Danish Registry: Dabigatran Safe, Effective in Real-World Use

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Treatment with the oral direct thrombin inhibitor dabigatran does not heighten the risk of either myocardial infarction (MI) or bleeding over warfarin therapy in patients with atrial fibrillation (A-fib), according to findings from a Danish post-approval study. The findings were scheduled to be published online March 26, 2013, ahead of print in the Journal of the American College of Cardiology.

In the pivotal RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, published in the New England Journal of Medicine in 2009, most bleeding measures favored dabigatran (Pradaxa; Boehringer-Ingelhiem, Ridgefield, CT) over warfarin. However, use of the novel anticoagulant at a dose of 150 mg was associated with a small but significant increase in MI in the study, and subsequent post-market reports raised concerns that bleeding might be elevated in real-world use.

Gregory Y.H. Lip, MD, of the University of Birmingham (Birmingham, United Kingdom), and colleagues used the Danish Registry of Medicinal Product Statistics to identify 4,978 anticoagulant naive patients who received dabigatran (110 mg or 150 mg twice daily) after its European approval in August 2011. They used propensity matching in a 1:2 ratio to identify 8,936 patients who received warfarin during the same time frame, with a median follow-up period of 10.5 months.

Mortality Lower with Dabigatran

The odds of stroke, systemic embolism, and major bleeding were similar between warfarin and dabigatran, irrespective of dose. Dabigatran 110 mg and 150 mg were each associated with a reduced risk of death, MI, pulmonary embolism, intracranial bleeding, and hospitalization. Gastrointestinal bleeding was lower with the 110-mg dabigatran dose vs. warfarin, but not with the 150-mg dose (table 1).

Table 1. Efficacy and Safety: Dabigatran vs. Warfarin

 

Dabigatran 110 mg
Adjusted HR (95% CI)

Dabigatran 150 mg
Adjusted HR (95% CI)

Stroke

0.73 (0.53-1.00)

1.18 (0.85-1.64)

Systemic Embolism

0.60 (0.19-1.60)

1.00 (0.26-3.35)

Death

0.79 (0.65-0.95)

0.57 (0.40-0.80)

MI

0.30 (0.18-0.49)

0.40 (0.21-0.70)

Pulmonary Embolism

0.33 (0.12-0.74)

0.24 (0.06-0.72)

Intracranial Bleeding

0.24 (0.08-0.56)

0.08 (0.01-0.40)

GI Bleeding

0.60 (0.37-0.93)

1.12 (0.67-1.83)

Major Bleeding

0.82 (0.59-1.12)

0.77 (0.51-1.13)

Hospitalization

0.53 (0.49-0.57)

0.86 (0.79-0.93)


Subgroup analysis restricted to patients receiving dabigatran for at least 1 year showed similar outcomes.

According to the paper, the Danish cohort was similar in age, gender, and stroke history to the RE-LY trial population but tended to be lower risk (mean CHADS2 score of 1.16 vs. 2.13) and had fewer comorbidities.

New Anticoagulants Should Be Used as Indicated

In an e-mail communication with TCTMD, Dr. Lip characterized the study as “reassuring,” and said it represents “everyday clinical practice.” He added that, “The initial concerns about an excess of bleeding events or myocardial infarction amongst dabigatran treated patients may be unfounded.”

Assuming that dabigatran is properly used, Dr. Lip said, there is no reason that the findings should not be generalizable to health-care systems in other regions such as the United States. He noted that a study derived from the US Food and Drug Administration’s Mini-Sentinel database, published online March 13, 2013, ahead of print in the New England Journal of Medicine provides similar reassurance about dabigatran—with no excess GI or intracranial bleeding—but did not adjust as fully for comorbidities or other possible sources of bias.

That being said, “[i]t is important to stress that we should use the new anticoagulant drugs correctly and in the appropriate patients—and monitor the renal function regularly. It is also important to consider age in relation to the choice of dabigatran dose,” he commented, adding that the 2012 focused update of the European Society of Cardiology guideline recommendations for A-fib “highlights that the novel oral anticoagulants should be used as they were studied in their respective large clinical trials.”

Dr. Lip pointed out that the introduction of so many warfarin alternatives has inspired a major shift in clinical practice by allowing for individually tailored therapy based on stroke risk scores, namely CHA2DS2-VASc. Since dabigatran was launched in Denmark, he reported, warfarin use has experienced a concurrent rise. “This positive development is most likely the result of an increased focus on identifying [A-fib] patients at high risk for stroke,” he said.

Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), explained in an interview with TCTMD that, unlike RE-LY, the current study shows both a mortality benefit and a reduction in pulmonary embolism with dabigatran. Dr. Lip et al, he said, rightfully “concluded [that] in everyday practice, not in the context of a well-funded trial where patient care is optimized, the results were essentially similar to a clinical trial, which is very reassuring.”

One question is how well warfarin patients were controlled, Dr. Ezekowitz added, reporting that the mean time in therapeutic range for RE-LY was 64%. Such data were not available from the Danish cohort, the paper notes.

Concerning dabigatran’s success in Denmark, he said, “I think dabigatran is an easy drug to use, provided you understand the pharmacology. The Danish population, physicians, and system are very sophisticated. Generally speaking, it’s one of the best health care systems in the world, and I think they obviously knew how to use the drug.”

Paired with the Mini-Sentinel results, “everything seems to be consistent here, when you look at a large database,” Dr. Ezekowitz concluded.

Note: Kim Dalton provided additional reporting for this story.

 


Source:
Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in ‘real world’ patients with atrial fibrillation: A prospective nationwide cohort study. J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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Disclosures
  • Dr. Lip reports serving as a consultant for AstraZeneca, Astrellas, and Merck and as a consultant and on the speaker’s bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi.
  • Dr. Ezekowitz reports serving as co-principal investigator for the RE-LY and X-ERT trials; receiving consulting fees, lecture fees, and grant support from Aryx Therapeutics and Boehringer-Ingelheim; consulting fees from Sanofi-Aventis; and lecture fees and grant support from Portola Pharmaceuticals.

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