Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Canadian Cardiovascular Congress 2010

Montreal, Quebec / October 23-27, 2010

The mechanisms underlying the age-related increase in atrial fibrillation (AF) include long-term effects of inflammatory insults on the vasculature, vascular remodelling and stiffness. Due to these changes, AF is difficult to reverse. The morbidity and mortality related to AF include a four- to fivefold increased risk of stroke; however, as emphasized here at the CCC by Dr. Elaine Hylek, Associate Professor of Medicine, Boston University School of Medicine, Massachusetts, the attributable risk of stroke in AF differs dramatically by age where in individuals between 50 and 59 years of age, only 1.5% of strokes are attributable to AF. In contrast, 1 in 4 strokes that occur in patients between the ages of 80 and 89 are attributable to the same arrhythmia.

In five seminal randomized controlled trials in which warfarin was compared to placebo, a convincing 64% relative risk reduction in stroke was demonstrated in favour of active therapy. Reassuringly, major hemorrhage rate in these trials was only 0.3% per year. Nevertheless, in 2006, the FDA demanded a boxed warning be placed on warfarin to alert physicians and patients to the important incidence of intracranial hemorrhage (ICH) related to warfarin use.

Moreover, INR targets for warfarin range from 2 to 3; <2 and the risk of stroke increases; INR >3.5 to 4, the odds of ICH increase. “Warfarin is a difficult drug; it’s imprecise and it’s difficult to get it into the 2 to 3 range,” Dr. Hylek remarked. Investigators have calculated that if patients are not within INR targets between 58 and 65% of the time, physicians need to rethink their therapy.

Here at the CCC, Dr. Jeffrey Weitz, Professor of Medicine, Biochemistry and Medical Sciences, McMaster University, Hamilton, Ontario, described further shortcomings of warfarin including, a slow onset of action necessitating overlap with i.v. anticoagulation, multiple food and drug interactions and the need for frequent INR monitoring. In contrast, new oral anticoagulants, including the factor Xa inhibitors rivaroxaban and apixaban, as well as the direct thrombin inhibitor (DTI) dabigatran, have rapid onset of action, obviating the need for overlap with i.v. agents. They can also be given in fixed doses; there are few food or drug interactions; perhaps most importantly, there is little or no need for INR monitoring.

Dr. Stuart Connolly, Professor of Medicine, McMaster University, noted that warfarin is substantially under-used in the elderly, as physicians are very concerned about bleeding risk; discontinuation rates from warfarin approach 50% in the first year.

Improvements over warfarin include the use of combination clopidogrel/ASA. In the ACTIVE study in AF patients not suitable for warfarin, there was a 28% reduction in stroke when clopidogrel was added to ASA, although there was an increase in the risk of major hemorrhage in ASA/clopidogrel. As Dr. Connolly observed, however, “More strokes were prevented than bleeds caused and many of the bleeds did not leave patients with major long-term disability”—unlike strokes in patients with AF, which are largely disabling, he added.

Advantages of Novel Oral Anticoagulation Strategies

Nevertheless, the real breakthrough in oral anticoagulation is being ushered in with the newer agents, as they all appear to offer substantial advantages over warfarin. In the large phase III RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial, the recently approved DTI dabigatran 110 and 150 mg b.i.d. was compared with open-label warfarin in a non-inferiority trial carried out in 18,113 patients with AF at moderate to high risk for stroke. “In point of fact,” Dr. Connolly told delegates, “we went beyond showing just non-inferiority with the higher dose of dabigatran, [such that] the higher dose was markedly superior to warfarin for the prevention of stroke or systemic embolism.”

Indeed, the 150-mg b.i.d. dose resulted in a 35% reduction in stroke and systemic embolic events (SEE) compared with warfarin, which was highly statistically significant (P<0.001), he added. Stroke rates were similar between the lower dose (110 mg b.i.d.) of dabigatran and warfarin; however, there was a large reduction in hemorrhagic stroke with 110 mg b.i.d., accompanied by a small increase in ischemic stroke—“so that overall, patients are almost certainly better off on dabigatran 110 mg b.i.d. than they are on warfarin because hemorrhagic strokes are fatal more than 50% of the time within a few weeks,” Dr. Connolly stated. In fact, both DTI doses dramatically decreased hemorrhagic stroke, he added.

The 110-mg b.i.d. dose also reduced major bleeding rates by 20% compared with warfarin (P=0.003) while the higher dose had about the same risk of major hemorrhage as warfarin; both DTI doses reduced the risk of life-threatening bleeds compared with warfarin. The only bleed that occurred more often in the presence of dabigatran was in the gastrointestinal (GI) tract, which may be related to the fact that a lot of the drug remains unabsorbed in the GI tract after ingestion.

Reductions in stroke were also consistently seen across the different subgroups analyzed in the RE-LY trial; while marked benefits against stroke did diminish in the elderly, the marked reduction in ICH seen with both DTI doses remained even in the elderly and was seen when compared to warfarin patients with exceptional INR control. Some drug interactions can affect plasma concentrations of dabigatran but most have relatively minor effects and relatively few dose adjustments are needed.

Results from the AVERROES (Apixaban VErsus acetylsalicylic acid to Reduce Rate Of Embolic Stroke) trial also showed that apixaban 5 mg b.i.d. in AF patients and one additional risk factor not suitable for warfarin use led to a 55% reduction in stroke compared to ASA 81 to 324 mg/day, with no increase in major hemorrhage. As Dr. Connolly calculated, the treatment of 1000 AF patients for 1 year with apixaban instead of ASA could be expected to prevent 18 strokes, 10 deaths and 31 CV hospitalizations over the course of that treatment. It is expected that apixaban will be superior to warfarin but this has not yet been shown. Dronedarone, a new antiarrhythmic now approved for AF, has been shown to reduce stroke risk in pivotal registration trials.

“The goal in patients with AF is stroke reduction and dabigatran 150 mg b.i.d. is way more effective than either warfarin or dabigatran 110 mg b.i.d. in most patients, so only when there is clear evidence that patients are at excessive risk of hemorrhage should we used the 110-mg b.i.d. dose,” Dr. Connolly stated. “We want to make the right choice in most patients by using 150 mg.”

Atrial Fibrillation Guidelines

New CCS guidelines on AF were also presented here at the CCC. Among the many chapters presented by committee chairs, stroke prevention in AF was pivotal. Among the most important recommendations on stroke prevention, as made by Stroke Prevention committee chair Dr. John Cairns, Professor of Medicine, Division of Cardiology, University of British Columbia, Vancouver, are the following:

• All patients with AF or atrial flutter (AFl) should be stratified using a predictive index for stroke such as CHADS2 and for the risk of bleeding and most patients should receive antithrombotic therapy.

• Patients at very low risk for stroke (CHADS2 0) should receive low-dose ASA; for those at low risk (CHADS2 1), either warfarin or dabigatran; for patients at moderate risk (CHADS2 2), either warfarin or dabigatran.

• Most patients should receive dabigatran, generally at a dose of 150 mg b.i.d, in preference to warfarin.

• Patients with AF/AFl with stable CAD should receive antithrombotic therapy based on their stroke risk: ASA for CHADS2 0; oral anticoagulation for CHADS2=1; warfarin is preferred over dabigatran.

• In hemodynamically stable patients with AF/AFl =48 hours or uncertain duration for whom electrical or pharmacological cardioversion is planned: warfarin or dabigatran for 3 weeks before and at least 4 weeks’ post-cardioversion. If AF/AFl persists or recurs, antithrombotic therapy using either oral anticoagulants or ASA as appropriate should be continued indefinitely.

Summary

Physicians have a vital role to play in the prevention of stroke with initiation of antithrombotic therapy for the vast majority of patients with AF/AFl. Very low-risk patients require only low-dose ASA; the rest require anticoagulation with warfarin or dabigatran at a dose of 150 mg b.i.d., the latter being the preferred anticoagulant in general. With dabigatran recently approved in Canada and the advent of other new oral anticoagulants, a new era of anticoagulation is about to be ushered in that promises to provide effective stroke prevention with little of the inconvenience and caution associated with current warfarin use. The 2010 CCS guidelines offer practical strategies for AF management and deserve careful reading.