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Diabetes drugs with cardiovascular benefits broaden cardiology’s turf
The dramatic reduction in cardiovascular death and heart failure hospitalization seen during treatment with empagliflozin (Jardiance) in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, for example, has prompted some cardiologists in the year since the first EMPA-REG report to become active prescribers of the drug to their patients who have type 2 diabetes and cardiovascular disease. The same evidence has driven other cardiologists who may not feel fully comfortable prescribing an antidiabetic drug on their own to enter into active partnerships with endocrinologists to work as a team to put diabetes patients with cardiovascular disease on empagliflozin.
In Dr. Fitchett’s practice, “if a patient with type 2 diabetes has an endocrinologist, then I will send a letter to that physician saying I think the patient should be on one of these drugs,” empagliflozin or liraglutide, he said. “If the patient is being treated by a primary care physician, then I will prescribe empagliflozin myself because most primary care physicians are not willing to prescribe it. I think more and more cardiologists are doing this. The great thing about empagliflozin and liraglutide is that they do not cause hypoglycemia and the adverse effect profiles are relatively good. As long as drug cost is not an issue, then as cardiologists we need to adjust glycemia control with cardiovascular benefit as we did years ago with statin treatment,” explained Dr. Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a senior collaborator and coauthor on the EMPA-REG study.
When results from the 4S [Scandinavian Simvastatin Survival Study] came out in 1994, proving that long-term statin treatment was both safe and increased survival in patients with coronary heart disease, “cardiologists took over lipid management from endocrinologists,” he recalled. “We now have a safe and simple treatment for glucose lowering that also cuts cardiovascular disease events, so cardiologists have to also be involved, at least to some extent. Their degree of involvement depends on their practice and who provides a patient’s primary diabetes care,” he said.
Cardiologists vary on empagliflozin
Other cardiologists are mixed in their take on personally prescribing antidiabetic drugs to high-risk patients with type 2 diabetes. Greg C. Fonarow, MD, has also aggressively taken to empagliflozin over the past year, especially for his patients with heart failure or at high risk for developing heart failure. The EMPA-REG results showed that empagliflozin’s potent impact on reducing cardiovascular death in patients linked closely with a reduction in heart failure hospitalizations. In his recent experience, endocrinologists as well as other physicians who care for patients with type 2 diabetes “are often reluctant to make any changes [in a patient’s hypoglycemic regimen], and in general they have not gravitated toward the treatments that have been shown to improve cardiovascular outcomes and instead focus solely on a patient’s hemoglobin A1c,” Dr. Fonarow said in an interview at the recent annual meeting of the Heart Failure Society of America.
He said he prescribes empagliflozin to patients with type 2 diabetes if they are hospitalized for heart failure or as outpatients, and he targets it to patients diagnosed with heart failure – including heart failure with preserved ejection fraction – as well as to patients with other forms of cardiovascular disease, closely following the EMPA-REG enrollment criteria. It’s too early in the experience with empagliflozin to use it preferentially in diabetes patients without cardiovascular disease or patients who in any other way fall outside the enrollment criteria for EMPA-REG, he said.
“I am happy to consult with their endocrinologist, or I tell patients to discuss this treatment with their endocrinologist. If the endocrinologist prescribes empagliflozin, great; if not, I feel an obligation to provide the best care I can to my patients. This is not a hard medication to use. The safety profile is good. Treatment with empagliflozin obviously has renal-function considerations, but that’s true for many drugs. The biggest challenge is what is covered by the patient’s insurance. We often need preauthorization.
“So far I have seen excellent responses in patients for both metabolic control and clinical responses in patients with heart failure. Their symptoms seem to improve,” said Dr. Fonarow, professor of medicine and co-chief of cardiology at the University of Southern California , Los Angeles.
While Dr. Fonarow cautioned that he also would not start empagliflozin in a patient with a HbA1c below 7%, he would seriously consider swapping out a patient’s drug for empagliflozin if it were a sulfonylurea or a dipeptidyl peptidase-4 inhibitor. He stopped short of suggesting a substitution of empagliflozin for metformin. In Dr. Fonarow’s opinion, the evidence for empagliflozin is also “more robust” than it has been for liraglutide or semaglutide. With what’s now known about the clinical impact of these drugs, he foresees a time when a combination between a SGLT-2 inhibitor, with its effect on heart failure, and a GLP-1 analogue, with its effect on atherosclerotic disease, may seem an ideal initial drug pairing for patients with type 2 diabetes and significant cardiovascular disease risk, with metformin relegated to a second-line role.
Other cardiologists endorsed a more collaborative approach to prescribing empagliflozin and liraglutide.
Another team-approach advocate is Robert O. Bonow, MD, cardiologist and professor of medicine at Northwestern University in Chicago. “Cardiologists are comfortable prescribing metformin and telling patients about lifestyle, but when it comes to newer antidiabetic drugs, that’s a new field, and a team approach may be best,” he said in an interview. “If possible, a cardiologist should have a friendly partnership with a diabetologist or endocrinologist who is expert in treating diabetes.” Many cardiologists now work in and for hospitals, and easy access to an endocrinologist is probably available, he noted.
But new analyses of the EMPA-REG data reported by Dr. Fitchett at the ESC congress showed that empagliflozin treatment exerted a similar benefit of reduced cardiovascular death regardless of whether patients had prevalent heart failure at entry into the study, incident heart failure during follow-up, or no heart failure of any sort.
Impact of heart failure in EMPA-REG
Roughly 10% of the 7,020 patients enrolled in EMPA-REG had heart failure at the time they entered the trial. During a median follow-up of just over 3 years, the incidence of new-onset heart failure – tallied as either a new heart failure hospitalization or a clinical episode deemed to be heart failure by an investigator – occurred in 4.6% of patients on empagliflozin and in 6.5% of patients in the placebo arm, a 1.9-percentage-point difference and a 30% relative risk reduction linked with empagliflozin use, Dr. Fitchett reported.
The main EMPA-REG outcome was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. This positive outcome in favor of empagliflozin treatment was primarily driven by a difference in the rate of cardiovascular death. In the new analysis, the relative reduction in cardiovascular deaths with empagliflozin compared with placebo was 29% among patients with prevalent heart failure at baseline, 35% among those who had an incident heart failure hospitalization during follow-up, 27% among patients with an incident heart failure episode diagnosed by an investigator during follow-up, 33% among the combined group of trial patients with any form of heart failure at trial entry or during the trial (those with prevalent heart failure at baseline plus those with an incident event), and 37% among the large number of patients in the trial who remained free from any indication of heart failure during follow-up.
In short, treatment with empagliflozin “reduced cardiovascular mortality by the same relative amount” regardless of whether patients did or did not have heart failure during the trial,” Dr. Fitchett concluded.
Additional secondary analyses from EMPA-REG reported at the ESC congress in August also documented that the benefit from empagliflozin treatment was roughly the same regardless of the age of patients enrolled in the trial and regardless of patients’ blood level of LDL cholesterol at entry into the study. These findings provide “confidence in the consistency of the effect” by empagliflozin, Dr. Fitchett said.
The endocrinologists’ view
“Most cardiologists are not thoroughly familiar with the full palette of medications for hyperglycemia. Selection of medication should not be made solely on the basis of results from a cardiovascular outcomes trial,” said Helena W. Rodbard, MD, a clinical endocrinologist in Rockville, Md.
“The EMPA-REG OUTCOMES and LEADER results are very exciting and encouraging. When all other factors are equal, the cardiovascular results could sway the decision about which medication to use. But an endocrinologist is in the best position to balance the many factors when choosing combination therapy and to set a target level for HbA1c, fasting blood glucose, and postprandial glucose, and to adjust therapy to minimize the risk of hypoglycemia,” Dr. Rodbard said in an interview.
He called empagliflozin a drug with “interesting promise,” especially for patients with incipient heart failure. The extra cardiovascular benefit from the GLP-1 analogues is “less settled,” although the liraglutide and semaglutide trial results are important and mean these drugs need more consideration and study. The EMPA-REG results were more clearly positive, he said.
“Metformin is still the initial drug” for most patients with type 2 diabetes, echoed Dr. Levy. Drugs like empagliflozin and liraglutide are usually used in combination with metformin.
“Like many endocrinologists, I have for some time used the oral SGLT-2 inhibitors and GLP-1 analogues in combination with metformin. It made sense before the recent cardiovascular data appeared, and it makes even more sense now,” said Dr. Jellinger, professor of clinical medicine and an endocrinologist at the University of Miami.
“Endocrinologists and diabetologists are aware that cardiologists have been taking a larger role in the care of patients with diabetes,” noted Dr. Rodbard. “I favor cardiologists and endocrinologists working in concert to improve the care of patients with diabetes.”
“Over the next few years, we will need to decide whether to treat patients with type 2 diabetes with an agent with proven benefits,” said Dr. Fitchett. “Until the results from EMPA-REG and the LEADER trial came out, there was no specific glucose-lowering agent that also reduced cardiovascular events. Some cardiologists might ask when they should get involved in managing patients with type 2 diabetes. What I would do for patients with a history of cardiovascular disease who develop new type 2 diabetes is start empagliflozin as their first drug,” Dr. Fitchett said, though he admitted that no evidence yet exists to back that approach.
The EMPA-REG trial was sponsored by Boehringer Ingelheim and by Eli Lilly, the companies that market empagliflozin. The LEADER trial was sponsored in part by Novo Nordisk, the company that markets liraglutide. Dr. Fitchett and Dr. Mentz were both researchers for EMPA-REG. Dr. Fitchett has been a consultant to AstraZeneca, Merck, and Amgen. Dr. Mentz has been an adviser to Boehringer Ingelheim. Dr. Fonarow has been an adviser to Amgen, Janssen, Novartis, and ZS Pharma. Dr. Bozkurt had no disclosures. Dr. Bonow has been a consultant to Gilead. Dr. Jellinger has been a speaker on behalf of Boehringer-Ingelheim, Novo Nordisk, Merck, and Janssen. Dr. Rodbard has been a consultant to or speaker for several drug companies including Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk. Dr. Levy has been a speaker on behalf of Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and AstraZeneca. Dr. Hellman had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The dramatic reduction in cardiovascular death and heart failure hospitalization seen during treatment with empagliflozin (Jardiance) in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, for example, has prompted some cardiologists in the year since the first EMPA-REG report to become active prescribers of the drug to their patients who have type 2 diabetes and cardiovascular disease. The same evidence has driven other cardiologists who may not feel fully comfortable prescribing an antidiabetic drug on their own to enter into active partnerships with endocrinologists to work as a team to put diabetes patients with cardiovascular disease on empagliflozin.
In Dr. Fitchett’s practice, “if a patient with type 2 diabetes has an endocrinologist, then I will send a letter to that physician saying I think the patient should be on one of these drugs,” empagliflozin or liraglutide, he said. “If the patient is being treated by a primary care physician, then I will prescribe empagliflozin myself because most primary care physicians are not willing to prescribe it. I think more and more cardiologists are doing this. The great thing about empagliflozin and liraglutide is that they do not cause hypoglycemia and the adverse effect profiles are relatively good. As long as drug cost is not an issue, then as cardiologists we need to adjust glycemia control with cardiovascular benefit as we did years ago with statin treatment,” explained Dr. Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a senior collaborator and coauthor on the EMPA-REG study.
When results from the 4S [Scandinavian Simvastatin Survival Study] came out in 1994, proving that long-term statin treatment was both safe and increased survival in patients with coronary heart disease, “cardiologists took over lipid management from endocrinologists,” he recalled. “We now have a safe and simple treatment for glucose lowering that also cuts cardiovascular disease events, so cardiologists have to also be involved, at least to some extent. Their degree of involvement depends on their practice and who provides a patient’s primary diabetes care,” he said.
Cardiologists vary on empagliflozin
Other cardiologists are mixed in their take on personally prescribing antidiabetic drugs to high-risk patients with type 2 diabetes. Greg C. Fonarow, MD, has also aggressively taken to empagliflozin over the past year, especially for his patients with heart failure or at high risk for developing heart failure. The EMPA-REG results showed that empagliflozin’s potent impact on reducing cardiovascular death in patients linked closely with a reduction in heart failure hospitalizations. In his recent experience, endocrinologists as well as other physicians who care for patients with type 2 diabetes “are often reluctant to make any changes [in a patient’s hypoglycemic regimen], and in general they have not gravitated toward the treatments that have been shown to improve cardiovascular outcomes and instead focus solely on a patient’s hemoglobin A1c,” Dr. Fonarow said in an interview at the recent annual meeting of the Heart Failure Society of America.
He said he prescribes empagliflozin to patients with type 2 diabetes if they are hospitalized for heart failure or as outpatients, and he targets it to patients diagnosed with heart failure – including heart failure with preserved ejection fraction – as well as to patients with other forms of cardiovascular disease, closely following the EMPA-REG enrollment criteria. It’s too early in the experience with empagliflozin to use it preferentially in diabetes patients without cardiovascular disease or patients who in any other way fall outside the enrollment criteria for EMPA-REG, he said.
“I am happy to consult with their endocrinologist, or I tell patients to discuss this treatment with their endocrinologist. If the endocrinologist prescribes empagliflozin, great; if not, I feel an obligation to provide the best care I can to my patients. This is not a hard medication to use. The safety profile is good. Treatment with empagliflozin obviously has renal-function considerations, but that’s true for many drugs. The biggest challenge is what is covered by the patient’s insurance. We often need preauthorization.
“So far I have seen excellent responses in patients for both metabolic control and clinical responses in patients with heart failure. Their symptoms seem to improve,” said Dr. Fonarow, professor of medicine and co-chief of cardiology at the University of Southern California , Los Angeles.
While Dr. Fonarow cautioned that he also would not start empagliflozin in a patient with a HbA1c below 7%, he would seriously consider swapping out a patient’s drug for empagliflozin if it were a sulfonylurea or a dipeptidyl peptidase-4 inhibitor. He stopped short of suggesting a substitution of empagliflozin for metformin. In Dr. Fonarow’s opinion, the evidence for empagliflozin is also “more robust” than it has been for liraglutide or semaglutide. With what’s now known about the clinical impact of these drugs, he foresees a time when a combination between a SGLT-2 inhibitor, with its effect on heart failure, and a GLP-1 analogue, with its effect on atherosclerotic disease, may seem an ideal initial drug pairing for patients with type 2 diabetes and significant cardiovascular disease risk, with metformin relegated to a second-line role.
Other cardiologists endorsed a more collaborative approach to prescribing empagliflozin and liraglutide.
Another team-approach advocate is Robert O. Bonow, MD, cardiologist and professor of medicine at Northwestern University in Chicago. “Cardiologists are comfortable prescribing metformin and telling patients about lifestyle, but when it comes to newer antidiabetic drugs, that’s a new field, and a team approach may be best,” he said in an interview. “If possible, a cardiologist should have a friendly partnership with a diabetologist or endocrinologist who is expert in treating diabetes.” Many cardiologists now work in and for hospitals, and easy access to an endocrinologist is probably available, he noted.
But new analyses of the EMPA-REG data reported by Dr. Fitchett at the ESC congress showed that empagliflozin treatment exerted a similar benefit of reduced cardiovascular death regardless of whether patients had prevalent heart failure at entry into the study, incident heart failure during follow-up, or no heart failure of any sort.
Impact of heart failure in EMPA-REG
Roughly 10% of the 7,020 patients enrolled in EMPA-REG had heart failure at the time they entered the trial. During a median follow-up of just over 3 years, the incidence of new-onset heart failure – tallied as either a new heart failure hospitalization or a clinical episode deemed to be heart failure by an investigator – occurred in 4.6% of patients on empagliflozin and in 6.5% of patients in the placebo arm, a 1.9-percentage-point difference and a 30% relative risk reduction linked with empagliflozin use, Dr. Fitchett reported.
The main EMPA-REG outcome was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. This positive outcome in favor of empagliflozin treatment was primarily driven by a difference in the rate of cardiovascular death. In the new analysis, the relative reduction in cardiovascular deaths with empagliflozin compared with placebo was 29% among patients with prevalent heart failure at baseline, 35% among those who had an incident heart failure hospitalization during follow-up, 27% among patients with an incident heart failure episode diagnosed by an investigator during follow-up, 33% among the combined group of trial patients with any form of heart failure at trial entry or during the trial (those with prevalent heart failure at baseline plus those with an incident event), and 37% among the large number of patients in the trial who remained free from any indication of heart failure during follow-up.
In short, treatment with empagliflozin “reduced cardiovascular mortality by the same relative amount” regardless of whether patients did or did not have heart failure during the trial,” Dr. Fitchett concluded.
Additional secondary analyses from EMPA-REG reported at the ESC congress in August also documented that the benefit from empagliflozin treatment was roughly the same regardless of the age of patients enrolled in the trial and regardless of patients’ blood level of LDL cholesterol at entry into the study. These findings provide “confidence in the consistency of the effect” by empagliflozin, Dr. Fitchett said.
The endocrinologists’ view
“Most cardiologists are not thoroughly familiar with the full palette of medications for hyperglycemia. Selection of medication should not be made solely on the basis of results from a cardiovascular outcomes trial,” said Helena W. Rodbard, MD, a clinical endocrinologist in Rockville, Md.
“The EMPA-REG OUTCOMES and LEADER results are very exciting and encouraging. When all other factors are equal, the cardiovascular results could sway the decision about which medication to use. But an endocrinologist is in the best position to balance the many factors when choosing combination therapy and to set a target level for HbA1c, fasting blood glucose, and postprandial glucose, and to adjust therapy to minimize the risk of hypoglycemia,” Dr. Rodbard said in an interview.
He called empagliflozin a drug with “interesting promise,” especially for patients with incipient heart failure. The extra cardiovascular benefit from the GLP-1 analogues is “less settled,” although the liraglutide and semaglutide trial results are important and mean these drugs need more consideration and study. The EMPA-REG results were more clearly positive, he said.
“Metformin is still the initial drug” for most patients with type 2 diabetes, echoed Dr. Levy. Drugs like empagliflozin and liraglutide are usually used in combination with metformin.
“Like many endocrinologists, I have for some time used the oral SGLT-2 inhibitors and GLP-1 analogues in combination with metformin. It made sense before the recent cardiovascular data appeared, and it makes even more sense now,” said Dr. Jellinger, professor of clinical medicine and an endocrinologist at the University of Miami.
“Endocrinologists and diabetologists are aware that cardiologists have been taking a larger role in the care of patients with diabetes,” noted Dr. Rodbard. “I favor cardiologists and endocrinologists working in concert to improve the care of patients with diabetes.”
“Over the next few years, we will need to decide whether to treat patients with type 2 diabetes with an agent with proven benefits,” said Dr. Fitchett. “Until the results from EMPA-REG and the LEADER trial came out, there was no specific glucose-lowering agent that also reduced cardiovascular events. Some cardiologists might ask when they should get involved in managing patients with type 2 diabetes. What I would do for patients with a history of cardiovascular disease who develop new type 2 diabetes is start empagliflozin as their first drug,” Dr. Fitchett said, though he admitted that no evidence yet exists to back that approach.
The EMPA-REG trial was sponsored by Boehringer Ingelheim and by Eli Lilly, the companies that market empagliflozin. The LEADER trial was sponsored in part by Novo Nordisk, the company that markets liraglutide. Dr. Fitchett and Dr. Mentz were both researchers for EMPA-REG. Dr. Fitchett has been a consultant to AstraZeneca, Merck, and Amgen. Dr. Mentz has been an adviser to Boehringer Ingelheim. Dr. Fonarow has been an adviser to Amgen, Janssen, Novartis, and ZS Pharma. Dr. Bozkurt had no disclosures. Dr. Bonow has been a consultant to Gilead. Dr. Jellinger has been a speaker on behalf of Boehringer-Ingelheim, Novo Nordisk, Merck, and Janssen. Dr. Rodbard has been a consultant to or speaker for several drug companies including Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk. Dr. Levy has been a speaker on behalf of Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and AstraZeneca. Dr. Hellman had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The dramatic reduction in cardiovascular death and heart failure hospitalization seen during treatment with empagliflozin (Jardiance) in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, for example, has prompted some cardiologists in the year since the first EMPA-REG report to become active prescribers of the drug to their patients who have type 2 diabetes and cardiovascular disease. The same evidence has driven other cardiologists who may not feel fully comfortable prescribing an antidiabetic drug on their own to enter into active partnerships with endocrinologists to work as a team to put diabetes patients with cardiovascular disease on empagliflozin.
In Dr. Fitchett’s practice, “if a patient with type 2 diabetes has an endocrinologist, then I will send a letter to that physician saying I think the patient should be on one of these drugs,” empagliflozin or liraglutide, he said. “If the patient is being treated by a primary care physician, then I will prescribe empagliflozin myself because most primary care physicians are not willing to prescribe it. I think more and more cardiologists are doing this. The great thing about empagliflozin and liraglutide is that they do not cause hypoglycemia and the adverse effect profiles are relatively good. As long as drug cost is not an issue, then as cardiologists we need to adjust glycemia control with cardiovascular benefit as we did years ago with statin treatment,” explained Dr. Fitchett, a cardiologist at St. Michael’s Hospital in Toronto and a senior collaborator and coauthor on the EMPA-REG study.
When results from the 4S [Scandinavian Simvastatin Survival Study] came out in 1994, proving that long-term statin treatment was both safe and increased survival in patients with coronary heart disease, “cardiologists took over lipid management from endocrinologists,” he recalled. “We now have a safe and simple treatment for glucose lowering that also cuts cardiovascular disease events, so cardiologists have to also be involved, at least to some extent. Their degree of involvement depends on their practice and who provides a patient’s primary diabetes care,” he said.
Cardiologists vary on empagliflozin
Other cardiologists are mixed in their take on personally prescribing antidiabetic drugs to high-risk patients with type 2 diabetes. Greg C. Fonarow, MD, has also aggressively taken to empagliflozin over the past year, especially for his patients with heart failure or at high risk for developing heart failure. The EMPA-REG results showed that empagliflozin’s potent impact on reducing cardiovascular death in patients linked closely with a reduction in heart failure hospitalizations. In his recent experience, endocrinologists as well as other physicians who care for patients with type 2 diabetes “are often reluctant to make any changes [in a patient’s hypoglycemic regimen], and in general they have not gravitated toward the treatments that have been shown to improve cardiovascular outcomes and instead focus solely on a patient’s hemoglobin A1c,” Dr. Fonarow said in an interview at the recent annual meeting of the Heart Failure Society of America.
He said he prescribes empagliflozin to patients with type 2 diabetes if they are hospitalized for heart failure or as outpatients, and he targets it to patients diagnosed with heart failure – including heart failure with preserved ejection fraction – as well as to patients with other forms of cardiovascular disease, closely following the EMPA-REG enrollment criteria. It’s too early in the experience with empagliflozin to use it preferentially in diabetes patients without cardiovascular disease or patients who in any other way fall outside the enrollment criteria for EMPA-REG, he said.
“I am happy to consult with their endocrinologist, or I tell patients to discuss this treatment with their endocrinologist. If the endocrinologist prescribes empagliflozin, great; if not, I feel an obligation to provide the best care I can to my patients. This is not a hard medication to use. The safety profile is good. Treatment with empagliflozin obviously has renal-function considerations, but that’s true for many drugs. The biggest challenge is what is covered by the patient’s insurance. We often need preauthorization.
“So far I have seen excellent responses in patients for both metabolic control and clinical responses in patients with heart failure. Their symptoms seem to improve,” said Dr. Fonarow, professor of medicine and co-chief of cardiology at the University of Southern California , Los Angeles.
While Dr. Fonarow cautioned that he also would not start empagliflozin in a patient with a HbA1c below 7%, he would seriously consider swapping out a patient’s drug for empagliflozin if it were a sulfonylurea or a dipeptidyl peptidase-4 inhibitor. He stopped short of suggesting a substitution of empagliflozin for metformin. In Dr. Fonarow’s opinion, the evidence for empagliflozin is also “more robust” than it has been for liraglutide or semaglutide. With what’s now known about the clinical impact of these drugs, he foresees a time when a combination between a SGLT-2 inhibitor, with its effect on heart failure, and a GLP-1 analogue, with its effect on atherosclerotic disease, may seem an ideal initial drug pairing for patients with type 2 diabetes and significant cardiovascular disease risk, with metformin relegated to a second-line role.
Other cardiologists endorsed a more collaborative approach to prescribing empagliflozin and liraglutide.
Another team-approach advocate is Robert O. Bonow, MD, cardiologist and professor of medicine at Northwestern University in Chicago. “Cardiologists are comfortable prescribing metformin and telling patients about lifestyle, but when it comes to newer antidiabetic drugs, that’s a new field, and a team approach may be best,” he said in an interview. “If possible, a cardiologist should have a friendly partnership with a diabetologist or endocrinologist who is expert in treating diabetes.” Many cardiologists now work in and for hospitals, and easy access to an endocrinologist is probably available, he noted.
But new analyses of the EMPA-REG data reported by Dr. Fitchett at the ESC congress showed that empagliflozin treatment exerted a similar benefit of reduced cardiovascular death regardless of whether patients had prevalent heart failure at entry into the study, incident heart failure during follow-up, or no heart failure of any sort.
Impact of heart failure in EMPA-REG
Roughly 10% of the 7,020 patients enrolled in EMPA-REG had heart failure at the time they entered the trial. During a median follow-up of just over 3 years, the incidence of new-onset heart failure – tallied as either a new heart failure hospitalization or a clinical episode deemed to be heart failure by an investigator – occurred in 4.6% of patients on empagliflozin and in 6.5% of patients in the placebo arm, a 1.9-percentage-point difference and a 30% relative risk reduction linked with empagliflozin use, Dr. Fitchett reported.
The main EMPA-REG outcome was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. This positive outcome in favor of empagliflozin treatment was primarily driven by a difference in the rate of cardiovascular death. In the new analysis, the relative reduction in cardiovascular deaths with empagliflozin compared with placebo was 29% among patients with prevalent heart failure at baseline, 35% among those who had an incident heart failure hospitalization during follow-up, 27% among patients with an incident heart failure episode diagnosed by an investigator during follow-up, 33% among the combined group of trial patients with any form of heart failure at trial entry or during the trial (those with prevalent heart failure at baseline plus those with an incident event), and 37% among the large number of patients in the trial who remained free from any indication of heart failure during follow-up.
In short, treatment with empagliflozin “reduced cardiovascular mortality by the same relative amount” regardless of whether patients did or did not have heart failure during the trial,” Dr. Fitchett concluded.
Additional secondary analyses from EMPA-REG reported at the ESC congress in August also documented that the benefit from empagliflozin treatment was roughly the same regardless of the age of patients enrolled in the trial and regardless of patients’ blood level of LDL cholesterol at entry into the study. These findings provide “confidence in the consistency of the effect” by empagliflozin, Dr. Fitchett said.
The endocrinologists’ view
“Most cardiologists are not thoroughly familiar with the full palette of medications for hyperglycemia. Selection of medication should not be made solely on the basis of results from a cardiovascular outcomes trial,” said Helena W. Rodbard, MD, a clinical endocrinologist in Rockville, Md.
“The EMPA-REG OUTCOMES and LEADER results are very exciting and encouraging. When all other factors are equal, the cardiovascular results could sway the decision about which medication to use. But an endocrinologist is in the best position to balance the many factors when choosing combination therapy and to set a target level for HbA1c, fasting blood glucose, and postprandial glucose, and to adjust therapy to minimize the risk of hypoglycemia,” Dr. Rodbard said in an interview.
He called empagliflozin a drug with “interesting promise,” especially for patients with incipient heart failure. The extra cardiovascular benefit from the GLP-1 analogues is “less settled,” although the liraglutide and semaglutide trial results are important and mean these drugs need more consideration and study. The EMPA-REG results were more clearly positive, he said.
“Metformin is still the initial drug” for most patients with type 2 diabetes, echoed Dr. Levy. Drugs like empagliflozin and liraglutide are usually used in combination with metformin.
“Like many endocrinologists, I have for some time used the oral SGLT-2 inhibitors and GLP-1 analogues in combination with metformin. It made sense before the recent cardiovascular data appeared, and it makes even more sense now,” said Dr. Jellinger, professor of clinical medicine and an endocrinologist at the University of Miami.
“Endocrinologists and diabetologists are aware that cardiologists have been taking a larger role in the care of patients with diabetes,” noted Dr. Rodbard. “I favor cardiologists and endocrinologists working in concert to improve the care of patients with diabetes.”
“Over the next few years, we will need to decide whether to treat patients with type 2 diabetes with an agent with proven benefits,” said Dr. Fitchett. “Until the results from EMPA-REG and the LEADER trial came out, there was no specific glucose-lowering agent that also reduced cardiovascular events. Some cardiologists might ask when they should get involved in managing patients with type 2 diabetes. What I would do for patients with a history of cardiovascular disease who develop new type 2 diabetes is start empagliflozin as their first drug,” Dr. Fitchett said, though he admitted that no evidence yet exists to back that approach.
The EMPA-REG trial was sponsored by Boehringer Ingelheim and by Eli Lilly, the companies that market empagliflozin. The LEADER trial was sponsored in part by Novo Nordisk, the company that markets liraglutide. Dr. Fitchett and Dr. Mentz were both researchers for EMPA-REG. Dr. Fitchett has been a consultant to AstraZeneca, Merck, and Amgen. Dr. Mentz has been an adviser to Boehringer Ingelheim. Dr. Fonarow has been an adviser to Amgen, Janssen, Novartis, and ZS Pharma. Dr. Bozkurt had no disclosures. Dr. Bonow has been a consultant to Gilead. Dr. Jellinger has been a speaker on behalf of Boehringer-Ingelheim, Novo Nordisk, Merck, and Janssen. Dr. Rodbard has been a consultant to or speaker for several drug companies including Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk. Dr. Levy has been a speaker on behalf of Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and AstraZeneca. Dr. Hellman had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
Pornography warps children’s concept of sex, sexual identity
SAN FRANCISCO – The pornography industry has taken over children’s sense of self and sexuality and warped their concept of what sex and a sexual identity is, said Gail Dines, PhD.
She challenged pediatricians to shape policy and help parents in wrangling back that control in a presentation at the annual meeting of the American Academy of Pediatrics.
The culprit, Dr. Dines charged, is the multibillion-dollar porn industry that exploded around the year 2000 with the Internet. Then, in 2011, the business model shifted to free pornography to hook young boys in their adolescence and hopefully maintain them as customers after age 18 when they could get their own credit cards.
The average age of a boy’s first encounter with pornography is age 11, explained Dr. Dines, a professor of sociology and women’s studies at Wheelock College in Chestnut Hill, Mass.
Instead of a father’s Playboy featuring a naked woman in a cornfield, as many male pediatricians in the room might have been introduced to pornography or sexuality, today’s youth are introduced via the brutalization and dehumanization of women, she said. Such experiences traumatize the children viewing them, who become confused about who they are if they are masturbating to images and video of sexual violence, and then they enter a cycle of retraumatization that engenders shame while bringing children back to those sites again and again.
“Hence, in the business model of free porn, you are building in trauma, which is building in addiction,” Dr. Dines said. The effects of this exposure and addiction, based on decades of research, include limited capacity for intimacy, a greater likelihood of using coercive tactics for sex, decreased empathy for rape victims, increased depression and anxiety, and, most recently, rates of erectile dysfunction in males aged 15-27 that mirror the rates in those aged 27-35.
“We have never brought up boys with access to hard core pornography 24-7,” Dr. Dines said. The best way to tackle hard-core pornography is a public health model that educates parents and pediatricians who can band together to raise awareness. Her organization, Culture Reframed, is attempting to do precisely that.
Dr. Dines founded the nonprofit Culture Reframed, which attempts to counter the effects of the pornography industry and media sexuality. Her presentation used no external funding.
SAN FRANCISCO – The pornography industry has taken over children’s sense of self and sexuality and warped their concept of what sex and a sexual identity is, said Gail Dines, PhD.
She challenged pediatricians to shape policy and help parents in wrangling back that control in a presentation at the annual meeting of the American Academy of Pediatrics.
The culprit, Dr. Dines charged, is the multibillion-dollar porn industry that exploded around the year 2000 with the Internet. Then, in 2011, the business model shifted to free pornography to hook young boys in their adolescence and hopefully maintain them as customers after age 18 when they could get their own credit cards.
The average age of a boy’s first encounter with pornography is age 11, explained Dr. Dines, a professor of sociology and women’s studies at Wheelock College in Chestnut Hill, Mass.
Instead of a father’s Playboy featuring a naked woman in a cornfield, as many male pediatricians in the room might have been introduced to pornography or sexuality, today’s youth are introduced via the brutalization and dehumanization of women, she said. Such experiences traumatize the children viewing them, who become confused about who they are if they are masturbating to images and video of sexual violence, and then they enter a cycle of retraumatization that engenders shame while bringing children back to those sites again and again.
“Hence, in the business model of free porn, you are building in trauma, which is building in addiction,” Dr. Dines said. The effects of this exposure and addiction, based on decades of research, include limited capacity for intimacy, a greater likelihood of using coercive tactics for sex, decreased empathy for rape victims, increased depression and anxiety, and, most recently, rates of erectile dysfunction in males aged 15-27 that mirror the rates in those aged 27-35.
“We have never brought up boys with access to hard core pornography 24-7,” Dr. Dines said. The best way to tackle hard-core pornography is a public health model that educates parents and pediatricians who can band together to raise awareness. Her organization, Culture Reframed, is attempting to do precisely that.
Dr. Dines founded the nonprofit Culture Reframed, which attempts to counter the effects of the pornography industry and media sexuality. Her presentation used no external funding.
SAN FRANCISCO – The pornography industry has taken over children’s sense of self and sexuality and warped their concept of what sex and a sexual identity is, said Gail Dines, PhD.
She challenged pediatricians to shape policy and help parents in wrangling back that control in a presentation at the annual meeting of the American Academy of Pediatrics.
The culprit, Dr. Dines charged, is the multibillion-dollar porn industry that exploded around the year 2000 with the Internet. Then, in 2011, the business model shifted to free pornography to hook young boys in their adolescence and hopefully maintain them as customers after age 18 when they could get their own credit cards.
The average age of a boy’s first encounter with pornography is age 11, explained Dr. Dines, a professor of sociology and women’s studies at Wheelock College in Chestnut Hill, Mass.
Instead of a father’s Playboy featuring a naked woman in a cornfield, as many male pediatricians in the room might have been introduced to pornography or sexuality, today’s youth are introduced via the brutalization and dehumanization of women, she said. Such experiences traumatize the children viewing them, who become confused about who they are if they are masturbating to images and video of sexual violence, and then they enter a cycle of retraumatization that engenders shame while bringing children back to those sites again and again.
“Hence, in the business model of free porn, you are building in trauma, which is building in addiction,” Dr. Dines said. The effects of this exposure and addiction, based on decades of research, include limited capacity for intimacy, a greater likelihood of using coercive tactics for sex, decreased empathy for rape victims, increased depression and anxiety, and, most recently, rates of erectile dysfunction in males aged 15-27 that mirror the rates in those aged 27-35.
“We have never brought up boys with access to hard core pornography 24-7,” Dr. Dines said. The best way to tackle hard-core pornography is a public health model that educates parents and pediatricians who can band together to raise awareness. Her organization, Culture Reframed, is attempting to do precisely that.
Dr. Dines founded the nonprofit Culture Reframed, which attempts to counter the effects of the pornography industry and media sexuality. Her presentation used no external funding.
EXPERT ANALYSIS FROM AAP 16
New criteria estimate systemic sclerosis to be more prevalent in primary biliary cholangitis patients
The use of outdated criteria for the identification of systemic sclerosis in primary biliary cholangitis likely led to an underestimation of the comorbidity’s prevalence.
Furthermore, more recent criteria estimate the prevalence of systemic sclerosis in primary biliary cholangitis to be around 23%.
[[{"fid":"172520","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Clinical appearance of acrosclerotic piece-meal necrosis of the first digit in a patient with systemic sclerosis.","field_file_image_credit[und][0][value]":"BMC Dermatology 2004, 4:11. doi:10.1186/1471-5945-4-11 ","field_file_image_caption[und][0][value]":""},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]In 1980, the American College of Rheumatology defined “highly specific but not sensitive” criteria for the identification of primary biliary cholangitis patients who also had systemic sclerosis, reported the study’s lead investigator Dr. Boyang Zheng of the University of Montreal Hospital Center and associates (J Rheumatol. 2016 Oct 28. doi: 10.3899/jrheum.160243).
In 2001, LeRoy and Medsger proposed and validated a new set of criteria that centrally required the observation of Raynaud phenomenon and “allowed for greater sensitivity and diagnosis of earlier disease by incorporating advances in nailfold capillary microscopy and [systemic sclerosis]–specific antibodies,” the investigators wrote.
Most recently, the ACR and the European League Against Rheumatism jointly developed new “weighted-point criteria endorsed for use in systemic sclerosis inclusion studies.” These new criteria, which were published in 2013, “the addition of at least a clinical or radiological feature to be positive.”
The purpose of this study, the first of its kind, according to investigators, was to compare the prevalence estimates of systemic sclerosis in primary biliary cholangitis patients as predicted by each of the three criteria sets.
A total of 100 patients who had previously been diagnosed with primary biliary cholangitis but not systemic sclerosis were recruited into the study. The majority of the patients were female (91%), the mean age at first visit was 57 years, and the mean primary biliary cholangitis Mayo score of disease severity and survival was 4.14.
At time of study enrollment, medical histories were obtained. All patients also underwent nailfold capillary microscopy, and serum samples were collected and analyzed for the presence of primary biliary cholangitis antibodies and the following systemic sclerosis–specific antibodies: anti–CENP-B, anti–topo I, anti–RNAP III, anti-Th/To.
Clinical data, presence of antibodies, and capillarascopic patterns were analyzed, and patients were retroactively evaluated for the fulfillment of each of the three systemic sclerosis criteria sets.
“A total of 23 patients satisfied at least one set of criteria, with 22 being positive for LeRoy and Medsger criteria, 17 for ACR/EULAR criteria, and only 1 for the ACR 1980 criteria,” Dr. Zheng and his associates reported.
The most frequent systemic sclerosis–associated features in the study population were Raynaud phenomenon (39%), systemic sclerosis antibodies (26%), abnormal nailfold capillary microscopy (20%), and capillary telangiectases (17%), while clinically evident skin changes were the most rare, investigators explained.
The 1980 ACR criteria likely led to an underestimation of systemic sclerosis in primary biliary cirrhosis, and given the benefit of early diagnosis and treatment of systemic sclerosis, patients with primary biliary cholangitis should be screened for Raynaud phenomenon and systemic sclerosis antibodies and undergo nailfold capillaroscopic microscopy, the investigators recommended.
“Clinicians need to remain alert for this sometimes insidious comorbidity,” the researchers added.
Dr. Zheng had no relevant financial disclosures.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
The use of outdated criteria for the identification of systemic sclerosis in primary biliary cholangitis likely led to an underestimation of the comorbidity’s prevalence.
Furthermore, more recent criteria estimate the prevalence of systemic sclerosis in primary biliary cholangitis to be around 23%.
[[{"fid":"172520","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Clinical appearance of acrosclerotic piece-meal necrosis of the first digit in a patient with systemic sclerosis.","field_file_image_credit[und][0][value]":"BMC Dermatology 2004, 4:11. doi:10.1186/1471-5945-4-11 ","field_file_image_caption[und][0][value]":""},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]In 1980, the American College of Rheumatology defined “highly specific but not sensitive” criteria for the identification of primary biliary cholangitis patients who also had systemic sclerosis, reported the study’s lead investigator Dr. Boyang Zheng of the University of Montreal Hospital Center and associates (J Rheumatol. 2016 Oct 28. doi: 10.3899/jrheum.160243).
In 2001, LeRoy and Medsger proposed and validated a new set of criteria that centrally required the observation of Raynaud phenomenon and “allowed for greater sensitivity and diagnosis of earlier disease by incorporating advances in nailfold capillary microscopy and [systemic sclerosis]–specific antibodies,” the investigators wrote.
Most recently, the ACR and the European League Against Rheumatism jointly developed new “weighted-point criteria endorsed for use in systemic sclerosis inclusion studies.” These new criteria, which were published in 2013, “the addition of at least a clinical or radiological feature to be positive.”
The purpose of this study, the first of its kind, according to investigators, was to compare the prevalence estimates of systemic sclerosis in primary biliary cholangitis patients as predicted by each of the three criteria sets.
A total of 100 patients who had previously been diagnosed with primary biliary cholangitis but not systemic sclerosis were recruited into the study. The majority of the patients were female (91%), the mean age at first visit was 57 years, and the mean primary biliary cholangitis Mayo score of disease severity and survival was 4.14.
At time of study enrollment, medical histories were obtained. All patients also underwent nailfold capillary microscopy, and serum samples were collected and analyzed for the presence of primary biliary cholangitis antibodies and the following systemic sclerosis–specific antibodies: anti–CENP-B, anti–topo I, anti–RNAP III, anti-Th/To.
Clinical data, presence of antibodies, and capillarascopic patterns were analyzed, and patients were retroactively evaluated for the fulfillment of each of the three systemic sclerosis criteria sets.
“A total of 23 patients satisfied at least one set of criteria, with 22 being positive for LeRoy and Medsger criteria, 17 for ACR/EULAR criteria, and only 1 for the ACR 1980 criteria,” Dr. Zheng and his associates reported.
The most frequent systemic sclerosis–associated features in the study population were Raynaud phenomenon (39%), systemic sclerosis antibodies (26%), abnormal nailfold capillary microscopy (20%), and capillary telangiectases (17%), while clinically evident skin changes were the most rare, investigators explained.
The 1980 ACR criteria likely led to an underestimation of systemic sclerosis in primary biliary cirrhosis, and given the benefit of early diagnosis and treatment of systemic sclerosis, patients with primary biliary cholangitis should be screened for Raynaud phenomenon and systemic sclerosis antibodies and undergo nailfold capillaroscopic microscopy, the investigators recommended.
“Clinicians need to remain alert for this sometimes insidious comorbidity,” the researchers added.
Dr. Zheng had no relevant financial disclosures.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
The use of outdated criteria for the identification of systemic sclerosis in primary biliary cholangitis likely led to an underestimation of the comorbidity’s prevalence.
Furthermore, more recent criteria estimate the prevalence of systemic sclerosis in primary biliary cholangitis to be around 23%.
[[{"fid":"172520","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Clinical appearance of acrosclerotic piece-meal necrosis of the first digit in a patient with systemic sclerosis.","field_file_image_credit[und][0][value]":"BMC Dermatology 2004, 4:11. doi:10.1186/1471-5945-4-11 ","field_file_image_caption[und][0][value]":""},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]In 1980, the American College of Rheumatology defined “highly specific but not sensitive” criteria for the identification of primary biliary cholangitis patients who also had systemic sclerosis, reported the study’s lead investigator Dr. Boyang Zheng of the University of Montreal Hospital Center and associates (J Rheumatol. 2016 Oct 28. doi: 10.3899/jrheum.160243).
In 2001, LeRoy and Medsger proposed and validated a new set of criteria that centrally required the observation of Raynaud phenomenon and “allowed for greater sensitivity and diagnosis of earlier disease by incorporating advances in nailfold capillary microscopy and [systemic sclerosis]–specific antibodies,” the investigators wrote.
Most recently, the ACR and the European League Against Rheumatism jointly developed new “weighted-point criteria endorsed for use in systemic sclerosis inclusion studies.” These new criteria, which were published in 2013, “the addition of at least a clinical or radiological feature to be positive.”
The purpose of this study, the first of its kind, according to investigators, was to compare the prevalence estimates of systemic sclerosis in primary biliary cholangitis patients as predicted by each of the three criteria sets.
A total of 100 patients who had previously been diagnosed with primary biliary cholangitis but not systemic sclerosis were recruited into the study. The majority of the patients were female (91%), the mean age at first visit was 57 years, and the mean primary biliary cholangitis Mayo score of disease severity and survival was 4.14.
At time of study enrollment, medical histories were obtained. All patients also underwent nailfold capillary microscopy, and serum samples were collected and analyzed for the presence of primary biliary cholangitis antibodies and the following systemic sclerosis–specific antibodies: anti–CENP-B, anti–topo I, anti–RNAP III, anti-Th/To.
Clinical data, presence of antibodies, and capillarascopic patterns were analyzed, and patients were retroactively evaluated for the fulfillment of each of the three systemic sclerosis criteria sets.
“A total of 23 patients satisfied at least one set of criteria, with 22 being positive for LeRoy and Medsger criteria, 17 for ACR/EULAR criteria, and only 1 for the ACR 1980 criteria,” Dr. Zheng and his associates reported.
The most frequent systemic sclerosis–associated features in the study population were Raynaud phenomenon (39%), systemic sclerosis antibodies (26%), abnormal nailfold capillary microscopy (20%), and capillary telangiectases (17%), while clinically evident skin changes were the most rare, investigators explained.
The 1980 ACR criteria likely led to an underestimation of systemic sclerosis in primary biliary cirrhosis, and given the benefit of early diagnosis and treatment of systemic sclerosis, patients with primary biliary cholangitis should be screened for Raynaud phenomenon and systemic sclerosis antibodies and undergo nailfold capillaroscopic microscopy, the investigators recommended.
“Clinicians need to remain alert for this sometimes insidious comorbidity,” the researchers added.
Dr. Zheng had no relevant financial disclosures.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
FROM THE JOURNAL OF RHEUMATOLOGY
Key clinical point:
Major finding: The prevalence of systemic sclerosis in primary biliary cholangitis, according to new criteria, is around 23%.
Data source: Evaluation of systemic sclerosis in 100 patients previously diagnosed with primary biliary cholangitis.
Disclosures: Dr. Zheng had no relevant financial disclosures.
In era of infliximab, ulcerative colitis surgical outcomes worsen
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
AT THE ACS CLINICAL CONGRESS
Key clinical point:
Major finding: Patients are 38% more likely to die in the hospital than they were 15 years ago.
Data source: The 18-year database review comprised more than 7,000 surgeries.
Disclosures: Dr. Abelson had no financial disclosures.
School-located influenza vaccination programs can be effective
School-located influenza vaccination (SLIV) increased seasonal influenza vaccination rates countywide and in both suburban and urban settings, a study found.
“Schools have a stake in influenza vaccination because immunization of schoolchildren can reduce absenteeism throughout the community. Nevertheless, only 6% of childhood influenza vaccinations occur at school. SLIV poses logistical challenges: obtaining parental consent, ordering and administering vaccine, and billing,” said Peter G. Szilagyi, MD, of Mattel Children’s Hospital, Los Angeles, and his associates.
From 2014 to 2015, 44 elementary schools were randomized in upstate New York in an organized cluster-randomized trial in which 19,776 children were eligible candidates. Seven percent of SLIV school students, 5% of suburban SLIV school students, and 9% of urban SLIV students were vaccinated at SLIV clinics. Children in SLIV schools had higher flu vaccination rates than did children in control schools countywide (54% vs. 47%, P less than .001) and in suburban (62% vs. 54%, P less than .001) and urban schools (44% vs. 39%; P less than .001).
SLIV did substitute for vaccination for urban settings serving more Vaccines for Children–covered students, but did not substitute for practice-based vaccination in the suburbs, where pediatricians often preorder influenza vaccine.
“SLIV, using Web-based consent, is a potential strategy to improve influenza vaccination coverage among large populations of children,” the researchers concluded.
Read the full story here: Pediatrics. 2016. doi: 10.1542/peds.2016-1746.
School-located influenza vaccination (SLIV) increased seasonal influenza vaccination rates countywide and in both suburban and urban settings, a study found.
“Schools have a stake in influenza vaccination because immunization of schoolchildren can reduce absenteeism throughout the community. Nevertheless, only 6% of childhood influenza vaccinations occur at school. SLIV poses logistical challenges: obtaining parental consent, ordering and administering vaccine, and billing,” said Peter G. Szilagyi, MD, of Mattel Children’s Hospital, Los Angeles, and his associates.
From 2014 to 2015, 44 elementary schools were randomized in upstate New York in an organized cluster-randomized trial in which 19,776 children were eligible candidates. Seven percent of SLIV school students, 5% of suburban SLIV school students, and 9% of urban SLIV students were vaccinated at SLIV clinics. Children in SLIV schools had higher flu vaccination rates than did children in control schools countywide (54% vs. 47%, P less than .001) and in suburban (62% vs. 54%, P less than .001) and urban schools (44% vs. 39%; P less than .001).
SLIV did substitute for vaccination for urban settings serving more Vaccines for Children–covered students, but did not substitute for practice-based vaccination in the suburbs, where pediatricians often preorder influenza vaccine.
“SLIV, using Web-based consent, is a potential strategy to improve influenza vaccination coverage among large populations of children,” the researchers concluded.
Read the full story here: Pediatrics. 2016. doi: 10.1542/peds.2016-1746.
School-located influenza vaccination (SLIV) increased seasonal influenza vaccination rates countywide and in both suburban and urban settings, a study found.
“Schools have a stake in influenza vaccination because immunization of schoolchildren can reduce absenteeism throughout the community. Nevertheless, only 6% of childhood influenza vaccinations occur at school. SLIV poses logistical challenges: obtaining parental consent, ordering and administering vaccine, and billing,” said Peter G. Szilagyi, MD, of Mattel Children’s Hospital, Los Angeles, and his associates.
From 2014 to 2015, 44 elementary schools were randomized in upstate New York in an organized cluster-randomized trial in which 19,776 children were eligible candidates. Seven percent of SLIV school students, 5% of suburban SLIV school students, and 9% of urban SLIV students were vaccinated at SLIV clinics. Children in SLIV schools had higher flu vaccination rates than did children in control schools countywide (54% vs. 47%, P less than .001) and in suburban (62% vs. 54%, P less than .001) and urban schools (44% vs. 39%; P less than .001).
SLIV did substitute for vaccination for urban settings serving more Vaccines for Children–covered students, but did not substitute for practice-based vaccination in the suburbs, where pediatricians often preorder influenza vaccine.
“SLIV, using Web-based consent, is a potential strategy to improve influenza vaccination coverage among large populations of children,” the researchers concluded.
Read the full story here: Pediatrics. 2016. doi: 10.1542/peds.2016-1746.
FROM PEDIATRICS
Cardiorespiratory fitness improves survival after depression
ROME – Cardiorespiratory fitness provided strong and graded protection against all-cause mortality and nonfatal MI in a study of more than 5,000 patients treated for depression, Amjad M. Ahmed, MD, reported at the annual congress of the European Society of Cardiology.
“These results highlight the importance of assessing fitness to identify risk as well as promoting an active lifestyle in patients with depression,” said Dr. Ahmed of Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia.
This analysis focused on the 5,128 subjects who were on antidepressant medication at the time of their treadmill test. Their baseline cardiorespiratory fitness, as estimated by achieved peak metabolic equivalents (METs) on the treadmill, varied inversely with their risks of acute MI and all-cause mortality in the years to come. However, the less fit a patient was, the greater the burden of traditional cardiovascular risk factors. For example, the prevalence of hypertension was 86% in patients who achieved fewer than 6 METs, 75% in those who achieved 6-9 METs, 62% in depressed patients who reached 10-11 METs, and 51% in those who achieved 12 METs or more.
For this reason, Dr. Ahmed and coinvestigators performed a Cox multivariate regression analysis adjusted extensively for potential confounders, including age, sex, race, cardiovascular risk factors, known coronary artery disease, the use of cardiovascular medications, and the reason for the referral for stress testing.
When an achieved MET below 6 was used as the reference standard, for every 1 MET above 6 that patients achieved, their adjusted risk of all-cause mortality decreased by 18%, and the risk of nonfatal MI fell by 8%.
Session cochair Martin Halle, MD, pointed out what he viewed as a major limitation of the study.
“You didn’t follow their physical fitness over time, so you can’t say that increasing their METs would bring a better prognosis,” said Dr. Halle, professor and chairman of the department of preventive and rehabilitative sports medicine at the Technical University of Munich.
Dr. Ahmed reported having no financial conflicts of interest related to the Henry Ford FIT Project.
ROME – Cardiorespiratory fitness provided strong and graded protection against all-cause mortality and nonfatal MI in a study of more than 5,000 patients treated for depression, Amjad M. Ahmed, MD, reported at the annual congress of the European Society of Cardiology.
“These results highlight the importance of assessing fitness to identify risk as well as promoting an active lifestyle in patients with depression,” said Dr. Ahmed of Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia.
This analysis focused on the 5,128 subjects who were on antidepressant medication at the time of their treadmill test. Their baseline cardiorespiratory fitness, as estimated by achieved peak metabolic equivalents (METs) on the treadmill, varied inversely with their risks of acute MI and all-cause mortality in the years to come. However, the less fit a patient was, the greater the burden of traditional cardiovascular risk factors. For example, the prevalence of hypertension was 86% in patients who achieved fewer than 6 METs, 75% in those who achieved 6-9 METs, 62% in depressed patients who reached 10-11 METs, and 51% in those who achieved 12 METs or more.
For this reason, Dr. Ahmed and coinvestigators performed a Cox multivariate regression analysis adjusted extensively for potential confounders, including age, sex, race, cardiovascular risk factors, known coronary artery disease, the use of cardiovascular medications, and the reason for the referral for stress testing.
When an achieved MET below 6 was used as the reference standard, for every 1 MET above 6 that patients achieved, their adjusted risk of all-cause mortality decreased by 18%, and the risk of nonfatal MI fell by 8%.
Session cochair Martin Halle, MD, pointed out what he viewed as a major limitation of the study.
“You didn’t follow their physical fitness over time, so you can’t say that increasing their METs would bring a better prognosis,” said Dr. Halle, professor and chairman of the department of preventive and rehabilitative sports medicine at the Technical University of Munich.
Dr. Ahmed reported having no financial conflicts of interest related to the Henry Ford FIT Project.
ROME – Cardiorespiratory fitness provided strong and graded protection against all-cause mortality and nonfatal MI in a study of more than 5,000 patients treated for depression, Amjad M. Ahmed, MD, reported at the annual congress of the European Society of Cardiology.
“These results highlight the importance of assessing fitness to identify risk as well as promoting an active lifestyle in patients with depression,” said Dr. Ahmed of Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia.
This analysis focused on the 5,128 subjects who were on antidepressant medication at the time of their treadmill test. Their baseline cardiorespiratory fitness, as estimated by achieved peak metabolic equivalents (METs) on the treadmill, varied inversely with their risks of acute MI and all-cause mortality in the years to come. However, the less fit a patient was, the greater the burden of traditional cardiovascular risk factors. For example, the prevalence of hypertension was 86% in patients who achieved fewer than 6 METs, 75% in those who achieved 6-9 METs, 62% in depressed patients who reached 10-11 METs, and 51% in those who achieved 12 METs or more.
For this reason, Dr. Ahmed and coinvestigators performed a Cox multivariate regression analysis adjusted extensively for potential confounders, including age, sex, race, cardiovascular risk factors, known coronary artery disease, the use of cardiovascular medications, and the reason for the referral for stress testing.
When an achieved MET below 6 was used as the reference standard, for every 1 MET above 6 that patients achieved, their adjusted risk of all-cause mortality decreased by 18%, and the risk of nonfatal MI fell by 8%.
Session cochair Martin Halle, MD, pointed out what he viewed as a major limitation of the study.
“You didn’t follow their physical fitness over time, so you can’t say that increasing their METs would bring a better prognosis,” said Dr. Halle, professor and chairman of the department of preventive and rehabilitative sports medicine at the Technical University of Munich.
Dr. Ahmed reported having no financial conflicts of interest related to the Henry Ford FIT Project.
AT THE ESC CONGRESS 2016
Key clinical point:
Major finding: For every 1-MET increase a patient on antidepressant medication achieved above 6 METs during a Bruce protocol treadmill exercise test, the risk of all-cause mortality during the subsequent 11.5 years decreased by an adjusted 18%.
Data source: A retrospective analysis of 5,128 patients on antidepressant medication who underwent a treadmill exercise test as part of the Henry Ford Exercise Testing Project and were then followed up for a median of 11.5 years.
Disclosures: The study presenter reported having no relevant financial conflicts.
A Better Way to Predict Colorectal Cancer Relapse?
Carcinoembryonic antigen (CEA) is often used as a marker for relapse in colorectal cancer. But in as many as 40% of recurrences, the serum CEA shows unmeasurable elevations. And some patients with resected colorectal cancer (CRC) have transient elevations of CEA levels; the false-positive rate during follow-up has been as high as 16%, say researchers from Kaohsiung Medical University, Taiwan. They propose “a more powerful tool”: a membrane array-based multigene biomarker assay, or biomarker chip, which detects circulating tumor cells in the peripheral blood.
Related: Colorectal Carcinoma and Emerging Targeted Therapies
The researchers conducted a study in 298 patients with CRC to test that alternative. The patients were enrolled after radical curative resection for primary CRC tumor; 82 were stage I, 102 were stage II, and 114 were stage III. Patients were followed for a median of 28.4 months, every 3 months for 3 years, then every 6 months. At each follow-up visit, laboratory studies included serum CEA levels. Elevated CEA levels were defined as 2 consecutive measurements of >5 ng/mL at a 3-month interval.
During the study period, 48 patients (16.1%) had postoperative relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%) had a total biomarker chip score higher than the cutoff value. Of the 48 who relapsed, 42 (87.5%) showed positive biochip results prior to relapse.
The positive biochip results were significantly associated with postoperative relapse. In fact, the biomarker chip was better for predicting relapse than were the postoperative serum CEA levels with higher sensitivity (87.5% vs 60.4%), specificity (92.0% vs 83.2%), positive predictive value (67.7% vs 40.8%), negative predictive value (97.5% vs 91.6%), and accuracy (91.3% vs 79.5%).
Moreover, the biochip predicted relapse “considerably earlier” than did CEA levels (10.7 vs 2.8 months). The researchers note that CRC-related deaths are largely attributable to clinical relapse. The sooner a relapse is diagnosed, the more amenable the tumor may be to resection, increasing the likelihood of long-term survival.
In sum, the biomarker chip would be a more accurate tool for predicting relapse, the researchers say. They also suggest that, in clinical practice, combining the 2 tests could enhance confidence in the diagnosis.
Source:
Chang YT, Huang MY, Huang CW, et al. PLoS One. 2016;11(10):e0163264.
doi: 10.1371/journal.pone.0163264.
Carcinoembryonic antigen (CEA) is often used as a marker for relapse in colorectal cancer. But in as many as 40% of recurrences, the serum CEA shows unmeasurable elevations. And some patients with resected colorectal cancer (CRC) have transient elevations of CEA levels; the false-positive rate during follow-up has been as high as 16%, say researchers from Kaohsiung Medical University, Taiwan. They propose “a more powerful tool”: a membrane array-based multigene biomarker assay, or biomarker chip, which detects circulating tumor cells in the peripheral blood.
Related: Colorectal Carcinoma and Emerging Targeted Therapies
The researchers conducted a study in 298 patients with CRC to test that alternative. The patients were enrolled after radical curative resection for primary CRC tumor; 82 were stage I, 102 were stage II, and 114 were stage III. Patients were followed for a median of 28.4 months, every 3 months for 3 years, then every 6 months. At each follow-up visit, laboratory studies included serum CEA levels. Elevated CEA levels were defined as 2 consecutive measurements of >5 ng/mL at a 3-month interval.
During the study period, 48 patients (16.1%) had postoperative relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%) had a total biomarker chip score higher than the cutoff value. Of the 48 who relapsed, 42 (87.5%) showed positive biochip results prior to relapse.
The positive biochip results were significantly associated with postoperative relapse. In fact, the biomarker chip was better for predicting relapse than were the postoperative serum CEA levels with higher sensitivity (87.5% vs 60.4%), specificity (92.0% vs 83.2%), positive predictive value (67.7% vs 40.8%), negative predictive value (97.5% vs 91.6%), and accuracy (91.3% vs 79.5%).
Moreover, the biochip predicted relapse “considerably earlier” than did CEA levels (10.7 vs 2.8 months). The researchers note that CRC-related deaths are largely attributable to clinical relapse. The sooner a relapse is diagnosed, the more amenable the tumor may be to resection, increasing the likelihood of long-term survival.
In sum, the biomarker chip would be a more accurate tool for predicting relapse, the researchers say. They also suggest that, in clinical practice, combining the 2 tests could enhance confidence in the diagnosis.
Source:
Chang YT, Huang MY, Huang CW, et al. PLoS One. 2016;11(10):e0163264.
doi: 10.1371/journal.pone.0163264.
Carcinoembryonic antigen (CEA) is often used as a marker for relapse in colorectal cancer. But in as many as 40% of recurrences, the serum CEA shows unmeasurable elevations. And some patients with resected colorectal cancer (CRC) have transient elevations of CEA levels; the false-positive rate during follow-up has been as high as 16%, say researchers from Kaohsiung Medical University, Taiwan. They propose “a more powerful tool”: a membrane array-based multigene biomarker assay, or biomarker chip, which detects circulating tumor cells in the peripheral blood.
Related: Colorectal Carcinoma and Emerging Targeted Therapies
The researchers conducted a study in 298 patients with CRC to test that alternative. The patients were enrolled after radical curative resection for primary CRC tumor; 82 were stage I, 102 were stage II, and 114 were stage III. Patients were followed for a median of 28.4 months, every 3 months for 3 years, then every 6 months. At each follow-up visit, laboratory studies included serum CEA levels. Elevated CEA levels were defined as 2 consecutive measurements of >5 ng/mL at a 3-month interval.
During the study period, 48 patients (16.1%) had postoperative relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%) had a total biomarker chip score higher than the cutoff value. Of the 48 who relapsed, 42 (87.5%) showed positive biochip results prior to relapse.
The positive biochip results were significantly associated with postoperative relapse. In fact, the biomarker chip was better for predicting relapse than were the postoperative serum CEA levels with higher sensitivity (87.5% vs 60.4%), specificity (92.0% vs 83.2%), positive predictive value (67.7% vs 40.8%), negative predictive value (97.5% vs 91.6%), and accuracy (91.3% vs 79.5%).
Moreover, the biochip predicted relapse “considerably earlier” than did CEA levels (10.7 vs 2.8 months). The researchers note that CRC-related deaths are largely attributable to clinical relapse. The sooner a relapse is diagnosed, the more amenable the tumor may be to resection, increasing the likelihood of long-term survival.
In sum, the biomarker chip would be a more accurate tool for predicting relapse, the researchers say. They also suggest that, in clinical practice, combining the 2 tests could enhance confidence in the diagnosis.
Source:
Chang YT, Huang MY, Huang CW, et al. PLoS One. 2016;11(10):e0163264.
doi: 10.1371/journal.pone.0163264.
Scoring formula consolidates stroke, bleeding risk in atrial fib patients
ROME – A new risk-stratification formula for atrial fibrillation patients starting oral anticoagulant therapy helps sort out their potential net benefit on edoxaban, compared with warfarin.
This risk score “could help guide selection of treatment” with a vitamin K antagonist such as warfarin or a new oral anticoagulant (NOAC) such as edoxaban, Christina L. Fanola, MD, said at the annual congress of the European Society of Cardiology.
“It’s a great time to think about this type of score, because so many more patients are being diagnosed with atrial fibrillation and there is a lot of clinical equipoise” over which anticoagulant to start patients on, said Dr. Fanola, a cardiologist at Brigham and Women’s Hospital in Boston. She said she and her associates hope to externally validate the score and test it in cohorts that received other NOACs, such as apixaban (Eliquis), dabigatran (Pradaxa), or rivaroxaban (Xarelto), but it is very possible that scoring might differ from one NOAC to the next. “Each NOAC may need its own scoring formula,” Dr. Fanola said in an interview.
A Cox proportional hazards model identified 10 demographic, clinical, and laboratory features that had significant, independent correlations to a primary outcome of disabling stroke, life-threatening bleeding, or death. After weighing the point allocation for each item by the strength of its association, the researchers developed a scoring formula in a model that could account for about 69% of the three combined adverse outcomes.
An analysis that applied the scoring formula back to the ENGAGE AF-TIMI 48 database showed that a low-risk score of 0-6 correlated with a 4% per year rate of disabling stroke, life-threatening bleed, or death; an intermediate-risk score of 7-9 correlated with a 10% per year incidence of this combined outcome, and a high-risk score of 10 or greater linked with a 21% annual event rate.
Dr. Fanola and her associates ran a further analysis that evaluated the efficacy of edoxaban, compared with warfarin, among the patients in each of these risk strata. The high-risk patients received a major benefit from edoxaban, with a 30% overall incidence of the combined endpoint during 3 years of follow-up, compared with a 51% rate among patients on warfarin, a 21-percentage-point reduction in adverse events. Intermediate-risk patients also received a significant benefit, with a 26% event rate on warfarin and an 18% rate on edoxaban. But low-risk patients had identical 10% event rates with either treatment.
These findings suggest that atrial fibrillation patients with a TIMI AF score that is high or intermediate would have a better chance for a good outcome on edoxaban, or perhaps a different NOAC, than on warfarin. Low-risk patients seem to have similar outcomes on edoxaban or warfarin, so other considerations can come into play for choosing between these drug options, such as the cost of treatment and the inconvenience of regular warfarin monitoring, Dr. Fanola said.
ENGAGE AF-TIMI 48 was sponsored by Daiichi Sankyo, the company that markets edoxaban. Dr. Fanola had no relevant financial disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
ROME – A new risk-stratification formula for atrial fibrillation patients starting oral anticoagulant therapy helps sort out their potential net benefit on edoxaban, compared with warfarin.
This risk score “could help guide selection of treatment” with a vitamin K antagonist such as warfarin or a new oral anticoagulant (NOAC) such as edoxaban, Christina L. Fanola, MD, said at the annual congress of the European Society of Cardiology.
“It’s a great time to think about this type of score, because so many more patients are being diagnosed with atrial fibrillation and there is a lot of clinical equipoise” over which anticoagulant to start patients on, said Dr. Fanola, a cardiologist at Brigham and Women’s Hospital in Boston. She said she and her associates hope to externally validate the score and test it in cohorts that received other NOACs, such as apixaban (Eliquis), dabigatran (Pradaxa), or rivaroxaban (Xarelto), but it is very possible that scoring might differ from one NOAC to the next. “Each NOAC may need its own scoring formula,” Dr. Fanola said in an interview.
A Cox proportional hazards model identified 10 demographic, clinical, and laboratory features that had significant, independent correlations to a primary outcome of disabling stroke, life-threatening bleeding, or death. After weighing the point allocation for each item by the strength of its association, the researchers developed a scoring formula in a model that could account for about 69% of the three combined adverse outcomes.
An analysis that applied the scoring formula back to the ENGAGE AF-TIMI 48 database showed that a low-risk score of 0-6 correlated with a 4% per year rate of disabling stroke, life-threatening bleed, or death; an intermediate-risk score of 7-9 correlated with a 10% per year incidence of this combined outcome, and a high-risk score of 10 or greater linked with a 21% annual event rate.
Dr. Fanola and her associates ran a further analysis that evaluated the efficacy of edoxaban, compared with warfarin, among the patients in each of these risk strata. The high-risk patients received a major benefit from edoxaban, with a 30% overall incidence of the combined endpoint during 3 years of follow-up, compared with a 51% rate among patients on warfarin, a 21-percentage-point reduction in adverse events. Intermediate-risk patients also received a significant benefit, with a 26% event rate on warfarin and an 18% rate on edoxaban. But low-risk patients had identical 10% event rates with either treatment.
These findings suggest that atrial fibrillation patients with a TIMI AF score that is high or intermediate would have a better chance for a good outcome on edoxaban, or perhaps a different NOAC, than on warfarin. Low-risk patients seem to have similar outcomes on edoxaban or warfarin, so other considerations can come into play for choosing between these drug options, such as the cost of treatment and the inconvenience of regular warfarin monitoring, Dr. Fanola said.
ENGAGE AF-TIMI 48 was sponsored by Daiichi Sankyo, the company that markets edoxaban. Dr. Fanola had no relevant financial disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
ROME – A new risk-stratification formula for atrial fibrillation patients starting oral anticoagulant therapy helps sort out their potential net benefit on edoxaban, compared with warfarin.
This risk score “could help guide selection of treatment” with a vitamin K antagonist such as warfarin or a new oral anticoagulant (NOAC) such as edoxaban, Christina L. Fanola, MD, said at the annual congress of the European Society of Cardiology.
“It’s a great time to think about this type of score, because so many more patients are being diagnosed with atrial fibrillation and there is a lot of clinical equipoise” over which anticoagulant to start patients on, said Dr. Fanola, a cardiologist at Brigham and Women’s Hospital in Boston. She said she and her associates hope to externally validate the score and test it in cohorts that received other NOACs, such as apixaban (Eliquis), dabigatran (Pradaxa), or rivaroxaban (Xarelto), but it is very possible that scoring might differ from one NOAC to the next. “Each NOAC may need its own scoring formula,” Dr. Fanola said in an interview.
A Cox proportional hazards model identified 10 demographic, clinical, and laboratory features that had significant, independent correlations to a primary outcome of disabling stroke, life-threatening bleeding, or death. After weighing the point allocation for each item by the strength of its association, the researchers developed a scoring formula in a model that could account for about 69% of the three combined adverse outcomes.
An analysis that applied the scoring formula back to the ENGAGE AF-TIMI 48 database showed that a low-risk score of 0-6 correlated with a 4% per year rate of disabling stroke, life-threatening bleed, or death; an intermediate-risk score of 7-9 correlated with a 10% per year incidence of this combined outcome, and a high-risk score of 10 or greater linked with a 21% annual event rate.
Dr. Fanola and her associates ran a further analysis that evaluated the efficacy of edoxaban, compared with warfarin, among the patients in each of these risk strata. The high-risk patients received a major benefit from edoxaban, with a 30% overall incidence of the combined endpoint during 3 years of follow-up, compared with a 51% rate among patients on warfarin, a 21-percentage-point reduction in adverse events. Intermediate-risk patients also received a significant benefit, with a 26% event rate on warfarin and an 18% rate on edoxaban. But low-risk patients had identical 10% event rates with either treatment.
These findings suggest that atrial fibrillation patients with a TIMI AF score that is high or intermediate would have a better chance for a good outcome on edoxaban, or perhaps a different NOAC, than on warfarin. Low-risk patients seem to have similar outcomes on edoxaban or warfarin, so other considerations can come into play for choosing between these drug options, such as the cost of treatment and the inconvenience of regular warfarin monitoring, Dr. Fanola said.
ENGAGE AF-TIMI 48 was sponsored by Daiichi Sankyo, the company that markets edoxaban. Dr. Fanola had no relevant financial disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2016
Key clinical point:
Major finding: Among high-risk patients, edoxaban cut adverse events by 21 percentage points, compared with warfarin.
Data source: ENGAGE AF-TIMI 48, a multicenter trial with 21,105 patients.
Disclosures: ENGAGE AF-TIMI 48 was sponsored by Daiichi Sankyo, the company that markets edoxaban (Savaysa). Dr. Fanola had no relevant financial disclosures.
Giving women HIV self-tests increases male partner testing
Providing Kenyan women attending prenatal or postpartum health care visits with HIV self-testing kits raised the rates of partner and couples testing to more than 90%, according to a report published online in PLOS Medicine.
HIV testing remains underused in many parts of sub-Saharan Africa, particularly among men, for reasons including social stigma, fear of poor prognosis, lack of awareness of HIV risk, fear that their results would be disclosed, inconvenience, and transportation costs. To assess one strategy for improving male testing rates, researchers performed a study at a hospital and two clinics in urban and suburban Kisumu, Kenya, where the HIV prevalence is approximately 20% among adult residents. 
The trial involved 600 women aged 18-39 years (mean age, 24 years) who were seeking either prenatal or postpartum health care and agreed to participate. They were randomly assigned to receive either a few HIV self-test kits plus counseling regarding HIV testing (intervention group) or counseling alone (control group) and followed for 3 months. A total of 95% of the women – 284 in the intervention group and 286 in the control group – completed the study, said Harsha Thirumurthy, PhD, of the department of health policy and management, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, and his associates.
At follow-up, 258 (90.8%) of the women in the intervention group reported that their partners had been tested for HIV, compared with 148 (51.7%) of the control group. This significant difference persisted across all subgroups of patients, regardless of study site and whether or not partners said they had been tested during the preceding year. “This result is encouraging since it suggests that the strategy of giving multiple self-tests to women can effectively increase access to HIV testing in hard-to-reach populations such as men who do not test regularly,” the investigators said (PLOS Med. 2016 Nov 8. doi: 10.1371/journal.pmed.1002166).
In three-fourths of the cases where male partners were tested for HIV, both members of the couple were tested together. This is beneficial because it helps women learn their partners’ HIV status, and because couples who test together are “more likely to adopt a range of HIV prevention and care behaviors,” Dr. Thirumurthy and his associates wrote.
Approximately one-third of the women who were eligible for this study declined to participate, often because they feared that their partners would become violent if offered an HIV self-test. Even women who did participate reported a high rate (27%) of partner violence at baseline. It is encouraging that none of the study participants reported any such incidents in response to the HIV testing, the investigators added.
The International Initiative for Impact Evaluation funded the study. Dr. Thirumurthy and his associates reported having no relevant financial disclosures.
Providing Kenyan women attending prenatal or postpartum health care visits with HIV self-testing kits raised the rates of partner and couples testing to more than 90%, according to a report published online in PLOS Medicine.
HIV testing remains underused in many parts of sub-Saharan Africa, particularly among men, for reasons including social stigma, fear of poor prognosis, lack of awareness of HIV risk, fear that their results would be disclosed, inconvenience, and transportation costs. To assess one strategy for improving male testing rates, researchers performed a study at a hospital and two clinics in urban and suburban Kisumu, Kenya, where the HIV prevalence is approximately 20% among adult residents.
The trial involved 600 women aged 18-39 years (mean age, 24 years) who were seeking either prenatal or postpartum health care and agreed to participate. They were randomly assigned to receive either a few HIV self-test kits plus counseling regarding HIV testing (intervention group) or counseling alone (control group) and followed for 3 months. A total of 95% of the women – 284 in the intervention group and 286 in the control group – completed the study, said Harsha Thirumurthy, PhD, of the department of health policy and management, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, and his associates.
At follow-up, 258 (90.8%) of the women in the intervention group reported that their partners had been tested for HIV, compared with 148 (51.7%) of the control group. This significant difference persisted across all subgroups of patients, regardless of study site and whether or not partners said they had been tested during the preceding year. “This result is encouraging since it suggests that the strategy of giving multiple self-tests to women can effectively increase access to HIV testing in hard-to-reach populations such as men who do not test regularly,” the investigators said (PLOS Med. 2016 Nov 8. doi: 10.1371/journal.pmed.1002166).
In three-fourths of the cases where male partners were tested for HIV, both members of the couple were tested together. This is beneficial because it helps women learn their partners’ HIV status, and because couples who test together are “more likely to adopt a range of HIV prevention and care behaviors,” Dr. Thirumurthy and his associates wrote.
Approximately one-third of the women who were eligible for this study declined to participate, often because they feared that their partners would become violent if offered an HIV self-test. Even women who did participate reported a high rate (27%) of partner violence at baseline. It is encouraging that none of the study participants reported any such incidents in response to the HIV testing, the investigators added.
The International Initiative for Impact Evaluation funded the study. Dr. Thirumurthy and his associates reported having no relevant financial disclosures.
Providing Kenyan women attending prenatal or postpartum health care visits with HIV self-testing kits raised the rates of partner and couples testing to more than 90%, according to a report published online in PLOS Medicine.
HIV testing remains underused in many parts of sub-Saharan Africa, particularly among men, for reasons including social stigma, fear of poor prognosis, lack of awareness of HIV risk, fear that their results would be disclosed, inconvenience, and transportation costs. To assess one strategy for improving male testing rates, researchers performed a study at a hospital and two clinics in urban and suburban Kisumu, Kenya, where the HIV prevalence is approximately 20% among adult residents.
The trial involved 600 women aged 18-39 years (mean age, 24 years) who were seeking either prenatal or postpartum health care and agreed to participate. They were randomly assigned to receive either a few HIV self-test kits plus counseling regarding HIV testing (intervention group) or counseling alone (control group) and followed for 3 months. A total of 95% of the women – 284 in the intervention group and 286 in the control group – completed the study, said Harsha Thirumurthy, PhD, of the department of health policy and management, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, and his associates.
At follow-up, 258 (90.8%) of the women in the intervention group reported that their partners had been tested for HIV, compared with 148 (51.7%) of the control group. This significant difference persisted across all subgroups of patients, regardless of study site and whether or not partners said they had been tested during the preceding year. “This result is encouraging since it suggests that the strategy of giving multiple self-tests to women can effectively increase access to HIV testing in hard-to-reach populations such as men who do not test regularly,” the investigators said (PLOS Med. 2016 Nov 8. doi: 10.1371/journal.pmed.1002166).
In three-fourths of the cases where male partners were tested for HIV, both members of the couple were tested together. This is beneficial because it helps women learn their partners’ HIV status, and because couples who test together are “more likely to adopt a range of HIV prevention and care behaviors,” Dr. Thirumurthy and his associates wrote.
Approximately one-third of the women who were eligible for this study declined to participate, often because they feared that their partners would become violent if offered an HIV self-test. Even women who did participate reported a high rate (27%) of partner violence at baseline. It is encouraging that none of the study participants reported any such incidents in response to the HIV testing, the investigators added.
The International Initiative for Impact Evaluation funded the study. Dr. Thirumurthy and his associates reported having no relevant financial disclosures.
FROM PLOS MEDICINE
Key clinical point: Providing Kenyan women attending prenatal or postpartum health care visits with HIV self-testing kits raised the rates of partner and couples testing to more than 90%.
Major finding: After 3 months, 258 women (90.8%) in the intervention group reported that their partners had been tested for HIV, compared with 148 (51.7%) of the control group.
Data source: A multicenter randomized trial involving 600 women in Kenya receiving prenatal or postpartum care, and their sexual partners.
Disclosures: The International Initiative for Impact Evaluation funded the study. Dr. Thirumurthy and his associates reported having no relevant financial disclosures.
FDA addresses unmet need in drug development guidance for female sexual dysfunction
On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.
The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.
Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”
With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.
On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.
Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.
And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.
Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.
On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.
The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.
Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”
With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.
On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.
Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.
And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.
Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.
On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.
The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.
Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”
With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.
On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.
Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.
And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.
Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.