Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial

Abstract

Aims: Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS.

Methods and results: In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event.

Conclusion: In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

Keywords: Acute coronary syndrome; Bleeding; DAPT; Myocardial infarction.

Figure 1

Distribution of minor and major bleeding and myocardial infarction in the TRACER trial. The Venn diagram shows patients experiencing minor or major bleeding (in red) and myocardial infarction (in blue). Smaller circles represent patients experiencing more than one event during follow-up. The intersection represents patients experiencing both myocardial infarction and bleeding during follow-up. MI, myocardial infarction.

Figure 2

Differential impact of myocardial infarction vs. bleeding on mortality. Blue rhombuses represent the magnitude (adjusted hazard ratio) of the impact on mortality of late myocardial infarction, whereas red rhombuses represent that of bleeding of different severity. On the right part of the figure, the estimate of the relative risk (ratio of the hazard ratios) for each category is presented. *The estimates of the impact of events on mortality is derived from Model 1, including BARC 3 bleeding as a single category. †The estimates of the impact of events on mortality is derived from Model 2, including BARC 3 bleeding subcategories separately. MI, myocardial infarction.

Figure 3

Evolution of the prognostic impact of minor and major bleeding vs. myocardial infarction over time. This figure shows the adjusted hazard ratio for mortality of myocardial infarction vs. minor (BARC 2) and major (BARC 3a–c) bleeding as a function of time elapsed after the event. Inside graph: The decline in hazard ratio as an exponential function of time in the first 30 days. Outside graph: The decline in hazard ratio for the first year after the event. Solid lines represent point estimates; dashed lines represent 95% confidence intervals. MI, myocardial infarction; BARC, Bleeding Academic Research Consortium.