Applying evidence-based antiplatelet therapy in patients following a myocardial infarction without percutaneous coronary revascularization

This editorial refers to ‘Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54’†, by R.H.M. Furtado et al., on page 1625. The optimal oral antithrombotic strategy for secondary prevention in patients with chronic coronary syndromes has become a murky quagmire. This clinical challenge has developed based on several factors including multiple clinically available antithrombotic agents, with various antithrombotic strategies, patient populations, and endpoints assessed in each clinical trial. Although it is understandable that broader enrolment criteria enhance study feasibility, there is growing evidence that mixing patients with recent myocardial infarctions (MIs) and those with stable ischaemic heart disease receiving percutaneous coronary intervention (PCI) adds to the clinician’s challenge of interpreting the ‘optimal’ antithrombotic strategy and the ideal duration of therapy. Patients with a prior MI not receiving revascularization have been studied less frequently but represent a large important population of chronic coronary syndromes. In this issue of the European Heart Journal, Furtado and colleagues review the subgroup of patients with a recent MI that have not undergone stenting (medical management) enrolled within 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.1 In brief, the PEGASUS-TIMI 54 trial enrolled patients with a spontaneous MI in the previous 1–3 years at increased risk of an ischaemic event and without high-risk bleeding characteristics. The cohort of medically managed patients not receiving intracoronary stenting represented one-fifth of the patients enrolled. These patients were more likely to have had a non-ST-segment elevation myocardial infarction (NSTEMI) qualifying event and had increased age (2 years older) and increased comorbidities including diabetes (7% higher), heart failure (2% higher), and chronic kidney disease (9% higher). Additionally, geographic variation exists in this subgroup, with nearly 60% enrolled in Eastern Europe or Asia, while in those receiving a stent >50% were enrolled in Western Europe or North America. Although coronary angiography was not mandated for enrolment (potentially under-represented), these subjects had substantially lower incidence of documented multivessel disease compared with those receiving a stent (30% vs. 67%). Additionally, 15% of those not receiving a stent had undergone a prior PCI in the form of balloon angioplasty. The ischaemic event rate in medical management patients was noticeably increased compared with stented patients, with a near doubling of the rate of major adverse cardiac events (MACE) and near tripling of the risk of cardiovascular (CV) and all-cause death. After adjusting for the baseline differences in the two patient cohorts there remained a 40% higher risk of MACE [adjusted hazard ratio (aHR) 1.41, 95% confidence intervals (CI) 1.15–1.73], 2.4 times higher risk of CV death (aHR 2.41, 95% CI 1.76–3.30), and a two-fold higher all-cause death (aHR 2.03, 95% CI 1.57–2.62), while there was no difference in TIMI major bleeding (aHR 0.85, 95% CI 0.40–1.81) or combined TIMI major and minor bleeding (aHR 1.14, 95% CI 0.61–2.12). Although the adjustments applied in this analysis were appropriate, we must remember that it is impossible to adjust for all potential known and unknown confounders, especially when the population under consideration includes vast geography with patients enrolled from across the globe. One specific confounder for consideration and reflection is the impact of socioeconomic variables and various international healthcare systems that are undefined in this analysis and may have contributed to patient outcomes. Suggested duration of antiplatelet therapy with ticagrelor and aspirin (ASA) in myocardial infarction patients without intracoronary stenting. Patients with myocardial infarction without percutaneous coronary stenting are at increased risk of recurrent ischaemic events compared with those receiving a stent. Although these medical management patients are a diverse population and clinicians need to assess the ischaemic and bleeding risk, for many the risk of recurrent ischaemic events is substantially increased compared with life-threatening or fatal bleeding events. A portion of these patients are cognitively impaired or have poor quality or anticipated quantity of life, and may justify abbreviated ticagrelor and ASA prior to converting to antiplatelet monotherapy (dark red bar) which is similar to high-bleeding risk patients where ASA monotherapy would be applied after a period of ticagrelor or alternatively clopidogrel-based dual antiplatelet therapy (DAPT) (light red bar). A significant group of patients warrant a ‘standard’ 12 months of DAPT after the index event prior to antiplatelet monotherapy (green bar). Finally, the group studied in PEGASUS-TIMI 54 who were managed medically without a stent were shown to have favourable outcomes when treated with ticagrelor and ASA compared with ASA alone for up to 6 years. In prior MI patients enrolled in PEGASUS-TIMI 54, medical management patients had consistent risk reduction relative to the overall study population, demonstrating a benefit of ticagrelor (pooled 90 mg or 60 mg twice daily) plus aspirin compared with aspirin alone. Although the benefit was homogenous in relative terms, the markedly increased absolute risk in the medical management cohort is associated with larger absolute benefits. Put in perspective, in post-MI patients not receiving a stent, approximately one MACE would be prevented for every 47 patients treated associated with one increased TIMI major bleed occurring in every 112 treated. Although not contiguous populations, it is interesting to note that a subgroup analysis from the Study of Platelet inhibition and Patient Outcomes (PLATO) demonstrated similar findings in NSTEMI patients treated with ticagrelor plus aspirin compared with aspirin and clopidogrel over the first year.2 Specifically, in a subgroup analysis from the PLATO study, NSTEMI patients not receiving revascularization were older with more comorbid medical conditions, and were approximately twice as likely to suffer a MACE event during follow-up. Again, although the relative benefit was homogenous to the overall trial results, the absolute benefit was increased relative to the higher absolute risk in the subgroup of patients not receiving revascularization. The benefit of revascularization may be debated in stable ischaemic heart disease patients but the evidence in MI supports revascularization in the majority of patients, which is outlined by the European Society of Cardiology Acute Coronary Syndrome guidelines.3 , 4 Although clinicians in countries without barriers (including financial) to cardiac catheterization may believe that the majority of MI patients receive revascularization and therefore the current discussion applies only to a small proportion of patients in their practice, observational data from comprehensive registries prove otherwise. An analysis of all patients (n = 25 921 over 6 years) with MI from a universally funded healthcare system in North America demonstrates that one-third (34%) are indeed managed medically without revascularization.5 As would be anticipated, medical management without stenting is employed more frequently in NSTEMI (45%), although it is not rare even in ST-segment elevation myocardial infarction patients (18%). Approximately half of medically managed patients had undergone cardiac catheterization, demonstrating that access to a catheterization laboratory is not the only rationale for not implanting intracoronary stents. Consistent with the publication by Furtado and colleagues,1 ‘real-world’ medically managed post-MI patients were older (>15 years older) with increased comorbid medical conditions. From the current analysis, it is not possible to determine the clinical rationale for not conducting contemporary PCI with stent implantation within PEGASUS-TIMI 54. The trial’s exclusion criteria and the local conscientious study investigators combine to ensure that patients with significant cognitive impairment or known life-limiting comorbidities were not enrolled, although both factors may influence post-MI revascularization decisions. The geographic variability raises the possibility of socioeconomic influences, which is supported by the utilization of balloon angioplasty without stent implantation in 15% of these patients—a strategy which is rarely employed for clinical reasons alone. This begs the question of whether other evidence-based therapies may influence patients’ long-term outcomes, such as application of optimal medical therapy and heart-healthy practices including cardiac rehabilitation. In patients that had received coronary angiography, the clinical rationale for not completing revascularization could vary from the extremes of coronary artery disease including absence of clinically significant coronary stenosis (MINOCA; myocardial infarction in the absence of coronary artery disease) to severe three-vessel coronary artery disease not amenable to PCI or coronary artery bypass graft (CABG). The current analysis expands our knowledge regarding the treatment of chronic coronary syndrome patients not receiving revascularization following an MI. The results are in contrast to the TRILOGY trial that failed to show improved outcomes with intensified antiplatelet therapy in medically managed patients treated with prasugrel and aspirin compared with clopidogrel and aspirin from the index event until ∼15 months.6 Although not directly comparable, the aforementioned results from the subgroups of medically managed patients in PLATO and currently in PEGASUS-TIMI 54 suggest that ticagrelor plus aspirin is effective in these patients. The other antithrombotic therapy worthy of consideration in this population of medically managed patients post-MI is the combination of rivaroxaban 2.5 mg twice daily with low-dose aspirin, although there has not been a publication directly assessing the population of patients with prior MI without revascularization. In the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial, nearly 70% of patients enrolled with coronary artery disease had suffered a prior MI on average 7 years earlier.7 Rivaroxaban 2.5 mg twice daily plus aspirin compared with aspirin alone reduced ischaemic events by 26% (MACE; HR 0.74, 95% CI 0.65–0.86). Future research may address two different lines of investigation. One should be focused on further improving safety with prolonged ticagrelor monotherapy which may preserve the ischaemic benefit shown in the current analysis while further decreasing bleeding (supported by recent publications).8 The other consideration would be to combine two predictable antithrombotic agents—rivaroxaban 2.5 mg and ticagrelor 60 mg twice daily (potentially in a combination pill)—to further enhance ischaemic event reduction. How should a practising medical professional apply the results of the current analysis to their daily practice? First, we must acknowledge that many patients following an MI are managed without stent implantation (between 1/5 and 1/3 of all MIs); these patients tend to be complex with multiple comorbidities, and their outcomes are substantially worst than for those receiving revascularization. Secondly, this population’s risk of recurrent MACE is substantially increased while their risk of major bleeding events appears similar to those receiving a stent, at least in the context of a clinical trial. Thirdly, the relative benefit of ticagrelor plus aspirin compared with aspirin alone was consistent with the main trial results, resulting in a larger absolute risk reduction in this population that have increased residual risk. Accordingly, clinicians should review their chronic coronary syndrome patients focused on assessing the risk of recurrent ischaemic events and apply appropriate evidence-based antithrombotic strategies in those without high-risk bleeding characteristics.