In the Real World, Dabigatran and Warfarin Give Equal Stroke Protection to A-fib Patients

Out in everyday clinical practice, dabigatran 150 mg and warfarin provide comparable ischemic stroke protection for patients with nonvalvular A-fib, pooled observational data suggest. The direct thrombin inhibitor, however, comes with a lower risk for intracranial bleeding and a greater risk of GI bleeding, especially in older populations.

Although the safety outcomes are consistent with what was seen in the RE-LY trial, that study also showed the same dose of dabigatran (Pradaxa; Boehringer Ingelheim) to be superior to warfarin for ischemic stroke prevention.

“There could be many reasons for the differences in our findings, such as differences in the quality of evidence of observational studies and RCTs or differences in the included study populations between the observational studies in our review and the RE-LY trial,” study author Robert Romanelli, PhD, MPH, of the Palo Alto Medical Foundation Research Institute (Palo Alto, CA), told TCTMD in an email.

He noted that the analysis, published online today ahead of print in the March issue of Circulation: Cardiovascular Quality and Outcomes, revealed areas for future research. In the paper, the researchers note that there are limited real-world data on the lower dabigatran doses, including the 75-mg dose approved in the United States but not studied in RE-LY.

Dabigatran, the first of the novel oral anticoagulants (NOACs) to get the nod from the FDA, was approved in 2010 based on the RE-LY results, providing an alternative to warfarin that did not require frequent blood testing and dose adjustment. Since then, observational studies have given information about the relative safety and effectiveness of the 2 drugs in clinical practice.

In the current analysis, Romanelli and colleagues explored real-world outcomes by pooling data from 7 retrospective cohort studies, 5 done in the United States and 1 each in Canada and Denmark. They included a total of 348,750 patients, with 56.6% taking warfarin, 40.2% dabigatran 150 mg, and 3.2% dabigatran 110 mg. Mean follow-up was 2.2 years.

Compared with warfarin, the risk of ischemic stroke was similar with both the 150-mg dose (HR 0.92; 95% CI 0.84-1.01) and 110-mg dose of dabigatran (HR 0.92; 95% CI 0.72-1.18). The risk of intracranial bleeding, however, was lower with both the higher dose (HR 0.44; 95% CI 0.34-0.59) and lower dose (HR 0.49; 95% CI 0.34-0.72).

GI bleeding was elevated with dabigatran 150 mg (HR 1.23; 95% CI 1.01-1.50), although in an analysis broken down by age, the risk was confined to patients 75 years and older. That risk was not seen with the lower dabigatran dose.

Putting Risk in Perspective

Referring to the excess GI bleeding, David Callans, MD, of the Hospital of the University of Pennsylvania (Philadelphia, PA), commented to TCTMD that “it could be an indictment of dabigatran 150 mg, but I suspect it’s more of an indictment of physicians not being attuned to the fact that many of those patients shouldn’t have been on that dose.”

Using the lower dose could have mitigated much of that problem, he said in an interview. He and the study authors both pointed out, however, that overall event rates are low.

“In the RE-LY trial, rates of ischemic stroke, intracranial bleeding, and gastrointestinal bleeding were 1.2%, 0.74%, and 1.02%, respectively, per year in the warfarin-treated group,” the authors write. “Unadjusted absolute event rates were similarly low among warfarin-treated patients in the observational studies included in this review, but varied across studies…. Given these low event rates, even large reductions in relative risk in dabigatran-treated patients would yield small absolute reductions in risk.”

Individualization Necessary

Romanelli and colleagues tout observational studies, with less strict inclusion and exclusion criteria, for their ability to expand on the knowledge gained from RCTs, noting that patients with severe renal impairment, active liver disease, or conditions associated with high bleeding risk were excluded from RE-LY.

Callans said this real-world study “is helpful in informing physicians how to take care of lots of patients,” but is less useful for informing the care of individual patients.

If patients are well controlled on warfarin and do not mind the routine testing, he said, they are best treated with warfarin rather than one of the NOACs. On the other hand, if patients are not in therapeutic range on warfarin, have good renal function, and do not want to undergo repeat blood testing, then dabigatran is a good choice, Callans said.

Considering the similar degree of stroke protection derived from dabigatran and warfarin and the lower risk of intracranial bleeding with the newer agent, dabigatran would be preferable for many patients, even with the greater risk of GI bleeding, he added.

“Stroke is the big problem, intracranial hemorrhage is the other thing that really focuses decision making, and the rest of it … needs to be figured out but isn’t nearly as important,” he said.

Source: 
Romanelli RJ, Nolting L, Dolginsky M, et al. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2016;Epub ahead of print.

Related Stories:

• Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients
• Dabigatran Carries Higher Risk of Major Bleeds, Lower Risk of Intracranial Hemorrhage
• Danish Registry: Dabigatran Safe, Effective in Real-World Use