TBD Meeting (3377-20)

Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.

The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at 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.

“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.

The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.

In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.

To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
 

TWILIGHT-COMPLEX findings

In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.

The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.

The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
 

Results are ‘reassuring’

At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.

“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.

She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.

“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”

Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.

The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.

Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).

SOURCE: Dangas GD. ACC 20, Abstract 410-09.

Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.

The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at 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.

“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.

The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.

In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.

To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
 

TWILIGHT-COMPLEX findings

In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.

The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.

The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
 

Results are ‘reassuring’

At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.

“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.

She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.

“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”

Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.

The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.

Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).

SOURCE: Dangas GD. ACC 20, Abstract 410-09.

Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.

The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at 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.

“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.

The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.

In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.

To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
 

TWILIGHT-COMPLEX findings

In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.

The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.

The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
 

Results are ‘reassuring’

At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.

“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.

She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.

“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”

Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.

The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.

Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).

SOURCE: Dangas GD. ACC 20, Abstract 410-09.

Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.

PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.

Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.

What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.

The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.

“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.

Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”

Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.

Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?

“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.

“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.

Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.

bjancin@mdedge.com

Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.

PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.

Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.

What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.

The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.

“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.

Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”

Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.

Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?

“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.

“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.

Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.

bjancin@mdedge.com

Transcatheter aortic valve replacement (TAVR) continued to show superiority over surgical replacement in terms of the primary composite endpoint in low-surgical-risk patients at 2 years of follow-up in the landmark randomized PARTNER 3 trial, but the between-group differences favoring the transcatheter procedure in some key outcomes have narrowed considerably, Michael J. Mack, MD, reported in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

“On the basis of 1-year data, many physicians were counseling patients that TAVR outcomes were better than surgery. Now we see that the outcomes are roughly the same at 2 years,” said Dr. Mack, who is medical director of cardiothoracic surgery and chairman of the Baylor Scott & White The Heart Hospital – Plano (Tex.) Research Center.

PARTNER 3 randomized 1,000 patients with severe symptomatic aortic stenosis with a tricuspid valve and a very low mean Society of Thoracic Surgeons risk score of 1.9% to TAVR with the Sapien 3 valve or surgical aortic valve replacement (SAVR). The 1-year results presented at ACC 2019 caused a huge stir, with the primary composite outcome of death, stroke, or cardiovascular rehospitalization occurring in 8.5% of TAVR patients and 15.6% of the SAVR group, representing a 48% relative risk reduction and a resounding win for TAVR (N Engl J Med. 2019 May 2;380:1695-705). At 2 years, the difference in the composite outcome remained statistically significant, but the gap had closed: 11.5% with TAVR and 17.4% with SAVR for a 37% relative risk reduction.

Moreover, the between-group difference in stroke, which at 1 year was significantly in favor of TAVR at 1.2% versus 3.3%, was no longer significant at 2 years, with rates of 2.4% versus 3.6%. Nor was the difference in mortality significant: 2.4% with TAVR, 3.2% with SAVR.

What was a statistically significant between-group difference at 2 years – and an eye-catching one at that – involved the cumulative incidence of valve thrombosis confirmed by CT or echocardiography: 2.6% in the TAVR arm, compared with 0.7% with SAVR, with most of these unwanted events coming in year 2.

The good news was there was no echocardiographic evidence of deterioration in valve structure or function in either study arm at 2 years. The mean gradients and aortic valve areas remained unchanged in both arms between 1 and 2 years, as did the frequency of mild or moderate paravalvular leak. Prospective follow-up will continue annually out to 10 years.

“I think it’s way too early to expect to see a signal, but I think it’s somewhat comforting at this point that there’s no signal of early structural valve deterioration,” Dr. Mack said.

Discussant Howard C. Hermann, MD, commented: “I guess the biggest concern in looking at the data is the increase in stroke and valve thrombosis, both numerically and relative to SAVR, between years 1 and 2.”

Dr. Mack offered a note of reassurance regarding the valve thrombosis findings: The rates he presented were based upon the now-outdated second Valve Academic Research Consortium (VARC-2) definition, per study protocol. When he and his coinvestigators recalculated the valve thrombosis rates using the contemporary VARC-3 definition of valve deterioration and bioprosthetic valve failure, the incidence was very low and not significantly different in the two study arms, at roughly 1%.

Dr. Hermann, professor of medicine and director of the cardiac catheterization laboratories at the University of Pennsylvania, Philadelphia, had a question: As a clinician taking care of TAVR patients, what clinical or hemodynamic findings should prompt an imaging study looking for valve thrombus or deterioration that might prompt initiating oral anticoagulation?

“If there’s a change in hemodynamics, an increasing valve gradient, if there’s increasing paravalvular leak, or if there’s a change in symptoms, that should prompt an imaging study. Only with confirmation of valve thrombosis on an imaging study should anticoagulation be considered. Oral anticoagulation is not benign: Of the six clinical events associated with valve thrombosis in the study, two were related to anticoagulation,” Dr. Mack replied.

“Regarding whether patients should receive warfarin or a novel anticoagulant, I don’t think we have evidence that there’s benefit to anything other than warfarin at the current time,” he added.

Dr. Mack reported receiving research support from Edwards Lifesciences, the sponsor of PARTNER 3, as well as from Abbott, Gore, and Medtronic.

bjancin@mdedge.com

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, 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.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, 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.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, 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.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said 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.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said 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.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said 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.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

The VOYAGER PAD results from more than 6,500 patients created the biggest evidence base by far ever collected from patients with symptomatic peripheral artery disease (PAD) who underwent a vascular intervention, and showed that the combination of twice-daily rivaroxaban and once-daily aspirin was safe and more effective than aspirin alone for reducing future thrombotic and ischemic events.

Following that report on March 28, a prespecified subgroup analysis presented the next day showed that adding clopidogrel to this two-drug combination produced no added efficacy but caused additional bleeding episodes, suggesting that the common practice of using clopidogrel plus aspirin in these patients, especially those who receive a stent in a peripheral artery, should either fall by the wayside or be used very briefly.

“In the absence of clear benefit, clopidogrel exposure along with aspirin and rivaroxaban should be minimized or avoided to reduce this risk,” William R. Hiatt, MD, said 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. But he also cautioned that “we did not control for clopidogrel use, and so the patients who received clopidogrel look different [from patients who did not receive clopidogrel]. We must be cautious in interpreting differences between patients on or off clopidogrel,” warned Dr. Hiatt, a lead investigator for VOYAGER PAD, professor for cardiovascular research at the University of Colorado at Denver in Aurora and president of the affiliated Colorado Prevention Center.

In addition to this substantial caveat, the finding that clopidogrel appeared to add no extra benefit to the rivaroxaban/aspirin regimen “contradicts some dogmas that have been in the field for decades,” Dr. Hiatt said. Use of dual-antiplatelet therapy (DAPT), in this setting usually aspirin and clopidogrel, in patients who have just undergone lower-extremity revascularization is “current dogma,” even though it is not based on any direct evidence for efficacy, but instead came on the scene as “an extrapolation from the coronary artery literature, where it does have some benefit, particularly after percutaneous coronary intervention,” he explained.

The only reported study results to examine use of DAPT in patients who underwent peripheral artery revascularization focused entirely on patients who had a surgical procedure and showed no added benefit from DAPT over aspirin only in a multicenter, randomized trial with 851 patients (J Vasc Surg. 2010 Oct;52[4]:825-33), Dr. Hiatt noted. In VOYAGER PAD, two-thirds of all patients underwent an endovascular, not surgical, peripheral intervention, and among those treated with clopidogrel, 91% had endovascular treatment.

“We’re not saying don’t use DAPT, but patients on three drugs are at higher bleeding risk than patients on two drugs. I think our data also suggest starting rivaroxaban immediately after a procedure [as was done in VOYAGER PAD], and not waiting to complete a course of DAPT,” Dr. Hiatt said.

Other experts embraced Dr. Hiatt’s take on these findings, while warning that it may take some time for the message to penetrate into practice.

The overall VOYAGER PAD results “are practice changing for vascular interventions; it was by an order of magnitude the largest vascular intervention trial ever conducted,” commented Sahil A. Parikh, MD, a designated discussant, interventional cardiologist, and director of endovascular services at New York–Presbyterian Medical Center. “The data suggest that the value of clopidogrel is questionable, but the added hazard is not questionable” when given to patients on top of rivaroxaban and aspirin. The results “certainly beg the question of whether one should use DAPT at all, and if so, for how long.”

Use of DAPT in patients undergoing peripheral revascularization, especially patients receiving a stent, has been “dogma,” Dr. Parikh agreed. “It’s been pounded into our heads that DAPT is standard care, so it will take some time to penetrate into the practicing community.”

“Could there be patients who could benefit from triple therapy? That’s possible, but it needs testing,” 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. “We’ve made terrific strides with the results from VOYAGER PAD,” and from the earlier COMPASS trial, which proved the benefit of rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease including many PAD patients (N Engl J Med. 2017 Oct 5;377[14]:1319-30). Use of rivaroxaban and aspirin in PAD patients based on the COMPASS results “is beginning to make an impact, but has a long way to go,” Dr. Creager said in an interview.

In late 2018, the Food and Drug Administration gave rivaroxaban a revised labeling that included an indication for patients with PAD based on the COMPASS findings. The VOYAGER PAD and COMPASS trials are especially noteworthy because “they opened a whole area [of study] in patients with peripheral vascular disease, ” he added.

The prespecified analysis that Dr. Hiatt reported analyzed outcomes among the 51% of patients enrolled in VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) who received clopidogrel during follow-up at the discretion of their treating physician and the outcomes among the remainder who did not. The two subgroups showed several statistically significant differences in the prevalence of various comorbidities and in some baseline demographic and clinical metrics, and the analyses that Dr. Hiatt reported did not attempt to correct for these differences. Patients who received clopidogrel had the drug on board for a median of 29 days, and about 58% received it for 30 days or less.

The main finding of his analysis was that “adding clopidogrel did not modify benefit at all” from the perspective of the primary endpoint of VOYAGER PAD, the incidence of a five-item list of adverse events (acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke, and cardiovascular death) during a median follow-up of 28 months (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052), said Dr. Hiatt. Among patients on clopidogrel, those treated with both rivaroxaban and aspirin had a 16.0% incidence of the primary endpoint, compared with an 18.3% rate among patients on aspirin only, for a 15% relative risk reduction, identical to the study’s primary result. Among patients not on clopidogrel, the primary endpoint occurred in 18.7% of patients on rivaroxaban plus aspirin and in 21.5% of those on aspirin only, a 14% relative risk reduction. The analyses also showed that adding clopidogrel appeared to increase the rate of bleeding episodes, particularly the incidence of major bleeds by the criteria of the International Society on Thrombosis and Haemostasis (ISTH), which rose among patients on aspirin alone from 3.3% without clopidogrel treatment to 4.9% with clopidogrel, and in patients on rivaroxaban plus aspirin these major bleeds increased from 5.4% with no clopidogrel to 6.5% with clopidogrel.

An especially revealing further analysis showed that, among those who also received rivaroxaban and aspirin, clopidogrel treatment for more than 30 days led to substantially more bleeding problems, compared with patients who received the drug for 30 days or less. Patients who received clopidogrel for more than 30 days as part of a triple-drug regimen had a 3.0% rate of major ISTH bleeds during 180 days of follow-up, compared with a 0.9% rate for patients in the aspirin-alone group who also received clopidogrel, a 2.1% between-group difference. In contrast, the difference in major ISTH bleeds between the two treatment arms in the subgroup who received clopidogrel for 30 days or less was 0.7%.

“What’s inarguable is that the course of clopidogrel should be as short as possible, probably not more than 30 days unless there is a real extenuating rationale,” commented designated discussant Gregory Piazza, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Hiatt leads has received research funding from Bayer and Janssen and from Amgen. Dr. Parikh has been a consultant to Terumo; has received research funding from Shockwave, Surmodics, and Trireme; has worked on trial monitoring for Boston Scientific and Silk Road; and has had other financial relationships with Abbott, Boston Scientific, and Medtronic. Dr. Creager had no disclosures. Dr. Piazza has received research grants from Bayer and Janssen, as well as Bristol-Myers Squibb, Diiachi, EKOS, and Portola, and he has been a consultant to Optum, Pfizer, and Thrombolex.

mzoler@mdedge.com

SOURCE: Hiatt WR et al. ACC 20, Abstract 406-13.

The VOYAGER PAD results from more than 6,500 patients created the biggest evidence base by far ever collected from patients with symptomatic peripheral artery disease (PAD) who underwent a vascular intervention, and showed that the combination of twice-daily rivaroxaban and once-daily aspirin was safe and more effective than aspirin alone for reducing future thrombotic and ischemic events.

Following that report on March 28, a prespecified subgroup analysis presented the next day showed that adding clopidogrel to this two-drug combination produced no added efficacy but caused additional bleeding episodes, suggesting that the common practice of using clopidogrel plus aspirin in these patients, especially those who receive a stent in a peripheral artery, should either fall by the wayside or be used very briefly.

“In the absence of clear benefit, clopidogrel exposure along with aspirin and rivaroxaban should be minimized or avoided to reduce this risk,” William R. Hiatt, MD, said 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. But he also cautioned that “we did not control for clopidogrel use, and so the patients who received clopidogrel look different [from patients who did not receive clopidogrel]. We must be cautious in interpreting differences between patients on or off clopidogrel,” warned Dr. Hiatt, a lead investigator for VOYAGER PAD, professor for cardiovascular research at the University of Colorado at Denver in Aurora and president of the affiliated Colorado Prevention Center.

In addition to this substantial caveat, the finding that clopidogrel appeared to add no extra benefit to the rivaroxaban/aspirin regimen “contradicts some dogmas that have been in the field for decades,” Dr. Hiatt said. Use of dual-antiplatelet therapy (DAPT), in this setting usually aspirin and clopidogrel, in patients who have just undergone lower-extremity revascularization is “current dogma,” even though it is not based on any direct evidence for efficacy, but instead came on the scene as “an extrapolation from the coronary artery literature, where it does have some benefit, particularly after percutaneous coronary intervention,” he explained.

The only reported study results to examine use of DAPT in patients who underwent peripheral artery revascularization focused entirely on patients who had a surgical procedure and showed no added benefit from DAPT over aspirin only in a multicenter, randomized trial with 851 patients (J Vasc Surg. 2010 Oct;52[4]:825-33), Dr. Hiatt noted. In VOYAGER PAD, two-thirds of all patients underwent an endovascular, not surgical, peripheral intervention, and among those treated with clopidogrel, 91% had endovascular treatment.

“We’re not saying don’t use DAPT, but patients on three drugs are at higher bleeding risk than patients on two drugs. I think our data also suggest starting rivaroxaban immediately after a procedure [as was done in VOYAGER PAD], and not waiting to complete a course of DAPT,” Dr. Hiatt said.

Other experts embraced Dr. Hiatt’s take on these findings, while warning that it may take some time for the message to penetrate into practice.

The overall VOYAGER PAD results “are practice changing for vascular interventions; it was by an order of magnitude the largest vascular intervention trial ever conducted,” commented Sahil A. Parikh, MD, a designated discussant, interventional cardiologist, and director of endovascular services at New York–Presbyterian Medical Center. “The data suggest that the value of clopidogrel is questionable, but the added hazard is not questionable” when given to patients on top of rivaroxaban and aspirin. The results “certainly beg the question of whether one should use DAPT at all, and if so, for how long.”

Use of DAPT in patients undergoing peripheral revascularization, especially patients receiving a stent, has been “dogma,” Dr. Parikh agreed. “It’s been pounded into our heads that DAPT is standard care, so it will take some time to penetrate into the practicing community.”

“Could there be patients who could benefit from triple therapy? That’s possible, but it needs testing,” 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. “We’ve made terrific strides with the results from VOYAGER PAD,” and from the earlier COMPASS trial, which proved the benefit of rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease including many PAD patients (N Engl J Med. 2017 Oct 5;377[14]:1319-30). Use of rivaroxaban and aspirin in PAD patients based on the COMPASS results “is beginning to make an impact, but has a long way to go,” Dr. Creager said in an interview.

In late 2018, the Food and Drug Administration gave rivaroxaban a revised labeling that included an indication for patients with PAD based on the COMPASS findings. The VOYAGER PAD and COMPASS trials are especially noteworthy because “they opened a whole area [of study] in patients with peripheral vascular disease, ” he added.

The prespecified analysis that Dr. Hiatt reported analyzed outcomes among the 51% of patients enrolled in VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) who received clopidogrel during follow-up at the discretion of their treating physician and the outcomes among the remainder who did not. The two subgroups showed several statistically significant differences in the prevalence of various comorbidities and in some baseline demographic and clinical metrics, and the analyses that Dr. Hiatt reported did not attempt to correct for these differences. Patients who received clopidogrel had the drug on board for a median of 29 days, and about 58% received it for 30 days or less.

The main finding of his analysis was that “adding clopidogrel did not modify benefit at all” from the perspective of the primary endpoint of VOYAGER PAD, the incidence of a five-item list of adverse events (acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke, and cardiovascular death) during a median follow-up of 28 months (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052), said Dr. Hiatt. Among patients on clopidogrel, those treated with both rivaroxaban and aspirin had a 16.0% incidence of the primary endpoint, compared with an 18.3% rate among patients on aspirin only, for a 15% relative risk reduction, identical to the study’s primary result. Among patients not on clopidogrel, the primary endpoint occurred in 18.7% of patients on rivaroxaban plus aspirin and in 21.5% of those on aspirin only, a 14% relative risk reduction. The analyses also showed that adding clopidogrel appeared to increase the rate of bleeding episodes, particularly the incidence of major bleeds by the criteria of the International Society on Thrombosis and Haemostasis (ISTH), which rose among patients on aspirin alone from 3.3% without clopidogrel treatment to 4.9% with clopidogrel, and in patients on rivaroxaban plus aspirin these major bleeds increased from 5.4% with no clopidogrel to 6.5% with clopidogrel.

An especially revealing further analysis showed that, among those who also received rivaroxaban and aspirin, clopidogrel treatment for more than 30 days led to substantially more bleeding problems, compared with patients who received the drug for 30 days or less. Patients who received clopidogrel for more than 30 days as part of a triple-drug regimen had a 3.0% rate of major ISTH bleeds during 180 days of follow-up, compared with a 0.9% rate for patients in the aspirin-alone group who also received clopidogrel, a 2.1% between-group difference. In contrast, the difference in major ISTH bleeds between the two treatment arms in the subgroup who received clopidogrel for 30 days or less was 0.7%.

“What’s inarguable is that the course of clopidogrel should be as short as possible, probably not more than 30 days unless there is a real extenuating rationale,” commented designated discussant Gregory Piazza, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Hiatt leads has received research funding from Bayer and Janssen and from Amgen. Dr. Parikh has been a consultant to Terumo; has received research funding from Shockwave, Surmodics, and Trireme; has worked on trial monitoring for Boston Scientific and Silk Road; and has had other financial relationships with Abbott, Boston Scientific, and Medtronic. Dr. Creager had no disclosures. Dr. Piazza has received research grants from Bayer and Janssen, as well as Bristol-Myers Squibb, Diiachi, EKOS, and Portola, and he has been a consultant to Optum, Pfizer, and Thrombolex.

mzoler@mdedge.com

SOURCE: Hiatt WR et al. ACC 20, Abstract 406-13.

The VOYAGER PAD results from more than 6,500 patients created the biggest evidence base by far ever collected from patients with symptomatic peripheral artery disease (PAD) who underwent a vascular intervention, and showed that the combination of twice-daily rivaroxaban and once-daily aspirin was safe and more effective than aspirin alone for reducing future thrombotic and ischemic events.

Following that report on March 28, a prespecified subgroup analysis presented the next day showed that adding clopidogrel to this two-drug combination produced no added efficacy but caused additional bleeding episodes, suggesting that the common practice of using clopidogrel plus aspirin in these patients, especially those who receive a stent in a peripheral artery, should either fall by the wayside or be used very briefly.

“In the absence of clear benefit, clopidogrel exposure along with aspirin and rivaroxaban should be minimized or avoided to reduce this risk,” William R. Hiatt, MD, said 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. But he also cautioned that “we did not control for clopidogrel use, and so the patients who received clopidogrel look different [from patients who did not receive clopidogrel]. We must be cautious in interpreting differences between patients on or off clopidogrel,” warned Dr. Hiatt, a lead investigator for VOYAGER PAD, professor for cardiovascular research at the University of Colorado at Denver in Aurora and president of the affiliated Colorado Prevention Center.

In addition to this substantial caveat, the finding that clopidogrel appeared to add no extra benefit to the rivaroxaban/aspirin regimen “contradicts some dogmas that have been in the field for decades,” Dr. Hiatt said. Use of dual-antiplatelet therapy (DAPT), in this setting usually aspirin and clopidogrel, in patients who have just undergone lower-extremity revascularization is “current dogma,” even though it is not based on any direct evidence for efficacy, but instead came on the scene as “an extrapolation from the coronary artery literature, where it does have some benefit, particularly after percutaneous coronary intervention,” he explained.

The only reported study results to examine use of DAPT in patients who underwent peripheral artery revascularization focused entirely on patients who had a surgical procedure and showed no added benefit from DAPT over aspirin only in a multicenter, randomized trial with 851 patients (J Vasc Surg. 2010 Oct;52[4]:825-33), Dr. Hiatt noted. In VOYAGER PAD, two-thirds of all patients underwent an endovascular, not surgical, peripheral intervention, and among those treated with clopidogrel, 91% had endovascular treatment.

“We’re not saying don’t use DAPT, but patients on three drugs are at higher bleeding risk than patients on two drugs. I think our data also suggest starting rivaroxaban immediately after a procedure [as was done in VOYAGER PAD], and not waiting to complete a course of DAPT,” Dr. Hiatt said.

Other experts embraced Dr. Hiatt’s take on these findings, while warning that it may take some time for the message to penetrate into practice.

The overall VOYAGER PAD results “are practice changing for vascular interventions; it was by an order of magnitude the largest vascular intervention trial ever conducted,” commented Sahil A. Parikh, MD, a designated discussant, interventional cardiologist, and director of endovascular services at New York–Presbyterian Medical Center. “The data suggest that the value of clopidogrel is questionable, but the added hazard is not questionable” when given to patients on top of rivaroxaban and aspirin. The results “certainly beg the question of whether one should use DAPT at all, and if so, for how long.”

Use of DAPT in patients undergoing peripheral revascularization, especially patients receiving a stent, has been “dogma,” Dr. Parikh agreed. “It’s been pounded into our heads that DAPT is standard care, so it will take some time to penetrate into the practicing community.”

“Could there be patients who could benefit from triple therapy? That’s possible, but it needs testing,” 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. “We’ve made terrific strides with the results from VOYAGER PAD,” and from the earlier COMPASS trial, which proved the benefit of rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease including many PAD patients (N Engl J Med. 2017 Oct 5;377[14]:1319-30). Use of rivaroxaban and aspirin in PAD patients based on the COMPASS results “is beginning to make an impact, but has a long way to go,” Dr. Creager said in an interview.

In late 2018, the Food and Drug Administration gave rivaroxaban a revised labeling that included an indication for patients with PAD based on the COMPASS findings. The VOYAGER PAD and COMPASS trials are especially noteworthy because “they opened a whole area [of study] in patients with peripheral vascular disease, ” he added.

The prespecified analysis that Dr. Hiatt reported analyzed outcomes among the 51% of patients enrolled in VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) who received clopidogrel during follow-up at the discretion of their treating physician and the outcomes among the remainder who did not. The two subgroups showed several statistically significant differences in the prevalence of various comorbidities and in some baseline demographic and clinical metrics, and the analyses that Dr. Hiatt reported did not attempt to correct for these differences. Patients who received clopidogrel had the drug on board for a median of 29 days, and about 58% received it for 30 days or less.

The main finding of his analysis was that “adding clopidogrel did not modify benefit at all” from the perspective of the primary endpoint of VOYAGER PAD, the incidence of a five-item list of adverse events (acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke, and cardiovascular death) during a median follow-up of 28 months (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052), said Dr. Hiatt. Among patients on clopidogrel, those treated with both rivaroxaban and aspirin had a 16.0% incidence of the primary endpoint, compared with an 18.3% rate among patients on aspirin only, for a 15% relative risk reduction, identical to the study’s primary result. Among patients not on clopidogrel, the primary endpoint occurred in 18.7% of patients on rivaroxaban plus aspirin and in 21.5% of those on aspirin only, a 14% relative risk reduction. The analyses also showed that adding clopidogrel appeared to increase the rate of bleeding episodes, particularly the incidence of major bleeds by the criteria of the International Society on Thrombosis and Haemostasis (ISTH), which rose among patients on aspirin alone from 3.3% without clopidogrel treatment to 4.9% with clopidogrel, and in patients on rivaroxaban plus aspirin these major bleeds increased from 5.4% with no clopidogrel to 6.5% with clopidogrel.

An especially revealing further analysis showed that, among those who also received rivaroxaban and aspirin, clopidogrel treatment for more than 30 days led to substantially more bleeding problems, compared with patients who received the drug for 30 days or less. Patients who received clopidogrel for more than 30 days as part of a triple-drug regimen had a 3.0% rate of major ISTH bleeds during 180 days of follow-up, compared with a 0.9% rate for patients in the aspirin-alone group who also received clopidogrel, a 2.1% between-group difference. In contrast, the difference in major ISTH bleeds between the two treatment arms in the subgroup who received clopidogrel for 30 days or less was 0.7%.

“What’s inarguable is that the course of clopidogrel should be as short as possible, probably not more than 30 days unless there is a real extenuating rationale,” commented designated discussant Gregory Piazza, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Hiatt leads has received research funding from Bayer and Janssen and from Amgen. Dr. Parikh has been a consultant to Terumo; has received research funding from Shockwave, Surmodics, and Trireme; has worked on trial monitoring for Boston Scientific and Silk Road; and has had other financial relationships with Abbott, Boston Scientific, and Medtronic. Dr. Creager had no disclosures. Dr. Piazza has received research grants from Bayer and Janssen, as well as Bristol-Myers Squibb, Diiachi, EKOS, and Portola, and he has been a consultant to Optum, Pfizer, and Thrombolex.

mzoler@mdedge.com

SOURCE: Hiatt WR et al. ACC 20, Abstract 406-13.

A second trial has shown benefit of stopping aspirin 3 months after stenting and continuing solely with ticagrelor monotherapy.

The Ticagrelor With or Without Aspirin in Acute Coronary Syndrome After PCI (TICO) study shows very similar results as the TWILIGHT trial reported last year. But whereas TWILIGHT enrolled a more general PCI population, TICO included only patients with acute coronary syndrome (ACS).

The South Korean TICO trial was presented today at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

Presenting the study, senior investigator Yangsoo Jang, MD, PhD, professor of cardiology at Yonsei University College of Medicine in Seoul, South Korea, concluded: “Ticagrelor monotherapy after 3-month dual antiplatelet therapy  showed a significantly lower risk of net adverse clinical events than currently recommended ticagrelor-based 12-month dual antiplatelet therapy. The reduced risk was mainly due to decreased major bleeding.”

These findings indicate that ticagrelor monotherapy “could be an optimal strategy that balances both ischemic and bleeding risks for patients with ACS,” he added.

Discussant of the TICO study, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, said: “This is an independent confirmation of TWILIGHT. To have two independent trials reaching the same conclusion — that the regimen of ticagrelor monotherapy after 3 months dual antiplatelet therapy essentially cuts major bleeding in half — is very comforting.”

Michelle O’Donoghue, MD, also from Brigham and Women’s and chair of the ACC session at which the study was presented, added, “A particular strength of this trial was that you had an all-ACS population.”

Enough to Change Guidelines?

Discussing the trial at an ACC press conference, Claire Duvernoy, MD, University of Michigan, Ann Arbor, suggested that the results from TICO and TWILIGHT together are “enough evidence to change the guidelines. I think we are there,” she added.  

“TICO adds to our expanding body of evidence for newer, more potent, P2Y12 inhibitors as monotherapy. This trial stands out as the only exclusive ACS study looking at this and the only trial enrolling a significant population of STEMI patients,” Duvernoy said.

She pointed out one caveat — the need to discontinue ticagrelor because of dyspnea, which she said occurs in around 10%-15% of patients in her practice.

“Also, both TICO and TWILIGHT used the latest second-generation drug-eluting stents, which may have better safety and allows us to get away with less antiplatelet therapy,” Duvernoy noted.  

The TICO trial, conducted at 38 centers in South Korea, enrolled 3056 patients with ACS (average age 61 years) undergoing PCI and stenting with the second-generation ultrathin biodegradable polymer-coated sirolimus-eluting stents (Biotronik).

All patients received ticagrelor plus aspirin for 3 months, then were randomly assigned to continue treatment with ticagrelor and aspirin or ticagrelor alone.

The primary study endpoint was a net clinical benefit composite of death, MI, stroke, stent thrombosis, revascularization, or TIMI major bleeding at 12 months. This occurred in 3.9% of those randomly assigned to ticagrelor alone vs 5.9% of those who continued on dual antiplatelet therapy, giving a hazard ratio of 0.66 (P = .01).

The curves separated early with a marked difference in event rate being seen at 3 months after randomization. At this point, rates of the composite endpoint were 1.4% in the ticagrelor monotherapy group vs 3.5% in the dual antiplatelet therapy group (HR, 0.41; P = .001). 

The benefit was driven by a reduced risk of major bleeding in the ticagrelor monotherapy group. At 1 year, the rate of TIMI major bleeding was 1.7% in the ticagrelor alone group vs 3% in the dual antiplatelet group (HR, 0.56; P = .02).

There was no difference in ischemic events between the two groups. The rate of death/MI/ stroke/stent thrombosis/revascularization at 1 year was 2.3% in the ticagrelor alone group vs 3.4% for those on dual antiplatelet therapy (P = .09)

Yang noted that limitations of the study included an open-label design, no placebo used, and exclusion of patients with an elevated risk for bleeding (defined as aged 80 years or older, having had a stroke within the past year, or having had brain surgery or a traumatic brain injury within the past 6 months).

As part of his discussion, Bhatt asked how these results can be reconciled with trials such as CHARISMA and PEGASUS, which showed higher rates of MI with abbreviated durations of dual antiplatelet therapy

Jang replied: “Maybe for STEMI patients, if the duration of [dual antiplatelet therapy] is prolonged ischemic events may be reduced, especially if clopidogrel is used. But my opinion is when ticagrelor or prasugrel are used — they are very strong P2Y12 inhibitors — you can reduce duration of dual therapy by dropping aspirin. I think aspirin just makes the bleeding.”

Also commenting on the TICO study, Jacqueline Tamis-Holland, MD, Mount Sinai Saint Luke’s Hospital, New York City, pointed out that there was an interaction between the number of diseased vessels, and asked for more information on the complexity of disease in the patients in this trial.

“We had very few CTOs (total chronic occlusions) and left main disease,” Jang replied. “Dual antiplatelet duration is related to total atherosclerotic burden I think, so if you have very high atherosclerotic burden and multivessel disease, dual therapy may be more important. But our data show that the ticagrelor monotherapy group is not inferior to conventional dual therapy, so this suggests that even in multivessel disease, 3 months dual antiplatelet therapy is enough if you use a potent agent like ticagrelor as monotherapy after.”

This study was funded by Biotronik, manufacturer of the stents used. Jang has disclosed no relevant financial relationships. Bhatt reports consultant fees/honoraria from Elsevier Practice Update Cardiology, Medtelligence/WebMD, MJH Life Sciences, and WebMD; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Medtronic, Novo Nordisk, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, sanofi-aventis, Synaptic, Takeda, The Medicines Company.

This article first appeared on Medscape.com.

A second trial has shown benefit of stopping aspirin 3 months after stenting and continuing solely with ticagrelor monotherapy.

The Ticagrelor With or Without Aspirin in Acute Coronary Syndrome After PCI (TICO) study shows very similar results as the TWILIGHT trial reported last year. But whereas TWILIGHT enrolled a more general PCI population, TICO included only patients with acute coronary syndrome (ACS).

The South Korean TICO trial was presented today at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

Presenting the study, senior investigator Yangsoo Jang, MD, PhD, professor of cardiology at Yonsei University College of Medicine in Seoul, South Korea, concluded: “Ticagrelor monotherapy after 3-month dual antiplatelet therapy  showed a significantly lower risk of net adverse clinical events than currently recommended ticagrelor-based 12-month dual antiplatelet therapy. The reduced risk was mainly due to decreased major bleeding.”

These findings indicate that ticagrelor monotherapy “could be an optimal strategy that balances both ischemic and bleeding risks for patients with ACS,” he added.

Discussant of the TICO study, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, said: “This is an independent confirmation of TWILIGHT. To have two independent trials reaching the same conclusion — that the regimen of ticagrelor monotherapy after 3 months dual antiplatelet therapy essentially cuts major bleeding in half — is very comforting.”

Michelle O’Donoghue, MD, also from Brigham and Women’s and chair of the ACC session at which the study was presented, added, “A particular strength of this trial was that you had an all-ACS population.”

Enough to Change Guidelines?

Discussing the trial at an ACC press conference, Claire Duvernoy, MD, University of Michigan, Ann Arbor, suggested that the results from TICO and TWILIGHT together are “enough evidence to change the guidelines. I think we are there,” she added.  

“TICO adds to our expanding body of evidence for newer, more potent, P2Y12 inhibitors as monotherapy. This trial stands out as the only exclusive ACS study looking at this and the only trial enrolling a significant population of STEMI patients,” Duvernoy said.

She pointed out one caveat — the need to discontinue ticagrelor because of dyspnea, which she said occurs in around 10%-15% of patients in her practice.

“Also, both TICO and TWILIGHT used the latest second-generation drug-eluting stents, which may have better safety and allows us to get away with less antiplatelet therapy,” Duvernoy noted.  

The TICO trial, conducted at 38 centers in South Korea, enrolled 3056 patients with ACS (average age 61 years) undergoing PCI and stenting with the second-generation ultrathin biodegradable polymer-coated sirolimus-eluting stents (Biotronik).

All patients received ticagrelor plus aspirin for 3 months, then were randomly assigned to continue treatment with ticagrelor and aspirin or ticagrelor alone.

The primary study endpoint was a net clinical benefit composite of death, MI, stroke, stent thrombosis, revascularization, or TIMI major bleeding at 12 months. This occurred in 3.9% of those randomly assigned to ticagrelor alone vs 5.9% of those who continued on dual antiplatelet therapy, giving a hazard ratio of 0.66 (P = .01).

The curves separated early with a marked difference in event rate being seen at 3 months after randomization. At this point, rates of the composite endpoint were 1.4% in the ticagrelor monotherapy group vs 3.5% in the dual antiplatelet therapy group (HR, 0.41; P = .001). 

The benefit was driven by a reduced risk of major bleeding in the ticagrelor monotherapy group. At 1 year, the rate of TIMI major bleeding was 1.7% in the ticagrelor alone group vs 3% in the dual antiplatelet group (HR, 0.56; P = .02).

There was no difference in ischemic events between the two groups. The rate of death/MI/ stroke/stent thrombosis/revascularization at 1 year was 2.3% in the ticagrelor alone group vs 3.4% for those on dual antiplatelet therapy (P = .09)

Yang noted that limitations of the study included an open-label design, no placebo used, and exclusion of patients with an elevated risk for bleeding (defined as aged 80 years or older, having had a stroke within the past year, or having had brain surgery or a traumatic brain injury within the past 6 months).

As part of his discussion, Bhatt asked how these results can be reconciled with trials such as CHARISMA and PEGASUS, which showed higher rates of MI with abbreviated durations of dual antiplatelet therapy

Jang replied: “Maybe for STEMI patients, if the duration of [dual antiplatelet therapy] is prolonged ischemic events may be reduced, especially if clopidogrel is used. But my opinion is when ticagrelor or prasugrel are used — they are very strong P2Y12 inhibitors — you can reduce duration of dual therapy by dropping aspirin. I think aspirin just makes the bleeding.”

Also commenting on the TICO study, Jacqueline Tamis-Holland, MD, Mount Sinai Saint Luke’s Hospital, New York City, pointed out that there was an interaction between the number of diseased vessels, and asked for more information on the complexity of disease in the patients in this trial.

“We had very few CTOs (total chronic occlusions) and left main disease,” Jang replied. “Dual antiplatelet duration is related to total atherosclerotic burden I think, so if you have very high atherosclerotic burden and multivessel disease, dual therapy may be more important. But our data show that the ticagrelor monotherapy group is not inferior to conventional dual therapy, so this suggests that even in multivessel disease, 3 months dual antiplatelet therapy is enough if you use a potent agent like ticagrelor as monotherapy after.”

This study was funded by Biotronik, manufacturer of the stents used. Jang has disclosed no relevant financial relationships. Bhatt reports consultant fees/honoraria from Elsevier Practice Update Cardiology, Medtelligence/WebMD, MJH Life Sciences, and WebMD; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Medtronic, Novo Nordisk, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, sanofi-aventis, Synaptic, Takeda, The Medicines Company.

This article first appeared on Medscape.com.

A second trial has shown benefit of stopping aspirin 3 months after stenting and continuing solely with ticagrelor monotherapy.

The Ticagrelor With or Without Aspirin in Acute Coronary Syndrome After PCI (TICO) study shows very similar results as the TWILIGHT trial reported last year. But whereas TWILIGHT enrolled a more general PCI population, TICO included only patients with acute coronary syndrome (ACS).

The South Korean TICO trial was presented today at the “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology.

Presenting the study, senior investigator Yangsoo Jang, MD, PhD, professor of cardiology at Yonsei University College of Medicine in Seoul, South Korea, concluded: “Ticagrelor monotherapy after 3-month dual antiplatelet therapy  showed a significantly lower risk of net adverse clinical events than currently recommended ticagrelor-based 12-month dual antiplatelet therapy. The reduced risk was mainly due to decreased major bleeding.”

These findings indicate that ticagrelor monotherapy “could be an optimal strategy that balances both ischemic and bleeding risks for patients with ACS,” he added.

Discussant of the TICO study, Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, said: “This is an independent confirmation of TWILIGHT. To have two independent trials reaching the same conclusion — that the regimen of ticagrelor monotherapy after 3 months dual antiplatelet therapy essentially cuts major bleeding in half — is very comforting.”

Michelle O’Donoghue, MD, also from Brigham and Women’s and chair of the ACC session at which the study was presented, added, “A particular strength of this trial was that you had an all-ACS population.”

Enough to Change Guidelines?

Discussing the trial at an ACC press conference, Claire Duvernoy, MD, University of Michigan, Ann Arbor, suggested that the results from TICO and TWILIGHT together are “enough evidence to change the guidelines. I think we are there,” she added.  

“TICO adds to our expanding body of evidence for newer, more potent, P2Y12 inhibitors as monotherapy. This trial stands out as the only exclusive ACS study looking at this and the only trial enrolling a significant population of STEMI patients,” Duvernoy said.

She pointed out one caveat — the need to discontinue ticagrelor because of dyspnea, which she said occurs in around 10%-15% of patients in her practice.

“Also, both TICO and TWILIGHT used the latest second-generation drug-eluting stents, which may have better safety and allows us to get away with less antiplatelet therapy,” Duvernoy noted.  

The TICO trial, conducted at 38 centers in South Korea, enrolled 3056 patients with ACS (average age 61 years) undergoing PCI and stenting with the second-generation ultrathin biodegradable polymer-coated sirolimus-eluting stents (Biotronik).

All patients received ticagrelor plus aspirin for 3 months, then were randomly assigned to continue treatment with ticagrelor and aspirin or ticagrelor alone.

The primary study endpoint was a net clinical benefit composite of death, MI, stroke, stent thrombosis, revascularization, or TIMI major bleeding at 12 months. This occurred in 3.9% of those randomly assigned to ticagrelor alone vs 5.9% of those who continued on dual antiplatelet therapy, giving a hazard ratio of 0.66 (P = .01).

The curves separated early with a marked difference in event rate being seen at 3 months after randomization. At this point, rates of the composite endpoint were 1.4% in the ticagrelor monotherapy group vs 3.5% in the dual antiplatelet therapy group (HR, 0.41; P = .001). 

The benefit was driven by a reduced risk of major bleeding in the ticagrelor monotherapy group. At 1 year, the rate of TIMI major bleeding was 1.7% in the ticagrelor alone group vs 3% in the dual antiplatelet group (HR, 0.56; P = .02).

There was no difference in ischemic events between the two groups. The rate of death/MI/ stroke/stent thrombosis/revascularization at 1 year was 2.3% in the ticagrelor alone group vs 3.4% for those on dual antiplatelet therapy (P = .09)

Yang noted that limitations of the study included an open-label design, no placebo used, and exclusion of patients with an elevated risk for bleeding (defined as aged 80 years or older, having had a stroke within the past year, or having had brain surgery or a traumatic brain injury within the past 6 months).

As part of his discussion, Bhatt asked how these results can be reconciled with trials such as CHARISMA and PEGASUS, which showed higher rates of MI with abbreviated durations of dual antiplatelet therapy

Jang replied: “Maybe for STEMI patients, if the duration of [dual antiplatelet therapy] is prolonged ischemic events may be reduced, especially if clopidogrel is used. But my opinion is when ticagrelor or prasugrel are used — they are very strong P2Y12 inhibitors — you can reduce duration of dual therapy by dropping aspirin. I think aspirin just makes the bleeding.”

Also commenting on the TICO study, Jacqueline Tamis-Holland, MD, Mount Sinai Saint Luke’s Hospital, New York City, pointed out that there was an interaction between the number of diseased vessels, and asked for more information on the complexity of disease in the patients in this trial.

“We had very few CTOs (total chronic occlusions) and left main disease,” Jang replied. “Dual antiplatelet duration is related to total atherosclerotic burden I think, so if you have very high atherosclerotic burden and multivessel disease, dual therapy may be more important. But our data show that the ticagrelor monotherapy group is not inferior to conventional dual therapy, so this suggests that even in multivessel disease, 3 months dual antiplatelet therapy is enough if you use a potent agent like ticagrelor as monotherapy after.”

This study was funded by Biotronik, manufacturer of the stents used. Jang has disclosed no relevant financial relationships. Bhatt reports consultant fees/honoraria from Elsevier Practice Update Cardiology, Medtelligence/WebMD, MJH Life Sciences, and WebMD; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Medtronic, Novo Nordisk, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, sanofi-aventis, Synaptic, Takeda, The Medicines Company.

This article first appeared on Medscape.com.

Oral apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was as effective as subcutaneous dalteparin (Fragmin, Pfizer) for cancer-related venous thromboembolism (VTE) without an increased risk of major bleeding, the CARAVAGGIO study suggests.

Over 6 months of follow-up, the primary efficacy outcome of recurrent thromboembolism occurred in 32 of 576 patients (5.6%) randomly assigned to apixaban and in 46 of 579 patients (7.9%) assigned dalteparin (hazard ratio, 0.63; 95% confidence interval, 0.37-1.07). The risk difference met the criteria for noninferiority (P < .001) but not for superiority (P = .09).

The risk for major bleeding was similar in the apixaban and dalteparin groups (3.8% and 4.0%; P = .60), including major gastrointestinal (GI) bleeds (11 vs 10 events). 

There was a numeric excess of clinically relevant nonmajor bleeding in the apixaban group (9.0% vs 6.0%; HR, 1.42; 95% CI, 0.88-2.30).

However, the site of this bleeding “was essentially the genitourinary tract and the upper respiratory tract, so again there was no increase in gastrointestinal bleeding, even when the clinically relevant major bleeding was considered,” said lead author Giancarlo Agnelli, MD, University of Perugia, Italy.

Taken together, “We believe that the findings of CARAVAGGIO expand the proportion of patients with cancer-associated thrombosis who are eligible for treatment with oral direct anticoagulants, including patients with gastrointestinal cancer,” he concluded.

The findings were presented online March 29 at the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC) and published simultaneously in the New England Journal of Medicine.

Major guidelines recommend the use of low-molecular-weight heparin (LMWH) for the treatment of cancer-related VTE but also support the use of edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) as an alternative based on data from the OKUSAI VTE and SELECT-D trials, respectively. But an increased risk for bleeding was observed among patients with GI cancer in both studies.

“The findings are of clinical relevance because we were able to confirm the efficacy of another [novel oral anticoagulant] NOAC but we have the absence of bleeding, GI bleeding in particular. This is an important point; this is what the clinical community is looking for,” Agnelli told theheart.org | Medscape Cardiology.

The recent ADAM VTE trial testing apixaban, a factor Xa inhibitor, vs dalteparin, a LMWH, reported no major bleeding among patients treated with apixaban (primary safety endpoint) and a significant reduction of VTE (secondary efficacy endpoint). But the trial included only 300 patients with cancer and a more selected population compared with the CARAVAGGIO trial, noted Chiara Melloni, MD, MHS, a cardiologist at Duke Clinical Research Institute, Durham, North Carolina, who was not involved with the trial.

“The trial presented today by Prof. Agnelli provides evidence that apixaban represents an additional valid option, next to edoxaban and rivaroxaban, for the treatment of VTE in cancer patients,” she told theheart.org | Medscape Cardiology in an email. “The subgroup analyses showed consistent results across all different subgroups, but a significant interaction was observed between age groups, with a more favorable profile among those less than 75 years old (and mostly among those <65 years old). This may require more investigation.”

The CARAVAGGIO investigators randomly assigned 576 consecutive patients with cancer who had newly diagnosed symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin 200 IU per kg once daily for 1 month followed by 150 U/kg once daily, both for a total of 6 months. Dose reduction was allowed for dalteparin but not for apixaban during the study.

Various types of cancer were included in the trial, including lung, breast, genitourinary, and upper GI.

The incidence of death was similar in the apixaban and dalteparin groups (23.4% vs 26.4%), with most deaths related to cancer (85.2% vs 88.2%, respectively).

During a discussion of the findings, panelist Bonnie Ky, MD, from the Hospital of the University of Pennsylvania in Philadelphia, and editor in chief of JACC: CardioOncology, congratulated the authors on an “excellent, well-done study” in a high-need cancer population suffering from a clinically significant burden of VTE, reported to be anywhere from 8% to 19% depending on tumor type.

“I was particularly impressed by the low rate of bleeding, which has been traditionally a concern with DOACs, as well the demonstration of noninferiority of apixaban,” she said.

Ky asked why the bleeding rate was lower than observed in other published studies and in whom clinicians shouldn’t be considering apixaban now.

Agnelli said that a head-to-head study is needed to compare the various oral anticoagulant agents but that the gastrointestinal bleeding rate is well known to be reduced with apixaban in patients with atrial fibrillation.

“So whether this is related to the drug or the administration twice daily, it’s something that can be discussed, but honestly the final solution would be to have a comparative study,” he said. “It’s going to be difficult, but it’s what we need.”

As to the clinical application of the data, Agnelli said, “The apixaban data actually extend the number of our patients who could receive the oral agents, including patients with GI cancer. So I do believe this indication about using DOACs in cancer patients will change and the indication expanded. But of course, we are building on something that was already known. We did not discover this all by ourselves.”

Panelist Robert M. Carey, MD, a leader in cardiovascular endocrinology and dean emeritus, University of Virginia School of Medicine  in Charlottesville, said the study “conclusively shows noninferiority” but asked for more detail on the subset of patients with GI malignancies and the bleeding rate there.

Agnelli replied that the proportion and number of these patients in CARAVAGGIO is the same as, if not slightly higher than, in other studies. “So we have a population that is representative of all the cancer population, including GI cancer,” he said, adding that subanalyses are underway correlating the site of cancer with the type of bleeding.

Agnes Y.Y. Lee, MD, University of British Columbia, Vancouver Coastal Health, and the British Cancer Agency, all in Vancouver, Canada, notes in a linked editorial that CARAVAGGIO excluded patients with primary and metastatic brain lesions and included few patients with cancers of the upper GI tract, with hematologic cancers, or receiving newer cancer therapies, such as checkpoint inhibitors.

She says clinicians will have to choose carefully which anticoagulant to use but that LMWH is “preferred in patients in whom drug-drug interaction is a concern and in those who have undergone surgery involving the upper gastrointestinal tract because absorption of all direct oral anticoagulants occurs in the stomach or proximal small bowel.”

Warfarin may also be the only option when cost is the “decision driver” in patients with cancer facing major financial healthcare burdens, Lee writes.

Duke’s Melloni also said the cost of oral anticoagulants needs to be taken into account and varies widely for patients based on their insurance and availability of other copay assistance programs. “It is therefore important to discuss with the patients upfront because if the patients are started but cannot afford long term, early discontinuation can impact their safety,” she said.

The trial was sponsored by FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti) and was funded by an unrestricted grant from the Bristol-Myers Squibb-Pfizer Alliance. Agnelli reports personal fees from Pfizer and Bayer Healthcare, and “other” from Daiichi Sankyo outside the submitted work. Melloni reports having no relevant conflicts of interest. Lee reports personal fees and nonfinancial support from Bayer; grants, personal fees, and nonfinancial support from Bristol-Myers Squibb; and personal fees from LEO Pharma, Pfizer, and Quercegen Pharmaceuticals outside the submitted work.

This article first appeared on Medscape.com.

Oral apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was as effective as subcutaneous dalteparin (Fragmin, Pfizer) for cancer-related venous thromboembolism (VTE) without an increased risk of major bleeding, the CARAVAGGIO study suggests.

Over 6 months of follow-up, the primary efficacy outcome of recurrent thromboembolism occurred in 32 of 576 patients (5.6%) randomly assigned to apixaban and in 46 of 579 patients (7.9%) assigned dalteparin (hazard ratio, 0.63; 95% confidence interval, 0.37-1.07). The risk difference met the criteria for noninferiority (P < .001) but not for superiority (P = .09).

The risk for major bleeding was similar in the apixaban and dalteparin groups (3.8% and 4.0%; P = .60), including major gastrointestinal (GI) bleeds (11 vs 10 events). 

There was a numeric excess of clinically relevant nonmajor bleeding in the apixaban group (9.0% vs 6.0%; HR, 1.42; 95% CI, 0.88-2.30).

However, the site of this bleeding “was essentially the genitourinary tract and the upper respiratory tract, so again there was no increase in gastrointestinal bleeding, even when the clinically relevant major bleeding was considered,” said lead author Giancarlo Agnelli, MD, University of Perugia, Italy.

Taken together, “We believe that the findings of CARAVAGGIO expand the proportion of patients with cancer-associated thrombosis who are eligible for treatment with oral direct anticoagulants, including patients with gastrointestinal cancer,” he concluded.

The findings were presented online March 29 at the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC) and published simultaneously in the New England Journal of Medicine.

Major guidelines recommend the use of low-molecular-weight heparin (LMWH) for the treatment of cancer-related VTE but also support the use of edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) as an alternative based on data from the OKUSAI VTE and SELECT-D trials, respectively. But an increased risk for bleeding was observed among patients with GI cancer in both studies.

“The findings are of clinical relevance because we were able to confirm the efficacy of another [novel oral anticoagulant] NOAC but we have the absence of bleeding, GI bleeding in particular. This is an important point; this is what the clinical community is looking for,” Agnelli told theheart.org | Medscape Cardiology.

The recent ADAM VTE trial testing apixaban, a factor Xa inhibitor, vs dalteparin, a LMWH, reported no major bleeding among patients treated with apixaban (primary safety endpoint) and a significant reduction of VTE (secondary efficacy endpoint). But the trial included only 300 patients with cancer and a more selected population compared with the CARAVAGGIO trial, noted Chiara Melloni, MD, MHS, a cardiologist at Duke Clinical Research Institute, Durham, North Carolina, who was not involved with the trial.

“The trial presented today by Prof. Agnelli provides evidence that apixaban represents an additional valid option, next to edoxaban and rivaroxaban, for the treatment of VTE in cancer patients,” she told theheart.org | Medscape Cardiology in an email. “The subgroup analyses showed consistent results across all different subgroups, but a significant interaction was observed between age groups, with a more favorable profile among those less than 75 years old (and mostly among those <65 years old). This may require more investigation.”

The CARAVAGGIO investigators randomly assigned 576 consecutive patients with cancer who had newly diagnosed symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin 200 IU per kg once daily for 1 month followed by 150 U/kg once daily, both for a total of 6 months. Dose reduction was allowed for dalteparin but not for apixaban during the study.

Various types of cancer were included in the trial, including lung, breast, genitourinary, and upper GI.

The incidence of death was similar in the apixaban and dalteparin groups (23.4% vs 26.4%), with most deaths related to cancer (85.2% vs 88.2%, respectively).

During a discussion of the findings, panelist Bonnie Ky, MD, from the Hospital of the University of Pennsylvania in Philadelphia, and editor in chief of JACC: CardioOncology, congratulated the authors on an “excellent, well-done study” in a high-need cancer population suffering from a clinically significant burden of VTE, reported to be anywhere from 8% to 19% depending on tumor type.

“I was particularly impressed by the low rate of bleeding, which has been traditionally a concern with DOACs, as well the demonstration of noninferiority of apixaban,” she said.

Ky asked why the bleeding rate was lower than observed in other published studies and in whom clinicians shouldn’t be considering apixaban now.

Agnelli said that a head-to-head study is needed to compare the various oral anticoagulant agents but that the gastrointestinal bleeding rate is well known to be reduced with apixaban in patients with atrial fibrillation.

“So whether this is related to the drug or the administration twice daily, it’s something that can be discussed, but honestly the final solution would be to have a comparative study,” he said. “It’s going to be difficult, but it’s what we need.”

As to the clinical application of the data, Agnelli said, “The apixaban data actually extend the number of our patients who could receive the oral agents, including patients with GI cancer. So I do believe this indication about using DOACs in cancer patients will change and the indication expanded. But of course, we are building on something that was already known. We did not discover this all by ourselves.”

Panelist Robert M. Carey, MD, a leader in cardiovascular endocrinology and dean emeritus, University of Virginia School of Medicine  in Charlottesville, said the study “conclusively shows noninferiority” but asked for more detail on the subset of patients with GI malignancies and the bleeding rate there.

Agnelli replied that the proportion and number of these patients in CARAVAGGIO is the same as, if not slightly higher than, in other studies. “So we have a population that is representative of all the cancer population, including GI cancer,” he said, adding that subanalyses are underway correlating the site of cancer with the type of bleeding.

Agnes Y.Y. Lee, MD, University of British Columbia, Vancouver Coastal Health, and the British Cancer Agency, all in Vancouver, Canada, notes in a linked editorial that CARAVAGGIO excluded patients with primary and metastatic brain lesions and included few patients with cancers of the upper GI tract, with hematologic cancers, or receiving newer cancer therapies, such as checkpoint inhibitors.

She says clinicians will have to choose carefully which anticoagulant to use but that LMWH is “preferred in patients in whom drug-drug interaction is a concern and in those who have undergone surgery involving the upper gastrointestinal tract because absorption of all direct oral anticoagulants occurs in the stomach or proximal small bowel.”

Warfarin may also be the only option when cost is the “decision driver” in patients with cancer facing major financial healthcare burdens, Lee writes.

Duke’s Melloni also said the cost of oral anticoagulants needs to be taken into account and varies widely for patients based on their insurance and availability of other copay assistance programs. “It is therefore important to discuss with the patients upfront because if the patients are started but cannot afford long term, early discontinuation can impact their safety,” she said.

The trial was sponsored by FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti) and was funded by an unrestricted grant from the Bristol-Myers Squibb-Pfizer Alliance. Agnelli reports personal fees from Pfizer and Bayer Healthcare, and “other” from Daiichi Sankyo outside the submitted work. Melloni reports having no relevant conflicts of interest. Lee reports personal fees and nonfinancial support from Bayer; grants, personal fees, and nonfinancial support from Bristol-Myers Squibb; and personal fees from LEO Pharma, Pfizer, and Quercegen Pharmaceuticals outside the submitted work.

This article first appeared on Medscape.com.

Oral apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was as effective as subcutaneous dalteparin (Fragmin, Pfizer) for cancer-related venous thromboembolism (VTE) without an increased risk of major bleeding, the CARAVAGGIO study suggests.

Over 6 months of follow-up, the primary efficacy outcome of recurrent thromboembolism occurred in 32 of 576 patients (5.6%) randomly assigned to apixaban and in 46 of 579 patients (7.9%) assigned dalteparin (hazard ratio, 0.63; 95% confidence interval, 0.37-1.07). The risk difference met the criteria for noninferiority (P < .001) but not for superiority (P = .09).

The risk for major bleeding was similar in the apixaban and dalteparin groups (3.8% and 4.0%; P = .60), including major gastrointestinal (GI) bleeds (11 vs 10 events). 

There was a numeric excess of clinically relevant nonmajor bleeding in the apixaban group (9.0% vs 6.0%; HR, 1.42; 95% CI, 0.88-2.30).

However, the site of this bleeding “was essentially the genitourinary tract and the upper respiratory tract, so again there was no increase in gastrointestinal bleeding, even when the clinically relevant major bleeding was considered,” said lead author Giancarlo Agnelli, MD, University of Perugia, Italy.

Taken together, “We believe that the findings of CARAVAGGIO expand the proportion of patients with cancer-associated thrombosis who are eligible for treatment with oral direct anticoagulants, including patients with gastrointestinal cancer,” he concluded.

The findings were presented online March 29 at the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC) and published simultaneously in the New England Journal of Medicine.

Major guidelines recommend the use of low-molecular-weight heparin (LMWH) for the treatment of cancer-related VTE but also support the use of edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) as an alternative based on data from the OKUSAI VTE and SELECT-D trials, respectively. But an increased risk for bleeding was observed among patients with GI cancer in both studies.

“The findings are of clinical relevance because we were able to confirm the efficacy of another [novel oral anticoagulant] NOAC but we have the absence of bleeding, GI bleeding in particular. This is an important point; this is what the clinical community is looking for,” Agnelli told theheart.org | Medscape Cardiology.

The recent ADAM VTE trial testing apixaban, a factor Xa inhibitor, vs dalteparin, a LMWH, reported no major bleeding among patients treated with apixaban (primary safety endpoint) and a significant reduction of VTE (secondary efficacy endpoint). But the trial included only 300 patients with cancer and a more selected population compared with the CARAVAGGIO trial, noted Chiara Melloni, MD, MHS, a cardiologist at Duke Clinical Research Institute, Durham, North Carolina, who was not involved with the trial.

“The trial presented today by Prof. Agnelli provides evidence that apixaban represents an additional valid option, next to edoxaban and rivaroxaban, for the treatment of VTE in cancer patients,” she told theheart.org | Medscape Cardiology in an email. “The subgroup analyses showed consistent results across all different subgroups, but a significant interaction was observed between age groups, with a more favorable profile among those less than 75 years old (and mostly among those <65 years old). This may require more investigation.”

The CARAVAGGIO investigators randomly assigned 576 consecutive patients with cancer who had newly diagnosed symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin 200 IU per kg once daily for 1 month followed by 150 U/kg once daily, both for a total of 6 months. Dose reduction was allowed for dalteparin but not for apixaban during the study.

Various types of cancer were included in the trial, including lung, breast, genitourinary, and upper GI.

The incidence of death was similar in the apixaban and dalteparin groups (23.4% vs 26.4%), with most deaths related to cancer (85.2% vs 88.2%, respectively).

During a discussion of the findings, panelist Bonnie Ky, MD, from the Hospital of the University of Pennsylvania in Philadelphia, and editor in chief of JACC: CardioOncology, congratulated the authors on an “excellent, well-done study” in a high-need cancer population suffering from a clinically significant burden of VTE, reported to be anywhere from 8% to 19% depending on tumor type.

“I was particularly impressed by the low rate of bleeding, which has been traditionally a concern with DOACs, as well the demonstration of noninferiority of apixaban,” she said.

Ky asked why the bleeding rate was lower than observed in other published studies and in whom clinicians shouldn’t be considering apixaban now.

Agnelli said that a head-to-head study is needed to compare the various oral anticoagulant agents but that the gastrointestinal bleeding rate is well known to be reduced with apixaban in patients with atrial fibrillation.

“So whether this is related to the drug or the administration twice daily, it’s something that can be discussed, but honestly the final solution would be to have a comparative study,” he said. “It’s going to be difficult, but it’s what we need.”

As to the clinical application of the data, Agnelli said, “The apixaban data actually extend the number of our patients who could receive the oral agents, including patients with GI cancer. So I do believe this indication about using DOACs in cancer patients will change and the indication expanded. But of course, we are building on something that was already known. We did not discover this all by ourselves.”

Panelist Robert M. Carey, MD, a leader in cardiovascular endocrinology and dean emeritus, University of Virginia School of Medicine  in Charlottesville, said the study “conclusively shows noninferiority” but asked for more detail on the subset of patients with GI malignancies and the bleeding rate there.

Agnelli replied that the proportion and number of these patients in CARAVAGGIO is the same as, if not slightly higher than, in other studies. “So we have a population that is representative of all the cancer population, including GI cancer,” he said, adding that subanalyses are underway correlating the site of cancer with the type of bleeding.

Agnes Y.Y. Lee, MD, University of British Columbia, Vancouver Coastal Health, and the British Cancer Agency, all in Vancouver, Canada, notes in a linked editorial that CARAVAGGIO excluded patients with primary and metastatic brain lesions and included few patients with cancers of the upper GI tract, with hematologic cancers, or receiving newer cancer therapies, such as checkpoint inhibitors.

She says clinicians will have to choose carefully which anticoagulant to use but that LMWH is “preferred in patients in whom drug-drug interaction is a concern and in those who have undergone surgery involving the upper gastrointestinal tract because absorption of all direct oral anticoagulants occurs in the stomach or proximal small bowel.”

Warfarin may also be the only option when cost is the “decision driver” in patients with cancer facing major financial healthcare burdens, Lee writes.

Duke’s Melloni also said the cost of oral anticoagulants needs to be taken into account and varies widely for patients based on their insurance and availability of other copay assistance programs. “It is therefore important to discuss with the patients upfront because if the patients are started but cannot afford long term, early discontinuation can impact their safety,” she said.

The trial was sponsored by FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti) and was funded by an unrestricted grant from the Bristol-Myers Squibb-Pfizer Alliance. Agnelli reports personal fees from Pfizer and Bayer Healthcare, and “other” from Daiichi Sankyo outside the submitted work. Melloni reports having no relevant conflicts of interest. Lee reports personal fees and nonfinancial support from Bayer; grants, personal fees, and nonfinancial support from Bristol-Myers Squibb; and personal fees from LEO Pharma, Pfizer, and Quercegen Pharmaceuticals outside the submitted work.

This article first appeared on Medscape.com.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

The guidelines allow for the addition of short-term clopidogrel to an oral anticoagulant (OAC) in patients with an established OAC indication, such as atrial fibrillation (AF), who undergo transcatheter aortic valve replacement (TAVR). But does the extra antithrombotic protection come with safety issues?

It apparently did in the POPULAR-TAVI trial, which saw an excess of major and minor bleeding in such patients already on an OAC when they underwent TAVR and who then took the antiplatelet agent for the next 3 months.

The patients who instead continued on their OAC as the only post-TAVR antithrombotic, compared with those on double therapy, showed a 37% lower 1-year risk of any bleeding, including major and disabling bleeding.

Importantly, they didn’t seem to pay a price in excess ischemic events, such as stroke or myocardial infarction (MI).

The trial argues against adding clopidogrel on top of OAC in TAVR patients with an OAC indication in order to reduce their risk of bleeding, Jurriën ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands, told theheart.org | Medscape Cardiology.

Whether the ischemic event risk was comparable with and without clopidogrel is less clear. “As the study is not powered for the ischemic end points, the answer is less definite. But we did not see a hint of a higher ischemic event rate, especially stroke, in the OAC-alone group,” ten Berg said.

“So we are pretty confident in saying that OAC alone is the optimal treatment.”

The results of POPULAR-TAVI were presented by Vincent Nijenhuis, MD, also from St. Antonius Hospital, on March 29 during the virtual presentation of the American College of Cardiology 2020 Scientific Session/World Congress of Cardiology. Nijenhuis is also first author on the trial’s simultaneous publication in the New England Journal of Medicine.

The only reason to add an antiplatelet in TAVR patients who need to be on an OAC for another indication is to prevent ischemic events like MI, stroke, or death, agreed George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, for theheart.org | Medscape Cardiology.

But that protection apparently wasn’t needed; for patients on OAC only, “the overall risk–benefit ratio was favorable for them both ways. Although the study is small, I think the findings would be clinically meaningful,” said Dangas, who was not involved in POPULAR-TAVI but was lead author on the GALILEO trial publication.

GALILEO tested a direct oral anticoagulant (DOAC) against dual antiplatelet therapy in patients undergoing TAVR but without a conventional OAC indication. The trial was halted because the DOAC group started to show an excess of bleeding, thromboembolic events, and mortality.

Most POPULAR-TAVI patients were on vitamin K antagonists, but about a quarter were taking DOACs. Clopidogrel was given on an open-label basis.

The trial suggests that, for TAVR patients with an indication for lifelong OAC, “it does appear to be safe to give only an anticoagulant, whether it’s warfarin or a DOAC, and not add clopidogrel,” Robert O. Bonow, MD, Northwestern University, Chicago, told theheart.org | Medscape Cardiology.

“The bottom line appears to be that it’s no worse, and is probably better in terms of bleeding events,” said Bonow, who wasn’t involved in POPULAR-TAVI.

But there are difficulties in interpreting the trial that stem from its design and other issues, he said. For example, it can’t really be concluded that adding an antiplatelet agent to OAC in such patients who undergo TAVR, according to commonly practiced techniques, will increase the risk of bleeding compared with OAC alone.

To begin with, Bonow said, substituting aspirin for clopidogrel might have produced better double-therapy results. But the bigger issues, Bonow said, center on the discretion its operators had in whether to maintain or suspend the patients’ OAC during the TAVR procedure, as well as the unusual bleeding definitions used in the trial.

The first POPULAR-TAVI primary end point was any bleeding that met Valve Academic Research Consortium (VARC) criteria; the second was nonprocedural bleeding that met the Bleeding Academic Research Consortium (BARC) definition.

“Because the VARC-2 classification does not distinguish between procedure-related and nonprocedure-related bleeding events, procedure-related events were defined as BARC type 4 severe bleeding,” the trial’s journal report states. Therefore, “most bleeding at the puncture site was counted as nonprocedure-related.”

It may be Bonow’s biggest issue with the trial, he said. “They’re terming these events that occurred periprocedurally, in the first day or first hours of the procedure, as being ‘nonprocedural’ because they didn’t represent severe BARC bleeding, where you have a subarachnoid hemorrhage or require transfusions.”

An editorial accompanying the trial report also knocks this aspect of the trial design. Although the trial “confirmed” a higher incidence of any bleeding in the double-therapy group, “there are concerns regarding the classification of bleeding and the reliability of secondary outcome analysis,” writes Frederick Feit, MD, NYU Grossman School of Medicine, New York City.

“Bleeding occurring during TAVI or the index hospitalization was unadvisedly defined as non-procedure related, even if it occurred at the access site,” the editorial notes.

Ten Berg noted that procedural bleeding is frequent in TAVI, but the VARC-2 definition doesn’t accommodate them. So “we also used the BARC definition for procedural bleeding, BARC-4,” he told theheart.org | Medscape Cardiology.

“However, BARC-4 describes bleeding during surgery, and it turned out that in POPULAR- TAVI only one patient had BARC-4 bleeding. So we do not at all agree with the editorial.”

Still, the trial’s reported event-rate curves show that “most of the step-up in bleeding, in either arm of the trial, occurred immediately,” Bonow observed. A more consistent, flat trend followed thereafter out to 3 months.

“So half of the bleeding in both arms of the trial occurred at the site of the arterial puncture. Though it wasn’t considered severe, it was indeed periprocedural,” Bonow said, interpreting the results.

The POPULAR-TAVI journal report says the procedures were performed according to local site protocols, and site physicians were allowed to decide whether to continue or suspend OAC. But “the trial protocol advised physicians to continue oral anticoagulation during admission for the TAVI procedure.”

Many of the patients, regardless of randomization group, “went through the procedure under full anticoagulation,” Dangas agreed. POPULAR-TAVI, it seems, “is the first anticoagulation study ever to start anticoagulation before the procedure.”

Bleeding event rates in the trial “are somewhat high because of this unusual procedural feature of the study,” Dangas said.

“It’s therefore not surprising that so much of the bleeding occurred in the first hours of the procedure itself,” observed Bonow.

The trial enrolled 313 patients in four European countries who were on OAC for an approved indication, predominantly AF, and underwent TAVR. Their mean age was about 81 years, and 45.4% were women. They were randomly assigned to receive or not receive clopidogrel in a loading dose, followed by 75 mg/d on top of their OAC for 3 months, and were followed out to a year.

All bleeding that met VARC-2 criteria, the first primary end point, occurred in 21.7% of the 157 patients on OAC alone and 34.6% of the 156 who received double therapy (risk ratio [RR], 0.63; 95% CI, 0.43 - 0.90; P = .011).

The second primary end point, “nonprocedural” bleeding that met BARC-4 criteria, occurred in 21.7% and 34.0%, respectively, of patients (RR, 0.64; 95% CI, 0.44 - 0.92; P = .015).

There were also two secondary composite outcomes. The first consisted of nonprocedural bleeding, cardiovascular (CV) death, any stroke, and MI, and was seen in 31.2% of patients on OAC alone and 45.5% of those on OAC plus clopidogrel (RR, 0.69; 95% CI, 0.51 - 0.92), an absolute difference that was within the prospectively defined noninferiority margins.

The other secondary end point — CV death, ischemic stroke, and MI — occurred in 13.4% of those receiving only OAC and 17.3% on added clopidogrel (RR, 0.77; 95% CI, 0.46 - 1.31), which was nonsignificant for superiority.

“Could they have done better by holding the anticoagulation, whether warfarin or a DOAC, during that time? That’s what I think many centers might do if they’re performing a TAVR,” Bonow said.

“It seems to me that could have been done in this trial as well: they could have stopped the anticoagulation, done the procedure, and started the anticoagulation after, the way you would normally in a patient getting a TAVR.”

Such a practice might have reduced the risk of procedural bleeding as it is usually defined in TAVR in both groups, thereby potentially blunting any difference in bleeding rate between the two groups.

“That’s my take on it.” Still, he said, the trial’s message remains: OAC without clopidogrel is safe in POPULAR-TAVI-like patients.

Nijenhuis had no disclosures. Ten Berg disclosed no industry ties. Disclosures for the other authors are in the report. Bonow has previously reported no disclosures. Dangas has previously disclosed receiving grants and fees from Bayer, fees from Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic. Feit discloses personal fees from Abbott Vascular and other relationships with Medtronic, Boston Scientific, and Sapheon.

This article first appeared on Medscape.com.

Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.

Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).

Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.

“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.

The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.

The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.

In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.

Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”

Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.

“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.

The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.

mzoler@mdedge.com

SOURCE: Raal F. ACC 20. Abstract 411-12.

Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.

Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).

Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.

“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.

The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.

The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.

In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.

Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”

Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.

“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.

The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.

mzoler@mdedge.com

SOURCE: Raal F. ACC 20. Abstract 411-12.

Evinacumab, the first agent from a new class of lipid-lowering drugs, showed a “remarkable” and unprecedented level of LDL-cholesterol lowering in a pivotal trial with 65 patients with homozygous familial hypercholesterolemia.

Monthly intravenous infusions of evinacumab cut LDL cholesterol levels by an average of 135 mg/dL from baseline, a 47% mean reduction, after 24 weeks of treatment in 43 homozygous familial hypercholesterolemia (HoFH) patients, Frederick Raal, MBChB, said on March 30 in a video presentation of his research at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Evinacumab is a human monoclonal antibody inhibitor of angiopoietin-like 3, a liver protein that boosts levels of LDL cholesterol and triglycerides (TG).

Another notable effect of the novel agent was that it was equally effective in the roughly one-third of patients with a minimal residual level of LDL receptor activity, patients know as having “null/null” mutations. “For the first time, we see HoFH patients getting to [lipid] targets that we never thought would be possible,” said Dr. Raal, professor and head of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. “This works in patients without residual LDL receptor function.” The drug was also generally very well tolerated, he said, causing no treatment-related serious adverse events during the brief treatment period of 24 weeks.

“One of the major, remarkable findings in this study was the effect on null/null patients,” which contrasts with the effects of other, more established drugs for treating dyslipidemia like statins and PCSK9 inhibitors, which work by increasing the number of LDL receptors on cells. The demonstrated efficacy and safety of evinacumab in null/null patients “is a definite advance,” commented Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis.

The placebo-controlled trial randomized patients at 30 sites in 11 countries who were at least 12 years old and had documented mutations in both of their LDL receptor genes and a serum level of LDL cholesterol that was at least 500 mg/dL on no treatment. Patients averaged about 40 years of age; about 30% had null/null mutations, more than 90% were on statin treatment, and about three-quarters were receiving regular treatment with a PCSK9 inhibitor. At baseline, LDL cholesterol levels averaged about 250 mg/dL.

The study’s primary endpoint was the between-group percentage change in LDL cholesterol level after 24 weeks, which fell by 47% from baseline with evinacumab treatment and increased by an average of 2% among 22 patients who received placebo injections; so evinacumab cut this measure by 49%, compared with placebo after 24 weeks, a statistically significant difference. A cut of baseline LDL cholesterol by at least 50% occurred in 56% of the evinacumab-treated patients and in 5% of controls.

In addition to its LDL reduction, another notable effect of evinacumab was that it trimmed baseline triglyceride levels by half, consistent with prior reports of the drug’s effect on this measure, although average triglyceride levels in the enrolled patients fell within the normal range prior to treatment.

Evinacumab “will probably be very effective in treating patients with hypertriglyceridemia; those studies are ongoing,” noted Dr. Raal. But, he added, “this drug will probably be reserved for severe” dyslipidemia cases, not for “the garden variety of moderate hypertriglyceridemia or hypercholesterolemia.”

Evinacumab “may be a fairly broad-spectrum lipid-lowering drug, but it should be reserved for severe cases,” agreed Dirk Blom, MBChB, head of lipidology at the University of Capetown, South Africa. “This will likely remain a fairly expensive drug, and we wouldn’t want to use it across the board, but for difficult to treat patients with either severe hypercholesterolemia or hypertriglyceridemia, I think this will have very significant advantages,” he commented.

“Drugs that reduce triglycerides by large amounts may prove to have cardiovascular disease benefits, but that remains to be proven in large, long-term outcome trials,” commented Deepak Bhatt, MD, professor of medicine at Harvard Medical School and executive director of interventional cardiology programs at Brigham and Women’s Hospital, both in Boston. “But for right now, for most patients with more common forms of elevated LDL cholesterol, the treatment options include statins, ezetimibe [Zetia], and PCSK9 inhibitors, and for more common levels of elevated triglycerides, it’s icosapent ethyl [Vascepa],” Dr. Bhatt said.

The study was sponsored by Regeneron, the company developing evinacumab and which is partially owned by Sanofi. Dr. Raal has received personal fees and/or research funding from Regeneron, Sanofi Aventis, Amgen, and The Medicines Company. Dr. Goldberg has received research funding and/or consulting fees from Regeneron and Sanofi, Akcea, Amarin, Amgen, Esperion, Ionis, Merck, Novartis, and Pfizer. Dr. Blom has been a consultant to and/or received research funding from Regeneron, Sanofi, Aegerium, Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Esperion, Gemphire, MSD, and Novo Nordisk. Dr. Bhatt has received research funding from many companies including Regeneron and Sanofi.

mzoler@mdedge.com

SOURCE: Raal F. ACC 20. Abstract 411-12.

Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

bjancin@mdedge.com

Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

bjancin@mdedge.com

Alirocumab achieved a mean 63-mg/dL reduction in LDL cholesterol in the ODYSSEY HoFH study, the largest-ever randomized, placebo-controlled clinical trial of lipid-lowering in adults with homozygous familial hypercholesterolemia (HoFH), Dirk Blom, MD, said in a video presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

bjancin@mdedge.com