Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Ricky D. Turgeon, Michael R. Kolber, Peter Loewen, Ursula Ellis, James P. McCormack, Vinayak Shenoy.
Current heart failure (HF) guidelines recommend titrating angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and beta-blockers (BBs) to target doses used in pivotal placebo-controlled randomized controlled trials (RCTs). Despite a number of RCTs comparing different doses (i.e. higher versus lower doses) of ACEIs, ARBs and BBs, the effects of higher versus lower doses on efficacy and safety remains unclear. For this reason, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of higher versus lower doses of ACEIs, ARBs and BBs in patients with HFrEF.
We searched MEDLINE, Embase and the Cochrane Central 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 safety outcomes, we pooled trials within and across drug classes.
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 ~2–4 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 0.87–1.02)], ARBs RR 0.96 (0.87–1.04), BBs RR 0.25 (0.06–1.01)] or all cause hospitalizations [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.86–1.02)], ARBs RR 0.98 (0.93–1.04), BBs RR 0.93 (0.39–2.24)]. However, all point estimates favoured higher doses. Higher doses of ARBs significantly reduced hospitalization for HF [RR 0.89 (0.80–0.99)– 2.8% ARR], and higher doses of ACEIs and ARBs significantly reduced HF worsening [RR 0.85 (0.79–0.92)– 5.1% ARR and 0.91 (0.84–0.99)– 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%.
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 sparse and imprecise. Higher doses increase the chance of adverse effects compared to lower doses. Evidence for BBs is inconclusive. These results support initially always starting at low doses of ACEIs/ARBs and only titrating the dose up if the patient tolerates dose increases.
Heart failure (HF) with reduced ejection fraction (HFrEF) is a prevalent condition with an overall poor prognosis. 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,, as these medications reduce morbidity and mortality compared to placebo.,, These results have led guideline authors to universally recommend starting these agents in most patients with (HFrEF).,
In this systematic review and meta-analysis of RCTs, higher doses of ACEIs were not statistically superior to the lower doses studied in terms of mortality or hospitalizations, but point estimates were in favour of higher doses. Higher doses of ACEIs statistically-significantly reduced the proportion of patients with episodes of worsening HF compared to lower doses. Similarly, higher doses of ARBs did not statistically reduce mortality or all-cause hospitalizations compared to lower doses, but point estimates were again in favour of higher doses. However, higher doses of ARBs did statistically reduced HF hospitalization and episodes of worsening HF compared to the lower doses studied. We did not find statistically-significant differences between higher and lower doses of BBs for any efficacy outcome, though results were imprecise due to few events, limiting the certainty of these findings. Higher doses increased the risk of discontinuation due to adverse events, hypotension, dizziness, and for ACEIs and ARBs, increased hyperkalemia and elevations in serum creatinine compared to lower doses.
Evidence comparing lower and higher doses of drugs in HFrEF is sparse and imprecise. 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. Effects of higher versus lower doses of these agents on other outcomes, as well as the impact of higher versus lower doses of BBs on any efficacy outcome, remain unclear. Higher doses importantly increase the risk of hypotension and agent-specific adverse effects (e.g. hyperkalemia, cough, creatinine rise) compared to lower doses. These results reinforce recommendations to start these agents at low doses, involve patients in dose titration decisions, carefully monitor for adverse effects after dose changes, and not be averse to lowering doses when tolerability issues arise.