Dabigatran

Risk for Bleeding With Dabigatran vs Warfarin in Atrial Fibrillation

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TAKE-HOME MESSAGE

  • Investigators in this retrospective cohort study examined the incidence of bleeding in patients with atrial fibrillation who were treated with either dabigatran or warfarin. Compared with warfarin therapy, treatment with dabigatran was associated with a higher risk for any bleeding (HR, 1.30), major bleeding (HR, 1.58), and gastrointestinal hemorrhage (HR, 1.85).
  • In contrast, the risk for intracranial hemorrhage was lower in patients treated with dabigatran compared with those treated with warfarin (HR, 0.32).

ABSTRACT

IMPORTANCE

It remains unclear whether dabigatran etexilate mesylate is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice.

OBJECTIVE

To compare the risk of bleeding associated with dabigatran and warfarin using Medicare data.

DESIGN, SETTING, AND PARTICIPANTS

In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011.

EXPOSURES

Dabigatran users (n = 1302) and warfarin users (n = 8102).

MAIN OUTCOMES AND MEASURES

We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities.

RESULTS

Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease.

CONCLUSIONS AND RELEVANCE

Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves.

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Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year.1 Mechanical valves are more durable than bioprosthetic valves2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprostheses.

Dabigatran etexilate (dabigatran) is an oral direct thrombin inhibitor that was shown to be effective as an anticoagulant in the treatment of patients with atrial fibrillation in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.4-6 Prompted by these data and the promising results of studies in animals, which showed the efficacy of dabigatran in preventing valve thrombosis,7-9 we conducted the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). The primary aim of RE-ALIGN was to validate a new regimen for the administration of dabigatran to prevent thromboembolic complications in patients with mechanical heart valves

DISCUSSION

The primary goal of RE-ALIGN was to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves. However, the trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group, as compared with the warfarin group. Most thromboembolic events among patients in the dabigatran group occurred in population A (patients who had started a study drug within 7 days after valve surgery), with fewer occurring in population B (patients who had undergone valve implantation more than 3 months before randomization). Excess bleeding events among patients receiving dabigatran occurred in the two study populations.

Possible explanations for the increase in thromboembolic complications with dabigatran include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin. Trough plasma levels of dabigatran in population A were lower during the first few weeks after surgery than they were subsequently, and low drug levels soon after valve surgery may have allowed for early formation of blood clots that were not clinically manifested until later. However, thromboembolic events also occurred among patients with higher trough plasma levels of dabigatran early after surgery and among those in population B who had higher plasma levels than those in population A, suggesting that lower-than-expected drug levels cannot fully explain the increase in the rate of thromboembolic events.

The choice of a target trough plasma level of 50 ng of dabigatran per milliliter was primarily based on data from the RE-LY trial, in which dabigatran at a dose of 150 mg twice daily, as compared with warfarin, had superior efficacy and similar safety in patients with atrial fibrillation. We cannot exclude the possibility that targeting a higher trough level of dabigatran would have been more effective for the prevention of thromboembolic complications. At the same time, it is likely that the use of higher dabigatran doses would have led to unacceptably high bleeding rates, since dabigatran caused excess bleeding at the doses studied. It is also possible that more frequent administration of dabigatran (e.g., three times a day) without an increase in the total daily dose might have resulted in higher trough and lower peak levels, thereby increasing antithrombotic efficacy and reducing bleeding, but this approach was not tested.

Differences in the mechanisms of action of dabigatran and warfarin may also in part explain our findings. In patients with atrial fibrillation, thrombi form in the left atrial appendage under low-flow, low-shear conditions in which thrombin generation is believed to be triggered by stasis and endothelial dysfunction.19 In contrast, in patients with a mechanical heart valve, coagulation activation and thrombin generation induced by the release of tissue factor from damaged tissues during surgery may partly explain the high risk of early thromboembolic complications. In addition, thrombin generation can be triggered by exposure of the blood to the artificial surface of the valve leaflets and sewing ring, which induce activation of the contact pathway of coagulation. The majority of thrombi in patients with prosthetic heart valves appear to arise from the sewing ring,20 which does not undergo endothelialization for at least several weeks after surgery. It is thought that the sewing ring becomes less thrombogenic once endothelial tissue has formed around it. Warfarin is likely to be more effective than dabigatran at suppressing coagulation activation because it inhibits the activation of both tissue factor–induced coagulation (by inhibiting the synthesis of coagulation factor VII) and contact pathway–induced coagulation by inhibiting the synthesis of factor IX), as well as inhibiting the synthesis of factor X and thrombin in the common pathway,21 whereas dabigatran exclusively inhibits thrombin.22 If contact activation is intense, the resulting thrombin generation may overwhelm local levels of dabigatran, which can lead to thrombus formation on the surface of the valve and related embolic complications.

RE-ALIGN was an open-label trial and thus subject to reporting biases. However, clinical outcomes were prespecified, objectively defined, and independently adjudicated by experts who were unaware of the study-group assignments, all factors that minimize the potential for bias.

The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve. The results may also be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves. Like dabigatran, the direct factor Xa inhibitors are effective for stroke prevention in patients with atrial fibrillation,23,24 but these data cannot be extrapolated to patients with mechanical heart valves because the mechanisms of thrombosis are different. Rivaroxaban has been successfully tested for the prevention of thromboembolic complications associated with mechanical heart valves in preclinical studies,25 but our study did not provide evidence of the safety and efficacy of the selected dosing algorithm, despite favorable results of preclinical studies.7-9

In conclusion, the results of our phase 2 study indicate that at the doses tested, dabigatran was not as effective as warfarin for the prevention of thromboembolic complications in patients with mechanical heart valves and was associated with an increased risk of bleeding. These results might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis. The use of dabigatran has no positive value and was associated with excess risk in patients with mechanical heart valves.

 

Source: NEJM

 

Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism.

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Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. Methods In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. Results In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Conclusions Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.

Source:NEJM

Dabigatran for Extended Treatment of Venous Thromboembolism.

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In clinical trials, the drug was compared with warfarin and placebo.

After an initial course of treatment for venous thromboembolism (VTE), extended warfarin therapy lowers risk for recurrent VTE — but at the expense of excess risk for bleeding. Dabigatran (Pradaxa) now has been examined for this indication in two placebo-controlled, industry-sponsored trials.

One trial included nearly 2900 VTE patients at especially high risk for recurrence; after initial treatment (mean, 7 months), they were randomized to receive either dabigatran or warfarin. During extended treatment that averaged 16 months, the incidence of symptomatic or fatal VTE was 1.8% with dabigatran and 1.3% with warfarin, a result that met criteria for “noninferiority” of dabigatran. Major or clinically relevant bleeding was significantly less common with dabigatran than with warfarin (5.6% vs. 10.2%).

Another trial included about 1300 VTE patients at lower risk for recurrence than patients in the first trial; after initial treatment (mean, 10 months), they were randomized to receive either dabigatran or placebo. During extended treatment that averaged 5.5 months, the incidence of symptomatic or fatal VTE was significantly lower with dabigatran than with placebo (0.4% vs. 5.6%). Major or clinically relevant bleeding was significantly more common with dabigatran than with placebo (5.3% vs. 1.8%).

Comment: Dabigatran’s efficacy was similar to that of warfarin and superior to that of placebo; dabigatran caused less bleeding than warfarin but more bleeding than placebo. One worrisome observation was a small excess of adverse coronary events with dabigatran in the high-risk trial — an outcome that has been noted in previous dabigatran trials (JW Cardiol Feb 15 2012). Dabigatran has not yet been FDA approved for deep venous thrombosis treatment or prophylaxis.

Source: Journal Watch General Medicine

Studies of Extended Anticoagulant Therapies for VTE Highlight Tradeoffs.

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For the extended treatment of venous thromboembolism, the newer anticoagulants dabigatran and apixaban show advantages and disadvantages compared with older therapies, according to three studies in the New England Journal of Medicine. (Physician’s First Watch covered the apixaban study when it was published online last December.)

The dabigatran studies, conducted by the manufacturer, included patients who had completed 3 months of initial therapy and whose risks for recurrence were judged to be either at equipoise or increased.

In one study, patients were randomized to dabigatran or warfarin treatment for up to 36 months. Regarding VTE recurrence, dabigatran (1.8%) was noninferior to warfarin (1.3%), and rates of major bleeding did not differ statistically. However, acute coronary syndromes were more frequent with dabigatran (0.9% vs. 0.2%).

The other study compared dabigatran with placebo for up to 12 months. Dabigatran proved superior to placebo in preventing VTE recurrence (0.4% vs. 5.6%). Dabigatran was associated with an almost threefold increased risk for major bleeds.

An editorialist examines the tradeoffs presented by the newer therapies and urges trials that compare them directly with one another, with warfarin, and with aspirin.

Source: NEJM

 

 

Dabigatran Shouldn’t Be Used in Patients with Mechanical Heart Valves .

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Dabigatran (Pradaxa) should not be prescribed to prevent blood clots or stroke in patients with mechanical heart valves, the FDA warned.

The warning follows the termination of a European clinical trial in which patients taking dabigatran had more frequent thromboembolic events than those on warfarin. Dabigatran patients also experienced more bleeding after valve surgery.

Patients with mechanical heart valves should be transitioned from dabigatran to another anticoagulant, the FDA recommends; stopping dabigatran use suddenly can increase blood clot and stroke risk.

Source: FDA MedWatch safety alert

 

Pradaxa Does Not Pose Higher Risk for Serious Bleeding .

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New patients taking dabigatran (Pradaxa) don’t have higher rates of bleeding than those on warfarin, according to the results of an FDA investigation. Despite that reassurance, patients may ask about a story in the New York Times about the bleeding risks associated with the drug.

The findings of the agency’s safety evaluation are consistent with those from the clinical trial used to approve the drug, says the FDA. However, this may do little to reassure critics who point out that, unlike warfarin, there is no way to reverse dabigatran’s anticoagulant effects. The Times reports that the drug has been linked to over 500 deaths in the U.S.

The FDA says it will continue evaluating “multiple sources of data” as part of an ongoing safety review. In the meantime, dosing recommendations should be carefully followed to reduce the risk for bleeding, especially in patients with renal impairment.

Source: FDA MedWatch safety alert

Dabigatran Associated with Increased Bleeding During Atrial Fibrillation Ablation

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Until the effects of dabigatran use during ablation are clearer, it should be withheld for at least 24 hours before the procedure.

In warfarin recipients with therapeutic international normalized ratios (INRs), uninterrupted warfarin treatment during radiofrequency ablation for atrial fibrillation (AF) has relatively convincingly been shown to reduce both thromboembolic and bleeding events. Dabigatran is increasingly prescribed as an alternative to warfarin in patients with nonvalvular AF. However, dabigatran’s half life ranges from 12 to 14 hours and is prolonged in patients with renal insufficiency. Given the lack of an antidote to reverse its effects, the drug’s safety and efficacy during ablation are not clear.

Investigators used prospective data from a multicenter registry to compare the results of AF ablation in 145 patients taking dabigatran with the results in a matched cohort of 145 warfarin recipients with therapeutic INRs. Dabigatran was withheld on the day of surgery and restarted 3 hours after ablation; warfarin treatment was uninterrupted. The rate of major bleeding (pericardial tamponade) was 6% with dabigatran and 1% with warfarin (P=0.009). The rate of thromboembolic complications was also higher with dabigatran than with warfarin (2% vs. 0%), but this difference was not statistically significant.

Comment: These findings are by no means definitive. All of the warfarin patients had therapeutic international normalized ratios — a more realistic control group would have been a matched sample of all warfarin recipients. The optimal role of dabigatran in patients with atrial fibrillation undergoing ablation has yet to be determined. We need more data before we open the floodgates, and an editorialist describes a number of alternative strategies for anticoagulation during AF ablation. Still, this report does provide some practical guidance: Dabigatran should be discontinued before the day of the ablation, probably for at least 24 hours.

Source: Journal Watch Cardiology

Dabigatran Associated with Higher MI and ACS Risks .

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Dabigatran users face increased risks for myocardial infarction and acute coronary syndrome (ACS) relative to those on control medications or placebo, according to a meta-analysis in the Archives of Internal Medicine.

Researchers examined outcomes in some 30,000 patients from seven randomized trials of dabigatran use in various settings (e.g., stroke prophylaxis, postsurgical prophylaxis of deep venous thrombosis). Overall, dabigatran was associated with significantly higher risks than control treatment; the risks remained elevated even when short-term studies were excluded. The increase in relative risk for MI or ACS was 33%, but the authors point out that the increase in absolute risk was modest, at 0.27%.

Commentators call the results “robust” and “alarming.” A separate editorial note says the findings “deserve serious consideration” when deciding whether to use dabigatran. Both commentaries say the study emphasizes the importance of continuing scrutiny after a drug’s approval.

Source:  Archives of Internal Medicine

 

FDA Explains Why It Approved the Higher Dose of Dabigatran

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The RE-LY study that led to the FDA’s approval of dabigatran compared two different regimens of the drug — 110 or 150 mg twice daily — against warfarin. Both were noninferior to warfarin, so why didn’t the FDA approve both, giving clinicians and patients a choice?

Writing in the New England Journal of Medicine, FDA scientists explain that the 110-mg dose, while superior to both warfarin and the 150-mg dose in reducing risk for major bleeding, carried a greater risk for stroke. The higher bleeding risk with the 150-mg dose, in the FDA’s judgment, was acceptable, given “that the irreversible effects of strokes and systemic emboli have greater clinical significance than nonfatal bleeding.”

In addition, patients who suffered a bleeding event while on the higher dose were unlikely to suffer another, even when they continued taking the medication at the higher dose.

Source: NEJM perspective