Can we stop using warfarin now???

Justification for continued use of warfarin (a vitamin K antagonist anticoagulant) in patients with non-valvular atrial fibrillation (NVAF) or many cases of venous thromboembolism is becoming more tenuous every day.

In the August 9, 2016 issue of JAMA, Pokorney et al., report data from a registry of patients taking warfarin. The authors specifically examined time in therapeutic range (TTR) over a 6 month and a one year period. In addition, they asked the question whether stability of INR over 6 months predicted stability over 1 year and whether stability at 6 months predicted ability for a patient to avoid supratherapeutic INR values. The report did not examine any link between bleeding events or ischemic strokes during time periods that patients were or were not in therapeutic range.

The results are not good – and are consistent with previous reports that demonstrate just how difficult achieving a therapeutic INR is for patients over time, as well as how easily even a very compliant patient can slip into a dangerous supratherapeutic range.

Previously, multiple authors have demonstrated that, at best, we can expect a median TTR around 50-60% in patients taking warfarin (Dlott et al., 2014; Rose et al., 2011; Rose et al., 2008). Pokorney and colleagues examined INR values of 3,749 patients over a one year period. The INR values were checked at least 3 times in 6 months and 6 times in 1 year. Over the course of the year, only 26% of patients were able to maintain therapeutic INR values between 2 and 3 at least 80% of the time. Even worse, only 10% of patients were able to maintain therapeutic range for the entire year. What is also alarming is that 36% of the patients that did maintain therapeutic INR values for at least 80% of the time also had at least one INR value that was well above the therapeutic range, placing that patient at risk for a significant bleeding event.

Speaking of bleeding events, while we do have options to rapidly reverse laboratory coagulation parameters (i.e PT and INR) using fresh frozen plasma (FFP) or four factor prothrombin complex concentrate (PCC), no study has demonstrated that any of these products lead to better patient outcomes for those experiencing a major bleed. Unfortunately, we also know that major bleeds on warfarin are more likely to be intracranial hemorrhages which are often rapidly fatal and clinically not reversible (Rivaroxaban, Apixaban and Dabigatran package insert).

On the other hand, the broad group of non-vitamin K anticoagulants, called NOACs (aka DOAC or TSOAC) present a safer profile for patient use with predictable pharmacodynamics and either direct reversal agents either with current commercial availability (eg. Idarucizumab) or rapidly progressing research trials with likely near-term availability (e.g .annexanet alfa). NOACs include the oral direct thrombin inhibitor, dabigatran [Pradaxa, Boehringer-Ingelheim] as well as the Factor Xa inhibitors: Rivaroxaban [Xarelto, Janssen Pharmaceuticals], Apixaban [Eliquis, Pfizer Inc.] and Edoxaban [Savaysa, Daiichi Sankyo].

Unless a patient has a contraindicated condition, such as a mechanical valve, these agents really should continue to move forward as the front line in stroke prevention for atrial fibrillation patients as well as for appropriate venous thromboembolism patients (i.e. stable pulmonary embolism patients and the majority of DVT patients). As a matter of fact, the 2016 American College of Chest Physicians (ACCP) guidelines now suggest a NOAC over warfarin (class 2b) for treatment of VTE.

Physicians must understand that there is increasingly overwhelming data supporting the use of NOACs over warfarin. With two of the agents (apixaban and dabigatran) demonstrating superiority and two of the agents demonstrating non-inferiority (rivaroxaban and edoxaban) in comparison to warfarin for stroke prevention, we are running out of excuses not to initiate NOAC treatment in newly diagnosed atrial fibrillation patients. Maybe more importantly, given the consistent data showing the inability to reach an acceptable time in therapeutic range amonst patients taking warfarin, we are also running out of excuses to switch patients from warfarin to a NOAC medication, even those patients or providers perceive that warfarin therapy has “worked” for the patient over a long period of time (i.e confusing luck with efficacy).

The availability of specific reversal agents may also be reassuring to both patients and physicians. Boehringer-Ingelheim received FDA approval for the use of Idarucizumab [Praxbind] to treat major bleeding events in patients taking dabigatran [Pradaxa] last year and Portola Inc., has developed a product that I am helping to test at Tampa General Hospital called Andexanet-alfa.

Praxbind is a fragmented monoclonal antibody that binds directly to Pradaxa and creates an inert complex while Andexanet is a Factor Xa decoy that captures and, thus, inactivates any Factor Xa inhibitor including Xarelto, Eliquis or Savaysa. The company has received a PDUFA date (deadline for approval) of August 17, 2016 from the FDA. In addition, we will continue to study the reversal agent to look for efficacy in patients undergoing emergent surgery.

We continue to see a number of patients that suffer devastating intracranial, often fatal, bleeds while taking warfarin. In addition, there are a large number of patients that have ischemic strokes even when compliant with their warfarin secondary to the difficulty of maintaining a therapeutic INR. Potentially, the availability of reversal agents and continued positive publications comparing NOACs to warfarin or utilizing NOACs in expanded situations (i.e prophylaxis of DVT and PE) will eventually lead to the cessation of use of warfarin in the majority of patients requiring anti-coagulation.

 

Jason W. Wilson, MD, MA, FAAEM is an emergency medicine physician at Tampa General Hospital. He serves as the Medical Director of the Office of Clinical Research and as the Associate Medical Director for the Emergency Department. He is an Assistant Professor in the Department of Internal Medicine at the Morsani College of Medicine. Over the past five years, Dr. Wilson has focused on anticoagulant research and served as the principal investigator for numerous anticoagulant and reversal agent related clinical studies. He has grant support, educational support and consulting arrangements with Janssen Pharmaceuticals, Pfizer Inc., Boehringer-Ingelheim and Astra-Zeneca.

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