Tailoring strategies to optimize ischaemic benefit vs. bleeding risk in individuals post-myocardial infarction

This editorial refers to ‘Temporal trends in bleeding events in acute myocardial infarction: insights from the SWEDEHEART registry’†, by M. Simonsson et al., on page 833. Patients presenting with myocardial infarction (MI) remain at significantly increased risk for subsequent ischaemic events and mortality,1 and benefit from optimal treatment strategies.2 Potent antiplatelet and antithrombotic therapies in conjunction with revascularization are used to minimize ischaemic risk after an MI, but such strategies are also associated with an increased risk of bleeding.3 Furthermore, risk factors for ischaemia and bleeding events such as age, female gender, clinical presentation, renal function, heart failure, etc., tend to overlap, making decision-making regarding optimal therapies difficult for clinicians.4 In this issue of the European Heart Journal,5 Simonsson et al. describe the time trends of in-hospital and out-of-hospital bleeding complications and ischaemic outcomes concurrent to the development of antithrombotic and invasive treatments for MI over the last two decades in almost all patients with MI in Sweden. The investigators report that the introduction of invasive and more potent antithrombotic treatments has been associated with an increase in bleeding events but concomitantly there has been a substantially greater reduction of ischaemic events including improved survival.5 Limitations of the analysis include the observational nature of registry data with possible unmeasured confounders, and causality assumptions should be made with caution. Furthermore, it would have been helpful to assess the associated prognostic value of ischaemic and bleeding events in this cohort. These results from a nationwide registry of the benefits of invasive and more potent antiplatelet/antithrombotic treatments, while reassuring, also open up the possibility that tailoring or optimizing the intensity and duration of antiplatelet and antithrombotic treatment to the risk of ischaemic and bleeding events in the individual patient may further improve hard clinical outcomes. An important component of post-MI therapy irrespective of revascularization is the use of dual antiplatelet therapy (DAPT).6 Since there is a trade-off between ischaemic and bleeding risks for any given DAPT regimen and duration, the use of risk scores might be useful to tailor DAPT type and duration to maximize ischaemic benefit while minimizing bleeding risks in an individual patient.7 The DAPT score developed from patients enrolled in the DAPT trial identified nine factors [age, congestive heart failure/low left ventricular ejection fraction (LVEF), vein graft stenting, MI at presentation, prior MI or percutaneous coronary intervention (PCI), diabetes, stent diameter <3 mm, smoking, and paclitaxel-eluting stent] as predictive of future ischaemic risk.8 A high-risk score (i.e. a score ≥2) selected patients with ischaemic benefit after a prolonged 30-month DAPT, with only a modest increase in bleeding risk. On the other hand, a low-risk score (<2) identified patients without ischaemic benefit from prolonging DAPT, but with a significant increase in moderate/major bleeding.8 Given lack of robust external validation, additional validation of the DAPT score is indicated particularly for less selected patients as compared with those recruited in the DAPT trial and those undergoing treatment with new-generation drug-eluting stents (DESs). The PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy (PRECISE-DAPT) study identified five factors (age, creatinine clearance, haemoglobin, white blood cell count, and prior spontaneous bleeding) as predictors of out-of-hospital bleeding in patients treated with DAPT.9 Individuals identified as being at high bleeding risk based on PRECISE-DAPT (PRECISE-DAPT score ≥25), had no ischaemic benefit with prolonged DAPT but had a remarkable bleeding burden. However, longer treatment in patients without high bleeding risk (PRECISE-DAPT score <25) was associated with significant reduction in the composite ischaemic endpoint of MI, definite stent thrombosis, stroke, and target vessel revascularization, with no increase in bleeding. Selecting a shorter than 12-month treatment duration in patients deemed at high bleeding risk upfront may therefore decrease bleeding risk, while patients at low bleeding risk might benefit from either standard (i.e. 12 months) or prolonged (i.e. >12 months) DAPT. It should be noted that none of these risk prediction models has been prospectively tested in the setting of randomized controlled studies and their value in improving patient outcomes remains speculative. A meta-analysis of extended DAPT in patients with prior MI with the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS–TIMI 54) trial and MI subgroups of studies with thienopyridines Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA), PROlonging Dual antiplatelet treatment after Grading stent-induced intimal hYperplasia study (PRODIGY), and Drug-eluting stent LATE (DES-LATE) with clopidogrel as well as Assessment by a Double Randomisation of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation 1 Year After Stenting-Interruption (ARCTIC-Interruption) and DAPT with clopidogrel or prasugrel reported that extended DAPT decreased the risk of major adverse cardiac and cerebrovascular events (MACCEs) compared with aspirin alone (6.4% vs. 7.5%; P = 0.001).10 It should be noted that while the reduction in cardiovascular mortality associated with prolonged DAPT was significant, the absolute risk reduction was small (0.3%) and there was no difference in all-cause mortality with extended therapy beyond 12 months. It seems reasonable to consider ticagrelor 60 mg b.i.d. as the agent of choice for prolonging DAPT beyond 12 months in stabilized post-MI patients at low bleeding risk based on the PEGASUS–TIMI 54 trial. It is clear that bleeding events after successful PCI for MI are independently associated with increased mortality and morbidity.11 Based on this, every effort should be made to minimize bleeding events with preferential use of radial access site, dosing and selection of P2Y12 inhibitors, and use of proton pump inhibitors (PPIs) when appropriate. Contemporary evidence also suggests considering discontinuation of P2Y12 inhibitor therapy post-MI after 6 months if the risk of bleeding is high. Of note, all bleeding events may not have similar prognostic implications. An analysis from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial reported that Bleeding Academic Research Consortium (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.12 Furthermore, intracranial and intraocular bleeding were associated with a mortality risk that was higher than for a MI. Based on totality of evidence, intensive antiplatelet and/or anticoagulant strategies may not be optimal in elderly patients with untreated or uncontrolled hypertension, in those with prior stroke and in those with significant renal or liver disease. In contrast, younger patients and patients who have undergone high-risk or complex stenting of the left main, a bifurcation or long or multiple lesions, or a thrombus-containing lesion, might benefit from prolonged use of more potent DAPT.4 Finally, it has been appropriately suggested that when a treatment decision is associated with a compromise between bleeding and ischaemic events, the endpoint of all-cause mortality can help clinicians and patients to choose the best strategy.13Figure 1 provides guidance to practising clinicians in selecting optimal antiplatelet/antithrombotic strategies in patients with MI based on available contemporary evidence. Also, patient empowerment and shared decision-making between patients and physicians are associated with better attitudes, beliefs, compliance, and outcomes, and is strongly encouraged when choosing antiplatelet and antithrombotic therapies post-MI while balancing risks vs. benefits. Strategies to increase clinican compliance with guidelines. Strategies to increase clinican compliance with guidelines. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.