Polypill Strategy for the Treatment of Patients After Acute Coronary Syndromes - A Multicenter Randomized Controlled Trial

Acute coronary syndrome (ACS) poses a major public health challenge in the United States. ACS, a constellation of acute cardiovascular conditions including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina, is a major determinant of morbidity and mortality across the United States. An American will suffer from an ACS event every 40 seconds, and ~1 million individuals have an ACS event annually. The absolute 30-day and 1-year mortality rates following an ACS event have remained high over the past several years. Myocardial infarction, a component of ACS, is one of the five most expensive admission diagnoses, with an estimated cost to the US health system of $12.1 billion annually.

The risk of major adverse cardiac events or death is high in the immediate post-ACS period. Despite effective pharmacotherapies and early revascularization, patients with ACS remain at an increased risk of post-MI complications, including recurrent ischemic events, heart failure, mechanical complications, and death in the first few weeks following the index event. The rate of major adverse cardiovascular events (MACE) is six-fold higher within the first 30 days compared with one-year post-discharge from the index MI event (41% vs. 6.4%, annualized).The 30-day risk-adjusted mortality following an ACS event in the U.S. is among the highest among developed countries, ranging from 12% (NSTEMI) to 18% (STEMI). These observations highlight the need for more aggressive implementation of evidence-based therapies in the post-ACS period.

Significant gaps exist in the optimal utilization of evidence-based therapies post-ACS. Treatment for ACS includes urgent revascularization followed by initiation of dual antiplatelet therapy (DAPT), which includes aspirin, a P2Y12 inhibitor, and a high-intensity statin. While rates of percutaneous coronary intervention (PCI) following an ACS event have increased substantially over the past two decades, utilization of evidence-based medical therapies, specifically DAPT and high-intensity statin therapy, in the post-MI period are suboptimal. Low utilization rates may reflect physician factors (such as inadequate prescribing) and/or patient factors (low adherence). Evidence from clinical registries suggests that low adherence may play the larger role, as the vast majority of post-ACS patients are prescribed DAPT and statins (>90% prescription rates). For example, in the TRANSLATE-ACS registry, a multicenter study of MI patients treated with PCI, approximately one-third of patients reported suboptimal adherence to prescribed cardiovascular medications in the first six weeks after their hospitalization. Similarly, in the multicenter ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get with the Guidelines) cohort of ~20,000 patients with ACS, the rates of non-adherence to P2Y12 and statin therapy within 90 days of the index event, assessed by the proportion of days covered (PDC), was 28% and 37%, respectively. Furthermore, non-adherence rates increase over time, reaching up to 50% by 12 months following the index ACS event.

Premature discontinuation of evidence-based therapies following an ACS event markedly increases the risk of an adverse event. Discontinuation of cardiac medications is associated with an increased risk of in-stent thrombosis, recurrent MI, and death, making optimal adherence in the subacute phase after ACS critical. For instance, among patients with an ACS event treated with a drug-eluting stent, premature discontinuation of P2Y12 inhibitor therapy is associated with a 9-fold higher risk of death. In-stent thrombosis is a severe complication with up to 45% risk of mortality, and the highest risk is within 30 days after stent placement. Discontinuing statin therapy after MI is associated with a 3-fold higher risk of death over a 1-year follow-up period.

There are important disparities in ACS outcomes by race and socioeconomic status. While the overall incidence of MI has declined over time, racial/ethnic disparities have persisted, with a higher risk of adverse outcomes among ACS patients of self-reported Black or Hispanic race/ethnicity. Black and Hispanic patients who present with ACS are younger on average and more likely to be uninsured and have less education. The risk of 30-day and 1-year mortality following an ACS event is significantly higher among patients of self-reported Black or Hispanic race/ethnicity (vs. white). In addition to racial/ethnic disparities, significant disparities in ACS outcomes have also been reported based on socioeconomic status. Specifically, individuals with low (vs. high) income or education levels and those living in socioeconomically disadvantaged neighborhoods have a higher risk of adverse outcomes following an ACS event. These disparities are driven by poor access to care, lower rates of revascularization, and less use of evidence-based therapies following an ACS.