Meta-analysis shows all four novel oral anticoagulants perform better than warfarin

Ruff, Christian MD
Christian Ruff

A first-of-its-kind meta-analysis comparing four new oral anticoagulants with warfarin has found they perform better than warfarin reducing stroke, intracranial haemorrhage and mortality in atrial fibrillation patients. The study was published ahead-of-print in The Lancet.

Christian T Ruff (Brigham and Women’s Hospital and Harvard Medical School, Boston, USA) and others undertook a prespecified meta-analysis of all patients (n=71,683) included in the four landmark randomised trials RE-LY (study of dabigatran/Pradaxa, Boehringer Ingelheim), ROCKET AF (study of rivaroxaban/Xarelto, Bayer Healthcare), ARISTOTLE (study of apixaban/Eliquis, Bristol-Myers Squibb and Pfizer) and ENGAGE AF-TIMI 48 (study of edoxaban/Lixiana, Daiichi Sankyo).

In the meta-analysis 42,411 participants received a new oral anticoagulant and 29,272 received warfarin. Ruff et al found that the new oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin, “The benefit was mainly driven by a large reduction in haemorrhagic stroke [130 events were reported in the novel oral anticoagulants group and 263 events in the warfarin group],” the authors write. They also reduced all-cause mortality and intracranial haemorrhage; however, the authors note, gastrointestinal bleeding was increased with the new oral anticoagulants.

The authors conclude: “The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.”

In an accompanying editorial, Torben Bjerregaard Larsen (Aalborg University Hospital, Aalborg, Denmark) and Gregory Lip (University of Birmingham, Birmingham, UK) write: “Such a meta-analysis assumes that all the novel oral anticoagulant drugs are the same (which they are not)[…] and that the randomised trials are homogenous, which again they are not. Indeed, Ruff and colleagues’ meta-analysis does not really answer the question of which novel oral anticoagulant is best, whether from an efficacy or safety perspective.”

Cardiac Rhythm News spoke to Ruff about the study.

What is the novelty of this meta-analysis?

It is the first study to include data from all four landmark trials in stroke prevention in atrial fibrillation comparing novel oral anticoagulants to warfarin, and we reviewed data from 71,683 patients. Another important feature is that we were able to assess the relative benefit of the new oral anticoagulants in important, clinically relevant subgroups. We know that the risk of stroke and bleeding vary considerably in atrial fibrillation patients. 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. We also observed an interesting finding when we investigated whether the benefit of the new oral anticoagulants was dependent on how well warfarin was managed during the trials, as assessed by the centre-based time in therapeutic range (above and below 66%). We showed that the reduction in stroke and systemic embolism seen with the novel oral anticoagulants was not dependent on how well warfarin was managed. These agents are more effective than warfarin even in patients who have well controlled international normalised ratios (INRs). However, the success in managing warfarin was important with respect to bleeding. There was even greater reduction in bleeding with the new oral anticoagulants compared with warfarin in patients who have difficulty maintaining a therapeutic INR.

Is warfarin still an option for stroke prevention in atrial fibrillation? If so, which patients may benefit best?

Warfarin will remain a legitimate option for stroke prevention in patients with atrial fibrillation. 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 very well in all of these trials and remains an effective and affordable anticoagulant.

Does this meta-analysis show us any differences between the four novel oral anticoagulants studied?

This meta-analysis combined data from all the trials and did not specifically look to see if one agent was better than another. The data suggest, however, that all the novel oral anticoagulants have similar relative benefits in reducing stroke, intracerebral haemorrage and mortality.