Table 1:

Summary of landmark randomized controlled trials in which treatments significantly reduced all-cause mortality

Study Cochrane bias risk * Run in Multi-centre Industry funded § Inclusion criteria Intervention Treatment duration Control **
Liggins and Howie 2 L N N Y Premature labour 24–36 wk Betamethasone phosphate plus betamethasone acetate 6 mg 1 d Cortisone acetate 6 mg
Guérin et al. 3 U2 N Y N Severe ARDS with ET for < 36 h Prone ventilation > 16 h/d 4 d Supine ventilation
Ramond et al. 4 L N Y N Alcoholic hepatitis on biopsy with DF > 32 or HE Prednisolone 40 mg/d for 28 d 28 d Placebo
Rivers et al. 5 L N N Y Age ≥ 18 yr, severe sepsis, septic shock or sepsis syndrome Goal-directed resuscitation for 6 h 6 h None
Sort et al. 6 U2 N Y N Age 18–80 yr, ascitic PMN > 250 Albumin 1.5 g/kg day 1, 1.0 g/kg day 3 3 d None
Herbrecht et al. 7 H(2,3) N Y Y Immunocompromised, definite or likely invasive aspergillosis Voriconazole 4–6 mg/kg/d 12 wk Amphotericin B 1–1.5 mg/kg
de Gans and van de Beek 8 L N Y Y Suspected meningitis Dexamethasone 10 mg IV every 6 h 4 d Placebo
Hypothermia after Cardiac Arrest Study Group 9 U3 N Y Y Witnessed cardiac arrest from VF or VT, ROSC within 60 min Hypothermia 32–34°C for 1 d 1 d Normothermia
García-Pagán et al. 10 H(2,3) N Y N Cirrhosis, acute variceal bleeding, treatment with EGD and VA drugs TIPS within 72 h Endoscopic treatment
Williams-Johnson et al. 11 L N Y Y Trauma, hemorrhage (or risk of such) Tranexamic acid 1 g IV bolus, over 8 h 8 h Placebo
CONSENSUS Trial Study Group 12 L N Y Y CHF, NYHA 4 Enalapril 2.5–20 mg twice daily Placebo
Finfer et al. 13 U3 N Y N Admitted to ICU for anticipated > 3 d Target glucose 4.5 to 6.0 mmol/L 4.2 d Target glucose ≤ 10 mmol/L
Rose et al. 14 U3 N Y Y CHF, NYHA 4, low peak oxygen consumption and a contraindication to transplantation Left ventricular assist device None
Malmberg et al. 15 H(1,2) N Y N Acute MI, treated diabetes or random glucose > 11.1 mmol/L IV insulin every 24 h, then subsequently 4 times/d ≥ 3 min “Conventional therapy”
Chen et al. 16 L N Y Y ST changes or LBBB within 24 h of symptoms Clopidogrel 75 mg/d plus ASA 162 mg/d 15 d ASA 162 mg/d
Pitt et al. 17 L N Y Y LVEF < 35, NYHA 3–4 Spironolactone 25–50 mg/d Placebo
Echt et al. 18 U1 Y Y N MI last 2 years, ≥ 6 PVC/h, LVEF < 55%, response to treatment Encainide or flecainide Placebo
MERIT-HF Study Group 19 L Y Y Y CHF and NYHA ≥ 2, LVEF < 40% Metoprolol XL 12.5–200 mg/d Placebo
Moss et al. 20 U2 N Y N Prior MI, LVEF < 30 ICD None
Chimowitz et al. 21 L N Y Y Age ≥ 40 yr, TIA or stroke from 50%–99% ICA stenosis, Rankin score ≤ 3 Warfarin INR 2–3 ASA 1300 mg/d
Bardy et al. 22 U2 N Y Y Age ≥ 18 yr, NYHA 2–3 CHF, LVEF < 35% Shock only, single-lead ICD None
Yusuf et al. 23 L Y Y Y CHF, LVEF < 35% Enalapril 2.5–10 mg twice daily Placebo
β-Blocker Heart Attack Trial 24 L N Y Y Age 30–69 yr, acute MI Propranolol 40–80 mg 3 times/d Placebo
Pfeffer et al. 25 L Y Y Y Age 21–80 yr, LVEF < 40%, 3–16 d post-MI Captopril 6.25–25 mg 3 times/d Placebo
Wallentin et al. 26 L N Y Y ACS presenting within 24-h onset Ticagrelor 90 mg twice daily Clopidogrel 75 mg/d
Farkouh et al. 27 H(2,3) N Y Y Diabetes, > 70% stenosis in ≥ 2 major epicardial vessels CABG PCI
Granger et al. 28 L N Y Y (Atrial fibrillation or atrial flutter) + (age ≥ 75 yr or previous stroke or TIA or systemic embolism or CHF or diabetes or hypertension) Apixaban 5 mg twice daily Warfarin INR 2–3
Yusuf et al. 29 L Y Y Y Age > 55 yr, CAD, stroke, PVD or diabetes, and (hypertension, increased total cholesterol, low HDL, cigarette smoking or microalbuminuria) Ramipril 10 mg/d Placebo
Gerstein et al. 30 U2 N Y Y Age 40–79 yr, type 2 diabetes and HbA 1C > 7.5%, high risk Intensive treatment targeting HbA 1C < 6% Treatment targeting HbA 1C 7%–7.9%
Ridker et al. 31 U3 Y Y Y LDL < 3.4, HS-CRP > 2 mg/L Rosuvastatin 20 mg/d Placebo
Davies et al. 32 U2 N Y Y Early breast cancer, tamoxifen 5 yr, disease-free Tamoxifen 5 yr None
  • Note: ACS = acute coronary syndrome, ARDS = adult respiratory distress syndrome, ASA = acetylsalicylic acid, CABG = coronary artery bypass graft, CAD = coronary artery disease, CHF = congestive heart failure, DF = discriminant function (an algorithm to risk stratify severity of alcoholic hepatitis), EGD = esophagogastroduodenoscopy, ET = endotracheal tube, HDL = high-density lipoprotein, HE = hepatic encephalopathy, HbA 1C = glycated hemoglobin, HS-CRP = high-sensitivity C-reactive protein, ICA = intracranial artery, ICD = implantable cardioverter-defibrillator, ICU = intensive care unit, INR = international normalized ratio, IV = intravenously, LBBB = left bundle branch block, LDL = low-density lipoprotein, LVEF = left ventricular ejection fraction, MI = myocardial infarction, N = no, NYHA = New York Heart Association Functional Classification, PVD = peripheral vascular disease, PCI = percutaneous coronary intervention, PMN = polymorphonuclear cells, PVC = premature ventricular contractions, ROSC = return of spontaneous circulation, TIA = transient ischemic attack, TIPS = transjugular intrahepatic portosystemic shunt, VA = vasoactive, VF = ventricular fibrillation, VT = ventricular tachycardia, XL = extended release, Y = yes, – = 1 procedure or surgery, ∞ = infinite or ongoing.

  • * Based on the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials 33 focusing on domains most relevant to this study (allocation concealment, double-blinding and completeness of follow-up). L = low risk, U = uncertain risk, H = high risk. 1 = no allocation concealment, 2 = no double-blinding, 3 = completeness of follow-up not cited or < 95%.

  • “Y” if study had prerandomization observation time followed by criteria necessary for randomization.

  • “Y” if patients were recruited at > 1 study site.

  • § “Y” if study cited financial support from any company.

  • Treatment for the intervention group.

  • ** Treatment for the control (or comparator) group.