Risk-benefit profiles favor new oral anticoagulants for A-fib

By Will Boggs MD

NEW YORK (Reuters Health) - Greater efficacy and similar risk profiles suggest that all four new oral anticoagulants (NOACs) may be preferred over warfarin for patients with nonvalvular atrial fibrillation, according to a new meta-analysis.

"Our data demonstrate that the relative benefit and safety is consistent across a wide range of subjects, including vulnerable populations such as the elderly, patients with a prior stroke, and those with renal dysfunction," Dr. Christian T. Ruff from Brigham and Women's Hospital and Harvard Medical School in Boston told Reuters Health by email.

Individual phase 3 trials have shown that dabigatran, rivaroxaban, apixaban, and edoxaban are at least as safe and effective as warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation.

"There are several novel features of this meta-analysis. It is the first to include data from all four phase 3 landmark trials (71,683 patients) comparing NOACs to warfarin for stroke prevention in atrial fibrillation," Dr. Ruff said. "Another important feature that was unique to his meta-analysis is that we were able to assess the relative benefit of the new oral anticoagulants in important, clinically relevant subgroups."

Allocation to a NOAC reduced the composite risk of stroke or systemic embolic events by 19% compared with warfarin (p<0.0001). Most of the benefit derived from a large reduction (51%) in hemorrhagic stroke (p<0.0001).

NOACs significantly reduced all-cause mortality (by 10% relative to warfarin; p=0.0003), but they were similar to warfarin in the prevention of ischemic stroke and myocardial infarction, the researchers in The Lancet, online December 4.

Major bleeding was non-significantly reduced by NOACs, relative to warfarin, but there was a substantial reduction in intracranial hemorrhage (by 52%; p<0.0001). This was countered, though, by significantly increased gastrointestinal bleeding with NOACs vs. warfarin (25% higher risk; p=0.043).

The benefits of NOACs versus warfarin in reducing stroke or systemic embolic events persisted across all subgroups examined.

The safety of NOACs compared with warfarin was also consistent across most subgroups, the exception being greater reductions in bleeding among patients with less consistent achievement of therapeutic warfarin levels.

"There was a robust and consistent benefit of the new oral anticoagulants in reducing stroke (primarily hemorrhagic stroke), mortality, and intracranial hemorrhage," Dr. Ruff concluded. "This benefit applies to a wide range of subjects that are at high risk of both stroke and bleeding."

"Warfarin will remain a legitimate option for stroke prevention in patients with atrial fibrillation," he added. "There are many patients in whom warfarin remains the only option, such as those with a mechanical heart valve or end-stage renal disease. Warfarin performed well in all of these trials and remains an effective and affordable anticoagulant."

Dr. Torben Bjerregaard Larsen, who co-wrote an editorial on the new findings, told Reuters Health by email that with the new anticoagulants, "We have a choice and can fit the drug to the patient from a clinical perspective, and of course take in the patient's own preferences."

Dr. Larsen, from Aalborg University Hospital in Denmark, recommends using the SAMe-TT2R2 score, a user-friendly, validated tool that helps physician identify which patients are likely to do well on warfarin and which are more likely to have poor anticoagulation control.

"We need more information on the value of NOACs versus warfarin in those with persistently high TTR, as an example, patients in self-managed treatment with vitamin K antagonists," he added.

Dr. David Spence from University of Western Ontario in London, Canada, has also studied the NOACs but was not involved in the new work. "It is virtually impossible to use warfarin well, and physicians' experiences with early bleeding on warfarin in real-world use of warfarin have made them unduly wary of anticoagulation," he told Reuters Health by email.

"Bleeding rates on warfarin in the clinical trials of NOACs were much lower than in real-world practice, so compared to real-world therapy, the NOACs are way better than warfarin," Dr. Spence said. "The availability of better, safer alternatives should make it possible to do a better job of stroke prevention."

Dr. Spence added, "Too many physicians will prescribe antiplatelet agents thinking they are safer, but in the AVERRROES study the risk of major bleeding was no higher on warfarin than on antiplatelet agents. Antiplatelet agents work only a third as well (as anticoagulants), so it is a major problem that so many patients in atrial fibrillation are not anticoagulated."

Dr. Kristian Filion from McGill University in Montreal, Canada, added a cautious note.

"Although the subgroup analyses suggest benefit with novel oral anticoagulants in many different types of patients, the generalizability of these results to atrial fibrillation patients seen in everyday clinical practice is unclear because of the inclusion and exclusion criteria used in the individual trials," Dr. Filion, who was not involved in the meta-analysis, told Reuters Health by email. "Ultimately, the potential harms and benefits regarding the choice of treatment need to be made based on the individual patient characteristics, and there remains a need for definitive data in this area."

The authors disclosed multiple ties to drugmakers.

SOURCES: http://bit.ly/1ethu1K and http://bit.ly/192n6ve

The Lancet 2013.

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