The prospect of a further reduction of thrombotic end points (stent thrombosis, acute coronary syndromes, ischemic stroke) may seem appealing and encouraging to clinicians, interventional cardiologists in particular. Be that as it may, are we willing to accept a further reduction in thrombotic events at the trade-off of increasing hemorrhagic risk?

Arguably, low-dose anticoagulation and antiplatelet agents with a different mechanisms of action provide improved thrombotic benefit. However, it would appear that such potent antithrombotic (anticoagulant/antiplatelet) regimens are associated with increased risk of hemorrhagic events. Increase in major bleeding events may offset ischemic benefits. Thus, where is the line between the safety and efficacy of antithrombotic therapy, and who should draw that line?

In the TRACER trial, vorapaxar was compared with placebo in 12,944 patients with non-ST-segment elevation myocardial infarction receiving standard therapy. The trial was terminated early because of safety concerns. Although vorapaxar added to standard therapy did not significantly reduce the primary composite end point (death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with hospitalization, or urgent coronary revascularization), rates of moderate and severe bleeding and intracranial hemorrhage were significantly greater in patients receiving vorapaxar. Concerns have been also reported with respect to other antiplatelet agents: prasugrel and ticagrelor.

In a recent analysis, Komocsi et al reported that the use of new oral anticoagulants (anti-Xa or direct thrombin inhibitors) after acute coronary syndromes is associated with a dramatic increase in major bleeding events. On the basis of the pooled results (7 prospective randomized placebo-controlled clinical trials involving 31,286 patients), the use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome was associated with an increase in major bleeding events (odds ratio 3.03; 95% confidence interval 2.20–4.16; p <0.001). For the net clinical benefit, treatment with new-generation oral anticoagulant agents provided no advantage over placebo (odds ratio 0.98; 95% confidence interval 0.90–1.06; p = 0.57).

We have to bear in mind that bleeding events are independently associated with a worse long-term prognosis across a wide spectrum of patients with coronary artery disease and that the risk of death progresses with increasing severity of bleeding.

When prescribing antithrombotic therapy (antiplatelet, anticoagulant, alone or in combination), we should balance its efficacy (suppression of ischemia) and safety (bleeding complications).

Therefore, it is pivotal to identify those patients at low-to-intermediate risk of bleeding (or high risk of atherothrombotic events) who will benefit most from such treatment without hemorrhagic complications.