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Peanut allergy pill gets thumbs-up from FDA advisory panel
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
FROM THE FDA ALLERGENIC PRODUCTS ADVISORY COMMITTEE MEETING
FDA issues warning for CDK 4/6 inhibitors
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
FDA approves mepolizumab for severe eosinophilic asthma in younger kids
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
according to a release from GlaxoSmithKline, which developed the drug. This is the first targeted biologic approved for this condition in this age group.
The approval is supported by both an open-label study in children aged 6-11 years and evidence from other trials conducted in adults and adolescents. The 52-week, long-term study in these younger patients investigated pharmacokinetics, pharmacodynamics, and safety, the last of which was shown to be similar to that seen in older patients.
Hypersensitivity reactions, such as anaphylaxis, rash, and bronchospasm, have been associated with mepolizumab. It should not be used to treat acute bronchospasm or status asthmaticus, nor should systemic or inhaled corticosteroids be stopped abruptly after initiating mepolizumab treatment. Common adverse events include headache, injection-site reactions, back pain, and fatigue. Injection site reactions (such as pain, erythema, and itching) occurred in 8% of mepolizumab patients treated with 100 mg of the drug versus 3% of placebo patients.
The monoclonal antibody targeting interleukin-5 was first approved for severe eosinophilic asthma in 2015 for ages 12 years and older and in ages 6 years and older in the European Union in August 2018. It inhibits IL-5 from binding to eosinophils, which reduces the presence of eosinophils in blood without completely eliminating them.
FDA approves tenapanor for IBS with constipation
The approval is based on a pair of phase 3, randomized, double-blind, placebo-controlled trials in patients meeting the Rome III criteria for IBS-C. Both trials had identical 12-week treatment phases, while trial 1 had a 14-week continuation phase, and trial 2 included a 4-week withdrawal period. The primary endpoint was proportion of responders in the 12-week treatment period; this was defined as a 30% reduction in abdominal pain score and an increase of at least one complete spontaneous bowel movement on average weekly for at least 6 of the first 12 treatment weeks, compared with placebo. Both trials met this endpoint, with trial 1 showing a 37% response rate with treatment versus 24% with placebo, and trial 2 showing rates of 27% and 19%, respectively. Improvements were seen as early as week 1 and were maintained through the end of treatment.
The most common treatment-related adverse event was diarrhea, with severe diarrhea reported in 2.5% of treated patients versus 0.2% of placebo patients. Discontinuation rates were low. Tenapanor is contraindicated in IBS-C patients younger than 6 years because of concerns about dehydration, and use should be avoided in patients aged 6-12 years. Safety and efficacy has not been established in patients younger than 18 years. Tenapanor is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
The full prescribing information can be found on the FDA website.
The approval is based on a pair of phase 3, randomized, double-blind, placebo-controlled trials in patients meeting the Rome III criteria for IBS-C. Both trials had identical 12-week treatment phases, while trial 1 had a 14-week continuation phase, and trial 2 included a 4-week withdrawal period. The primary endpoint was proportion of responders in the 12-week treatment period; this was defined as a 30% reduction in abdominal pain score and an increase of at least one complete spontaneous bowel movement on average weekly for at least 6 of the first 12 treatment weeks, compared with placebo. Both trials met this endpoint, with trial 1 showing a 37% response rate with treatment versus 24% with placebo, and trial 2 showing rates of 27% and 19%, respectively. Improvements were seen as early as week 1 and were maintained through the end of treatment.
The most common treatment-related adverse event was diarrhea, with severe diarrhea reported in 2.5% of treated patients versus 0.2% of placebo patients. Discontinuation rates were low. Tenapanor is contraindicated in IBS-C patients younger than 6 years because of concerns about dehydration, and use should be avoided in patients aged 6-12 years. Safety and efficacy has not been established in patients younger than 18 years. Tenapanor is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
The full prescribing information can be found on the FDA website.
The approval is based on a pair of phase 3, randomized, double-blind, placebo-controlled trials in patients meeting the Rome III criteria for IBS-C. Both trials had identical 12-week treatment phases, while trial 1 had a 14-week continuation phase, and trial 2 included a 4-week withdrawal period. The primary endpoint was proportion of responders in the 12-week treatment period; this was defined as a 30% reduction in abdominal pain score and an increase of at least one complete spontaneous bowel movement on average weekly for at least 6 of the first 12 treatment weeks, compared with placebo. Both trials met this endpoint, with trial 1 showing a 37% response rate with treatment versus 24% with placebo, and trial 2 showing rates of 27% and 19%, respectively. Improvements were seen as early as week 1 and were maintained through the end of treatment.
The most common treatment-related adverse event was diarrhea, with severe diarrhea reported in 2.5% of treated patients versus 0.2% of placebo patients. Discontinuation rates were low. Tenapanor is contraindicated in IBS-C patients younger than 6 years because of concerns about dehydration, and use should be avoided in patients aged 6-12 years. Safety and efficacy has not been established in patients younger than 18 years. Tenapanor is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
The full prescribing information can be found on the FDA website.
NDMA found in samples of ranitidine, FDA says
According to the Food and Drug Administration,
“NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a prepared statement issued on Sept. 13, 2019. “The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines.”
Dr. Woodcock said that the agency is working with industry partners to determine whether the low levels of NDMA in ranitidine pose a risk to patients, and it plans to post that information when it becomes available. For now, “patients should be able to trust that their medicines are as safe as they can be and that the benefits of taking them outweigh any risk to their health,” she said. “Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.”
Dr. Woodcock emphasized that the FDA is not suggesting that individuals stop taking ranitidine at this time. “However, patients taking prescription ranitidine who wish to discontinue use should talk to their health care professional about other treatment options,” she said. “People taking OTC ranitidine could consider using other OTC medicines approved for their condition. There are multiple drugs on the market that are approved for the same or similar uses as ranitidine.”
She advised consumers and health care professionals to report any adverse reactions with ranitidine to the FDA’s MedWatch program to help the agency better understand the problem.
According to the Food and Drug Administration,
“NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a prepared statement issued on Sept. 13, 2019. “The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines.”
Dr. Woodcock said that the agency is working with industry partners to determine whether the low levels of NDMA in ranitidine pose a risk to patients, and it plans to post that information when it becomes available. For now, “patients should be able to trust that their medicines are as safe as they can be and that the benefits of taking them outweigh any risk to their health,” she said. “Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.”
Dr. Woodcock emphasized that the FDA is not suggesting that individuals stop taking ranitidine at this time. “However, patients taking prescription ranitidine who wish to discontinue use should talk to their health care professional about other treatment options,” she said. “People taking OTC ranitidine could consider using other OTC medicines approved for their condition. There are multiple drugs on the market that are approved for the same or similar uses as ranitidine.”
She advised consumers and health care professionals to report any adverse reactions with ranitidine to the FDA’s MedWatch program to help the agency better understand the problem.
According to the Food and Drug Administration,
“NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a prepared statement issued on Sept. 13, 2019. “The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines.”
Dr. Woodcock said that the agency is working with industry partners to determine whether the low levels of NDMA in ranitidine pose a risk to patients, and it plans to post that information when it becomes available. For now, “patients should be able to trust that their medicines are as safe as they can be and that the benefits of taking them outweigh any risk to their health,” she said. “Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.”
Dr. Woodcock emphasized that the FDA is not suggesting that individuals stop taking ranitidine at this time. “However, patients taking prescription ranitidine who wish to discontinue use should talk to their health care professional about other treatment options,” she said. “People taking OTC ranitidine could consider using other OTC medicines approved for their condition. There are multiple drugs on the market that are approved for the same or similar uses as ranitidine.”
She advised consumers and health care professionals to report any adverse reactions with ranitidine to the FDA’s MedWatch program to help the agency better understand the problem.
FDA approves nintedanib for scleroderma interstitial lung disease
The Food and Drug Administration has approved nintedanib (Ofev) for the rare but sometimes deadly form of interstitial lung disease that’s caused by systemic sclerosis, or scleroderma.
Although scleroderma itself is rare, half of those patients present with scleroderma-related interstitial lung disease (SSc-ILD), and it remains the leading cause of death in scleroderma patients because it can lead to loss of pulmonary function. Nintedanib appears to slow the progress of SSc-ILD and is the first treatment approved for it, according to a news release from the FDA.
The approval is based on a randomized, double-blind, placebo-controlled trial of 576 patients aged 20-79 years with SSc-ILD. The primary efficacy endpoint was forced vital capacity, and patients on nintedanib showed less decline than did those on placebo.
The most frequent serious adverse event reported in this trial was pneumonia (2.8% with nintedanib vs. 0.3% with placebo). Adverse reactions that led to permanent dose reductions occurred in 34% of nintedanib patients and 4% of placebo-treated patients; the most common of these was diarrhea.
The full prescribing information, which is available on the FDA website, includes warnings for patients with moderate to severe hepatic impairment, elevated liver enzymes, and drug-induced liver injury, as well as those with gastrointestinal disorders. Nintedanib may cause embryo-fetal toxicity, so women of childbearing age should be counseled to avoid pregnancy while taking this drug.
Nintedanib received both Priority Review and Orphan Drug designation. The former meant the FDA intends to take action on the application within 6 months because the agency has determined that, if approved, it would have important effects on treatment of a serious condition. The latter provides incentives to assist and encourage development of drugs for rare diseases. The drug was approved in 2014 for adult patients with idiopathic pulmonary fibrosis, another interstitial lung disease.
The full release is available on the FDA website.
The Food and Drug Administration has approved nintedanib (Ofev) for the rare but sometimes deadly form of interstitial lung disease that’s caused by systemic sclerosis, or scleroderma.
Although scleroderma itself is rare, half of those patients present with scleroderma-related interstitial lung disease (SSc-ILD), and it remains the leading cause of death in scleroderma patients because it can lead to loss of pulmonary function. Nintedanib appears to slow the progress of SSc-ILD and is the first treatment approved for it, according to a news release from the FDA.
The approval is based on a randomized, double-blind, placebo-controlled trial of 576 patients aged 20-79 years with SSc-ILD. The primary efficacy endpoint was forced vital capacity, and patients on nintedanib showed less decline than did those on placebo.
The most frequent serious adverse event reported in this trial was pneumonia (2.8% with nintedanib vs. 0.3% with placebo). Adverse reactions that led to permanent dose reductions occurred in 34% of nintedanib patients and 4% of placebo-treated patients; the most common of these was diarrhea.
The full prescribing information, which is available on the FDA website, includes warnings for patients with moderate to severe hepatic impairment, elevated liver enzymes, and drug-induced liver injury, as well as those with gastrointestinal disorders. Nintedanib may cause embryo-fetal toxicity, so women of childbearing age should be counseled to avoid pregnancy while taking this drug.
Nintedanib received both Priority Review and Orphan Drug designation. The former meant the FDA intends to take action on the application within 6 months because the agency has determined that, if approved, it would have important effects on treatment of a serious condition. The latter provides incentives to assist and encourage development of drugs for rare diseases. The drug was approved in 2014 for adult patients with idiopathic pulmonary fibrosis, another interstitial lung disease.
The full release is available on the FDA website.
The Food and Drug Administration has approved nintedanib (Ofev) for the rare but sometimes deadly form of interstitial lung disease that’s caused by systemic sclerosis, or scleroderma.
Although scleroderma itself is rare, half of those patients present with scleroderma-related interstitial lung disease (SSc-ILD), and it remains the leading cause of death in scleroderma patients because it can lead to loss of pulmonary function. Nintedanib appears to slow the progress of SSc-ILD and is the first treatment approved for it, according to a news release from the FDA.
The approval is based on a randomized, double-blind, placebo-controlled trial of 576 patients aged 20-79 years with SSc-ILD. The primary efficacy endpoint was forced vital capacity, and patients on nintedanib showed less decline than did those on placebo.
The most frequent serious adverse event reported in this trial was pneumonia (2.8% with nintedanib vs. 0.3% with placebo). Adverse reactions that led to permanent dose reductions occurred in 34% of nintedanib patients and 4% of placebo-treated patients; the most common of these was diarrhea.
The full prescribing information, which is available on the FDA website, includes warnings for patients with moderate to severe hepatic impairment, elevated liver enzymes, and drug-induced liver injury, as well as those with gastrointestinal disorders. Nintedanib may cause embryo-fetal toxicity, so women of childbearing age should be counseled to avoid pregnancy while taking this drug.
Nintedanib received both Priority Review and Orphan Drug designation. The former meant the FDA intends to take action on the application within 6 months because the agency has determined that, if approved, it would have important effects on treatment of a serious condition. The latter provides incentives to assist and encourage development of drugs for rare diseases. The drug was approved in 2014 for adult patients with idiopathic pulmonary fibrosis, another interstitial lung disease.
The full release is available on the FDA website.
Some HCV medications associated with serious liver injury
Many of the affected patients had signs or symptoms of moderate to severe liver impairment (Child-Pugh class B or C), and given that these medications – glecaprevir/pibrentasvir (Mavyret), elbasvir/grazoprevir (Zepatier), and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) – are not indicated for such patients, they should not have been prescribed in the first place, the FDA noted in the drug safety communication. Some cases had other preexisting risk factors, such as liver cancer, alcohol abuse, or serious medical illnesses associated with liver problems.
In most cases, impairment or decompensation occurred within the first 4 weeks of starting treatment, and symptoms resolved or new-onset worsening of liver function improved after stopping. These medicines have been widely used and, among patients with no or mild liver impairment, have been shown to be safe and effective.
Health care professionals should continue prescribing these medicines as indicated; they should assess patients at baseline for severity of liver disease and other risk factors and closely monitor these patients after for signs and symptoms of worsening liver function. Patients should be aware that the risk of injury is rare and continue taking prescribed medicines; if they develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, they should talk with their health care professional but should continue taking the medications in question until instructed to do otherwise.
The full communication is available on the FDA website and includes more facts about these drugs and information for patients and health care professionals.
Many of the affected patients had signs or symptoms of moderate to severe liver impairment (Child-Pugh class B or C), and given that these medications – glecaprevir/pibrentasvir (Mavyret), elbasvir/grazoprevir (Zepatier), and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) – are not indicated for such patients, they should not have been prescribed in the first place, the FDA noted in the drug safety communication. Some cases had other preexisting risk factors, such as liver cancer, alcohol abuse, or serious medical illnesses associated with liver problems.
In most cases, impairment or decompensation occurred within the first 4 weeks of starting treatment, and symptoms resolved or new-onset worsening of liver function improved after stopping. These medicines have been widely used and, among patients with no or mild liver impairment, have been shown to be safe and effective.
Health care professionals should continue prescribing these medicines as indicated; they should assess patients at baseline for severity of liver disease and other risk factors and closely monitor these patients after for signs and symptoms of worsening liver function. Patients should be aware that the risk of injury is rare and continue taking prescribed medicines; if they develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, they should talk with their health care professional but should continue taking the medications in question until instructed to do otherwise.
The full communication is available on the FDA website and includes more facts about these drugs and information for patients and health care professionals.
Many of the affected patients had signs or symptoms of moderate to severe liver impairment (Child-Pugh class B or C), and given that these medications – glecaprevir/pibrentasvir (Mavyret), elbasvir/grazoprevir (Zepatier), and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) – are not indicated for such patients, they should not have been prescribed in the first place, the FDA noted in the drug safety communication. Some cases had other preexisting risk factors, such as liver cancer, alcohol abuse, or serious medical illnesses associated with liver problems.
In most cases, impairment or decompensation occurred within the first 4 weeks of starting treatment, and symptoms resolved or new-onset worsening of liver function improved after stopping. These medicines have been widely used and, among patients with no or mild liver impairment, have been shown to be safe and effective.
Health care professionals should continue prescribing these medicines as indicated; they should assess patients at baseline for severity of liver disease and other risk factors and closely monitor these patients after for signs and symptoms of worsening liver function. Patients should be aware that the risk of injury is rare and continue taking prescribed medicines; if they develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, they should talk with their health care professional but should continue taking the medications in question until instructed to do otherwise.
The full communication is available on the FDA website and includes more facts about these drugs and information for patients and health care professionals.
Farxiga gets Fast Track status from FDA
The Food and Drug Administration has given Fast Track designation to the development of dapagliflozin (Farxiga) to delay progression of renal failure and to prevent cardiovascular and renal death in patients with chronic kidney disease with and without type 2 diabetes, according to a release from AstraZeneca.
The Fast Track designation is meant to accelerate the development and review process for the treatment of serious conditions that have unmet therapeutic needs.
Dapagliflozin, an oral daily sodium-glucose transporter 2 inhibitor, is approved both as a monotherapy and a component of combination therapy for the improvement of glycemic control in patients with type 2 diabetes, according to the release. It is given as an adjunct to diet and exercise, and has also shown additional benefits of weight loss and reduction in blood pressure.
A phase 3, randomized, placebo-controlled trial, DAPA-CVD (NCT03036150), is currently underway to evaluate the drug’s efficacy specifically in terms of renal outcomes and cardiovascular mortality in patients with chronic kidney disease, with and without type 2 diabetes. Participants receive once-daily dapagliflozin or placebo in addition to standard care.
Taking dapagliflozin carries risks of hypotension, renal impairment, hypoglycemia, and other concerns. The most common adverse reactions (5% or greater incidence) include female genital mycotic infections, nasopharyngitis, and urinary tract infections. Full prescribing information can be found on the agency’s website.
The Food and Drug Administration has given Fast Track designation to the development of dapagliflozin (Farxiga) to delay progression of renal failure and to prevent cardiovascular and renal death in patients with chronic kidney disease with and without type 2 diabetes, according to a release from AstraZeneca.
The Fast Track designation is meant to accelerate the development and review process for the treatment of serious conditions that have unmet therapeutic needs.
Dapagliflozin, an oral daily sodium-glucose transporter 2 inhibitor, is approved both as a monotherapy and a component of combination therapy for the improvement of glycemic control in patients with type 2 diabetes, according to the release. It is given as an adjunct to diet and exercise, and has also shown additional benefits of weight loss and reduction in blood pressure.
A phase 3, randomized, placebo-controlled trial, DAPA-CVD (NCT03036150), is currently underway to evaluate the drug’s efficacy specifically in terms of renal outcomes and cardiovascular mortality in patients with chronic kidney disease, with and without type 2 diabetes. Participants receive once-daily dapagliflozin or placebo in addition to standard care.
Taking dapagliflozin carries risks of hypotension, renal impairment, hypoglycemia, and other concerns. The most common adverse reactions (5% or greater incidence) include female genital mycotic infections, nasopharyngitis, and urinary tract infections. Full prescribing information can be found on the agency’s website.
The Food and Drug Administration has given Fast Track designation to the development of dapagliflozin (Farxiga) to delay progression of renal failure and to prevent cardiovascular and renal death in patients with chronic kidney disease with and without type 2 diabetes, according to a release from AstraZeneca.
The Fast Track designation is meant to accelerate the development and review process for the treatment of serious conditions that have unmet therapeutic needs.
Dapagliflozin, an oral daily sodium-glucose transporter 2 inhibitor, is approved both as a monotherapy and a component of combination therapy for the improvement of glycemic control in patients with type 2 diabetes, according to the release. It is given as an adjunct to diet and exercise, and has also shown additional benefits of weight loss and reduction in blood pressure.
A phase 3, randomized, placebo-controlled trial, DAPA-CVD (NCT03036150), is currently underway to evaluate the drug’s efficacy specifically in terms of renal outcomes and cardiovascular mortality in patients with chronic kidney disease, with and without type 2 diabetes. Participants receive once-daily dapagliflozin or placebo in addition to standard care.
Taking dapagliflozin carries risks of hypotension, renal impairment, hypoglycemia, and other concerns. The most common adverse reactions (5% or greater incidence) include female genital mycotic infections, nasopharyngitis, and urinary tract infections. Full prescribing information can be found on the agency’s website.
Calquence earns breakthrough designation for CLL monotherapy
The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.
The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.
Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.
Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.
The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.
The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.
Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.
Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.
The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.
The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.
Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.
Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.
FDA’s low-risk TAVR okay set to propel case volume
With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.
But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.
The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.
“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.
The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.
For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.
Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.
How will low-risk TAVR affect lower-volume sites?
More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.
“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.
One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.
Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.
“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.
In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.
“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.
“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”
Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”
Who still gets SAVR?
Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.
“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.
“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.
A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”
Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.
Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.
As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.
“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.
“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”
Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”
What now?
Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?
In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.
Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.
With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.
But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.
The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.
“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.
The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.
For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.
Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.
How will low-risk TAVR affect lower-volume sites?
More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.
“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.
One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.
Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.
“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.
In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.
“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.
“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”
Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”
Who still gets SAVR?
Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.
“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.
“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.
A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”
Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.
Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.
As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.
“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.
“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”
Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”
What now?
Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?
In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.
Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.
With the Food and Drug Administration’s approval of two different pairs of transcatheter aortic valve replacement systems for patients at low surgical risk, U.S. case volume for the procedure should markedly rise given that patients at low surgical risk form the largest risk subgroup among patients with aortic stenosis severe enough to warrant valve replacement.
But even as transcatheter aortic valve replacement (TAVR) now becomes the predominant approach for fixing severely stenotic aortic valves regardless of a patient’s risk level, the procedure remains less optimal than surgical aortic valve replacement (SAVR) in selected patients, putting an onus on clinicians to identify and alert patients for whom the transcatheter approach is questionable.
The anticipated surge in TAVR cases for low-risk patients after the FDA’s Aug. 16, 2019, decision will also likely lead to more hospitals offering TAVR. That development will test whether recently enacted rules from the Centers for Medicare & Medicaid Services on procedure-volume minimums for TAVR programs – at least 20 cases a year (or 40 within 2 years) at centers that also perform at least 300 percutaneous coronary interventions annually – lead to outcomes at lower-volume centers that come reasonably close to the outcomes at higher-volume programs for low-risk patients.
“The paradigm has definitely shifted from SAVR as the gold standard to TAVR as the primary treatment for aortic stenosis. This opens TAVR to the vast majority of patients with aortic stenosis,” roughly three-quarters of patients with aortic valve stenosis severe enough to need valve replacement, said Joseph C. Cleveland Jr., MD, a cardiothoracic surgeon and professor of surgery at the University of Colorado at Denver, Aurora.
The actual, immediate increase in TAVR patients may not be quite as large as this fraction suggests. That’s in part because many patients in the low-risk category based on their surgical risk score already have been judged to have higher-risk features by heart-valve teams that has allowed such patients to undergo TAVR, said John D. Carroll, MD, professor of medicine and director of interventional cardiology at the University of Colorado.
For several years, U.S. rates of TAVR have exceeded SAVR, he noted, and in 2018 U.S. programs performed roughly 58,000 TAVR procedures and about 25,000 SAVRs, according to data collected by the Transcatheter Valve Therapy (TVT) Registry run by the Society of Thoracic Surgeons and the American College of Cardiology. Dr. Carroll is vice chair of the steering committee for this registry, which was mandated by the FDA in 2011 when the agency first allowed TAVR onto the U.S. market and is designed to capture every TAVR case performed in routine U.S. practice.
Despite this caveat, “there will be substantial growth in TAVR. Going forward, there will be more of a shift from SAVR to TAVR. That is what the results of the low-risk trials did,” Dr. Carroll predicted. In addition, the coming growth in TAVR numbers will stem from more than just low-risk patients whom a month ago would have undergone SAVR but now undergo TAVR instead. The availability of TAVR as an option for a wider range of patients should help boost public awareness that a nonsurgical way exists to treat severe aortic stenosis, plus the aging of baby boomers is on the verge of generating a substantial wave of new patients, a wave so high that Dr. Carroll called it a looming “tsunami” of patients needing TAVR.
How will low-risk TAVR affect lower-volume sites?
More TAVR patients will inevitably mean more U.S. sites offering the procedure, experts agreed. “We anticipate more low-volume programs,” Dr. Carroll said.
“Approval of TAVR for low-risk patients will result in a significant increase in the number of programs offering it. Approximately 1,100 U.S. programs offer SAVR, and as of now about 600 of these programs also offer TAVR. Health systems face the risk of losing patients if they don’t offer TAVR now that low-risk patients can be treated,” observed Sreekanth Vemulapalli, MD, a cardiologist at Duke University, Durham, N.C. who has run several studies using TVT Registry data and serves as liaison between the registry and its analytic center at Duke.
One of these studies, published earlier in 2019, showed that, among more than 96,000 registry patients who underwent transfemoral TAVR during 2015-2017 at 554 U.S. centers, those treated at sites that fell into the bottom quartile for case volume had an adjusted 30-day mortality rate that was 21% higher relative to patients treated at centers in the top quartile, a statistically significant difference (N Engl J Med. 2019 Jun 27;380[26]:2541-50). The absolute difference in adjusted 30-day mortality between the lowest and highest quartiles was 0.54%, roughly 1 additional death for every 200 patients. The TAVR centers in the lowest-volume quartile performed 5-36 cases/year, averaging 27 TAVRs/year; those in the highest quartile performed 86-371 TAVRs annually with an overall quartile average of 143 procedures/year.
Dr. Vemulapalli and others cautioned that TAVR case volume is currently serving as a surrogate, and imperfect, marker for program quality until TAVR programs generate enough data to allow a directly measured, risk-adjusted, outcome-driven assessment of performance. In the study he and his associates published in June, the 140 TAVR programs in the lowest-volume quartile showed a “high” level of variability in their adjusted mortality rates. Despite this limitation, the prospect that new TAVR programs will soon open to meet growing TAVR demand from low-risk patients poses the question of how these programs will perform during their start-up days (and possibly beyond), when case volumes may be light, especially if sites open in more remote sections of the United States.
“Will the real-world results of TAVR in low-risk patients match the fantastic results in the two low-risk TAVR trials?” wondered Dr. Carroll, referring to the PARTNER 3 (N Engl J Med. 2019 May 2;380[18]:1695-1705) and Evolut Low-Risk Patients trial (N Engl J Med. 2019 May 2;380[18]:1706-15). “It’s unknown whether a site just starting to do TAVRs will get the same results. The sites that participated in the low-risk trials were mostly high-volume sites.” On the other hand, TVT Registry data have shown that patients with surgical risk that was judged prohibitive, high, or intermediate all have had overall real-world outcomes that match what was seen in the relevant TAVR trials.
In addition, some experts view a modest drop in 30-day survival among patients treated at lower-volume TAVR sites as a reasonable trade-off for easier access for patients seeking this life-changing treatment.
“We need to ensure that patients have access to this treatment option,” said Catherine M. Otto, MD, professor of medicine and director of the Heart Valve Clinic at the University of Washington, Seattle. The potentially better outcomes produced at larger TAVR programs “need to be balanced against having a greater number of programs to ensure access for more patients and allow patients to be treated closer to home,” she said in an interview. She suggested that the potential exists to use telemedicine to link larger and more experienced TAVR programs with smaller and newer programs to help boost their performance.
“There is no perfect solution or metric to ensure high quality while also allowing for adequate access. As indications for TAVR expand we need to maintain vigilance and accountability as the therapy is dispersed to more patients at more centers,” said Brian R. Lindman, MD, medical director of the Structural Heat and Valve Center at Vanderbilt University, Nashville, Tenn. “We also need to insure that certain groups of patients have adequate access to this therapy. Adequate access to TAVR and high-quality clinical outcomes are both important goals.”
Plus, “the volume relationship may be less important,” in lower-risk patients, suggested Dr. Cleveland in an interview. Low-risk patients are younger and have fewer comorbidities and less vascular disease. “Low-volume centers should be able to treat these patients,” he said. Despite that, he personally supported the higher volume minimum for TAVR of 50 cases/year that the ACC, STS, and other U.S. professional societies recommended to CMS during public comment on the proposed rules. “We’ll see whether the increased access is worth this volume minimum.”
Who still gets SAVR?
Given the inherent attraction TAVR holds over SAVR for patients, heart-valve teams will need to convey the right message to patients who may be better served with surgical replacement despite the added trauma and recovery time it produces.
“The decision to perform TAVR or SAVR should now be based on a patient’s expected longevity as well as patient preferences and values, and not on the patient’s estimated surgical risk, except for the highest-risk patients in whom TAVR is recommended,” said Dr. Otto. A patient’s age, comorbidities, and overall life expectancy now move to center stage when deciding the TAVR or SAVR question, along with individual anatomic considerations, the possible need for concurrent procedures, and of course what the patient prefers including their willingness and ability to remain on lifelong anticoagulation if they receive a durable mechanical valve. Dr. Otto outlined this new landscape of the heart-valve team’s decision making process in an editorial she recently published (N Engl J Med. 2019 May 2;380[18]: 1769-70) that accompanied publication of PARTNER 3 and the Evolut Low-Risk Patients trial.
“For some patients there will be clear benefit from one approach, but for many patients, particularly those at low surgical risk, both TAVR and SAVR are technically feasible. For these patients it’s essential that the heart-valve team provide unbiased information to guide patients,” Dr. Otto said. The ideal person to provide this unbiased presentation of the pros and cons would be a cardiologist experienced with valve disease but not actively involved in performing valve-replacement procedures.
A big issue younger patients must confront is what remains unknown about long-term durability of TAVR valves. Dr. Otto called this “the most important missing piece of information. We only have robust data out to about 5 years. If TAVR valve will be durable for 15-20 years, then TAVR will become preferred even in younger patients.”
Even after TAVR became available to intermediate-risk patients in 2016, the median age of U.S. patients undergoing TAVR hardly budged, and has recently stood at about 81 years, Dr. Carroll noted. “With low-risk patients, we expect to see this change,” as more patients now who are in their 70s, 60s, and younger start to routinely undergo TAVR. As more younger patients with life expectancies on the order of 30 years consider TAVR, issues of valve durability “enter the discussion,” he said. “We need data to 10, 15 years,” and in its low-risk approval the FDA mandated manufacturers to follow these patients for at least 10 years. Although valve-in-valve replacement of failed TAVR valves is an option, it’s not always a smooth fix with the potential for prosthesis-patient mismatch (J Am Coll Cardiol. 2018 Dec 4;72[22]:2701-11) and resulting hemodynamic problems, Dr. Carroll said.
Bicuspid-valve replacement with TAVR is another big unknown, largely because these patients were excluded from the TAVR trials. A recently published analysis of the 2,726 patients with a bicuspid aortic valve who underwent TAVR anyway in routine U.S. practice between June 2015 and November 2018 and were in the TVT Registry (about 3% of all TAVR patients during this period) showed that these patients had similar mortality, compared with the tricuspid-valve patients, but a significantly increased stroke rate (JAMA. 2019 Jun 11;321[22]:2193-202). The authors concluded that a prospective, randomized study of TAVR, compared with SAVR, is needed for these patients, and many others in the field agree.
As availability of TAVR grows and public awareness increases, heart-valve teams may find it challenging sometimes to help patients understand the upsides of SAVR for their individual clinical needs when TAVR is superficially so much more attractive.
“The desire to avoid the prolonged hospitalization and recovery from SAVR is a huge driver of patient preference,” noted Dr. Carroll.
“It’s hard to tell a 55 year old to think about another procedure they may need when they are 65 or 70 if they undergo TAVR now rather than SAVR. They don’t want open-heart surgery; I hear that all the time,” Dr. Cleveland said. “If I were a 55-year-old aortic valve patient I’d strongly consider TAVR, too.”
Financial consideration at the site performing the interventions can also be a factor. “Differential costs and payments associated with SAVR and TAVR create different financial incentives for health systems between these two procedures,” noted Dr. Vemulapalli. “There likely needs to be a system that creates equal incentives to do SAVR or TAVR so that the decision between them can come down to just the patient and heart-valve team. We need further data and decision aids to help better define which patients will likely do better with SAVR and which with TAVR.”
What now?
Since the first large TAVR trials started in 2007, their main thrust has been to prove the efficacy and safety of TAVR in patients at sequentially less risk of undergoing SAVR. Now that this series of comparisons has ended, where will TAVR research turn its attention?
In addition to the big outstanding issues of TAVR-valve long-term durability, and the efficacy and safety of TAVR for replacing bicuspid valves, other big questions and issues loom. They include the optimal anticoagulant regimen for preventing leaflet thrombosis, reducing the need for pacemakers, reducing strokes, the applicability of TAVR to patients with less severe aortic stenosis, the impact of treating severe but asymptomatic aortic valve obstruction, optimizing valve-in-valve outcomes, and further improvements to valve design, hemodynamics, and delivery. In short, the question of TAVR’s suitability for patients regardless of their surgical risk may have now been answered, but many questions remain about the best way to use and to optimize this technology.
Dr. Cleveland and Dr. Carroll have participated in TAVR trials but had no personal financial disclosures. Dr. Otto had no disclosures. Dr. Vemulapalli has received personal fees from Janssen, Novella, Premiere, and Zafgen, and research funding from Boston Scientific and Abbott Vascular. Dr. Lindman has been a consultant to Medtronic, has served as an advisor to Roche, and has received research funding from Edwards Lifesciences.