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The Quest for a Therapeutic Trifecta
Novel oral anticoagulants present new options — and new questions — for triple therapy.
Cover illustration © Lisa Clark
After decades of exclusive reliance on vitamin K antagonists such as warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, the advent of novel oral anticoagulants offers potent new options for managing this population.
These new agents have demonstrated favorable results in terms of efficacy, safety and ease of use, and do not require the same level of international normalized ratio (INR) monitoring as warfarin (Coumadin, Bristol-Myers Squibb).
“There is a revolution in progress with the novel oral anticoagulants,” said Christopher P. Cannon, MD, senior physician, cardiovascular division at Brigham and Women’s Hospital, Boston. “With these agents, not only is there improved ease of use and less monitoring, but there’s also oftentimes a better safety profile, and better efficacy in some cases.”
Christopher P.
Cannon
Currently, three novel anticoagulants are FDA approved: apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Janssen Pharmaceuticals).
As the uptake of these newer agents in clinical practice continues to increase, a new dilemma has presented itself to today’s interventionalist: whether to incorporate these potent, but relatively untested, new agents into triple therapy in patients with AF also undergoing PCI.
“It’s a very difficult conundrum,” said Roxana Mehran, MD, professor of medicine in cardiology, health evidence and policy at the Icahn School of Medicine, Mount Sinai Medical Center, New York, and Associate Medical Editor of Cardiology Today’s Intervention. “Unfortunately, at this time, there’s really not a great guideline to tell us what to do for these patients, and we still don’t know whether these novel oral anticoagulants would be more efficacious in this population.”
Improvements over Warfarin
Of the three approved medications, two — rivaroxaban and apixaban — are factor Xa inhibitors, and one, dabigatran, is a direct thrombin inhibitor. A third factor Xa inhibitor, edoxaban (Daiichi Sankyo), has not yet received FDA approval.
“What is interesting about these agents is that they are not dependent on the vitamin K pathway; they’re extremely efficient in working against thrombin,” Mehran said. “They don’t need the kind of monitoring necessary with warfarin, and there is no variability in response based on dietary intake.”
Cannon said the newer agents are also much faster acting and have a more direct mechanism of action.
“These agents are actually antithrombotic agents that directly block the clotting factors, whereas warfarin simply decreases how many clotting factors your liver makes, and that’s quite different,” he said. “Functionally, the biggest difference is that warfarin takes 5 days at a minimum, or several days, to get active, and it’s often a couple of weeks before you can get into the therapeutic range. And these other agents are therapeutic within 1 hour. So, there’s a huge difference in the pharmacokinetics and the pharmacologic effect.”
According to Duane Pinto, MD, MPH, associate professor at Harvard Medical School, Boston, the new anticoagulants also facilitate patient adherence through ease of use.
“There are several improvements, including fixed-dose regimens, and the fact that patients don’t need to have INR monitoring or repeated blood tests. There’s less unpredictability in the therapeutic effect,” Pinto said. “As such, there is benefit, for both providers and patients, with regard to avoiding events and ease of use.”
Additionally, a study published in JAMA Neurology reported that novel oral anticoagulants were associated with a 50% decrease in relative risk of intracranial hemorrhage.
Dominick J. Angiolillo, MD, PhD, associate professor and the medical director of the cardiovascular research program at the College of Medicine – Jacksonville, University of Florida, said that such findings have led to the eager adoption of these drugs into clinical practice.
Dominick J.
Angiolillo
“Studies have consistently shown that these agents are associated with favorable safety profiles, and most notably a reduction in intracranial hemorrhage — the most dreaded of bleeding complications,” he said. “As a result, these agents are welcome to clinical practice, and their uptake has increased steadily over the past several years.”
Cannon said at this early stage in their uptake, novel oral anticoagulants do come with some financial drawbacks.
“Many of us want to offer these agents to our patients, but there is a disconnect in that the insurance companies don’t want to pay, and there are a lot of roadblocks, in general, as far as payment is concerned,” he said. “But we have our patients’ best interests in mind, and we’re working toward overcoming that.”
Indications, Contraindications Abound
Cannon said that although AF is clearly the most important indication for the novel anticoagulants, they have shown utility for other conditions as well.
“The agents have been studied in various indications, and the biggest one thus far is AF,” he said. “But they have also been tested and are said to be beneficial in patients with acute deep vein thrombosis (DVT), acute pulmonary embolism, and also in prophylaxis against DVT in surgery patients.”
Conversely, there are some patients in whom the novel anticoagulants would not be appropriate, Cannon said.
“There are a few areas where these agents don’t work, such as in patients with mechanical heart valves,” he said.
Angiolillo said there are also some patients in whom the novel anticoagulants might pose a higher risk.
“You would need to be careful with patients who have more advanced kidney disease, which may be a concern with the novel oral anticoagulants,” he said. “And, overall, you need to be careful in patients with a high risk for bleeding. One concern with these anticoagulants has been the lack of an antidote. So that needs to be taken into consideration as well.”
An antidote may be on the way for one of the oral anticoagulants, however, as in late June, Boehringer Ingelheim announced that the FDA granted breakthrough therapy designation to its investigational drug idarucizumab, which is being evaluated as an antidote for dabigatran.
Multiple Risks for the AF/PCI Patient
For patients with AF undergoing PCI, physicians are required to walk a fine line between minimizing risk of cerebrovascular events and stent thrombosis without inducing bleeding events. The concern is that because these newer agents are more potent anticoagulants, they may proportionally increase the bleeding risk.
Mehran discussed the risks inherent to “triple therapy,” or dual antiplatelet therapy plus an anticoagulant — with any combination of agents.
“As an interventionalist who is taking care of patients undergoing stenting, I’d say between 8% and 10% of these patients also have AF,” Mehran said. “When these patients come in for stenting, they are actually leaving with three agents, two antiplatelets and an anticoagulant. That combination really portends a huge risk for bleeding, which has been well-documented in large registries and clinical trials.”
Roxana Mehran
According to Pinto, the safety and efficacy of using these powerful new anticoagulants with antiplatelet agents in triple therapy is not yet fully understood.
“A lot of this is controversial, and there’s not a lot of information on it,” he said. “You have two or three competing factors at work — you want to have the best therapy for the stent and the treatment for the syndrome the person is suffering from, whether it’s an MI or the person is undergoing high-risk PCI. You also face the increased risk for bleeding. So that’s what people are struggling with, and up to this point, there’s been a lot of variability in practice.”
Angiolillo, who practices in Florida, said he treats a large number of elderly patients, who, in addition to their inherently higher risk for both bleeding and thrombosis, find themselves requiring triple-therapy regimens, which further elevate both risks.
“Elderly patients have a greater likelihood of having both AF and CAD,” he said. “And these are patients who, by definition, are already at high risk for bleeding and thrombosis. So it’s not trivial. There’s much to learn, and an answer is needed.”
WOEST: A Potential New Paradigm
One significant conundrum regarding triple therapy is the attempt to understand which combination of drugs will yield the best safety and efficacy for patients with AF undergoing PCI.
One important study on best practices for triple therapy was the WOEST trial. In this 2012 study of 573 patients, researchers found that a treatment regimen consisting of an oral anticoagulant and clopidogrel, minus aspirin, yielded a lower rate of bleeding at 1 year than a regimen of aspirin, clopidogrel and an anticoagulant.
“In the WOEST trial, investigators treated patients with triple therapy, and then were very bold and dropped aspirin,” Cannon said. “They found that there was a huge reduction in bleeding, and no increase in thrombotic events. Mortality was also lower in the group who had double therapy as opposed to triple therapy. So these data have gotten everyone excited.”
A recommendation for a WOEST-type strategy was recently added to the “AHA/ACC/HRS Guidelines for the Management of Patients with Atrial Fibrillation,” which were published in March.
The recommendation states: “Following coronary revascularization (percutaneous or surgical) in patients with AF and a CHADS2-VASc score >2, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with oral anticoagulants but without aspirin.”
“This was a class IIb recommendation, something to consider — dropping aspirin,” Cannon said. “People are interested in it.”
Also a class IIb recommendation in the new guidelines was the suggestion to use bare-metal stents to shorten the duration of DAPT.
“There is a huge unmet need among patients with AF who undergo PCI,” Mehran said. “In some scenarios, physicians are using bare-metal stents because they want to stop DAPT as soon as possible, and just go to a single anticoagulant. But there’s never been a trial on this, and it is truly an unmet need. We need to better understand how to best manage these patients.”
Studies Continue with Newer Agents
Several studies are now underway evaluating the novel oral anticoagulants as part of a triple-therapy regimen, and also as part of a WOEST strategy. Cannon is the lead investigator for the RE-DUAL PCI trial, which will evaluate dabigatran in various combination regimens.
“There are two doses (of dabigatran) that have been tested, and both are available worldwide, but only the higher dose was deemed worthy by the FDA,” he said. “But we’re testing both in the trial, without aspirin. We’re using a WOEST approach, and then for the control arm, we’re using almost a WOEST approach; we’re starting with triple therapy, and then after a month following bare-metal stent implantation we’re dropping aspirin. Then, in 3 months, we’re dropping aspirin in the drug-eluting stent group. So that’s interesting, and it’s just getting started.”
Cannon also discussed the ongoing PIONEER AF trial, which is assessing two rivaroxaban regimens and one vitamin K regimen.
“The PIONEER AF trial is examining two rivaroxaban strategies; one is using a slightly reduced dose — 15 mg instead of 20 mg — and it’s doing the WOEST strategy of no aspirin,” he said. “The second strategy is using what the FDA recently rejected for the third time — a quarter dose of rivaroxaban plus aspirin and clopidogrel compared with standard triple therapy.”
Angiolillo said these trials are likely to add to the current knowledge base about the use of novel oral anticoagulants in this unique patient population.
“Both of these trials have different arms looking at how to combine the novel oral anticoagulants with antiplatelet therapy, and considering some dose modifications of the novel oral anticoagulants in order to minimize the risk for bleeding complications while also maintaining efficacy,” he said.
Evolving Strategies
As more information becomes available through these ongoing studies, cardiologists will likely have clearer guidance about the optimum doses and combinations of the novel oral anticoagulants agents in triple therapy. In the meantime, however, there is a seemingly infinite range of possibilities, and not enough knowledge on how to “mix and match.”
Duane Pinto
“If a patient comes into the cath lab and needs triple therapy, the common practice has been to use some combination of aspirin, clopidogrel and warfarin,” Pinto said. “But if we now include the newer antiplatelet agents, such as ticagrelor [Brilinta, AstraZeneca] and prasugrel [Effient, Daiichi Sankyo/Eli Lilly], and the newer anticoagulants, you can imagine the multitude of combinations that are possible. At this point, the efficacy of each of these different combinations is not well studied.”
In an effort to better understand the preferences of cardiologists regarding triple therapy strategies, Cannon was one of several researchers to conduct a study on this topic. Of the cardiologists surveyed, only 8.8% said they preferred the novel oral anticoagulants as the first-line treatment in the context of triple therapy.
“Responders commented on the lack of supporting clinical data for the new agents when combined with DAPT, and cited lack of reversibility of novel oral anticoagulants compared with warfarin as reasons for their choice of treatment,” Cannon and colleagues wrote.
Moreover, Cannon said that the study respondents demonstrated openness to a WOEST-type strategy.
“We did this about a year ago, and what we saw was that there was roughly a 50/50 split in terms of wanting to drop something,” he said. “The WOEST study was small, but it was the first approach to doing something that could decrease bleeding and yet not increase thrombotic events. So everyone would love to see more data on this.”
Cannon added that although some clinicians would rather take a conservative approach toward novel oral anticoagulants pending further data, these agents do have promise in triple therapy.
“Depending on the dosage or drug, you could have either equal or less bleeding with all of these agents,” Cannon said. “Even if they had similar overall major bleeding, they had about a 50% reduction in intracranial hemorrhage, and of course, that’s the worst thing. If you can cut that in half by switching to the new agent alone, that makes a big difference.”
Pinto said he looks forward to future findings on these exciting new agents.
“The novel agents are definitely an improvement for not only ease of use, but also outcomes for many patients; however, with this subset of patients needing stenting for ACS, we don’t know how to combine these with DAPT in the best mix-and-match strategy,” he said. “There may be a desire to use what’s new in this population, but we need to know the right way to proceed. The PIONEER AF and RE-DUAL PCI trials will provide an important piece of the puzzle.”
Mehran agreed that these studies are likely to yield important information, and may have a valuable impact on the care of patients with AF undergoing PCI.
“We can do better in these patients,” she said. “So, it’s going to be very exciting. If we can find the best possible therapy in our patients undergoing stenting who also have atrial fibrillation, we can make an important impact.” – by Jennifer Byrne