Vitamin K Independent Anticoagulants: The Next Chapter in Atrial Fibrillation Stroke Prevention

Atrial fibrillation (AF), the most common cardiac arrhythmia, affects more than 3 million people in the United States and 3–5% of people over 65. The prevalence of AF continues to increase, and projections forecast the number afflicted with AF to increase to 15 million by 2050.¹ Although AF can affect quality of life and cardiac status, the largest risk is thromboembolic stroke. Compared to those in normal sinus rhythm, the risk of stroke is at least fivefold.² Much of this risk can be negated with the use of anticoagulants such as warfarin. However, warfarin is often troublesome for patients secondary to vacillating INR values, frequent INR checks, dietary restrictions, and interactions with other medications.

Also, the incidence of AF increases with age, so many elderly patients are not considered anticoagulation candidates secondary to risks of fall and intracranial hemorrhage. It is suggested that the number of patients not anticoagulated for AF is as high as 50%.³ With such a large population of unprotected patients with AF, alternative treatment strategies such as newer anticoagulants have been well received, and left atrial appendage (LAA) protection devices are also intensely being evaluated.

Dabigatran (Boehringer Ingelheim), a newer anticoagulant recently approved, is a renally cleared direct thrombin inhibitor with a half-life of 16-17 hours with effect within 30 minutes to 2 hours of administration. Drug interactions with dabigatran only include rifampin. RE-LY (The Randomized Evaluation of Long-term Anticoagulation) was a noninferiority study randomizing over 18,000 patients with stroke risk factors (average CHADS2 score of 2.1) to fixed doses of dabigatran of either 110 or 150 mg versus adjusted-dose warfarin.⁴ Approximately 20% of patients included in this trial had a prior stroke or transient ischemic attack. Patients excluded were those with severe heart valve disorder, recent stroke, creatinine clearance

It was found that the 110 mg dose of dabigatran had similar rates of stroke and systemic embolism compared to warfarin (3.02% vs. 3.3%) with lower events of major hemorrhage (5.35% vs. 6.17%). In comparison, the 150 mg dose was superior to warfarin in terms of stroke and systemic embolism (2.2% vs. 3.3%, NNT = 91) but was no different in rates of major hemorrhage (6.17% vs. 6.59%). Although bleeding was similar, 150 mg of dabigatran showed significantly less intracranial bleeding but increased gastrointestinal bleeding in subgroup analysis. Interestingly, there was a trend toward decreased all-cause mortality with dabigatran.⁴

One major caveat of the trial was that the discontinuation rate of either dose of dabigatran at 1 year and 2 years was approximately 15% and 20%, respectively, compared to 10% and 17% with warfarin. The majority of the discontinuation rate was due to the increased incidence of dyspepsia. Although the trial reported increased events of myocardial infarction with dabigatran, further analysis did not support this trend. Hepatotoxicity, which was the undoing of ximelagatran, the first oral direct thrombin inhibitor, was not an issue with dabigatran.⁴

Dabigatran has been priced at $6.75 per day, which by a cost-effectiveness analysis shows it to be comparable to warfarin.⁵ The FDA has approved only the 150 mg dose; patients with renal dysfunction, as defined as a creatinine clearance of 15–30 ml/min, can take a reduced dose of 75 mg bid. Assuming normal renal function, holding two doses of dabigatran will allow for clearance of the drug, and would allow patients to proceed with elective surgery. There is no antidote for dabigatran besides withholding the drug and trying supportive measures. However, if bleeding issues still persist, dialysis can be considered as the drug is dialyzable.

For cardiologists and electrophysiologists, dabigatran could be revolutionary, as many years have passed since a new approved treatment option for stroke prevention and AF has come to fruition. Anticoagulation clinics and genotype testing for warfarin resistance will become more obsolete.

Potential Applications Awaiting Clinical Evidence

Besides stroke prevention in patients with AF, other potential areas of increased use will likely be post AF ablation and post cardioversion. In terms of AF ablation, low-risk patients are routinely anticoagulated for three months post ablation. Currently physicians are performing ablations on patients with an INR >2, or bridging them with enoxaparin post ablation. Dabigatran may make enoxaparin bridging obsolete and the post-ablation process much simpler for patients. Similarly, for many patients who require cardioversion with a subtherapeutic INR, dabigatran administration followed by transesophageal echocardiogram will allow patients to proceed with cardioversion without enoxaparin or heparin bridging. Although dabigatran seems poised to be the next blockbuster drug, a few flaws may still exist. These include the bid dosing schedule, the ever-present bleeding risk, and the gastrointestinal side effects.

Rivaroxaban (Bayer Schering Pharma AG) is a once daily dosing medicine that likely will also be added to our armamentarium of anticoagulants. Rivaroxaban, a factor Xa inhibitor, was shown to be noninferior to warfarin with respect to stroke and non-central nervous system embolism in the ROCKET AF (Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial presented at the 2010 American Heart Association annual meeting. Like dabigatran, total bleeding rates were similar to warfarin and there was significantly less fatal bleeding and intracranial hemorrhage.6 Although superiority over warfarin was not met on an intention to treat analysis, it was superior on an on treatment analysis. Debate over this point continues, but a once daily drug noninferior to warfarin in stroke prevention for patients with AF is on the horizon. Another factor Xa inhibitor, apixaban (Bristol-Myers Squibb and Pfizer), was shown to be more effective in preventing stroke and systemic embolism in patients with AF when compared with aspirin in the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes) trial.⁷ This was accomplished without raising the risk of bleeding as compared with aspirin. Patients in this trial were deemed unsuitable for warfarin therapy. Apixaban is a bid dosed drug, and the next hurdle will be a head-to-head comparison with warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation) trial.

Even though dabigatran has added to our treatment of AF, and given the fact that more treatment options are on the way, there still will be a portion of patients who have an intolerance to these drugs via side effects or bleeding complications. Options for these patients in the future may include Atritech’s WATCHMAN LAA Closure Device, which was studied in the PROTECT-AF trial, and AGA Medical’s Amplatzer Septal Occluder (ASO), which is currently under investigation. This is an exciting time for physicians treating patients with AF, and dabigatran is the first chain in this reaction.

References

1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–125.

2. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257–354.

3. Stafford RS, Singer DE. Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998;97:1231–1233.

4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. Epub 2009 Aug 30.

5. Freeman JV, Zhu RP, Owens DK, et al. Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation. Ann Intern Med 2010 Nov 3.

6. Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, presented at American Heart Association 2010.

7. Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, presented at the European Society of Cardiology 2010 Congress.