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risk of death by >20%. These trials mostly enrolled patients with STEMI, making the evidence for their benefit in NSTEMI less robust. In addition, since these trials were performed, the clinical scenario has changed dramatically, with improvements in invasive strategies and associated pharmacotherapy resulting in an improved prognosis for patients with ACS.718 Modern observational studies and meta-analyses of these trials have yielded mixed results, with some studies suggesting a benefit of beta-blocker therapy irrespective of LVEF, and others reaching the opposite conclusion.557,800,802–804 There is only one small, open-label trial, CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial), that randomized 801 STEMI patients with successful PPCI and preserved LVEF to carvedilol or control.805 During a 3-year follow-up, the incidence of a composite of all-cause death, MI, hospitalization for HF, and hospitalization for ACS was not significantly different between the two groups. However, the trial was underpowered and therefore this scientific question remains open. There are four ongoing pragmatic prospective large-scale RCTs in Europe randomizing ACS patients without reduced LVEF to beta-blocker or control: REBOOT-CNIC (TREatment With Beta-blockers After myOcardial Infarction withOut Reduced Ejection fracTion), 8468 ACS patients with LVEF >40%; REDUCE-SWEDEHEART (Evaluation of Decreased Usage of Betablockers After Myocardial Infarction in the SWEDEHEART Registry), 5000 ACS patients with LVEF ≥50% (NCT03278509); BETAMI (BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function), 10 000 ACS patients with LVEF >40%; and DANBLOCK (Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction), 3570 ACS patients with LVEF >40%.806–808 The duration of beta-blocker therapy after uncomplicated ACS is also another controversial topic. There are some observational studies suggesting that the clinical benefit of beta-blocker therapy is restricted to the first year after the index ACS event, but the non-randomized nature of the studies limits their conclusions.809 There are two ongoing large-scale RCTs testing the impact of beta-blocker withdrawal after 6–12 months following uncomplicated ACS in patients with preserved LVEF: AβYSS (Beta Blocker Interruption After Uncomplicated Myocardial Infarction; NCT03498066) and SMART-DECISION (Long-term Beta-blocker Therapy After Acute Myocardial Infarction; NCT04769362).810

13.3.4 Nitrates and calcium channel blockers

Intravenous nitrates may be useful during the acute phase in STEMI patients with hypertension or HF, provided there is no hypotension or RV infarction. In the ISIS-4 (Fourth International Study of Infarct Survival) trial, oral nitrates had no survival benefit in MI patients.811 Their use is therefore restricted to the control of residual angina, as recommended in the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.195 Calcium channel blocker use was not associated with prognostic benefit in a systematic review including 28 trials.812 Calcium channel blocker use can be considered in the context of residual angina and for blood pressure control as recommended in the 2021 ESC Guidelines on CVD prevention and the 2019 ESC Guidelines for the diagnosis and management of CCS.195,646

13.3.5 Renin–angiotensin–aldosterone system

inhibitors Angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to improve outcomes in post-MI patients with additional conditions, such as clinical HF and/or LVEF ≤40%, diabetes, CKD, and/or hypertension.813–817 A systematic overview of (old) trials of ACE inhibition early in STEMI showed that their use is associated with a small but significant reduction in 30-day mortality, especially in anterior MIs.818

In the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, valsartan was found to be non-inferior to captopril in patients with a recent MI plus HF and/or LVEF ≤40%.819 There is established evidence that patients with heart failure with reduced ejection fraction (HFrEF), regardless of aetiology, benefit from ACE inhibitors.820–823 Angiotensin receptor/neprilysin inhibitors (ARNI) have been shown to be superior to ACE inhibitors in patients with established HF (of different aetiologies) and LVEF ≤40%.824 However, in the more recent PARADISE-MI (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI), a dedicated study in patients with recent ACS (1–7 days) complicated by HF and/or LVEF ≤40%, an ARNI combination (sacubitril plus valsartan) was not associated with a significantly lower incidence of death from CV causes or incident HF in comparison to the active comparator ramipril.825 In general, ACE inhibitors (or sacubitril plus valsartan as a replacement for them) are recommended for patients with established HFrEF regardless of the aetiology.557 These agents may be considered for patients with HF with mildly reduced ejection fraction.557 Patients who tolerate neither ACE inhibitors nor ARNI are recommended to be treated with an angiotensin receptor blocker. In the Eplerenone Post-AMI Heart failure Efficacy and SUrvival Study (EPHESUS), the mineralocorticoid receptor antagonist (MRA) eplerenone was associated with reduced mortality and CV hospitalizations in patients with a recent MI and LV dysfunction with symptoms of either HF or diabetes.826 The Double-Blind, Randomized, Placebo-Controlled Trial Evaluating The Safety And Efficacy Of Early Treatment With Eplerenone In Patients With Acute Myocardial Infarction (REMINDER) trial randomized 1012 patients with acute STEMI without HF to eplerenone or placebo within 24 h of symptom onset.827 The primary endpoint was the composite of CV mortality, rehospitalization, or extended initial hospital stay due to diagnosis of HF, sustained VT or VF, ejection fraction ≤40%, or elevated BNP/NT-pro BNP at 1 month or more after randomization. Eplerenone was associated with a significant reduction in the primary composite endpoint, although this difference was primarily driven by BNP levels.827

13.3.6 Medications for diabetes

13.3.6.1. Sodium–glucose co-transporter 2 inhibitors Pharmacological blockade of SGLT2 induces glycosuria with lowering of plasma glucose levels, improving glycaemic control without hypoglycaemia, and leading to reductions in weight and blood pressure.828 In patients with type 2 diabetes and established ASCVD, three trials (with empagliflozin, canagliflozin, and dapagliflozin) have demonstrated significant CV benefits.656,829,830 In a meta-analysis of these three trials, MACE were reduced by 11%, with no clear effect on stroke or MI. This benefit was only seen in patients with established ASCVD.698 The benefits of SGLT2 inhibitors may relate more to cardio-renal haemodynamic effects than to atherosclerosis.646 Further recommendations for patients with diabetes can be found in the current ESC Guidelines on diabetes, pre-diabetes,and cardiovascular diseases.831 In patients with HF regardless of their LVEF, dapagliflozin and empagliflozin have been shown to significantly reduce the risk of worsening HF or CV death, both in the presence or absence of type 2 Downloaded from academic.oup.com/eurheartj/article/44/38/3720/7243210 by guest on 07 October 2026