Patients with heart failure with reduced ejection fraction and predominant central sleep apnea pose treatment challenges. A system review and meta-analysis of randomized controlled trials (RCTs) were undertaken. Electronic searches of digital repositories, journals, specialty society and manufacturer websites, manual searches of reference sections of RCTs, and published clinical guidelines were performed. Studies were graded for bias. Meta-analytic random effects models were used. Outcomes of interest included: sleep, cardiovascular, mortality, and quality of life (QoL). Grading of recommendations assessment, development and evaluation was performed. Nineteen randomized studies were identified that met the inclusion criteria of apnea hypopnea index (AHI) ≥10, predominant central sleep apnea (CSA), and heart failure with reduced ejection fraction (HFrEF) ≤50%. Most trials examined adaptive servo ventilation (ASV) (8 studies) and continuous positive airway pressure (CPAP) (9 studies). Bias existed in that: 15 of 19 (79%) of the trials lacked blinding, 10 of 19 were manufacturer funded, and with attrition in 8 of 19 studies. In meta-analysis, ASV performed better than control on sleep but not on QoL or cardiovascular outcomes, including mortality. CPAP demonstrated positive short-term outcomes on sleep, cardiovascular, and QoL (3 months). Longer-term cardiovascular and mortality data did not show benefit. Drug therapies demonstrated a positive clinical effect short term on sleep outcomes only. Transvenous phrenic nerve stimulation (TPNS) demonstrated positive treatment outcomes on sleep and QoL at 6 months. Evidence suggests improvement in cardiovascular outcomes with TPNS. In conclusion, ASV and CPAP therapies improve sleep, but long-term QoL or cardiovascular benefit was lacking. TPNS exhibited positive outcomes on sleep and QoL at 6 months with positive trends in CV outcomes.