New-generation oral anticoagulants represent advance in management of nonvalvular AF

Cardiologists have more therapeutic options than ever before to care for patients with nonvalvular atrial fibrillation.

The recent approvals of apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) in December, rivaroxaban (Xarelto, Janssen Pharmaceuticals) in 2011 and dabigatran (Pradaxa, Boehringer Ingelheim) in 2010 have brought stroke prevention to the forefront in the management of patients with nonvalvular AF. Looking ahead, the factor Xa inhibitor, edoxaban (Lixiana, Daiichi Sankyo), is under investigation in the ENGAGE AF-TIMI 48 trial.

This month, Cardiology Today is publishing part two of an expert round table on how to position new agents for AF and stroke prevention for the right patient. The first part of the discussion, published in the January 2013 issue, focused on similarities of the novel therapies; safety and dosing; reversibility; dangers of serious bleeds; and classification scores. Now, Carl J. Pepine, MD, Chief Medical Editor of Cardiology Today, and three experts in cardiology switch the conversation to bridging therapy; MI signals with dabigatran; cost; and opinions on future management of this patient population.

Round Table Participants

Moderator

Carl J. Pepine, MD

Cardiology Today Chief Medical Editor

Division Director Emeritus, Eminent Scholar Emeritus and Professor of Medicine, Division of Cardiovascular Medicine, University of Florida College of Medicine

Richard C. Becker, MD, MEd

Director, Cardiovascular Thrombosis Center

Member of the Divisions of Cardiology and Hematology, Duke University Medical Center

Christopher B. Granger, MD

Professor of Medicine, Duke University Medical Center

Director, Cardiac Care Unit

Clinical Trialist, Duke Clinical Research Institute

Albert L. Waldo, MD

Pritchard Professor of Cardiology and Professor of Medicine, Case Western Reserve University

Associate Chief of Cardiovascular Medicine for Academic Affairs, University Hospitals Case Medical Center

Member of the Arrhythmia Disorders section, Cardiology Today Editorial Board

When and how to bridge therapy

Carl J. Pepine, MD: Let’s discuss the topic of bridging. Whether an artifact of the long duration of action of warfarin or not, it seems to me that the issue of bridging has emerged — whether you should bridge, how you should bridge and in whom?

Richard C. Becker, MD, MEd: In general, and in the absence of evidence, clinicians are not sure which patients should be bridged. This question forms the basis for a randomized, placebo-controlled trial with low-molecular-weight heparin that is being coordinated through the Duke Clinical Research Institute known as the BRIDGE trial.

The phenomenon of bridging is very much connected to the pharmacology of warfarin — specifically, its long half-life, slow onset of anticoagulant effect and similarly prolonged offset of effect. Dr. Granger previously pointed out the interruptions for surgery and other procedures analyzed in the RE-LY trial. While not a study of bridging per se, the information is clinically useful and underscores the importance of creatinine clearance on the pharmacokinetics and pharmacodynamics of dabigatran. Clinicians require similar analyses for rivaroxaban and apixaban from the ROCKET AF and ARISTOTLE trials, respectively, to guide optimal decision-making with these oral anticoagulants.

Where I’ve seen difficulties with new-generation oral anticoagulants is following procedures. It is evident that this is the end-result of clinicians being accustomed to a slow onset of action with warfarin. Now, there is a class of drugs with a peak anticoagulant effect within 2 to 3 hours of administration, a time when systemic anticoagulation may carry risk for bleeding if achieved too early. At my institution, the bleeding complications we’ve seen have all been in the early postoperative period.

Pepine: So give us your recommendations.

Becker: When using dabigatran I have been successful following the drug labeling, which is firmly rooted in creatinine clearance and basic pharmacology and the anticipated risk for bleeding that is procedure-specific. One can employ a similar approach with rivaroxaban and apixaban, being mindful of their respective half-lives. The decision for resuming therapy after a procedure must be governed by the risks for thrombosis and bleeding. I cannot overemphasize to clinicians the importance of remembering the rapid onset of action for the novel oral anticoagulants.

Christopher B. Granger, MD: As Dr. Becker rightfully points out, we may get fooled there because we’re used to resuming the evening of a surgery or procedure, for example, and then think it would also be reasonable to restart one of the novel agents, not fully acknowledging that the warfarin is going to take a few days and the new agent is going to lead to peak plasma concentrations approximately 2 hours later. Generally, we need to be more thoughtful about when to resume therapy. Perhaps the next day for many procedures is a more reasonable time than the evening of the procedure.

MI signals with dabigatran

Pepine: The other issue on the table is the MI signal with dabigatran. That seems to have just been extinguished. The initial explanation that I saw for that is that warfarin was beneficial in terms of preventing MI. It wasn’t a direct effect of dabigatran. But, on the other hand, if that was the case then why didn’t it show up with rivaroxaban in ROCKET AF, for example, or with apixaban?

Albert L. Waldo, MD: That’s a fair question. I like to point to the Active W trial. If you look at Active W, which is clopidogrel and aspirin vs. warfarin, warfarin was better than clopidogrel and aspirin for preventing an MI. Are antiplatelet agents prothrombotic? Warfarin is just more effective.

Granger: I’m not sure it was significant, but it was lower. If you look at the total dabigatran experience, even risk vs. placebo, there seems to be a signal for some modest increased risk for MI. The analyses from RE-LY are reassuring. If you look at patients who had coronary disease/prior MI, dabigatran still holds up as having an overall benefit for reducing overall vascular events. I don’t think we should overplay it, but I think it was over-criticized early on and is less of a criticism now.

With the other drugs, especially apixaban, numerically there were fewer MIs than with warfarin, although with small numbers. It’s because of this signal of higher MI with dabigatran that many of us feel more comfortable including low-dose aspirin. But when we use even low-dose aspirin with warfarin, or one of the new agents, there is a meaningful increased risk for bleeding. Some of the guidelines, including the Canadian guidelines (ACCP), are particularly strong in recommending that after 1 year of stable coronary disease when you’re using warfarin for AF, stop the aspirin. At the American Heart Association’s 2012 Scientific Sessions in November, we presented data from the ARISTOTLE trial showing that even for patients who were not on aspirin who had prior coronary disease, numerically there were fewer MIs with apixaban than with warfarin, which reinforces the idea that, at least with apixaban and probably rivaroxaban too, there simply is not any signal for a concern about MI and there still is a small signal with dabigatran.

Pepine: So, then what could be the basis for this?

Becker: This is an area of active investigation. Thrombin inhibition may counter-balance activated protein C and thrombomodulin — vital components of the vasculature’s natural barrier to unwanted thrombus formation. At the AHA Scientific Sessions, one of our former fellows, Mark Chan, MBBS, MHSc, MRCP, FACC, presented his work from ROCKET Japan. Mark found that there is up-regulation of thrombomodulin among patients receiving rivaroxaban. The opposite effect was observed in warfarin-treated patients. Whether this is important clinically will require additional study.

Other issues related to use

Waldo: One question I have is why hasn’t warfarin use started to decrease? It’s still vastly more used than the alternatives.

Pepine: Do you think it is all related to the cost?

Becker: I believe cost is part of it. I also think patients who have been on warfarin previously, as much as they dislike monitoring, most find comfort in being seen on a regular basis by a pharmacist or a clinician. The clinic environment is very comforting for a lot of patients. If you give them a drug and say, “I’ll see you in a year,” that just doesn’t register with these patients. It also doesn’t register with clinicians who have been using warfarin for a long time.

There are values and preferences, and the patient is a pivotal part of the decision. To this end, new is not necessarily better to an informed consumer who prefers a drug with a well-characterized track record. Being cautious is not uncommon in health care and applies to both patients and providers. With that being said, each new-generation oral anticoagulant has performed well in registration clinical trials.

Waldo: In that regard, here is a true story. The first person to whom I offered a new oral anticoagulant was the former chief of neurology at our institution. He was rate-controlled, had indications for anticoagulation and had been on warfarin for a long time. He had done very well. After dabigatran was approved, I said to him, “We have a new drug. It looks pretty good with some real advantages. Would you like to consider it?” He asked, “How long as warfarin been around.” I said, “Almost 60 years.” He asked, “How long has dabigatran?” I responded, “A few months.” He said, “Call me in 5 years.” There’s some wisdom in that.

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New agents for the future

Pepine: I will ask each of you for a brief take-home message.

Granger: We have a great opportunity with these new agents. The single most important thing is to use these new agents in a way that we assure that all patients who are eligible for an oral anticoagulant who are at risk for stroke are on one, be that warfarin or one of these new agents.

Especially for patients who are currently not anticoagulated at all, for those who are newly diagnosed with AF and for those who have not done so well on warfarin — which is, in fact, the majority of patients — those are the ones that we should be targeting as the first priority for the use of these new agents, understanding that they are more expensive and many patients will not be able to afford them.

Becker: This generation of oral anticoagulants, without question, represents an advance in the management of patients with nonvalvular AF. It’s important for clinicians to understand the pharmacology of these drugs because they are new and they are different from the vitamin K antagonists.

The clinician also must understand that while drug-drug interactions are not as common as with warfarin, there are drug-drug interactions for each one of these agents so we must be aware.

Third, although routine anticoagulant monitoring is not required with the new drugs, patient monitoring is required, in particular looking at creatinine clearance, seeing your patients, screening for bleeding complications, features of stroke and so on. The management part of the new generation of drugs should not be any different. We still have to care for the patients.

Waldo: It’s always good to be last, just to quote Mark Twain. “They know all there is to know and I know the rest.”

I would emphasize that the biggest issue in anticoagulation has been with patients who haven’t had any contraindication to anticoagulation, but do not take it. In the past we had only warfarin, and 40% to 50% of the patients who had absolute indications for anticoagulation and no contraindication didn’t get it. The big problem is that a lot of patients were fearful of warfarin for a dozen different reasons or more. These new drugs are an improvement on some of the issues related to reluctance to be anticoagulated.

I think these drugs should make life easier for the patient at less critical risk and with superb efficacy. I think it’s a reason to be excited about these advances.

Pepine: Thank you. I believe we are all working toward the same goal: reducing the risk for debilitating stroke in these patients with AF. With the new agents, we are better prepared to achieve this goal.

Disclosure: Becker reports research support from Johnson & Johnson and scientific advisories for Bayer, Bristol-Myers Squibb, Boehringer Ingelheim and Daiichi Sankyo. Granger reports research grants/contracts and consulting/other services from Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer. Pepine reports no relevant financial disclosures. Waldo reports consulting for AtriCure, Daiichi Sankyo and Janssen Pharmaceuticals, and is a speaker for Janssen Pharmaceuticals.