ACEI Trials in Acute Coronary Syndrome 1. Captopril Trials name : ISIS-4 Problems : Suspected Acute MI Format : Double-blinded multi centre RCT Treatment : Oral Isosorbide Mononitrate (MR) or Oral Captopril or IV Magnesium Control : Standard therapy Population : 58050 Inclusion criteria : Within 24 h of the onset of symptoms of suspected acute MI No clear indications for, or contraindications to, any one of the study treatments The only exception was that patients who were to be given non-study nitrate for just a few days could still be entered. (Such use of non-study nitrates was recorded at randomisation to allow separate analysis of the effects of the 1-month study nitrate regimen among patients who were not, at the time of randomisation, being given non-study nitrates.) Exclusion criteria : Specified not by the protocol but by the responsible physician Suggested that caution should be taken with hypotension, cardiogenic shock, poor peripheral perfusion, or cases whether the chance of death was either very low or very high. Follow-up : 5 weeks Primary endpoint : 5-week mortality Secondary endpoint(s) : (-) Details : (-) Brief summary: Captopril shows benefit post-MI within 5 weeks, no nitrate/magnesium benefit Captopril (vs placebo) -Small but significant reduction in 5 week mortality, maintained for 1 year -Greatest advantage in high risk patients No survival benefit for ISMN or magnesium at 5 weeks ISMN well tolerated Source 1. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet. 1995 Mar 18;345(8951):669-85. PMID: 7661937. 2. Lisinopril Trials name : GISSI-3 Problem : AMI and preserved LVEF Format : Multicenter, open label, 2x2 factorial design, randomized trial Treatment : Lisinopril OR GTN (glyceryl trinitrate) (IV->PO) OR both Control : Placebo Population : 19,394 patients Inclusion criteria : Typical chest pain accompanied by ST changes, either: ->1mm ST elevation or depression in a limb leads ->2mm ST elevation or depression in a chest leads Admitted to CCU within 24h of symptom onset Exclusion criteria : Severe CHF requiring any of study drugs Killip class 4 High risk of further serious hemodynamic deterioration after treatment with vasodilators, judged by SBP <100 mmHg Contraindications to study drugs: -History of renal failure (creatinine > 2mg/dl, proteinuria >500mg/24h, or both) -History of bilateral renal artery stenosis -Documented allergy to study drug -Other life-threatening disorders Follow-up : 6 months Primary endpoint : Mortality at 6 weeks, Composite of death, CHF, LVEF 35%, 45% akinesis/dyskinesis Secondary endpoint(s) : Clinical CHF LVEF >35% >45% akinesis/dyskinesis Reinfarction Post-infarction angina CABG PTCA SBP <90 mmHg for >1 h Cardiogenic shock Renal dysfunction Stroke Details : Brief summary: Lisinopril reduced mortality within 24h of AMI. No benefit from GTN. -Lisinopril within 24h of AMI --Significantly reduced mortality @ 6w by 11% -No survival benefit from GTN -Benefits present in pre-defined high risk populations of females & those >70 years old Source : GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. Lancet. 1994 May 7;343(8906):1115-22. PMID: 7910229. ARB trials in Acute Coronary Syndrome Moreover, in patients with ACS and systolic dysfunction, treatment with ARBs was not associated with a benefit in patient outcomes compared to ACE inhibitors. Source : 1. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet. 2002;360:752–760. doi: 10.1016/S0140-6736(02)09895-1. 2. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau J-L, Køber L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–1906. doi: 10.1056/NEJMoa032292. Prior to our knowledge there are no clinical trials investigating ARBs in ACS patients with preserved left-ventricular function. Source : Tscharre, Maximilian et al. “Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?.” Cardiovascular drugs and therapy vol. 35,6 (2021): 1183-1190. doi:10.1007/s10557-020-07128-0 1. Valsartan Trials name : VALIANT Problem : Left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction Format : Randomized trial Treatment : Captopril, Valsartan, or both Control : Standard theraphy Population : 14,703 patients Inclusion criteria : Patients were eligible if they were >= 18 years of age and developed clinical or radiological signs of heart failure and/or evidence of depressed left ventricular (LV) systolic function with an ejection fraction of <40% or a reduced echocardiographic wall motion index between 12 hours and 10 days after AMI. Exclusion criteria : Cardiogenic shock and a serum creatinine concentration >2.5 mg/dL Follow-up : 3 year Primary endpoint : Cardiovascular mortality in 3 year Secondary endpoint(s) : readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest Details : Brief summary: Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received betablockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Outcomes were similar with captopril and valsartan, and combination therapy with both agents caused more adverse events without offering advantages. Source White, H. D. (2005). Mortality and Morbidity Remain High Despite Captopril and/or Valsartan Therapy in Elderly Patients With Left Ventricular Systolic Dysfunction, Heart Failure, or Both After Acute Myocardial Infarction: Results From the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation, 112(22), 3391–3399. doi:10.1161/circulationaha.105.5 2. Losartan Trials name : OPTIMAAL Problem : Acute myocardial infarction and heart failure during the acute phase or a new Q-wave anterior infarction or reinfarction Format : Multinational, double-blinded randomized trial, parallel-group study Treatment : Losartan (50 mg once daily) or captopril (50 mg three times daily) Control : Standard theraphy Population : 5477 patients Inclusion criteria : Baseline acute myocardial infarction was defined as fulfilling at least two of the following criteria: a history of typical chest pain for longer than 20 min, ST elevation on electrocardiograph, or an increase in cardiac markers to above the decision level. Acute myocardial infarction and signs or symptoms of heart failure during the acute phase as suggested by one or more of the following: treatment with diuretic or intravenous vasodilator therapy for heart failure, pulmonary rales, third heart sound, persistent sinus tachycardia (100 bpm) or radiographic evidence of pulmonary congestion. Patients with an acute myocardial infarction and an ejection fraction of less than 35% or a leftventricular enddiastolic dimension of greater than 65 mm (optional) and/or a new Q-wave anteriorwall acute myocardial infarction, or any reinfarction with previous pathological Q-waves in the anterior wall were also eligible. Exclusion criteria : supine systolic arterial blood pressure of less than 100 mm Hg at the time of randomisation, current receipt of an ACE inhibitor or angiotensin II antagonist, unstable angina, haemodynamically significant stenotic valvular heart disease, haemodynamically significant dysrhythmia, and planned coronary revascularisation Follow-up : 4 years Primary endpoint : All-cause mortality Secondary endpoint(s) : Sudden cardiac death or resuscitated, cardiac arrest, fatal or non-fatal reinfarction, fatal or non-fatal stroke Details : - Brief summary: Thereis non-significant difference in total mortality in favour of captopril, ACE inhibitors should remain first-choice treatment in patients after complicated acute myocardial infarction. Losartan cannot be generally recommended in this population. However, it was better tolerated than captopril. Source Dickstein, K., & Kjekshus, J. (2002). Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. The Lancet, 360(9335), 752–760. doi:10.1016/s0140-6736(02)09895-1 ARNI vs ACEI in ACS 1. Sacubitril/Valsartan vs Ramipril Trials name : PARADISE-MI Problem : Acute myocardial infarction 0.5-7 days with LVEF <40% and/or pulmonary congestion Format : Multinational, double-blinded, double dummy, randomized trial Treatment : Sacubitril/valsartan (target dose 97/103 mg BID) or ramipril (target 5 mg BID). Control : Standard theraphy Population : 5,661 patients Inclusion criteria : Presentation with AMI Left ventricular ejection fraction (LVEF) ≤40% with or without pulmonary congestion Plus one of the following: age ≥70 years, atrial fibrillation, estimated glomerular filtration rate (eGFR) <60, diabetes mellitus, prior MI, LVEF <30%, Killip class ≥III, ST-segment elevation MI (STEMI) without reperfusion Exclusion criteria : Prior heart failure (HF) Clinical instability eGFR <30 Follow-up : 23 months Primary endpoint : Cardiovascular (CV) death, first HF hospitalization, or outpatient HF Secondary endpoint(s) : CV death/MI/stroke, All-cause mortality, Total HF hospitalization, outpatient HF events, and CV mortality, Hypotension Details : Brief summary: The combination sacubitril/valsartan did not reduce the primary endpoint in a contemporary enriched AMI population, compared with ramipril. Source Jering KS, Claggett B, Pfeffer MA, et al. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE‐MI): design and baseline characteristics. Eur J Heart Fail 2021;Apr 12: ARNI vs ACEI in ACS 1. Sacubitril/Valsartan vs Ramipril Trials name : PARADISE-MI Problem : Acute myocardial infarction 0.5-7 days with LVEF <40% and/or pulmonary congestion Format : Multinational, double-blinded, double dummy, randomized trial Treatment : Sacubitril/valsartan (target dose 97/103 mg BID) or ramipril (target 5 mg BID). Control : Standard theraphy Population : 5,661 patients Inclusion criteria : Presentation with AMI Left ventricular ejection fraction (LVEF) ≤40% with or without pulmonary congestion Plus one of the following: age ≥70 years, atrial fibrillation, estimated glomerular filtration rate (eGFR) <60, diabetes mellitus, prior MI, LVEF <30%, Killip class ≥III, ST-segment elevation MI (STEMI) without reperfusion Exclusion criteria : Prior heart failure (HF) Clinical instability eGFR <30 Follow-up : 23 months Primary endpoint : Cardiovascular (CV) death, first HF hospitalization, or outpatient HF Secondary endpoint(s) : CV death/MI/stroke, All-cause mortality, Total HF hospitalization, outpatient HF events, and CV mortality, Hypotension Details : Brief summary: The combination sacubitril/valsartan did not reduce the primary endpoint in a contemporary enriched AMI population, compared with ramipril. Source Jering KS, Claggett B, Pfeffer MA, et al. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE‐MI): design and baseline characteristics. Eur J Heart Fail 2021;Apr 12:
