Table 1

A summary of the key randomised controlled trials of RAAS modulating drugs in the field of heart failure

StudyTreatmentControlKey inclusion criteriaKey findings
1987CONSENSUSEnalaprilPlaceboEF<35%, NYHA class IVA significant reduction in all-cause mortality and cardiac mortality, significant decrease in NYHA class
1991SOLVD-TEnalaprilPlaceboEF<35%, ∼90% NYHA class II–IIIA significant reduction in all-cause mortality with a significant reduction in a combined outcome of death or hospitalisation
1992SOLVD-PEnalaprilPlaceboEF<35%, NYHA class I–II, not on any medications for heart failureA significant reduction in the combined outcome of all-cause mortality or heart failure hospitalisation
1999CIBIS IIBisoprololPlaceboEF<35%, NYHA class III–IVSignificant reduction in all-cause mortality, significantly fewer sudden cardiac deaths
1999RALESSpironolactonePlaceboEF<35%, NYHA class III–IV, on an ACE inhibitorsSignificant reduction in cardiovascular and all-cause mortality as well as hospitalisation and NYHA class. Significantly more gynaecomastia, no significant increase in the occurrence of serious hyperkalaemia
2000MERIT-HFMetoprololPlaceboEF<40%, NYHA class II–IVSignificant decrease in all-cause mortality, sudden deaths and deaths from worsening heart failure
2001VALHEFTValsartan and ACE inhibitorsPlaceboEF<40%, NYHA class II–IV, >92% also on an ACE inhibitorSignificant decrease in cardiovascular hospitalisation, no significant decrease in all-cause or cardiovascular mortality
2002COPERNICUSCarvedilolPlaceboEF<25%, symptoms of heart failure at rest or on minimal exertionSignificantly reduced the rate of death and hospitalisation, patients reported feeling better via a patient global assessment
2003CHARM-ADDEDCandesartan and ACE inhibitorsPlaceboEF<35%, NYHA class II–IV, >98.8% on an ACE inhibitorSignificant reduction in a combined outcome of heart failure admission and cardiovascular death, no significant decrease in all-cause mortality of cardiovascular mortality
2003CHARM-ALTERNATIVECandesartanPlaceboEF<40%, NYHA class II–IV, intolerant to ACE inhibitorsSignificant reduction in cardiovascular death or hospital admission, significant reduction in heart failure hospitalisation and cardiovascular mortality. No significant reduction in all-cause mortality
2003EPHESUSEplerenonePlaceboEF<40%, patients post-MI with signs of heart failure or diabetesSignificant reduction in cardiovascular and all-cause mortality as well as hospitalisation. Significantly more hyperkalaemia but less hypokalaemia
2011EMPHASIS-HFEplerenonePlaceboEF<35%, NYHA class IIStopped early after 21 months. Significant reduction in cardiovascular and all-cause mortality as well as hospitalisation. Significantly more hyperkalaemia
2014PARADIGM-HFSacubitril-valsartanEnalaprilEF<35%, NYHA class II–IVSignificant reduction in all-cause mortality, significant reduction in combined cardiovascular deaths or first hospitalisation. No significant increase in angiooedema
  • EF, ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; RAAS, renin-angiotensin-aldosterone system.