Cover Story

A Balancing Act

Experts weigh benefits, risks of antithrombotic therapy in patients with atrial fibrillation undergoing PCI.

For patients undergoing PCI, dual antiplatelet therapy plays an important role in preventing thrombotic events. For some patients, however, particularly those with atrial fibrillation who require an anticoagulant for stroke prevention, the risks of treatment may outweigh the benefits.

“In determining the best approach for antithrombotic therapy in patients on oral anticoagulation for AF, it can be difficult to balance the prevention of thrombosis with the risk for bleeding,” Pascal Vranckx, MD, PhD, medical director of the cardiac ICU at Hartcentrum Hasselt and a member of the faculty of medicine and life sciences at Hasselt University in Belgium, told Cardiology Today’s Intervention.

Pascal Vranckx

In this era of new research and novel drugs, though, interventional cardiologists are making progress in learning how best to address the increased risk for bleeding conferred when DAPT is stacked on top of anticoagulation in this patient population. Trials such as WOEST, PIONEER-AF PCI and RE-DUAL PCI, for instance, suggest that an oral anticoagulant plus a single antiplatelet agent — a P2Y12 inhibitor — may be most advantageous in these patients. Other large trials are also currently underway.

“In the past, our entire focus was on reducing ischemic events,” Roxana Mehran, MD, associate medical editor of Cardiology Today’s Intervention and professor of medicine at Icahn School of Medicine at Mount Sinai, said during an interview. “We knew bleeding was an issue, but we felt like there was no way out. Now, we have added direct oral anticoagulants — which are as effective or, in some cases, more effective than vitamin K antagonists for stroke prevention — to our armamentarium and we also have clinical trials showing that dropping aspirin will reduce bleeding, so our standard of care is shifting.”

A Multifaceted Issue

Source: © Lisa Clark

Currently, patients with AF represent approximately 5% to 8% of the population undergoing PCI. Unfortunately, a major challenge in this patient population is the need to mitigate risks for bleeding and ischemic events, according to C. Michael Gibson, MS, MD, professor of medicine at Harvard Medical School and chief of clinical research at Beth Israel Deaconess Medical Center.

“The same risk factors that put a patient at risk for ischemia are the same risk factors that put a patient at risk for bleeding, so it’s a tightrope walk getting it right,” he told Cardiology Today’s Intervention.

Furthermore, as the population ages, the prevalence of AF and the probability for CAD requiring coronary interventions will increase, said Dominick J. Angiolillo, MD, PhD, professor of medicine, medical director of the Cardiovascular Research Program and program director of the Interventional Cardiology Fellowship Program at the University Florida College of Medicine – Jacksonville.

“There is definitely a need to define antithrombotic strategies for this ever-growing patient population to reduce the risk for bleeding complications while simultaneously maintaining efficacy, which is a frequent problem in clinical practice,” Angiolillo, a member of the Cardiology Today’s Intervention Editorial Board, said in an interview.

In the past, as a way to balance these risks, “triple therapy” — the addition of DAPT to an oral anticoagulant — became the mainstay of treatment in these patients. The concept was built on existing knowledge, evidence and clinical concerns, but the strategy is problematic, experts told Cardiology Today’s Intervention.

Dominick J. Angiolillo

“A patient who is treated with a stent has the theoretical need — and I underscore theoretical — to be on DAPT with aspirin and a P2Y12 inhibitor as well as an oral anticoagulant because of the presence of AF,” Angiolillo said. “We know that DAPT protects against arterial thrombotic complications, including stent thrombosis, while the oral anticoagulant prevents cardioembolic events. However, triple therapy is associated with a more than fourfold increase in bleeding complications, which is a known predictor of adverse outcomes, including mortality.”

Although the complexity of this patient population is primarily responsible for the complicated nature of antithrombotic therapy after PCI, the field has also been hindered by a lack of data, according to Renato Lopes, MD, MHS, PhD, professor of medicine in the division of cardiology at Duke University Medical Center.

“The problem with many previous trials is that this population has not been extensively studied,” he told Cardiology Today’s Intervention, noting that patients who required DAPT for CAD were often excluded from trials of oral anticoagulants. “The good news is that data from trials examining these patients have emerged during the past few years, and there are even more on the horizon.”

‘Abandoning Aspirin’

Multiple trials have investigated strategies to reduce the risk for bleeding while still reaping the benefits of antithrombotic therapy in patients with AF.

Experts who spoke with Cardiology Today’s Intervention credited one study in particular — the WOEST trial — with propelling the field forward. The trial, which was published in The Lancet in 2013, demonstrated a significant reduction in bleeding risk with an oral anticoagulant and clopidogrel only — or “double therapy” — when compared with an oral anticoagulant, clopidogrel and aspirin (See Table).

“The researchers for WOEST, which was a bold study, were the first to dare to drop aspirin, and it worked,” Christopher P. Cannon, MD, senior physician at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said in an interview.

Despite the promising data, the study’s small size gave physicians pause, Christopher B. Granger, MD, professor of medicine at Duke University, told Cardiology Today’s Intervention.

“WOEST was the first to challenge the paradigm of triple therapy, but we all thought of it as more of a hypothesis-generating study as opposed to a definitive study,” said. “However, it may well turn out to be correct.”

Christopher B. Granger

Results from WOEST, he noted, appear to be playing out in larger, more recent trials, including PIONEER-AF PCI and RE-DUAL PCI (See Table).

The PIONEER-AF PCI study, which was published in The New England Journal of Medicine in 2016, also showed reduced bleeding risk in patients who received double therapy with low-dose rivaroxaban (Xarelto, Janssen/Bayer) and a P2Y12 inhibitor only or very low-dose rivaroxaban and DAPT, compared with standard therapy with a vitamin K antagonist plus DAPT. Similarly, in RE-DUAL PCI, which was published in NEJM in 2017, bleeding risk was lower in patients who received double therapy with dabigatran (Pradaxa, Boeheringer Ingelheim) and a P2Y12 inhibitor only, compared with triple therapy using warfarin as the oral anticoagulant.

“Overall, the PIONEER-AF PCI and RE-DUAL PCI studies validated with greater power the WOEST hypothesis (ie, less bleeding with the dropping of aspirin) and cumulatively add strength to the concept that abandoning aspirin might improve safety toward bleeding in stented patients on dual antithrombotic therapy with a novel oral anticoagulant and a P2Y12 inhibitor,” Vranckx wrote in an email to Cardiology Today’s Intervention.

The question of efficacy, however, remains unclear, as none of the trials were powered to detect differences in prevention of ischemic events. Moreover, in RE-DUAL PCI, there was a numeric, although not significant, trend toward an increase in MI and stent thrombosis in the dabigatran 110-mg twice-daily arm, he noted.

“While there is no apparent major increase in ischemic events, some concern remains on the subject,” Vranckx said.

A Multitude of Options

Although recent trials lend credence to the concept of double therapy, many pieces are still missing from the puzzle, according to Lopes.

WOEST, PIONEER-AF PCI and RE-DUAL PCI may have opened the door to a novel treatment strategy, but they also raised questions regarding the optimal combination of drugs, appropriate duration of therapy and whether removing aspirin from the equation is actually responsible for the decrease in bleeding risk associated with double therapy, he noted.

Outside of the setting of PCI, pivotal AF trials generally favor the direct oral anticoagulants, including dabigatran, rivaroxaban, apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and edoxaban (Savaysa, Daiichi Sankyo), over vitamin K antagonists.

“One of the key observations that we have seen in trials without antiplatelet therapy is a dramatically lower risk for intracranial hemorrhage with the direct oral anticoagulants vs. warfarin, and this was reflected in RE-DUAL PCI,” Cannon told Cardiology Today’s Intervention. “Additionally, their immediate effect prevents the need for bridging with aspirin or low-molecular-weight heparin that can occur with warfarin.”

Christopher P. Cannon

The direct oral anticoagulants are also more convenient, according to Mehran.

“They offer a consistency in treatment and have a direct effect without any issues related to food intake or dietary intake that are often seen with vitamin K antagonists,” she said. “There also is no need for checking INR, and we know that as long as the patients are taking the medication at the prescribed dose, they’re getting consistent benefit in anticoagulation.”

The primary problem, however, is that WOEST, PIONEER-AF PCI and RE-DUAL PCI, although similar in concept, evaluated and compared different drugs, doses and strategies, according to Lopes.

“The question we cannot answer is how much of the reduction in bleeding seen in PIONEER-AF PCI and RE-DUAL PCI is attributable to our use of a better agent, such as dabigatran or rivaroxaban, instead of warfarin, and how much is because we have dropped aspirin,” he said.

Selection of the appropriate antiplatelet agent is also a common issue, according to Granger. Although this concern has taken a backseat as researchers focus on double therapy and direct oral anticoagulants, the availability of several P2Y12 inhibitors adds another dimension to an already complex problem.

“In most cases, we believe it makes the most sense to use clopidogrel, but it is a legitimate question whether it is acceptable to use ticagrelor (Brilinta, AstraZeneca) or prasugrel (Effient, Daiichi Sankyo/Eli Lilly) in this setting,” he said.

Renato D. Lopes

Overall, with novel agents and little data, physicians are likely overwhelmed with the number of therapeutic strategies, according to Lopes.

“Today, after factoring in drugs, dose and duration of treatment, we have at least a million combinations of ways to treat these patients,” he told Cardiology Today’s Intervention. “What we need are randomized trials so we can tease out two or three of the best evidence-based approaches.”

Ongoing Trials

Fortunately, Mehran noted, physicians will not need to wait much longer to have answers to some of these important questions. The ENTRUST-AF-PCI and AUGUSTUS trials, for which data are expected to be available next year, will shed more light on the topic of antithrombotic therapy in patients with AF, she said.

The ENTRUST-AF-PCI trial, for which Vranckx is a study co-chair, is comparing edoxaban plus a P2Y12 inhibitor with standard triple therapy with a vitamin K antagonist in patients with AF who underwent successful PCI. The study will help complete the dataset regarding the use of novel oral anticoagulants in this patient population, he noted.

“ENTRUST-AF-PCI is the most pragmatic trial and very close to daily clinical practice and current guidelines and is also powered for superiority for the bleeding endpoint,” Vranckx said.

AUGUSTUS, however, will add to the existing evidence in a different way by offering a more complete picture in terms of treatment strategies in this patient population, experts told Cardiology Today’s Intervention.

“It is a robust, excellent study with randomization and a unique design,” Mehran said.

Roxana Mehran

The AUGUSTUS trial, for which Lopes is principal investigator, has a 2x2 factorial design in which patients who require anticoagulants and antiplatelet therapy are treated with a P2Y12 inhibitor and are randomly assigned apixaban or warfarin. Patients will also be assigned in a double-blind fashion to aspirin or placebo. In this way, the researchers can compare triple therapy with warfarin, triple therapy with apixaban, double therapy with warfarin and a P2Y12 inhibitor only and double therapy with apixaban and a P2Y12 inhibitor only.

“This will allow us to investigate how much of the benefit in terms of bleeding is related to apixaban — the novel oral anticoagulant — and how much is related to removing aspirin,” Lopes said.

Moreover, AUGUSTUS will not only include patients who have undergone PCI but also those with ACS who are medically managed, he noted.

“Should the results from ENTRUST-AF-PCI and AUGUSTUS show that a novel oral anticoagulant without aspirin or with a short duration of aspirin plus a P2Y12 inhibitor is a safe and effective approach, physicians will be reassured that double therapy with a direct oral anticoagulant is the preferred strategy,” Granger said.

“With the current trials, we’re at least halfway there. The robustness of the AUGUSTUS trial will provide additional insights and near-definitive answers,” Angiolillo said.

Current Practice

Even as they await more answers, interventional cardiologists have worked to incorporate the existing knowledge into clinical practice.

Before publication of the most recent trials, the 2014 American College of Cardiology/American Heart Association non-ST-elevation ACS guideline and a discussion in the 2016 ACC/AHA focused update to the guideline on DAPT duration recommended minimizing the duration of triple therapy to limit bleeding risk; the use of proton pump inhibitors in patients with a history of gastrointestinal bleeding; assessment of ischemic and bleeding risks using validated risk predictors, such as CHA2DS2-VASc and HAS-BLED scores; clopidogrel be used as the P2Y12 inhibitor of choice; use of low-dose aspirin; and consideration of a target INR of 2 to 2.5 when warfarin is used.

A consensus statement addressing the topic drafted by experts in the United States in Canada was also published in 2016 in Circulation: Cardiovascular Interventions.

“In that statement, we embraced the two trials that were available at the time, which were WOEST and ISAR-Triple,” Angiolillo, lead author of the consensus statement, told Cardiology Today’s Intervention.

With the publication of PIONEER-AF PCI and RE-DUAL PCI, however, Angiolillo and colleagues have been working on an update to the 2016 consensus statement that is expected to be released in the summer of 2018.

“We sought input from physicians and researchers with different areas of expertise, ranging from basic science to antiplatelet agents to anticoagulants to clinical trial design, so that we could offer a pragmatic approach of the different steps that a physician should keep in mind when approaching a patient with AF,” he said. “The statement extends beyond antithrombotic therapy to discuss evaluation of the patient before the procedure, in the cath lab and after PCI.”

Currently, experts told Cardiology Today’s Intervention that that triple therapy, although still being used, has become less popular.

“There has been a shift toward using double therapy vs. triple therapy in practice, and that mood has tracked with the evidence,” Cannon said. “WOEST was small, but we have been desperately seeking a solution. Then, with the publication of PIONEER-AF PCI and RE-DUAL PCI, we have more evidence and physicians have become more interested in a double-therapy strategy.”

Angiolillo noted, however, that many physicians still struggle with the concept of dropping aspirin at the time of hospital discharge.

“There has been a clear paradigm shift in interventional pharmacology where, for the past several decades, we’ve built our antithrombotic approaches on top of aspirin, but with that, we have consistently found more bleeding,” he said. “It’s definitely going to take some time before double therapy will be routinely embraced in clinical practice.”

Nevertheless, as the field awaits more evidence, including the results of AUGUSTUS, caution and individualizing therapy are key, according to Gibson.

C. Michael Gibson

“All physicians have to pick the right combination of drugs that maximizes effectiveness and minimizes bleeding, and those combinations may be different for different patients,” he told Cardiology Today’s Intervention. “We should make sure to talk to our patients, inform them of the risks of each treatment option with respect to stroke vs. bleeding events and engage in shared decision-making.” - by Melissa Foster

Disclosures: Angiolillo reports he received consultant fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi and The Medicines Company; compensation for participation in review activities from CeloNova and St. Jude Medical; and institutional research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical and RenalGuard Solutions. Cannon reports he served as an adviser or consultant for Alnylam Pharmaceuticals, Amgen, Arisaph Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Kowa Pharmaceuticals America; Merck & Company, Pfizer, Regeneron, Sanofi and Takeda, and he received research grants from Amgen, Arisaph Pharmaceuticals, Boehringer Ingelhim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, Merck & Co. and Takeda Pharmaceuticals North America. Gibson reports he served as consultant for Amarin, Amgen, Bayer HealthCare Pharmaceuticals, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences, Ortho-McNeil-Janssen Pharmaceuticals, Johnson & Johnson, The Medicines Company, Novo Nordisk, Pfizer, PharmaMar, Roche Diagnostics, St. Francis Hospital and St. Jude Medical; he received research grants from Angel Medical Systems, Bayer HealthCare Pharmaceuticals, CSL Behring, Ortho-McNeil-Janssen, Johnson & Johnson and Portola Pharmaceuticals; he received royalties as a contributor from UpToDate in Cardiovascular Medicine; and he received research grant funding or served as a past speaker or consultant for Abbott Laboratories, Angel Medical Systems, Atrium Medical Corp., Archemix, AstraZeneca, Baxter, Biogen Idec, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, British Biotech, Ciba Geigy Corp., Consensus Medical Communications, Cytori Therapeutics, Daiichi Sankyo, Exeter Group, FibroGen, FoldRx, Genentech, GlaxoSmithKline, Google, Heartscape Technologies, Ikaria, Ischemix, Merck & Co., Medtronic Vascular, Navigant, Novartis, Pfizer, Pocket Medicine, Point Biomedical Corp., Portola Pharmaceuticals, Regado Biosciences, Sanofi Aventis, Schering-Plough, Smith Kline Beecham, St. Jude Medical, Stealth BioTherapeutics, The Medicines Company, TImi3 Systems, Volcano Corp and Walk Vascular. Granger reports he received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Duke Clinical Research Institute, Glaxo-SmithKline, Janssen, Medtronic Foundation, Novartis and Pfizer; and he received fees for consulting or other services from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Medscape, Medtronic, Medtronic Foundation, Merck, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex and Verseon. Lopes reports he received research grants from Amgen, Bristol-Myers Squibb, Glaxo-SmithKline, Medtronic, Pfizer and Sanofi Aventis; he received fees for consulting or other services from Bayer AG, Boehringer Ingelheim and Bristol-Myers Squibb; and he received fees for educational activities or lectures from Pfizer. Mehran reports she received consultant fees from AstraZeneca, Bayer, CSL Behring, Janssen Pharmaceuticals, Merck & Co., Osprey Medical, Regado Biosciences, The Medicines Company and Watermark Consulting; she has equity in Claret Medical and Elixir Medical Corp.; she gave industry-sponsored lectures for PlatformQ and Sanofi Aventis; she served on the scientific advisory board for Abbott Laboratories, AstraZeneca, Boston Scientific, Covidien, Janssen Pharmaceuticals, Merck & Co., The Medicines Company and Sanofi Aventis; and she participated in other activities for Covidien. Vranckx reports he received speaking or consultant fees from Bayer Healthcare, Daiichi Sankyo and Terumo.

For patients undergoing PCI, dual antiplatelet therapy plays an important role in preventing thrombotic events. For some patients, however, particularly those with atrial fibrillation who require an anticoagulant for stroke prevention, the risks of treatment may outweigh the benefits.

“In determining the best approach for antithrombotic therapy in patients on oral anticoagulation for AF, it can be difficult to balance the prevention of thrombosis with the risk for bleeding,” Pascal Vranckx, MD, PhD, medical director of the cardiac ICU at Hartcentrum Hasselt and a member of the faculty of medicine and life sciences at Hasselt University in Belgium, told Cardiology Today’s Intervention.

Pascal Vranckx

In this era of new research and novel drugs, though, interventional cardiologists are making progress in learning how best to address the increased risk for bleeding conferred when DAPT is stacked on top of anticoagulation in this patient population. Trials such as WOEST, PIONEER-AF PCI and RE-DUAL PCI, for instance, suggest that an oral anticoagulant plus a single antiplatelet agent — a P2Y12 inhibitor — may be most advantageous in these patients. Other large trials are also currently underway.

“In the past, our entire focus was on reducing ischemic events,” Roxana Mehran, MD, associate medical editor of Cardiology Today’s Intervention and professor of medicine at Icahn School of Medicine at Mount Sinai, said during an interview. “We knew bleeding was an issue, but we felt like there was no way out. Now, we have added direct oral anticoagulants — which are as effective or, in some cases, more effective than vitamin K antagonists for stroke prevention — to our armamentarium and we also have clinical trials showing that dropping aspirin will reduce bleeding, so our standard of care is shifting.”

A Multifaceted Issue

Source: © Lisa Clark

Currently, patients with AF represent approximately 5% to 8% of the population undergoing PCI. Unfortunately, a major challenge in this patient population is the need to mitigate risks for bleeding and ischemic events, according to C. Michael Gibson, MS, MD, professor of medicine at Harvard Medical School and chief of clinical research at Beth Israel Deaconess Medical Center.

“The same risk factors that put a patient at risk for ischemia are the same risk factors that put a patient at risk for bleeding, so it’s a tightrope walk getting it right,” he told Cardiology Today’s Intervention.

Furthermore, as the population ages, the prevalence of AF and the probability for CAD requiring coronary interventions will increase, said Dominick J. Angiolillo, MD, PhD, professor of medicine, medical director of the Cardiovascular Research Program and program director of the Interventional Cardiology Fellowship Program at the University Florida College of Medicine – Jacksonville.

PAGE BREAK

“There is definitely a need to define antithrombotic strategies for this ever-growing patient population to reduce the risk for bleeding complications while simultaneously maintaining efficacy, which is a frequent problem in clinical practice,” Angiolillo, a member of the Cardiology Today’s Intervention Editorial Board, said in an interview.

In the past, as a way to balance these risks, “triple therapy” — the addition of DAPT to an oral anticoagulant — became the mainstay of treatment in these patients. The concept was built on existing knowledge, evidence and clinical concerns, but the strategy is problematic, experts told Cardiology Today’s Intervention.

Dominick J. Angiolillo

“A patient who is treated with a stent has the theoretical need — and I underscore theoretical — to be on DAPT with aspirin and a P2Y12 inhibitor as well as an oral anticoagulant because of the presence of AF,” Angiolillo said. “We know that DAPT protects against arterial thrombotic complications, including stent thrombosis, while the oral anticoagulant prevents cardioembolic events. However, triple therapy is associated with a more than fourfold increase in bleeding complications, which is a known predictor of adverse outcomes, including mortality.”

Although the complexity of this patient population is primarily responsible for the complicated nature of antithrombotic therapy after PCI, the field has also been hindered by a lack of data, according to Renato Lopes, MD, MHS, PhD, professor of medicine in the division of cardiology at Duke University Medical Center.

“The problem with many previous trials is that this population has not been extensively studied,” he told Cardiology Today’s Intervention, noting that patients who required DAPT for CAD were often excluded from trials of oral anticoagulants. “The good news is that data from trials examining these patients have emerged during the past few years, and there are even more on the horizon.”

‘Abandoning Aspirin’

Multiple trials have investigated strategies to reduce the risk for bleeding while still reaping the benefits of antithrombotic therapy in patients with AF.

Experts who spoke with Cardiology Today’s Intervention credited one study in particular — the WOEST trial — with propelling the field forward. The trial, which was published in The Lancet in 2013, demonstrated a significant reduction in bleeding risk with an oral anticoagulant and clopidogrel only — or “double therapy” — when compared with an oral anticoagulant, clopidogrel and aspirin (See Table).

“The researchers for WOEST, which was a bold study, were the first to dare to drop aspirin, and it worked,” Christopher P. Cannon, MD, senior physician at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said in an interview.

PAGE BREAK

Despite the promising data, the study’s small size gave physicians pause, Christopher B. Granger, MD, professor of medicine at Duke University, told Cardiology Today’s Intervention.

“WOEST was the first to challenge the paradigm of triple therapy, but we all thought of it as more of a hypothesis-generating study as opposed to a definitive study,” said. “However, it may well turn out to be correct.”

Christopher B. Granger

Results from WOEST, he noted, appear to be playing out in larger, more recent trials, including PIONEER-AF PCI and RE-DUAL PCI (See Table).

The PIONEER-AF PCI study, which was published in The New England Journal of Medicine in 2016, also showed reduced bleeding risk in patients who received double therapy with low-dose rivaroxaban (Xarelto, Janssen/Bayer) and a P2Y12 inhibitor only or very low-dose rivaroxaban and DAPT, compared with standard therapy with a vitamin K antagonist plus DAPT. Similarly, in RE-DUAL PCI, which was published in NEJM in 2017, bleeding risk was lower in patients who received double therapy with dabigatran (Pradaxa, Boeheringer Ingelheim) and a P2Y12 inhibitor only, compared with triple therapy using warfarin as the oral anticoagulant.

“Overall, the PIONEER-AF PCI and RE-DUAL PCI studies validated with greater power the WOEST hypothesis (ie, less bleeding with the dropping of aspirin) and cumulatively add strength to the concept that abandoning aspirin might improve safety toward bleeding in stented patients on dual antithrombotic therapy with a novel oral anticoagulant and a P2Y12 inhibitor,” Vranckx wrote in an email to Cardiology Today’s Intervention.

The question of efficacy, however, remains unclear, as none of the trials were powered to detect differences in prevention of ischemic events. Moreover, in RE-DUAL PCI, there was a numeric, although not significant, trend toward an increase in MI and stent thrombosis in the dabigatran 110-mg twice-daily arm, he noted.

“While there is no apparent major increase in ischemic events, some concern remains on the subject,” Vranckx said.

A Multitude of Options

Although recent trials lend credence to the concept of double therapy, many pieces are still missing from the puzzle, according to Lopes.

WOEST, PIONEER-AF PCI and RE-DUAL PCI may have opened the door to a novel treatment strategy, but they also raised questions regarding the optimal combination of drugs, appropriate duration of therapy and whether removing aspirin from the equation is actually responsible for the decrease in bleeding risk associated with double therapy, he noted.

Outside of the setting of PCI, pivotal AF trials generally favor the direct oral anticoagulants, including dabigatran, rivaroxaban, apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and edoxaban (Savaysa, Daiichi Sankyo), over vitamin K antagonists.

PAGE BREAK

“One of the key observations that we have seen in trials without antiplatelet therapy is a dramatically lower risk for intracranial hemorrhage with the direct oral anticoagulants vs. warfarin, and this was reflected in RE-DUAL PCI,” Cannon told Cardiology Today’s Intervention. “Additionally, their immediate effect prevents the need for bridging with aspirin or low-molecular-weight heparin that can occur with warfarin.”

Christopher P. Cannon

The direct oral anticoagulants are also more convenient, according to Mehran.

“They offer a consistency in treatment and have a direct effect without any issues related to food intake or dietary intake that are often seen with vitamin K antagonists,” she said. “There also is no need for checking INR, and we know that as long as the patients are taking the medication at the prescribed dose, they’re getting consistent benefit in anticoagulation.”

The primary problem, however, is that WOEST, PIONEER-AF PCI and RE-DUAL PCI, although similar in concept, evaluated and compared different drugs, doses and strategies, according to Lopes.

“The question we cannot answer is how much of the reduction in bleeding seen in PIONEER-AF PCI and RE-DUAL PCI is attributable to our use of a better agent, such as dabigatran or rivaroxaban, instead of warfarin, and how much is because we have dropped aspirin,” he said.

Selection of the appropriate antiplatelet agent is also a common issue, according to Granger. Although this concern has taken a backseat as researchers focus on double therapy and direct oral anticoagulants, the availability of several P2Y12 inhibitors adds another dimension to an already complex problem.

“In most cases, we believe it makes the most sense to use clopidogrel, but it is a legitimate question whether it is acceptable to use ticagrelor (Brilinta, AstraZeneca) or prasugrel (Effient, Daiichi Sankyo/Eli Lilly) in this setting,” he said.

Renato D. Lopes

Overall, with novel agents and little data, physicians are likely overwhelmed with the number of therapeutic strategies, according to Lopes.

“Today, after factoring in drugs, dose and duration of treatment, we have at least a million combinations of ways to treat these patients,” he told Cardiology Today’s Intervention. “What we need are randomized trials so we can tease out two or three of the best evidence-based approaches.”

Ongoing Trials

Fortunately, Mehran noted, physicians will not need to wait much longer to have answers to some of these important questions. The ENTRUST-AF-PCI and AUGUSTUS trials, for which data are expected to be available next year, will shed more light on the topic of antithrombotic therapy in patients with AF, she said.

PAGE BREAK

The ENTRUST-AF-PCI trial, for which Vranckx is a study co-chair, is comparing edoxaban plus a P2Y12 inhibitor with standard triple therapy with a vitamin K antagonist in patients with AF who underwent successful PCI. The study will help complete the dataset regarding the use of novel oral anticoagulants in this patient population, he noted.

“ENTRUST-AF-PCI is the most pragmatic trial and very close to daily clinical practice and current guidelines and is also powered for superiority for the bleeding endpoint,” Vranckx said.

AUGUSTUS, however, will add to the existing evidence in a different way by offering a more complete picture in terms of treatment strategies in this patient population, experts told Cardiology Today’s Intervention.

“It is a robust, excellent study with randomization and a unique design,” Mehran said.

Roxana Mehran

The AUGUSTUS trial, for which Lopes is principal investigator, has a 2x2 factorial design in which patients who require anticoagulants and antiplatelet therapy are treated with a P2Y12 inhibitor and are randomly assigned apixaban or warfarin. Patients will also be assigned in a double-blind fashion to aspirin or placebo. In this way, the researchers can compare triple therapy with warfarin, triple therapy with apixaban, double therapy with warfarin and a P2Y12 inhibitor only and double therapy with apixaban and a P2Y12 inhibitor only.

“This will allow us to investigate how much of the benefit in terms of bleeding is related to apixaban — the novel oral anticoagulant — and how much is related to removing aspirin,” Lopes said.

Moreover, AUGUSTUS will not only include patients who have undergone PCI but also those with ACS who are medically managed, he noted.

“Should the results from ENTRUST-AF-PCI and AUGUSTUS show that a novel oral anticoagulant without aspirin or with a short duration of aspirin plus a P2Y12 inhibitor is a safe and effective approach, physicians will be reassured that double therapy with a direct oral anticoagulant is the preferred strategy,” Granger said.

“With the current trials, we’re at least halfway there. The robustness of the AUGUSTUS trial will provide additional insights and near-definitive answers,” Angiolillo said.

PAGE BREAK

Current Practice

Even as they await more answers, interventional cardiologists have worked to incorporate the existing knowledge into clinical practice.

Before publication of the most recent trials, the 2014 American College of Cardiology/American Heart Association non-ST-elevation ACS guideline and a discussion in the 2016 ACC/AHA focused update to the guideline on DAPT duration recommended minimizing the duration of triple therapy to limit bleeding risk; the use of proton pump inhibitors in patients with a history of gastrointestinal bleeding; assessment of ischemic and bleeding risks using validated risk predictors, such as CHA2DS2-VASc and HAS-BLED scores; clopidogrel be used as the P2Y12 inhibitor of choice; use of low-dose aspirin; and consideration of a target INR of 2 to 2.5 when warfarin is used.

A consensus statement addressing the topic drafted by experts in the United States in Canada was also published in 2016 in Circulation: Cardiovascular Interventions.

“In that statement, we embraced the two trials that were available at the time, which were WOEST and ISAR-Triple,” Angiolillo, lead author of the consensus statement, told Cardiology Today’s Intervention.

With the publication of PIONEER-AF PCI and RE-DUAL PCI, however, Angiolillo and colleagues have been working on an update to the 2016 consensus statement that is expected to be released in the summer of 2018.

“We sought input from physicians and researchers with different areas of expertise, ranging from basic science to antiplatelet agents to anticoagulants to clinical trial design, so that we could offer a pragmatic approach of the different steps that a physician should keep in mind when approaching a patient with AF,” he said. “The statement extends beyond antithrombotic therapy to discuss evaluation of the patient before the procedure, in the cath lab and after PCI.”

Currently, experts told Cardiology Today’s Intervention that that triple therapy, although still being used, has become less popular.

“There has been a shift toward using double therapy vs. triple therapy in practice, and that mood has tracked with the evidence,” Cannon said. “WOEST was small, but we have been desperately seeking a solution. Then, with the publication of PIONEER-AF PCI and RE-DUAL PCI, we have more evidence and physicians have become more interested in a double-therapy strategy.”

Angiolillo noted, however, that many physicians still struggle with the concept of dropping aspirin at the time of hospital discharge.

“There has been a clear paradigm shift in interventional pharmacology where, for the past several decades, we’ve built our antithrombotic approaches on top of aspirin, but with that, we have consistently found more bleeding,” he said. “It’s definitely going to take some time before double therapy will be routinely embraced in clinical practice.”

Nevertheless, as the field awaits more evidence, including the results of AUGUSTUS, caution and individualizing therapy are key, according to Gibson.

C. Michael Gibson

“All physicians have to pick the right combination of drugs that maximizes effectiveness and minimizes bleeding, and those combinations may be different for different patients,” he told Cardiology Today’s Intervention. “We should make sure to talk to our patients, inform them of the risks of each treatment option with respect to stroke vs. bleeding events and engage in shared decision-making.” - by Melissa Foster

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Disclosures: Angiolillo reports he received consultant fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi and The Medicines Company; compensation for participation in review activities from CeloNova and St. Jude Medical; and institutional research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical and RenalGuard Solutions. Cannon reports he served as an adviser or consultant for Alnylam Pharmaceuticals, Amgen, Arisaph Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Kowa Pharmaceuticals America; Merck & Company, Pfizer, Regeneron, Sanofi and Takeda, and he received research grants from Amgen, Arisaph Pharmaceuticals, Boehringer Ingelhim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, Merck & Co. and Takeda Pharmaceuticals North America. Gibson reports he served as consultant for Amarin, Amgen, Bayer HealthCare Pharmaceuticals, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences, Ortho-McNeil-Janssen Pharmaceuticals, Johnson & Johnson, The Medicines Company, Novo Nordisk, Pfizer, PharmaMar, Roche Diagnostics, St. Francis Hospital and St. Jude Medical; he received research grants from Angel Medical Systems, Bayer HealthCare Pharmaceuticals, CSL Behring, Ortho-McNeil-Janssen, Johnson & Johnson and Portola Pharmaceuticals; he received royalties as a contributor from UpToDate in Cardiovascular Medicine; and he received research grant funding or served as a past speaker or consultant for Abbott Laboratories, Angel Medical Systems, Atrium Medical Corp., Archemix, AstraZeneca, Baxter, Biogen Idec, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, British Biotech, Ciba Geigy Corp., Consensus Medical Communications, Cytori Therapeutics, Daiichi Sankyo, Exeter Group, FibroGen, FoldRx, Genentech, GlaxoSmithKline, Google, Heartscape Technologies, Ikaria, Ischemix, Merck & Co., Medtronic Vascular, Navigant, Novartis, Pfizer, Pocket Medicine, Point Biomedical Corp., Portola Pharmaceuticals, Regado Biosciences, Sanofi Aventis, Schering-Plough, Smith Kline Beecham, St. Jude Medical, Stealth BioTherapeutics, The Medicines Company, TImi3 Systems, Volcano Corp and Walk Vascular. Granger reports he received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Duke Clinical Research Institute, Glaxo-SmithKline, Janssen, Medtronic Foundation, Novartis and Pfizer; and he received fees for consulting or other services from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Medscape, Medtronic, Medtronic Foundation, Merck, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex and Verseon. Lopes reports he received research grants from Amgen, Bristol-Myers Squibb, Glaxo-SmithKline, Medtronic, Pfizer and Sanofi Aventis; he received fees for consulting or other services from Bayer AG, Boehringer Ingelheim and Bristol-Myers Squibb; and he received fees for educational activities or lectures from Pfizer. Mehran reports she received consultant fees from AstraZeneca, Bayer, CSL Behring, Janssen Pharmaceuticals, Merck & Co., Osprey Medical, Regado Biosciences, The Medicines Company and Watermark Consulting; she has equity in Claret Medical and Elixir Medical Corp.; she gave industry-sponsored lectures for PlatformQ and Sanofi Aventis; she served on the scientific advisory board for Abbott Laboratories, AstraZeneca, Boston Scientific, Covidien, Janssen Pharmaceuticals, Merck & Co., The Medicines Company and Sanofi Aventis; and she participated in other activities for Covidien. Vranckx reports he received speaking or consultant fees from Bayer Healthcare, Daiichi Sankyo and Terumo.