RAAS inhibitor dose in HFrEF

Studies reviewed: ATLAS, High Enalapril Dose Study, NETWORK, HEAAL

Bottom line: The available evidence evaluating dose-response of ACEIs/ARBs in HFrEF have several caveats that require close scrutiny. With that said, pushing the ACEI/ARB dose appears to:

  • Further reduces the risk of HF hospitalizations over 4-5 years (NNT 25-34);

  • Increases the risk of side-effects such as lightheadedness (NNH 15), renal dysfunction (NNH 34) & hyperkalemia (NNH 50). 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.




    • 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 @ 0.5-4.7 years

Internal validity

  • 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
  • Allocation, performance, detection bias
    • ATLAS, NETWORK, HEAAL: Low risk of these biases, as they were all double-blind RCTs with unclear sequence generation and allocation concealment
    • The High Enalapril Dose Study is at high risk of these biases as it was a non-blinded RCT with possibly compromised allocation concealment as demonstrated by several baseline imbalances
  • Attrition bias: Low risk as all reported intention-to-treat analyses with low loss-to-follow-up
  • Selective outcome reporting bias: Low risk as all reported on key objective outcomes (death & HF hospitalization)
  • Other: 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 trials reported here, the ATLAS & HEAAL trials are the most generalizable to a real-world HFrEF population
    • Both ATLAS & HEAAL included only HFrEF patients & used "high" doses that were attainable by >90% of patients in the trial
  • 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)
  • The NETWORK trial enrolled a mixed population of patients with HFrEF & HFpEF
  • Only HEAAL reported background HF medical therapy & none reported device therapy