Postponement of Death by Pharmacological Heart Failure Treatment: A Meta-Analysis of Randomized Clinical Trials.

Hansen, Morten Rix; Hróbjartsson, Asbjørn; Videbæk, Lars; Ennis, Zandra Nymand; Pareek, Manan; Paulsen, Niels Herluf; Broe, Martin; Olesen, Morten; Pottegård, Anton; Damkier, Per; Hallas, Jesper

BACKGROUND Outcome postponement has been proposed as an effect measure for preventive drug treatment. It describes the average delay of the investigated unwanted clinical event, achieved by taking medication. The objective was to estimate postponement of death for the following heart failure medications compared to placebo: Beta-blockers, angiotensin converting enzyme - inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARB), ARB added to ACE-inhibitors, aldosterone-antagonists, ivabradine, and renin-antagonists. METHODS We searched Medline and Embase from inception of databases until October 2017. Eligibility criteria were randomized placebo-controlled heart failure trials, including at least 1000 participants, with survival as a prespecified outcome and a minimum trial duration of 1 year. We calculated the outcome postponement by modeling the area between survival curves. This area was modeled on the basis of the hazard ratio or relative risk, the rate of mortality in the placebo group, and the trial duration. All results were standardized to a 3-year trial duration to ensure comparability between treatments. RESULTS We identified 14 eligible trials, with a total of 52,014 patients. The results in terms of postponement of all-cause mortality was: beta-blockers 43.7 days (95% confidence interval (95% CI), 20.8 - 66.5), ACE-inhibitors 41.0 days (95% CI, 18.8 - 63.3) and aldosterone-antagonists 41.3 days (95% CI, 14.3 - 68.4). CONCLUSION The modeled outcome postponement estimates reiterate ACE-inhibitors, beta-blockers, and aldosterone antagonists as the mainstay of heart failure treatment. Furthermore, ivabradine or ARB added to ACE-inhibitors results in no statistically significant gain in survival. SYSTEMATIC REVIEW REGISTRATION The systematic review was registered in PROSPERO CRD42018080963.