TBD Meeting (3377-20)

Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Mohammed Haneefa Nizamudeen/Getty Images

“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.

That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.

The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.

The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.

Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.

These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.

A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.

The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.

A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.

That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”

While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.

Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.

“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.

Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.

“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.

Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).

The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.

[email protected]

SOURCE: Boehm M. ACC 2020, Abstract 406-15.

Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Mohammed Haneefa Nizamudeen/Getty Images

“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.

That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.

The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.

The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.

Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.

These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.

A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.

The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.

A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.

That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”

While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.

Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.

“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.

Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.

“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.

Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).

The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.

[email protected]

SOURCE: Boehm M. ACC 2020, Abstract 406-15.

Catheter-based renal denervation took a step closer to attaining legitimacy as a nonpharmacologic treatment for hypertension with presentation of the primary results of the SPYRAL HTN-OFF MED pivotal trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Mohammed Haneefa Nizamudeen/Getty Images

“We saw clinically meaningful blood pressure reductions at 3 months,” reported Michael Boehm, MD, chief of cardiology at Saarland University Hospital in Homburg, Germany.

That’s encouraging news, as renal denervation (RDN) was nearly abandoned as a potential treatment for hypertension in the wake of the unexpectedly negative results of the SYMPLICITY HTN-3 trial (N Engl J Med. 2014;370:1393-401). However, post hoc analysis of the trial revealed significant shortcomings in design and execution, and a more rigorous development program for the percutaneous device-based therapy is well underway.

The SPYRAL HTN-OFF MED pivotal trial was designed under Food and Drug Administration guidance to show whether RDN reduces blood pressure in patients with untreated hypertension. The prospective study included 331 off-medication patients in nine countries who were randomized to RDN or a sham procedure, then followed in double-blind fashion for 3 months.

The primary outcome was change in 24-hour ambulatory systolic blood pressure from baseline to 3 months. From a mean baseline 24-hour ambulatory blood pressure of 151.4/98 mm Hg, patients in the RDN group averaged a 4.7 mm Hg decrease in 24-hour SBP, which was 4 mm Hg more than in sham-treated controls. Statistically, this translated to a greater than 99.9% probability that RDN was superior to sham therapy. The RDN group also experienced a mean 3.7–mm Hg reduction in 24-hour DBP, compared with a 0.8–mm Hg decrease in controls.

Office SBP – the secondary endpoint – decreased by a mean of 9.2 mm Hg with RDN, compared with 2.5 mm Hg in controls.

These results probably understate the true antihypertensive effect of RDN for two reasons, Dr. Boehm noted. For one, previous studies have shown that the magnitude of blood pressure lowering continues to increase for up to 1-2 years following the procedure, whereas the off-medication assessment in SPYRAL HTN-OFF MED ended at 3 months for ethical and safety reasons. Also, 17% of patients in the control arm were withdrawn from the study and placed on antihypertensive medication because their office SBP reached 180 mm Hg or more, as compared to 9.6% of the RDN group.

A key finding was that RDN lowered blood pressure around the clock, including nighttime and early morning, the hours of greatest cardiovascular risk and a time when some antihypertensive medications are less effective at blood pressure control, the cardiologist observed.

The RDN safety picture was reassuring, with no strokes, myocardial infarctions, major bleeding, or acute deterioration in kidney function.

A surprising finding was that, even though participants underwent blood and urine testing for the presence of antihypertensive drugs at baseline to ensure they were off medication, and were told they would be retested at 3 months, 5%-9% nonetheless tested positive at the second test.

That elicited a comment from session chair Richard A. Chazal, MD, of Fort Myers, Fla.: “I must say, as a clinician who sometimes has trouble getting his patients to take antihypertensives, it’s fascinating that some of the people that you asked not to take the medications were taking them.”

While the primary outcome in SPYRAL HTN-OFF MED was the 3-month reduction in blood pressure while off of antihypertensive medication, the ongoing second phase of the trial may have greater clinical relevance. At 3 months, participants are being placed on antihypertensive medication and uptitrated to target, with unblinding at 6 months. The purpose is to see how many RDN recipients don’t need antihypertensive drugs, as well as whether those that do require less medication than the patients who didn’t undergo RDN.

Dr. Boehm characterized RDN as a work in progress. Two major limitations that are the focus of intense research are the lack of a predictor as to which patients are most likely to respond to what is after all an invasive procedure, and the current inability intraprocedurally to tell if sufficient RDN has been achieved.

“Frankly speaking, there is no technology during the procedure to see how efficacious the procedure was,” he explained.

Discussant Dhanunaja Lakkireddy, MD, deemed the mean 4.7–mm Hg reduction in 24-hour SBP “reasonably impressive – that’s actually a pretty good number for an antihypertensive clinical trial.” He was also favorably impressed by RDN’s safety in a 44-site study.

“The drops in blood pressure are not enough to really make a case for renal denervation to be a standalone therapy. But adding it as an adjunct to standard medications may be a very reasonable strategy to adopt. This is a fantastic signal for something that can be brought along as a long-term add-on to antihypertensive medications,” commented Dr. Lakkireddy, chair of the ACC Electrophysiology Council and medical director of the Kansas City Heart Rhythm Institute.

Simultaneous with Dr. Boehm’s presentation, the SPYRAL HTN-OFF MED Pivotal Trial details were published online (Lancet 2020 Mar 29. doi: 10.1016/S0140-6736(20)30554-7).

The study was sponsored by Medtronic. Dr. Boehm reported serving as a consultant to that company and Abbott, Amgen, Astra, Boehringer-Ingelheim, Cytokinetics, Novartis, ReCor, Servier, and Vifor.

[email protected]

SOURCE: Boehm M. ACC 2020, Abstract 406-15.

The long-sought goal of measuring the quality of U.S. transcatheter aortic valve replacement (TAVR) programs by patient outcomes rather than by the surrogate measure of case volume is about to be realized.

Starting more or less immediately, the U.S. national register for all TAVR cases that’s mandated by Food and Drug Administration labeling of these devices and run through a collaboration of the American College of Cardiology and the Society of Thoracic Surgeons will start applying a newly developed and validated five-item metric for measuring 30-day patient outcomes and designed to gauge the quality of TAVR programs.

At first, the only recipients of the data will be the programs themselves, but starting in about a year, by sometime in 2021, the STS/ACC TVT (transcatheter valve therapy) Registry will start to make its star-based rating of TAVR programs available to the public, Nimesh D. Desai, MD, said on March 29 at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. These societies already make star-based ratings of U.S. programs available to the public for several other types of cardiac interventions, including coronary artery bypass surgery and MI management.

The new, composite metric based on 30-day outcome data “is appropriate for high-stakes applications such as public reporting,” said Dr. Desai, a thoracic surgeon and director of thoracic aortic surgery research at the University of Pennsylvania in Philadelphia. “We’re confident this model can be used for public reporting. It’s undergone extensive testing of its validity.” The steering committee of the STS/ACC TVT Registry commissioned development of the metric, and it’s now “considered approved,” and ready for use, he explained.

To create the new metric, Dr. Desai and his associates used data from 52,561 patients who underwent transfemoral TAVR during 2015-2017 at any of 301 U.S. sites. These data came from a total pool of more than 114,000 patients at 556 sites, but data from many sites weren’t usable because they were not adequately complete. The researchers then identified the top four measures taken during the 30 days following intervention (hospitalization included) that best correlated with 1-year survival and patients’ quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire: stroke; major, life-threatening, or disabling bleed; acute kidney injury (stage III); and moderate or severe paravalvular leak. These outcomes “matter most to patients,” Dr. Desai said.

They used these four outcomes plus 30-day mortality to calculate the programs’ ratings. Among the 52,561 patients, 14% had at least one of these adverse outcomes. The researchers then used a logistic regression model that adjusted for 46 measured variables to calculate how each program performed relative to the average performance of all the programs. Programs with outcomes that fell within the 95% confidence intervals of average performance were rated as performing as expected; those outside rated as performing either better or worse than expected. The results showed 34 centers (11%) had worse than expected outcomes and 25 (8%) had better than expected outcomes, Dr. Desai said.

“This is a major step forward in measuring TAVR quality,” commented Michael Mack, MD, a cardiac surgeon with Baylor Scott & White Health in Dallas who has been very active in studying TAVR. “Until now, we used volume as a surrogate for quality, but the precision was not great. This is an extremely welcome metric.” The next step is to eventually use 1-year follow-up data instead of 30-day outcomes, he added.

“With the rapid expansion of TAVR over the past 6-8 years, we’re now at the point to start to do this. It’s an ethical obligation This will be one of the most high-fidelity, valid models for public reporting” of clinical outcomes,” said Joseph Cleveland, MD, a professor of surgery at the University of Colorado at Denver in Aurora. “It’s reassuring that about 90% of the program performed as expected or better than expected,” he added.

“Transparency and outcomes should drive how TAVR is delivered,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medicine Heart Institute in Phoenix who estimated that he performs about 150 TAVR procedures annually. “This is a step forward. I’ve been waiting for this for a long time. Until now, volume has been used as a surrogate outcome, but we know it’s not accurate. I’m confident that this model is a good starting point.” But Dr. Pershad also had concern that this new approach “can lend itself to some degree of gaming,” like a bleeding event getting classified as minor when it was really major, or outlier patients getting dropped from reports.

The temptation to cut corners may be higher for TAVR than it’s been for the cardiac-disease metrics that already get publicly reported, like bypass surgery and myocardial infarction management, because of TAVR’s higher cost and higher profile, Dr. Pershad said. Existing measures “have not been as linked to financial disincentive as TAVR might be” because TAVR reimbursements can run as high as $50,000 per case. “The stakes with TAVR are higher,” he said.

Ultimately, the reliable examination of TAVR outcomes that this new metric allows may lead to a shake-up of TAVR programs, Dr. Pershad predicted. “This is clearly a step toward closing down some programs that [consistently] underperform.”

The STS/ACC TVT Registry receives no commercial funding. Dr. Desai has been a consultant to, speaker on behalf of, and received research funding from Gore, and he has also spoken on behalf of Cook, Medtronic, and Terumo Aortic. Dr. Cleveland, Dr. Mack, and Dr. Pershad had no disclosures.

[email protected]

The long-sought goal of measuring the quality of U.S. transcatheter aortic valve replacement (TAVR) programs by patient outcomes rather than by the surrogate measure of case volume is about to be realized.

Starting more or less immediately, the U.S. national register for all TAVR cases that’s mandated by Food and Drug Administration labeling of these devices and run through a collaboration of the American College of Cardiology and the Society of Thoracic Surgeons will start applying a newly developed and validated five-item metric for measuring 30-day patient outcomes and designed to gauge the quality of TAVR programs.

At first, the only recipients of the data will be the programs themselves, but starting in about a year, by sometime in 2021, the STS/ACC TVT (transcatheter valve therapy) Registry will start to make its star-based rating of TAVR programs available to the public, Nimesh D. Desai, MD, said on March 29 at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. These societies already make star-based ratings of U.S. programs available to the public for several other types of cardiac interventions, including coronary artery bypass surgery and MI management.

The new, composite metric based on 30-day outcome data “is appropriate for high-stakes applications such as public reporting,” said Dr. Desai, a thoracic surgeon and director of thoracic aortic surgery research at the University of Pennsylvania in Philadelphia. “We’re confident this model can be used for public reporting. It’s undergone extensive testing of its validity.” The steering committee of the STS/ACC TVT Registry commissioned development of the metric, and it’s now “considered approved,” and ready for use, he explained.

To create the new metric, Dr. Desai and his associates used data from 52,561 patients who underwent transfemoral TAVR during 2015-2017 at any of 301 U.S. sites. These data came from a total pool of more than 114,000 patients at 556 sites, but data from many sites weren’t usable because they were not adequately complete. The researchers then identified the top four measures taken during the 30 days following intervention (hospitalization included) that best correlated with 1-year survival and patients’ quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire: stroke; major, life-threatening, or disabling bleed; acute kidney injury (stage III); and moderate or severe paravalvular leak. These outcomes “matter most to patients,” Dr. Desai said.

They used these four outcomes plus 30-day mortality to calculate the programs’ ratings. Among the 52,561 patients, 14% had at least one of these adverse outcomes. The researchers then used a logistic regression model that adjusted for 46 measured variables to calculate how each program performed relative to the average performance of all the programs. Programs with outcomes that fell within the 95% confidence intervals of average performance were rated as performing as expected; those outside rated as performing either better or worse than expected. The results showed 34 centers (11%) had worse than expected outcomes and 25 (8%) had better than expected outcomes, Dr. Desai said.

“This is a major step forward in measuring TAVR quality,” commented Michael Mack, MD, a cardiac surgeon with Baylor Scott & White Health in Dallas who has been very active in studying TAVR. “Until now, we used volume as a surrogate for quality, but the precision was not great. This is an extremely welcome metric.” The next step is to eventually use 1-year follow-up data instead of 30-day outcomes, he added.

“With the rapid expansion of TAVR over the past 6-8 years, we’re now at the point to start to do this. It’s an ethical obligation This will be one of the most high-fidelity, valid models for public reporting” of clinical outcomes,” said Joseph Cleveland, MD, a professor of surgery at the University of Colorado at Denver in Aurora. “It’s reassuring that about 90% of the program performed as expected or better than expected,” he added.

“Transparency and outcomes should drive how TAVR is delivered,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medicine Heart Institute in Phoenix who estimated that he performs about 150 TAVR procedures annually. “This is a step forward. I’ve been waiting for this for a long time. Until now, volume has been used as a surrogate outcome, but we know it’s not accurate. I’m confident that this model is a good starting point.” But Dr. Pershad also had concern that this new approach “can lend itself to some degree of gaming,” like a bleeding event getting classified as minor when it was really major, or outlier patients getting dropped from reports.

The temptation to cut corners may be higher for TAVR than it’s been for the cardiac-disease metrics that already get publicly reported, like bypass surgery and myocardial infarction management, because of TAVR’s higher cost and higher profile, Dr. Pershad said. Existing measures “have not been as linked to financial disincentive as TAVR might be” because TAVR reimbursements can run as high as $50,000 per case. “The stakes with TAVR are higher,” he said.

Ultimately, the reliable examination of TAVR outcomes that this new metric allows may lead to a shake-up of TAVR programs, Dr. Pershad predicted. “This is clearly a step toward closing down some programs that [consistently] underperform.”

The STS/ACC TVT Registry receives no commercial funding. Dr. Desai has been a consultant to, speaker on behalf of, and received research funding from Gore, and he has also spoken on behalf of Cook, Medtronic, and Terumo Aortic. Dr. Cleveland, Dr. Mack, and Dr. Pershad had no disclosures.

[email protected]

The long-sought goal of measuring the quality of U.S. transcatheter aortic valve replacement (TAVR) programs by patient outcomes rather than by the surrogate measure of case volume is about to be realized.

Starting more or less immediately, the U.S. national register for all TAVR cases that’s mandated by Food and Drug Administration labeling of these devices and run through a collaboration of the American College of Cardiology and the Society of Thoracic Surgeons will start applying a newly developed and validated five-item metric for measuring 30-day patient outcomes and designed to gauge the quality of TAVR programs.

At first, the only recipients of the data will be the programs themselves, but starting in about a year, by sometime in 2021, the STS/ACC TVT (transcatheter valve therapy) Registry will start to make its star-based rating of TAVR programs available to the public, Nimesh D. Desai, MD, said on March 29 at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. These societies already make star-based ratings of U.S. programs available to the public for several other types of cardiac interventions, including coronary artery bypass surgery and MI management.

The new, composite metric based on 30-day outcome data “is appropriate for high-stakes applications such as public reporting,” said Dr. Desai, a thoracic surgeon and director of thoracic aortic surgery research at the University of Pennsylvania in Philadelphia. “We’re confident this model can be used for public reporting. It’s undergone extensive testing of its validity.” The steering committee of the STS/ACC TVT Registry commissioned development of the metric, and it’s now “considered approved,” and ready for use, he explained.

To create the new metric, Dr. Desai and his associates used data from 52,561 patients who underwent transfemoral TAVR during 2015-2017 at any of 301 U.S. sites. These data came from a total pool of more than 114,000 patients at 556 sites, but data from many sites weren’t usable because they were not adequately complete. The researchers then identified the top four measures taken during the 30 days following intervention (hospitalization included) that best correlated with 1-year survival and patients’ quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire: stroke; major, life-threatening, or disabling bleed; acute kidney injury (stage III); and moderate or severe paravalvular leak. These outcomes “matter most to patients,” Dr. Desai said.

They used these four outcomes plus 30-day mortality to calculate the programs’ ratings. Among the 52,561 patients, 14% had at least one of these adverse outcomes. The researchers then used a logistic regression model that adjusted for 46 measured variables to calculate how each program performed relative to the average performance of all the programs. Programs with outcomes that fell within the 95% confidence intervals of average performance were rated as performing as expected; those outside rated as performing either better or worse than expected. The results showed 34 centers (11%) had worse than expected outcomes and 25 (8%) had better than expected outcomes, Dr. Desai said.

“This is a major step forward in measuring TAVR quality,” commented Michael Mack, MD, a cardiac surgeon with Baylor Scott & White Health in Dallas who has been very active in studying TAVR. “Until now, we used volume as a surrogate for quality, but the precision was not great. This is an extremely welcome metric.” The next step is to eventually use 1-year follow-up data instead of 30-day outcomes, he added.

“With the rapid expansion of TAVR over the past 6-8 years, we’re now at the point to start to do this. It’s an ethical obligation This will be one of the most high-fidelity, valid models for public reporting” of clinical outcomes,” said Joseph Cleveland, MD, a professor of surgery at the University of Colorado at Denver in Aurora. “It’s reassuring that about 90% of the program performed as expected or better than expected,” he added.

“Transparency and outcomes should drive how TAVR is delivered,” commented Ashish Pershad, MD, an interventional cardiologist at Banner-University Medicine Heart Institute in Phoenix who estimated that he performs about 150 TAVR procedures annually. “This is a step forward. I’ve been waiting for this for a long time. Until now, volume has been used as a surrogate outcome, but we know it’s not accurate. I’m confident that this model is a good starting point.” But Dr. Pershad also had concern that this new approach “can lend itself to some degree of gaming,” like a bleeding event getting classified as minor when it was really major, or outlier patients getting dropped from reports.

The temptation to cut corners may be higher for TAVR than it’s been for the cardiac-disease metrics that already get publicly reported, like bypass surgery and myocardial infarction management, because of TAVR’s higher cost and higher profile, Dr. Pershad said. Existing measures “have not been as linked to financial disincentive as TAVR might be” because TAVR reimbursements can run as high as $50,000 per case. “The stakes with TAVR are higher,” he said.

Ultimately, the reliable examination of TAVR outcomes that this new metric allows may lead to a shake-up of TAVR programs, Dr. Pershad predicted. “This is clearly a step toward closing down some programs that [consistently] underperform.”

The STS/ACC TVT Registry receives no commercial funding. Dr. Desai has been a consultant to, speaker on behalf of, and received research funding from Gore, and he has also spoken on behalf of Cook, Medtronic, and Terumo Aortic. Dr. Cleveland, Dr. Mack, and Dr. Pershad had no disclosures.

[email protected]

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.

In the COMPASS trial of patients with stable coronary or peripheral artery disease (PAD), the combination of aspirin plus rivaroxaban, 2.5 mg twice daily, provided a larger absolute benefit on cardiovascular endpoints — including a threefold greater reduction in all-cause mortality — in patients with diabetes compared with the overall population.

The results of the diabetes subset of the COMPASS trial were presented by Deepak Bhatt, MD, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts, on March 28 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). They were also simultaneously published online in Circulation.

“Use of dual pathway inhibition with low-dose rivaroxaban plus aspirin is particularly attractive in high-risk patients such as those with diabetes,” Bhatt concluded.

The COMPASS trial was first reported in 2017 and showed a new low dose of rivaroxaban (2.5-mg twice-daily; Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin, 100 mg once daily, was associated with a reduction in ischemic events and mortality and a superior net clinical benefit, balancing ischemic benefit with severe bleeding, compared with aspirin alone for secondary prevention in patients with stable atherosclerotic vascular disease.

But clinicians have been slow to prescribe rivaroxaban in this new and very large population.

“It’s been more than 2 years now since main COMPASS results, and there isn’t a sense that this therapy has really caught on,” chair of the current ACC session at which the diabetes subgroup results were presented, Hadley Wilson, MD, Sanger Heart and Vascular Institute, Charlotte, North Carolina, commented:

He asked Bhatt whether the diabetes subgroup may be “the tipping point that will make people aware of rivaroxaban and then that may trickle down to other patients.”

Bhatt said that he hoped that would be the case. “We as a steering committee of this trial could say the results were positive so rivaroxaban should now be used in everyone with stable coronary or peripheral arterial disease, but that is impractical and as you out point out it hasn’t happened,” he replied.

“In PAD/vascular medicine we have embraced this new therapy. In the broader cardiology world there are a lot of patients with stable coronary arterial disease at high ischemic risk who could take rivaroxaban, but its use is bound to be limited by it being a branded drug and the fact that there is a bleeding risk,” Bhatt explained.

“I think we need to identify patients with the highest ischemic risk and focus drugs such as these with a financial cost and a bleeding risk on those who most likely will derive the greatest absolute reduction in risk,” he said. “The PAD subgroup is one group where this is the case, and now we have shown the diabetes subgroup is another. And there is no incremental bleeding risk in this group over the whole population, so they get a much greater benefit without a greater risk. I hope this helps get rivaroxaban at the new lower dose used much more often.”

A total of 18,278 patients were randomly assigned to the combination of rivaroxaban and aspirin or aspirin alone in the COMPASS trial. Of these, 6922 had diabetes mellitus at baseline and 11,356 did not have diabetes.

Results from the current analysis show a consistent and similar relative risk reduction for benefit of rivaroxaban plus aspirin vs placebo plus aspirin in patients both with and without diabetes for the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI), or stroke, with a hazard ratio of 0.74 for patients with diabetes and 0.77 for those without diabetes, the researchers report.

Because of the higher baseline risk in the diabetes subgroup, these patients had numerically larger absolute risk reductions with rivaroxaban than those without diabetes for the primary efficacy endpoint at 3 years (2.3% vs 1.4%) and for all-cause mortality (1.9% vs 0.6%).

These results translate into a number needed to treat (NNT) with rivaroxaban for 3 years to prevent one CV death, MI, or stroke of 44 for the diabetes group vs 73 for the nondiabetes group; the NNT to prevent one all-cause death was 54 for the diabetes group vs 167 for the nondiabetes group, the authors write.

Because the bleeding hazards were similar among patients with and without diabetes, the absolute net clinical benefit (MI, stroke, cardiovascular death, or bleeding leading to death or symptomatic bleeding into a critical organ) for rivaroxaban was “particularly favorable” in the diabetes group (2.7% fewer events in the diabetes group vs 1.0% fewer events in the nondiabetes group), they add.

Panelist at the ACC Featured Clinical Research session at which these results were presented, Jennifer Robinson, MD, University of Iowa College of Public Health, Iowa City, asked Bhatt how clinicians were supposed to decide which of the many new agents now becoming available for patients with stable coronary artery disease to prescribe first.

“We often forget about rivaroxaban when we’re thinking about what to add next for our secondary prevention patients,” she said. “You also led the REDUCE-IT trial showing benefit of icosapent ethyl, icosapent ethyl icosapent ethyl icosapent ethyl and there is also ezetimibe, PCSK9 inhibitors and SGLT2 inhibitors. For your patients with coronary disease who are already on a high dose statin which one of these would you add next?”

“That is what physicians need to ponder all the time,” Bhatt replied. “And when a patient has several risk factors that are not well controlled, I guess it’s all important. I go through a checklist with my patients and try and figure what they’re not on that could further reduce their risk.”

“In the COMPASS trial there was an overall positive result with rivaroxaban in the whole population. And now we have shown that patients with diabetes had an even greater absolute risk reduction. That pattern has also been seen with other classes of agents including the statins, PCSK9 inhibitors, and icosapent ethyl,” Bhatt noted.

“In patients with diabetes, I will usually target whatever is standing out most at that time. If their glycemic control is completely out of whack, then that is what I would focus on first, and these days often with a SGLT2 inhibitor or GLP-1 agonist. If the LDL was out of control, I would add ezetimibe or a PCSK9 inhibitor. If the triglycerides were high, I would add icosapent ethyl. If multiple things were out of control, I would usually focus on the number most out of kilter first and try not to forget about everything else.”

But Bhatt noted that the challenge with rivaroxaban is that there is no test of thrombosis risk that would prompt the physician to take action. “Basically, the doctor just has to remember to do it. In that regard I would consider whether patients are at low bleeding risk and are they still at high ischemic risk despite controlling other risk factors and, if so, then I would add this low dose of rivaroxaban.”

Another panel member, Sekar Kathiresan, MD, asked Bhatt whether he recommended using available scores to assess the bleeding/thrombosis risk/benefits of adding an antithrombotic.

Bhatt replied: “That’s a terrific question. I guess the right answer is that we should be doing that, but in reality I have to concede that I don’t use these scores. They have shown appropriate C statistics in populations, but they are not fantastic in individual patients.”

“I have to confess that I use the eyeball test. There is nothing as good at predicting future bleeding as past bleeding. So if a patient has had bleeding problems on aspirin alone I wouldn’t add rivaroxaban. But if a patient hasn’t bled before, especially if they had some experience of dual antiplatelet therapy, then they would be good candidates for a low vascular dose of rivaroxaban,” he said.

“It is not as easy as with other drugs as there is always a bleeding trade-off with an antithrombotic. There is no such thing as a free lunch. So patients need careful assessment when considering prescribing rivaroxaban and regular reassessment over time to check if they have had any bleeding,” he added.

The COMPASS study was funded by Bayer. Bhatt reports honoraria from Bayer via the Population Health Research Institute for his role on the COMPASS trial and other research funding from Bayer to the Brigham & Women’s Hospital.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20544-ACC. Presented March 28, 2020.

Circulation. Published online March 28, 2020. Full text.

This article first appeared on Medscape.com.

Transcatheter aortic valve replacement (TAVR) was not inferior to conventional surgery with respect to death from any cause at 1 year in a new real-world study in patients age 70 years or older with severe symptomatic aortic stenosis at increased operative risk due to age or comorbidity.

The UK TAVI study was presented March 29 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

The trial involved a broad group of patients who were treated at every medical center that performs the transcatheter procedure across the United Kingdom.

“The importance of this trial is that it confirms the effectiveness of the TAVR strategy in a real-world setting,” said lead author, William D. Toff, MD, professor of cardiology at the University of Leicester, United Kingdom.

Previous clinical trials have found TAVR to be noninferior or superior to open-heart surgery for various patient groups, but most trials have been limited to medical centers that perform a high volume of procedures or focus on the use of specific types of replacement valves, he noted.

“Our results are concordant with those from earlier trials in intermediate- and low-risk patients, but those earlier trials were performed in the best centers and had many exclusion criteria. We have replicated those results in populations more representative of the real world.”

“I think it is a very important message that supports the findings in earlier trials that were focused on showing whether TAVR can work under ideal conditions, while our trial shows that it does work in real-world clinical practice,” he added.

The UK TAVI trial enrolled 913 patients referred for treatment of severe aortic stenosis at 34 UK sites from 2014 to 2018. They were randomly assigned to receive TAVR or open-heart surgery.

Enrollment was limited to participants age 70 years or older (with additional risk factors) or age 80 years or older (with or without additional risk factors). The average age was 81 years.

Overall, participants were at intermediate to low risk from surgery, with a median Society of Thoracic Surgeons (STS) risk score of 2.6%. However, researchers did not specify a particular risk score cutoff for enrollment.

“This allowed the trial to evolve along with changes in guidelines and practice regarding TAVR over the course of the study and to reflect physicians’ nuanced, real-world approach to considering risk in decision-making rather than taking a formulaic approach,” Toff said.

At 1 year, the rate of death from any cause (the primary endpoint) was 4.6% in the TAVR group and 6.6% in the surgery group, a difference that met the trial’s prespecified threshold for noninferiority of TAVR.

Rates of death from cardiovascular disease or stroke were also similar between the two groups.

Patients who received TAVR had a significantly higher rate of vascular complications (4.8%) than those receiving surgery (1.3%).

TAVR patients were also more likely to have a pacemaker implanted. This occurred in 12.2% of TAVR patients and 6.6% of those undergoing surgery.

In addition, patients who underwent TAVR had a higher rate of aortic regurgitation. Mild aortic regurgitation occurred at 1 year in 38.3% of the TAVR group and 11.7% of the surgery group, whereas moderate regurgitation occurred in 2.3% of TAVR patients and 0.6% of surgery patients.

On the other hand, patients undergoing TAVR had a significantly lower rate of major bleeding complications, which occurred in 6.3% of patients having TAVR and 17.1% of those undergoing surgery.

TAVR was also associated with a shorter hospital stay, fewer days in intensive care, and a faster improvement in functional capacity and quality of life. Functional capacity and quality-of-life measures at 6 weeks after the procedure were better in the TAVR group but by 1 year they were similar in the two groups.

“Longer follow-up is required to confirm sustained clinical benefit and valve durability to inform clinical practice, particularly in younger patients,” Toff concluded.

“The results from our trial and others are encouraging, but patients need to be fully informed and know that the long-term durability of the TAVR valves and the long-term implications of the increased risk of aortic regurgitation are still uncertain,” he added.

The researchers plan to continue to track outcomes for a minimum of 5 years.

Discussant of the UK TAVI trial at an ACC press conference, Julia Grapsa, MD, Guys and St Thomas NHS Trust, London, United Kingdom, said it was a well-designed study.

“It was impressive to see so many UK sites and the age range of patients from 70 to 91 years, and the shorter hospital stays and functional recoveries as well as reduced major bleeding in the TAVR group,” Grapsa said.

“But something that was very striking to me was the increase in moderate aortic regurgitation in the TAVR arm, 2.3% versus 0.6% in the surgical arm, so it is very important to keep following these patients long term,” she added.

In answer to a question during the main session about using age alone as an inclusion criterion in those over 80 years old, Toff said, “We were more comfortable taking all comers over 80 years of age because of the uncertainty about TAVR is more in relation to its durability and the clinical significance of the aortic regurgitation, which may have consequences in the longer term. But the longer term for the over 80s is obviously less of a problem than for those in their 70s.”

This study was funded by the UK National Institute for Health Research Health Technology Assessment Programme. Toff reports no disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20410-ACC. Presented March 29, 2020.

This article first appeared on Medscape.com.

Transcatheter aortic valve replacement (TAVR) was not inferior to conventional surgery with respect to death from any cause at 1 year in a new real-world study in patients age 70 years or older with severe symptomatic aortic stenosis at increased operative risk due to age or comorbidity.

The UK TAVI study was presented March 29 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

The trial involved a broad group of patients who were treated at every medical center that performs the transcatheter procedure across the United Kingdom.

“The importance of this trial is that it confirms the effectiveness of the TAVR strategy in a real-world setting,” said lead author, William D. Toff, MD, professor of cardiology at the University of Leicester, United Kingdom.

Previous clinical trials have found TAVR to be noninferior or superior to open-heart surgery for various patient groups, but most trials have been limited to medical centers that perform a high volume of procedures or focus on the use of specific types of replacement valves, he noted.

“Our results are concordant with those from earlier trials in intermediate- and low-risk patients, but those earlier trials were performed in the best centers and had many exclusion criteria. We have replicated those results in populations more representative of the real world.”

“I think it is a very important message that supports the findings in earlier trials that were focused on showing whether TAVR can work under ideal conditions, while our trial shows that it does work in real-world clinical practice,” he added.

The UK TAVI trial enrolled 913 patients referred for treatment of severe aortic stenosis at 34 UK sites from 2014 to 2018. They were randomly assigned to receive TAVR or open-heart surgery.

Enrollment was limited to participants age 70 years or older (with additional risk factors) or age 80 years or older (with or without additional risk factors). The average age was 81 years.

Overall, participants were at intermediate to low risk from surgery, with a median Society of Thoracic Surgeons (STS) risk score of 2.6%. However, researchers did not specify a particular risk score cutoff for enrollment.

“This allowed the trial to evolve along with changes in guidelines and practice regarding TAVR over the course of the study and to reflect physicians’ nuanced, real-world approach to considering risk in decision-making rather than taking a formulaic approach,” Toff said.

At 1 year, the rate of death from any cause (the primary endpoint) was 4.6% in the TAVR group and 6.6% in the surgery group, a difference that met the trial’s prespecified threshold for noninferiority of TAVR.

Rates of death from cardiovascular disease or stroke were also similar between the two groups.

Patients who received TAVR had a significantly higher rate of vascular complications (4.8%) than those receiving surgery (1.3%).

TAVR patients were also more likely to have a pacemaker implanted. This occurred in 12.2% of TAVR patients and 6.6% of those undergoing surgery.

In addition, patients who underwent TAVR had a higher rate of aortic regurgitation. Mild aortic regurgitation occurred at 1 year in 38.3% of the TAVR group and 11.7% of the surgery group, whereas moderate regurgitation occurred in 2.3% of TAVR patients and 0.6% of surgery patients.

On the other hand, patients undergoing TAVR had a significantly lower rate of major bleeding complications, which occurred in 6.3% of patients having TAVR and 17.1% of those undergoing surgery.

TAVR was also associated with a shorter hospital stay, fewer days in intensive care, and a faster improvement in functional capacity and quality of life. Functional capacity and quality-of-life measures at 6 weeks after the procedure were better in the TAVR group but by 1 year they were similar in the two groups.

“Longer follow-up is required to confirm sustained clinical benefit and valve durability to inform clinical practice, particularly in younger patients,” Toff concluded.

“The results from our trial and others are encouraging, but patients need to be fully informed and know that the long-term durability of the TAVR valves and the long-term implications of the increased risk of aortic regurgitation are still uncertain,” he added.

The researchers plan to continue to track outcomes for a minimum of 5 years.

Discussant of the UK TAVI trial at an ACC press conference, Julia Grapsa, MD, Guys and St Thomas NHS Trust, London, United Kingdom, said it was a well-designed study.

“It was impressive to see so many UK sites and the age range of patients from 70 to 91 years, and the shorter hospital stays and functional recoveries as well as reduced major bleeding in the TAVR group,” Grapsa said.

“But something that was very striking to me was the increase in moderate aortic regurgitation in the TAVR arm, 2.3% versus 0.6% in the surgical arm, so it is very important to keep following these patients long term,” she added.

In answer to a question during the main session about using age alone as an inclusion criterion in those over 80 years old, Toff said, “We were more comfortable taking all comers over 80 years of age because of the uncertainty about TAVR is more in relation to its durability and the clinical significance of the aortic regurgitation, which may have consequences in the longer term. But the longer term for the over 80s is obviously less of a problem than for those in their 70s.”

This study was funded by the UK National Institute for Health Research Health Technology Assessment Programme. Toff reports no disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20410-ACC. Presented March 29, 2020.

This article first appeared on Medscape.com.

Transcatheter aortic valve replacement (TAVR) was not inferior to conventional surgery with respect to death from any cause at 1 year in a new real-world study in patients age 70 years or older with severe symptomatic aortic stenosis at increased operative risk due to age or comorbidity.

The UK TAVI study was presented March 29 at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

The trial involved a broad group of patients who were treated at every medical center that performs the transcatheter procedure across the United Kingdom.

“The importance of this trial is that it confirms the effectiveness of the TAVR strategy in a real-world setting,” said lead author, William D. Toff, MD, professor of cardiology at the University of Leicester, United Kingdom.

Previous clinical trials have found TAVR to be noninferior or superior to open-heart surgery for various patient groups, but most trials have been limited to medical centers that perform a high volume of procedures or focus on the use of specific types of replacement valves, he noted.

“Our results are concordant with those from earlier trials in intermediate- and low-risk patients, but those earlier trials were performed in the best centers and had many exclusion criteria. We have replicated those results in populations more representative of the real world.”

“I think it is a very important message that supports the findings in earlier trials that were focused on showing whether TAVR can work under ideal conditions, while our trial shows that it does work in real-world clinical practice,” he added.

The UK TAVI trial enrolled 913 patients referred for treatment of severe aortic stenosis at 34 UK sites from 2014 to 2018. They were randomly assigned to receive TAVR or open-heart surgery.

Enrollment was limited to participants age 70 years or older (with additional risk factors) or age 80 years or older (with or without additional risk factors). The average age was 81 years.

Overall, participants were at intermediate to low risk from surgery, with a median Society of Thoracic Surgeons (STS) risk score of 2.6%. However, researchers did not specify a particular risk score cutoff for enrollment.

“This allowed the trial to evolve along with changes in guidelines and practice regarding TAVR over the course of the study and to reflect physicians’ nuanced, real-world approach to considering risk in decision-making rather than taking a formulaic approach,” Toff said.

At 1 year, the rate of death from any cause (the primary endpoint) was 4.6% in the TAVR group and 6.6% in the surgery group, a difference that met the trial’s prespecified threshold for noninferiority of TAVR.

Rates of death from cardiovascular disease or stroke were also similar between the two groups.

Patients who received TAVR had a significantly higher rate of vascular complications (4.8%) than those receiving surgery (1.3%).

TAVR patients were also more likely to have a pacemaker implanted. This occurred in 12.2% of TAVR patients and 6.6% of those undergoing surgery.

In addition, patients who underwent TAVR had a higher rate of aortic regurgitation. Mild aortic regurgitation occurred at 1 year in 38.3% of the TAVR group and 11.7% of the surgery group, whereas moderate regurgitation occurred in 2.3% of TAVR patients and 0.6% of surgery patients.

On the other hand, patients undergoing TAVR had a significantly lower rate of major bleeding complications, which occurred in 6.3% of patients having TAVR and 17.1% of those undergoing surgery.

TAVR was also associated with a shorter hospital stay, fewer days in intensive care, and a faster improvement in functional capacity and quality of life. Functional capacity and quality-of-life measures at 6 weeks after the procedure were better in the TAVR group but by 1 year they were similar in the two groups.

“Longer follow-up is required to confirm sustained clinical benefit and valve durability to inform clinical practice, particularly in younger patients,” Toff concluded.

“The results from our trial and others are encouraging, but patients need to be fully informed and know that the long-term durability of the TAVR valves and the long-term implications of the increased risk of aortic regurgitation are still uncertain,” he added.

The researchers plan to continue to track outcomes for a minimum of 5 years.

Discussant of the UK TAVI trial at an ACC press conference, Julia Grapsa, MD, Guys and St Thomas NHS Trust, London, United Kingdom, said it was a well-designed study.

“It was impressive to see so many UK sites and the age range of patients from 70 to 91 years, and the shorter hospital stays and functional recoveries as well as reduced major bleeding in the TAVR group,” Grapsa said.

“But something that was very striking to me was the increase in moderate aortic regurgitation in the TAVR arm, 2.3% versus 0.6% in the surgical arm, so it is very important to keep following these patients long term,” she added.

In answer to a question during the main session about using age alone as an inclusion criterion in those over 80 years old, Toff said, “We were more comfortable taking all comers over 80 years of age because of the uncertainty about TAVR is more in relation to its durability and the clinical significance of the aortic regurgitation, which may have consequences in the longer term. But the longer term for the over 80s is obviously less of a problem than for those in their 70s.”

This study was funded by the UK National Institute for Health Research Health Technology Assessment Programme. Toff reports no disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 20-LB-20410-ACC. Presented March 29, 2020.

This article first appeared on Medscape.com.

The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.

However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.

In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.

The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.

Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.

However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”

Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.

“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”

Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.

“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.

Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”

“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.

“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”

The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.

In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.

After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).

A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).

“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.

There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.

The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.

Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.

As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”

“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.

The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.

The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.

This article first appeared on Medscape.com.

The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.

However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.

In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.

The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.

Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.

However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”

Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.

“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”

Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.

“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.

Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”

“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.

“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”

The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.

In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.

After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).

A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).

“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.

There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.

The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.

Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.

As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”

“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.

The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.

The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.

This article first appeared on Medscape.com.

The largest trial to date investigating the clinical utility of using genetic testing to detect clopidogrel loss-of-function genotype to guide antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) missed its primary endpoint of a 50% reduction in cardiovascular events at 1 year.

However, the TAILOR-PCI trial did show a 34% reduction in such events at 1 year, as well as a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.

In addition, a post hoc analysis found a significant 79% reduction in the rate of adverse events in the first 3 months of treatment among patients who received genetically guided therapy compared with those who did not.

The study was presented March 28 during the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

“Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not,” concluded Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.

Pereira said the post hoc analysis of the first 3 months of treatment was particularly interesting. “This period immediately after PCI is when patients are at the highest risk for adverse events. We now know that antiplatelet drug therapy is critical during the first 3 months after PCI. Our findings suggest that the lion’s share of the benefit of genetically guided therapy may occur during this high-risk period,” he noted.

However, he added, “Because this wasn’t a preplanned analysis, we can’t draw firm conclusions from it, but it merits further study.”

Asked during an ACC virtual press conference how these results may influence clinical practice, Pereira said he hopes it changes practice toward genotyping.

“We set a very high standard in trying to achieve a 50% reduction in events, but we did see a 34% reduction. I think the probability of the results being true is very high,” he said. “I hope people pay attention to that. I’m not sure what the guidelines will do, but I believe if clopidogrel genetic information is made available to the physician, not changing therapy in a patient who has the loss-of-function gene will now be very difficult.”

Discussant of the trial, Roxana Mehran, MD, Mount Sinai Hospital, New York City, said she thought the results were good enough clinically to justify using genotyping to guide therapy.

“The trial showed an absolute 1.8% reduction and a relative 34% reduction in cardiovascular events, which did not quite meet the P value for significance, and they are supported by a significant reduction in multiple events, and a large difference at 3 months, although these are not primary analyses. So, for me this trial has shown that tailoring antiplatelet therapy by genetic testing is beneficial,” she said.

Another outside commentator, Patrick O’Gara, MD, Brigham and Women’s Hospital, Boston, Massachusetts, described TAILOR-PCI as a “terrific study.”

“Together with the study presented last year showing genotype-guided clopidogrel treatment was noninferior to ticagrelor/prasugrel in STEMI [non-ST-segment elevation myocardial infarction] patients, it chips away at the biologic appropriateness of targeting therapies based on genetic risk,” he said.

“I would hate people to focus on the fact the primary endpoint was missed by one hundredth of a percentage point but hope they would rather consider the bigger picture of making this genotype test more available and accessible to inform clinical decision making,” O’Gara added. “It just makes too much sense to ignore this potential.”

The TAILOR-PCI trial enrolled 5302 patients from 40 centers in the United States, Canada, Mexico, and South Korea who had undergone PCI with stenting. They were randomly assigned to genetic testing for the clopidogrel loss-of-function variant or a group that received standard treatment (clopidogrel) without genetic testing.

In the genetic testing group, 35% of patients were found to have the clopidogrel loss-of-function variant and were therefore prescribed ticagrelor, whereas those without the loss-of-function variant received clopidogrel.

After 1 year, the primary endpoint, a composite of cardiovascular death, MI, stroke, definite or probable stent thrombosis, and severe recurrent ischemia, occurred in 35 patients (4%) of the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group (adjusted hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43 - 1.02; P = .56).

A prespecified analysis of total events (rather than just analysis of first event per patient) showed a 40% reduction in the genotyped group (HR, 0.60; 95% CI, 0.41 - 0.89; P = .011).

“Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy,” Pereira said.

There was no difference in the safety endpoint of TIMI major bleeding or minor bleeding between the two groups: 1.9% in the genetically guided group vs 1.6% in the conventional treatment group.

The results did not differ between various subgroups in the trial, including race or ethnicity. Although Asian patients have a higher occurrence of the clopidogrel loss-of-function gene, the event risk reductions were similar in Asian and white patients in the study.

Pereira said the study may have been underpowered because of recent improvements in care. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, but during the trial, greater use of drug-coated stents and other treatments significantly reduced the expected rate of adverse events and made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, he explained.

As part of the discussion, Mehran pointed out that more than 80% of the patients in the trial had acute coronary syndrome (ACS) and yet were being sent home on clopidogrel, which she said she found “daunting.”

“This begs the question of whether they were lower-risk patients and not really the hot unstable ACS patients with large thrombus burden where we see higher event rates,” Mehran commented. She also noted the results must be considered in the new era of platelet monotherapy, where aspirin is being withdrawn, and asked whether clopidogrel monotherapy would be considered safe without aspirin on board.

The researchers are planning a cost-effectiveness analysis of genetically guided therapy based on these data, and they are also continuing to follow patients over the longer term.

The TAILOR-PCI study was funded by the Mayo Clinic in collaboration with the National Heart, Lung, and Blood Institute. Spartan Bioscience Inc supplied the genetic tests used. Pereira reports no relevant disclosures.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology. Abstract 20-LB-20309-ACC. Presented March 28, 2020.

This article first appeared on Medscape.com.

A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Frontline Medical News

This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.

“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).

Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.

The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.

A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.

Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.

“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.

Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”

“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.

Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.

“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.

“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.

“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.

Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.

[email protected]

A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Frontline Medical News

This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.

“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).

Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.

The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.

A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.

Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.

“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.

Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”

“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.

Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.

“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.

“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.

“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.

Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.

[email protected]

A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Frontline Medical News

This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.

“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).

Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.

The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.

A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.

Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.

“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.

Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”

“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.

Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.

“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.

“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.

“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.

Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.

[email protected]

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.

The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.

“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”

“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.

Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.

VOYAGER PAD trial

The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).

Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.

“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.

[email protected]

SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.

From the Society for Thoracic Surgeons (STS)/ACC Transcatheter Valve Therapy (TVT) Registry, the group identified 120,080 patients who had TAVR at 559 US sites, from January 2016 to March 2019.

During this time, the percentage of procedures that were done using conscious sedation almost doubled, plateauing in the final 6 months.

And the proportion of sites using any conscious sedation during TAVR increased from 50% to 76%.

The use of this procedure varied widely among the sites: 26% performed >80% of TAVR with conscious sedation, and 13% did not perform any TAVR cases with conscious sedation.

In hospitals in the lowest and highest quartiles of use of conscious sedation during TAVR, this type of sedation was used in a median of 0% of TAVR cases and 91% of cases, respectively.

The researchers used instrumental variable analysis to compare outcomes in patients whose type of anesthesia would differ if they went to a hospital with high or low use of conscious sedation.

Using this method, the use of conscious sedation was associated with a 0.2% absolute risk difference in in-hospital death, the primary study endpoint (P = .010).

And compared with general anesthesia, conscious sedation during TAVR was also associated with a lower rate of 30-day death (2.0% vs 2.5%, respectively), fewer days in the hospital (3.5 vs 4.3 days), and a higher rate of being discharged to home (88.9% vs 86.1%, all P < .001).

“Our results would not apply to those patients who always receive general anesthesia, even at high conscious sedation use centers (eg, patients with severe lung disease on oxygen or significant right ventricular dysfunction),” the authors caution.

Study limitations, next steps

A study limitation is that the registry data did not specify the type of conscious sedation that was used, Cohen acknowledged.

This could vary. For example, a patient could be given a very powerful sedative such as propofol (Diprivan), and his or her respiration and oxygen saturation would be monitored, and an anesthesiologist would be always present. Or the patient could receive sedation like that for angioplasty — diazepam (Valium) or midazolam (Versed) and a narcotic — without an anesthesiologist.

It would be useful to look at the TAVR volumes and compare outcomes within different TAVR volume quartiles, Tang suggested.

In low-volume centers, the anesthesiologist may be uncomfortable with complex cases, whereas larger academic centers would perform more complex procedures and may paradoxically have a slightly higher rate of complications, he speculated.

Future research should investigate what drives the differences in the use of conscious sedation, the authors suggest.

Cohen reports institutional grant support and consulting fees from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. Butala is funded by the John S. LaDue Memorial Fellowship at Harvard Medical School and reports consulting fees and ownership interest in HiLabs, outside the submitted work. The disclosures of the other authors are listed with the original article.

This article first appeared on Medscape.com.

From the Society for Thoracic Surgeons (STS)/ACC Transcatheter Valve Therapy (TVT) Registry, the group identified 120,080 patients who had TAVR at 559 US sites, from January 2016 to March 2019.

During this time, the percentage of procedures that were done using conscious sedation almost doubled, plateauing in the final 6 months.

And the proportion of sites using any conscious sedation during TAVR increased from 50% to 76%.

The use of this procedure varied widely among the sites: 26% performed >80% of TAVR with conscious sedation, and 13% did not perform any TAVR cases with conscious sedation.

In hospitals in the lowest and highest quartiles of use of conscious sedation during TAVR, this type of sedation was used in a median of 0% of TAVR cases and 91% of cases, respectively.

The researchers used instrumental variable analysis to compare outcomes in patients whose type of anesthesia would differ if they went to a hospital with high or low use of conscious sedation.

Using this method, the use of conscious sedation was associated with a 0.2% absolute risk difference in in-hospital death, the primary study endpoint (P = .010).

And compared with general anesthesia, conscious sedation during TAVR was also associated with a lower rate of 30-day death (2.0% vs 2.5%, respectively), fewer days in the hospital (3.5 vs 4.3 days), and a higher rate of being discharged to home (88.9% vs 86.1%, all P < .001).

“Our results would not apply to those patients who always receive general anesthesia, even at high conscious sedation use centers (eg, patients with severe lung disease on oxygen or significant right ventricular dysfunction),” the authors caution.

Study limitations, next steps

A study limitation is that the registry data did not specify the type of conscious sedation that was used, Cohen acknowledged.

This could vary. For example, a patient could be given a very powerful sedative such as propofol (Diprivan), and his or her respiration and oxygen saturation would be monitored, and an anesthesiologist would be always present. Or the patient could receive sedation like that for angioplasty — diazepam (Valium) or midazolam (Versed) and a narcotic — without an anesthesiologist.

It would be useful to look at the TAVR volumes and compare outcomes within different TAVR volume quartiles, Tang suggested.

In low-volume centers, the anesthesiologist may be uncomfortable with complex cases, whereas larger academic centers would perform more complex procedures and may paradoxically have a slightly higher rate of complications, he speculated.

Future research should investigate what drives the differences in the use of conscious sedation, the authors suggest.

Cohen reports institutional grant support and consulting fees from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. Butala is funded by the John S. LaDue Memorial Fellowship at Harvard Medical School and reports consulting fees and ownership interest in HiLabs, outside the submitted work. The disclosures of the other authors are listed with the original article.

This article first appeared on Medscape.com.

From the Society for Thoracic Surgeons (STS)/ACC Transcatheter Valve Therapy (TVT) Registry, the group identified 120,080 patients who had TAVR at 559 US sites, from January 2016 to March 2019.

During this time, the percentage of procedures that were done using conscious sedation almost doubled, plateauing in the final 6 months.

And the proportion of sites using any conscious sedation during TAVR increased from 50% to 76%.

The use of this procedure varied widely among the sites: 26% performed >80% of TAVR with conscious sedation, and 13% did not perform any TAVR cases with conscious sedation.

In hospitals in the lowest and highest quartiles of use of conscious sedation during TAVR, this type of sedation was used in a median of 0% of TAVR cases and 91% of cases, respectively.

The researchers used instrumental variable analysis to compare outcomes in patients whose type of anesthesia would differ if they went to a hospital with high or low use of conscious sedation.

Using this method, the use of conscious sedation was associated with a 0.2% absolute risk difference in in-hospital death, the primary study endpoint (P = .010).

And compared with general anesthesia, conscious sedation during TAVR was also associated with a lower rate of 30-day death (2.0% vs 2.5%, respectively), fewer days in the hospital (3.5 vs 4.3 days), and a higher rate of being discharged to home (88.9% vs 86.1%, all P < .001).

“Our results would not apply to those patients who always receive general anesthesia, even at high conscious sedation use centers (eg, patients with severe lung disease on oxygen or significant right ventricular dysfunction),” the authors caution.

Study limitations, next steps

A study limitation is that the registry data did not specify the type of conscious sedation that was used, Cohen acknowledged.

This could vary. For example, a patient could be given a very powerful sedative such as propofol (Diprivan), and his or her respiration and oxygen saturation would be monitored, and an anesthesiologist would be always present. Or the patient could receive sedation like that for angioplasty — diazepam (Valium) or midazolam (Versed) and a narcotic — without an anesthesiologist.

It would be useful to look at the TAVR volumes and compare outcomes within different TAVR volume quartiles, Tang suggested.

In low-volume centers, the anesthesiologist may be uncomfortable with complex cases, whereas larger academic centers would perform more complex procedures and may paradoxically have a slightly higher rate of complications, he speculated.

Future research should investigate what drives the differences in the use of conscious sedation, the authors suggest.

Cohen reports institutional grant support and consulting fees from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. Butala is funded by the John S. LaDue Memorial Fellowship at Harvard Medical School and reports consulting fees and ownership interest in HiLabs, outside the submitted work. The disclosures of the other authors are listed with the original article.

This article first appeared on Medscape.com.

There has been a dramatic rise in hypertension-related deaths in the United States between 2007 and 2017, a new study shows. The authors, led by Lakshmi Nambiar, MD, Larner College of Medicine, University of Vermont, Burlington, analyzed data from the Centers for Disease Control and Prevention, which collates information from every death certificate in the country, amounting to more than 10 million deaths.

They found that age-adjusted hypertension-related deaths had increased from 18.3 per 100,000 in 2007 to 23.0 per 100,000 in 2017 (P < .001 for decade-long temporal trend).

Nambiar reported results of the study at an American College of Cardiology 2020/World Congress of Cardiology press conference on March 19. It was also published online on the same day in the Journal of the American College of Cardiology.

She noted that death rates due to cardiovascular disease have been falling over the past 20 years largely attributable to statins to treat high cholesterol and stents to treat coronary artery disease. But since 2011, the rate of decline in cardiovascular deaths has slowed. One contributing factor is an increase in heart failure-related deaths but there hasn’t been any data in recent years on hypertension-related deaths.

“Our data show an increase in hypertension-related deaths in all age groups, in all regions of the United States, and in both sexes. These findings are alarming and warrant further investigation, as well as preventative efforts,” Nambiar said. “This is a public health emergency that has not been fully recognized,” she added.

“We were surprised to see how dramatically these deaths were increasing, and we think this is related to the rise in diabetes, obesity, and the aging of the population. We need targeted public health measures to address some of those factors,” Nambiar told Medscape Medical News.

“We are winning the battle against coronary artery disease with statins and stents but we are not winning the battle against hypertension,” she added.
 

Worst Figures in Rural South

Results showed that hypertension-related deaths increased in both rural and urban regions, but the increase was much steeper in rural areas — a 72% increase over the decade compared with a 20% increase in urban areas.

The highest death risk was identified in the rural South, which demonstrated an age-adjusted 2.5-fold higher death rate compared with other regions (P < .001).

The urban South also demonstrated increasing hypertension-related cardiovascular death rates over time: age-adjusted death rates in the urban South increased by 27% compared with all other urban regions (P < .001).

But the absolute mortality rates and slope of the curves demonstrate the highest risk in patients in the rural South, the researchers report. Age-adjusted hypertension-related death rates increased in the rural South from 23.9 deaths per 100,000 in 2007 to 39.5 deaths per 100,000 in 2017.

Nambiar said the trends in the rural South could be related to social factors and lack of access to healthcare in the area, which has been exacerbated by failure to adopt Medicaid expansion in many of the states in this region.

“When it comes to the management of hypertension you need to be seen regularly by a primary care doctor to get the best treatment and regular assessments,” she stressed.

Chair of the ACC press conference at which the data were presented, Martha Gulati, MD, University of Arizona School of Medicine, Phoenix, said: “In this day and time, there is less smoking, which should translate into lower rates of hypertension, but these trends reported here are very different from what we would expect and are probably associated with the rise in other risk factors such as diabetes and obesity, especially in the rural South.”

Nambiar praised the new ACC/AHA hypertension guidelines that recommend a lower diagnostic threshold, “so more people now fit the criteria for raised blood pressure and need treatment.”

“It is important for all primary care physicians and cardiologists to recognize the new threshold and treat people accordingly,” she said. “High blood pressure is the leading cause of cardiovascular disease. If we can control it better, we may be able to control some of this increased mortality we are seeing.”

This article first appeared on Medscape.com.

There has been a dramatic rise in hypertension-related deaths in the United States between 2007 and 2017, a new study shows. The authors, led by Lakshmi Nambiar, MD, Larner College of Medicine, University of Vermont, Burlington, analyzed data from the Centers for Disease Control and Prevention, which collates information from every death certificate in the country, amounting to more than 10 million deaths.

They found that age-adjusted hypertension-related deaths had increased from 18.3 per 100,000 in 2007 to 23.0 per 100,000 in 2017 (P < .001 for decade-long temporal trend).

Nambiar reported results of the study at an American College of Cardiology 2020/World Congress of Cardiology press conference on March 19. It was also published online on the same day in the Journal of the American College of Cardiology.

She noted that death rates due to cardiovascular disease have been falling over the past 20 years largely attributable to statins to treat high cholesterol and stents to treat coronary artery disease. But since 2011, the rate of decline in cardiovascular deaths has slowed. One contributing factor is an increase in heart failure-related deaths but there hasn’t been any data in recent years on hypertension-related deaths.

“Our data show an increase in hypertension-related deaths in all age groups, in all regions of the United States, and in both sexes. These findings are alarming and warrant further investigation, as well as preventative efforts,” Nambiar said. “This is a public health emergency that has not been fully recognized,” she added.

“We were surprised to see how dramatically these deaths were increasing, and we think this is related to the rise in diabetes, obesity, and the aging of the population. We need targeted public health measures to address some of those factors,” Nambiar told Medscape Medical News.

“We are winning the battle against coronary artery disease with statins and stents but we are not winning the battle against hypertension,” she added.
 

Worst Figures in Rural South

Results showed that hypertension-related deaths increased in both rural and urban regions, but the increase was much steeper in rural areas — a 72% increase over the decade compared with a 20% increase in urban areas.

The highest death risk was identified in the rural South, which demonstrated an age-adjusted 2.5-fold higher death rate compared with other regions (P < .001).

The urban South also demonstrated increasing hypertension-related cardiovascular death rates over time: age-adjusted death rates in the urban South increased by 27% compared with all other urban regions (P < .001).

But the absolute mortality rates and slope of the curves demonstrate the highest risk in patients in the rural South, the researchers report. Age-adjusted hypertension-related death rates increased in the rural South from 23.9 deaths per 100,000 in 2007 to 39.5 deaths per 100,000 in 2017.

Nambiar said the trends in the rural South could be related to social factors and lack of access to healthcare in the area, which has been exacerbated by failure to adopt Medicaid expansion in many of the states in this region.

“When it comes to the management of hypertension you need to be seen regularly by a primary care doctor to get the best treatment and regular assessments,” she stressed.

Chair of the ACC press conference at which the data were presented, Martha Gulati, MD, University of Arizona School of Medicine, Phoenix, said: “In this day and time, there is less smoking, which should translate into lower rates of hypertension, but these trends reported here are very different from what we would expect and are probably associated with the rise in other risk factors such as diabetes and obesity, especially in the rural South.”

Nambiar praised the new ACC/AHA hypertension guidelines that recommend a lower diagnostic threshold, “so more people now fit the criteria for raised blood pressure and need treatment.”

“It is important for all primary care physicians and cardiologists to recognize the new threshold and treat people accordingly,” she said. “High blood pressure is the leading cause of cardiovascular disease. If we can control it better, we may be able to control some of this increased mortality we are seeing.”

This article first appeared on Medscape.com.

There has been a dramatic rise in hypertension-related deaths in the United States between 2007 and 2017, a new study shows. The authors, led by Lakshmi Nambiar, MD, Larner College of Medicine, University of Vermont, Burlington, analyzed data from the Centers for Disease Control and Prevention, which collates information from every death certificate in the country, amounting to more than 10 million deaths.

They found that age-adjusted hypertension-related deaths had increased from 18.3 per 100,000 in 2007 to 23.0 per 100,000 in 2017 (P < .001 for decade-long temporal trend).

Nambiar reported results of the study at an American College of Cardiology 2020/World Congress of Cardiology press conference on March 19. It was also published online on the same day in the Journal of the American College of Cardiology.

She noted that death rates due to cardiovascular disease have been falling over the past 20 years largely attributable to statins to treat high cholesterol and stents to treat coronary artery disease. But since 2011, the rate of decline in cardiovascular deaths has slowed. One contributing factor is an increase in heart failure-related deaths but there hasn’t been any data in recent years on hypertension-related deaths.

“Our data show an increase in hypertension-related deaths in all age groups, in all regions of the United States, and in both sexes. These findings are alarming and warrant further investigation, as well as preventative efforts,” Nambiar said. “This is a public health emergency that has not been fully recognized,” she added.

“We were surprised to see how dramatically these deaths were increasing, and we think this is related to the rise in diabetes, obesity, and the aging of the population. We need targeted public health measures to address some of those factors,” Nambiar told Medscape Medical News.

“We are winning the battle against coronary artery disease with statins and stents but we are not winning the battle against hypertension,” she added.
 

Worst Figures in Rural South

Results showed that hypertension-related deaths increased in both rural and urban regions, but the increase was much steeper in rural areas — a 72% increase over the decade compared with a 20% increase in urban areas.

The highest death risk was identified in the rural South, which demonstrated an age-adjusted 2.5-fold higher death rate compared with other regions (P < .001).

The urban South also demonstrated increasing hypertension-related cardiovascular death rates over time: age-adjusted death rates in the urban South increased by 27% compared with all other urban regions (P < .001).

But the absolute mortality rates and slope of the curves demonstrate the highest risk in patients in the rural South, the researchers report. Age-adjusted hypertension-related death rates increased in the rural South from 23.9 deaths per 100,000 in 2007 to 39.5 deaths per 100,000 in 2017.

Nambiar said the trends in the rural South could be related to social factors and lack of access to healthcare in the area, which has been exacerbated by failure to adopt Medicaid expansion in many of the states in this region.

“When it comes to the management of hypertension you need to be seen regularly by a primary care doctor to get the best treatment and regular assessments,” she stressed.

Chair of the ACC press conference at which the data were presented, Martha Gulati, MD, University of Arizona School of Medicine, Phoenix, said: “In this day and time, there is less smoking, which should translate into lower rates of hypertension, but these trends reported here are very different from what we would expect and are probably associated with the rise in other risk factors such as diabetes and obesity, especially in the rural South.”

Nambiar praised the new ACC/AHA hypertension guidelines that recommend a lower diagnostic threshold, “so more people now fit the criteria for raised blood pressure and need treatment.”

“It is important for all primary care physicians and cardiologists to recognize the new threshold and treat people accordingly,” she said. “High blood pressure is the leading cause of cardiovascular disease. If we can control it better, we may be able to control some of this increased mortality we are seeing.”

This article first appeared on Medscape.com.

A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.

This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.

Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.

Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.

In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).

PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).

However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.

SBP and cardiovascular outcomes in HFpEF

In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.

Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.

Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.

In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”

“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.

Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.

[email protected]

SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.

A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.

This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.

Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.

Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.

In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).

PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).

However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.

SBP and cardiovascular outcomes in HFpEF

In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.

Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.

Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.

In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”

“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.

Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.

[email protected]

SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.

A target systolic blood pressure (SBP) of 120-129 mm Hg in patients with heart failure with preserved ejection fraction proved to be the sweet spot with the lowest rates of major adverse cardiovascular and renal events in a new analysis from the landmark PARAGON-HF trial.

This finding from the largest-ever randomized, controlled study in heart failure with preserved ejection fraction (HFpEF) strengthens support for current U.S. joint hypertension guidelines, which call for a target SBP less than 130 mm Hg in patients with HFpEF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803), a recommendation based upon weak evidence until now. That’s because the SPRINT trial, the major impetus for adoption of intensive blood pressure control in the current guidelines, excluded patients with symptomatic HF, Scott D. Solomon, MD, and coinvestigators noted in their new analysis. The study was published in the Journal of the American College of Cardiology and had been planned for presentation during the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

The new analysis from PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) also ruled out the SBP-lowering effect of sacubitril/valsartan (Entresto) as the explanation for the combination drug’s demonstrated beneficial impact on outcomes in the subgroup with an SBP of 120-129 mm Hg. That wasn’t actually a surprise. Indeed, the new study had two hypotheses: one, that the relationship between SBP and cardiovascular and renal outcomes in HFpEF would follow a J-shaped curve, and two, that sacubitril/valsartan’s blood pressure–lowering effect would not account for the drug’s outcome benefits in the subset of HFpEF patients with an SBP in the sweet spot of 120-129 mm Hg. Both hypotheses were borne out, noted Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

“These data strongly support that additional mechanisms other than blood pressure–lowering account for the benefit. But this is not surprising. The same can be said for most of the therapies that work in heart failure,” he said in an interview.

Take, for example, spironolactone. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), another major trial in which Dr. Solomon played a leadership role, the beneficial effect of spironolactone on clinical outcomes also proved unrelated to the drug’s blood pressure–lowering effect.

Other known effects of sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, or ARNI, might in theory account for the observed clinical benefits in ARNI-treated patients with an on-treatment SBP of 120-129 mm Hg in PARAGON-HF. These include improved left atrial remodeling, an increase in natriuretic peptides, and improved myocardial relaxation. However, the current lack of understanding of the basic mechanistic processes underlying the varied clinical expressions of HFpEF is a major factor contributing to the lack of any proven-effective therapy for this extremely common and costly disorder, according to Dr. Solomon and coinvestigators.

In contrast to HFpEF, for which to date there is no proven treatment, heart failure with reduced ejection fraction sacubitril/valsartan has a class I recommendation on the strength of its performance in significantly reducing cardiovascular deaths and heart failure hospitalizations in the PARADIGM-HF trial (N Engl J Med. 2014 Sep 11;371:993-1004).

PARAGON-HF included 4,822 patients with symptomatic HFpEF who were randomized to sacubitril/valsartan at 97/103 mg b.i.d. or valsartan at 160 mg b.i.d. As previously reported (N Engl J Med. 2019 Oct 24;381[17]:1609-20), at an average follow-up of 35 months, the primary outcome – a composite of total hospitalizations for heart failure and cardiovascular death – occurred at a rate of 12.8 events per 100 patient-years in the sacubitril/valsartan group and 14.6 per 100 patient-years in the valsartan arm, for a 13% relative risk reduction that narrowly missed statistical significance (P = .059).

However, sacubitril/valsartan showed significant benefit on some prespecified secondary endpoints, including worsening renal function, change in New York Heart Association class, and quality of life. Women, who notably accounted for 52% of study participants, appeared to benefit from sacubitril/valsartan more than men as evidenced by their 27% relative risk reduction in the primary endpoint. Also, in the roughly half of PARAGON-HF participants with a baseline left ventricular ejection fraction of 45%-57%, treatment with sacubitril/valsartan resulted in a statistically significant 22% relative risk reduction in the primary endpoint, compared with valsartan alone.

SBP and cardiovascular outcomes in HFpEF

In the new analysis, Dr. Solomon and coworkers examined outcomes based on baseline and mean achieved SBP quartiles regardless of treatment arm. In an unadjusted analysis, the primary composite endpoint occurred at a rate of 15.2 events/100 patient-years in HFpEF patients with an achieved SBP below 120 mm Hg, 11.4/100 patient-years at 120-129 mm Hg, 12.2/100 patient-years at 130-139 mm Hg, and 15.6/100 patient-years at 140 mm Hg or more. Further, in a multivariate regression analysis extensively adjusted for atrial fibrillation, sex, race, and numerous other potential confounders, the group with an achieved SBP of 120-129 mm Hg continued to fare best. The adjusted risks for the primary endpoint were 11% and 21% higher in patients in the first and third quartiles of achieved SBP, compared with those at 120-129 mm Hg, although neither trend reached statistical significance. But patients in the top quartile, with an achieved SBP of 140 mm Hg or more, had a highly significant 56% increase in risk, compared with patients in the second-lowest SBP quartile.

Change in blood pressure from baseline to week 48 had no impact on quality of life or high-sensitivity troponin T. However, each 10–mm Hg lowering of SBP was associated with a modest 2.1% reduction in log-transformed N-terminal of the prohormone brain natriuretic peptide.

Sacubitril/valsartan reduced SBP by an average of 5.2 mm Hg more than valsartan alone at 4 weeks regardless of baseline SBP. And the combo drug had a significantly greater SBP-lowering effect in women than men, by a margin of 6.3 mm Hg versus 4.0 mm Hg. But a Cox regression analysis showed that in women, as in the study population as a whole, sacubitril/valsartan’s SBP-lowering effects didn’t account for the drug’s impact on outcomes.

In an editorial accompanying publication of the new PARAGON-HF blood pressure analysis (J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.024), Hector O. Ventura, MD, and colleagues at the Ochsner Clinic in New Orleans observed that the study results “lend some credence to the prognostic relationship of blood pressure in HFpEF, but whether they should serve as a therapeutic target or are merely a prognostic surrogate determined by other pathogenic factors, such as vascular ventricular uncoupling or aortic stiffness on one hand when blood pressure is greater than 140 mm Hg, or a reduced cardiac performance indicated by reduced blood pressure to less than 120 mm Hg, remains uncertain.”

“What is certain, however, is that the relationship and contributions of hypertension in manifest HFpEF are complex, multifactorial and likely go well beyond a simplistic framework of hemodynamic influences,” they added.

Dr. Solomon has received research grants from and serves as a consultant to Novartis, which funded PARAGON-HF, and has similar financial relationships with more than a dozen other pharmaceutical companies. Dr. Ventura reported having no relevant financial interests.

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SOURCE: Solomon SD et al. J Am Coll Cardiol. 2020 Mar 16. doi: 10.1016/j.jacc.2020.02.009.