Preventing Stroke and Other Complications of Atrial Fibrillation: Towards a Post-Warfarin Era?
To tackle the delicate balance between having blood that clots too readily or not readily enough, evolution has come up with a complex scheme involving a cascade of proteins and platelets—a scheme that allows ample opportunity for things to go wrong and ample potential targets for correcting errors. For many years two agents (oral warfarin and injected heparin and later developments from them) have been the main choices for clinicians seeking, for example, to prevent venous thromboembolism after hip or knee surgery or to avoid embolic strokes in patients with atrial fibrillation. The ideal drug would be one that can be given by mouth, does not require routine monitoring, has rapid action, does not carry the risk of bleeding or other toxicity (including drug-drug interactions) and whose effects can be readily reversed. The past decade or so has seen a huge number of candidates. Not all have stayed the course but a dozen or so are now under development or already licensed as direct thrombin inhibitors or as direct or indirect inhibitors of coagulation factor Xa.
THREE NOVEL AGENTS
This column will chiefly focus on patients with atrial fibrillation and on the three drugs that currently appear to be leading the field both in terms of publications and clinically—namely, rivaroxaban, dabigatran and apixaban. On the basis of chart reviews and product leaflets it has been estimated that 60% or more of patients seen at the Johns Hopkins, Baltimore coagulation clinics might be eligible for treatment with one these three agents (K.L. Carter, et al., J Thromb. Thrombolysis 34: 437-45, 2012).
The accompanying Table 1 collects some recent reports on this trio of compounds, including 2012 meta-analyses (or similar) that cover all three, and also two review articles (of several). Table 1 includes a couple of pointers to publications in another clinically important area—namely, venous thromboembolism (Steffen and Braunwald, Fox et al.). A consensus is emerging from the clinical trial data and from a large number of reviews and commentaries that viable and safe (subject to long-term follow-up) alternatives to warfarin are now available.
Has the time come for apixaban to replace warfarin as the anticoagulant of choice in atrial fibrillation?
For a wider look at the most significant studies involving this trio of novel anticoagulants, in the treatment of atrial fibrillation as well as other conditions, Table 2 features the most-cited papers over the last five years, based on a search of Thomson Reuters Web of Science on the keywords “rivaroxaban,” “dabigatran,” or “apixaban.”
Three of these papers, all from the New England Journal of Medicine, report Phase III clinical trials on each of the respective compounds for atrial fibrillation: dabigatran in paper #1, with more than 1,000 citations to date; rivaroxaban in paper #6; and apixaban in paper #7.
ADVANTAGES AND DISADVANTAGES
At this writing, the latest review (Table 1, Alberts et al.) summarized the advantages of the novel agents as “predictable anticoagulant effects, low propensity for drug interactions, and lower rates of intracranial haemorrhage,” while disadvantages include the need for rapidly effective antidotes, the possibility of higher rates of gastrointestinal hemorrhage, and greater costs. Head-to-head (direct) comparisons of these novel agents have not yet been done, though an indirect comparison has (Table 1, Fox et al.), concluding that for secondary prevention of stroke in atrial fibrillation, apixaban, dabigatran, and rivaroxaban "had broadly similar efficacy."
Only last month, a secondary analysis of the results of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, Granger et al., Table 2, paper #7 ) showed that the benefit found for apixaban (reduced strokes, reduced bleeding, reduced mortality) held across all risk groups (R.D. Lopes, et al,. Lancet 380: 1749-58, 2012), prompting the question, “has the time come for apixaban to replace warfarin as the anticoagulation of choice in atrial fibrillation”? The answer? “[P]robably not, at least not yet” (V.S. Vassiliou P.D. Flynn, Lancet 380:1718-20, 2012), and the reasons for this caution illustrate the difficulty of answering all legitimate questions in a single trial design—a difficulty, it should be said, not limited to apixaban. As noted above, there is the question of cost effectiveness (the number of patients needed to be treated with apixaban to prevent one thromboembolic or hemorrhagic event or death could be around 100) and also the ability to reverse anticoagulation urgently in some circumstances.
Mr. David W. Sharp, M.A. (Cambridge), formerly deputy editor of The Lancet, is a freelance writer in Minchinhampton, UK.
The data and citation records included in this report are from Thomson Reuters Web of KnowledgeSM. Web of KnowledgeSM is a registered trademark of Thomson Reuters. All rights reserved.