Is Warfarin 'Dead'? CCC Meeting Debate Suggests Otherwise

Marlene Busko

October 21, 2013

MONTREAL, QC — In an entertaining debate at the Canadian Cardiovascular Congress (CCC) 2013 entitled "Is warfarin dead for stroke prevention in atrial fibrillation (AF)?" the take-home message was that warfarin is still alive and well—largely because a significant number of patients do not qualify for the newer, very expensive oral anticoagulants[1].

Dr Paul Dorian (University of Toronto, ON) contended that warfarin is an effective rat poison but is obsolete for preventing stroke in AF. Dr L Brent Mitchell (University of Calgary, AB) argued convincingly that warfarin is the appropriate choice for stroke prevention in many patients with AF, so warfarin is not "dead."

Cochair Dr Jafna Cox (Dalhousie University, Halifax, NS) told heartwire that he "thought it was a foregone conclusion that the novel oral anticoagulants were so clearly going to trump warfarin," but Mitchell showed that a significant number of patients do not qualify for the newer agents.

"If you have a patient who is doing absolutely fine on warfarin . . . I agree and I think most experts agree, there is no compelling reason to switch," he observed. However, the newer agents are easier to use in appropriate patients "who have an issue with INR monitoring, food interactions, [and] drug interactions."

The debaters highlighted how "tried and true," inexpensive warfarin is still useful—notably for patients with valvular heart disease—whereas the newer agents are easier to use but very expensive, so most regulatory bodies have chosen to say the patient must fail warfarin first, cochair Dr Blair O'Neill (University of Alberta, Edmonton) noted.

Dorian's Case: Warfarin Has "Ceased to Be"

Warfarin is dead like the parrot in the Monty Python sketch and obsolete like cumbersome early mobile phones, Dorian told the audience. "I think we all agree that warfarin is hard to use and take . . . often causes bleeding, [has an impractical antidote], and as a consequence . . . its optimal benefits are . . . not realized," he said.

"I don't have to belabor the fact that [keeping the INR therapeutic range] is hard to do and is often not achieved," Dorian observed. In fact, probably two-thirds of patients in community practice who are receiving warfarin have imperfect INR control.

Once the INR is above 3, the risks of hemorrhage and thrombosis rise, he noted. As a result, warfarin is the second-most common drug-related complication—after hypoglycemia—that leads to a visit to an emergency room.

"For our elderly patients who are . . . about to start an anticoagulant for stroke prevention, warfarin is fraught with very considerable hazard for bleeding early on—not less than about a 3.5% risk of major bleeding per month for at least a five-year window," Dorian noted, citing an Ontario study of patients over age 65. It showed that in the first 30 days after starting warfarin, the risk of hospitalization for a major bleed was as high as 16% for patients with a high CHADS2 score[2].

While taking an anticoagulant, patients who are unfortunate enough to have a major bleed requiring hospitalization are more likely to die if they were taking warfarin as opposed to a newer agent, he pointed out.

The newer agents represent a viable alternative, he stated. They have a 1% "small but not trivial" absolute benefit over warfarin—similar to the size of other benefits in cardiovascular medicine, such as that of tissue plasminogen activator (tPA) over streptokinase. The risk of intracranial hemorrhage is lower with the newer agents than with warfarin. Patients are also less likely to discontinue dabigatran (Pradaxa, Boehringer Ingelheim) than warfarin.

For all these reasons, he argued, warfarin should be considered obsolete.

A second opinion . . .

Not so fast, Mitchell declared. He presented a graph based on data from the Prevention of Thromboembolic Events – European Registry in Atrial Fibrillation (PREFER in AF), 18 months after the 2010 European Society of Cardiology guidelines placed the newer oral anticoagulants on a par with warfarin for stroke prevention for some patients with AF—long enough for practice habits to begin changing. This showed that "in every country, including Germany where [novel oral anticoagulants] NOACs are reimbursed, the vast majority of anticoagulants prescribed for this purpose are for warfarin," he said. The ratio of vitamin-K-antagonist prescriptions to novel-oral-anticoagulant prescriptions was 13:1.

"There are some patients whose preferred oral anticoagulant should be warfarin," he stressed and went on to enumerate which ones.

First, findings from the Dabigatran Etexilate in Patients With Mechanical Heart Valves (RE-ALIGN) trial show that "clearly we should not be using these newer agents—we should be using warfarin—in patients with mechanical prosthetic heart valves." Based on the Central Registry of the German Competence Network on Atrial Fibrillation (AFNET) database, about 5.1% of patients with AF have valvular AF.

Other patients who should receive warfarin instead of the newer drugs include those with rheumatic mitral valvular disease (3.7% of patients with AF), hyperthyroidism (6.7%), or estimated creatinine clearance <30 mL/min (3.7%). Therefore, at least 20% of AF patents do not qualify for the newer agents, he summarized.

Moreover, if good INR is attained while taking warfarin, the enhanced effectiveness with the newer oral anticoagulants vs warfarin disappears, the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study showed.

Finally, warfarin is not "dead" because the new drugs are so much more expensive. "I've tried not to talk about cost-effectiveness, because that's not how doctors think when . . . standing in front of a patient," Mitchell said. However, based on an analysis of time in the therapeutic range in subgroups of RE-LY data, the number needed to treat to prevent one stroke or thromboembolism in the patients enrolled by the quartile of RE-LY enrolling centers with the best INR control was 1429; the excess cost of dabigatran without INRs over warfarin with INRs for one year is $3000; so the cost to prevent one stroke in such patients is $4 million.

"This highlights why our payers have said 'show us why you can't keep warfarin in the therapeutic range, before we try to prevent a stroke at a cost of $4 million.' "

So who won the debate? Dorian had presented a stuffed rat to Mitchell as a memento, and the audience voted that the rat won the debate.

Mitchell discloses that he was involved in the RE-LY trial. The other speakers had no relevant disclosures.


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