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Treatment–risk paradox in acute coronary syndromes

Despite the dramatic decline in mortality associated with coronary heart disease (CAD) over the past several decades in western countries, CAD still accounts for approximately one-third of all deaths in individuals over the age of 35 years. With regards to the acute manifestation of the disease, there has been a relative increase in non-ST elevation acute coronary syndromes (NSTE-ACS) in relation to ST elevation myocardial infarction (STEMI) over time. The clinical spectrum of NSTE-ACS is heterogeneous and may range from patients free of symptoms at presentation to patients with ongoing ischaemia, electrical or haemodynamic instability, or even cardiac arrest. In NSTE-ACS, quantitative assessment of ischaemic risk by means of scores appears superior to clinical assessment alone and, among the different risk scores, the Global Registry of Acute Coronary Events (GRACE) risk score provides the most accurate stratification of risk both on admission and at the time of discharge. In this issue of the European Heart Journal, Owen et al. investigate whether guideline-directed therapies and management improve survival in patients presenting with NSTE-ACS when stratified according to the GRACE risk score. They report that guideline-directed treatment was less frequently used among high-risk patients, though in this group it provided the greatest benefit, translating into a survival advantage persisting over the longer-term. In fact, the study showed that both receipt of optimal care and the proportion of care received decreased with increasing GRACE risk score category. Of note, survival benefit was also seen in those at lower risk, though this was not statistically significant. Finally, the authors clearly show that the three pillars of treatment—pharmacological therapies, invasive coronary strategies, and lifestyle interventions—all improve long-term outcomes of NSTE-ACS patients, and their beneficial effects on survival are synergistic. Among the strengths of the study, it is worth mentioning the large sample size (N > 180 000 individuals) derived from a whole-country, single-health-system, prospective observational cohort and the longterm follow-up (maximum 8.4 and median 2.3 years, respectively). Limitations of the analysis include the use of administrative audit data with possible missing or inaccurate data, and the use of only all-cause mortality instead of cardiac-specific mortality data, since non-cardiovascular deaths may not be attributable to NSTE-ACS care. Overall, this large and robust cohort study provides important insight into the so-called treatment–risk paradox: higher-risk patients are less likely to receive optimal guideline-directed therapy despite the fact that these individuals benefit the most from it (Figure 1). Certainly, evidence from prior studies also suggests that optimal guideline-directed therapies improve survival in patients with NSTEACS. One analysis reported that the combination of guideline-based medical therapies was independently and strongly associated with lower 6 month mortality in patients with NSTE-ACS. Furthermore, the absolute benefit was greater for NSTE-ACS patients at high ischaemic risk with a gradient of mortality benefit identified according to the risk score. In other words, the higher the patient’s risk, the greater the absolute and relative survival advantage from treatment. Despite documented evidence of greater benefit in high-risk individuals, a treatment–risk paradox has been reported for patients in several NSTE-ACS studies. Data from 1549 patients from the German Chest Pain Unit registry documented a substantial treatment gap in higher-risk individuals. In that study, higher-risk NSTE-ACS patients less frequently received early invasive coronary angiography and coronary interventions, despite the larger benefit expected. Accordingly, high-risk patients not undergoing an early invasive strategy had higher in-hospital as well as 4 month mortality. The elderly are a particularly vulnerable group in this regard. Despite being a high-risk group, multiple studies have consistently reported that older patients are far less likely to undergo coronary revascularization following NSTE-ACS. Data from 11 732 NSTE-ACS patients from three consecutive Canadian registries demonstrated that use of an early invasive approach was associated with a reduction in 1 year mortality across all age groups, but the absolute difference was greatest in patients aged >_ 75 years. The rate of angiography following