OBJECTIVES: Treatment with renin–angiotensin–aldosterone system inhibitors (RAASi) in patients with heart failure (HF) is established clinical practice to reduce the incidence of adverse cardiovascular (CV) events, hospitalisations, and mortality. However, many patients discontinue RAASi due to the increased risk of hyperkalaemia. A systematic review (SR) was conducted to confirm whether: i) there are long-term clinical benefits for patients with HF treated with RAASi; ii) RAASi affects disease progression of HF, and iii) discontinuation/down-titration of RAASi affects patients’ long-term CV health. METHODS: Electronic databases (Medline, Embase, Cochrane) were interrogated to identify randomised controlled trials (RCTs) published between 1998 and January 2019. Eligible RCTs were those that included RAASi-treated adults with HF reporting long-term measures of clinical benefit (CV events, hospitalisation, and mortality) and measures of disease progression (changes in left ventricular ejection fraction [LVEF] and New York Heart Association [NYHA] class). RESULTS: Of the 12,761 publications screened, 42 RCTs reported the clinical benefits of RAASi and 17 RCTs measured disease progression following treatment. RAASi statistically significantly reduced the long-term endpoints ‘all-cause mortality’ (4/7 studies), ‘CV-mortality’ (4/7 studies; 6/7 reported a risk reduction), and ‘HF hospitalisation’ (7/8 studies) versus placebo. For measures of disease progression following treatment, RAASi statistically significantly increased LVEF (5/6 studies) and improved NYHA class (5/8 studies) versus placebo. No RCTs examined long-term outcomes following discontinuation or down-titration of RAASi; however, 8 RCTs reported the clinical effects of varied doses of RAASi. Low-dose RAASi significantly increased the risk of composite endpoints ‘CV mortality or HF hospitalisation’ (3/3 studies) and ‘all-cause mortality and all-cause hospitalisation’ (3/4 studies) compared with higher doses. CONCLUSIONS: This SR provides evidence that RAASi treatment confers long term clinical benefit and delays disease progression in patients with HF. Further RCT evidence would continue to develop our understanding on the long-term outcomes of discontinuing/down-titrating RAASi therapies.