#174 Target/higher dosing of medications in heart failure—is it necessary?
CLINICAL QUESTION
Does getting to target/higher doses of heart failure (HF) medications improve outcomes and/or increase side effects?
BOTTOM LINE
In HF patients, higher dose angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and angiotensin receptor blockers (ARB) versus lower doses result in non-significant improvements in mortality, and inconsistent decreases in HF hospitalizations. Higher doses cause more dizziness or hypotension (4-15%), dose reductions (20%), and stopping (2-8%). Starting on low doses and focusing on tolerability is essential.
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EVIDENCE
Largest randomized controlled trials (usually Class 2 HF), comparing high versus low dose.
- Beta-blockers:
- MOCHA:1 345 patients; BID carvedilol 25 mg versus 6.25 mg x6 months.
- No statistical difference in:
- Mortality: 1% versus 6%.
- Cardiovascular hospitalizations: Both 11%.
- Dizziness: 24% versus 38%.
- Bradycardia: 12% versus 1%, Number Needed to Harm (NNH)=10.
- No statistical difference in:
- J-CHF:2 364 patients; BID carvedilol 10 mg versus 1.25 mg x3 years.
- No statistical difference in death/hospitalization for HF/cardiovascular disease (21% versus 23%).
- More required dose reduction (23% versus 0.7%), NNH=5.
- Meta-regression confirms lack of increased dose benefit.3
- MOCHA:1 345 patients; BID carvedilol 25 mg versus 6.25 mg x6 months.
- ACE inhibitors:
- ATLAS:4 3,164 patients (77% class 3 HF); lisinopril 32.5-35 mg versus
2.5-5 mg x4 years:
- No statistical difference in:
- Mortality: 43% versus 45%.
- Any hospitalization: 37% versus 39%.
- Decreased mortality plus hospitalization (80% versus 84%), NNT=25.
- More dizziness (19% versus 12%) and hypotension (11% versus 7%).
- No statistical difference in:
- NETWORK:5 1,532 ACE naïve patients, BID enalapril 10 mg versus 2.5 mg x6 months:
- No statistical difference in:
- Death/HF hospitalization or worsening symptoms: 15% versus 13%.
- More treatment withdrawals (27% versus 19%), NNH=13.
- No statistical difference in:
- ATLAS:4 3,164 patients (77% class 3 HF); lisinopril 32.5-35 mg versus
2.5-5 mg x4 years:
- ARBs:
- HEAAL:6 3,846 patients; losartan 150 mg versus 50 mg x4.7 years:
- Death/HF admission: 43% versus 47%, NNT=30.
- HF admission: 23% versus 26%, NNT=35.
- Similar overall mortality: 33% versus 35%.
- More hypotension and hyperkalemia: NNH~30 each.
- Death/HF admission: 43% versus 47%, NNT=30.
- HEAAL:6 3,846 patients; losartan 150 mg versus 50 mg x4.7 years:
- Smaller studies report similar.7-9
- Evidence supports “triple therapy” in HF: Beta-blocker, ACE/ARB, and aldosterone antagonists.10
- Target doses often unattainable, even in clinical trials.
- Only ~50% achieve 50% of target doses.11
- Despite inconsistent RCT evidence, guidelines still recommend trying to achieve target/higher doses12 based in part on non-dose response HF studies (CONSENSUS13 MERIT14 and VALIANT15).
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