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<h4>Background</h4>Readmission following hospital discharge is common and is a major financial burden on healthcare systems.<h4>Objectives</h4>Our objectives were to 1) identify studies describing post-discharge interventions and their efficacy with respect to reducing risk of mortality and rate of hospital readmission; and 2) identify intervention characteristics associated with efficacy.<h4>Methods</h4>A systematic review of the literature was performed. We searched MEDLINE, PubMed, Cochrane, EMBASE and CINAHL. Our selection criteria included randomized controlled trials comparing post-discharge interventions with usual care on rates of hospital readmission and mortality in high-risk chronic disease patient populations. We used random effects meta-analyses to estimate pooled risk ratios for all-cause and cause-specific mortality as well as all-cause and cause-specific hospitalization.<h4>Results</h4>We included 31 randomized controlled trials encompassing 9654 patients (24 studies in CHF, 4 in COPD, 1 in both CHF and COPD, 1 in CKD and 1 in an undifferentiated population). Meta-analysis showed post-discharge interventions reduced cause-specific (RR = 0.71, 95% CI = 0.63-0.80) and all cause (RR = 0.90, 95% CI = 0.81-0.99) hospitalization, all-cause (RR = 0.73, 95% CI = 0.65-0.83) and cause-specific mortality (RR = 0.68, 95% CI = 0.54-0.84) in CHF studies, and all-cause hospitalization (RR = 0.52, 95% CI = 0.32-0.83) in COPD studies. The inclusion of a cardiac nurse in the multidisciplinary team was associated with greater efficacy in reducing all-cause mortality among patients discharged after heart failure admission (HR = 0.64, 95% CI = 0.54-0.75 vs. HR = 0.87, 95% CI = 0.73-1.03).<h4>Conclusions</h4>Post-discharge interventions reduced all-cause mortality, cause-specific mortality, and cause-specific hospitalization in CHF patients and all-cause hospitalization in COPD patients. The presence of a cardiac nurse was associated with greater efficacy in included studies. Additional research is needed on the impact of post-discharge intervention strategies in COPD and CKD patients.