Mitchel L. Zoler, PhD

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration’s Arthritis Advisory Committee, together with an added complement of dermatologists and gastroenterologists, unanimously recommended during meetings on July 12 and 13 that the agency license a biosimilar Humira (adalimumab) that is made by Amgen and a biosimilar Enbrel (etanercept) that is made by Sandoz for many of the same indications held by the reference drugs.

The FDA advisory panel that endorsed biosimilar Humira recommended the agent’s approval in a 26-0 vote for many, but not all of the indications currently assigned to Humira itself: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis in patients at least 4 years old, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

A slightly different group of 20 advisory panel members (without any gastroenterologists) voted 20-0 in favor of the FDA granting biosimilar Enbrel all five of the indications now held by Enbrel: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and plaque psoriasis.

The biosimilar Humira and the biosimilar Enbrel are, respectively, the third and fourth candidate biosimilars to emerge from the FDA’s development program and receive advisory committee scrutiny and support. The first agent through the process, biosimilar filgrastim (Zarxio) received FDA approval in 2015 and is available in the United States. Although the second biosimilar through the process, the tumor necrosis factor inhibitor Inflectra that is biosimilar Remicade (infliximab), received FDA approval in April of this year, it has not yet become available for sale, although a spokeswoman for the company that will market it, Pfizer, said that the company expects to start U.S. sales of Inflectra before the end of 2016.

While the Arthritis Advisory Committee ended each of its daylong deliberations for each of the two candidate biosimilars with unanimous support, the panelists’ discussions among themselves and with FDA staffers reflected some uncertainty with the biosimilar concept, especially during the first day when they focused on biosimilar Humira. The major sticking point revolved around the regulatory pathway to approval first established by the Biologics Price Competition and Innovation Act of 2009 and subsequently refined by the FDA that allows a candidate biosimilar to establish its biosimilarity primarily though the results of analytical studies that establish that the candidate molecule is highly similar to the reference molecule. This approval scheme uses clinical trials in a confirmatory role to establish biosimilarity rather than as the linchpin of approval.

It also means that the FDA can grant clinical indications to the biosimilar drug based not on the results from clinical trials, but based entirely on what have already been demonstrated as safe and effective clinical applications for the reference drug. For example, the biosimilar Humira underwent testing in two clinical studies showing similar efficacy and safety as Humira in patients with rheumatoid arthritis and in patients with plaque psoriasis, but received endorsements based on extrapolations for an additional five indications. Biosimilar Enbrel was compared with Enbrel in patients with plaque psoriasis only and still received extrapolated indications for the additional four rheumatologic conditions.

“This is a new level of extrapolation, across indications,” noted Sarah E. Streett, MD, a gastroenterologist at Stanford (Calif.) University, one of several panelists who initially voiced uncertainty about the concept.

But FDA staffer Nikolay P. Nikolov, MD, who led the agency’s presentation, assured the panelists that the concept of extrapolation was at the heart of biosimilar development and regulatory assessment.

“We have confidence from the data that the two molecules [the reference drug and biosimilar drug] are so similar that we can rely on the safety and efficacy of the reference product. The premise of our approach to biosimilars is that this is not a new molecule that we know nothing about.”

The other uncertainty about biosimilar Humira and biosimilar Enbrel that raised concerns of many panelists were the prospects for nonmedical switching once these drugs reach the market. Nonmedical switching refers to when an insurance company or pharmacy benefit manager substitutes a biosimilar for a reference drug without approval from or even the knowledge of the prescribing physician or the patient. Many of the people who spoke during the public forum period on both days of hearings voiced their concerns about this prospect.

“Nonmedical switching is a major concern of clinicians and policy makers, and we need greater clarification from the FDA,” said committee chair Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.

“I see a remarkable disconnect between the public’s concerns [about nonmedical switching] and the charge to the committee. These are essential issues that need a forum to be aired out,” said panelist Steven F. Solga, MD, chief of gastroenterology at St. Luke’s Hospital in Bethlehem, Pa.

Dr. Nikolov assured committee members that the FDA recognized this concern and was working on it. “We appreciate the disconnect between the charge and the concerns of the community. I assure you that the issues brought up will be part of our discussions so we can get this [biosimilar pathway] implemented the right way.”

According to the FDA’s regulations, a biosimilar designation does not allow for nonmedical switching, something that could only happen under a related but distinct designation known as interchangeability. During the committee meeting on July 13, a FDA staffer said that the agency is currently developing guidance for an “interchangeable” designation and plans to have it available before then end of 2016.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

In a 26-0 vote, the Food and Drug Administration’s arthritis advisory committee recommended July 12 that the agency license an Amgen product as biosimilar to Humira (adalimumab) for seven distinct indications: rheumatoid arthritis, juvenile idiopathic arthritis (in patients at least 4 years old), psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, adult Crohn’s disease, and adult ulcerative colitis.

Developing Story

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.

This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.

Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.

NSAIDs

The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).

“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.

Metformin

Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m². The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.

Antihypertensives, biologics, and more

Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.

The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.

Managing myriad meds

The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.

“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”

Dr. Page had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

When a Food and Drug Administration advisory committee met on June 28 to consider a new indication for the type 2 diabetes drug empagliflozin – reduction of cardiovascular mortality in patients with type 2 diabetes with existing cardiovascular disease or at high risk for cardiovascular disease – an inevitable question was, How will this matter to empagliflozin?

Empagliflozin (Jardiance) received FDA approval in 2014 for treating patients with type 2 diabetes. In 2015, an unexpected result from the EMPA-REG OUTCOME trial showed that treatment of such high-risk diabetes patients with empagliflozin led to a dramatic and still unexplained 38% relative risk reduction in cardiovascular disease (CVD) death, compared with placebo (a 2.2% absolute risk reduction) during a median 2.6 years of treatment and 3.1 years of total follow-up. This surprising result from a trial designed to test empagliflozin’s CVD safety but not its preventive efficacy first went public in a report at the European Association for the Study of Diabetes annual meeting in Stockholm in September 2015 and in a simultaneously published article (N Engl J Med. 2015;373:2117-28).

So the drug is already on the U.S. market, and its remarkable effect on CVD mortality in a selected population is already on record. Will translating this into a FDA-approved indication mean anything more?

The short answer is it probably will, especially for persuading health insurance payers to cover the substantial cost for prescribing empagliflozin. The other end an added FDA indication achieves is objective confirmation that the CVD mortality benefit seen in the EMPA-REG OUTCOME trial was real and could be anticipated in routine practice.

Some clinicians have already concluded this was a believable result, and that it gives empagliflozin an edge above other oral hypoglycemic drugs for patients who match the study’s enrollment criteria.

“Based on available evidence, the sodium-glucose cotransporter-2 inhibitors [the class that includes empagliflozin] are the preferred therapy for patients with type 2 diabetes and CVD or at high risk for CVD in patients treated with metformin or where metformin is not tolerated. It also should be given preference in patients with or at risk for heart failure,” Gregg C. Fonarow, MD, professor and associate chief of cardiology at the University of California, Los Angeles, said in an interview.

“I am using [empagliflozin] in addition to metformin and aggressive lifestyle changes in patients with established CVD and uncontrolled type 2 diabetes,” said another cardiologist, Alison L. Bailey, MD.

But Dr. Bailey also highlighted her concern about the extra cost to patients for empagliflozin, especially if their insurer wouldn’t pay for it.

“Metformin should be the first step based on it’s documented efficacy and cost. I would then add empagliflozin to most of my patients who can get the drug without financial burden,” she told me in an interview.

If an insurer balks at paying for empagliflozin, or if the patient has little or no drug insurance, the financial burden could be substantial. The cost of a month on empagliflozin at the dosage used in the EMPA-REG OUTCOME study is about $415 from one web-based drug supplier, compared with a monthly price of about $6 for a typical monthly regimen of generic metformin. Over the course of a year, that’s about $5,000, compared with $72.

Empagliflozin is “an expensive drug with limited experience,” commented Prakash Deedwania, MD, a cardiologist at the University of California, San Francisco, in Fresno. Metformin, the current linchpin oral agent for treating most patients with type 2 diabetes, has the advantages of low cost and a large, worldwide track record of efficacy and safety, he added.

An FDA indication for reducing cardiovascular disease mortality in selected patients with type 2 diabetes would set empagliflozin apart as the only oral hypoglycemic drug recognized to have this activity and might help grease the wheels for reimbursement.

“Patients can only get the medications their insurance covers. I have a feeling that this indication might help drive coverage,” commented Abraham Thomas, MD, an endocrinologist at New York University, when explaining his vote in favor of the new indication as a member of the FDA advisory committee.

Mitchel L. Zoler/Frontline Medical News

The other consequence from a positive FDA decision would be a strong statement of confidence that the EMPA-REG OUTCOME result is real. Clearly not everyone on the advisory panel was convinced. The panel’s vote split 12 in favor of the FDA granting the indication and 11 votes against, and many panelists said they found it very hard to balance the powerful result on the one hand against the inexplicable mechanism of the effect and the fact that the mortality benefit came from left field, without prespecification in the study’s design. Now it’s on the FDA’s shoulders to make a decision after parsing the vote, the panelists’ comments, the data, and concerns.

“An FDA-approved indication for reduction in cardiovascular death would be influential with physicians and patients,” predicted Dr. Fonarow.

A FDA imprimatur on the cardiovascular mortality benefit would help buttress belief in the EMPA-REG OUTCOME result and might help drive better reimbursement coverage. A thumbs down will likely dampen enthusiasm in and practicality of the treatment until additional, corroborative data appear.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

When a Food and Drug Administration advisory committee met on June 28 to consider a new indication for the type 2 diabetes drug empagliflozin – reduction of cardiovascular mortality in patients with type 2 diabetes with existing cardiovascular disease or at high risk for cardiovascular disease – an inevitable question was, How will this matter to empagliflozin?

Empagliflozin (Jardiance) received FDA approval in 2014 for treating patients with type 2 diabetes. In 2015, an unexpected result from the EMPA-REG OUTCOME trial showed that treatment of such high-risk diabetes patients with empagliflozin led to a dramatic and still unexplained 38% relative risk reduction in cardiovascular disease (CVD) death, compared with placebo (a 2.2% absolute risk reduction) during a median 2.6 years of treatment and 3.1 years of total follow-up. This surprising result from a trial designed to test empagliflozin’s CVD safety but not its preventive efficacy first went public in a report at the European Association for the Study of Diabetes annual meeting in Stockholm in September 2015 and in a simultaneously published article (N Engl J Med. 2015;373:2117-28).

So the drug is already on the U.S. market, and its remarkable effect on CVD mortality in a selected population is already on record. Will translating this into a FDA-approved indication mean anything more?

The short answer is it probably will, especially for persuading health insurance payers to cover the substantial cost for prescribing empagliflozin. The other end an added FDA indication achieves is objective confirmation that the CVD mortality benefit seen in the EMPA-REG OUTCOME trial was real and could be anticipated in routine practice.

Some clinicians have already concluded this was a believable result, and that it gives empagliflozin an edge above other oral hypoglycemic drugs for patients who match the study’s enrollment criteria.

“Based on available evidence, the sodium-glucose cotransporter-2 inhibitors [the class that includes empagliflozin] are the preferred therapy for patients with type 2 diabetes and CVD or at high risk for CVD in patients treated with metformin or where metformin is not tolerated. It also should be given preference in patients with or at risk for heart failure,” Gregg C. Fonarow, MD, professor and associate chief of cardiology at the University of California, Los Angeles, said in an interview.

“I am using [empagliflozin] in addition to metformin and aggressive lifestyle changes in patients with established CVD and uncontrolled type 2 diabetes,” said another cardiologist, Alison L. Bailey, MD.

But Dr. Bailey also highlighted her concern about the extra cost to patients for empagliflozin, especially if their insurer wouldn’t pay for it.

“Metformin should be the first step based on it’s documented efficacy and cost. I would then add empagliflozin to most of my patients who can get the drug without financial burden,” she told me in an interview.

If an insurer balks at paying for empagliflozin, or if the patient has little or no drug insurance, the financial burden could be substantial. The cost of a month on empagliflozin at the dosage used in the EMPA-REG OUTCOME study is about $415 from one web-based drug supplier, compared with a monthly price of about $6 for a typical monthly regimen of generic metformin. Over the course of a year, that’s about $5,000, compared with $72.

Empagliflozin is “an expensive drug with limited experience,” commented Prakash Deedwania, MD, a cardiologist at the University of California, San Francisco, in Fresno. Metformin, the current linchpin oral agent for treating most patients with type 2 diabetes, has the advantages of low cost and a large, worldwide track record of efficacy and safety, he added.

An FDA indication for reducing cardiovascular disease mortality in selected patients with type 2 diabetes would set empagliflozin apart as the only oral hypoglycemic drug recognized to have this activity and might help grease the wheels for reimbursement.

“Patients can only get the medications their insurance covers. I have a feeling that this indication might help drive coverage,” commented Abraham Thomas, MD, an endocrinologist at New York University, when explaining his vote in favor of the new indication as a member of the FDA advisory committee.

Mitchel L. Zoler/Frontline Medical News

The other consequence from a positive FDA decision would be a strong statement of confidence that the EMPA-REG OUTCOME result is real. Clearly not everyone on the advisory panel was convinced. The panel’s vote split 12 in favor of the FDA granting the indication and 11 votes against, and many panelists said they found it very hard to balance the powerful result on the one hand against the inexplicable mechanism of the effect and the fact that the mortality benefit came from left field, without prespecification in the study’s design. Now it’s on the FDA’s shoulders to make a decision after parsing the vote, the panelists’ comments, the data, and concerns.

“An FDA-approved indication for reduction in cardiovascular death would be influential with physicians and patients,” predicted Dr. Fonarow.

A FDA imprimatur on the cardiovascular mortality benefit would help buttress belief in the EMPA-REG OUTCOME result and might help drive better reimbursement coverage. A thumbs down will likely dampen enthusiasm in and practicality of the treatment until additional, corroborative data appear.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

When a Food and Drug Administration advisory committee met on June 28 to consider a new indication for the type 2 diabetes drug empagliflozin – reduction of cardiovascular mortality in patients with type 2 diabetes with existing cardiovascular disease or at high risk for cardiovascular disease – an inevitable question was, How will this matter to empagliflozin?

Empagliflozin (Jardiance) received FDA approval in 2014 for treating patients with type 2 diabetes. In 2015, an unexpected result from the EMPA-REG OUTCOME trial showed that treatment of such high-risk diabetes patients with empagliflozin led to a dramatic and still unexplained 38% relative risk reduction in cardiovascular disease (CVD) death, compared with placebo (a 2.2% absolute risk reduction) during a median 2.6 years of treatment and 3.1 years of total follow-up. This surprising result from a trial designed to test empagliflozin’s CVD safety but not its preventive efficacy first went public in a report at the European Association for the Study of Diabetes annual meeting in Stockholm in September 2015 and in a simultaneously published article (N Engl J Med. 2015;373:2117-28).

So the drug is already on the U.S. market, and its remarkable effect on CVD mortality in a selected population is already on record. Will translating this into a FDA-approved indication mean anything more?

The short answer is it probably will, especially for persuading health insurance payers to cover the substantial cost for prescribing empagliflozin. The other end an added FDA indication achieves is objective confirmation that the CVD mortality benefit seen in the EMPA-REG OUTCOME trial was real and could be anticipated in routine practice.

Some clinicians have already concluded this was a believable result, and that it gives empagliflozin an edge above other oral hypoglycemic drugs for patients who match the study’s enrollment criteria.

“Based on available evidence, the sodium-glucose cotransporter-2 inhibitors [the class that includes empagliflozin] are the preferred therapy for patients with type 2 diabetes and CVD or at high risk for CVD in patients treated with metformin or where metformin is not tolerated. It also should be given preference in patients with or at risk for heart failure,” Gregg C. Fonarow, MD, professor and associate chief of cardiology at the University of California, Los Angeles, said in an interview.

“I am using [empagliflozin] in addition to metformin and aggressive lifestyle changes in patients with established CVD and uncontrolled type 2 diabetes,” said another cardiologist, Alison L. Bailey, MD.

But Dr. Bailey also highlighted her concern about the extra cost to patients for empagliflozin, especially if their insurer wouldn’t pay for it.

“Metformin should be the first step based on it’s documented efficacy and cost. I would then add empagliflozin to most of my patients who can get the drug without financial burden,” she told me in an interview.

If an insurer balks at paying for empagliflozin, or if the patient has little or no drug insurance, the financial burden could be substantial. The cost of a month on empagliflozin at the dosage used in the EMPA-REG OUTCOME study is about $415 from one web-based drug supplier, compared with a monthly price of about $6 for a typical monthly regimen of generic metformin. Over the course of a year, that’s about $5,000, compared with $72.

Empagliflozin is “an expensive drug with limited experience,” commented Prakash Deedwania, MD, a cardiologist at the University of California, San Francisco, in Fresno. Metformin, the current linchpin oral agent for treating most patients with type 2 diabetes, has the advantages of low cost and a large, worldwide track record of efficacy and safety, he added.

An FDA indication for reducing cardiovascular disease mortality in selected patients with type 2 diabetes would set empagliflozin apart as the only oral hypoglycemic drug recognized to have this activity and might help grease the wheels for reimbursement.

“Patients can only get the medications their insurance covers. I have a feeling that this indication might help drive coverage,” commented Abraham Thomas, MD, an endocrinologist at New York University, when explaining his vote in favor of the new indication as a member of the FDA advisory committee.

Mitchel L. Zoler/Frontline Medical News

The other consequence from a positive FDA decision would be a strong statement of confidence that the EMPA-REG OUTCOME result is real. Clearly not everyone on the advisory panel was convinced. The panel’s vote split 12 in favor of the FDA granting the indication and 11 votes against, and many panelists said they found it very hard to balance the powerful result on the one hand against the inexplicable mechanism of the effect and the fact that the mortality benefit came from left field, without prespecification in the study’s design. Now it’s on the FDA’s shoulders to make a decision after parsing the vote, the panelists’ comments, the data, and concerns.

“An FDA-approved indication for reduction in cardiovascular death would be influential with physicians and patients,” predicted Dr. Fonarow.

A FDA imprimatur on the cardiovascular mortality benefit would help buttress belief in the EMPA-REG OUTCOME result and might help drive better reimbursement coverage. A thumbs down will likely dampen enthusiasm in and practicality of the treatment until additional, corroborative data appear.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration approved the first fully absorbable vascular scaffold designed for use in coronary arteries, the Absorb GT1 bioresorbable vascular scaffold system, made by Abbott.

Concurrent with the FDA’s announcement on July 5, the company said that it plans to start immediate commercial rollout of the Absorb bioresorbable vascular scaffold (BVS). Initial availability will be limited to the roughly 100 most active sites that participated in the ABSORB III trial, the pivotal study that established noninferiority of the BVS, compared with a state-of-the-art metallic coronary stent during 1-year follow-up, according to a company spokesman.

However, the ABSORB III results, reported in October 2015, failed to document any superiority of the BVS, compared with a metallic stent. The potential advantages of a BVS remain for now unproven, and are based on the potential long-term advantages of using devices in percutaneous coronary interventions that slowly degrade away and thereby eliminate a residual metallic structure in a patient’s coronaries and the long-term threat they could pose for thrombosis or interference with subsequent coronary procedures.

“All the potential advantages are hypothetical at this point,” said Hiram G. Bezerra, MD, an investigator in the ABSORB III trial and director of the cardiac catheterization laboratory at University Hospitals Case Medical Center in Cleveland. However, “if you have a metallic stent it lasts a lifetime, creating a metallic cage” that could interfere with a possible later coronary procedure or be the site for thrombus formation. Disappearance of the BVS also creates the possibility for eventual restoration of more normal vasomotion in the coronary wall, said Dr. Bezerra, a self-professed “enthusiast” for the BVS alternative.

A major limiting factor for BVS use today is coronary diameter because the Absorb BVS is bulkier than metallic stents. The ABSORB III trial limited use of the BVS to coronary vessels with a reference-vessel diameter by visual assessment of at least 2.5 mm, with an upper limit of 3.75 mm. Other limiting factors can be coronary calcification and tortuosity, although Dr. Bezerra said that these obstacles are usually overcome with a more time-consuming procedure if the operator is committed to placing a BVS.

Another variable will be the cost of the BVS. According to the Abbott spokesman, the device “will be priced so that it will be broadly accessible to hospitals.” Also, the Absorb BVS will receive payer reimbursement comparable to a drug-eluting stent using existing reimbursement codes, the spokesman said. Abbott will require inexperienced operators to take a training course to learn proper placement technique.

Dr. Bezerra admitted that he is probably an outlier in his plan to quickly make the BVS a mainstay of his practice. “I think adoption will be slow in the beginning” for most U.S. operators, he predicted. One of his Cleveland colleagues who spoke about the near-term prospects BVS use last October when the ABSORB III results came out predicted that immediate use might occur in about 10%-15% of patients undergoing percutaneous coronary interventions, similar to the usage level in Europe where this BVS has been available for several years.

Dr. Bezerra has been a consultant to Abbott and St. Jude. He was an investigator on the ABSORB III trial.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration approved the first fully absorbable vascular scaffold designed for use in coronary arteries, the Absorb GT1 bioresorbable vascular scaffold system, made by Abbott.

Concurrent with the FDA’s announcement on July 5, the company said that it plans to start immediate commercial rollout of the Absorb bioresorbable vascular scaffold (BVS). Initial availability will be limited to the roughly 100 most active sites that participated in the ABSORB III trial, the pivotal study that established noninferiority of the BVS, compared with a state-of-the-art metallic coronary stent during 1-year follow-up, according to a company spokesman.

However, the ABSORB III results, reported in October 2015, failed to document any superiority of the BVS, compared with a metallic stent. The potential advantages of a BVS remain for now unproven, and are based on the potential long-term advantages of using devices in percutaneous coronary interventions that slowly degrade away and thereby eliminate a residual metallic structure in a patient’s coronaries and the long-term threat they could pose for thrombosis or interference with subsequent coronary procedures.

“All the potential advantages are hypothetical at this point,” said Hiram G. Bezerra, MD, an investigator in the ABSORB III trial and director of the cardiac catheterization laboratory at University Hospitals Case Medical Center in Cleveland. However, “if you have a metallic stent it lasts a lifetime, creating a metallic cage” that could interfere with a possible later coronary procedure or be the site for thrombus formation. Disappearance of the BVS also creates the possibility for eventual restoration of more normal vasomotion in the coronary wall, said Dr. Bezerra, a self-professed “enthusiast” for the BVS alternative.

A major limiting factor for BVS use today is coronary diameter because the Absorb BVS is bulkier than metallic stents. The ABSORB III trial limited use of the BVS to coronary vessels with a reference-vessel diameter by visual assessment of at least 2.5 mm, with an upper limit of 3.75 mm. Other limiting factors can be coronary calcification and tortuosity, although Dr. Bezerra said that these obstacles are usually overcome with a more time-consuming procedure if the operator is committed to placing a BVS.

Another variable will be the cost of the BVS. According to the Abbott spokesman, the device “will be priced so that it will be broadly accessible to hospitals.” Also, the Absorb BVS will receive payer reimbursement comparable to a drug-eluting stent using existing reimbursement codes, the spokesman said. Abbott will require inexperienced operators to take a training course to learn proper placement technique.

Dr. Bezerra admitted that he is probably an outlier in his plan to quickly make the BVS a mainstay of his practice. “I think adoption will be slow in the beginning” for most U.S. operators, he predicted. One of his Cleveland colleagues who spoke about the near-term prospects BVS use last October when the ABSORB III results came out predicted that immediate use might occur in about 10%-15% of patients undergoing percutaneous coronary interventions, similar to the usage level in Europe where this BVS has been available for several years.

Dr. Bezerra has been a consultant to Abbott and St. Jude. He was an investigator on the ABSORB III trial.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The Food and Drug Administration approved the first fully absorbable vascular scaffold designed for use in coronary arteries, the Absorb GT1 bioresorbable vascular scaffold system, made by Abbott.

Concurrent with the FDA’s announcement on July 5, the company said that it plans to start immediate commercial rollout of the Absorb bioresorbable vascular scaffold (BVS). Initial availability will be limited to the roughly 100 most active sites that participated in the ABSORB III trial, the pivotal study that established noninferiority of the BVS, compared with a state-of-the-art metallic coronary stent during 1-year follow-up, according to a company spokesman.

However, the ABSORB III results, reported in October 2015, failed to document any superiority of the BVS, compared with a metallic stent. The potential advantages of a BVS remain for now unproven, and are based on the potential long-term advantages of using devices in percutaneous coronary interventions that slowly degrade away and thereby eliminate a residual metallic structure in a patient’s coronaries and the long-term threat they could pose for thrombosis or interference with subsequent coronary procedures.

“All the potential advantages are hypothetical at this point,” said Hiram G. Bezerra, MD, an investigator in the ABSORB III trial and director of the cardiac catheterization laboratory at University Hospitals Case Medical Center in Cleveland. However, “if you have a metallic stent it lasts a lifetime, creating a metallic cage” that could interfere with a possible later coronary procedure or be the site for thrombus formation. Disappearance of the BVS also creates the possibility for eventual restoration of more normal vasomotion in the coronary wall, said Dr. Bezerra, a self-professed “enthusiast” for the BVS alternative.

A major limiting factor for BVS use today is coronary diameter because the Absorb BVS is bulkier than metallic stents. The ABSORB III trial limited use of the BVS to coronary vessels with a reference-vessel diameter by visual assessment of at least 2.5 mm, with an upper limit of 3.75 mm. Other limiting factors can be coronary calcification and tortuosity, although Dr. Bezerra said that these obstacles are usually overcome with a more time-consuming procedure if the operator is committed to placing a BVS.

Another variable will be the cost of the BVS. According to the Abbott spokesman, the device “will be priced so that it will be broadly accessible to hospitals.” Also, the Absorb BVS will receive payer reimbursement comparable to a drug-eluting stent using existing reimbursement codes, the spokesman said. Abbott will require inexperienced operators to take a training course to learn proper placement technique.

Dr. Bezerra admitted that he is probably an outlier in his plan to quickly make the BVS a mainstay of his practice. “I think adoption will be slow in the beginning” for most U.S. operators, he predicted. One of his Cleveland colleagues who spoke about the near-term prospects BVS use last October when the ABSORB III results came out predicted that immediate use might occur in about 10%-15% of patients undergoing percutaneous coronary interventions, similar to the usage level in Europe where this BVS has been available for several years.

Dr. Bezerra has been a consultant to Abbott and St. Jude. He was an investigator on the ABSORB III trial.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Now that the interleukin-17 inhibitor secukinumab and tumor necrosis factor inhibitors are competing options for treatment of patients with ankylosing spondylitis, the companies that make those drugs must feel pressure to find some sort of advantage for their agents.

How else to explain the remarkable pair of similar post hoc analyses presented in June at the European Congress of Rheumatology in London? One of the analyses was funded by Novartis – the company that markets secukinumab (Cosentyx) – and included several Novartis employees as coauthors. The second study, presented immediately afterward in the main session at the meeting devoted to ankylosing spondylitis (AS) treatments, had backing from AbbVie, which markets adalimumab (Humira), the largest-selling tumor necrosis factor inhibitor worldwide, and had several AbbVie employees as coauthors.

Both analyses used a “matching adjusted indirect comparison,” a fairly new way to compare the performance of interventions studied in two totally independent trials by propensity matching patients from each of the two trials. It’s purportedly a way to make a legitimate comparison in the absence of head-to-head data.

Making the two reports even more surreal was their use of essentially the same data.

The first report came from Walter P. Maksymowych, MD, an AS clinician and researcher from the University of Alberta, who with his coauthors used data collected on secukinumab in the MEASURE 1 pivotal trial and on adalimumab in the ATLAS pivotal trial. He spent much of his presentation describing the methods behind the indirect comparison, and I don’t think I can be blamed for calling the results of this Novartis-sponsored analysis predictable: overall better performance by secukinumab, compared “indirectly” with adalimumab for clinical responses and patient quality of life.

Mitchel L. Zoler/Frontline Medical News

The second report, the one sponsored by AbbVie, came from Keith A. Betts, PhD, a biostatistician who works for the Analysis Group, an international consulting firm. He also used the ATLAS database as the source for adalimumab outcomes, and differed marginally from Dr. Maksymowych by taking data on secukinumab patients from both the MEASURE 1 and MEASURE 2 pivotal trials. Although Dr. Betts also used the matching adjusted indirect comparison approach and broadened his data source modestly, his results showed a distinctly different outcome: similar efficacy for the two drugs. Dr. Betts also included a cost efficacy analysis, and in this part adalimumab showed superior performance after he factored in the cost per responding AS patient.

During the combined discussion period following the two talks, both presenters defended the legitimacy of their approaches, although Dr. Maksymowych conceded that these indirect comparisons are “hypothesis generating rather than producing a definitive answer.” But a couple of active European AS researchers rose to comment from the floor and discredit the whole process.

“These two presentations show why I am not a proponent of indirect comparisons. The statistical models squeeze the data until they confess,” said Robert Landewé, MD, an AS specialist at the University of Amsterdam. “This is now a commercial rather than a scientific clash between two important drugs. I challenge these companies to perform a head-to-head trial. Indirect comparisons are not good,” he concluded, to a round of audience applause.

“There are so many methodological issues,” said Désirée van der Heijde, MD, another Dutch AS clinician and researcher who rose to critique both studies. “The only thing you can rely on is head-to-head trials.”

I later spoke with Dr. Maksymowych, and he expressed some pessimism about the prospects for a fully-powered, head-to-head trial of an interleukin-17 inhibitor and tumor necrosis factor inhibitor because it would need to enroll so many patients. “Randomized studies of active comparators need to be huge because it’s hard to show improvements when the response rates are high,” he said. Plus, he added, it isn’t entirely about a drug’s efficacy against AS spinal symptoms anyway.

“We also have to think about the impact of treatment on other aspects of this disease, such as psoriasis and colitis, as well as radiographic disease progression,” he said. These aspects of the activity of both classes of drugs have not received much study in AS patients until now.

In other words, the battle between treatment options for AS has just begun, and seems likely to be fought on many fronts.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Now that the interleukin-17 inhibitor secukinumab and tumor necrosis factor inhibitors are competing options for treatment of patients with ankylosing spondylitis, the companies that make those drugs must feel pressure to find some sort of advantage for their agents.

How else to explain the remarkable pair of similar post hoc analyses presented in June at the European Congress of Rheumatology in London? One of the analyses was funded by Novartis – the company that markets secukinumab (Cosentyx) – and included several Novartis employees as coauthors. The second study, presented immediately afterward in the main session at the meeting devoted to ankylosing spondylitis (AS) treatments, had backing from AbbVie, which markets adalimumab (Humira), the largest-selling tumor necrosis factor inhibitor worldwide, and had several AbbVie employees as coauthors.

Both analyses used a “matching adjusted indirect comparison,” a fairly new way to compare the performance of interventions studied in two totally independent trials by propensity matching patients from each of the two trials. It’s purportedly a way to make a legitimate comparison in the absence of head-to-head data.

Making the two reports even more surreal was their use of essentially the same data.

The first report came from Walter P. Maksymowych, MD, an AS clinician and researcher from the University of Alberta, who with his coauthors used data collected on secukinumab in the MEASURE 1 pivotal trial and on adalimumab in the ATLAS pivotal trial. He spent much of his presentation describing the methods behind the indirect comparison, and I don’t think I can be blamed for calling the results of this Novartis-sponsored analysis predictable: overall better performance by secukinumab, compared “indirectly” with adalimumab for clinical responses and patient quality of life.

Mitchel L. Zoler/Frontline Medical News

The second report, the one sponsored by AbbVie, came from Keith A. Betts, PhD, a biostatistician who works for the Analysis Group, an international consulting firm. He also used the ATLAS database as the source for adalimumab outcomes, and differed marginally from Dr. Maksymowych by taking data on secukinumab patients from both the MEASURE 1 and MEASURE 2 pivotal trials. Although Dr. Betts also used the matching adjusted indirect comparison approach and broadened his data source modestly, his results showed a distinctly different outcome: similar efficacy for the two drugs. Dr. Betts also included a cost efficacy analysis, and in this part adalimumab showed superior performance after he factored in the cost per responding AS patient.

During the combined discussion period following the two talks, both presenters defended the legitimacy of their approaches, although Dr. Maksymowych conceded that these indirect comparisons are “hypothesis generating rather than producing a definitive answer.” But a couple of active European AS researchers rose to comment from the floor and discredit the whole process.

“These two presentations show why I am not a proponent of indirect comparisons. The statistical models squeeze the data until they confess,” said Robert Landewé, MD, an AS specialist at the University of Amsterdam. “This is now a commercial rather than a scientific clash between two important drugs. I challenge these companies to perform a head-to-head trial. Indirect comparisons are not good,” he concluded, to a round of audience applause.

“There are so many methodological issues,” said Désirée van der Heijde, MD, another Dutch AS clinician and researcher who rose to critique both studies. “The only thing you can rely on is head-to-head trials.”

I later spoke with Dr. Maksymowych, and he expressed some pessimism about the prospects for a fully-powered, head-to-head trial of an interleukin-17 inhibitor and tumor necrosis factor inhibitor because it would need to enroll so many patients. “Randomized studies of active comparators need to be huge because it’s hard to show improvements when the response rates are high,” he said. Plus, he added, it isn’t entirely about a drug’s efficacy against AS spinal symptoms anyway.

“We also have to think about the impact of treatment on other aspects of this disease, such as psoriasis and colitis, as well as radiographic disease progression,” he said. These aspects of the activity of both classes of drugs have not received much study in AS patients until now.

In other words, the battle between treatment options for AS has just begun, and seems likely to be fought on many fronts.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Now that the interleukin-17 inhibitor secukinumab and tumor necrosis factor inhibitors are competing options for treatment of patients with ankylosing spondylitis, the companies that make those drugs must feel pressure to find some sort of advantage for their agents.

How else to explain the remarkable pair of similar post hoc analyses presented in June at the European Congress of Rheumatology in London? One of the analyses was funded by Novartis – the company that markets secukinumab (Cosentyx) – and included several Novartis employees as coauthors. The second study, presented immediately afterward in the main session at the meeting devoted to ankylosing spondylitis (AS) treatments, had backing from AbbVie, which markets adalimumab (Humira), the largest-selling tumor necrosis factor inhibitor worldwide, and had several AbbVie employees as coauthors.

Both analyses used a “matching adjusted indirect comparison,” a fairly new way to compare the performance of interventions studied in two totally independent trials by propensity matching patients from each of the two trials. It’s purportedly a way to make a legitimate comparison in the absence of head-to-head data.

Making the two reports even more surreal was their use of essentially the same data.

The first report came from Walter P. Maksymowych, MD, an AS clinician and researcher from the University of Alberta, who with his coauthors used data collected on secukinumab in the MEASURE 1 pivotal trial and on adalimumab in the ATLAS pivotal trial. He spent much of his presentation describing the methods behind the indirect comparison, and I don’t think I can be blamed for calling the results of this Novartis-sponsored analysis predictable: overall better performance by secukinumab, compared “indirectly” with adalimumab for clinical responses and patient quality of life.

Mitchel L. Zoler/Frontline Medical News

The second report, the one sponsored by AbbVie, came from Keith A. Betts, PhD, a biostatistician who works for the Analysis Group, an international consulting firm. He also used the ATLAS database as the source for adalimumab outcomes, and differed marginally from Dr. Maksymowych by taking data on secukinumab patients from both the MEASURE 1 and MEASURE 2 pivotal trials. Although Dr. Betts also used the matching adjusted indirect comparison approach and broadened his data source modestly, his results showed a distinctly different outcome: similar efficacy for the two drugs. Dr. Betts also included a cost efficacy analysis, and in this part adalimumab showed superior performance after he factored in the cost per responding AS patient.

During the combined discussion period following the two talks, both presenters defended the legitimacy of their approaches, although Dr. Maksymowych conceded that these indirect comparisons are “hypothesis generating rather than producing a definitive answer.” But a couple of active European AS researchers rose to comment from the floor and discredit the whole process.

“These two presentations show why I am not a proponent of indirect comparisons. The statistical models squeeze the data until they confess,” said Robert Landewé, MD, an AS specialist at the University of Amsterdam. “This is now a commercial rather than a scientific clash between two important drugs. I challenge these companies to perform a head-to-head trial. Indirect comparisons are not good,” he concluded, to a round of audience applause.

“There are so many methodological issues,” said Désirée van der Heijde, MD, another Dutch AS clinician and researcher who rose to critique both studies. “The only thing you can rely on is head-to-head trials.”

I later spoke with Dr. Maksymowych, and he expressed some pessimism about the prospects for a fully-powered, head-to-head trial of an interleukin-17 inhibitor and tumor necrosis factor inhibitor because it would need to enroll so many patients. “Randomized studies of active comparators need to be huge because it’s hard to show improvements when the response rates are high,” he said. Plus, he added, it isn’t entirely about a drug’s efficacy against AS spinal symptoms anyway.

“We also have to think about the impact of treatment on other aspects of this disease, such as psoriasis and colitis, as well as radiographic disease progression,” he said. These aspects of the activity of both classes of drugs have not received much study in AS patients until now.

In other words, the battle between treatment options for AS has just begun, and seems likely to be fought on many fronts.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

ROCKVILLE, MD. – In a 12-11 vote, a Food and Drug Administration advisory panel just barely came down in favor of the agency adding a new labeling entry to the already-approved diabetes drug empagliflozin (Jardiance) that would say the drug reduces cardiovascular mortality.

While several members of the panel wished the FDA’s staff good luck in weighing both the evidence and the advisory committee’s closely split endorsement when deciding whether to grant this unprecedented labeling to a diabetes drug, the fact that a majority of panelists favored this course marked a watershed moment in the development of new agents for treating hyperglycemia.

Mitchel L. Zoler/Frontline Medical News

“It’s the first time we have evidence that a diabetes drug can reduce cardiovascular risk. That’s never been seen before, and it’s huge,” said Marvin A. Konstam, MD, a temporary member of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) and chief physician executive of the cardiovascular center at Tufts Medical Center in Boston. “The question is whether or not this effect is real, and the vote was 50-50, but I think there is a good chance it’s real, and, if so, it’s a game changer,” Dr. Konstam said in an interview. He voted in favor of the new labeling, and, like many of his colleagues on the panel, he admitted to agonizing over the decision during the postvote comment period.

What he and the other committee members struggled with was a remarkably strong effect by empagliflozin on reducing cardiovascular mortality by a relative 38%, compared with placebo, in more than 7,000 patients with type 2 diabetes selected for their high cardiovascular disease risk. The major sticking point was that the study enrolled patients into a randomized, placebo-controlled trial that was primarily designed to test the drug’s cardiovascular safety and not its efficacy, and where cardiovascular death was not even a prespecified secondary endpoint.

“It’s very hard to go from safety to superiority in one study,” said Peter W.F. Wilson, MD, who voted against the added indication. Like many panel members who voted no, Dr. Wilson said that any claim to preventing cardiovascular mortality with empagliflozin should meet the standard FDA requirement to have consistent results from at least two studies. “This is the first drug in its class [the sodium-glucose cotransporter 2 inhibitors], and we should have a high bar for the quality of the evidence,” said Dr. Wilson, professor of medicine and public health at Emory University in Atlanta.

“There is substantial evidence [to support the mortality claim], but not yet to the extent to put it on the label,” said another voter on the no side, Judith Fradkin, MD, also a temporary committee member and director of the division of diabetes, endocrinology and metabolic diseases at the National Institutes of Health. The data collected so far in favor of the mortality claim “are very compelling, but what I couldn’t get past is my long-standing belief that a positive result to a study’s secondary outcome is hypothesis generating. We need a second study to put this on the label,” Dr. Fradkin said.

That dramatic and highly meaningful clinical effect of empagliflozin on cardiovascular mortality jumped out at the investigators who ran the EMPA-REG OUTCOME trial as well as to many others from the moment the results had their unveiling less than a year ago, at the annual meeting of the European Association for the Study of Diabetes in Stockholm, and in a concurrently published article (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

Mitchel L. Zoler/Frontline Medical News

The primary efficacy endpoint placed into the EMPA-REG OUTCOME safety trial as the study developed following the 2008 FDA mandate for cardiovascular safety trials for all new hypoglycemic drugs was a three-part, combined-outcome endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke. Although this primary, combined endpoint had a statistically significant but much more modest benefit with a 14% relative risk reduction, compared with placebo, “the benefit was all driven by the reduction in cardiovascular death that had an astonishing P value of less than .0001 with no suggestion of benefit or risk for MI or stroke,” said Stuart Pocock, PhD, professor of medical statistics at the London School of Hygiene and Tropical Medicine who appeared before the committee as a consultant brought in by the applicant, Boehringer Ingelheim.

The total 309 cardiovascular deaths seen during the study that led to this finding provided more data than most cardiovascular trials, and while in some respects, the cardiovascular benefit seemed “too good to be true,” it also turned out that “the data were so strong that they overwhelm skepticism,” Dr. Pocock told the panel while presenting some advanced statistical test results to prove this assertion. The trial results showed “overwhelming evidence of benefit, beyond a reasonable doubt,” and while cardiovascular death was just one part of the efficacy endpoint, “mortality merits special attention,” he said. The statistical analyses also showed an equally robust 32% relative risk reduction in all-cause mortality, and both the cardiovascular and all-cause death benefits seen in EMPA-REG OUTCOME were consistent across both dosages of empagliflozin tested in the study (10 mg and 25 mg daily) and across the sensitivity analyses applied by the investigators.

“These are convincing data, but I’m not comfortable enough that these robust data would be reproduced in a second trial,” said panel chair Robert J. Smith, MD, who voted against the indication.

An additional limitation acting against the proposed new labeling, according to several panel members, is that the mechanism by which empagliflozin might exert protection against cardiovascular death remains unknown, with no suggestion in the trial results that it acts by protecting patients against ischemic disease.

Current opinion also splits among clinicians on how empagliflozin, which has had FDA approval since 2014 as an option for treating type 2 diabetes, should be used in routine practice to treat diabetes patients with high cardiovascular risk who match those enrolled in the EMPA-REG OUTCOME trial. Dr. Smith urged a cautious approach.

“I think it’s important [for prescribers] to wait to hear from the FDA. If the cardiovascular mortality benefit was proven, then it would be an important option given the magnitude of cardiovascular disease and death as a consequence of type 2 diabetes. But people should be cautious in drawing their own interpretations of the data,” Dr. Smith, professor of medicine at Brown University in Providence, R.I., said in an interview. For the time being, metformin remains the top oral drug for most of these patients because of its proven effectiveness and low cost, he added.

But others have already been active in prescribing empagliflozin to at-risk patients with type 2 diabetes based on last year’s EMPA-REG OUTCOME report.

“I am using it in addition to metformin and aggressive lifestyle changes in patients with established cardiovascular disease and uncontrolled type 2 diabetes,” commented Alison L. Bailey, MD, a cardiologist at the Erlanger Health System and University of Tennessee in Chattanooga. “A patient’s health insurance status must be taken into account as empagliflozin can be a significant financial burden, but if all other things are equal and cost is not prohibitive, I am definitely using this in my patients with type 2 diabetes and cardiovascular disease. I think there are enough data to warrant its use first line in patients who can get the drug without a financial burden,” she said in an interview.

Dr. Konstam cautioned that “just because empagliflozin may have a cardiovascular effect does not make it a cardiovascular drug. As a cardiologist I am not comfortable prescribing this drug. When it comes to diabetes management ,you need to take many things into consideration, most notably blood sugar and hemoglobin A_1c,” which are usually best managed by a diabetologist or experienced primary care physician, he said.

Dr. Konstam, Dr. Wilson, Dr. Fradkin, and Dr. Smith had no relevant financial disclosures. Dr. Pocock is a consultant to Boehringer Ingelheim. Dr. Bailey has received research grants from CSL Behring.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

LONDON – Patients with ankylosing spondylitis who remained on long-term treatment with a nonsteroidal anti-inflammatory drug and a tumor necrosis factor inhibitor had significantly less new spinal-bone formation in a cross-sectional analysis of a multicenter cohort of 527 U.S. patients.

A related analysis of the same cohort also showed significantly less ankylosing spondylitis (AS) progression as measured by radiographic progression among patients who received treatment with a tumor necrosis factor–alpha (TNF) inhibitor for 2.1-3.5 years regardless of their treatment with a nonsteroidal anti-inflammatory drug (NSAID), although this link trended to a stronger effect among the patients taking both, Lianne S. Gensler, MD, reported in a pair of posters at the European Congress of Rheumatology.

These finding suggest “there may be synergy between NSAIDs and TNF inhibitors [for slowing or preventing progression] in a select group of AS patients at high risk for progression,” said Dr. Gensler, a rheumatologist and director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco.

But Dr. Gensler also cautioned that these findings are merely “hypothesis generating” and should not be used as a rationale to place or maintain AS patients on long-term treatment with an NSAID, a TNF inhibitor, or both drugs.

“You treat the disease burden. The message is absolutely not to always put AS patients on both types of drugs. When an AS patient is well controlled on a TNF inhibitor alone, I would not tell them to also take a NSAID,” she said in an interview. “This is only relevant for patients who require treatment with both drug classes because of their clinical status.”

As the list of treatment options for patients with AS grows – it now includes NSAIDs, TNF inhibitors, and the interleukin-17 inhibitor secukinumab (Cosentyx) – the impact of these agents on disease progression as assessed by radiography and new bone formation becomes a new dimension to start to consider in addition to the standard criterion of immediate clinical response, Dr. Gensler explained. AS progression “is another factor to think about as we decide on treatment strategies. There is growing evidence that long-term treatment with a tumor necrosis factor inhibitor and with a NSAID have potential roles in disease modification.” But the evidence is indirect, from cohort studies that make cause and effect assessments difficult because of possible unidentified confounding factors, she noted.

“There has never been a randomized, controlled trial examining the disease-modifying effects of a TNF inhibitor because you can’t keep patients on placebo for a long enough time to see this benefit,” Dr. Gensler said. It takes a long time to see progression in AS patients, she noted.

A prior cohort analysis run by Dr. Gensler and her associates found evidence for an effect of long-term treatment with a TNF inhibitor and reduced AS progression measured using the modified Stoke AS Spine Score (mSASSS), compared with AS patients not on a TNF inhibitor in a propensity-score matched analysis of 334 patients. A link between TNF inhibitor use and a discernible difference in mSASSS only occurred when patients were on TNF inhibitor treatment for at least 3.9 years (Arthritis Rheum. 2013 Oct;65[10]:2645-54). In addition, a separate report at the EULAR congress on 168 AS patients maintained on treatment with secukinumab for 2 years showed evidence for slowed progression of mSASSS scores, compared with historical controls as well as with similar patients who were not on secukinumab treatment for as long a period of time.

The new analysis reported by Dr. Gensler looked at 527 AS patients in the multicenter Prospective Study of Outcomes in AS cohort followed for a median of 3.7 years. Clinicians participating in this cohort saw patients every 6 months, and radiographic assessments by mSASSS and for new bone formation occurred every 2 years. At entry into the registry, about 57% of patients received a TNF inhibitor and about 63% received an NSAID, with a third on an NSAID only, 27% on a TNF inhibitor only, 30% on both drugs, and 10% receiving neither drug.

The analysis showed that among patients followed for 2.1-3.5 years, the fraction of patients on a TNF inhibitor who showed progression of their mSASSS was 77% lower than patients not on a TNF inhibitor, a statistically significant difference, Dr. Gensler reported. The researchers saw no statistically significant difference in mSASSS progression rates between the patients on a TNF inhibitor at baseline and those not on a TNF inhibitor at baseline among patients followed for 2 years and among those followed for more than 3.5 years, although the analysis did show nominally higher levels of response among TNF-inhibitor users followed for more than 3.5 years. Dr. Gensler speculated that one reason for the loss of a statistically significant difference during longer follow-up could be that fewer patients reached these levels of prolonged follow-up, making statistically significant differences harder to see. This analysis also showed a strong trend for less progression among the patients treated with an NSAID, a 51% relative reduction in mSASSS progression, compared with patients not taking an NSAID, but this relationship just missed statistical significance.

A second analysis by Dr. Gensler and her associates used data from the same cohort but focused on new bone formation during follow-up. This analysis again showed a statistically significant, 72% reduction in this outcome among patients taking a TNF inhibitor at baseline, compared with those not on a TNF inhibitor, when followed for 2.1-3.5 years, with no statistically significant relationship seen among patients followed for less or more time, Dr. Gensler reported. However, the results from this analysis also showed a statistically significant impact from NSAID treatment: Patients on a TNF inhibitor and an NSAID at baseline had 67% less new bone formation, compared with those who received a TNF inhibitor but were not on an NSAID at baseline.

Dr. Gensler has been a consultant to or investigator funded by AbbVie, Amgen, Janssen, Novartis, and UCB. The Prospective Study of Outcomes in Ankylosing Spondylitis receives no commercial support.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Patients with ankylosing spondylitis who remained on long-term treatment with a nonsteroidal anti-inflammatory drug and a tumor necrosis factor inhibitor had significantly less new spinal-bone formation in a cross-sectional analysis of a multicenter cohort of 527 U.S. patients.

A related analysis of the same cohort also showed significantly less ankylosing spondylitis (AS) progression as measured by radiographic progression among patients who received treatment with a tumor necrosis factor–alpha (TNF) inhibitor for 2.1-3.5 years regardless of their treatment with a nonsteroidal anti-inflammatory drug (NSAID), although this link trended to a stronger effect among the patients taking both, Lianne S. Gensler, MD, reported in a pair of posters at the European Congress of Rheumatology.

These finding suggest “there may be synergy between NSAIDs and TNF inhibitors [for slowing or preventing progression] in a select group of AS patients at high risk for progression,” said Dr. Gensler, a rheumatologist and director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco.

But Dr. Gensler also cautioned that these findings are merely “hypothesis generating” and should not be used as a rationale to place or maintain AS patients on long-term treatment with an NSAID, a TNF inhibitor, or both drugs.

“You treat the disease burden. The message is absolutely not to always put AS patients on both types of drugs. When an AS patient is well controlled on a TNF inhibitor alone, I would not tell them to also take a NSAID,” she said in an interview. “This is only relevant for patients who require treatment with both drug classes because of their clinical status.”

As the list of treatment options for patients with AS grows – it now includes NSAIDs, TNF inhibitors, and the interleukin-17 inhibitor secukinumab (Cosentyx) – the impact of these agents on disease progression as assessed by radiography and new bone formation becomes a new dimension to start to consider in addition to the standard criterion of immediate clinical response, Dr. Gensler explained. AS progression “is another factor to think about as we decide on treatment strategies. There is growing evidence that long-term treatment with a tumor necrosis factor inhibitor and with a NSAID have potential roles in disease modification.” But the evidence is indirect, from cohort studies that make cause and effect assessments difficult because of possible unidentified confounding factors, she noted.

“There has never been a randomized, controlled trial examining the disease-modifying effects of a TNF inhibitor because you can’t keep patients on placebo for a long enough time to see this benefit,” Dr. Gensler said. It takes a long time to see progression in AS patients, she noted.

A prior cohort analysis run by Dr. Gensler and her associates found evidence for an effect of long-term treatment with a TNF inhibitor and reduced AS progression measured using the modified Stoke AS Spine Score (mSASSS), compared with AS patients not on a TNF inhibitor in a propensity-score matched analysis of 334 patients. A link between TNF inhibitor use and a discernible difference in mSASSS only occurred when patients were on TNF inhibitor treatment for at least 3.9 years (Arthritis Rheum. 2013 Oct;65[10]:2645-54). In addition, a separate report at the EULAR congress on 168 AS patients maintained on treatment with secukinumab for 2 years showed evidence for slowed progression of mSASSS scores, compared with historical controls as well as with similar patients who were not on secukinumab treatment for as long a period of time.

The new analysis reported by Dr. Gensler looked at 527 AS patients in the multicenter Prospective Study of Outcomes in AS cohort followed for a median of 3.7 years. Clinicians participating in this cohort saw patients every 6 months, and radiographic assessments by mSASSS and for new bone formation occurred every 2 years. At entry into the registry, about 57% of patients received a TNF inhibitor and about 63% received an NSAID, with a third on an NSAID only, 27% on a TNF inhibitor only, 30% on both drugs, and 10% receiving neither drug.

The analysis showed that among patients followed for 2.1-3.5 years, the fraction of patients on a TNF inhibitor who showed progression of their mSASSS was 77% lower than patients not on a TNF inhibitor, a statistically significant difference, Dr. Gensler reported. The researchers saw no statistically significant difference in mSASSS progression rates between the patients on a TNF inhibitor at baseline and those not on a TNF inhibitor at baseline among patients followed for 2 years and among those followed for more than 3.5 years, although the analysis did show nominally higher levels of response among TNF-inhibitor users followed for more than 3.5 years. Dr. Gensler speculated that one reason for the loss of a statistically significant difference during longer follow-up could be that fewer patients reached these levels of prolonged follow-up, making statistically significant differences harder to see. This analysis also showed a strong trend for less progression among the patients treated with an NSAID, a 51% relative reduction in mSASSS progression, compared with patients not taking an NSAID, but this relationship just missed statistical significance.

A second analysis by Dr. Gensler and her associates used data from the same cohort but focused on new bone formation during follow-up. This analysis again showed a statistically significant, 72% reduction in this outcome among patients taking a TNF inhibitor at baseline, compared with those not on a TNF inhibitor, when followed for 2.1-3.5 years, with no statistically significant relationship seen among patients followed for less or more time, Dr. Gensler reported. However, the results from this analysis also showed a statistically significant impact from NSAID treatment: Patients on a TNF inhibitor and an NSAID at baseline had 67% less new bone formation, compared with those who received a TNF inhibitor but were not on an NSAID at baseline.

Dr. Gensler has been a consultant to or investigator funded by AbbVie, Amgen, Janssen, Novartis, and UCB. The Prospective Study of Outcomes in Ankylosing Spondylitis receives no commercial support.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Patients with ankylosing spondylitis who remained on long-term treatment with a nonsteroidal anti-inflammatory drug and a tumor necrosis factor inhibitor had significantly less new spinal-bone formation in a cross-sectional analysis of a multicenter cohort of 527 U.S. patients.

A related analysis of the same cohort also showed significantly less ankylosing spondylitis (AS) progression as measured by radiographic progression among patients who received treatment with a tumor necrosis factor–alpha (TNF) inhibitor for 2.1-3.5 years regardless of their treatment with a nonsteroidal anti-inflammatory drug (NSAID), although this link trended to a stronger effect among the patients taking both, Lianne S. Gensler, MD, reported in a pair of posters at the European Congress of Rheumatology.

These finding suggest “there may be synergy between NSAIDs and TNF inhibitors [for slowing or preventing progression] in a select group of AS patients at high risk for progression,” said Dr. Gensler, a rheumatologist and director of the Ankylosing Spondylitis Clinic at the University of California, San Francisco.

But Dr. Gensler also cautioned that these findings are merely “hypothesis generating” and should not be used as a rationale to place or maintain AS patients on long-term treatment with an NSAID, a TNF inhibitor, or both drugs.

“You treat the disease burden. The message is absolutely not to always put AS patients on both types of drugs. When an AS patient is well controlled on a TNF inhibitor alone, I would not tell them to also take a NSAID,” she said in an interview. “This is only relevant for patients who require treatment with both drug classes because of their clinical status.”

As the list of treatment options for patients with AS grows – it now includes NSAIDs, TNF inhibitors, and the interleukin-17 inhibitor secukinumab (Cosentyx) – the impact of these agents on disease progression as assessed by radiography and new bone formation becomes a new dimension to start to consider in addition to the standard criterion of immediate clinical response, Dr. Gensler explained. AS progression “is another factor to think about as we decide on treatment strategies. There is growing evidence that long-term treatment with a tumor necrosis factor inhibitor and with a NSAID have potential roles in disease modification.” But the evidence is indirect, from cohort studies that make cause and effect assessments difficult because of possible unidentified confounding factors, she noted.

“There has never been a randomized, controlled trial examining the disease-modifying effects of a TNF inhibitor because you can’t keep patients on placebo for a long enough time to see this benefit,” Dr. Gensler said. It takes a long time to see progression in AS patients, she noted.

A prior cohort analysis run by Dr. Gensler and her associates found evidence for an effect of long-term treatment with a TNF inhibitor and reduced AS progression measured using the modified Stoke AS Spine Score (mSASSS), compared with AS patients not on a TNF inhibitor in a propensity-score matched analysis of 334 patients. A link between TNF inhibitor use and a discernible difference in mSASSS only occurred when patients were on TNF inhibitor treatment for at least 3.9 years (Arthritis Rheum. 2013 Oct;65[10]:2645-54). In addition, a separate report at the EULAR congress on 168 AS patients maintained on treatment with secukinumab for 2 years showed evidence for slowed progression of mSASSS scores, compared with historical controls as well as with similar patients who were not on secukinumab treatment for as long a period of time.

The new analysis reported by Dr. Gensler looked at 527 AS patients in the multicenter Prospective Study of Outcomes in AS cohort followed for a median of 3.7 years. Clinicians participating in this cohort saw patients every 6 months, and radiographic assessments by mSASSS and for new bone formation occurred every 2 years. At entry into the registry, about 57% of patients received a TNF inhibitor and about 63% received an NSAID, with a third on an NSAID only, 27% on a TNF inhibitor only, 30% on both drugs, and 10% receiving neither drug.

The analysis showed that among patients followed for 2.1-3.5 years, the fraction of patients on a TNF inhibitor who showed progression of their mSASSS was 77% lower than patients not on a TNF inhibitor, a statistically significant difference, Dr. Gensler reported. The researchers saw no statistically significant difference in mSASSS progression rates between the patients on a TNF inhibitor at baseline and those not on a TNF inhibitor at baseline among patients followed for 2 years and among those followed for more than 3.5 years, although the analysis did show nominally higher levels of response among TNF-inhibitor users followed for more than 3.5 years. Dr. Gensler speculated that one reason for the loss of a statistically significant difference during longer follow-up could be that fewer patients reached these levels of prolonged follow-up, making statistically significant differences harder to see. This analysis also showed a strong trend for less progression among the patients treated with an NSAID, a 51% relative reduction in mSASSS progression, compared with patients not taking an NSAID, but this relationship just missed statistical significance.

A second analysis by Dr. Gensler and her associates used data from the same cohort but focused on new bone formation during follow-up. This analysis again showed a statistically significant, 72% reduction in this outcome among patients taking a TNF inhibitor at baseline, compared with those not on a TNF inhibitor, when followed for 2.1-3.5 years, with no statistically significant relationship seen among patients followed for less or more time, Dr. Gensler reported. However, the results from this analysis also showed a statistically significant impact from NSAID treatment: Patients on a TNF inhibitor and an NSAID at baseline had 67% less new bone formation, compared with those who received a TNF inhibitor but were not on an NSAID at baseline.

Dr. Gensler has been a consultant to or investigator funded by AbbVie, Amgen, Janssen, Novartis, and UCB. The Prospective Study of Outcomes in Ankylosing Spondylitis receives no commercial support.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler