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. 2017 Jan;63(1):e20.

Higher medication doses in heart failure?

James McCormack 1, Finlay A McAlister 2, Michael R Kolber 3
PMCID: PMC5257235  PMID: 28115456

Clinical question

Does getting patients to target or using higher doses of heart failure (HF) medications improve outcomes?

Bottom line

In HF, higher-dose angiotensin-converting enzyme inhibitors (ACEIs), β-blockers (BBs), and angiotensin receptor blockers (ARBs) result in non-significant improvements in mortality, inconsistent decreases in HF hospitalizations, and more dizziness or hypotension (4% to 15%), dose reductions (20%), and stopping medication (2% to 8%). Starting patients on low doses and focusing on tolerability is essential.

Evidence

The largest RCTs, usually in patients with class II HF, of high versus low doses found the following.

  • For BBs:
    • -The MOCHA1 trial (N = 345) compared 25 mg with 6.25 mg of carvedilol twice daily for 6 months.
      • —There was no statistical difference in mortality (1% vs 6%), cardiovascular hospitalizations (both 11%), or dizziness (24% vs 38%), but increased bradycardia (12% vs 1%, NNH = 10).
    • -The J-CHF2 trial (N = 364) compared 10 mg with 1.25 mg of carvedilol twice daily for 3 years.
      • —The was no difference in death, HF hospitalization, and cardiovascular disease (21% vs 23%), but an increase in dose reductions (23% vs 0.7%, NNH = 5).
    • -Meta-regression confirmed lack of dose benefit.3
  • For ACEIs:
    • -The ATLAS4 trial (N = 3164, 77% class III HF) compared 32.5 to 35 mg with 2.5 to 5 mg of lisinopril for 4 years.
      • —There was no difference in mortality (43% vs 45%) or any hospitalization (37% vs 39%), but there was decreased mortality plus hospitalization (80% vs 84%, NNT = 25), and there was more dizziness (19% vs 12%) and hypotension (11% vs 7%).
    • -The NETWORK5 trial (1532 ACEI-naïve patients) compared 10 with 2.5 mg of enalapril twice daily for 6 months.
      • —There was no difference in death, HF hospitalization, or worsening symptoms (15% vs 13%), but more treatment withdrawals (27% vs 19%, NNH = 13).
  • For ARBs:
    • -The HEAAL6 trial (N = 3846) compared 150 mg with 50 mg of losartan for 4.7 years.
      • —There was decreased death plus HF admission (43% vs 47%, NNT = 30) and HF admission (23% vs 26%, NNT = 35), similar mortality (33% vs 35%), and more hypotension and hyperkalemia (NNH about 30).

Context

  • Target doses are often unattainable, even in clinical trials: about 50% of patients achieve 50% of target doses.7

  • Despite inconsistent RCT evidence, guidelines recommend trying to achieve targets and using higher doses,8 based in part on non–dose-response HF studies.9–11

Implementation

Aldosterone antagonists, ACEIs, ARBs, and BBs reduce morbidity and mortality in HF patients with reduced (< 40%) left ventricular ejection fraction; benefits have not been shown with preserved ejection fraction.12 Aldosterone antagonists have similar benefit but are prescribed less often.13 Ideally, patients should be taking ACEIs, ARBs, BBs, or aldosterone antagonists, but which to start first and how to optimize tolerability is unknown. After initiation or dose increases, monitor for adverse events (eg, hypotension, bradycardia, dizziness, and electrolyte or creatinine abnormalities).12

Tools for Practice

Tools for Practice articles in Canadian Family Physician (CFP) are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in CFP are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.

Footnotes

Competing interests

None declared

The opinions expressed in Tools for Practice articles are those of the authors and do not necessarily mirror the perspective and policy of the Alberta College of Family Physicians.

References

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