Medical management: the dark side of acute coronary syndromes

In this issue of European Heart Journal Cardiovascular Pharmacology a substudy of the Italian EYESHOT Registry focused on medically managed patients is published.1 In it, the authors describe the antithrombotic therapy employed in hospital in the roughly 30% of patients with acute coronary syndromes (ACS) who did not undergo coronary revascularization during index hospitalization, that is, who were medically managed. Guidelines recommend an invasive strategy for a majority of patients with ACS.2–5 However, still a substantial proportion of ACS patients are currently medically managed,6,7 as shown again in this 2585 patient cohort study. This is particularly true for patients with non-ST-segment elevation ACS (NSTEACS) in whom the rate of medical management (MM) was more than three times higher than for ST-segment elevation myocardial infarction (STEMI) patients (42.7 vs. 12.6%). The reasons for MM are varied (Figure 1). The first reason is the decision not to send the patient for coronary angiography. That would be expected in low-risk patients, in whom coronary angiography is not initially recommended. However, the current study shows that patients who did not undergo coronary angiography were older, had a greater cardiovascular burden, presented more comorbidities, and developed more complications in hospital. These findings are consistent with several other registries from all over the world.6,8–12 What is the reason for this risk paradox? It is understandable that MM may be preferred in a minority of patients, such as those of very advanced age with dementia or severe dependence, or those with heavy comorbidity, particularly with severe renal dysfunction or malignancy at an advanced stage in whom prognosis, risk, or quality of life may be conditioned by non-cardiac conditions. And this is, in fact, part of the picture in this study. However, the most important determinant of MM is the lack of a catheterization laboratory in the hospital, something that is not related to the patient’s risk. It is a shame that in the era in which networks for STEMI care have become the standard of care, high-risk patients with NSTEACS are not transferred to centres with catheterization laboratory for reasons different from potential futility or patient preference. Unfortunately, the current study shows again that having a catheterization laboratory in hospital remains the main determinant of receiving coronary angiography in these patients as in the past years.8,11,13 Moreover, the majority of independent predictors of not receiving coronary angiography during hospitalization and of not undergoing coronary revascularization after coronary angiography are known to be associated with a worse prognosis. In addition to the evidences from clinical trials,14 several studies have shown that medical management is an independent predictor of an increased long-term mortality risk in real life.11,15,16 For this reason, there is an obvious need to improve compliance with guidelines, particularly in NSTEACS patients, and advance in reinforcing the use of risk stratification and effective hospital networking for non-emergent transfers, which currently show a highly variable pattern.17 Reasons for and average frequencies of medical management for patients presenting with non-ST-segment elevation acute coronary syndromes. ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, significant coronary artery disease; CAG, coronary angiography; PCI, percutaneous coronary intervention; Revasc, coronary revascularization. There is large room for improvement in risk stratification and putting into practice risk-driven therapies for ACS patients. While overcoming the risk paradox for NSTEACS patients has revealed to be a Herculean labour in the last years, a second approach to reduce the disadvantage of medically managed patients was attempted. The TRILOGY-ACS trial tested the intensification of dual antiplatelet therapy with prasugrel instead of clopidogrel for a median follow-up of 17 months in 9326 medically managed NSTEACS patients to reduce cardiovascular outcomes. Contrary to what might have been expected according to observations from subgroups of the CURE and PLATO trials comparing clopidogrel with placebo18 and ticagrelor with clopidogrel,19,20 respectively, on top of aspirin, increasing antiplatelet potency with prasugrel failed to show a beneficial effect in medically managed patients as it did not translate into any significant benefit.21 Interestingly, patients who underwent coronary angiography did seem to have some benefit with prasugrel compared with those who did not.22 The EYESHOT registry found that medically managed patients not only did not undergo coronary revascularization but received a different antithrombotic therapy during hospitalization compared with those who were revascularized, including a higher use of low molecular weight heparin and lower use of newer P2Y12 inhibitors, prasugrel and ticagrelor, as recommended by current guidelines. However, baseline risk differences instead of treatment most likely explain the large increase in hospital mortality found in these patients. Post-discharge events may have been influenced by the different treatment. Unfortunately, follow-up results were not provided in EYESHOT. Although there are basically no exceptions to prioritizing reperfusion therapy in the early treatment of STEMI, and this is universally accepted, that is not the case for patients with NSTEACS in whom a risk paradox for an invasive strategy is frequently found. The high short- and long-term event rate of medically managed patients pinpoints the clinical challenge. For this reason, there are a number of urgent needs to improve the management of these patients. First, to understand better the key factors leading physicians to decide to not indicate an invasive strategy for moderate- to high-risk patients and/or, later on, coronary revascularization in those with severe coronary artery disease. Second, to develop better tools to identify which patients would benefit from an invasive strategy even in the case of advanced age or important comorbidity or, alternatively, those who will not. Current information about the benefit/risk ratios in NSTEACS patients in whom decisions are difficult to be made is very limited. We need to define the role of advanced age, geriatric syndromes23—frailty in particular24—and severe comorbidity25 in clinical decision-making. The development of risk models to identify patients unlikely to benefit from an invasive strategy, as done for other interventions,26 will also facilitate defining the high-risk patients in whom medical management may be the preferred option in terms of risk improvement. Multicentre randomized controlled trials enrolling older patients,27 and patients with comorbidities, especially those with moderate to advanced renal dysfunction are challenging but strongly needed. Third, more research is needed on effective interventions to optimize patient care and facilitate changing practices to avoid patients with potential gain being deprived of the opportunity of coronary revascularization. Finally, although it is very unlikely that a good drug therapy may overcome the consequences of a wrong strategy, there will be a substantial proportion of patients with NSTEACS who will receive medical management for different reasons, appropriately or inappropriately. Defining the optimal medical therapy for these patients, including antithrombotic therapies and other drugs with different mechanisms, is still an unmet need. The high short- and long-term event rate of medically managed patients with ACS, the uncertainties about the reasons for the risk paradox in selecting an invasive strategy, the chronic difficulties to correct this anomaly, and the shortness of evidences about the best treatment for these patients explain why medical management can be defined as the dark side of ACS.