The cumulative evidence base informing almost every aspect of myocardial infarction acute coronary syndrome care (ACS) is expansive and has been associated with a decline in the rate of mortality. Within the context of current-era clinical trials of ST-segment elevation myocardial infarction, 30-day mortality rates of 4–5% have now been reported for high-risk individuals ^1,2 with similar rates reported among the non-ST-segment elevation ACS populations.^3,4 However, large observational studies still report substantially higher rates of in-hospital death than those observed in these studies^.5,6 Furthermore, recent clinical trials with novel treatment approaches have not provided further reductions in mortality or recurrent ischemic outcomes and have seen a shift in focus toward improved alternate outcomes such as bleeding.^7,8 Have we reached a ceiling in mortality reduction with modern pharmacological and invasive approaches? Do we need to look beyond the questions of therapeutic innovation to provide further reductions in mortality from myocardial infarction?

While early clinical studies evaluating the efficacy of aspirin, reperfusion therapy, and angiotensin-converting enzyme inhibition demonstrated the substantial clinical benefits of these agents in terms of mortality, more modest reductions in events observed in recent trials have led to a greater reliance on non-fatal clinical events and composite end-points. For example, placebo-controlled studies of fibrinolysis and percutaneous coronary intervention (PCI) provided approximately 5% absolute risk reductions in 30-day death, while more recent attempts to refine approaches to reperfusion with bolus fibrinolytic agents and improved anti-platelet and anti-thrombin therapies have not led to mortality reductions. Also, attempts to couple a fibrinolytic and emergent PCI within a facilitated PCI strategy have not been associated with further reductions in mortality despite the hope for both earlier and more sustained reperfusion. The ASSENT-4 (Assessment of the Safety and Efficacy of a New Thrombolytic Agent) study randomized 1,667 patients to receive tenecteplase or tenecteplase and emergent PCI. Patients randomized to receive tenecteplase and emergent PCI experienced greater in-hospital mortality than those receiving tenecteplase alone (6% versus 3%; p=0.0105), with associated higher rates of intracerebral bleeding, re-infarction, and urgent revascularization.⁴ More novel approaches aimed at reducing mortality following myocardial infarction such as suppressing the inflammatory response via the compliment pathway have also failed to reduce mortality. In the APEX (Assessment of Pexelizumab in Acute Myocardial Infarction) study of 5,745 patients, those randomized to pexelizumab had no benefit for 30-day death (pexelizumab 4.06% versus placebo 3.92%; p=not significant).²

Similar observations can be made in the trials in non-ST-elevation ACS. While trials of invasive versus conservative approaches suggest overall benefits of an early invasive approach, these benefits are largely in terms of reducing recurrent ischemia or myocardial infarction, rather than death. Furthermore, these benefits have not been consistently seen in all studies. Attempts to extend the benefit of the invasive strategy to patients with occluded arteries without symptoms of angina in the Open Artery Theory (OAT) study demonstrated no benefit in terms of reduced mortality (fouryear mortality: PCI 9.1% versus conservative 9.4%; p=not significant) and a trend for an excess in recurrent myocardial infarction (PCI 6.9% versus 5.0%; p=0.08).⁹ Likewise, refinement of percutaneous revascularization in acute infarction with drug-eluting stents has been associated with reduced rates of repeat revascularization, but no reduction in mortality, and more recent registry data suggest an increase in late mortality with the broader implementation of this technology.10 Consequently, at least in the nearterm, it is unlikely that mortality from myocardial infarction will be further substantially reduced by innovations in pharmacological or device therapy.

However, opportunities for the reduction of morbidity and mortality from myocardial infarction remain. Several registries spanning US and European clinical practice have documented the incomplete application of evidencebased therapies among patients presenting with acute coronary syndromes.¹¹ Observations from these registries demonstrate an association between the application of clinical guidelines-advocated therapies and improved survival. At a hospital level, observations among 64,775 patients drawn from 350 US centers showed that higher rates of adherence to guidelines correlated with lower rates of in-hospital mortality.5 At the patient level, a clear gradient of increasing mortality risk can be observed among patients with acute coronary syndromes discharged on fewer evidence-based secondary prevention therapies. In a study of 1,385 patients, being discharged on all guidelines-advocated therapies was associated with a 10-fold lower risk of mortality by six months compared with the risk in those discharged on none (odds ratio (OR) 0.10, 95% confidence interval (CI) 0.03–0.42; p<0.0001).¹²