The bleeding costs of intensive vs. less intensive antithrombotic strategies: a meta-regression analysis

AIMS: Antithrombotic therapy is a cornerstone of secondary prevention of atherosclerotic cardiovascular disease (ASCVD). The main drawback of antithrombotic therapy is the associated bleeding risk. The correlation between the magnitude of antithrombotic efficacy and the severity of bleeding risk remains unclear, rendering the comparative evaluation of antithrombotic regimens based on their therapeutic advantages and risks challenging. This study aims to establish a benchmark for evaluating the trade-off between ASCVD prevention and bleeding risk through a systematic analysis of extant trial data. METHODS AND RESULTS: Meta-regression analysis. We searched PubMed and Embase and extracted trials comparing antithrombotic treatments in patients with established ASCVD. We extracted data on major adverse cardiovascular events (MACE) reduction and bleeding events. A weighted generalized additive regression was used for data analysis. Our analysis included 50 studies, comprising a total of 357 711 patients with coronary artery disease (63%), cerebrovascular events (28%), and peripheral arterial disease (15%). Overall, ASCVD event reduction by intensification of antithrombotic therapy correlates with an increased risk of intracranial haemorrhage. Also, the reduction in the composite of acute coronary syndrome and stroke is associated with an increased risk of fatal haemorrhage. When regimens not routinely used in current practice are excluded, the increased risk of intracranial haemorrhage with intensified antithrombotic treatment is attenuated to non-significant, but ASCVD event reduction still correlates with an increased risk in fatal haemorrhage. The analyses and figures we present can serve as a benchmark to compare results of future trials on antithrombotic regimens for ASCVD to other (contemporary) regimens. CONCLUSION: With currently used antithrombotic regimens, ASCVD event reduction by more intensive treatment no longer increases risk of intracranial bleeding. Fatal haemorrhage remains a seemingly inevitable cost of ASCVD reduction by antithrombotic treatment intensification, albeit at low absolute risks.