Sue Hughes

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

Worst Figures in Rural South

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

Worst Figures in Rural South

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

Worst Figures in Rural South

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

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

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

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

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

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

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

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

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

This article first appeared on Medscape.com.

LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
 

There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.

However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.

“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.

“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.

“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”

Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).

Endogenous nitric oxide

The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.

The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.

The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.

Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.

“Shaking up the field”

There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”

“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.

Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.

They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.

Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.

“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.

In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).

Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.

The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.

This article first appeared on Medscape.com.

LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
 

There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.

However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.

“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.

“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.

“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”

Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).

Endogenous nitric oxide

The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.

The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.

The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.

Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.

“Shaking up the field”

There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”

“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.

Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.

They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.

Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.

“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.

In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).

Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.

The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.

This article first appeared on Medscape.com.

LOS ANGELES – A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.
 

There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.

However, “In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated,” Dr. Hill said in an interview.

“In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11,” he said. “We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.

“The drug works really well in patients who do not get thrombolysis, but it doesn’t work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive,” he added.

“This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before,” Dr. Hill noted. “Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results.”

Dr. Hill, professor of neurology at the University of Calgary (Alta.), presented results of the ESCAPE-NA1 trial on Feb. 20 at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30258-0).

Endogenous nitric oxide

The new agent – known as NA1 or nerinetide – is a 20-amino-acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. “It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death,” Dr. Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.

The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, he said.

The trial included 1,105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.

Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.

“Shaking up the field”

There is still more work to do, Dr. Hill said. “We don’t fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up. This is a totally new drug, and we have to think carefully about where it could fit in.”

“The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis,” he said.

Another possibility would be to withhold thrombolysis and give nerinetide instead. “It may be that thrombolysis is not needed if patients are receiving thrombectomy – this is being suggested now in initial studies,” Hill stated.

They also chose a very select group of patients – those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. “We have to work out how to expand that population,” he said.

Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.

“Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings,” he said.

In an accompanying comment in The Lancet, Graeme J. Hankey, MD, of the University of Western Australia, Perth, noted that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored (Lancet. 2020 Feb 20; doi: 10.1016/S0140-6736(20)30316-0).

Dr. Hankey also pointed out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.

The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he added.

This article first appeared on Medscape.com.

A new study suggests that the 0.25-mg/kg dose of the thrombolytic tenecteplase (TNK) is just as good at facilitating reperfusion of the blocked artery in patients with ischemic large-vessel stroke prior to planned thrombectomy as the higher 0.4-mg/kg dose.
 

The EXTEND-IA TNK Part 2 trial was presented today at the American Stroke Association’s International Stroke Conference (ISC) 2020 in Los Angeles and was published online simultaneously (JAMA. 2020 Feb 20. doi: 10.1001/jama.2020.1511).

“We found the 0.4-mg/kg dose was no better than 0.25 mg/kg. There was absolutely no perceptible difference, so it appears that 0.25 mg/kg is enough,” lead investigator Bruce Campbell, MBBS, PhD, said in an interview.

“Our study was conducted in patients with large-vessel occlusions heading for thrombectomy, but I think the results can be extrapolated to patients with smaller occlusions too,” he added.

The study also showed that one-fifth of patients given tenecteplase experienced reperfusion before thrombectomy was performed. The percentage rose to one-third among patients from rural areas, whose longer times in transport led to an increase in the time between thrombolysis and thrombectomy.

“I think these data are as good as we’re going to get on the optimal dose of TNK. Our endpoint was reperfusion rates – a good, solid biological marker of benefit – but if a difference in clinical outcomes is wanted, that would take a trial of several thousand patients, which is never likely to be done,” said Dr. Campbell, who is from the Department of Neurology at the Royal Melbourne Hospital, Australia.

The researchers note that tenecteplase has a practical advantage over alteplase in that it is given as a bolus injection, whereas alteplase is given as bolus followed by a 1-hour infusion.

Results from the first EXTEND-IA TNK study suggested that tenecteplase 0.25 mg/kg produced higher reperfusion rates than alteplase (N Engl J Med. 2018;378:1573-82). However, the larger NOR-TEST study found no difference in efficacy or safety between a 0.4-mg/kg dose of tenecteplase and alteplase in patients with mild stroke (Lancet Neurol. 2017 Oct;16[10]:781-8).

TNK use in stroke varies around the world. The drug is not licensed for use in stroke anywhere, which Dr. Campbell attributes to a lack of incentive for the manufacturer, Genentech/Boehringer Ingelheim. That company also markets alteplase, the main thrombolytic used in stroke.

But many countries have now included TNK in their stroke guidelines, Dr. Campbell noted. “This has only recently occurred in the U.S., where it has a 2b recommendation, and the dose recommendations are somewhat confusing, advocating 0.25 mg/kg in large-vessel occlusions [as was used in the first EXTEND IA study] and 0.4 mg/kg in non–large vessel occlusions [from the NOR-TEST trial].

“This makes no biological sense whatsoever, recommending a higher dose for smaller occlusions, but that is just a literal translation of the design of the two major studies. I’m hoping our current results will help clarify the dosage issue and that might encourage more use of TNK altogether,” he commented.

For the current study, conducted in Australia and New Zealand, 300 patients who had experienced ischemic large-vessel stroke within 4.5 hours of symptom onset and who were scheduled for endovascular thrombectomy were randomly assigned to receive open-label thrombolysis with tenecteplase 0.4 mg/kg or 0.25 mg/kg.

The primary outcome, reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, occurred in 19.3% of both groups. There was also no difference in any of the functional-outcome secondary endpoints or all-cause mortality between the two doses.

“While we didn’t find any extra benefit of the 0.4-mg/kg dose over the 0.25-mg/kg dose, we also didn’t find any extra harm, and this gives us reassurance in the emergency situation if the weight of the patient is overestimated; then we have a window of safety,” Dr. Campbell commented. “While there was a nonsignificant numerical increase in intracranial hemorrhage in the 0.4-mg/kg group, the excess bleeds were caused by puncturing of the vessels during thrombectomy, so I don’t think we can blame the TNK dose for that.

Better reperfusion than with alteplase?

Noting that the original EXTEND-IA TNK study showed higher reperfusion rates with tenecteplase vs alteplase and a trend toward better outcomes on the mRS scale, Campbell reported that a pooled analysis of the TNK results from the current study with those from the first study confirmed these findings.

“We found a doubling in the rate of reperfusion with TNK vs. alteplase, and the [modified Rankin Scale] shift analysis remained positive,” he said.

“I think we say with confidence that TNK is at least as good as alteplase and probably better, but further studies comparing the two agents are ongoing,” he added.

Of note, for the 41 patients from rural areas in the current study, in whom the time from thrombolysis to thrombectomy was longer (152 min vs. 41 min for patients from urban areas), reperfusion rates were higher (34% vs 17%), and there was no difference in dosage between the two groups.

Commenting on these latest results in an interview, Nicola Logallo, MD, of Haukeland University Hospital, Bergen, Norway, who was part of the NOR-TEST trial, said: “There is some evidence supporting the use of TNK 0.4 mg/kg in mild stroke patients, based mainly on the results from the NOR-TEST trial, and the use of TNK 0.25 mg/kg in patients undergoing thrombectomy, based on Dr. Campbell’s previous EXTEND-TNK trial. Dr. Campbell’s new study confirms that probably the higher dose of TNK does not add any advantages in terms of clinical outcome.”

Hemorrhagic complications appear to be similar in the two groups, Dr. Logallo said. “Overall, the 0.25-mg/kg TNK dose could therefore be considered as the most convenient and sensible, at least in patients undergoing thrombectomy. When it comes to the remaining stroke patients receiving thrombolysis, it remains unclear which is the best dose, but studies such as TASTE, NOR-TEST 2, AcT, and ATTEST-2 will hopefully answer this question within the next years.”

Also commenting on the study, Michael Hill, MD, professor of neurology at University of Calgary, Alberta, Canada, said the results “confirm that a good proportion of patients given TNK reperfuse before the angiogram and clarifies the dose. This is useful information.”

Dr. Hill said TNK is used routinely in some countries – mainly in Australia and Norway, where the studies have been conducted – but there is now a movement toward use of TNK in North America, too.

“Studies so far suggest that it could be more effective than alteplase, and as it is more fibrin specific, it could be safer. It is also easier to give with a bolus dose, but perhaps the biggest driver might be that it is cheaper than alteplase. Momentum is building, and many leading investigators are now conducting new studies with TNK with several more studies coming out in the next year or so,” Dr. Hill added.

The EXTEND-IA TNK Part 2 trial was supported by grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. Campbell reports receiving grants from both institutions during the conduct of the study.
 

This article first appeared on Medscape.com.

A new study suggests that the 0.25-mg/kg dose of the thrombolytic tenecteplase (TNK) is just as good at facilitating reperfusion of the blocked artery in patients with ischemic large-vessel stroke prior to planned thrombectomy as the higher 0.4-mg/kg dose.
 

The EXTEND-IA TNK Part 2 trial was presented today at the American Stroke Association’s International Stroke Conference (ISC) 2020 in Los Angeles and was published online simultaneously (JAMA. 2020 Feb 20. doi: 10.1001/jama.2020.1511).

“We found the 0.4-mg/kg dose was no better than 0.25 mg/kg. There was absolutely no perceptible difference, so it appears that 0.25 mg/kg is enough,” lead investigator Bruce Campbell, MBBS, PhD, said in an interview.

“Our study was conducted in patients with large-vessel occlusions heading for thrombectomy, but I think the results can be extrapolated to patients with smaller occlusions too,” he added.

The study also showed that one-fifth of patients given tenecteplase experienced reperfusion before thrombectomy was performed. The percentage rose to one-third among patients from rural areas, whose longer times in transport led to an increase in the time between thrombolysis and thrombectomy.

“I think these data are as good as we’re going to get on the optimal dose of TNK. Our endpoint was reperfusion rates – a good, solid biological marker of benefit – but if a difference in clinical outcomes is wanted, that would take a trial of several thousand patients, which is never likely to be done,” said Dr. Campbell, who is from the Department of Neurology at the Royal Melbourne Hospital, Australia.

The researchers note that tenecteplase has a practical advantage over alteplase in that it is given as a bolus injection, whereas alteplase is given as bolus followed by a 1-hour infusion.

Results from the first EXTEND-IA TNK study suggested that tenecteplase 0.25 mg/kg produced higher reperfusion rates than alteplase (N Engl J Med. 2018;378:1573-82). However, the larger NOR-TEST study found no difference in efficacy or safety between a 0.4-mg/kg dose of tenecteplase and alteplase in patients with mild stroke (Lancet Neurol. 2017 Oct;16[10]:781-8).

TNK use in stroke varies around the world. The drug is not licensed for use in stroke anywhere, which Dr. Campbell attributes to a lack of incentive for the manufacturer, Genentech/Boehringer Ingelheim. That company also markets alteplase, the main thrombolytic used in stroke.

But many countries have now included TNK in their stroke guidelines, Dr. Campbell noted. “This has only recently occurred in the U.S., where it has a 2b recommendation, and the dose recommendations are somewhat confusing, advocating 0.25 mg/kg in large-vessel occlusions [as was used in the first EXTEND IA study] and 0.4 mg/kg in non–large vessel occlusions [from the NOR-TEST trial].

“This makes no biological sense whatsoever, recommending a higher dose for smaller occlusions, but that is just a literal translation of the design of the two major studies. I’m hoping our current results will help clarify the dosage issue and that might encourage more use of TNK altogether,” he commented.

For the current study, conducted in Australia and New Zealand, 300 patients who had experienced ischemic large-vessel stroke within 4.5 hours of symptom onset and who were scheduled for endovascular thrombectomy were randomly assigned to receive open-label thrombolysis with tenecteplase 0.4 mg/kg or 0.25 mg/kg.

The primary outcome, reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, occurred in 19.3% of both groups. There was also no difference in any of the functional-outcome secondary endpoints or all-cause mortality between the two doses.

“While we didn’t find any extra benefit of the 0.4-mg/kg dose over the 0.25-mg/kg dose, we also didn’t find any extra harm, and this gives us reassurance in the emergency situation if the weight of the patient is overestimated; then we have a window of safety,” Dr. Campbell commented. “While there was a nonsignificant numerical increase in intracranial hemorrhage in the 0.4-mg/kg group, the excess bleeds were caused by puncturing of the vessels during thrombectomy, so I don’t think we can blame the TNK dose for that.

Better reperfusion than with alteplase?

Noting that the original EXTEND-IA TNK study showed higher reperfusion rates with tenecteplase vs alteplase and a trend toward better outcomes on the mRS scale, Campbell reported that a pooled analysis of the TNK results from the current study with those from the first study confirmed these findings.

“We found a doubling in the rate of reperfusion with TNK vs. alteplase, and the [modified Rankin Scale] shift analysis remained positive,” he said.

“I think we say with confidence that TNK is at least as good as alteplase and probably better, but further studies comparing the two agents are ongoing,” he added.

Of note, for the 41 patients from rural areas in the current study, in whom the time from thrombolysis to thrombectomy was longer (152 min vs. 41 min for patients from urban areas), reperfusion rates were higher (34% vs 17%), and there was no difference in dosage between the two groups.

Commenting on these latest results in an interview, Nicola Logallo, MD, of Haukeland University Hospital, Bergen, Norway, who was part of the NOR-TEST trial, said: “There is some evidence supporting the use of TNK 0.4 mg/kg in mild stroke patients, based mainly on the results from the NOR-TEST trial, and the use of TNK 0.25 mg/kg in patients undergoing thrombectomy, based on Dr. Campbell’s previous EXTEND-TNK trial. Dr. Campbell’s new study confirms that probably the higher dose of TNK does not add any advantages in terms of clinical outcome.”

Hemorrhagic complications appear to be similar in the two groups, Dr. Logallo said. “Overall, the 0.25-mg/kg TNK dose could therefore be considered as the most convenient and sensible, at least in patients undergoing thrombectomy. When it comes to the remaining stroke patients receiving thrombolysis, it remains unclear which is the best dose, but studies such as TASTE, NOR-TEST 2, AcT, and ATTEST-2 will hopefully answer this question within the next years.”

Also commenting on the study, Michael Hill, MD, professor of neurology at University of Calgary, Alberta, Canada, said the results “confirm that a good proportion of patients given TNK reperfuse before the angiogram and clarifies the dose. This is useful information.”

Dr. Hill said TNK is used routinely in some countries – mainly in Australia and Norway, where the studies have been conducted – but there is now a movement toward use of TNK in North America, too.

“Studies so far suggest that it could be more effective than alteplase, and as it is more fibrin specific, it could be safer. It is also easier to give with a bolus dose, but perhaps the biggest driver might be that it is cheaper than alteplase. Momentum is building, and many leading investigators are now conducting new studies with TNK with several more studies coming out in the next year or so,” Dr. Hill added.

The EXTEND-IA TNK Part 2 trial was supported by grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. Campbell reports receiving grants from both institutions during the conduct of the study.
 

This article first appeared on Medscape.com.

A new study suggests that the 0.25-mg/kg dose of the thrombolytic tenecteplase (TNK) is just as good at facilitating reperfusion of the blocked artery in patients with ischemic large-vessel stroke prior to planned thrombectomy as the higher 0.4-mg/kg dose.
 

The EXTEND-IA TNK Part 2 trial was presented today at the American Stroke Association’s International Stroke Conference (ISC) 2020 in Los Angeles and was published online simultaneously (JAMA. 2020 Feb 20. doi: 10.1001/jama.2020.1511).

“We found the 0.4-mg/kg dose was no better than 0.25 mg/kg. There was absolutely no perceptible difference, so it appears that 0.25 mg/kg is enough,” lead investigator Bruce Campbell, MBBS, PhD, said in an interview.

“Our study was conducted in patients with large-vessel occlusions heading for thrombectomy, but I think the results can be extrapolated to patients with smaller occlusions too,” he added.

The study also showed that one-fifth of patients given tenecteplase experienced reperfusion before thrombectomy was performed. The percentage rose to one-third among patients from rural areas, whose longer times in transport led to an increase in the time between thrombolysis and thrombectomy.

“I think these data are as good as we’re going to get on the optimal dose of TNK. Our endpoint was reperfusion rates – a good, solid biological marker of benefit – but if a difference in clinical outcomes is wanted, that would take a trial of several thousand patients, which is never likely to be done,” said Dr. Campbell, who is from the Department of Neurology at the Royal Melbourne Hospital, Australia.

The researchers note that tenecteplase has a practical advantage over alteplase in that it is given as a bolus injection, whereas alteplase is given as bolus followed by a 1-hour infusion.

Results from the first EXTEND-IA TNK study suggested that tenecteplase 0.25 mg/kg produced higher reperfusion rates than alteplase (N Engl J Med. 2018;378:1573-82). However, the larger NOR-TEST study found no difference in efficacy or safety between a 0.4-mg/kg dose of tenecteplase and alteplase in patients with mild stroke (Lancet Neurol. 2017 Oct;16[10]:781-8).

TNK use in stroke varies around the world. The drug is not licensed for use in stroke anywhere, which Dr. Campbell attributes to a lack of incentive for the manufacturer, Genentech/Boehringer Ingelheim. That company also markets alteplase, the main thrombolytic used in stroke.

But many countries have now included TNK in their stroke guidelines, Dr. Campbell noted. “This has only recently occurred in the U.S., where it has a 2b recommendation, and the dose recommendations are somewhat confusing, advocating 0.25 mg/kg in large-vessel occlusions [as was used in the first EXTEND IA study] and 0.4 mg/kg in non–large vessel occlusions [from the NOR-TEST trial].

“This makes no biological sense whatsoever, recommending a higher dose for smaller occlusions, but that is just a literal translation of the design of the two major studies. I’m hoping our current results will help clarify the dosage issue and that might encourage more use of TNK altogether,” he commented.

For the current study, conducted in Australia and New Zealand, 300 patients who had experienced ischemic large-vessel stroke within 4.5 hours of symptom onset and who were scheduled for endovascular thrombectomy were randomly assigned to receive open-label thrombolysis with tenecteplase 0.4 mg/kg or 0.25 mg/kg.

The primary outcome, reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, occurred in 19.3% of both groups. There was also no difference in any of the functional-outcome secondary endpoints or all-cause mortality between the two doses.

“While we didn’t find any extra benefit of the 0.4-mg/kg dose over the 0.25-mg/kg dose, we also didn’t find any extra harm, and this gives us reassurance in the emergency situation if the weight of the patient is overestimated; then we have a window of safety,” Dr. Campbell commented. “While there was a nonsignificant numerical increase in intracranial hemorrhage in the 0.4-mg/kg group, the excess bleeds were caused by puncturing of the vessels during thrombectomy, so I don’t think we can blame the TNK dose for that.

Better reperfusion than with alteplase?

Noting that the original EXTEND-IA TNK study showed higher reperfusion rates with tenecteplase vs alteplase and a trend toward better outcomes on the mRS scale, Campbell reported that a pooled analysis of the TNK results from the current study with those from the first study confirmed these findings.

“We found a doubling in the rate of reperfusion with TNK vs. alteplase, and the [modified Rankin Scale] shift analysis remained positive,” he said.

“I think we say with confidence that TNK is at least as good as alteplase and probably better, but further studies comparing the two agents are ongoing,” he added.

Of note, for the 41 patients from rural areas in the current study, in whom the time from thrombolysis to thrombectomy was longer (152 min vs. 41 min for patients from urban areas), reperfusion rates were higher (34% vs 17%), and there was no difference in dosage between the two groups.

Commenting on these latest results in an interview, Nicola Logallo, MD, of Haukeland University Hospital, Bergen, Norway, who was part of the NOR-TEST trial, said: “There is some evidence supporting the use of TNK 0.4 mg/kg in mild stroke patients, based mainly on the results from the NOR-TEST trial, and the use of TNK 0.25 mg/kg in patients undergoing thrombectomy, based on Dr. Campbell’s previous EXTEND-TNK trial. Dr. Campbell’s new study confirms that probably the higher dose of TNK does not add any advantages in terms of clinical outcome.”

Hemorrhagic complications appear to be similar in the two groups, Dr. Logallo said. “Overall, the 0.25-mg/kg TNK dose could therefore be considered as the most convenient and sensible, at least in patients undergoing thrombectomy. When it comes to the remaining stroke patients receiving thrombolysis, it remains unclear which is the best dose, but studies such as TASTE, NOR-TEST 2, AcT, and ATTEST-2 will hopefully answer this question within the next years.”

Also commenting on the study, Michael Hill, MD, professor of neurology at University of Calgary, Alberta, Canada, said the results “confirm that a good proportion of patients given TNK reperfuse before the angiogram and clarifies the dose. This is useful information.”

Dr. Hill said TNK is used routinely in some countries – mainly in Australia and Norway, where the studies have been conducted – but there is now a movement toward use of TNK in North America, too.

“Studies so far suggest that it could be more effective than alteplase, and as it is more fibrin specific, it could be safer. It is also easier to give with a bolus dose, but perhaps the biggest driver might be that it is cheaper than alteplase. Momentum is building, and many leading investigators are now conducting new studies with TNK with several more studies coming out in the next year or so,” Dr. Hill added.

The EXTEND-IA TNK Part 2 trial was supported by grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. Campbell reports receiving grants from both institutions during the conduct of the study.
 

This article first appeared on Medscape.com.

The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.

The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.

The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.

Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”

The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.

Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.

In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.

The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.

“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”

Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”

He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.

Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.

“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.

“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
 

No price change foreseen

Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.

Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.

“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.

“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”

Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.

“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
 

Some still unsure

But not everyone is in full agreement with the broad indication granted.

One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.

“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.

“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.

However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.

Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.

The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.

The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.

Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”

The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.

Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.

In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.

The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.

“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”

Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”

He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.

Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.

“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.

“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
 

No price change foreseen

Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.

Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.

“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.

“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”

Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.

“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
 

Some still unsure

But not everyone is in full agreement with the broad indication granted.

One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.

“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.

“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.

However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.

Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The newly approved U.S. indication for icosapent ethyl (Vascepa; Amarin) is broadly in line with the entry criteria for the REDUCE-IT trial and includes a large high-risk primary-prevention population, as well as those with established cardiovascular disease (CVD). The drug, thus, could well be used by millions of patients in the United States alone.

The high-dose, purified eicosapentaenoic acid product was approved last week by the Food and Drug Administration for cardiovascular risk reduction among adults already taking maximally tolerated statins with triglyceride levels of 150 mg/dL or higher who have either established CVD or diabetes and two or more additional risk factors for CVD.

The approval is based largely on the REDUCE-IT trial’s finding of a 25% reduction in risk for major adverse cardiovascular events versus placebo. The FDA stated that the approval is the first for an agent with this specific indication.

Noting that it recognizes the need for additional medical treatments for CVD, the FDA says the new approval “will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke, and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”

The drug was unanimously recommended for approval by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee last month. But while the committee all agreed on its use in patients with established CVD, which made up 70% of the REDUCE-IT population, they were divided on whether the indication should be extended to the high-risk primary-prevention population, who made up just 30% of patients in the study.

Nonetheless, the FDA has gone for a broad indication based on the whole REDUCE-IT population.

In a conference call following the approval, Steven Ketchum, PhD, chief scientific officer at Amarin, pointed out that the primary-prevention population stipulated in the new approval differed very slightly from the REDUCE-IT enrollment criteria.

The trial specified that patients with diabetes should be older than 50 with one other cardiovascular risk factor, whereas the approved population is for diabetes and two cardiovascular risk factors. But as these two risk factors are not specified, they could include age, cigarette smoking, hypertension or use of an antihypertensive agent, low HDL cholesterol, high C-reactive protein, body mass index above 25 kg/m2, renal dysfunction, retinopathy, albuminuria, or an ankle branchial index below 0.9, Dr. Ketchum said.

“So while the label asks for two other risk factors, one of these could be age; so we believe the label is actually slightly broader than the REDUCE-IT inclusion criteria, and doctors have been left with significant leeway to decide which risk factors to consider on top of diabetes.”

Deepak Bhatt, MD, the lead investigator of REDUCE-IT, described the Vascepa approval as “the most significant event in the field of cardiovascular prevention since the introduction of statins nearly 3 decades ago.”

He commended the FDA on “a very evidence-based, prescriber-friendly, and most importantly, patient-friendly label,” which he said was in line with guidelines from multiple professional societies that have already incorporated the REDUCE-IT findings for secondary prevention and diabetic primary prevention.

Dr. Bhatt, who is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, said the label essentially matches the REDUCE-IT population.

“The entry criteria for REDUCE-IT was fasting triglycerides greater than or equal to 150 mg/dL, with a 10% variance allowed (giving a minimum triglyceride value of 135 mg/dL). In actuality, we ended up with about 10% of the population with triglycerides between 100 and 150 mg/dL, and they had a similar degree of benefit as those with higher levels,” he reported.

“In the label, the 150 mg/dL does not specify fasting, and in fact many practices have moved away from fasting lipid measurements for the sake of patient comfort,” Dr. Bhatt added. “On average, nonfasting levels are about 50 mg/dL higher, so the label essentially mirrors those we studied, with the FDA applying good common sense and not being overly dogmatic about the exact wording of the trial inclusion criteria.”
 

No price change foreseen

Vascepa is already on the market for patients with very high triglyceride levels, and the company says it is not increasing the current price of about $300 a month, which is “relatively low, compared to other new breakthrough drugs.” However, it says it expects sales to grow from vastly increased volume based on the new indication.

Dr. Bhatt noted that REDUCE-IT cost-effectiveness data presented at the recent American Heart Association scientific sessions found the drug to be cost saving in the majority of cases. “That is something that is quite rare in cost-effectiveness research,” he said.

“Now, the key challenge is to identify and treat appropriate patients,” Dr. Bhatt noted. He says this task will largely fall on cardiologists, endocrinologists, and primary care physicians, though stroke neurologists, nephrologists, and vascular medicine specialists will also have patients for whom the data are relevant.

“I believe the drug will ultimately be widely prescribed, initially by subspecialists, but by primary care physicians also. It is overall very well tolerated, safe, and easy to use,” he said. “Much like statin prescription started in subspecialty practices but then became quite common in primary care, I envision the same happening with icosapent ethyl.”

Lipid expert Roger Blumenthal, MD, who was not involved in the REDUCE-IT trial, also welcomed the new approval for Vascepa.

“The indication is very appropriate; it is great to have another disease-modifying medication in our prevention toolkit,” Dr. Blumenthal, who is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, said in an interview.
 

Some still unsure

But not everyone is in full agreement with the broad indication granted.

One expert who has reservations is James de Lemos, MD, professor of medicine at the University of Texas, Dallas, who sat on the FDA advisory committee that assessed the drug last month.

“I would have preferred a narrower label for now, limited to the secondary prevention indication, because I felt that REDUCE-IT did not include sufficient numbers of patients to justify the high-risk primary-prevention indication. We need an adequately powered, randomized, controlled trial to establish the risk/benefit and cost/benefit in primary prevention, and with this broad label, I worry there will be little incentive for the company to pursue this,” Dr. de Lemos commented in an interview.

“This is a slippery slope, and we should not allow broad indications that extend to primary prevention for drugs that were studied in mixed secondary- and primary-prevention patients, with the results driven by the secondary-prevention subset. These two subgroups are fundamentally different populations in whom the pathophysiology and the background treatments are very different,” he added.

However, Dr. de Lemos acknowledged that he would use Vascepa for some high-risk primary-prevention patients in his practice – those with diabetes, high triglycerides, and multiple risk factors. “I just wish we had more data coming so that I could be more certain of the benefit in this group,” he said.

Dr. Bhatt disclosed sitting on advisory boards for Cardax, Cereno Scientific, Medscape Cardiology, PhaseBio, and Regado Biosciences; conducting unfunded research in association with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda; and receiving research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, and Forest Laboratories. Dr. De Lemos reported receiving grant and consulting income from Roche Diagnostics and Abbott Diagnostics; and consulting for Ortho Clinical Diagnostics. Dr. Blumenthal has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.