TCT: Dabi, roxy and apixaban--when is warfarin still useful?
SAN FRANCISCO—Now with dabigatran and rivaroxaban on the anticoagulation market, warfarin, after nearly 40 years of being the lone wolf for prevention of stroke in atrial fibrillation (AF) patients, finally has some competition. However, when is warfarin still acceptable and cost-effective?  This is what Matthew R. Reynolds, MD, MSc, Harvard Clinical Research Institute and the VA Healthcare System, both in Boston, questioned during a presentation Nov. 9 at the 23rd annual Transcatheter Cardiovascular Therapeutics (TCT) symposium.

“When is warfarin still acceptable?” asked Reynolds. “While it is tempting to say never ... a safe answer is when newer agents are contraindicated, not well tolerated or lack proven efficacy.”

Reynolds noted that previous studies have shown that all three drugs—rivaroxaban (Xarelto, Bayer/Johnson & Johnson), dabigatran (Pradaxa, Boehringer Ingelheim) and apixaban (Bristol-Myers Squibb/Pfizer—seem to be more effective in reducing the risk of intracranial hemorrhage (HR between 0.4 - 0.7 range). Additionally, Reynolds said that all-cause mortality rates are similar and these agents reduced a patient's risk of mortality by almost 10 percent.

When is warfarin still useful in the clinical setting? The following four scenarios could be ones where warfarin could still be used:
  • When newer agents are contraindicated, not tolerated, or lack proven efficacy;
  • When significant drug-drug interactions cannot be avoided;
  • When the incremental costs of new drugs are not justified by the incremental benefits; and
  • When INR control is excellent.
One of the major contraindications with these novel anticoagulants is renal insufficiency, Reynolds noted. This is particularly specific to dabigatran, which is 80 percent renally extracted. In comparison, rivaroxaban and apixaban only require a 36 and 25 percent renal clearance. However, Reynolds offered that "the safety of these drugs in patients with renal efficiency is still not well established."

Additionally, dabigatran, rivaroxaban and apixaban have a limited proof of efficacy in patients with valvular AF, those with mechanical heart valves and those with cardioversion and other rhythm control interventions.

In an assessment of cost-effectiveness of dabigatran in non-valvular atrial fibrillation, C. Michael Gibson, MD, speculated that the annual cost of Pradaxa would be $2,884 vs. an annual cost of $1,761 for warfarin and INR monitoring, resulting in $33,274 per year life saved, due to the reduction of mortality seen. Another previous study estimated that the average wholesale price of dabigatran would be $7.90 per day, Reynolds said, which would result in about a $10,000 to $20,000 quality adjusted life years.

"I would like to think that an agent or device or procedure comes along that adds cost to the healthcare system, that in a rational role that we would target that to patients who are most likely to benefit," Reynolds offered.

“Dabigatran, rivaroxaban and apixaban offer important advantages over warfarin, including consistent reductions in the risk of intracranial hemorrhage and 8 to 10 percent relative reduction in total mortality," Reynolds concluded.

Additionally, Reynolds offered that these three agents also decreased rates of intracranial hemorrhage, however, major bleeding event rates were not consistent across previous trials.

Reynolds noted that the high 150 mg dose of dabigatran would be preferred for any patient who had a CHADS score of 3 or above, or for those with a CHADS score of 2 who had a moderate to high risk of bleeding.

Lastly, Reynolds offered that dabigatran is “probably more cost-effective by conventional U.S. standards, however, its cost-effectiveness may be modified by the potential risk to patients."

However, he did offer that risk prediction tools for bleeding are still necessary.