosuvastatin therapy
Participants were randomly assigned in a 1:1 ratio to receive rosuvastatin 20 mg daily or a matching placebo in a double-blind fashion.
End points
The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. Secondary end points were the individual components of the primary end point.
Statistical analysis
The study was powered to detect a 25% reduction in the primary end point among those treated with rosuvastatin. The trial was designed to run until 520 end point events had occurred. However, on March 29, 2008, after the first prespecified interim analysis, the Data and Safety Monitoring Board stopped the trial due to a significant reduction in the primary end point in the rosuvastatin group. As in most randomized clinical trials, all analyses were done on an intention-to-treat basis. Prespecified subgroup analyses were also performed.
STUDY RESULTS
Patient recruitment and eligibility
Between February 4, 2003, and December 15, 2006, a total of 89,890 people were screened. Of these, 17,802 met the inclusion and exclusion criteria and were included in the study. Of the 72,088 people who were excluded, 25,993 (36.1%) had an hs-CRP level below 2 mg/L and 37,611 (52.2%) had an LDL-C level of 130 mg/dL or higher.
A not-so-healthy population
The aim of the investigators was to include relatively healthy people. The median age was 66 years, about 16% of participants were current smokers, about 11% had a family history of heart disease, and about 41% met the criteria for metabolic syndrome, all conditions that are associated with elevated hs-CRP.25 Of note, the median hs-CRP level was 4.2 mg/L, a level indicating higher global risk according to the American College of Cardiology/American Heart Association consensus statement.26
Reduction in lipid levels and hs-CRP
By 12 months, in the rosuvastatin group, the median LDL-C level had fallen by 50% (from 108 to 55 mg/dL), and the median hs-CRP level had fallen by 37% (from 4.2 to 2.2 mg/L). Additionally, the triglyceride level had fallen by 17%. The high-density lipoprotein cholesterol levels did not change significantly.
Impact on end points
Adverse events
WHAT DOES THIS MEAN?
Is lower LDL-C better?
The JUPITER trial is the latest of several statin trials that have shown significant reductions in major adverse cardiovascular events when LDL-C was lowered below what has been recommended by the current guidelines.27,28
In 2002, the Heart Protection Study29 showed a significant reduction in major adverse cardiovascular events in patients at high risk of coronary artery disease if they received simvastatin (Zocor), even if they had LDL-C levels lower than 100 mg/dL at baseline. Similarly, the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial30 showed a 16% relative risk reduction in a composite end point in patients presenting with acute coronary syndrome if they received intensive statin therapy.
These two studies led to an update by the National Cholesterol Education Program (Adult Treatment Panel III), suggesting an optimal LDL-C goal of less than 70 mg/dL in those with coronary artery disease or its risk equivalent (ie, diabetes mellitus, peripheral vascular disease). Furthermore, in support of the “lower is better” theory, a number of studies that used intravascular ultrasonography have shown regression of coronary plaque with aggressive LDL-C lowering. Notably, in a Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (the ASTEROID trial),5 rosuvastatin 40 mg daily caused significant plaque regression while lowering LDL-C to 61 mg/dL over a 24-month period.
A number of high-dose statin trials have shown that lowering LDL-C to less than 70 mg/dL significantly reduces major adverse cardiovascular events.31–39 The JUPITER trial was unique in that it extended these findings to people without known coronary disease (ie, primary prevention) or elevated cholesterol but with elevated levels of a marker of inflammation—hs-CRP. In view of the JUPITER results and of studies using intravascular ultrasonography in the primary prevention setting, it seems clear that lowering LDL-C to levels less than 70 mg/dL also reduces both atherosclerotic plaque progression and the rate of first major adverse cardiovascular events in primary prevention in patients at higher global risk.
Did the study prove that reducing hs-CRP lowers risk?
Measuring hs-CRP levels has been extensively studied in apparently healthy populations, stable angina, unstable angina, and other cardiovascular settings.18,21,40–43 It has been shown to have significant prognostic implications in a number of primary and secondary trials.44 Additionally, those with elevated LDL-C and hs-CRP levels benefit the most from statin therapy.16,45,46 Animal studies have also provided some evidence that CRP may play a role in atherogenesis.47,48 However, recent clinical and genetic studies have raised doubt about the direct causal relationship between CRP and coronary artery disease,23,49,50 and epidemiologic studies have questioned its usefulness as a marker of risk.51,52
The JUPITER study adds little to clear up the controversy about whether hs-CRP is a mechanistic participant in atherosclerotic disease. However, it also shows that this issue is somewhat irrelevant, in that selection of patients for high-potency statin therapy solely on the basis of high hs-CRP without other indications for lipid-lowering therapy clearly reduces risk and improves survival.
JUPITER did not examine whether people with higher hs-CRP levels benefited more from statin therapy than those with lower levels. The hypothesis-generating data for JUPITER came from an analysis of changes in hs-CRP and LDL-C in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).16 Thus, JUPITER did not include people with both low LDL-C and low hs-CRP because, in the AFCAPS/TexCAPS analysis, those with low LDL-C and low hs-CRP had extremely low event rates and no clinical efficacy of statin therapy, despite good LDL-C reduction. In marked contrast, those with low LDL-C but elevated hs-CRP had high event rates and large relative risk reductions— hence the need for JUPITER to prospectively test this hypothesis. Nevertheless, the initial results of JUPITER as presented do not yet make it clear that there is a dose-response relationship between higher levels of hs-CRP and a greater reduction in events, even in a cohort with elevated hs-CRP at baseline. This analysis will no doubt be forthcoming in another manuscript from Ridker and colleagues. Specifically, it will be of interest to examine whether those with the highest hs-CRP levels benefited the most from rosuvastatin on both an absolute and relative scale, and whether those with the greatest hs-CRP reduction also benefited more. With the present data available from JUPITER, a reasonable interpretation is that an elevated hs-CRP simply widens the inclusion criterion for those for whom high-potency statin therapy improves clinical outcomes.53
Better markers are needed
Even with a nonspecific marker such as hs-CRP, patients at higher global risk and with LDL-C below the recommended levels could be identified and treated aggressively. This benefit, however, required that approximately 100 people be treated with rosuvastatin for 2 years to prevent one event. Additionally, only 20% of all patients screened were eligible for the trial. Therefore, one could argue that its generalizability is limited.
Markers of risk that are more specific and sensitive are needed to identify people at higher global risk who would otherwise be considered to be at low risk with the current risk assessment tools. A number of such inflammatory and oxidative markers are under development.54–60
Absolute vs relative risk reduction and the public health burden
The 44% reduction in the number of primary end point events in the rosuvastatin group was considerable in relative terms. However, in absolute terms, 95 people had to be treated for up to 2 years in order to prevent one event.53 In making recommendations, the United States Department of Health and Human Services has to consider the clinical benefit of a test or a drug in light of its cost. With health care costs increasing, many agencies are refusing to pay for therapies on the basis of cost or small absolute benefit.
While we do not have the answer as to whether treating 95 people for 2 years to see one benefit is cost-effective, one thing is clear: the field of medicine is in desperate need of a better way to identify individuals who may benefit from a test or therapy.61 Additionally, we think it is important to note that the “numbers-needed-to-treat” (95 at 2 years and 25 at 5 years) derived from JUPITER are actually smaller than the values observed in the AFCAPS/TexCAPS and the West of Scotland Coronary Prevention Study.62,63 This suggests that statin therapy is at least as cost-effective in those with elevated hs-CRP as in those with elevated LDL-C. Even our most robust therapies are effective in only a minority of patients treated.61
Should ‘healthy’ people be tested for hs-CRP?
In 2003, we wrote in this journal21 that measuring hs-CRP may add to the current risk-prediction models by identifying people at increased risk who would otherwise not be considered as such by current risk models. The US Centers for Disease Control and Prevention and the American Heart Association have also stated that measuring hs-CRP in those at intermediate risk may be reasonable.26
The JUPITER investigators intended to study a relatively healthy population, but, as we mentioned, a close look at the cohort’s baseline characteristics indicates a substantial proportion met the criteria for metabolic syndrome. Therefore, one could challenge whether we really need hs-CRP in such a population to identify who will benefit from statin therapy.
We agree with the recommendation from the Centers for Disease Control and Prevention and the American Heart Association that measuring hs-CRP in people at intermediate risk is a reasonable option.26 We also believe that hs-CRP should be tested as a secondary risk factor, in combination with blood pressure, lipids, diabetes, smoking, serum creatinine, and fasting blood glucose. Factors such as obesity, sedentary lifestyle, family history of heart disease, and emotional and physical stress should also be considered.
Safety of high-dose statin therapy
High-dose statin therapy has been well tolerated in clinical trials, but rates of discontinuation have been higher (7%–10%) than with moderate-dose therapy (4%–5%).64 Fortunately, the rates of serious adverse events have in general been low. For example, with simvastatin 80 mg, the rates of myopathy and rhabdomyolysis were quite low.31
Rates of elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with high-dose statin therapy have been reported to be below 1.3%. Studies have shown that reducing LDL-C to below 100 mg/dL is associated with a higher incidence of ALT and AST elevations. However, these elevations have usually been benign and often return to normal when the drug is reduced in dose or withdrawn.
In previous studies of rosuvastatin,65 the incidence of myopathy and liver function abnormalities was less than 0.1%. Rates of proteinuria were similarly low, and in many patients renal function actually improved on rosuvastatin.66,67 Furthermore, rosuvastatin may have different pharmacokinetic properties than atorvastatin (Lipitor) and simvastatin, which may result in a lower incidence of musculoskeletal toxicity.68,69
In general, the incidence of cancer has been similar in those treated with high-dose statins and those treated with placebo. The Treating to New Targets trial70 suggested that the incidence of cancer was higher with atorvastatin 80 mg daily than with 20 mg daily. However, a meta-analysis of 14 trials of moderate-dose statin therapy did not show any evidence of increased cancer rates with these agents.70 Indeed, in JUPITER, there was a reduction in cancer-related mortality rates, which could have been due to chance.
The JUPITER trial also showed an increase in the physician-reported incidence of diabetes mellitus with rosuvastatin. This is an important finding, and it may be a class effect because modest increases have similarly been reported with other statins in other major trials, eg, with pravastatin (Pravachol) in PROSPER, simvastatin in the Heart Protection Study, and atorvastatin in PROVE-IT. However, even in those with diabetes or impaired fasting glucose, the reduction in the rate of major adverse events is significant. For example, in JUPITER, almost all of the cases of “incident diabetes” were in those with impaired fasting glucose at baseline, and this group had nearly a 50% reduction in rates of myocardial infarction, stroke, and cardiovascular death. Therefore, on balance, the modest risk of earlier diagnosis of diabetes with statin therapy seems substantially offset by the marked reduction in rates of major adverse cardiovascular events in people with diabetes and impaired fasting glucose on statin therapy.
TAKE-HOME POINTS
The JUPITER trial, like previous high-dose statin trials, calls into question whether current LDL-C guidelines are appropriate for people at higher global risk with otherwise “normal” LDL-C levels.27,28 This trial heralds a new era in preventive therapy because it extends beyond LDL-C as an indication for statin therapy within the primary prevention setting. Statins have revolutionized the therapy of cardiovascular disease, and they continue to show benefit even in the “healthy.”
Clearly, hs-CRP serves as a nonlipid marker to identify those who may benefit from statin therapy. Nonetheless, more specific and sensitive markers (or panels) of cardiovascular risk are necessary. In the future, we will need markers that not only identify people at higher global risk, but that also tell us who would benefit from certain medical or surgical therapies. Elevated hs-CRP in a patient who otherwise would not be a candidate for statin therapy should trigger a reassessment of the risks vs benefits of statin therapy—JUPITER teaches us that statin therapy will benefit these patients.
Aggressive lifestyle modification that encompasses a balanced diet, routine exercise, and smoking cessation should be applied in both primary and secondary prevention. Additionally, risk factors such as elevated blood pressure and hyperlipidemia should be aggressively treated with appropriate medications.
The medical community has struggled with two important questions for the past 10 years: When it comes to the low-density lipoprotein cholesterol (LDL-C) level, how low should one go and at what cost? And are there other markers of risk that can identify a higher-risk subpopulation in relatively healthy people? The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) provided partial answers for these questions by finding that a highly potent statin lowered the risk of cardiovascular events in patients with “normal” LDL-C but elevated levels of high-sensitivity C-reactive protein (hs-CRP).1
In this article, we will critically evaluate the methods, results, and conclusions of the JUPITER trial. Additionally, we will discuss its limitations and areas of uncertainty.
BEFORE JUPITER
The LDL-C-lowering drugs called statins have revolutionized cardiovascular medicine.2 They are beneficial in both the primary prevention setting and in acute coronary syndromes, stable angina, and unstable angina and can halt the progression of coronary artery disease—in some cases even resulting in modest regression of plaque.3–6
Many experts have credited the reduction in LDL-C as being the sole factor responsible for the decrease in major adverse events seen with statin therapy.7 However, statins have other, non-lipid-lowering properties, including anti-inflammatory and antioxidant effects, that may also contribute to their benefits.8–15
One of the anti-inflammatory actions of statins is evidenced by lower levels of the acute-phase reactant CRP.10,11,15,16 Measuring systemic CRP levels with a highly sensitive assay (yielding the so-called high-sensitivity or hs-CRP level) provides significant clinical prognostic value across a spectrum of clinical situations, ranging from risk screening in apparently healthy people to stable and unstable angina.17–22 People with higher hs-CRP levels are, on average, at higher risk of adverse cardiovascular events. However, controversy remains as to whether hs-CRP plays a mechanistic role in plaque formation and acute complications. Indeed, recent genetic studies argue strongly that hs-CRP lies outside the mechanistic path of atherosclerosis.23 Nonetheless, an overwhelming amount of data indicates that hs-CRP serves as a marker of disease.17–21
Nissen et al10 showed that the rate of progression of atherosclerosis is lower when the levels of atherogenic lipoproteins and hs-CRP are both lowered with statin therapy. Simultaneously, Ridker et al11 showed that patients who have lower hs-CRP levels after statin therapy have better clinical outcomes than those with higher hs-CRP levels, regardless of their achieved level of LDL-C.
Collectively, these studies and others have led some to believe that, in people with relatively low LDL-C but persistently elevated hs-CRP, statin therapy may reduce the rate of events.15,24 The JUPITER trial was undertaken to test this hypothesis.
JUPITER STUDY DESIGN
JUPITER was designed to see whether highly potent statin therapy is beneficial in people with elevated hs-CRP who otherwise do not meet the criteria for lipid-lowering therapy. The study was conducted at 1,315 sites in 26 countries. It was sponsored by AstraZeneca, the maker of rosuvastatin (Crestor).
Inclusion and exclusion criteria
All participants had to be free of known cardiovascular disease, have an LDL-C level lower than 130 mg/dL, and have an hs-CRP level of 2.0 mg/L or greater. Patients were excluded if they were previous or current users of lipid-lowering drugs; had severe arthritis, lupus, or inflammatory bowel disease; or were taking immune-modulating drugs such as cyclosporine (Sandimmune, others), tacrolimus (Prograf), azathioprine (Azasan, Imuran), or long-term oral corticosteroids.
Rosuvastatin therapy
Participants were randomly assigned in a 1:1 ratio to receive rosuvastatin 20 mg daily or a matching placebo in a double-blind fashion.
End points
The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. Secondary end points were the individual components of the primary end point.
Statistical analysis
The study was powered to detect a 25% reduction in the primary end point among those treated with rosuvastatin. The trial was designed to run until 520 end point events had occurred. However, on March 29, 2008, after the first prespecified interim analysis, the Data and Safety Monitoring Board stopped the trial due to a significant reduction in the primary end point in the rosuvastatin group. As in most randomized clinical trials, all analyses were done on an intention-to-treat basis. Prespecified subgroup analyses were also performed.
STUDY RESULTS
Patient recruitment and eligibility
Between February 4, 2003, and December 15, 2006, a total of 89,890 people were screened. Of these, 17,802 met the inclusion and exclusion criteria and were included in the study. Of the 72,088 people who were excluded, 25,993 (36.1%) had an hs-CRP level below 2 mg/L and 37,611 (52.2%) had an LDL-C level of 130 mg/dL or higher.
A not-so-healthy population
The aim of the investigators was to include relatively healthy people. The median age was 66 years, about 16% of participants were current smokers, about 11% had a family history of heart disease, and about 41% met the criteria for metabolic syndrome, all conditions that are associated with elevated hs-CRP.25 Of note, the median hs-CRP level was 4.2 mg/L, a level indicating higher global risk according to the American College of Cardiology/American Heart Association consensus statement.26
Reduction in lipid levels and hs-CRP
By 12 months, in the rosuvastatin group, the median LDL-C level had fallen by 50% (from 108 to 55 mg/dL), and the median hs-CRP level had fallen by 37% (from 4.2 to 2.2 mg/L). Additionally, the triglyceride level had fallen by 17%. The high-density lipoprotein cholesterol levels did not change significantly.
Impact on end points
Adverse events
WHAT DOES THIS MEAN?
Is lower LDL-C better?
The JUPITER trial is the latest of several statin trials that have shown significant reductions in major adverse cardiovascular events when LDL-C was lowered below what has been recommended by the current guidelines.27,28
In 2002, the Heart Protection Study29 showed a significant reduction in major adverse cardiovascular events in patients at high risk of coronary artery disease if they received simvastatin (Zocor), even if they had LDL-C levels lower than 100 mg/dL at baseline. Similarly, the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial30 showed a 16% relative risk reduction in a composite end point in patients presenting with acute coronary syndrome if they received intensive statin therapy.
These two studies led to an update by the National Cholesterol Education Program (Adult Treatment Panel III), suggesting an optimal LDL-C goal of less than 70 mg/dL in those with coronary artery disease or its risk equivalent (ie, diabetes mellitus, peripheral vascular disease). Furthermore, in support of the “lower is better” theory, a number of studies that used intravascular ultrasonography have shown regression of coronary plaque with aggressive LDL-C lowering. Notably, in a Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (the ASTEROID trial),5 rosuvastatin 40 mg daily caused significant plaque regression while lowering LDL-C to 61 mg/dL over a 24-month period.
A number of high-dose statin trials have shown that lowering LDL-C to less than 70 mg/dL significantly reduces major adverse cardiovascular events.31–39 The JUPITER trial was unique in that it extended these findings to people without known coronary disease (ie, primary prevention) or elevated cholesterol but with elevated levels of a marker of inflammation—hs-CRP. In view of the JUPITER results and of studies using intravascular ultrasonography in the primary prevention setting, it seems clear that lowering LDL-C to levels less than 70 mg/dL also reduces both atherosclerotic plaque progression and the rate of first major adverse cardiovascular events in primary prevention in patients at higher global risk.
Did the study prove that reducing hs-CRP lowers risk?
Measuring hs-CRP levels has been extensively studied in apparently healthy populations, stable angina, unstable angina, and other cardiovascular settings.18,21,40–43 It has been shown to have significant prognostic implications in a number of primary and secondary trials.44 Additionally, those with elevated LDL-C and hs-CRP levels benefit the most from statin therapy.16,45,46 Animal studies have also provided some evidence that CRP may play a role in atherogenesis.47,48 However, recent clinical and genetic studies have raised doubt about the direct causal relationship between CRP and coronary artery disease,23,49,50 and epidemiologic studies have questioned its usefulness as a marker of risk.51,52
The JUPITER study adds little to clear up the controversy about whether hs-CRP is a mechanistic participant in atherosclerotic disease. However, it also shows that this issue is somewhat irrelevant, in that selection of patients for high-potency statin therapy solely on the basis of high hs-CRP without other indications for lipid-lowering therapy clearly reduces risk and improves survival.
JUPITER did not examine whether people with higher hs-CRP levels benefited more from statin therapy than those with lower levels. The hypothesis-generating data for JUPITER came from an analysis of changes in hs-CRP and LDL-C in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).16 Thus, JUPITER did not include people with both low LDL-C and low hs-CRP because, in the AFCAPS/TexCAPS analysis, those with low LDL-C and low hs-CRP had extremely low event rates and no clinical efficacy of statin therapy, despite good LDL-C reduction. In marked contrast, those with low LDL-C but elevated hs-CRP had high event rates and large relative risk reductions— hence the need for JUPITER to prospectively test this hypothesis. Nevertheless, the initial results of JUPITER as presented do not yet make it clear that there is a dose-response relationship between higher levels of hs-CRP and a greater reduction in events, even in a cohort with elevated hs-CRP at baseline. This analysis will no doubt be forthcoming in another manuscript from Ridker and colleagues. Specifically, it will be of interest to examine whether those with the highest hs-CRP levels benefited the most from rosuvastatin on both an absolute and relative scale, and whether those with the greatest hs-CRP reduction also benefited more. With the present data available from JUPITER, a reasonable interpretation is that an elevated hs-CRP simply widens the inclusion criterion for those for whom high-potency statin therapy improves clinical outcomes.53
Better markers are needed
Even with a nonspecific marker such as hs-CRP, patients at higher global risk and with LDL-C below the recommended levels could be identified and treated aggressively. This benefit, however, required that approximately 100 people be treated with rosuvastatin for 2 years to prevent one event. Additionally, only 20% of all patients screened were eligible for the trial. Therefore, one could argue that its generalizability is limited.
Markers of risk that are more specific and sensitive are needed to identify people at higher global risk who would otherwise be considered to be at low risk with the current risk assessment tools. A number of such inflammatory and oxidative markers are under development.54–60
Absolute vs relative risk reduction and the public health burden
The 44% reduction in the number of primary end point events in the rosuvastatin group was considerable in relative terms. However, in absolute terms, 95 people had to be treated for up to 2 years in order to prevent one event.53 In making recommendations, the United States Department of Health and Human Services has to consider the clinical benefit of a test or a drug in light of its cost. With health care costs increasing, many agencies are refusing to pay for therapies on the basis of cost or small absolute benefit.
While we do not have the answer as to whether treating 95 people for 2 years to see one benefit is cost-effective, one thing is clear: the field of medicine is in desperate need of a better way to identify individuals who may benefit from a test or therapy.61 Additionally, we think it is important to note that the “numbers-needed-to-treat” (95 at 2 years and 25 at 5 years) derived from JUPITER are actually smaller than the values observed in the AFCAPS/TexCAPS and the West of Scotland Coronary Prevention Study.62,63 This suggests that statin therapy is at least as cost-effective in those with elevated hs-CRP as in those with elevated LDL-C. Even our most robust therapies are effective in only a minority of patients treated.61
Should ‘healthy’ people be tested for hs-CRP?
In 2003, we wrote in this journal21 that measuring hs-CRP may add to the current risk-prediction models by identifying people at increased risk who would otherwise not be considered as such by current risk models. The US Centers for Disease Control and Prevention and the American Heart Association have also stated that measuring hs-CRP in those at intermediate risk may be reasonable.26
The JUPITER investigators intended to study a relatively healthy population, but, as we mentioned, a close look at the cohort’s baseline characteristics indicates a substantial proportion met the criteria for metabolic syndrome. Therefore, one could challenge whether we really need hs-CRP in such a population to identify who will benefit from statin therapy.
We agree with the recommendation from the Centers for Disease Control and Prevention and the American Heart Association that measuring hs-CRP in people at intermediate risk is a reasonable option.26 We also believe that hs-CRP should be tested as a secondary risk factor, in combination with blood pressure, lipids, diabetes, smoking, serum creatinine, and fasting blood glucose. Factors such as obesity, sedentary lifestyle, family history of heart disease, and emotional and physical stress should also be considered.
Safety of high-dose statin therapy
High-dose statin therapy has been well tolerated in clinical trials, but rates of discontinuation have been higher (7%–10%) than with moderate-dose therapy (4%–5%).64 Fortunately, the rates of serious adverse events have in general been low. For example, with simvastatin 80 mg, the rates of myopathy and rhabdomyolysis were quite low.31
Rates of elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with high-dose statin therapy have been reported to be below 1.3%. Studies have shown that reducing LDL-C to below 100 mg/dL is associated with a higher incidence of ALT and AST elevations. However, these elevations have usually been benign and often return to normal when the drug is reduced in dose or withdrawn.
In previous studies of rosuvastatin,65 the incidence of myopathy and liver function abnormalities was less than 0.1%. Rates of proteinuria were similarly low, and in many patients renal function actually improved on rosuvastatin.66,67 Furthermore, rosuvastatin may have different pharmacokinetic properties than atorvastatin (Lipitor) and simvastatin, which may result in a lower incidence of musculoskeletal toxicity.68,69
In general, the incidence of cancer has been similar in those treated with high-dose statins and those treated with placebo. The Treating to New Targets trial70 suggested that the incidence of cancer was higher with atorvastatin 80 mg daily than with 20 mg daily. However, a meta-analysis of 14 trials of moderate-dose statin therapy did not show any evidence of increased cancer rates with these agents.70 Indeed, in JUPITER, there was a reduction in cancer-related mortality rates, which could have been due to chance.
The JUPITER trial also showed an increase in the physician-reported incidence of diabetes mellitus with rosuvastatin. This is an important finding, and it may be a class effect because modest increases have similarly been reported with other statins in other major trials, eg, with pravastatin (Pravachol) in PROSPER, simvastatin in the Heart Protection Study, and atorvastatin in PROVE-IT. However, even in those with diabetes or impaired fasting glucose, the reduction in the rate of major adverse events is significant. For example, in JUPITER, almost all of the cases of “incident diabetes” were in those with impaired fasting glucose at baseline, and this group had nearly a 50% reduction in rates of myocardial infarction, stroke, and cardiovascular death. Therefore, on balance, the modest risk of earlier diagnosis of diabetes with statin therapy seems substantially offset by the marked reduction in rates of major adverse cardiovascular events in people with diabetes and impaired fasting glucose on statin therapy.
TAKE-HOME POINTS
The JUPITER trial, like previous high-dose statin trials, calls into question whether current LDL-C guidelines are appropriate for people at higher global risk with otherwise “normal” LDL-C levels.27,28 This trial heralds a new era in preventive therapy because it extends beyond LDL-C as an indication for statin therapy within the primary prevention setting. Statins have revolutionized the therapy of cardiovascular disease, and they continue to show benefit even in the “healthy.”
Clearly, hs-CRP serves as a nonlipid marker to identify those who may benefit from statin therapy. Nonetheless, more specific and sensitive markers (or panels) of cardiovascular risk are necessary. In the future, we will need markers that not only identify people at higher global risk, but that also tell us who would benefit from certain medical or surgical therapies. Elevated hs-CRP in a patient who otherwise would not be a candidate for statin therapy should trigger a reassessment of the risks vs benefits of statin therapy—JUPITER teaches us that statin therapy will benefit these patients.
Aggressive lifestyle modification that encompasses a balanced diet, routine exercise, and smoking cessation should be applied in both primary and secondary prevention. Additionally, risk factors such as elevated blood pressure and hyperlipidemia should be aggressively treated with appropriate medications.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207.
- Topol EJ. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 2004; 350:1562–1564.
- Cannon CP, Murphy SA, Braunwald E. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353:93–96.
- Cohen DJ, Carrozza JP, Baim DS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341:1853–1854.
- Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556–1565.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071–1080.
- Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46:1855–1862.
- Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103:276–283.
- Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005; 96:24F–33F.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352:29–38.
- Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352:20–28.
- Shishehbor MH, Aviles RJ, Brennan ML, et al. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003; 289:1675–1680.
- Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108:426–431.
- Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21:1712–1719.
- Shishehbor MH, Patel T, Bhatt DL. Using statins to treat inflammation in acute coronary syndromes: Are we there yet? Cleve Clin J Med 2006; 73:760–766.
- Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959–1965.
- Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98:731–733.
- Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836–843.
- Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285:2481–2485.
- Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 2001; 47:403–411.
- Shishehbor MH, Bhatt DL, Topol EJ. Using C-reactive protein to assess cardiovascular disease risk. Cleve Clin J Med 2003; 70:634–640.
- Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979.
- Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359:1897–1908.
- Ridker PM. Are statins anti-inflammatory? Issues in the design and conduct of the pravastatin inflammation C-reactive protein evaluation. Curr Cardiol Rep 2000; 2:269–273.
- Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107:391–397.
- Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511.
- Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497.
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227–239.
- Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract 2002; 56:53–56.
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504.
- de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292:1307–1316.
- LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425–1435.
- Liem AH, van Boven AJ, Veeger NJ, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J 2002; 23:1931–1937.
- Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437–2445.
- Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999; 341:70–76.
- Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of highdose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46:1405–1410.
- Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285:1711–1718.
- Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287:3215–3222.
- Patel TN, Shishehbor MH, Bhatt DL. A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J 2007; 28:664–672.
- Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med 2000; 45:391–418.
- Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813–1818.
- Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–2011.
- Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005; 112:25–31.
- Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49:2129–2138.
- Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64–70.
- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100:230–235.
- Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 2005; 96:714–716.
- Schwedler SB, Amann K, Wernicke K, et al. Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation 2005; 112:1016–1023.
- Pfister R, Hellmich M. Multiple biomarkers and cardiovascular risk. N Engl J Med 2008; 359:760.
- Schunkert H, Samani NJ. Elevated C-reactive protein in atherosclerosis— chicken or egg? N Engl J Med 2008; 359:1953–1955.
- Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387–1397.
- Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? Arch Intern Med 2002; 162:867–869.
- Hlatky MA. Expanding the orbit of primary prevention—moving beyond JUPITER. N Engl J Med 2008; 359:2280–2282.
- Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep 2004; 6:243–250.
- Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25:1102–1111.
- Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 2008; 299:1265–1276.
- Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 2008; 52:24–32.
- Hakonarson H, Thorvaldsson S, Helgadottir A, et al. Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 2005; 293:2245–2256.
- Ky B, Burke A, Tsimikas S, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008; 51:1653–1662.
- Levy AP, Levy JE, Kalet-Litman S, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 2007; 27:134–140.
- Mukherjee D, Topol EJ. Pharmacogenomics in cardiovascular diseases. Curr Probl Cardiol 2003; 28:317–347
- West of Scotland Coronary Prevention Study: identification of highrisk groups and comparison with other cardiovascular intervention trials. Lancet 1996; 348:1339–1342.
- Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–1622.
- Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49:1753–1762.
- Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf 2004; 3:547–557.
- Kasiske BL, Wanner C, O’Neill WC. An assessment of statin safety by nephrologists. Am J Cardiol 2006; 97:82C–85C.
- McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87:28B–32B.
- Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006; 97:44C–51C.
- Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94:1140–1146.
- Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–1278.
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207.
- Topol EJ. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 2004; 350:1562–1564.
- Cannon CP, Murphy SA, Braunwald E. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353:93–96.
- Cohen DJ, Carrozza JP, Baim DS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999; 341:1853–1854.
- Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556–1565.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071–1080.
- Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46:1855–1862.
- Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103:276–283.
- Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005; 96:24F–33F.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352:29–38.
- Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352:20–28.
- Shishehbor MH, Aviles RJ, Brennan ML, et al. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003; 289:1675–1680.
- Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108:426–431.
- Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21:1712–1719.
- Shishehbor MH, Patel T, Bhatt DL. Using statins to treat inflammation in acute coronary syndromes: Are we there yet? Cleve Clin J Med 2006; 73:760–766.
- Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959–1965.
- Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98:731–733.
- Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836–843.
- Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285:2481–2485.
- Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 2001; 47:403–411.
- Shishehbor MH, Bhatt DL, Topol EJ. Using C-reactive protein to assess cardiovascular disease risk. Cleve Clin J Med 2003; 70:634–640.
- Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979.
- Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008; 359:1897–1908.
- Ridker PM. Are statins anti-inflammatory? Issues in the design and conduct of the pravastatin inflammation C-reactive protein evaluation. Curr Cardiol Rep 2000; 2:269–273.
- Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107:391–397.
- Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511.
- Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497.
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227–239.
- Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract 2002; 56:53–56.
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504.
- de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292:1307–1316.
- LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425–1435.
- Liem AH, van Boven AJ, Veeger NJ, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J 2002; 23:1931–1937.
- Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437–2445.
- Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999; 341:70–76.
- Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of highdose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46:1405–1410.
- Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285:1711–1718.
- Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287:3215–3222.
- Patel TN, Shishehbor MH, Bhatt DL. A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J 2007; 28:664–672.
- Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med 2000; 45:391–418.
- Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813–1818.
- Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–2011.
- Cushman M, Arnold AM, Psaty BM, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005; 112:25–31.
- Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49:2129–2138.
- Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64–70.
- Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100:230–235.
- Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 2005; 96:714–716.
- Schwedler SB, Amann K, Wernicke K, et al. Native C-reactive protein increases whereas modified C-reactive protein reduces atherosclerosis in apolipoprotein E-knockout mice. Circulation 2005; 112:1016–1023.
- Pfister R, Hellmich M. Multiple biomarkers and cardiovascular risk. N Engl J Med 2008; 359:760.
- Schunkert H, Samani NJ. Elevated C-reactive protein in atherosclerosis— chicken or egg? N Engl J Med 2008; 359:1953–1955.
- Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350:1387–1397.
- Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? Arch Intern Med 2002; 162:867–869.
- Hlatky MA. Expanding the orbit of primary prevention—moving beyond JUPITER. N Engl J Med 2008; 359:2280–2282.
- Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep 2004; 6:243–250.
- Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005; 25:1102–1111.
- Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 2008; 299:1265–1276.
- Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 2008; 52:24–32.
- Hakonarson H, Thorvaldsson S, Helgadottir A, et al. Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 2005; 293:2245–2256.
- Ky B, Burke A, Tsimikas S, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008; 51:1653–1662.
- Levy AP, Levy JE, Kalet-Litman S, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 2007; 27:134–140.
- Mukherjee D, Topol EJ. Pharmacogenomics in cardiovascular diseases. Curr Probl Cardiol 2003; 28:317–347
- West of Scotland Coronary Prevention Study: identification of highrisk groups and comparison with other cardiovascular intervention trials. Lancet 1996; 348:1339–1342.
- Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–1622.
- Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49:1753–1762.
- Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin Drug Saf 2004; 3:547–557.
- Kasiske BL, Wanner C, O’Neill WC. An assessment of statin safety by nephrologists. Am J Cardiol 2006; 97:82C–85C.
- McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87:28B–32B.
- Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006; 97:44C–51C.
- Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94:1140–1146.
- Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–1278.
KEY POINTS
- LDL-C is the current gold standard diagnostic marker of risk, and elevated values should be aggressively treated in both primary and secondary prevention.
- The optional LDL-C goal of 70 mg/dL for patients at high risk may need to be extended to others at higher global risk, such as those with elevated hs-CRP.
- Although elevated hs-CRP may identify some people with low LDL-C who are nevertheless at higher global risk, more sensitive and specific markers of risk are needed.
Boosting Blood Cells for Transplant Patients
Erratum (2008;82:317-318)
What's Eating You? Native and Imported Fire Ants
October 2008 Instant Poll Results
BIOIDENTICAL HT: WHERE DO YOU STAND?
A 54-year-old woman, recently menopausal, complains of hot flushes that make her miserable. After an evaluation, including an endocrine work-up, you recommend hormone therapy (HT). She promptly asks about bioidentical hormones, which she has read about on the Internet and heard about from friends. In your practice, the next step would be to:
COMMENTS
“I would educate her on the facts about bioidenticals but, if she insists, I would let her have them.”
“I employ a combination of the three options.”
“As a specialty, we need to be clear on terminology: There are pharmaceutical bioidentical hormones.”
“I explain to patients that estradiol—the medication in Estrace, Vivelle, etc.—is bioidentical.”
BIOIDENTICAL HT: WHERE DO YOU STAND?
A 54-year-old woman, recently menopausal, complains of hot flushes that make her miserable. After an evaluation, including an endocrine work-up, you recommend hormone therapy (HT). She promptly asks about bioidentical hormones, which she has read about on the Internet and heard about from friends. In your practice, the next step would be to:
COMMENTS
“I would educate her on the facts about bioidenticals but, if she insists, I would let her have them.”
“I employ a combination of the three options.”
“As a specialty, we need to be clear on terminology: There are pharmaceutical bioidentical hormones.”
“I explain to patients that estradiol—the medication in Estrace, Vivelle, etc.—is bioidentical.”
BIOIDENTICAL HT: WHERE DO YOU STAND?
A 54-year-old woman, recently menopausal, complains of hot flushes that make her miserable. After an evaluation, including an endocrine work-up, you recommend hormone therapy (HT). She promptly asks about bioidentical hormones, which she has read about on the Internet and heard about from friends. In your practice, the next step would be to:
COMMENTS
“I would educate her on the facts about bioidenticals but, if she insists, I would let her have them.”
“I employ a combination of the three options.”
“As a specialty, we need to be clear on terminology: There are pharmaceutical bioidentical hormones.”
“I explain to patients that estradiol—the medication in Estrace, Vivelle, etc.—is bioidentical.”
ROUNDTABLE: PART 1 OF 2: Using mesh to repair prolapse calls for more than a kit—it takes skill
MICKEY M. KARRAM, MD, moderator, is Director of Urogynecology at Good Samaritan Hospital and Voluntary Professor of ObGyn at the University of Cincinnati School of Medicine in Cincinnati, Ohio.
SHLOMO RAZ, MD, is Professor of Urology and Chief of Pelvic Medicine and Reconstructive Urology at UCLA School of Medicine in Los Angeles.
VINCENT LUCENTE, MD, MBA, is Founder and Director of the Institute for Female Pelvic Medicine and Reconstructive Surgery in Allentown, Pa, and Clinical Professor of ObGyn at Temple University School of Medicine in Philadelphia.
MARK D. WALTERS, MD, is Professor and Vice Chair of Gynecology, Section of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, at the Cleveland Clinic in Cleveland, Ohio.
Mesh kits for repairing prolapse are proliferating like crazy, just as they did for midurethral sling procedures. But mesh augmentation of prolapse surgeries requires more than a prepackaged assortment of tools and materials. In this article, moderator Mickey M. Karram, MD, and a panel of nationally recognized urogynecologists and urologists describe the literature on mesh augmentation and discuss indications, contraindications, techniques, applicable cases, and the considerable training required.
In Part 2, which will appear in the February issue of OBG Management, the panel tackles the thorny topic of complications, including erosion, extrusion, foreshortening of the vagina, dyspareunia, and pain. Their discussion focuses on ways to avoid these problems, and methods for correcting them.
Do we have enough data?
DR. KARRAM: To start, let’s quickly review the peer-reviewed literature on the use of mesh augmentation during surgery for pelvic organ prolapse.
DR. WALTERS: Until recently, most data concerned open abdominal sacrocolpopexy (ASC) using polypropylene or Merseline mesh. There is significant clinical experience with this operation, and multiple cohort studies show long-term cure rates of 78% to 100% for apical prolapse.1
At least two randomized controlled trials have compared open ASC with sutured vaginal colpopexy procedures, and ASC is certainly equal to—perhaps better than—all transvaginal sutured repairs.2,3
With ASC, most recurrences affect the distal half of the vagina and involve one or more of the following:
- anterior or posterior vaginal wall prolapse (or both)
- stress urinary incontinence (SUI)
- distal rectocele.1,3
Mesh erosion occurs in 3.4% of cases and is usually easily managed.1 Other complications, including bowel injury, tend to be related to access, regardless of whether the operation is performed via laparotomy or laparoscopy.
Robotic sacrocolpopexy has become popular in recent years, and we will probably see data on this approach as we gain experience.
When it comes to vaginal mesh kits, the peer-reviewed literature is just beginning to expand, with many studies being presented at international meetings. For anterior and, possibly, apical vaginal prolapse, the cure rate after use of a mesh kit appears to be as high as, or higher than, the rate for sutured repairs.4 This high rate of anatomic cure is balanced somewhat by additional cost and complications involving mesh and the kits.
For posterior vaginal wall prolapse and rectocele, I firmly believe, based on our research and that of others, that sutured repairs are superior to graft-augmented surgery.5
DR. KARRAM: What are the indications and contraindications for mesh augmentation of prolapse repair ( FIGURES 1 and 2 )?
DR. LUCENTE: I believe mesh is indicated in any patient in need of surgical repair of pelvic organ prolapse who is seeking optimal durability and is willing to accept the known risks of the surgery.
The issue becomes more complex when it comes to contraindications. Absolute contraindications are fairly obvious; they include medically unstable patients and those who may have an inactive infectious process within the pelvis or even undiagnosed abnormal uterine bleeding.
At our center, because the potential for dyspareunia and pelvic discomfort is our biggest concern, we have developed a profile of the patient who is more likely to develop these complaints. The profile includes any patient who has a chronic pain disorder of any type, but especially chronic pelvic pain disorders such as endometriosis and vulvodynia. Other risk factors appear to be a history of pelvic surgery involving any permanent material, suture or mesh, and young age.
So if we have a patient in her late 30s who has undergone reconstructive surgery using permanent sutures and who has an element of chronic pelvic pain, we would counsel her strongly to consider surgical options other than the use of synthetic mesh.
DR. WALTERS: The main indications for mesh-augmented prolapse repair are recurrent posthysterectomy vaginal vault prolapse, for which I usually perform ASC, and recurrent cystocele or anteriorapical prolapse, for which I use one of the anterior mesh kits.
I still think sutured repairs—by that, I mean uterosacral ligament or sacrospinous colpopexy with sutured rectocele repair—work best for recurrent posterior wall and posteriorapical prolapse. I don’t use mesh augmentation for rectocele.
The main contraindication to mesh augmentation, as I see it, is a history of mesh complications. If I am repairing a mesh complication such as erosion or pain, I do not place another mesh.
Medical issues that might increase mesh complications, such as diabetes, steroid use, or severe vaginal atrophy, would, at the very least, make me consider carefully whether mesh augmentation is appropriate. The literature is not clear on this, so mesh could still be used if the surgeon thinks it is necessary.
DR. KARRAM: I haven’t found a definitive indication for mesh augmentation. We have used biologic meshes empirically, but I am not convinced that they really add long-term durability, regardless of whether they are used in the anterior or posterior vaginal segment.
Our published durability rate for traditional suture-type repairs is in the range of 85% at 5 years out.6 Even if I assumed that mesh would give me 100% 5-year durability, this rate would have to be at the expense of some erosion, pain, and other complications unique to mesh. I do not think that the potential improvement in durability is worth these potential complications.
FIGURE 1 When the pelvic support system is intact, prolapse is rare
In the normal pelvis, organs are supported by a complex web of muscles, fascia, and connective tissue.
FIGURE 2 Mesh augmentation seeks to enhance the durability of repair
One type of mesh in final position. Mesh-augmented repair restores the vaginal apex and lends support to the walls of the vagina.
DR. KARRAM: If you are doing a lot of mesh repairs, you are obviously content with the results and feel that the few complications you are seeing are outweighed by the advantages mesh confers. How do you avoid extrusion and avert creation of a painful vagina?
DR. RAZ: Most of our cases are recurrent prolapse after failed vaginal or abdominal repair. I am indeed using a significant amount of soft polypropylene mesh for reconstructive procedures. As with the use of any other synthetic material, low-grade infection can develop after a few weeks or months. I use copious irrigation with antibiotic solution during reconstruction.
To avoid extrusion, I perform deep, rather than superficial, dissection of the vaginal wall to allow for better coverage of the mesh. For posterior mesh reconstruction, I cover the mesh with pararectal fascia to prevent erosion.
For mesh-augmented procedures, I cut the mesh myself in the operating room ( FIGURE 3 ). For a sling, I use a 10 cm × 1 cm soft polypropylene mesh. For a grade 3 or 4 cystocele, I use a trapezoid of soft polypropylene mesh with several points of fixation:
- at the sacrouterine ligament
- lateral to the obturator fascia
- distal to the bladder neck.
I always repair the vault at the same time.
For vault prolapse, I use a segment of soft polypropylene mesh in the shape of an apron with two arms (1 cm × 4 cm) and a central segment (4 cm × 7 cm). I support the vault using number 1-0 delayed absorbable suture and mesh. From outside the vaginal wall, in the posterolateral deep vaginal wall (inside the peritoneum), I incorporate the origin of the sacrouterine ligament and one arm of the mesh in the groove between the colon and levator ani, 15 cm from the introitus. I bring the suture 1 cm from the original entrance. A separate set of sutures brings the perirectal fascia together with the sacrouterine ligaments and perivesical fascia to close the peritoneal cavity. I tie the vault-suspension sutures, providing support to the cuff in a high posterior position (12 to 15 cm from the introitus).
In selected cases of significant recurrent rectocele, I use a rectangle of soft polypropylene mesh anchored to the origin of the sacrouterine ligament and distal to the perineal membrane. The mesh is covered by the pararectal fascia.
We have not seen vaginal, urethral, or bladder erosion in 1,800 cases of our distal urethral Prolene sling procedure using 10 cm × 1 cm soft mesh. In patients who have significant cystocele, vault prolapse, and recurrent rectocele, our vaginal erosion rate is 3%. We have never encountered rectal, bladder, or bowel perforation using our technique.
DR. LUCENTE: We often use mesh and are more than simply content with our results—we are extremely pleased, and so are our patients. Having said that, our techniques have definitely evolved over the past few years, as we’ve focused on how to decrease exposure and, more recently, optimize sexual function and vaginal comfort.
First, to avoid exposure, the most critical step is precise hydrodissection and distention of the true vesicovaginal space. This step can only be achieved through careful tactile guidance of the needle tip into the space, where it should remain while hydrodissection is performed. Always remember, sharp dissection “follows” hydrodissection. If you place the needle bevel within the vaginal wall, you will “split” the vaginal wall—as during standard colporrhaphy—which will lead to a high exposure rate.
Second, to avoid dyspareunia, it’s essential to pay close attention to POP-Q measurements, especially vaginal length, to ensure that the reconstruction restores the same length without foreshortening. This approach entails leaving the cervix in most patients who have a shorter vagina, and making sure that the mesh is secured above the ischial spine in younger, sexually active patients who have demonstrated a higher risk of postoperative deep, penetrating dyspareunia, compared with older, less sexually active patients.
Also paramount is to ensure that you have manually displaced the vagina inwardly as much as possible before deploying or setting the mesh. If you simply try to suture secure the mesh with the vagina incised open, without the ability to deploy the mesh with a closed, displaced vagina (to mimic deep penetration), it is difficult, if not impossible, to properly set the mesh for optimal comfort.
In the early days of midurethral pubovaginal slings using polypropylene, the adage was “looser is better than tighter.” This is even truer for transvaginal mesh.
DR. KARRAM: Dr. Walters, please describe your current surgical procedure of choice without mesh and explain why you haven’t adopted mesh for routine repairs.
DR. WALTERS: About 20% of my prolapse surgeries—usually for posthysterectomy or recurrent vaginal vault prolapse—involve ASC with placement of polypropylene mesh. I perform most of these cases through a Pfannenstiel incision, but I’ve also done them laparoscopically. Several of my partners perform ASC laparoscopically and robotically.
For the other 80% of my patients who have prolapse, I perform repairs transvaginally, usually using high bilateral uterosacralligament vaginal-vault suspension. We have learned to suture higher and slightly more medial on the uterosacral ligaments to attain greater vaginal depth and minimize ureteral obstruction. We use two or three sutures on each uterosacral ligament, usually a combination of permanent and delayed absorbable sutures.
I am also performing more sacrospinous ligament suspensions because this operation is being studied by the Pelvic Floor Disorders Network. Properly performed, it is an excellent surgery for apical prolapse. But, as with most of our surgeries for prolapse, recurrent anterior wall prolapse remains a problem.
Like you, Dr. Karram, we’ve studied our group’s anatomic and functional outcomes very carefully for more than 10 years and are mostly satisfied with our cure and complication rates. Although our anatomic outcomes with these surgeries are not always perfect, our reoperation rate for prolapse is only about 5%, with a high level of satisfaction in 88% to 92% of patients.
DR. RAZ: Unaugmented reconstruction fails in more than 30% of cases. Some patients who have significant prolapse and attenuated tissue think that this tissue will become healthier or stronger after reconstructive surgery, but that isn’t the case. In these situations, excision and plication make no clinical sense.
The problem is that we have yet to identify the ideal surrogate for poor-quality tissue. Most of us use polypropylene mesh in different variations. We need a better material that will be nonimmunogenic, well tolerated, and easily incorporated without erosion. Xenograft-like derivatives of dermis, or allografts such as cadaveric fascia, have failed over the long term because the body reabsorbs the graft without forming any new connective tissue.
FIGURE 3 Mesh can be cut in the OR to custom-fit a patient
Hand-cut mesh and points of placement.
PHOTO: SHLOMO RAZ, MD
Is a kit a valuable aid?
DR. KARRAM: If a surgeon wants to augment a repair, what are the advantages of a packaged mesh kit, compared with simply cutting the mesh and performing surgery without a kit?
DR. WALTERS: The advantages of a packaged mesh kit are the convenience involved and the ability to consistently perform the same operation with the same product. That facilitates learning, teaching, and research. It also helps us understand the published literature a little better because “custom” prolapse repairs are operator-dependent and difficult to apply generally to a population of surgeons.
These advantages are most clearly apparent with midurethral sling mesh kits, which have almost revolutionized surgery for stress incontinence. I don’t believe mesh kits for prolapse are there yet, but they certainly have potential.
DR. RAZ: I’m opposed to the use of kits. They are industry-driven. One company has made $1 billion selling them. Imagine a patient who undergoes placement of a sling kit ($1,000), cystocele kit ($1,500), and posterior mesh kit ($1,500). How can our healthcare system sustain this burden, especially when there is no real evidence that a kit improves the operation, and given the incredible complication rate that we see?
Moreover, the kits contain a single-use needle and passer and a precut segment of polypropylene mesh. But every patient is different and requires a unique size or shape of mesh. I don’t believe that a surgeon who knows pelvic anatomy needs a kit to perform mesh-augmented reconstruction. We can buy the same segment of mesh for $200 to $400, cut it as needed, and perform the same operation advertised by industry.
For surgeons who prefer a kit, the tools that are included should be made reusable.
DR. LUCENTE: In my opinion, the primary advantage of a commercially available transvaginal mesh delivery system—notice, I avoided the word “kit,” because I think there are plenty of negative connotations associated with it—is the ability to deliver the mesh in a “tension”-free manner.
One alternative that many people pursue is cutting the mesh to size and using sutures to hold it in place while tissue ingrowth occurs. However, the hernia literature suggests that suturing mesh in place increases the risk of postoperative discomfort at the site of implantation. The true cause of the discomfort remains unclear, but it is thought to arise from nerve tethering or traction at the pre-committed points of attachment before the host tissue and mesh interface have adjusted or settled with tissue ingrowth.
All neuropathic complications of mesh implantation have been shown in the current hernia literature to be increased with the use of sutures.7 Also, as previously mentioned, it is extremely difficult to set or adjust the mesh with the vaginal incision remaining “open,” which is a downside to suture techniques.
What training is necessary to use a kit?
DR. KARRAM: Mesh kits are aggressively promoted by industry, with close to half a dozen different kits to be available soon. What is the minimum amount of training one should have before utilizing these kits?
DR. WALTERS: The surgeon should at least know how to perform traditional sutured prolapse repairs and SUI surgery and be able to perform cystoscopy. Ideally, the surgeon should undergo training on a cadaver with a skilled and experienced user of the mesh kit. The surgeon also should carefully review the risks and benefits of mesh kits with the patient and inform the patient that he or she is in the early learning curve of a particular surgery. The informed patient should have a right to refuse mesh-augmented prolapse surgery after the consent process.
DR. LUCENTE: I’m glad you asked this question. I strongly believe that surgical expertise and proficiency within gynecology need to be more effectively addressed by us all. We have a situation in our field in which techniques and technology are widening the gap between what is possible and what the surgeon is comfortable doing safely.
It’s incumbent on all of us, especially those who are in a leadership position as a chairperson or chief of a division, to work with our physician staff and faculty to optimize surgical skill and patient outcomes, including safety, with new technologies.
As for the minimal amount of training needed, that’s extremely variable. It depends on the current skill set of the physician and his or her ability to pick up the mechanics of the surgery as it is taught through a cadaver lab or preceptorship. It’s regrettable that some physicians lack the objectivity and insight to judge their own skill set. This, again, is the time for a chairperson or chief of a division to step up to the plate and ensure proper credentialing and demonstration of proficiency.
It is unrealistic to expect industry to decide who should or should not utilize this truly breakthrough technology. That is our responsibility as physicians.
DR. KARRAM: At a minimum, I think any surgeon utilizing a kit should have a firm understanding of pelvic floor anatomy and experience performing traditional repairs:
- intraperitoneal procedures such as Mc-Call culdoplasty and uterosacral suspension
- sacrospinous suspension
- retropubic procedures and anti-incontinence operations such as pubovaginal slings.
This three-dimensional understanding of the pelvic floor is mandatory if one is to assume that blind passage of trocars through potentially dangerous spaces is the wave of the future.
DR. RAZ: You need to be a pelvic surgeon, know your anatomy, and know how to manage complications if you are going to use one of these kits. You should stick to the surgery that works best in your hands. Industry cannot teach you to be a good pelvic surgeon; it takes lifelong experience.
DR. KARRAM: If you have a patient who is sexually inactive with pelvic organ prolapse, would you prefer a mesh repair or an obliterative procedure? And why?
DR. WALTERS: If the patient is sexually inactive—especially if she is older and definitely will not be in the future—it makes absolutely no sense to perform a mesh-augmented repair. A traditional, somewhat tight, sutured repair works fine in this setting and carries very low risk.
In fact, our group and others have found that, in carefully selected patients, partial colpectomy and colpocleisis procedures (without grafts) have among the highest cure and satisfaction rates of all surgeries we perform for prolapse; they also have relatively low risk.8 Recurrent prolapse after an obliterative procedure is rare; most of the dissatisfaction relates to postoperative voiding difficulties or persistent or de novo urinary incontinence.
DR. KARRAM: I also prefer an obliterative procedure. I see no reason to bring in the cost and potential for complications that mesh repair entails. An obliterative procedure should produce an anatomic success rate close to 100%, with minimal complications. It also can be performed quickly with minimal anesthesia and convalescence.
DR. LUCENTE: My response is based on a clinical study that my associate, Dr. Miles Murphy, has performed, comparing a transvaginal mesh procedure with a LaForte operation for severe pelvic organ prolapse.9 Both patient groups were well satisfied with the result, and success rates were comparable. However, the group that underwent the transvaginal mesh procedure had a shorter operative time.
As a result of these studies, we tend to prefer transvaginal mesh repair. Even though the woman may be sexually inactive, the procedure preserves vaginal function, and we all know that life has a way of being unpredictable. Her situation may change so that she once again desires sexual function.
However, for a very elderly woman—one in her late 80s or 90s—who has severe or extreme prolapse with a very large procidentia and vaginal length measuring, say, 13 cm beyond the introitus, I do prefer an obliterative procedure.
DR. RAZ: I agree. I would not offer a sexually inactive patient an obliterative procedure. You never know what the future will hold.
Mesh repair can be performed safely, provided the surgeon has good knowledge of anatomic landmarks and knows how to manage any potential complications that may arise.
1. Nygaard IE, McCreery R, Brubaker L, et al. Pelvic Floor Disorders Network. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol. 2004;104:805-823.
2. Benson JT, Lucente V, McClellan E. Vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: a prospective randomized study with long-term outcome evaluation. Am J Obstet Gynecol. 1996;175:1418-1421;discussion 1421-1422.
3. Maher CF, Qatawneh AM, Dwyer PL, Carey MP, Cornish A, Schluter PJ. Abdominal sacral colpopexy or vaginal sacrospinous colpopexy for vaginal vault prolapse: a prospective randomized study. Am J Obstet Gynecol. 2004;190:20-26.
4. Murphy M. Society of Gynecologic Surgeons Systematic Review Group. Clinical practice guidelines on vaginal graft use from the Society of Gynecologic Surgeons. Obstet Gynecol. 2008;112:1123-1130.
5. Paraiso MF, Barber MD, Muir TW, Walters MD. Rectocele repair: a randomized trial of three surgical procedures including graft augmentation. Am J Obstet Gynecol. 2006;195:1762-1771.
6. Silva WA, Pauls RN, Segal JL, Rooney CM, Kleeman SD, Karram MM. Uterosacral ligament vault suspension: five-year outcomes. Obstet Gynecol 2006;108:255-263.
7. EU Hernia Trialists Collaboration. Repair of groin hernia with synthetic mesh: meta-analysis of randomized controlled trials. Ann Surg. 2002;235:322-332.
8. Barber MD, Amundsen C, Paraiso MFR, Weidner A, Romero A, Walters MD. Quality of life after surgery for genital prolapse in elderly women: obliterative and reconstructive surgery. Int Urogynecol J. 2007;18:799-806.
9. Murphy M, van Raalte H, Mercurio E, Haff R, Wiseman B, Lucente VR. Incontinence-related quality of life and sexual function following the tension-free vaginal tape vs the “inside-out” tension-free vaginal tape obturator. Int Urogynecol J. 2008;19:481-487.
MICKEY M. KARRAM, MD, moderator, is Director of Urogynecology at Good Samaritan Hospital and Voluntary Professor of ObGyn at the University of Cincinnati School of Medicine in Cincinnati, Ohio.
SHLOMO RAZ, MD, is Professor of Urology and Chief of Pelvic Medicine and Reconstructive Urology at UCLA School of Medicine in Los Angeles.
VINCENT LUCENTE, MD, MBA, is Founder and Director of the Institute for Female Pelvic Medicine and Reconstructive Surgery in Allentown, Pa, and Clinical Professor of ObGyn at Temple University School of Medicine in Philadelphia.
MARK D. WALTERS, MD, is Professor and Vice Chair of Gynecology, Section of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, at the Cleveland Clinic in Cleveland, Ohio.
Mesh kits for repairing prolapse are proliferating like crazy, just as they did for midurethral sling procedures. But mesh augmentation of prolapse surgeries requires more than a prepackaged assortment of tools and materials. In this article, moderator Mickey M. Karram, MD, and a panel of nationally recognized urogynecologists and urologists describe the literature on mesh augmentation and discuss indications, contraindications, techniques, applicable cases, and the considerable training required.
In Part 2, which will appear in the February issue of OBG Management, the panel tackles the thorny topic of complications, including erosion, extrusion, foreshortening of the vagina, dyspareunia, and pain. Their discussion focuses on ways to avoid these problems, and methods for correcting them.
Do we have enough data?
DR. KARRAM: To start, let’s quickly review the peer-reviewed literature on the use of mesh augmentation during surgery for pelvic organ prolapse.
DR. WALTERS: Until recently, most data concerned open abdominal sacrocolpopexy (ASC) using polypropylene or Merseline mesh. There is significant clinical experience with this operation, and multiple cohort studies show long-term cure rates of 78% to 100% for apical prolapse.1
At least two randomized controlled trials have compared open ASC with sutured vaginal colpopexy procedures, and ASC is certainly equal to—perhaps better than—all transvaginal sutured repairs.2,3
With ASC, most recurrences affect the distal half of the vagina and involve one or more of the following:
- anterior or posterior vaginal wall prolapse (or both)
- stress urinary incontinence (SUI)
- distal rectocele.1,3
Mesh erosion occurs in 3.4% of cases and is usually easily managed.1 Other complications, including bowel injury, tend to be related to access, regardless of whether the operation is performed via laparotomy or laparoscopy.
Robotic sacrocolpopexy has become popular in recent years, and we will probably see data on this approach as we gain experience.
When it comes to vaginal mesh kits, the peer-reviewed literature is just beginning to expand, with many studies being presented at international meetings. For anterior and, possibly, apical vaginal prolapse, the cure rate after use of a mesh kit appears to be as high as, or higher than, the rate for sutured repairs.4 This high rate of anatomic cure is balanced somewhat by additional cost and complications involving mesh and the kits.
For posterior vaginal wall prolapse and rectocele, I firmly believe, based on our research and that of others, that sutured repairs are superior to graft-augmented surgery.5
DR. KARRAM: What are the indications and contraindications for mesh augmentation of prolapse repair ( FIGURES 1 and 2 )?
DR. LUCENTE: I believe mesh is indicated in any patient in need of surgical repair of pelvic organ prolapse who is seeking optimal durability and is willing to accept the known risks of the surgery.
The issue becomes more complex when it comes to contraindications. Absolute contraindications are fairly obvious; they include medically unstable patients and those who may have an inactive infectious process within the pelvis or even undiagnosed abnormal uterine bleeding.
At our center, because the potential for dyspareunia and pelvic discomfort is our biggest concern, we have developed a profile of the patient who is more likely to develop these complaints. The profile includes any patient who has a chronic pain disorder of any type, but especially chronic pelvic pain disorders such as endometriosis and vulvodynia. Other risk factors appear to be a history of pelvic surgery involving any permanent material, suture or mesh, and young age.
So if we have a patient in her late 30s who has undergone reconstructive surgery using permanent sutures and who has an element of chronic pelvic pain, we would counsel her strongly to consider surgical options other than the use of synthetic mesh.
DR. WALTERS: The main indications for mesh-augmented prolapse repair are recurrent posthysterectomy vaginal vault prolapse, for which I usually perform ASC, and recurrent cystocele or anteriorapical prolapse, for which I use one of the anterior mesh kits.
I still think sutured repairs—by that, I mean uterosacral ligament or sacrospinous colpopexy with sutured rectocele repair—work best for recurrent posterior wall and posteriorapical prolapse. I don’t use mesh augmentation for rectocele.
The main contraindication to mesh augmentation, as I see it, is a history of mesh complications. If I am repairing a mesh complication such as erosion or pain, I do not place another mesh.
Medical issues that might increase mesh complications, such as diabetes, steroid use, or severe vaginal atrophy, would, at the very least, make me consider carefully whether mesh augmentation is appropriate. The literature is not clear on this, so mesh could still be used if the surgeon thinks it is necessary.
DR. KARRAM: I haven’t found a definitive indication for mesh augmentation. We have used biologic meshes empirically, but I am not convinced that they really add long-term durability, regardless of whether they are used in the anterior or posterior vaginal segment.
Our published durability rate for traditional suture-type repairs is in the range of 85% at 5 years out.6 Even if I assumed that mesh would give me 100% 5-year durability, this rate would have to be at the expense of some erosion, pain, and other complications unique to mesh. I do not think that the potential improvement in durability is worth these potential complications.
FIGURE 1 When the pelvic support system is intact, prolapse is rare
In the normal pelvis, organs are supported by a complex web of muscles, fascia, and connective tissue.
FIGURE 2 Mesh augmentation seeks to enhance the durability of repair
One type of mesh in final position. Mesh-augmented repair restores the vaginal apex and lends support to the walls of the vagina.
DR. KARRAM: If you are doing a lot of mesh repairs, you are obviously content with the results and feel that the few complications you are seeing are outweighed by the advantages mesh confers. How do you avoid extrusion and avert creation of a painful vagina?
DR. RAZ: Most of our cases are recurrent prolapse after failed vaginal or abdominal repair. I am indeed using a significant amount of soft polypropylene mesh for reconstructive procedures. As with the use of any other synthetic material, low-grade infection can develop after a few weeks or months. I use copious irrigation with antibiotic solution during reconstruction.
To avoid extrusion, I perform deep, rather than superficial, dissection of the vaginal wall to allow for better coverage of the mesh. For posterior mesh reconstruction, I cover the mesh with pararectal fascia to prevent erosion.
For mesh-augmented procedures, I cut the mesh myself in the operating room ( FIGURE 3 ). For a sling, I use a 10 cm × 1 cm soft polypropylene mesh. For a grade 3 or 4 cystocele, I use a trapezoid of soft polypropylene mesh with several points of fixation:
- at the sacrouterine ligament
- lateral to the obturator fascia
- distal to the bladder neck.
I always repair the vault at the same time.
For vault prolapse, I use a segment of soft polypropylene mesh in the shape of an apron with two arms (1 cm × 4 cm) and a central segment (4 cm × 7 cm). I support the vault using number 1-0 delayed absorbable suture and mesh. From outside the vaginal wall, in the posterolateral deep vaginal wall (inside the peritoneum), I incorporate the origin of the sacrouterine ligament and one arm of the mesh in the groove between the colon and levator ani, 15 cm from the introitus. I bring the suture 1 cm from the original entrance. A separate set of sutures brings the perirectal fascia together with the sacrouterine ligaments and perivesical fascia to close the peritoneal cavity. I tie the vault-suspension sutures, providing support to the cuff in a high posterior position (12 to 15 cm from the introitus).
In selected cases of significant recurrent rectocele, I use a rectangle of soft polypropylene mesh anchored to the origin of the sacrouterine ligament and distal to the perineal membrane. The mesh is covered by the pararectal fascia.
We have not seen vaginal, urethral, or bladder erosion in 1,800 cases of our distal urethral Prolene sling procedure using 10 cm × 1 cm soft mesh. In patients who have significant cystocele, vault prolapse, and recurrent rectocele, our vaginal erosion rate is 3%. We have never encountered rectal, bladder, or bowel perforation using our technique.
DR. LUCENTE: We often use mesh and are more than simply content with our results—we are extremely pleased, and so are our patients. Having said that, our techniques have definitely evolved over the past few years, as we’ve focused on how to decrease exposure and, more recently, optimize sexual function and vaginal comfort.
First, to avoid exposure, the most critical step is precise hydrodissection and distention of the true vesicovaginal space. This step can only be achieved through careful tactile guidance of the needle tip into the space, where it should remain while hydrodissection is performed. Always remember, sharp dissection “follows” hydrodissection. If you place the needle bevel within the vaginal wall, you will “split” the vaginal wall—as during standard colporrhaphy—which will lead to a high exposure rate.
Second, to avoid dyspareunia, it’s essential to pay close attention to POP-Q measurements, especially vaginal length, to ensure that the reconstruction restores the same length without foreshortening. This approach entails leaving the cervix in most patients who have a shorter vagina, and making sure that the mesh is secured above the ischial spine in younger, sexually active patients who have demonstrated a higher risk of postoperative deep, penetrating dyspareunia, compared with older, less sexually active patients.
Also paramount is to ensure that you have manually displaced the vagina inwardly as much as possible before deploying or setting the mesh. If you simply try to suture secure the mesh with the vagina incised open, without the ability to deploy the mesh with a closed, displaced vagina (to mimic deep penetration), it is difficult, if not impossible, to properly set the mesh for optimal comfort.
In the early days of midurethral pubovaginal slings using polypropylene, the adage was “looser is better than tighter.” This is even truer for transvaginal mesh.
DR. KARRAM: Dr. Walters, please describe your current surgical procedure of choice without mesh and explain why you haven’t adopted mesh for routine repairs.
DR. WALTERS: About 20% of my prolapse surgeries—usually for posthysterectomy or recurrent vaginal vault prolapse—involve ASC with placement of polypropylene mesh. I perform most of these cases through a Pfannenstiel incision, but I’ve also done them laparoscopically. Several of my partners perform ASC laparoscopically and robotically.
For the other 80% of my patients who have prolapse, I perform repairs transvaginally, usually using high bilateral uterosacralligament vaginal-vault suspension. We have learned to suture higher and slightly more medial on the uterosacral ligaments to attain greater vaginal depth and minimize ureteral obstruction. We use two or three sutures on each uterosacral ligament, usually a combination of permanent and delayed absorbable sutures.
I am also performing more sacrospinous ligament suspensions because this operation is being studied by the Pelvic Floor Disorders Network. Properly performed, it is an excellent surgery for apical prolapse. But, as with most of our surgeries for prolapse, recurrent anterior wall prolapse remains a problem.
Like you, Dr. Karram, we’ve studied our group’s anatomic and functional outcomes very carefully for more than 10 years and are mostly satisfied with our cure and complication rates. Although our anatomic outcomes with these surgeries are not always perfect, our reoperation rate for prolapse is only about 5%, with a high level of satisfaction in 88% to 92% of patients.
DR. RAZ: Unaugmented reconstruction fails in more than 30% of cases. Some patients who have significant prolapse and attenuated tissue think that this tissue will become healthier or stronger after reconstructive surgery, but that isn’t the case. In these situations, excision and plication make no clinical sense.
The problem is that we have yet to identify the ideal surrogate for poor-quality tissue. Most of us use polypropylene mesh in different variations. We need a better material that will be nonimmunogenic, well tolerated, and easily incorporated without erosion. Xenograft-like derivatives of dermis, or allografts such as cadaveric fascia, have failed over the long term because the body reabsorbs the graft without forming any new connective tissue.
FIGURE 3 Mesh can be cut in the OR to custom-fit a patient
Hand-cut mesh and points of placement.
PHOTO: SHLOMO RAZ, MD
Is a kit a valuable aid?
DR. KARRAM: If a surgeon wants to augment a repair, what are the advantages of a packaged mesh kit, compared with simply cutting the mesh and performing surgery without a kit?
DR. WALTERS: The advantages of a packaged mesh kit are the convenience involved and the ability to consistently perform the same operation with the same product. That facilitates learning, teaching, and research. It also helps us understand the published literature a little better because “custom” prolapse repairs are operator-dependent and difficult to apply generally to a population of surgeons.
These advantages are most clearly apparent with midurethral sling mesh kits, which have almost revolutionized surgery for stress incontinence. I don’t believe mesh kits for prolapse are there yet, but they certainly have potential.
DR. RAZ: I’m opposed to the use of kits. They are industry-driven. One company has made $1 billion selling them. Imagine a patient who undergoes placement of a sling kit ($1,000), cystocele kit ($1,500), and posterior mesh kit ($1,500). How can our healthcare system sustain this burden, especially when there is no real evidence that a kit improves the operation, and given the incredible complication rate that we see?
Moreover, the kits contain a single-use needle and passer and a precut segment of polypropylene mesh. But every patient is different and requires a unique size or shape of mesh. I don’t believe that a surgeon who knows pelvic anatomy needs a kit to perform mesh-augmented reconstruction. We can buy the same segment of mesh for $200 to $400, cut it as needed, and perform the same operation advertised by industry.
For surgeons who prefer a kit, the tools that are included should be made reusable.
DR. LUCENTE: In my opinion, the primary advantage of a commercially available transvaginal mesh delivery system—notice, I avoided the word “kit,” because I think there are plenty of negative connotations associated with it—is the ability to deliver the mesh in a “tension”-free manner.
One alternative that many people pursue is cutting the mesh to size and using sutures to hold it in place while tissue ingrowth occurs. However, the hernia literature suggests that suturing mesh in place increases the risk of postoperative discomfort at the site of implantation. The true cause of the discomfort remains unclear, but it is thought to arise from nerve tethering or traction at the pre-committed points of attachment before the host tissue and mesh interface have adjusted or settled with tissue ingrowth.
All neuropathic complications of mesh implantation have been shown in the current hernia literature to be increased with the use of sutures.7 Also, as previously mentioned, it is extremely difficult to set or adjust the mesh with the vaginal incision remaining “open,” which is a downside to suture techniques.
What training is necessary to use a kit?
DR. KARRAM: Mesh kits are aggressively promoted by industry, with close to half a dozen different kits to be available soon. What is the minimum amount of training one should have before utilizing these kits?
DR. WALTERS: The surgeon should at least know how to perform traditional sutured prolapse repairs and SUI surgery and be able to perform cystoscopy. Ideally, the surgeon should undergo training on a cadaver with a skilled and experienced user of the mesh kit. The surgeon also should carefully review the risks and benefits of mesh kits with the patient and inform the patient that he or she is in the early learning curve of a particular surgery. The informed patient should have a right to refuse mesh-augmented prolapse surgery after the consent process.
DR. LUCENTE: I’m glad you asked this question. I strongly believe that surgical expertise and proficiency within gynecology need to be more effectively addressed by us all. We have a situation in our field in which techniques and technology are widening the gap between what is possible and what the surgeon is comfortable doing safely.
It’s incumbent on all of us, especially those who are in a leadership position as a chairperson or chief of a division, to work with our physician staff and faculty to optimize surgical skill and patient outcomes, including safety, with new technologies.
As for the minimal amount of training needed, that’s extremely variable. It depends on the current skill set of the physician and his or her ability to pick up the mechanics of the surgery as it is taught through a cadaver lab or preceptorship. It’s regrettable that some physicians lack the objectivity and insight to judge their own skill set. This, again, is the time for a chairperson or chief of a division to step up to the plate and ensure proper credentialing and demonstration of proficiency.
It is unrealistic to expect industry to decide who should or should not utilize this truly breakthrough technology. That is our responsibility as physicians.
DR. KARRAM: At a minimum, I think any surgeon utilizing a kit should have a firm understanding of pelvic floor anatomy and experience performing traditional repairs:
- intraperitoneal procedures such as Mc-Call culdoplasty and uterosacral suspension
- sacrospinous suspension
- retropubic procedures and anti-incontinence operations such as pubovaginal slings.
This three-dimensional understanding of the pelvic floor is mandatory if one is to assume that blind passage of trocars through potentially dangerous spaces is the wave of the future.
DR. RAZ: You need to be a pelvic surgeon, know your anatomy, and know how to manage complications if you are going to use one of these kits. You should stick to the surgery that works best in your hands. Industry cannot teach you to be a good pelvic surgeon; it takes lifelong experience.
DR. KARRAM: If you have a patient who is sexually inactive with pelvic organ prolapse, would you prefer a mesh repair or an obliterative procedure? And why?
DR. WALTERS: If the patient is sexually inactive—especially if she is older and definitely will not be in the future—it makes absolutely no sense to perform a mesh-augmented repair. A traditional, somewhat tight, sutured repair works fine in this setting and carries very low risk.
In fact, our group and others have found that, in carefully selected patients, partial colpectomy and colpocleisis procedures (without grafts) have among the highest cure and satisfaction rates of all surgeries we perform for prolapse; they also have relatively low risk.8 Recurrent prolapse after an obliterative procedure is rare; most of the dissatisfaction relates to postoperative voiding difficulties or persistent or de novo urinary incontinence.
DR. KARRAM: I also prefer an obliterative procedure. I see no reason to bring in the cost and potential for complications that mesh repair entails. An obliterative procedure should produce an anatomic success rate close to 100%, with minimal complications. It also can be performed quickly with minimal anesthesia and convalescence.
DR. LUCENTE: My response is based on a clinical study that my associate, Dr. Miles Murphy, has performed, comparing a transvaginal mesh procedure with a LaForte operation for severe pelvic organ prolapse.9 Both patient groups were well satisfied with the result, and success rates were comparable. However, the group that underwent the transvaginal mesh procedure had a shorter operative time.
As a result of these studies, we tend to prefer transvaginal mesh repair. Even though the woman may be sexually inactive, the procedure preserves vaginal function, and we all know that life has a way of being unpredictable. Her situation may change so that she once again desires sexual function.
However, for a very elderly woman—one in her late 80s or 90s—who has severe or extreme prolapse with a very large procidentia and vaginal length measuring, say, 13 cm beyond the introitus, I do prefer an obliterative procedure.
DR. RAZ: I agree. I would not offer a sexually inactive patient an obliterative procedure. You never know what the future will hold.
Mesh repair can be performed safely, provided the surgeon has good knowledge of anatomic landmarks and knows how to manage any potential complications that may arise.
MICKEY M. KARRAM, MD, moderator, is Director of Urogynecology at Good Samaritan Hospital and Voluntary Professor of ObGyn at the University of Cincinnati School of Medicine in Cincinnati, Ohio.
SHLOMO RAZ, MD, is Professor of Urology and Chief of Pelvic Medicine and Reconstructive Urology at UCLA School of Medicine in Los Angeles.
VINCENT LUCENTE, MD, MBA, is Founder and Director of the Institute for Female Pelvic Medicine and Reconstructive Surgery in Allentown, Pa, and Clinical Professor of ObGyn at Temple University School of Medicine in Philadelphia.
MARK D. WALTERS, MD, is Professor and Vice Chair of Gynecology, Section of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, at the Cleveland Clinic in Cleveland, Ohio.
Mesh kits for repairing prolapse are proliferating like crazy, just as they did for midurethral sling procedures. But mesh augmentation of prolapse surgeries requires more than a prepackaged assortment of tools and materials. In this article, moderator Mickey M. Karram, MD, and a panel of nationally recognized urogynecologists and urologists describe the literature on mesh augmentation and discuss indications, contraindications, techniques, applicable cases, and the considerable training required.
In Part 2, which will appear in the February issue of OBG Management, the panel tackles the thorny topic of complications, including erosion, extrusion, foreshortening of the vagina, dyspareunia, and pain. Their discussion focuses on ways to avoid these problems, and methods for correcting them.
Do we have enough data?
DR. KARRAM: To start, let’s quickly review the peer-reviewed literature on the use of mesh augmentation during surgery for pelvic organ prolapse.
DR. WALTERS: Until recently, most data concerned open abdominal sacrocolpopexy (ASC) using polypropylene or Merseline mesh. There is significant clinical experience with this operation, and multiple cohort studies show long-term cure rates of 78% to 100% for apical prolapse.1
At least two randomized controlled trials have compared open ASC with sutured vaginal colpopexy procedures, and ASC is certainly equal to—perhaps better than—all transvaginal sutured repairs.2,3
With ASC, most recurrences affect the distal half of the vagina and involve one or more of the following:
- anterior or posterior vaginal wall prolapse (or both)
- stress urinary incontinence (SUI)
- distal rectocele.1,3
Mesh erosion occurs in 3.4% of cases and is usually easily managed.1 Other complications, including bowel injury, tend to be related to access, regardless of whether the operation is performed via laparotomy or laparoscopy.
Robotic sacrocolpopexy has become popular in recent years, and we will probably see data on this approach as we gain experience.
When it comes to vaginal mesh kits, the peer-reviewed literature is just beginning to expand, with many studies being presented at international meetings. For anterior and, possibly, apical vaginal prolapse, the cure rate after use of a mesh kit appears to be as high as, or higher than, the rate for sutured repairs.4 This high rate of anatomic cure is balanced somewhat by additional cost and complications involving mesh and the kits.
For posterior vaginal wall prolapse and rectocele, I firmly believe, based on our research and that of others, that sutured repairs are superior to graft-augmented surgery.5
DR. KARRAM: What are the indications and contraindications for mesh augmentation of prolapse repair ( FIGURES 1 and 2 )?
DR. LUCENTE: I believe mesh is indicated in any patient in need of surgical repair of pelvic organ prolapse who is seeking optimal durability and is willing to accept the known risks of the surgery.
The issue becomes more complex when it comes to contraindications. Absolute contraindications are fairly obvious; they include medically unstable patients and those who may have an inactive infectious process within the pelvis or even undiagnosed abnormal uterine bleeding.
At our center, because the potential for dyspareunia and pelvic discomfort is our biggest concern, we have developed a profile of the patient who is more likely to develop these complaints. The profile includes any patient who has a chronic pain disorder of any type, but especially chronic pelvic pain disorders such as endometriosis and vulvodynia. Other risk factors appear to be a history of pelvic surgery involving any permanent material, suture or mesh, and young age.
So if we have a patient in her late 30s who has undergone reconstructive surgery using permanent sutures and who has an element of chronic pelvic pain, we would counsel her strongly to consider surgical options other than the use of synthetic mesh.
DR. WALTERS: The main indications for mesh-augmented prolapse repair are recurrent posthysterectomy vaginal vault prolapse, for which I usually perform ASC, and recurrent cystocele or anteriorapical prolapse, for which I use one of the anterior mesh kits.
I still think sutured repairs—by that, I mean uterosacral ligament or sacrospinous colpopexy with sutured rectocele repair—work best for recurrent posterior wall and posteriorapical prolapse. I don’t use mesh augmentation for rectocele.
The main contraindication to mesh augmentation, as I see it, is a history of mesh complications. If I am repairing a mesh complication such as erosion or pain, I do not place another mesh.
Medical issues that might increase mesh complications, such as diabetes, steroid use, or severe vaginal atrophy, would, at the very least, make me consider carefully whether mesh augmentation is appropriate. The literature is not clear on this, so mesh could still be used if the surgeon thinks it is necessary.
DR. KARRAM: I haven’t found a definitive indication for mesh augmentation. We have used biologic meshes empirically, but I am not convinced that they really add long-term durability, regardless of whether they are used in the anterior or posterior vaginal segment.
Our published durability rate for traditional suture-type repairs is in the range of 85% at 5 years out.6 Even if I assumed that mesh would give me 100% 5-year durability, this rate would have to be at the expense of some erosion, pain, and other complications unique to mesh. I do not think that the potential improvement in durability is worth these potential complications.
FIGURE 1 When the pelvic support system is intact, prolapse is rare
In the normal pelvis, organs are supported by a complex web of muscles, fascia, and connective tissue.
FIGURE 2 Mesh augmentation seeks to enhance the durability of repair
One type of mesh in final position. Mesh-augmented repair restores the vaginal apex and lends support to the walls of the vagina.
DR. KARRAM: If you are doing a lot of mesh repairs, you are obviously content with the results and feel that the few complications you are seeing are outweighed by the advantages mesh confers. How do you avoid extrusion and avert creation of a painful vagina?
DR. RAZ: Most of our cases are recurrent prolapse after failed vaginal or abdominal repair. I am indeed using a significant amount of soft polypropylene mesh for reconstructive procedures. As with the use of any other synthetic material, low-grade infection can develop after a few weeks or months. I use copious irrigation with antibiotic solution during reconstruction.
To avoid extrusion, I perform deep, rather than superficial, dissection of the vaginal wall to allow for better coverage of the mesh. For posterior mesh reconstruction, I cover the mesh with pararectal fascia to prevent erosion.
For mesh-augmented procedures, I cut the mesh myself in the operating room ( FIGURE 3 ). For a sling, I use a 10 cm × 1 cm soft polypropylene mesh. For a grade 3 or 4 cystocele, I use a trapezoid of soft polypropylene mesh with several points of fixation:
- at the sacrouterine ligament
- lateral to the obturator fascia
- distal to the bladder neck.
I always repair the vault at the same time.
For vault prolapse, I use a segment of soft polypropylene mesh in the shape of an apron with two arms (1 cm × 4 cm) and a central segment (4 cm × 7 cm). I support the vault using number 1-0 delayed absorbable suture and mesh. From outside the vaginal wall, in the posterolateral deep vaginal wall (inside the peritoneum), I incorporate the origin of the sacrouterine ligament and one arm of the mesh in the groove between the colon and levator ani, 15 cm from the introitus. I bring the suture 1 cm from the original entrance. A separate set of sutures brings the perirectal fascia together with the sacrouterine ligaments and perivesical fascia to close the peritoneal cavity. I tie the vault-suspension sutures, providing support to the cuff in a high posterior position (12 to 15 cm from the introitus).
In selected cases of significant recurrent rectocele, I use a rectangle of soft polypropylene mesh anchored to the origin of the sacrouterine ligament and distal to the perineal membrane. The mesh is covered by the pararectal fascia.
We have not seen vaginal, urethral, or bladder erosion in 1,800 cases of our distal urethral Prolene sling procedure using 10 cm × 1 cm soft mesh. In patients who have significant cystocele, vault prolapse, and recurrent rectocele, our vaginal erosion rate is 3%. We have never encountered rectal, bladder, or bowel perforation using our technique.
DR. LUCENTE: We often use mesh and are more than simply content with our results—we are extremely pleased, and so are our patients. Having said that, our techniques have definitely evolved over the past few years, as we’ve focused on how to decrease exposure and, more recently, optimize sexual function and vaginal comfort.
First, to avoid exposure, the most critical step is precise hydrodissection and distention of the true vesicovaginal space. This step can only be achieved through careful tactile guidance of the needle tip into the space, where it should remain while hydrodissection is performed. Always remember, sharp dissection “follows” hydrodissection. If you place the needle bevel within the vaginal wall, you will “split” the vaginal wall—as during standard colporrhaphy—which will lead to a high exposure rate.
Second, to avoid dyspareunia, it’s essential to pay close attention to POP-Q measurements, especially vaginal length, to ensure that the reconstruction restores the same length without foreshortening. This approach entails leaving the cervix in most patients who have a shorter vagina, and making sure that the mesh is secured above the ischial spine in younger, sexually active patients who have demonstrated a higher risk of postoperative deep, penetrating dyspareunia, compared with older, less sexually active patients.
Also paramount is to ensure that you have manually displaced the vagina inwardly as much as possible before deploying or setting the mesh. If you simply try to suture secure the mesh with the vagina incised open, without the ability to deploy the mesh with a closed, displaced vagina (to mimic deep penetration), it is difficult, if not impossible, to properly set the mesh for optimal comfort.
In the early days of midurethral pubovaginal slings using polypropylene, the adage was “looser is better than tighter.” This is even truer for transvaginal mesh.
DR. KARRAM: Dr. Walters, please describe your current surgical procedure of choice without mesh and explain why you haven’t adopted mesh for routine repairs.
DR. WALTERS: About 20% of my prolapse surgeries—usually for posthysterectomy or recurrent vaginal vault prolapse—involve ASC with placement of polypropylene mesh. I perform most of these cases through a Pfannenstiel incision, but I’ve also done them laparoscopically. Several of my partners perform ASC laparoscopically and robotically.
For the other 80% of my patients who have prolapse, I perform repairs transvaginally, usually using high bilateral uterosacralligament vaginal-vault suspension. We have learned to suture higher and slightly more medial on the uterosacral ligaments to attain greater vaginal depth and minimize ureteral obstruction. We use two or three sutures on each uterosacral ligament, usually a combination of permanent and delayed absorbable sutures.
I am also performing more sacrospinous ligament suspensions because this operation is being studied by the Pelvic Floor Disorders Network. Properly performed, it is an excellent surgery for apical prolapse. But, as with most of our surgeries for prolapse, recurrent anterior wall prolapse remains a problem.
Like you, Dr. Karram, we’ve studied our group’s anatomic and functional outcomes very carefully for more than 10 years and are mostly satisfied with our cure and complication rates. Although our anatomic outcomes with these surgeries are not always perfect, our reoperation rate for prolapse is only about 5%, with a high level of satisfaction in 88% to 92% of patients.
DR. RAZ: Unaugmented reconstruction fails in more than 30% of cases. Some patients who have significant prolapse and attenuated tissue think that this tissue will become healthier or stronger after reconstructive surgery, but that isn’t the case. In these situations, excision and plication make no clinical sense.
The problem is that we have yet to identify the ideal surrogate for poor-quality tissue. Most of us use polypropylene mesh in different variations. We need a better material that will be nonimmunogenic, well tolerated, and easily incorporated without erosion. Xenograft-like derivatives of dermis, or allografts such as cadaveric fascia, have failed over the long term because the body reabsorbs the graft without forming any new connective tissue.
FIGURE 3 Mesh can be cut in the OR to custom-fit a patient
Hand-cut mesh and points of placement.
PHOTO: SHLOMO RAZ, MD
Is a kit a valuable aid?
DR. KARRAM: If a surgeon wants to augment a repair, what are the advantages of a packaged mesh kit, compared with simply cutting the mesh and performing surgery without a kit?
DR. WALTERS: The advantages of a packaged mesh kit are the convenience involved and the ability to consistently perform the same operation with the same product. That facilitates learning, teaching, and research. It also helps us understand the published literature a little better because “custom” prolapse repairs are operator-dependent and difficult to apply generally to a population of surgeons.
These advantages are most clearly apparent with midurethral sling mesh kits, which have almost revolutionized surgery for stress incontinence. I don’t believe mesh kits for prolapse are there yet, but they certainly have potential.
DR. RAZ: I’m opposed to the use of kits. They are industry-driven. One company has made $1 billion selling them. Imagine a patient who undergoes placement of a sling kit ($1,000), cystocele kit ($1,500), and posterior mesh kit ($1,500). How can our healthcare system sustain this burden, especially when there is no real evidence that a kit improves the operation, and given the incredible complication rate that we see?
Moreover, the kits contain a single-use needle and passer and a precut segment of polypropylene mesh. But every patient is different and requires a unique size or shape of mesh. I don’t believe that a surgeon who knows pelvic anatomy needs a kit to perform mesh-augmented reconstruction. We can buy the same segment of mesh for $200 to $400, cut it as needed, and perform the same operation advertised by industry.
For surgeons who prefer a kit, the tools that are included should be made reusable.
DR. LUCENTE: In my opinion, the primary advantage of a commercially available transvaginal mesh delivery system—notice, I avoided the word “kit,” because I think there are plenty of negative connotations associated with it—is the ability to deliver the mesh in a “tension”-free manner.
One alternative that many people pursue is cutting the mesh to size and using sutures to hold it in place while tissue ingrowth occurs. However, the hernia literature suggests that suturing mesh in place increases the risk of postoperative discomfort at the site of implantation. The true cause of the discomfort remains unclear, but it is thought to arise from nerve tethering or traction at the pre-committed points of attachment before the host tissue and mesh interface have adjusted or settled with tissue ingrowth.
All neuropathic complications of mesh implantation have been shown in the current hernia literature to be increased with the use of sutures.7 Also, as previously mentioned, it is extremely difficult to set or adjust the mesh with the vaginal incision remaining “open,” which is a downside to suture techniques.
What training is necessary to use a kit?
DR. KARRAM: Mesh kits are aggressively promoted by industry, with close to half a dozen different kits to be available soon. What is the minimum amount of training one should have before utilizing these kits?
DR. WALTERS: The surgeon should at least know how to perform traditional sutured prolapse repairs and SUI surgery and be able to perform cystoscopy. Ideally, the surgeon should undergo training on a cadaver with a skilled and experienced user of the mesh kit. The surgeon also should carefully review the risks and benefits of mesh kits with the patient and inform the patient that he or she is in the early learning curve of a particular surgery. The informed patient should have a right to refuse mesh-augmented prolapse surgery after the consent process.
DR. LUCENTE: I’m glad you asked this question. I strongly believe that surgical expertise and proficiency within gynecology need to be more effectively addressed by us all. We have a situation in our field in which techniques and technology are widening the gap between what is possible and what the surgeon is comfortable doing safely.
It’s incumbent on all of us, especially those who are in a leadership position as a chairperson or chief of a division, to work with our physician staff and faculty to optimize surgical skill and patient outcomes, including safety, with new technologies.
As for the minimal amount of training needed, that’s extremely variable. It depends on the current skill set of the physician and his or her ability to pick up the mechanics of the surgery as it is taught through a cadaver lab or preceptorship. It’s regrettable that some physicians lack the objectivity and insight to judge their own skill set. This, again, is the time for a chairperson or chief of a division to step up to the plate and ensure proper credentialing and demonstration of proficiency.
It is unrealistic to expect industry to decide who should or should not utilize this truly breakthrough technology. That is our responsibility as physicians.
DR. KARRAM: At a minimum, I think any surgeon utilizing a kit should have a firm understanding of pelvic floor anatomy and experience performing traditional repairs:
- intraperitoneal procedures such as Mc-Call culdoplasty and uterosacral suspension
- sacrospinous suspension
- retropubic procedures and anti-incontinence operations such as pubovaginal slings.
This three-dimensional understanding of the pelvic floor is mandatory if one is to assume that blind passage of trocars through potentially dangerous spaces is the wave of the future.
DR. RAZ: You need to be a pelvic surgeon, know your anatomy, and know how to manage complications if you are going to use one of these kits. You should stick to the surgery that works best in your hands. Industry cannot teach you to be a good pelvic surgeon; it takes lifelong experience.
DR. KARRAM: If you have a patient who is sexually inactive with pelvic organ prolapse, would you prefer a mesh repair or an obliterative procedure? And why?
DR. WALTERS: If the patient is sexually inactive—especially if she is older and definitely will not be in the future—it makes absolutely no sense to perform a mesh-augmented repair. A traditional, somewhat tight, sutured repair works fine in this setting and carries very low risk.
In fact, our group and others have found that, in carefully selected patients, partial colpectomy and colpocleisis procedures (without grafts) have among the highest cure and satisfaction rates of all surgeries we perform for prolapse; they also have relatively low risk.8 Recurrent prolapse after an obliterative procedure is rare; most of the dissatisfaction relates to postoperative voiding difficulties or persistent or de novo urinary incontinence.
DR. KARRAM: I also prefer an obliterative procedure. I see no reason to bring in the cost and potential for complications that mesh repair entails. An obliterative procedure should produce an anatomic success rate close to 100%, with minimal complications. It also can be performed quickly with minimal anesthesia and convalescence.
DR. LUCENTE: My response is based on a clinical study that my associate, Dr. Miles Murphy, has performed, comparing a transvaginal mesh procedure with a LaForte operation for severe pelvic organ prolapse.9 Both patient groups were well satisfied with the result, and success rates were comparable. However, the group that underwent the transvaginal mesh procedure had a shorter operative time.
As a result of these studies, we tend to prefer transvaginal mesh repair. Even though the woman may be sexually inactive, the procedure preserves vaginal function, and we all know that life has a way of being unpredictable. Her situation may change so that she once again desires sexual function.
However, for a very elderly woman—one in her late 80s or 90s—who has severe or extreme prolapse with a very large procidentia and vaginal length measuring, say, 13 cm beyond the introitus, I do prefer an obliterative procedure.
DR. RAZ: I agree. I would not offer a sexually inactive patient an obliterative procedure. You never know what the future will hold.
Mesh repair can be performed safely, provided the surgeon has good knowledge of anatomic landmarks and knows how to manage any potential complications that may arise.
1. Nygaard IE, McCreery R, Brubaker L, et al. Pelvic Floor Disorders Network. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol. 2004;104:805-823.
2. Benson JT, Lucente V, McClellan E. Vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: a prospective randomized study with long-term outcome evaluation. Am J Obstet Gynecol. 1996;175:1418-1421;discussion 1421-1422.
3. Maher CF, Qatawneh AM, Dwyer PL, Carey MP, Cornish A, Schluter PJ. Abdominal sacral colpopexy or vaginal sacrospinous colpopexy for vaginal vault prolapse: a prospective randomized study. Am J Obstet Gynecol. 2004;190:20-26.
4. Murphy M. Society of Gynecologic Surgeons Systematic Review Group. Clinical practice guidelines on vaginal graft use from the Society of Gynecologic Surgeons. Obstet Gynecol. 2008;112:1123-1130.
5. Paraiso MF, Barber MD, Muir TW, Walters MD. Rectocele repair: a randomized trial of three surgical procedures including graft augmentation. Am J Obstet Gynecol. 2006;195:1762-1771.
6. Silva WA, Pauls RN, Segal JL, Rooney CM, Kleeman SD, Karram MM. Uterosacral ligament vault suspension: five-year outcomes. Obstet Gynecol 2006;108:255-263.
7. EU Hernia Trialists Collaboration. Repair of groin hernia with synthetic mesh: meta-analysis of randomized controlled trials. Ann Surg. 2002;235:322-332.
8. Barber MD, Amundsen C, Paraiso MFR, Weidner A, Romero A, Walters MD. Quality of life after surgery for genital prolapse in elderly women: obliterative and reconstructive surgery. Int Urogynecol J. 2007;18:799-806.
9. Murphy M, van Raalte H, Mercurio E, Haff R, Wiseman B, Lucente VR. Incontinence-related quality of life and sexual function following the tension-free vaginal tape vs the “inside-out” tension-free vaginal tape obturator. Int Urogynecol J. 2008;19:481-487.
1. Nygaard IE, McCreery R, Brubaker L, et al. Pelvic Floor Disorders Network. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol. 2004;104:805-823.
2. Benson JT, Lucente V, McClellan E. Vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: a prospective randomized study with long-term outcome evaluation. Am J Obstet Gynecol. 1996;175:1418-1421;discussion 1421-1422.
3. Maher CF, Qatawneh AM, Dwyer PL, Carey MP, Cornish A, Schluter PJ. Abdominal sacral colpopexy or vaginal sacrospinous colpopexy for vaginal vault prolapse: a prospective randomized study. Am J Obstet Gynecol. 2004;190:20-26.
4. Murphy M. Society of Gynecologic Surgeons Systematic Review Group. Clinical practice guidelines on vaginal graft use from the Society of Gynecologic Surgeons. Obstet Gynecol. 2008;112:1123-1130.
5. Paraiso MF, Barber MD, Muir TW, Walters MD. Rectocele repair: a randomized trial of three surgical procedures including graft augmentation. Am J Obstet Gynecol. 2006;195:1762-1771.
6. Silva WA, Pauls RN, Segal JL, Rooney CM, Kleeman SD, Karram MM. Uterosacral ligament vault suspension: five-year outcomes. Obstet Gynecol 2006;108:255-263.
7. EU Hernia Trialists Collaboration. Repair of groin hernia with synthetic mesh: meta-analysis of randomized controlled trials. Ann Surg. 2002;235:322-332.
8. Barber MD, Amundsen C, Paraiso MFR, Weidner A, Romero A, Walters MD. Quality of life after surgery for genital prolapse in elderly women: obliterative and reconstructive surgery. Int Urogynecol J. 2007;18:799-806.
9. Murphy M, van Raalte H, Mercurio E, Haff R, Wiseman B, Lucente VR. Incontinence-related quality of life and sexual function following the tension-free vaginal tape vs the “inside-out” tension-free vaginal tape obturator. Int Urogynecol J. 2008;19:481-487.