Medicare-Based Studies Tackle Dabigatran GI, ICH, Major Bleeding Issues

November 03, 2014

PITTSBURGH, PA and SILVER SPRING, MD — Two new studies provide more data on the bleeding risks among patients with atrial fibrillation (AF) treated with dabigatran (Pradaxa, Boehringer Ingelheim), with one showing that the novel oral anticoagulant carries a significantly higher risk of major bleeding, as well as gastrointestinal bleeding, when compared with warfarin.

In the first report, published in JAMA: Internal Medicine, Dr Inmaculada Hernandez (University of Pittsburgh, PA) and colleagues report that dabigatran was associated with a 30% greater risk of any bleeding event, a 58% greater risk of major bleeding, and an 85% greater risk of gastrointestinal bleeding vs warfarin among patients who initiated anticoagulant therapy following a new diagnosis of AF[1].

In the second analysis, which was published October 30, 2014 in Circulation, there was no increased risk of major bleeding with dabigatran, but the direct-thrombin inhibitor was associated with a 28% greater risk of gastrointestinal hemorrhage[2].

"The levels of risk were similar in direction and magnitude with those observed in the randomized trial RE-LY, where dabigatran 150-mg twice daily was compared with adjusted-dose warfarin therapy," according to Dr David Graham (Food and Drug Administration, Silver Spring, MD), the lead author of the Circulation report.

In both analyses, treatment with dabigatran was associated with a significantly lower risk of intracranial hemorrhage, a reduction of about 65% compared with warfarin.

Clarifying the Bleeding Risks with Dabigatran

Dr Yuting Zhang (University of Pittsburgh), the senior investigator of the report published in JAMA: Internal Medicine, spoke with heartwire and said the main motivation for the analysis, which included 1302 dabigatran-treated patients and 8102 warfarin users, stemmed partly from previous reports suggesting a higher risk of bleeding with the agent and another suggesting those concerns might be unneeded.

"There was an earlier report from last year indicating there was no major difference in bleeding between warfarin and dabigatran, but that study didn't really adjust for patient characteristics," Zhang told heartwire . "But now we have Medicare data, which is nationally representative data, and we wanted to look in the real-world practice setting to see if there were any bleeding differences between dabigatran users after we adjusted for patient differences."

That earlier report, which was based on an analysis of the US Food and Drug Administration's Mini-Sentinel database and was reported by heartwire , showed there was no difference in rates of gastrointestinal bleeding and intracranial hemorrhage among dabigatran users compared with warfarin-treated patients. As noted at the time, the FDA review had limitations, as it was based on inpatient diagnosis codes, did not adjust for confounding variables, and did not include a detailed medical record review.

In the analysis by Hernandez, Zhang, and colleagues, they looked at a 5% random sample of Medicare beneficiaries in 2010 and 2011 from the Centers for Medicare and Medicaid Services (CMS). After adjustment for baseline characteristics using propensity-score weighting, the adjusted incidence of major bleeding was 9.0% in the dabigatran users vs 5.9% in the warfarin group. Intracranial bleeding was significantly lower with dabigatran.

Adjusted Incidence of Bleeding by Treatment

Severity of bleeding and bleeding site Warfarin, n=8102 (%) Dabigatran, n=1302 (%) P
Any bleeds 26.5 32.7 <0.001
Major bleeding 5.9 9.0 <0.001
Intracranial bleeding 1.8 0.6 <0.001
Gastrointestinal bleeding 10.0 17.4 <0.001
Hematuria 8.8 12.0 <0.001
Vaginal bleeding 0.3 0.7 0.003
Hemarthrosis 0.2 0.5 0.007
Hemoptysis 1.4 2.0 0.03

Older patients (>75 years) were at a higher risk of bleeding compared with younger patients, as were those with chronic kidney disease. Compared with white patients, black individuals treated with dabigatran also had a significant higher risk of bleeding.

Association Among Bleeding Events, Treatment, and Age

Variable Hazard ratio for major bleeding (95% CI) Hazard ratio for any bleeding (95% CI)
Dabigatran vs warfarin overall 1.58 (1.36–1.83) 1.30 (1.20–1.41)
65 to 74 y vs <65 y 0.77 (0.56–1.04) 0.94 (0.81–1.09)
75 y vs <65 years 1.48 (1.12–1.96) 1.01 (0.88–1.17)
Black vs white patients 2.09 (1.68–2.60) 1.16 (1.01–1.34)
Chronic kidney disease 1.55 (1.32–1.82) 1.11 (1.02–1.21)

To heartwire , Zhang said other reports have suggested that dabigatran is associated with a higher risk of gastrointestinal bleeding compared with warfarin users. The present study represents a newly diagnosed cohort, patients who haven't been exposed to any anticoagulant for AF. The study did not separate bleeding risk by dosage, mainly because there were few patients treated with the 75-mg dose.

As for the clinical implications, Zhang said that physicians should be aware of their patient's baseline risk for bleeding, such as those who are older or those with chronic kidney disease. "But all physicians do need to balance stroke prevention and the risk of bleeding," said Zhang. "The higher dose of dabigatran has been shown to be better in terms of preventing stroke. So it's trade-off, but there should be monitoring of those patients treated with 150 mg."

She added that the analysis includes patients treated with the drug in 2010 and 2011, just after dabigatran was approved. Given that it's been on the market for a few years, Zhang said she expects future analyses to show a lower real-world incidence of bleeding as physicians get better at selecting appropriate patients and in managing the bleeding risks.

Another FDA Study

The study led by Graham and colleagues from the Food and Drug Administration and CMS also included cohorts of propensity-matched elderly patients enrolled in Medicare. All patients were treated with dabigatran or warfarin for nonvalvular AF between 2010 and 2012. In total, there were more 67 000 new users of dabigatran and 273 920 new users of warfarin.

Among 67 207 propensity-matched individuals, dabigatran use was associated with a significantly lower risk of ischemic stroke, intracranial hemorrhage, and mortality. The adjusted hazard ratios were 0.80, 0.34, and 0.86, respectively. There was a significant 28% higher risk of gastrointestinal bleeding with dabigatran, but there was no observed risk of major bleeding. There was also no difference in MI events between the two treatments.

In a subgroup analysis, men 85 years of age or older and women 75 years of age or older had a significantly increased risk of major gastrointestinal bleeding with dabigatran. The researchers did not observe a higher risk of bleeding among patients with chronic kidney disease or among those using prescription antiplatelet drugs.

Among the 16% of patients treated the 75-mg dose of dabigatran, none of clinical-end-point comparisons against warfarin were significantly different. With the 75-mg twice daily dose, however, there remained a significantly lower risk of intracranial hemorrhage compared with warfarin, report Graham et al.

Hernandez, Zhang, and colleagues report they have no financially relevant relationships. Graham et al report they have no financially relevant relationships.

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