Evidence Continues to Support Dabigatran Treatment in A-fib

LOS ANGELES, CAIn the treatment of patients with atrial fibrillation (A-fib), warfarin alternatives like dabigatran seem to hold the key to successful treatment, according to a study presented November 7, 2012, at the American Heart Association Scientific Sessions. Another presentation in the same session showed that vitamin K antagonists are poorly controlled in the majority of A-fib patients, a phenomenon associated with worse outcomes.

Dabigatran is Reliable

In the noninferiority RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial (Connolly SJ, et al. NEJM. 2009;361:1139-1151), researchers compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin in 18,113 patients at risk of stroke from nonvalvular A-fib. After a median follow-up of 2 years, both doses of dabigatran proved noninferior to warfarin with regard to the primary endpoint of stroke or systemic embolism, with the higher dose showing superiority over warfarin.

For the RELY-ABLE study, Stuart J. Connolly, MD, of McMaster University (Hamilton, Canada), and colleagues included 5,851 patients who completed the RE-LY study and were still taking dabigatran. These patients continued dabigatran 110 mg (n = 2,914) or 150 mg (n = 2,937) for a mean of 2.3 years.

Patients treated with both doses of dabigatran had low rates of stroke and major bleeding. Both doses were associated with low rates of hemorrhagic stroke, though dabigatran 150 mg had a lower rate of ischemic stroke and a higher relative rate of major bleeding. Both doses had similar mortality rates (table 1).

Table 1. Clinical Outcomes

 

Dabigatran 150 mg

Dabigatran 110 mg

HR (95% CI)

All Stroke
Ischemic
Hemorrhagic

1.24%
1.15%
0.13%

1.38%
1.24%
0.14%

0.89 (0.66-1.21)
0.92 (0.67-1.27)
0.89 (0.34-2.30)

MI

0.69%

0.72%

0.96 (0.63-1.45)

Major Bleeding

3.74%

2.99%

1.26 (1.04-1.53)

Total Mortality

3.10%

3.02%

0.97 (0.80-1.19)


Poor Warfarin Control Common, Catastrophic

In another presentation, Ajay K. Kakkar, MD, of the Thrombosis Research Institute (London, United Kingdom), described the findings from cohort 1 of the GARFIELD registry. The study was designed to eventually include 55,000 patients with newly diagnosed nonvalvular A-fib plus 1 additional risk factor in 5 cohorts from more than 1,000 randomly selected sites in 235 countries. Cohort 1 included 10,537 consecutive patients enrolled at 543 sites in 19 countries from December 2009 to October 2011.

After a mean of 11.9 months follow-up, patients on warfarin (n = 5,724) had lower rates of death (1.7% vs. 2.9%) and stroke (1.1% vs. 1.5%), but higher rates of major bleeding (0.8% vs. 0.4%) compared with those not treated with vitamin K antagonists (n = 4,247).

As predicted, patients with more risk factors had higher rates of death, major bleeding, and stroke compared with those who had minimal risk factors.

Importantly, a high proportion of patients were not properly controlled on warfarin (< 60% in therapeutic range; n = 2,657), and these patients had higher rates of adverse events (table 2).

Table 2. Adverse Events by Warfarin Control

 

Time in Therapeutic Range ≥ 60%
(n = 2,009)

Time in Therapeutic Range < 60%
(n = 2,657)

Control Unknown
(n = 1,058)

Stroke

0.9%

1.3%

0.8%

Major Bleeding

0.5%

1.00%

0.5%

Death

0.9%

1.7%

3.4%


“Mortality represents the greatest burden early in the natural history of . . . atrial fibrillation,” Dr. Kakkar concluded. “But the burden of stroke and death increases with an increasing number of risk factors in this population. . . . Anticoagulation is poorly controlled in the majority of patients who receive a vitamin K antagonist and the poor anticoagulation control is associated with substantially worse outcomes for stroke, bleeding, and death compared with patients who are anticoagulated and well-controlled.”

The Real World is ‘Messy’

Discussant Robert P. Giugliano, MD, SM, of Brigham and Women’s Hospital (Boston, MA), said that while the information that can potentially come out of the GARFIELD registry will be valuable, “these data are really an interim report.” However, he said he looks forward to seeing what might be discovered in the future, and the data give weight to the importance of maintaining proper warfarin control.

As for RELY-ABLE, Dr. Giugliano disagreed with the title of the study, claiming that due to the inclusion criteria, the trial was not randomized like the authors claimed in the original RE-LY study. “This introduces a form of informative censoring and it really un-does the randomization so therefore I would consider this an observational study, more like a registry” he said, adding that P values and hazard ratios should not be used.

Overall, Dr. Giugliano said that while observational trials complement randomized studies, “I have this real unease about this unbridled enthusiasm, this irrational exuberance for ‘real-world’ experience, because the real world is pretty complicated and quite messy.”


Sources:
1. Connolly SJ. Randomized comparison of the effects of two doses of dabigatran etexilate on clinical outcomes over 4.3 years: Results of the Rely-able double-blind randomized trial. Presented at: American Heart Association Scientific Sessions; November 7, 2012; Los Angeles, CA.

2. Kakkar AK. Antithrombotic treatments and associated outcomes in patients with atrial fibrillation: The global anticoagulant registry in the field (GARFIELD). Presented at: American Heart Association Scientific Sessions; November 7, 2012; Los Angeles, CA.

 

 

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Evidence Continues to Support Dabigatran Treatment in A-fib

LOS ANGELES, CA—In the treatment of patients with atrial fibrillation (A fib), warfarin alternatives like dabigatran seem to hold the key to successful treatment, according to a study presented November 7, 2012, at the American Heart Association Scientific Sessions. Another
Disclosures
  • Dr. Connolly reports serving as a consultant to and receiving research support and honoraria from Boehringer Ingelheim.
  • Dr. Kakkar reports receiving research support from Bayer HealthCare.
  • Dr. Giugliano reports receiving research support from and serving as a consultant to Amgen and Merck, and receiving honoraria from Merck.

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