Improving outcomes after acute coronary events: what works and what doesn’t

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Risk assessment before and after acute coronary syndrome (ACS) is an important first step in the management of such patients.1,2 While classical risk factors such as age, blood pressure, lipids, and diabetes, as well as biomarkers, are commonly used, their predictive power at the individual level is still limited. The non-coding genome plays a key role in genetic programming, during development, and in health and cardiovascular disease. About 99% of human genes do not encode proteins but are transcriptionally active, giving rise to a broad spectrum of non-coding RNAs (ncRNAs) with regulatory and structural functions which appear to represent novel candidates to improve diagnostics and prognosis,3,4 as outlined in the review article ‘Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives’ by Wolfgang Poller and colleagues from the Charite Universitätsmedizin Berlin in Germany.5 Beyond that, ncRNAs provide new therapeutic targets currently being tested in clinical trials. New therapeutic tools were developed from endogenous ncRNAs serving as blueprints such as RNA interference-mediating drugs which mimic functions of endogenous small interfering RNAs and are versatile tools for silencing any protein-encoding or non-coding RNA target. Pioneering trials include RNA drugs targeting proprotein convertase subtilisin/kexin type 9 (PCSK9)6 or apolipoprotein(a) and resulting in highly significant lowering of LDL cholesterol or lipoprotein(a), respectively. Novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. Nitric oxide or NO is an important regulator of cardiovascular function.7 In pre-clinical models, inhalation of NO during myocardial ischaemia and after reperfusion confers cardioprotection. In their article entitled ‘Nitric oxide for inhalation in ST-elevation myocardialinfarction (NOMI): a multicentre, double-blind, randomized controlled trial’, Stefan P. Janssens and the NOMI Investigators report the results of their double-blind, placebo-controlled study on NO inhalation at a dose of 80 ppm for 4 h in 250 patients with ST-elevation myocardial infarction or STEMI.8 Overall, infarct size at 48–72 h was 18.0 ± 13.4% with NO and 19.4 ± 15.4% in controls. Subgroup analysis indicated consistency across clinical confounders of infarct size, but significant treatment interaction with nitroglycerin, resulting in smaller infarct size after NO, in nitroglycerin-naïve patients. The myocardial salvage index and left ventricular volumes were similar in both groups. Kaplan–Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with NO at 4 months and 1 year. Thus, inhalation of NO in STEMI is safe, but does not reduce infarct size. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerin warrant further studies, a perspective that is further explored in an Editorial by Borja Ibanez from Madrid, Spain.9 Another widely used small molecule in infarction is oxygen, which Robin Hofmann and colleagues tested in the DETO2X-SWEDEHEART trial report in their article ‘Oxygen therapy in ST-elevation myocardial infarction’.10 They randomized 2807 patients with suspected STEMI to receive oxygen at 6 L/min for 6–12 h or ambient air. All-cause death, rehospitalization for infarction, cardiogenic shock, or stent thrombosis at 1 year occurred in 6.3% of patients allocated to oxygen and in 7.5% allocated to ambient air. The primary composite endpoint was consistent across all subgroups, as well as at different time points, such as during hospital stay, at 30 days, and follow-up for up to 1356 days. Thus, routine use of supplemental oxygen in non-hypoxaemic patients with STEMI undergoing primary percutaneous coronary intervention (PCI) does not improve outcome and should not be routinely used. Diabetes is a known risk predictor of cardiovascular outcomes.11–13 However, the GRACE risk score, a powerful predictor of prognosis after an ACS, does not include a glucometabolic measure. In their article entitled ‘Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes’, Sudipta Chattopadhyay and colleagues from the Milton Keynes University Hospital in Buckinghamshire, UK investigated whether 2 h post-load plasma glucose would improve this risk score-based prognostic models after an ACS in patients without diabetes mellitus.14 During 41 months of follow-up, major adverse cardiac events occurred more frequently in the upper post-load plasma glucose quartiles, while fasting plasma glucose did not predict events (Figure 1). Post-load plasma glucose significantly improved prognostic models including the GRACE score. Thus, post-load, but not fasting plasma glucose is an independent predictor of adverse outcome after an ACS and improves the predictability of the GRACE score. These intriguing findings are put into context in an Editorial by Lars Ryden from the Karolinska Hospital in Stockholm, Sweden.15 The event free survival in the quartiles of 2 h post-load glucose (from Chattopadhyay S, George A, John J, Sathyapalan T. Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes. See pages 2740–2745). The event free survival in the quartiles of 2 h post-load glucose (from Chattopadhyay S, George A, John J, Sathyapalan T. Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes. See pages 2740–2745). Dual antiplatelet therapy is a crucial preventive strategy after ACS.16–18 However, while this strategy reduces ischaemic risk, it increases the risk of bleeding.19,20 Guided de-escalation of P2Y12 inhibitors may be an effective alternative strategy in ACS patients undergoing PCI. However, safety and efficacy of such a strategy may differ in relation to a patient’s age.21 In their article ‘Age and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: results from the randomized TROPICAL-ACS trial’, Dirk Sibbing and the TROPICAL-ACS Investigators assessed the impact of age on clinical outcomes following guided de-escalation of antiplatelet treatment in ACS patients.22 Patients were randomly assigned to either prasugrel for 12 months (control group) or to a guided de-escalation regimen with 1 week of prasugrel followed by 1 week of clopidogrel and platelet function testing-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge (de-escalation group). In patients ≤70 years, the 1-year incidence of cardiovascular death, myocardial infarction, stroke, or bleeding was significantly lower in the de-escalation (5.9%) than in the control group (8.3%; Figure 2). In contrast, in patients >70 years, events were higher without differences between groups. Of note, an increasing relative risk reduction was observed in the primary endpoint by decreasing age due to significant reductions in bleeding. Thus, the effectiveness of guided de-escalation for P2Y12 inhibitors depends on a patient’s age, with younger, but not elderly patients deriving a net clinical benefit. These clinically important findings are further discussed in an Editorial by Olivier Varenne from the Hôpital Cochin in Paris, France.23 Kaplan–Meier curves for the primary endpoint for the optimum cut-off for age (57 years) at 12 months follow-up. (A) Outcomes across study groups for patients ≤57 years (n = 1186). (B) Outcomes across study groups in patients >57 years (n = 1424) (from Sibbing D, Gross L, Trenk D, Jacobshagen C, Geisler T, Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Parma R, Felix SB, Neumann F-J, Hausleiter J, Baylacher M, Koltowski L, Mehilli J, Huber K, Huczek Z, Aradi D, Massberg S, on behalf of the TROPICAL-ACS Investigators. Age and outcomes following guided deescalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: results from the randomized TROPICAL-ACS trial. See pages 2749–2758). Kaplan–Meier curves for the primary endpoint for the optimum cut-off for age (57 years) at 12 months follow-up. (A) Outcomes across study groups for patients ≤57 years (n = 1186). (B) Outcomes across study groups in patients >57 years (n = 1424) (from Sibbing D, Gross L, Trenk D, Jacobshagen C, Geisler T, Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Parma R, Felix SB, Neumann F-J, Hausleiter J, Baylacher M, Koltowski L, Mehilli J, Huber K, Huczek Z, Aradi D, Massberg S, on behalf of the TROPICAL-ACS Investigators. Age and outcomes following guided deescalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: results from the randomized TROPICAL-ACS trial. See pages 2749–2758). The editors hope that readers of this issue of the European Heart Journal will find it of interest.