This meta-analysis showed that dabigatran was associated with increased risk for acute coronary events. Conversely, the greater likelihood for coronary events for the other oral direct thrombin inhibitor, ximelagatran, was not statistically significant. The excess risk associated with dabigatran was comparable to the findings of the earlier meta-analysis.3
Conversely, the risk for MI/ACS was lower for rivaroxaban, and a non-statistically significant reduction was observed for apixaban. Therefore, it appeared that the coronary risk differed between oral direct thrombin inhibitors and anti-Xa agents. Although the variation in the use of antiplatelet agents could have accounted for some of these differences, it was interesting to note that dabigatran was associated with a higher and rivaroxaban was associated with a lower risk for MI/ACS in clinical studies of ACS patients. Majority of them would have been treated with at least one antiplatelet agent. Therefore, based on these findings, those with heightened coronary risk, the use of anti-Xa agents may be preferable to direct thrombin inhibitors.
While both ximelagatran and low-molecular-weight heparins were able to reduce platelet activation, thrombin generation35
and endogenous thrombin potential,36
the time reduction for endogenous thrombin potential was greater for dalteparin compared with ximelagatran.36
Conversely, rivaroxaban was superior to dalteparin in preventing thrombin generation following hip and knee replacement surgery37
and reduces tissue factor induced platelet aggregation.38
In vitro studies indicated that direct thrombin inhibitors were associated with paradoxical coagulation compared with factor Xa inhibitors,39
which was likely mediated by preventing thrombin-induced activation of Protein C. This is a natural anticoagulant and part of the negative feedback system after thrombin generation. Furthermore, inflammatory markers were increased with long-term use of direct oral thrombin inhibitors.40
Urinary 11-dehydrothromboxane β2 was elevated for those receiving dabigatran compared with warfarin among 502 patients with atrial fibrillation and not treated with aspirin.41
But the preliminary results from a substudy of the RE-LY trial did not show this relationship.42
Nonetheless, taken together, the differences in thrombotic, inflammatory and platelet pathways could have accounted for some of the differences in coronary events. Furthermore, there was discordance in the main findings of SPORTIF III25
and SPORTIF V.26
Although both studies were similar in design, there were important dissimilarities. SPORTIF III25
was conducted in Europe, Asia plus Australasia and SPORTIF V26
was performed in North America. The design of the latter study26
was double-blind but SPORTIF III was an open-label trial.25
Of note, the primary endpoint, consisting of stroke and systemic embolism, was 2.3% per year for the warfarin group and 1.6% per year for the ximelagatran group in SPORTIF III.25
Conversely, it was 1.2% per year for the warfarin group and 1.6% per year for the ximelagatran group in SPORTIF V.26
There were also differences in the occurrence of major bleeding complications (A). The authors attributed the differences to better dose regulation, control of hypertension or hyperlipidaemia, other differences in patient characteristics or management or chance.26
Evaluation for a summarised risk for major bleeding complications among these studies has been challenging because of the marked variation in study protocol and endpoint definition (). Although there was little difference in major bleeding complications for the four agents when compared with control, the rates were higher for rivaroxaban32
in ACS patients, and influenced this outcome. Likely, several of these patients were receiving antiplatelet therapy, and probably treated with these two agents. Indeed, major bleeding complication rates have been noted to increase by 40–70% among those receiving aspirin plus clopidogrel in the RE-LY trial.43
Majority of these ACS patients were receiving dual antiplatelet agents. Not surprisingly, when these trials were excluded from analysis, evidence for heterogeneity was lost. Therefore, extreme caution has to be exercised when considering combining antiplatelet and antithrombotic agents because of the high bleeding risk.
Definition of major bleeding complication and use of antiplatelet agents
Despite differences in the risks for MI/ACS and major bleeding complications, all-cause mortality was lower among those treated with dabigatran, rivaroxabn and apixaban compared with control. Better survival was also observed among patients with ACS treated with oral anticoagulation. All-cause and vascular mortalities were significantly lower among those receiving moderate intensity of warfarin plus aspirin compared to aspirin alone.44
Part of the reason for lower mortality for patients treated with novel antithrombotic agents may be related to the lower rates of haemorrhagic stroke for those with atrial fibrillation.27
If this finding is real then it may supersede the shortfalls of these agents such as lack of antidote for reversal of effects and assay to determine its therapeutic efficacy.
There are several limitations in the study. Importantly, there were differences in study population, protocol and procedures. Duration of follow-up varied considerably across trials. Individual patient outcome information was also not available. Definitions of outcome measures varied considerably in the studies and there were subjective elements in adjudication, especially for bleeding complications. Furthermore, not all the outcomes were reported in every trial. Silent MI may be actively sought out for in some studies, especially after revascularisation procedures, with routine electrocardiography or cardiac enzyme assays. But this approach may not be adopted in other trials. While this difference could have accounted for variation observed among studies, it was less likely to impact on the results within a study. Another limitation was that there was only one author in the study; there may be potential bias in study appraisal and selection stages. However, this concern is mitigated somewhat by relatively small total number of trials and fairly well-defined outcome measures. Nonetheless, these findings were instructive in providing insight on the relative occurrence adverse cardiovascular events impacting on the choice of these agents in specific patient subsets requiring anticoagulation. As with any results from meta-analyses, a firm conclusion can only be drawn from well-conducted, adequately powered randomised trials.