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The Official Newspaper of the American Association for Thoracic Surgery
There is Still Time to Register for the Heart Valve Summit: Medical, Surgical and Interventional Decision Making
October 5-7, 2017
Radisson Blu Aqua Hotel
Chicago, IL, USA
Be in Chicago as the renowned faculty on the cutting edge of clinically relevant data for valvular heart disease management leads this interdisciplinary course that combines the most relevant medical, surgical and interventional options for patient care. The American College of Cardiology and the American Association for Thoracic Surgery are once again bringing together cardiologists and surgeons in a cooperative, case-based course to address the rapid advances in the treatment of valvular heart disease.
With the tradition of interactivity and practical decision making, the unique Heart Valve Summit is designed to engage participants in discussions, debates and potential controversies surrounding real-world cases.
The Heart Valve Summit will highlight:
• Basics of the Aortic Valve
• Cardiac Network Trials
• Decision Making: Recurrent Mitral Valve Regurgitation
• Degenerative Mitral Anatomy and Physiology
• Difficult Choices and Scenarios
• Ischemic Mitral Regurgitation
• Mitral Endocarditis
• Mitral Valve Replacement
• Preparing for the Future in Mitral Valve Treatment
• TAVR
• The Future of Transcatheter Mitral Interventions
• Transcatheter Aortic Valve Replacement - Indications and Devices
• The Asymptomatic Patient with Advanced Valve Disease
• Treatment of Aortic Valve Disease
• Valve Disease and the Right Ventricle
Course Directors
David H. Adams
Steven F. Bolling
Robert O. Bonow
Howard C. Herrmann
Nurse Planner
Michele Mistovich
To register and reserve housing, visit: www.aats.org/valve
October 5-7, 2017
Radisson Blu Aqua Hotel
Chicago, IL, USA
Be in Chicago as the renowned faculty on the cutting edge of clinically relevant data for valvular heart disease management leads this interdisciplinary course that combines the most relevant medical, surgical and interventional options for patient care. The American College of Cardiology and the American Association for Thoracic Surgery are once again bringing together cardiologists and surgeons in a cooperative, case-based course to address the rapid advances in the treatment of valvular heart disease.
With the tradition of interactivity and practical decision making, the unique Heart Valve Summit is designed to engage participants in discussions, debates and potential controversies surrounding real-world cases.
The Heart Valve Summit will highlight:
• Basics of the Aortic Valve
• Cardiac Network Trials
• Decision Making: Recurrent Mitral Valve Regurgitation
• Degenerative Mitral Anatomy and Physiology
• Difficult Choices and Scenarios
• Ischemic Mitral Regurgitation
• Mitral Endocarditis
• Mitral Valve Replacement
• Preparing for the Future in Mitral Valve Treatment
• TAVR
• The Future of Transcatheter Mitral Interventions
• Transcatheter Aortic Valve Replacement - Indications and Devices
• The Asymptomatic Patient with Advanced Valve Disease
• Treatment of Aortic Valve Disease
• Valve Disease and the Right Ventricle
Course Directors
David H. Adams
Steven F. Bolling
Robert O. Bonow
Howard C. Herrmann
Nurse Planner
Michele Mistovich
To register and reserve housing, visit: www.aats.org/valve
October 5-7, 2017
Radisson Blu Aqua Hotel
Chicago, IL, USA
Be in Chicago as the renowned faculty on the cutting edge of clinically relevant data for valvular heart disease management leads this interdisciplinary course that combines the most relevant medical, surgical and interventional options for patient care. The American College of Cardiology and the American Association for Thoracic Surgery are once again bringing together cardiologists and surgeons in a cooperative, case-based course to address the rapid advances in the treatment of valvular heart disease.
With the tradition of interactivity and practical decision making, the unique Heart Valve Summit is designed to engage participants in discussions, debates and potential controversies surrounding real-world cases.
The Heart Valve Summit will highlight:
• Basics of the Aortic Valve
• Cardiac Network Trials
• Decision Making: Recurrent Mitral Valve Regurgitation
• Degenerative Mitral Anatomy and Physiology
• Difficult Choices and Scenarios
• Ischemic Mitral Regurgitation
• Mitral Endocarditis
• Mitral Valve Replacement
• Preparing for the Future in Mitral Valve Treatment
• TAVR
• The Future of Transcatheter Mitral Interventions
• Transcatheter Aortic Valve Replacement - Indications and Devices
• The Asymptomatic Patient with Advanced Valve Disease
• Treatment of Aortic Valve Disease
• Valve Disease and the Right Ventricle
Course Directors
David H. Adams
Steven F. Bolling
Robert O. Bonow
Howard C. Herrmann
Nurse Planner
Michele Mistovich
To register and reserve housing, visit: www.aats.org/valve
Preventive upstream therapy prevents progression of atrial fib
BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.
“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.
She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.
“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.
RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.
The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.
“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.
Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.
“In recent years enormous efforts have been put into treating symptoms of AF, but clearly we have failed to control the epidemic of AF in our societies, probably because we’ve been aiming only at treating symptoms, not treating the causes,” observed Dr. Brugada of the University of Barcelona.
He added, however, that the RACE 3 intervention didn’t go far enough.
“It’s a bit of a disappointment that there is no change in BMI seen after 1 year. Zero. That probably means the rehabilitation program wasn’t strong enough. Yet, the study results are positive, so if we used physical training in a stronger way to get a reduction in body weight and BMI, probably the outcome would be even greater,” he said.
To be maximally effective, an upstream intervention for AF should also address two other important risk factors for the arrhythmia: heavy alcohol drinking and obstructive sleep apnea, the electrophysiologist added.
The RACE 3 trial was supported by the Netherlands Heart Foundation and the Netherlands Heart Institute. Dr. van Gelder reported having no relevant financial interests.
Dr. van Gelder discussed the RACE 3 trial and results in a video interview.
BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.
“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.
She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.
“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.
RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.
The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.
“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.
Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.
“In recent years enormous efforts have been put into treating symptoms of AF, but clearly we have failed to control the epidemic of AF in our societies, probably because we’ve been aiming only at treating symptoms, not treating the causes,” observed Dr. Brugada of the University of Barcelona.
He added, however, that the RACE 3 intervention didn’t go far enough.
“It’s a bit of a disappointment that there is no change in BMI seen after 1 year. Zero. That probably means the rehabilitation program wasn’t strong enough. Yet, the study results are positive, so if we used physical training in a stronger way to get a reduction in body weight and BMI, probably the outcome would be even greater,” he said.
To be maximally effective, an upstream intervention for AF should also address two other important risk factors for the arrhythmia: heavy alcohol drinking and obstructive sleep apnea, the electrophysiologist added.
The RACE 3 trial was supported by the Netherlands Heart Foundation and the Netherlands Heart Institute. Dr. van Gelder reported having no relevant financial interests.
Dr. van Gelder discussed the RACE 3 trial and results in a video interview.
BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.
“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.
She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.
“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.
RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.
The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.
“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.
Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.
“In recent years enormous efforts have been put into treating symptoms of AF, but clearly we have failed to control the epidemic of AF in our societies, probably because we’ve been aiming only at treating symptoms, not treating the causes,” observed Dr. Brugada of the University of Barcelona.
He added, however, that the RACE 3 intervention didn’t go far enough.
“It’s a bit of a disappointment that there is no change in BMI seen after 1 year. Zero. That probably means the rehabilitation program wasn’t strong enough. Yet, the study results are positive, so if we used physical training in a stronger way to get a reduction in body weight and BMI, probably the outcome would be even greater,” he said.
To be maximally effective, an upstream intervention for AF should also address two other important risk factors for the arrhythmia: heavy alcohol drinking and obstructive sleep apnea, the electrophysiologist added.
The RACE 3 trial was supported by the Netherlands Heart Foundation and the Netherlands Heart Institute. Dr. van Gelder reported having no relevant financial interests.
Dr. van Gelder discussed the RACE 3 trial and results in a video interview.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: At 1 year, 75% of patients with baseline persistent atrial fibrillation who received a four-pronged program of upstream risk factor modification were in sinus rhythm, compared with 63% of controls.
Data source: RACE 3 was a multicenter, randomized, nonblinded clinical trial including 245 patients with a recent history of persistent atrial fibrillation and heart failure.
Disclosures: The RACE 3 trial was supported by the Netherlands Heart Foundation and the Netherlands Heart Institute. The presenter reported having no relevant financial interests.
Young adults lead the ranks of recently insured
The uninsured rate for young adults fell 50% from 2010 to 2016, according to the Agency for Healthcare Research and Quality.
In the first quarter of 2010, 30.6% of adults aged 18-29 years did not have health insurance at the time they were interviewed for the National Health Interview Survey. By the last quarter of 2016, that figure was down to 15.4%, a drop of nearly 50%, the AHRQ said in its annual National Healthcare Quality and Disparities Report.
For the total population under age 65 years, the uninsured rate dropped from 17.5% in the first quarter of 2010 to 10.8% in the fourth quarter of 2016, the AHRQ said, for an overall decline of 38%.
The uninsured rate for young adults fell 50% from 2010 to 2016, according to the Agency for Healthcare Research and Quality.
In the first quarter of 2010, 30.6% of adults aged 18-29 years did not have health insurance at the time they were interviewed for the National Health Interview Survey. By the last quarter of 2016, that figure was down to 15.4%, a drop of nearly 50%, the AHRQ said in its annual National Healthcare Quality and Disparities Report.
For the total population under age 65 years, the uninsured rate dropped from 17.5% in the first quarter of 2010 to 10.8% in the fourth quarter of 2016, the AHRQ said, for an overall decline of 38%.
The uninsured rate for young adults fell 50% from 2010 to 2016, according to the Agency for Healthcare Research and Quality.
In the first quarter of 2010, 30.6% of adults aged 18-29 years did not have health insurance at the time they were interviewed for the National Health Interview Survey. By the last quarter of 2016, that figure was down to 15.4%, a drop of nearly 50%, the AHRQ said in its annual National Healthcare Quality and Disparities Report.
For the total population under age 65 years, the uninsured rate dropped from 17.5% in the first quarter of 2010 to 10.8% in the fourth quarter of 2016, the AHRQ said, for an overall decline of 38%.
Five outside-the-box ideas for fixing the individual insurance market
With Republican efforts to “repeal and replace” the Affordable Care Act stalled, tentative bipartisan initiatives are in the works to shore up the fragile individual insurance market that serves roughly 17 million Americans.
The Senate Health, Education, Labor and Pensions Committee launches hearings the week Congress returns in September on “stabilizing premiums in the individual insurance market” that will feature state governors and insurance commissioners. A bipartisan group in the House is also working to come up with compromise proposals.
Both before and after implementation of the federal health law, this market – serving people who don’t get coverage through work or the government – has proved problematic. Before the law, many people with preexisting health conditions could not get insurance at any price. Now, consumers in the individual market often face higher out-of-pocket costs and fewer choices of health care providers and insurers than in past years. More than 12 million people buy that insurance through the ACA’s marketplaces, while another 5 million buy it outside of the exchanges.
Policy makers generally agree on what immediate efforts to stabilize the market might include. At the top of most lists is ensuring federal payment of subsidies to insurers to pay the out-of-pocket expenses – such as deductibles and copayments – to protect customers with the lowest incomes. Insurers also want the federal government to continue enforcing the requirement that most Americans either have insurance or pay a tax penalty, and continuing efforts to get uninsured people to sign up for coverage during the upcoming open enrollment period, from Nov. 1 to Dec. 15. Those efforts are essential, insurers say, to help keep healthy customers in their risk pools to defray the costs of beneficiaries with medical needs.
But what about ideas that go beyond the oft-repeated ones? Here are five proposals that are more controversial but generating buzz.
1. Allow people into Medicare starting at age 55.
Getting slightly younger people into Medicare, the federal program for the disabled and Americans 65 and older, is a longtime goal of Democrats. It dates at least to the Clinton administration and was nearly included in the Affordable Care Act in 2010. A Medicare buy-in is not exactly the same as a “public option,” which many Democrats, including former President Barack Obama, have embraced. A true public option would offer government coverage to those of any age.
Lowering the age for Medicare eligibility (whether by allowing people to purchase coverage early or letting them join on the same terms as those aged 65) is controversial. Some Democrats support it as a first step toward a single-payer, Medicare-for-all system. Most Republicans oppose it on those same grounds – as a step toward government-run health care.
But proponents argue it would help the current individual market by excluding the oldest people, thereby lowering the average age of the risk pool. Since older patients, on average, cost more to insure, the change could lower premiums for everyone left in the ACA market. That’s the stated goal of a Medicare buy-in bill introduced earlier this month by Sen. Debbie Stabenow (D-Mich.) and seven other Democratic senators. That bill would allow Obamacare market customers ages 55-64 to purchase Medicare coverage instead, but would also let them use ACA tax credits if they are eligible for those. The cost of such policies, however, has not been worked out.
“The way we’ve structured it actually both helps Medicare by having younger people in that pool, and it helps private insurance by taking higher-cost individuals out of their pool,” Sen. Stabenow told The Detroit News.
Conservative health analysts don’t buy that, though. “This is just a way of saying we’re going to take these people out of the exchanges and put them where there are bigger subsidies,” said Joseph Antos of the conservative-leaning American Enterprise Institute (AEI).
2. Allow people to ‘buy in’ to Medicaid.
An alternative to letting people buy in to Medicare is letting them buy in to Medicaid, the joint federal-state program for those with low incomes.
Medicaid buy-ins already exist – for example, in 2005 Congress passed the Family Opportunity Act, which allows families earning up to three times the poverty level to purchase Medicaid coverage for their disabled children who aren’t otherwise eligible. Medicaid has typically provided richer benefits for those with disabilities than private health insurance.
Earlier this year, Gov. Brian Sandoval (R-Nev.) vetoed a bill that would have allowed Nevada residents to buy Medicaid coverage through the state’s insurance exchange.
Now Sen. Brian Schatz (D-Hawaii) is pushing a federal Medicaid buy-in plan, which he described to Vox.com last week. It would give states the option to allow people with incomes over current Medicaid eligibility thresholds to pay a premium to join the program. Like the Medicare buy-in bill, it would allow those who qualify for federal tax credits to use them to pay the premiums.
The proposal would also raise the amounts Medicaid pays to doctors, hospitals and other health care providers to the same level as it pays for Medicare patients. Traditionally, low Medicaid payment rates have kept many doctors, particularly specialists, from taking Medicaid.
As with the Medicare expansion, the idea of a further Medicaid expansion does not sit well with conservative policy analysts. “It’s completely unworkable,” Avik Roy of the Foundation for Research on Equal Opportunity, told Vox. He predicted it would raise Medicaid spending by $2 trillion over 10 years.
3. Get younger adults off their parents’ insurance and back into the individual market.
Allowing young adults up to age 26 to stay on their parents’ health plans is unquestionably one of the most popular ACA provisions. Democrats have touted it proudly while Republicans have dared not touch it in almost any of their overhaul proposals.
Yet what has been a boon to 3 million young adults (and a relief to their parents) has come at a cost to the individual marketplace itself, where only an estimated 28% of those buying coverage in state exchanges were ages 18-34 in 2016. That is well below the 40% most analysts said was necessary to keep the market stable.
“Frankly, it was really stupid,” to keep those young people out of the individual market, said Mr. Antos of AEI. The result has been a lack of people in the risk pool who are “young, healthy and whose parents will pay their premiums.”
But rolling back that piece of the law might be nearly impossible, said Mr. Antos, because “this is a middle-class giveaway.”
4. Require insurers who participate in other government programs to offer marketplace coverage.
One clear shortcoming of the individual marketplace is a lack of insurer competition, particularly in rural areas. While there appear to be no counties left with no company offering coverage for the coming year, the percentage of counties with only one insurer seems certain to rise from 2017’s 33%.
In an effort to more strongly encourage private companies to step up and offer coverage, several analysts have suggested tying access to participation in other government programs to a willingness to offer individual ACA policies as well.
For example, some have suggested insurers be required to provide policies in the marketplaces as a condition of being able to offer coverage to federal workers. Others have suggested that private insurers who offer profitable Medicare Advantage plans could also be required to offer individual exchange coverage, although the same rural areas with a lack of private individual market insurers also tend to lack Medicare Advantage coverage.
5. Let people use HSA contributions to pay health insurance premiums.
A little-noticed provision in one of the versions of the Senate GOP health bill that failed to pass in July would have allowed people to use money from tax-preferred health savings accounts (HSAs) to pay their insurance premiums. A little-noticed proposal from a group of ideologically diverse health care experts included a similar idea.
HSAs are linked to high-deductible insurance plans, and consumers use the money in the account to pay their out-of-pocket expenses. The money put into the account and the earnings are not taxable.
With a few exceptions, people with HSAs have not been allowed to use those funds to pay monthly premiums. But the change would be one way to provide relief to people who buy their own insurance, earn too much to get federal premium subsidies, and cannot deduct premiums from their taxes because they are not technically self-employed. Such people, though likely small in number, have been disproportionately hurt by rising premiums in the individual market since the ACA took full effect.
Still, the change would involve some trade-offs.
Roy Ramthun, who helped design HSAs as a Senate staffer in the early 2000s and helped implement them while at the Treasury Department during the George W. Bush administration, said that, generally, “Republicans have preferred to subsidize insurance premiums through tax deductions and credits and leave the HSA for out-of-pocket expenses.” Allowing premiums to be paid from HSA funds, he said, “could eat up the entire balance of the account and leave nothing for out-of-pocket expenses.” There are limits to how much money can be put into an HSA. For 2017, the maximum is $3,400 for an individual and $6,750 for a family.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
With Republican efforts to “repeal and replace” the Affordable Care Act stalled, tentative bipartisan initiatives are in the works to shore up the fragile individual insurance market that serves roughly 17 million Americans.
The Senate Health, Education, Labor and Pensions Committee launches hearings the week Congress returns in September on “stabilizing premiums in the individual insurance market” that will feature state governors and insurance commissioners. A bipartisan group in the House is also working to come up with compromise proposals.
Both before and after implementation of the federal health law, this market – serving people who don’t get coverage through work or the government – has proved problematic. Before the law, many people with preexisting health conditions could not get insurance at any price. Now, consumers in the individual market often face higher out-of-pocket costs and fewer choices of health care providers and insurers than in past years. More than 12 million people buy that insurance through the ACA’s marketplaces, while another 5 million buy it outside of the exchanges.
Policy makers generally agree on what immediate efforts to stabilize the market might include. At the top of most lists is ensuring federal payment of subsidies to insurers to pay the out-of-pocket expenses – such as deductibles and copayments – to protect customers with the lowest incomes. Insurers also want the federal government to continue enforcing the requirement that most Americans either have insurance or pay a tax penalty, and continuing efforts to get uninsured people to sign up for coverage during the upcoming open enrollment period, from Nov. 1 to Dec. 15. Those efforts are essential, insurers say, to help keep healthy customers in their risk pools to defray the costs of beneficiaries with medical needs.
But what about ideas that go beyond the oft-repeated ones? Here are five proposals that are more controversial but generating buzz.
1. Allow people into Medicare starting at age 55.
Getting slightly younger people into Medicare, the federal program for the disabled and Americans 65 and older, is a longtime goal of Democrats. It dates at least to the Clinton administration and was nearly included in the Affordable Care Act in 2010. A Medicare buy-in is not exactly the same as a “public option,” which many Democrats, including former President Barack Obama, have embraced. A true public option would offer government coverage to those of any age.
Lowering the age for Medicare eligibility (whether by allowing people to purchase coverage early or letting them join on the same terms as those aged 65) is controversial. Some Democrats support it as a first step toward a single-payer, Medicare-for-all system. Most Republicans oppose it on those same grounds – as a step toward government-run health care.
But proponents argue it would help the current individual market by excluding the oldest people, thereby lowering the average age of the risk pool. Since older patients, on average, cost more to insure, the change could lower premiums for everyone left in the ACA market. That’s the stated goal of a Medicare buy-in bill introduced earlier this month by Sen. Debbie Stabenow (D-Mich.) and seven other Democratic senators. That bill would allow Obamacare market customers ages 55-64 to purchase Medicare coverage instead, but would also let them use ACA tax credits if they are eligible for those. The cost of such policies, however, has not been worked out.
“The way we’ve structured it actually both helps Medicare by having younger people in that pool, and it helps private insurance by taking higher-cost individuals out of their pool,” Sen. Stabenow told The Detroit News.
Conservative health analysts don’t buy that, though. “This is just a way of saying we’re going to take these people out of the exchanges and put them where there are bigger subsidies,” said Joseph Antos of the conservative-leaning American Enterprise Institute (AEI).
2. Allow people to ‘buy in’ to Medicaid.
An alternative to letting people buy in to Medicare is letting them buy in to Medicaid, the joint federal-state program for those with low incomes.
Medicaid buy-ins already exist – for example, in 2005 Congress passed the Family Opportunity Act, which allows families earning up to three times the poverty level to purchase Medicaid coverage for their disabled children who aren’t otherwise eligible. Medicaid has typically provided richer benefits for those with disabilities than private health insurance.
Earlier this year, Gov. Brian Sandoval (R-Nev.) vetoed a bill that would have allowed Nevada residents to buy Medicaid coverage through the state’s insurance exchange.
Now Sen. Brian Schatz (D-Hawaii) is pushing a federal Medicaid buy-in plan, which he described to Vox.com last week. It would give states the option to allow people with incomes over current Medicaid eligibility thresholds to pay a premium to join the program. Like the Medicare buy-in bill, it would allow those who qualify for federal tax credits to use them to pay the premiums.
The proposal would also raise the amounts Medicaid pays to doctors, hospitals and other health care providers to the same level as it pays for Medicare patients. Traditionally, low Medicaid payment rates have kept many doctors, particularly specialists, from taking Medicaid.
As with the Medicare expansion, the idea of a further Medicaid expansion does not sit well with conservative policy analysts. “It’s completely unworkable,” Avik Roy of the Foundation for Research on Equal Opportunity, told Vox. He predicted it would raise Medicaid spending by $2 trillion over 10 years.
3. Get younger adults off their parents’ insurance and back into the individual market.
Allowing young adults up to age 26 to stay on their parents’ health plans is unquestionably one of the most popular ACA provisions. Democrats have touted it proudly while Republicans have dared not touch it in almost any of their overhaul proposals.
Yet what has been a boon to 3 million young adults (and a relief to their parents) has come at a cost to the individual marketplace itself, where only an estimated 28% of those buying coverage in state exchanges were ages 18-34 in 2016. That is well below the 40% most analysts said was necessary to keep the market stable.
“Frankly, it was really stupid,” to keep those young people out of the individual market, said Mr. Antos of AEI. The result has been a lack of people in the risk pool who are “young, healthy and whose parents will pay their premiums.”
But rolling back that piece of the law might be nearly impossible, said Mr. Antos, because “this is a middle-class giveaway.”
4. Require insurers who participate in other government programs to offer marketplace coverage.
One clear shortcoming of the individual marketplace is a lack of insurer competition, particularly in rural areas. While there appear to be no counties left with no company offering coverage for the coming year, the percentage of counties with only one insurer seems certain to rise from 2017’s 33%.
In an effort to more strongly encourage private companies to step up and offer coverage, several analysts have suggested tying access to participation in other government programs to a willingness to offer individual ACA policies as well.
For example, some have suggested insurers be required to provide policies in the marketplaces as a condition of being able to offer coverage to federal workers. Others have suggested that private insurers who offer profitable Medicare Advantage plans could also be required to offer individual exchange coverage, although the same rural areas with a lack of private individual market insurers also tend to lack Medicare Advantage coverage.
5. Let people use HSA contributions to pay health insurance premiums.
A little-noticed provision in one of the versions of the Senate GOP health bill that failed to pass in July would have allowed people to use money from tax-preferred health savings accounts (HSAs) to pay their insurance premiums. A little-noticed proposal from a group of ideologically diverse health care experts included a similar idea.
HSAs are linked to high-deductible insurance plans, and consumers use the money in the account to pay their out-of-pocket expenses. The money put into the account and the earnings are not taxable.
With a few exceptions, people with HSAs have not been allowed to use those funds to pay monthly premiums. But the change would be one way to provide relief to people who buy their own insurance, earn too much to get federal premium subsidies, and cannot deduct premiums from their taxes because they are not technically self-employed. Such people, though likely small in number, have been disproportionately hurt by rising premiums in the individual market since the ACA took full effect.
Still, the change would involve some trade-offs.
Roy Ramthun, who helped design HSAs as a Senate staffer in the early 2000s and helped implement them while at the Treasury Department during the George W. Bush administration, said that, generally, “Republicans have preferred to subsidize insurance premiums through tax deductions and credits and leave the HSA for out-of-pocket expenses.” Allowing premiums to be paid from HSA funds, he said, “could eat up the entire balance of the account and leave nothing for out-of-pocket expenses.” There are limits to how much money can be put into an HSA. For 2017, the maximum is $3,400 for an individual and $6,750 for a family.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
With Republican efforts to “repeal and replace” the Affordable Care Act stalled, tentative bipartisan initiatives are in the works to shore up the fragile individual insurance market that serves roughly 17 million Americans.
The Senate Health, Education, Labor and Pensions Committee launches hearings the week Congress returns in September on “stabilizing premiums in the individual insurance market” that will feature state governors and insurance commissioners. A bipartisan group in the House is also working to come up with compromise proposals.
Both before and after implementation of the federal health law, this market – serving people who don’t get coverage through work or the government – has proved problematic. Before the law, many people with preexisting health conditions could not get insurance at any price. Now, consumers in the individual market often face higher out-of-pocket costs and fewer choices of health care providers and insurers than in past years. More than 12 million people buy that insurance through the ACA’s marketplaces, while another 5 million buy it outside of the exchanges.
Policy makers generally agree on what immediate efforts to stabilize the market might include. At the top of most lists is ensuring federal payment of subsidies to insurers to pay the out-of-pocket expenses – such as deductibles and copayments – to protect customers with the lowest incomes. Insurers also want the federal government to continue enforcing the requirement that most Americans either have insurance or pay a tax penalty, and continuing efforts to get uninsured people to sign up for coverage during the upcoming open enrollment period, from Nov. 1 to Dec. 15. Those efforts are essential, insurers say, to help keep healthy customers in their risk pools to defray the costs of beneficiaries with medical needs.
But what about ideas that go beyond the oft-repeated ones? Here are five proposals that are more controversial but generating buzz.
1. Allow people into Medicare starting at age 55.
Getting slightly younger people into Medicare, the federal program for the disabled and Americans 65 and older, is a longtime goal of Democrats. It dates at least to the Clinton administration and was nearly included in the Affordable Care Act in 2010. A Medicare buy-in is not exactly the same as a “public option,” which many Democrats, including former President Barack Obama, have embraced. A true public option would offer government coverage to those of any age.
Lowering the age for Medicare eligibility (whether by allowing people to purchase coverage early or letting them join on the same terms as those aged 65) is controversial. Some Democrats support it as a first step toward a single-payer, Medicare-for-all system. Most Republicans oppose it on those same grounds – as a step toward government-run health care.
But proponents argue it would help the current individual market by excluding the oldest people, thereby lowering the average age of the risk pool. Since older patients, on average, cost more to insure, the change could lower premiums for everyone left in the ACA market. That’s the stated goal of a Medicare buy-in bill introduced earlier this month by Sen. Debbie Stabenow (D-Mich.) and seven other Democratic senators. That bill would allow Obamacare market customers ages 55-64 to purchase Medicare coverage instead, but would also let them use ACA tax credits if they are eligible for those. The cost of such policies, however, has not been worked out.
“The way we’ve structured it actually both helps Medicare by having younger people in that pool, and it helps private insurance by taking higher-cost individuals out of their pool,” Sen. Stabenow told The Detroit News.
Conservative health analysts don’t buy that, though. “This is just a way of saying we’re going to take these people out of the exchanges and put them where there are bigger subsidies,” said Joseph Antos of the conservative-leaning American Enterprise Institute (AEI).
2. Allow people to ‘buy in’ to Medicaid.
An alternative to letting people buy in to Medicare is letting them buy in to Medicaid, the joint federal-state program for those with low incomes.
Medicaid buy-ins already exist – for example, in 2005 Congress passed the Family Opportunity Act, which allows families earning up to three times the poverty level to purchase Medicaid coverage for their disabled children who aren’t otherwise eligible. Medicaid has typically provided richer benefits for those with disabilities than private health insurance.
Earlier this year, Gov. Brian Sandoval (R-Nev.) vetoed a bill that would have allowed Nevada residents to buy Medicaid coverage through the state’s insurance exchange.
Now Sen. Brian Schatz (D-Hawaii) is pushing a federal Medicaid buy-in plan, which he described to Vox.com last week. It would give states the option to allow people with incomes over current Medicaid eligibility thresholds to pay a premium to join the program. Like the Medicare buy-in bill, it would allow those who qualify for federal tax credits to use them to pay the premiums.
The proposal would also raise the amounts Medicaid pays to doctors, hospitals and other health care providers to the same level as it pays for Medicare patients. Traditionally, low Medicaid payment rates have kept many doctors, particularly specialists, from taking Medicaid.
As with the Medicare expansion, the idea of a further Medicaid expansion does not sit well with conservative policy analysts. “It’s completely unworkable,” Avik Roy of the Foundation for Research on Equal Opportunity, told Vox. He predicted it would raise Medicaid spending by $2 trillion over 10 years.
3. Get younger adults off their parents’ insurance and back into the individual market.
Allowing young adults up to age 26 to stay on their parents’ health plans is unquestionably one of the most popular ACA provisions. Democrats have touted it proudly while Republicans have dared not touch it in almost any of their overhaul proposals.
Yet what has been a boon to 3 million young adults (and a relief to their parents) has come at a cost to the individual marketplace itself, where only an estimated 28% of those buying coverage in state exchanges were ages 18-34 in 2016. That is well below the 40% most analysts said was necessary to keep the market stable.
“Frankly, it was really stupid,” to keep those young people out of the individual market, said Mr. Antos of AEI. The result has been a lack of people in the risk pool who are “young, healthy and whose parents will pay their premiums.”
But rolling back that piece of the law might be nearly impossible, said Mr. Antos, because “this is a middle-class giveaway.”
4. Require insurers who participate in other government programs to offer marketplace coverage.
One clear shortcoming of the individual marketplace is a lack of insurer competition, particularly in rural areas. While there appear to be no counties left with no company offering coverage for the coming year, the percentage of counties with only one insurer seems certain to rise from 2017’s 33%.
In an effort to more strongly encourage private companies to step up and offer coverage, several analysts have suggested tying access to participation in other government programs to a willingness to offer individual ACA policies as well.
For example, some have suggested insurers be required to provide policies in the marketplaces as a condition of being able to offer coverage to federal workers. Others have suggested that private insurers who offer profitable Medicare Advantage plans could also be required to offer individual exchange coverage, although the same rural areas with a lack of private individual market insurers also tend to lack Medicare Advantage coverage.
5. Let people use HSA contributions to pay health insurance premiums.
A little-noticed provision in one of the versions of the Senate GOP health bill that failed to pass in July would have allowed people to use money from tax-preferred health savings accounts (HSAs) to pay their insurance premiums. A little-noticed proposal from a group of ideologically diverse health care experts included a similar idea.
HSAs are linked to high-deductible insurance plans, and consumers use the money in the account to pay their out-of-pocket expenses. The money put into the account and the earnings are not taxable.
With a few exceptions, people with HSAs have not been allowed to use those funds to pay monthly premiums. But the change would be one way to provide relief to people who buy their own insurance, earn too much to get federal premium subsidies, and cannot deduct premiums from their taxes because they are not technically self-employed. Such people, though likely small in number, have been disproportionately hurt by rising premiums in the individual market since the ACA took full effect.
Still, the change would involve some trade-offs.
Roy Ramthun, who helped design HSAs as a Senate staffer in the early 2000s and helped implement them while at the Treasury Department during the George W. Bush administration, said that, generally, “Republicans have preferred to subsidize insurance premiums through tax deductions and credits and leave the HSA for out-of-pocket expenses.” Allowing premiums to be paid from HSA funds, he said, “could eat up the entire balance of the account and leave nothing for out-of-pocket expenses.” There are limits to how much money can be put into an HSA. For 2017, the maximum is $3,400 for an individual and $6,750 for a family.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
VIDEO: Clopidogrel bests ticagrelor in PCI for ACS in real-world study
BARCELONA – Patients who underwent percutaneous coronary intervention for acute coronary syndrome using newer-generation drug-eluting stents backed by ticagrelor-based dual-antiplatelet therapy had significantly higher net adverse event rates at 1 year than did those with clopidogrel-based DAPT in the CHANGE DAPT study, Clemens von Birgelen, MD, reported at the annual congress of the European Society of Cardiology.
Based upon the CHANGE DAPT findings and those from other recent studies, it would be appropriate to revise ESC and American College of Cardiology/American Heart Association guidelines, which now give the newer, more potent platelet inhibitors ticagrelor (Brilinta) or prasugrel (Effient) preferential status as the P2Y12 inhibitor of choice over clopidogrel, added Dr. von Birgelen, professor of cardiology at the University of Twente in Enschede, the Netherlands, and codirector of the department of cardiology at Thoraxcentrum Twente.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“With the newer drug-eluting stents we see lower ischemic event rates, so the DAPT side effects due to bleeding become more important at this time. It could be that patients with ACS who are undergoing PCI may no longer need the most potent DAPT. Perhaps less potent DAPT with clopidogrel may be sufficient when using these more modern devices,” Dr. von Birgelen said in an interview.
CHANGE DAPT was a prospective, observational registry study that compared 1-year clinical outcomes in 2,062 consecutive ACS patients treated by PCI at Thoraxcentrum Twente, a high-volume PCI center. Half of the patients were treated before the primary DAPT regimen in the region changed from clopidogrel-based to ticagrelor-based DAPT on May 1, 2014, while the other half underwent PCI after the switch. This unique registry study design avoids selection bias, whereby cardiologists might preferentially use clopidogrel – the less potent P2Y12 inhibitor – in frailer patients.
The primary endpoint was the 1-year composite of all-cause mortality, any MI, stroke, or major bleeding. The rate was 7.8% in the ticagrelor period and significantly lower at 5.1% in the clopidogrel period. This difference was driven by the significantly lower major bleeding rate in the clopidogrel group: 1.2% versus 2.7% with ticagrelor-based DAPT.
The increased risk of bleeding associated with ticagrelor wasn’t offset by any advantage in term of ischemic events; indeed, the rate of such events was actually numerically lower with clopidogrel-based DAPT, albeit not statistically significantly so. Definite or probable stent thrombosis occurred in 0.6% of the clopidogrel group and 0.8% of the ticagrelor group, while the composite of cardiac death, MI, or stroke occurred in 3.7% of patients on clopidogrel-based DAPT compared with 4.7% on ticagrelor.
The two patient groups were closely similar at baseline in most respects, although the ticagrelor group was, on average, 1 year older, reflecting the more recent increased willingness of interventional cardiologists to utilize PCI in patients of advanced age. In terms of procedural differences, the ticagrelor group was more likely to undergo a transradial rather than transfemoral approach, less likely to receive a glycoprotein IIb/IIIa inhibitor, and more likely to get a proton pump inhibitor.
“All three of those factors should have reduced the bleeding risk during that second period,” Dr. von Birgelen observed.
In a propensity score–adjusted analysis taking account of the few between-group differences, ticagrelor-based DAPT was associated with a 1.75-fold increased risk of the primary endpoint and a 2.75-fold increased risk of major bleeding.
He noted that the CHANGE DAPT results are consistent with those of TOPIC, a 646-patient, single-center randomized trial conducted in Marseille. In TOPIC, after 1 month on ticagrelor- or prasugrel-backed DAPT, half of patients were switched to vastly less expensive clopidogrel for the remaining 11 months of DAPT. The result in the switched group was a marked decrease in bleeding with no increased risk of ischemic events.
“I see our study as a piece in a mosaic of studies and real-world registries with a similar message that have recently been reported,” the cardiologist said. “I hope the ESC looks carefully at these data.”
Session cochair Laura Mauri, MD, said that while it’s important to look at real-world observational data such as CHANGE DAPT to see if the results of randomized trials are generalizable, she’s not surprised by the evidence of increased risk of bleeding with a more potent agent such as ticagrelor.
“Why there’s a lack of benefit demonstrated, I think, is the bigger question,” said Dr. Mauri, professor of medicine at Harvard Medical School, Boston. “It could be related to changes in procedures over time, with procedures being conducted in a more complex manner, or some other residual confounding. I think whenever we see an observational study that changes the nature of the benefit that we see, it needs to be investigated more deeply. I don’t think it’s time to dismiss the results of very large randomized trials that show a meaningful benefit for the potent agents in the setting of ACS.”
CHANGE DAPT was an investigator-initiated study conducted without external funding. Dr. von Birgelen reported having no financial conflicts of interest.
BARCELONA – Patients who underwent percutaneous coronary intervention for acute coronary syndrome using newer-generation drug-eluting stents backed by ticagrelor-based dual-antiplatelet therapy had significantly higher net adverse event rates at 1 year than did those with clopidogrel-based DAPT in the CHANGE DAPT study, Clemens von Birgelen, MD, reported at the annual congress of the European Society of Cardiology.
Based upon the CHANGE DAPT findings and those from other recent studies, it would be appropriate to revise ESC and American College of Cardiology/American Heart Association guidelines, which now give the newer, more potent platelet inhibitors ticagrelor (Brilinta) or prasugrel (Effient) preferential status as the P2Y12 inhibitor of choice over clopidogrel, added Dr. von Birgelen, professor of cardiology at the University of Twente in Enschede, the Netherlands, and codirector of the department of cardiology at Thoraxcentrum Twente.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“With the newer drug-eluting stents we see lower ischemic event rates, so the DAPT side effects due to bleeding become more important at this time. It could be that patients with ACS who are undergoing PCI may no longer need the most potent DAPT. Perhaps less potent DAPT with clopidogrel may be sufficient when using these more modern devices,” Dr. von Birgelen said in an interview.
CHANGE DAPT was a prospective, observational registry study that compared 1-year clinical outcomes in 2,062 consecutive ACS patients treated by PCI at Thoraxcentrum Twente, a high-volume PCI center. Half of the patients were treated before the primary DAPT regimen in the region changed from clopidogrel-based to ticagrelor-based DAPT on May 1, 2014, while the other half underwent PCI after the switch. This unique registry study design avoids selection bias, whereby cardiologists might preferentially use clopidogrel – the less potent P2Y12 inhibitor – in frailer patients.
The primary endpoint was the 1-year composite of all-cause mortality, any MI, stroke, or major bleeding. The rate was 7.8% in the ticagrelor period and significantly lower at 5.1% in the clopidogrel period. This difference was driven by the significantly lower major bleeding rate in the clopidogrel group: 1.2% versus 2.7% with ticagrelor-based DAPT.
The increased risk of bleeding associated with ticagrelor wasn’t offset by any advantage in term of ischemic events; indeed, the rate of such events was actually numerically lower with clopidogrel-based DAPT, albeit not statistically significantly so. Definite or probable stent thrombosis occurred in 0.6% of the clopidogrel group and 0.8% of the ticagrelor group, while the composite of cardiac death, MI, or stroke occurred in 3.7% of patients on clopidogrel-based DAPT compared with 4.7% on ticagrelor.
The two patient groups were closely similar at baseline in most respects, although the ticagrelor group was, on average, 1 year older, reflecting the more recent increased willingness of interventional cardiologists to utilize PCI in patients of advanced age. In terms of procedural differences, the ticagrelor group was more likely to undergo a transradial rather than transfemoral approach, less likely to receive a glycoprotein IIb/IIIa inhibitor, and more likely to get a proton pump inhibitor.
“All three of those factors should have reduced the bleeding risk during that second period,” Dr. von Birgelen observed.
In a propensity score–adjusted analysis taking account of the few between-group differences, ticagrelor-based DAPT was associated with a 1.75-fold increased risk of the primary endpoint and a 2.75-fold increased risk of major bleeding.
He noted that the CHANGE DAPT results are consistent with those of TOPIC, a 646-patient, single-center randomized trial conducted in Marseille. In TOPIC, after 1 month on ticagrelor- or prasugrel-backed DAPT, half of patients were switched to vastly less expensive clopidogrel for the remaining 11 months of DAPT. The result in the switched group was a marked decrease in bleeding with no increased risk of ischemic events.
“I see our study as a piece in a mosaic of studies and real-world registries with a similar message that have recently been reported,” the cardiologist said. “I hope the ESC looks carefully at these data.”
Session cochair Laura Mauri, MD, said that while it’s important to look at real-world observational data such as CHANGE DAPT to see if the results of randomized trials are generalizable, she’s not surprised by the evidence of increased risk of bleeding with a more potent agent such as ticagrelor.
“Why there’s a lack of benefit demonstrated, I think, is the bigger question,” said Dr. Mauri, professor of medicine at Harvard Medical School, Boston. “It could be related to changes in procedures over time, with procedures being conducted in a more complex manner, or some other residual confounding. I think whenever we see an observational study that changes the nature of the benefit that we see, it needs to be investigated more deeply. I don’t think it’s time to dismiss the results of very large randomized trials that show a meaningful benefit for the potent agents in the setting of ACS.”
CHANGE DAPT was an investigator-initiated study conducted without external funding. Dr. von Birgelen reported having no financial conflicts of interest.
BARCELONA – Patients who underwent percutaneous coronary intervention for acute coronary syndrome using newer-generation drug-eluting stents backed by ticagrelor-based dual-antiplatelet therapy had significantly higher net adverse event rates at 1 year than did those with clopidogrel-based DAPT in the CHANGE DAPT study, Clemens von Birgelen, MD, reported at the annual congress of the European Society of Cardiology.
Based upon the CHANGE DAPT findings and those from other recent studies, it would be appropriate to revise ESC and American College of Cardiology/American Heart Association guidelines, which now give the newer, more potent platelet inhibitors ticagrelor (Brilinta) or prasugrel (Effient) preferential status as the P2Y12 inhibitor of choice over clopidogrel, added Dr. von Birgelen, professor of cardiology at the University of Twente in Enschede, the Netherlands, and codirector of the department of cardiology at Thoraxcentrum Twente.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“With the newer drug-eluting stents we see lower ischemic event rates, so the DAPT side effects due to bleeding become more important at this time. It could be that patients with ACS who are undergoing PCI may no longer need the most potent DAPT. Perhaps less potent DAPT with clopidogrel may be sufficient when using these more modern devices,” Dr. von Birgelen said in an interview.
CHANGE DAPT was a prospective, observational registry study that compared 1-year clinical outcomes in 2,062 consecutive ACS patients treated by PCI at Thoraxcentrum Twente, a high-volume PCI center. Half of the patients were treated before the primary DAPT regimen in the region changed from clopidogrel-based to ticagrelor-based DAPT on May 1, 2014, while the other half underwent PCI after the switch. This unique registry study design avoids selection bias, whereby cardiologists might preferentially use clopidogrel – the less potent P2Y12 inhibitor – in frailer patients.
The primary endpoint was the 1-year composite of all-cause mortality, any MI, stroke, or major bleeding. The rate was 7.8% in the ticagrelor period and significantly lower at 5.1% in the clopidogrel period. This difference was driven by the significantly lower major bleeding rate in the clopidogrel group: 1.2% versus 2.7% with ticagrelor-based DAPT.
The increased risk of bleeding associated with ticagrelor wasn’t offset by any advantage in term of ischemic events; indeed, the rate of such events was actually numerically lower with clopidogrel-based DAPT, albeit not statistically significantly so. Definite or probable stent thrombosis occurred in 0.6% of the clopidogrel group and 0.8% of the ticagrelor group, while the composite of cardiac death, MI, or stroke occurred in 3.7% of patients on clopidogrel-based DAPT compared with 4.7% on ticagrelor.
The two patient groups were closely similar at baseline in most respects, although the ticagrelor group was, on average, 1 year older, reflecting the more recent increased willingness of interventional cardiologists to utilize PCI in patients of advanced age. In terms of procedural differences, the ticagrelor group was more likely to undergo a transradial rather than transfemoral approach, less likely to receive a glycoprotein IIb/IIIa inhibitor, and more likely to get a proton pump inhibitor.
“All three of those factors should have reduced the bleeding risk during that second period,” Dr. von Birgelen observed.
In a propensity score–adjusted analysis taking account of the few between-group differences, ticagrelor-based DAPT was associated with a 1.75-fold increased risk of the primary endpoint and a 2.75-fold increased risk of major bleeding.
He noted that the CHANGE DAPT results are consistent with those of TOPIC, a 646-patient, single-center randomized trial conducted in Marseille. In TOPIC, after 1 month on ticagrelor- or prasugrel-backed DAPT, half of patients were switched to vastly less expensive clopidogrel for the remaining 11 months of DAPT. The result in the switched group was a marked decrease in bleeding with no increased risk of ischemic events.
“I see our study as a piece in a mosaic of studies and real-world registries with a similar message that have recently been reported,” the cardiologist said. “I hope the ESC looks carefully at these data.”
Session cochair Laura Mauri, MD, said that while it’s important to look at real-world observational data such as CHANGE DAPT to see if the results of randomized trials are generalizable, she’s not surprised by the evidence of increased risk of bleeding with a more potent agent such as ticagrelor.
“Why there’s a lack of benefit demonstrated, I think, is the bigger question,” said Dr. Mauri, professor of medicine at Harvard Medical School, Boston. “It could be related to changes in procedures over time, with procedures being conducted in a more complex manner, or some other residual confounding. I think whenever we see an observational study that changes the nature of the benefit that we see, it needs to be investigated more deeply. I don’t think it’s time to dismiss the results of very large randomized trials that show a meaningful benefit for the potent agents in the setting of ACS.”
CHANGE DAPT was an investigator-initiated study conducted without external funding. Dr. von Birgelen reported having no financial conflicts of interest.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The 1-year composite endpoint of all-cause mortality, MI, stroke, or major bleeding occurred in 5.1% of ACS patients who underwent PCI using newer-generation drug-eluting stents followed by clopidogrel-based DAPT, compared with 7.8% who received ticagrelor-based DAPT.
Data source: This unique design for a prospective observational registry study compared 1-year outcomes in 2,062 consecutive ACS patients who underwent PCI at a single high-volume center, half before a regional switch from clopidogrel- to ticagrelor-based DAPT and half afterward.
Disclosures: CHANGE DAPT was an investigator-initiated study conducted without external funding. The presenter reported having no financial conflicts of interest.
Dr. Clyde Yancy: CANTOS wows, opens new therapeutic avenues
BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”
Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.
“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.
“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.
BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”
Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.
“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.
“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.
BARCELONA – For Clyde Yancy, MD, presentation of the bombshell CANTOS trial results at the annual congress of the European Congress of Cardiology made for “a really good day.”
Those results showed that inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer. But further, they introduced a new way of identifying and treating patients for secondary prevention.
“Here is an alternative way to get to cardiovascular events; here is bringing inflammation right to the front page of what we do as cardiologists to prevent events; here is a brand-new agent that is a monoclonal antibody against interleukin that may be modifying this risk, and … a remarkable advantage that really needs to be replicated,” said Dr. Yancy, chief of medicine-cardiology at Northwestern University in Chicago, in a video interview.
“This is a really good day” because we’ve got new things to think about, new ways to approach our patients, and [we may soon be] entering the realm where we’ll want personalized therapy based on the unique phenotype a patient represents, and think about the pathways to disease through these brand new schemes” that are helping us understand the burden of disease, he declared.
AT THE ESC CONGRESS 2017
VIDEO: Anacetrapib doubles HDL, but patients gain from its modest LDL cut
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“As a clinician, this was an interesting and important result,” said Dr. Landray, professor of medicine and epidemiology at the University of Oxford (England).
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
The same uncertainty about lipoprotein particle functionality applies to the LDL-cholesterol lowering by anacetrapib. Are the consequences of this reduction similar to the benefits seem with LDL lowering by statins?
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
The same uncertainty about lipoprotein particle functionality applies to the LDL-cholesterol lowering by anacetrapib. Are the consequences of this reduction similar to the benefits seem with LDL lowering by statins?
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
The same uncertainty about lipoprotein particle functionality applies to the LDL-cholesterol lowering by anacetrapib. Are the consequences of this reduction similar to the benefits seem with LDL lowering by statins?
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“As a clinician, this was an interesting and important result,” said Dr. Landray, professor of medicine and epidemiology at the University of Oxford (England).
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“As a clinician, this was an interesting and important result,” said Dr. Landray, professor of medicine and epidemiology at the University of Oxford (England).
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Patients treated with anacetrapib had a statistically significant 9% decrease in major coronary events, compared with placebo-treated controls.
Data source: REVEAL, a multicenter, pivotal trial with 30,449 patients treated for about 4 years.
Disclosures: REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
VIDEO: Prescription-strength ibuprofen worsens blood pressure more than other NSAIDs
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Incident hypertension occurred within 4 months in 23.2% of arthritis patients on ibuprofen, compared with 10.3% taking celecoxib and 19% on naproxen.
Data source: This was a randomized, double-blind, multicenter, prospective trial including 444 arthritis patients at increased cardiovascular risk who underwent 4 months of ambulatory blood pressure monitoring after being assigned to prescription-strength ibuprofen, naproxen, or celecoxib.
Disclosures: The PRECISION-ABPM trial was sponsored by Pfizer. The presenter reported having no financial conflicts of interest.
Pembrolizumab showed ‘promising’ antitumor activity in small-cell lung cancer
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Pembrolizumab showed antitumor activity and was usually safe for treating extensive-stage small cell lung cancer.
Major finding: The objective response rate was 33%. Two patients developed grade 3 or worse treatment-related adverse events, which included fatal mesenteric ischemia and colitis.
Data source: A phase 1b open-label trial of 24 patients with PD-L1–positive extensive-stage small cell lung cancer.
Disclosures: Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
VIDEO: Rivaroxaban plus aspirin cut cardiovascular events in stable patients
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
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Key clinical point:
Major finding: The dual regimen reduced the combined rate of cardiovascular disease events by 24%, compared with aspirin alone.
Data source: COMPASS is a multicenter, randomized controlled trial with 27,395 patients.
Disclosures: COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.