According to the current practice guideline in United States, dabigatran has been recommended for use as a secondary prevention of stroke in patients who are treated for non-valvular AF. Several studies showed dabigatran to be more effective compared to warfarin, however, the bleeding events associated with 110 and 150 mg dabigatran have seldom been previously studied through meta-analyses.
Dabigatran etexilate is a reversible competitive antagonist of thrombin [10, 11]. Thrombin works by converting fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and further increasing thrombin production via the activation of factors V and VIII. It also activates platelets in order to initiate several cellular processes.
According to the European (EU) label, a 150 mg dabigatran dosage should be considered the standard or preferred dosage, and should be recommended to all corresponding patients with non-valvular AF, except for those patients who are aged > 80 years, patients who have increased risks of bleeding indicated by a HAS-BLED score of more than 3, and those who are being treated with verapamil at baseline [12]. However, even if a drug to drug interaction has been observed with P-glycoprotein inhibitor verapamil and dabigatran etexilate, whereby the former increased the bioavailability of the latter, this interaction could probably be minimized if verapamil is administered 2-h post dabigatran [13].
Results of this analysis showed that both dosages of dabigatran were associated with similar rates of major and fatal bleeding. However, minor bleeding significantly favored a low dose of dabigatran. Moreover, results for stroke and systemic embolism were not statistically significant. Also, this current result showed a high dose of dabigatran to be associated with a significantly lower mortality rate in these patients who were treated for AF. In addition, when data from observational studies were excluded, 110 mg dabigatran was associated with a significantly lower rate of major and minor bleeding, extracranial bleeding and GI bleeding.
Similar to this analysis, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed a constant rate of several clinical outcomes between these two different dosage regimens of dabigatran. However, a 150 mg dosage was more effective, while a 110 mg dosage was associated with lower major bleeding [14]. Moreover, intracerebral hemorrhage was lower in both groups. Another sub-study from the RE-LY trial showed a higher dose of dabigatran (150 mg) to be associated with significantly fewer strokes while 110 mg dabigatran was associated with a significantly lower rate of major bleeding. But however, these dose regimens were compared to warfarin [15].
In contrast to the current results which showed a higher dosage of dabigatran to significantly reduce mortality compared to a lower dosage, the RE-LY and RE-LY ABLE trials showed a similar mortality rate associated with the different doses of dabigatran [14]. 150 mg dabigatran was associated with a mortality rate of 3.43% and 110 mg dabigatran was associated with 3.55% death per annum. However, it should be noted that in these trials, the follow-up periods were longer, up to 6.7 years, which was not the case in the current analysis. In addition, the fact that 150 mg dabigatran reduced mortality rate by up to 12% whereas 110 mg dabigatran reduced mortality by only 9% when compared to warfarin should also not be ignored [16, 17].
Several other factors should also be considered prior to the use of dabigatran. For example, renal impairment could be a concern in these patients. Research has shown renal impairment to increase the risk of stroke and bleeding in patients with AF. The RELY trial which demonstrated 150 mg dabigatran to be superior compared to warfarin in the prevention of stroke and 110 mg dabigatran to significantly reduce the risk of bleeding among 18,113 patients with non-valvular AF, excluded approximately 80% of patients with renal impairment [18]. It would be worth to know that when these outcomes were investigated in relation to the renal function/impairment, both dosages of dabigatran were consistent. However, when the Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations were considered, 110 and 150 mg dabigatran significantly showed a decline in major bleeding rate among patients with glomerular filtration rate greater than 80 mL/min [19]. In addition, the CHADS2 score which is significantly better in predicting ischemic stroke and thromboembolism should also be taken into consideration prior to the selection of an oral anticoagulation therapy for these patients with non-valvular AF [20]. Also, dabigatran use is contraindicated if concomitantly used with other oral anticoagulants, as well as with systemic ketoconazole, cyclosporine, itraconazole, tacrolimus and dronedarone.
This current analysis compared bleeding events and other adverse clinical outcomes which were associated with 110 mg versus 150 mg dabigatran respectively. In terms of anticoagulants, studies showed dabigatran to be an alternative cost-saving drug, compared to warfarin [21]. However, because only a few studies comparing the different dosage of dabigatran in patients with AF have been published, further research is recommended to completely solve this issue.
Novelty
This analysis is new in several ways. It is among the first meta-analyses comparing bleeding events associated with a low (110 mg) versus a high (150 mg) dose of dabigatran. Since several hospitals still use warfarin, and because research assessing the efficacy and safety of dabigatran is still limited, several interests and concerns would be raised about the application of dabigatran which is available in two different dosages. Will a low dose result in an increased risk of stroke? Or will a high dose result in a high risk of bleeding in patients who are suffering from AF? This analysis is expected to partly provide answers to these questions. However, further research is required to confirm these answers.
Limitations
Several limitations should be considered in this analysis. First of all, due to a small number of patients which was analyzed, this analysis might not generate robust results. Moreover, an increased level of heterogeneity was observed when analyzing GI bleeding, major bleeding and stroke, and this could be another limitation of this analysis. Several adverse outcomes such as intra-ocular bleeding, pericardial bleeding and so on, were not analyzed since they were reported only in one study. At least two studies were required for comparison. Furthermore, the follow up period was ignored in this analysis, and this might have had an impact on the outcomes and the number of events which occurred, indirectly affecting the results which were obtained.