hyperkalemia, cough, creatinine rise) compared to lower doses. AKR1C3-IN-1 Register of Controlled Trials (CENTRAL) via Ovid from inception to April 25th, 2018 and opentrials.net and clinicaltrials.gov for relevant trials that compared different doses of medications in heart failure. We analyzed trials by drug class (ACEIs, ARBs, and BBs) for efficacy outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalizations, HF hospitalizations, HF worsening). For security outcomes, we pooled trials within and across drug classes. Results Our meta-analysis consisted of 14 RCTs. Using GRADE criteria, the quality of evidence for ACEIs and ARBs was assessed as generally moderate for efficacy and high for adverse effects, whereas overall quality for BBs was very low to low. Over ~2C4 years higher versus lower doses of ACEIs, ARBs or BBs did not significantly reduce all-cause mortality [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.87C1.02)], ARBs RR 0.96 (0.87C1.04), BBs RR 0.25 (0.06C1.01)] or all cause hospitalizations [ACEIs relative risk (RR) AKR1C3-IN-1 0.94 (95% confidence interval 0.86C1.02)], ARBs RR 0.98 (0.93C1.04), BBs RR 0.93 (0.39C2.24)]. However, all point estimates favoured higher doses. Higher doses of ARBs significantly reduced hospitalization for HF [RR 0.89 (0.80C0.99)C 2.8% ARR], and higher doses of ACEIs and ARBs significantly reduced HF worsening [RR 0.85 (0.79C0.92)C 5.1% ARR and 0.91 (0.84C0.99)C 3.2% ARR, respectively] compared to lower doses. None of the differences between higher versus lower doses of BBs were significant; however, precision was low. Higher doses of these medications compared to lower doses increased the risk of discontinuation due to adverse events, hypotension, dizziness, and for ACEIs and ARBs, increased hyperkalemia and elevations in serum creatinine. Absolute increase in harms for adverse effects ranged from ~ 3 to 14%. Conclusions Higher doses of ACEIs and ARBs reduce the risk of HF worsening compared to lower doses, and higher doses of ARBs also reduce the risk of HF hospitalization but the evidence is usually sparse and imprecise. Higher doses increase the chance of adverse effects compared to lower doses. Evidence for BBs AKR1C3-IN-1 is usually inconclusive. These results support initially usually starting at low doses of ACEIs/ARBs FJX1 and only titrating the dose up if the patient tolerates dose increases. Introduction Heart failure (HF) with reduced ejection portion (HFrEF) is usually a prevalent condition with an overall poor prognosis.[1] The combination of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-2 receptor blocker (ARB) plus a beta-blocker (BB) is first-line therapy for HFrEF management,[1],[2] as these medications reduce morbidity and mortality compared to placebo.[3],[4],[5] These results have led guideline authors to universally recommend starting these agents in most patients with (HFrEF).[1],[2] The approach recommended by guidelines when initiating these medications is usually to start at a low-to-moderate dose and titrate as tolerated to the target doses used in placebo-controlled randomized controlled trials (RCTs).[1],[2] However, many patients are unable to achieve and maintain target doses due to adverse effects, with most patients only achieving ~50% of the target dose.[6] Despite a number of RCTs comparing different doses (i.e. higher versus lower doses) of ACEIs, ARBs and BBs, the effects of higher versus AKR1C3-IN-1 lower doses on efficacy and security remains unclear. For this reason, we performed a systematic review and meta-analysis to evaluate the efficacy and security of higher versus lower doses of ACEIs, ARBs and BBs in patients with HFrEF. Methods Design Systematic review with meta-analysis in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.[7] Search strategy We searched MEDLINE, Embase and the AKR1C3-IN-1 Cochrane Central Register of Controlled Trials (CENTRAL) via Ovid from inception to April 25th, 2018 using keywords and subject headings for the following concepts: heart failure, ACEI, ARB, BB, dose, and randomized controlled trial (observe S1 Appendix for MEDLINE search strategy). We also searched opentrials.net and clinicaltrials.gov for relevant RCTs, and hand-searched bibliographies of included studies. Eligibility criteria and outcomes We included parallel RCTs published in English evaluating different doses of the.