COMMENTARY

NOACs Are Favored Over Warfarin: I'm (Almost) Okay With That

John Mandrola, MD

Disclosures

February 27, 2017

We are past the tipping point with the new oral anticoagulant drugs (NOACs), or direct oral anticoagulants (DOACs). Their dominance over warfarin has arrived.

How certain are we that this is the right call?

A global registry study called GLORIA-AF[1] recently published in the Journal of the American College of Cardiology reported something I see happening in my practice: the choice of anticoagulant for patients with nonvalvular atrial fibrillation (AF) is moving strongly away from warfarin and toward the NOAC drugs, dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals), edoxaban (Savaysa/Lixiana, Daiichi Sankyo), and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). The authors report that prescriptions for NOAC drugs outnumbered warfarin—48% to 32%. These numbers are from November 2011 through December 2014. I suspect today's figures would favor NOACs by an even wider margin. In my community, nearly every hospitalized patient with AF started on anticoagulants receives a NOAC.

NOAC Advantages

Reasons for NOAC dominance are obvious:

First is ease of use. These days everyone is rushed—both patients and clinicians. From the clinician's standpoint, in new cases of AF, there's much to explain already. Adding warfarin education to a barrage of information on AF seems unnecessary. NOAC convenience also persists after the initiation phase. The new drugs don't require frequent testing or dietary restrictions, and they interact with far fewer drugs than warfarin.

I used to dismiss the convenience factor. Warfarin's difficulty to use was not a bug; it was a feature. Patients with AF given warfarin would have to focus on their illness and they would have to interact more with the healthcare system. I believed these were good things.

Dr Victor Montori from the Mayo Clinic changed my mind. He and his team of advocates for minimally disruptive medicine[2] rightly argue that convenience is important because less time spent being a patient is more time spent enjoying life. You don't think about this much until you or your family engage the morass that is our US healthcare system. Plus, adherence with the more convenient NOAC drugs may be better than warfarin.[3]

The second major reason NOACs are taking off is growing comfort that we can forego monitoring of their anticoagulant effects. Decades of warfarin use have conditioned our brains to assume that all anticoagulation drugs require measurement of their effects. The pharmacology of the NOAC drugs—namely, that taking X dose of NOAC leads to Y level of effect in the majority of people—is well established.

Enough time has passed and enough experience gained with the new drugs to believe the pharmacologists. One caveat: you can quibble about marked variation in plasma levels of dabigatran—which is a prodrug (and direct thrombin inhibitor).[4] The reliable-metabolism premise is stronger for the three factor Xa inhibitors.

No Alarm Bells With Real-World Experience

The third reason for NOAC preference is a collective ease about efficacy and safety. Randomized controlled trials showed that NOACs were as good as or better than warfarin.[5] Then real-world data confirmed these results.[6] Although patients don't present to emergency departments or clinics to announce the absence of strokes, neither I nor my colleagues see trends of NOAC failures. Our experience matches the published evidence.

Perhaps the best evidence of NOAC efficacy is around the time of AF ablation. Embolic protection for a procedure in which we leave catheters in the arterial circulation for hours and injure the left atrial endothelial lining with ablation is like a stress test for an anticoagulant. Compelling evidence from numerous centers suggest NOACs pass the test: the drugs provide similar periprocedural safety and efficacy compared with warfarin.[7,8] This is exactly what I have seen over the past 5 years. When I talk with colleagues, it's what they have seen. Again, experience matches evidence.

Caveats and Doubters Remain

Yet nothing in science and medicine is certain. Every medical decision should be couched in probabilistic terms. There are smart people who remain less convinced of NOAC superiority. Research pharmacologists at the University of British Columbia have written important critiques in the Cochrane Database of Systematic Reviews on both factor Xa and direct thrombin inhibitors vs vitamin K antagonists for the prevention of stroke in AF.[9,10] They point to numerous limitations and bias in the trials. For instance, one of their concerns is the claim that apixaban provides a mortality benefit over warfarin. In ARISTOTLE, apixaban reduced the rate of all-cause death compared with warfarin by a statistically significant 0.42%. The problem was that the number of patients with missing data on vital statistics was 2.1%—fivefold greater than the absolute benefit. Enthusiasm makes it easier to skip over this sort of nuance.

Another issue these pharmacologists and others[11,12] point to is the possibility of research misconduct in the industry-sponsored NOAC trials. Boehringer Ingelheim paid $650 million to settle state and federal lawsuits alleging that the company knew of the internal bleeding risks of dabigatran, concealed internal studies rather than warn patients, and even destroyed evidence requested by the court.

More recent news concerning faulty international normalized ratio (INR) devices used in the pivotal ROCKET-AF (rivaroxaban) trial add to concerns of study misconduct. In a detailed report, Deborah Cohen, associate editor of the BMJ, culled evidence that led her and other experts to question the results of the ROCKET-AF trial until independent analysis is done.[13] ROCKET-AF investigators countered with two analyses published in the New England Journal of Medicine that upheld the main results of ROCKET-AF.[14,15]

The ARISTOTLE (apixaban) trial also had irregularities. An analysis of publicly available documents describe FDA inspections of clinical sites in which significant evidence of objectionable practices reported seven official-action-indicated (OAI) events for the ARISTOTLE trial.[16] OAI events represent the most severe classification of FDA inspections. In this case, events included falsification of data and inaccurate adverse event reporting. One study site in China altered patient records and if data from that site were removed, the mortality benefit in the overall trial was no longer statistically significant.

Final Judgment

My (probabilistic) guess is that time will prove our embrace of the new anticoagulants was the right call. It's a good bet, but it's not a sure bet. Many clinicians were quite sure that treating depression in adolescents with paroxetine or high-dose imipramine was beneficial. That was until independent researchers reanalyzed the famous Study 329 and found no evidence of efficacy of the drugs and an increase in harm.[17]

Unlikely is such a major reversal with the NOAC drugs. Being wrong, however, would be costly. Millions of people take these drugs.

Independent analyses of the NOAC trials greatly lessens the chance of making a huge mistake. I'm no trialist, but common sense holds that a good result would be made great with confirmation. And you don't have to be a conspiracist to question resistance to sharing seemingly compelling data.

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