RAAS inhibitor dose in HFrEF

Reference: Turgeon RD, et al. Higher versus lower doses of ACE inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction: Systematic review and meta-analysis. PLoS ONE 14(2):e0212907

Bottom line:

The available evidence evaluating dose-response of medications in HFrEF have several caveats that require close scrutiny. With that said, pushing the dose of ACE inhibitors and ARBs appears to:

  • Further reduces the risk of HF worsening or HF hospitalizations over 4-5 years;

  • Increases the risk of side-effects such as lightheadedness, renal dysfunction & hyperkalemia. These are generally predictable, reversible, and manageable with holding or decreasing the ACEI/ARB dose.

The decision to aim for target ACEI/ARB doses must account for the consequences & severity of all of these events in an individual, rather than the relative size of the NNT versus NNHs. For example, HF hospitalizations impair patient quality of life, are costly to the healthcare system, & put patients at risk for numerous complications, such as hospital-acquired infections, VTE, & deconditioning. The severity of ACEI/ARB-related renal dysfunction can range from dialysis-dependent renal failure to a slight creatinine bump that's reversible upon decreasing the ACEI/ARB dose, & most often falls in the latter category.


Inclusion criteria from key trials

Baseline patient characteristics from key trials

Interventions in key trials


    • I: High-dose lisinopril (32.5-35 mg PO once daily)

      • 91% achieved target dose

      • 27% discontinued study drug

    • C: Low-dose lisinopril (2.5-5 mg PO once daily)

      • 31% discontinued study drug

  • High Enalapril Dose Study

    • I: High-dose enalapril (30 mg BID - 3x target dose in SOLVD)

      • ~45% achieved target dose by year 1

      • Mean achieved dose ~20 mg BID

    • C: Standard target-dose enalapril (10 mg BID)

      • ~80% achieved target dose by year 1

      • Mean achieved dose ~10 mg BID

    • Both groups started at 2.5 mg BID, uptitrated q1 week to target dose


    • I-1: Standard target-dose enalapril (10 mg BID)

    • I-2: Half target-dose enalapril (5 mg BID)

    • C: Low-dose enalapril (2.5 mg BID)

    • All started at 2.5 mg BID; standard/half-dose groups doubled after 1 week; standard-dose further doubled 1 week later


    • I: Losartan 150 mg once daily

      • Initial 50 mg daily, then uptitrated over 3 weeks

      • 94% achieved target dose

    • C: Losartan 50 mg once daily

Results (meta-analysis forest plots available in the open-access article)

Risk of bias


Other issues

  • Inadequate follow-up duration

    • The High Enalapril Dose Study and NETWORK were both at substantial risk of a type 2 error, i.e. falsely concluding that higher doses did not result in additional benefits, as they had short follow-up periods of 6-12 months that may not adequately capture the potential benefits of targeting a higher ACEI dose

  • Contamination bias: High risk

    • The ATLAS trial reported that ~20% of patients in each group started open-label ACEI therapy, which increased overall "ACEI dose" in the low-dose ACEI group and minimized potential differences in outcomes between the 2 treatment groups

  • Run-in phases

    • ATLAS & HEAAL both had active run-in phases to exclude patients prior to randomization who would not tolerate a low-moderate dose of the study drug

      • Safety data from these studies will be lower than seen in an unselected real-world population


  • Of the 4 key trials, ATLAS & HEAAL, which both included only HFrEF patients & used “high” doses that were attainable by >90% of patients in the trial, are the most generalizable to a real-world HFrEF population

  • The High Enalapril Dose Study enrolled a population that is approximately 10 years younger than the usual mean age for HF trials. This is reflected in the higher proportion of patients who could achieve the 10 mg BID dose (80% versus 50% in SOLVD)

  • Background HF medical therapy was seldom reported & none reported device therapy