Canadian Update to the AF Guidelines: Role for Dabigatran Already in Place

October 27, 2010

Editor's note: On October 27, one day after this story was published, Health Canada announced it had approved dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug will be marketed as Pradax.

October 27, 2010 (Montreal, Quebec City) — The Canadian Cardiovascular Society (CCS) released new guidelines for the treatment of atrial fibrillation this week at the Canadian Cardiovascular Congress 2010, and in the soon-to-be-published document experts make specific recommendations on the use of catheter ablation, as well as new recommendations on some of the newer anticoagulant and antiarrhythmic medications.

Dr Michelle Graham

Dr Michelle Graham (University of Edmonton, AB), the chair of the CCS guidelines committee, said that the burden of atrial fibrillation continues to grow in Canada and worldwide, but the emergence of new treatments and procedures necessitated an update to the Canadian guidelines, which were last updated in 2004.

The new treatment recommendations incorporate the new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim), recently approved by the US Food and Drug Administration (FDA) for the prevention of stroke and systemic embolism in patients with atrial fibrillation, even though the drug is not yet approved in Canada. Graham told heartwire that the purpose of including dabigatran in the 2010 recommendations is to have the guidelines as current as possible, and that includes making recommendations on drugs expected to soon be in the armamentarium of practicing clinicians.

"The guidelines are very cutting edge," said Graham. "It has recommendations for drugs that are not yet approved, so those recommendations are going to be held back unless the drugs get approved. We've gone so far as to assess the drugs that have been evaluated in clinical trials, so that we actually have a position on them. If Health Canada approves the drugs before the guidelines are published, the recommendations are in. If they don't approve the drugs, then recommendations won't be included in the update. It's very contemporary."

The decision to include dabigatran in the Canadian guidelines prior to its regulatory approval stands in contrast to that of the American writing group for the recently released American Heart Association (AHA)/American Stroke Association guidelines on secondary stroke prevention, which opted not to include the new drug until it was officially approved by the FDA--it was not at the time of writing.

The GRADE System

In addition to the changes in treatment, the CCS guidelines committee has adopted a new system to evaluate the quality of clinical evidence supporting the various recommendations. Specifically, the group moves away from the American College of Cardiology (ACC)/AHA model to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, one that is currently used by the American College of Chest Physicians and World Health Organization. The approach qualifies the clinical evidence--classifying it as very low, low, moderate, or high--and rates its strength as either strong or conditional.

The Role for Dabigatran (When It's Approved)

Dr Allan Skanes

Regarding the new anticoagulant, Dr Allan Skanes (University of Western Ontario, London), chair of the atrial-fibrillation guidelines committee, noted that Health Canada has not yet made a ruling on dabigatran, but he would like to have the 150-mg and 110-mg doses available for clinicians.

"The higher dose is better than warfarin," he said. "The higher dose reduces stroke more than warfarin without an increase in bleeding. The 110-mg dose is equivalent in preventing stroke, but with fewer bleeds. So you can see a paradigm, depending on the patient's stroke and bleeding risks, where you might choose the lower dose, being equivalent in stroke prevention, while trying to reduce the risk of bleeding. In general, though, in the guidelines we're trying to recommend the higher dose for most people. The nuances in the text will try to clarify that there are certainly people for whom the lower dose is appropriate."

Specifically, the CCS atrial fibrillation writing group recommends:

  • Based on its safety and efficacy profile, dabigatran is preferred over warfarin. Overall, the 150-mg dose of dabigatran is preferred over the 110-mg dose (conditional recommendation, high-quality evidence).

  • For patients at low risk of stroke (CHADS2 score=1), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence). However, based on individual risk/benefit considerations, aspirin is a reasonable alternative (conditional recommendation, moderate-quality evidence).

  • For patients at moderate to high risk of stroke (CHADS2 >2), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence).

As previously reported by heartwire , an FDA advisory panel in September voted 9 to 0 to recommend that dabigatran be approved, and the FDA followed through on that advice October 20. The drug is available in two doses: 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily. Debates about the approved dosing are circulating (see the discussion in the heartwire forum), but the agency felt that because there were numerically more ischemic strokes with the 110-mg dose of dabigatran when compared with warfarin, and because this dose was only statistically noninferior to warfarin in terms of efficacy, they opted for a 75-mg dose for a small subset of patients unable to take the higher dose.

To heartwire , Skanes said the data supporting the use of dabigatran is strong, with high-quality evidence from the 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study.

"We've been asked, 'How can you make a strong recommendation from one trial?'" said Skanes. "Well, that single trial includes more patients than all the trials with warfarin combined, so if that's enough evidence for strength there, then we felt an argument could be made supporting the use of dabigatran. Plus, this trial isn't going to be repeated."

The Role of Catheter Ablation

In addition to incorporating dabigatran into the Canadian guidelines, the atrial-fibrillation committee also provided guidance on the use of radiofrequency catheter ablation. According to the committee, catheter ablation is recommended in patients "who remain symptomatic following adequate trials of antiarrhythmic drug therapy and in whom a rhythm-control strategy remains desired."

"If you fail an antiarrhythmic drug, we have a conditional recommendation that ablation can then be considered," said Skanes. "It's based on patients with mild to moderate heart disease, and it's pretty wide sweeping, as long as you have a reasonably normal heart, structurally, and if you fail a drug, we suggest it as an alternative. It's a conditional recommendation, moderate in its quality of evidence. The European guidelines did something very similar."

Skanes said the panel discussed whether the data were sufficient enough to make ablation a "strong" rather than "conditional" recommendation. The problem with ablation, despite its efficacy, remains the risk of the procedure. "In the future, if the complication rate became exceedingly small, or if we had improvements in hard end points--that ablation was to reduce cardiovascular hospitalizations, stroke, cardiovascular end points--then the recommendation would likely change," said Skanes.

Other Recommendations

Regarding rate- and rhythm-control strategies, the atrial-fibrillation committee recommends "liberalizing" heart-rate targets to less than 100 beats per minute in patients with persistent/permanent atrial fibrillation or atrial flutter (strong recommendation, high-quality evidence). For rhythm control, the goal of therapy should be to improve patient symptoms and clinical outcomes and not necessarily the elimination of atrial fibrillation (strong recommendation, moderate-quality evidence).

Regarding dronedarone (Multaq, Sanofi-Aventis), a first-line agent, Skanes said the newer drug is well tolerated and has a better side-effect profile than amiodarone.

Not addressed in the guidelines is the role of factor Xa inhibitors rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Bristol-Myers Squibb/Pfizer), as both are still being tested in clinical trials. Rivaroxaban is being tested for stroke prevention in the ROCKET-AF study, which is due to be reported at the AHA meeting in November, while apixaban is currently being studied in a similar trial, called ARISTOTLE, with results expected next year. Recently, data from the AVERROES study showed that patients with atrial fibrillation and unable to take warfarin who were given apixaban had a significantly lower risk of stroke and systemic embolic events compared with similar patients treated with aspirin. Of note, Bristol-Myers Squibb and Pfizer announced today that they had initiated their FDA application for apixiban's approval.

"Other drugs are around the corner, so I anticipate we're going to be doing an update to the guidelines next year to figure out what we're going to do, especially if we have more than one of these agents approved and available," said Skanes. "We've gone from one drug that's 1000 years old to boom! Rags to riches."

In addition to the updated atrial-fibrillation guidelines, the CCS also updated new guidelines on antiplatelet therapy and refractory angina, as well position statements on smoking cessation, inpatient referral to cardiac rehabilitation, and standardizing the investigational approaches for patients with syncope.