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#174 Target/higher dosing of medications in heart failure—is it necessary?

Does getting to target/higher doses of heart failure (HF) medications improve outcomes and/or increase side effects?

In HF patientshigher dose angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and angiotensin receptor blockers (ARB) versus lower doses result in non-significant improvements in mortalityand inconsistent decreases in HF hospitalizationsHigher 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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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.   
    • J-CHF:2 364 patientsBID 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  
  • 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: 
        • Mortality43% 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%).   
    • NETWORK:5 1,532 ACE naïve patientsBID enalapril 10 mg versus 2.5 mg x6 months: 
      • No statistical difference in:  
        • Death/HF hospitalization or worsening symptoms15% versus 13%.  
      • More treatment withdrawals (27% versus 19%), NNH=13. 
  • 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 hyperkalemiaNNH~30 each. 
  • 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). 

gregory Stroh December 12, 2023

As in many cases the Canadian guidelines refuse to align with study evidence and exams and colleague pressure continue to not pay attention to the evidence. Frustrating when you practice conservative prescribing and even the specialist insist on upwind doses of meds.

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  • James McCormack BSc(Pharm) PharmD
  • Michael R Kolber BSc MD CCFP MSc

1. Bristow MR, Gilbert EM, Abraham WT, et al. Circulation. 1996; 94:2807-16.

2. Okamoto H, Hori M, Matsuzaki M, et al. Int J Cardiol. 2013; 164:238-44.

3. McAlister FA, Wiebe N, Ezekowitz JA, et al. Ann Intern Med. 2009; 150:784-94.

4. Packer M, Poole-Wilson PA, Armstrong PW, et al. Circulation. 1999; 100:2312-8.

5. Poole-Wilson PA on behalf of NETWORK Investigators. Eur Heart J. 1998; 19:481-9.

6. Konstam MA, Neaton JD, Dickstein K, et al. Lancet. 2009; 374:1840-8.

7. Hori M, Sasayama S, Kitabatake A, et al. Am Heart J. 2004; 147:324-30.

8. Clement DL, De Buyzere M, Tomas M, et al. Acta Cardiol. 2000; 55(I):1-7.

9. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al. J Am Coll Cardiol. 2000; 36:2090-5.

10. Lindblad AJ, Allan GM. Can Fam Physician. 2014; 60:e104.

11. Tavazzi L, Maggioni AP, Borer JS. Eur Heart J. 2013; 34:2792-4.

12. McKelvie RS, Moe GW, Ezekowitz JA, et al. Can J Cardiol. 2013; 29:168-81.

13. The CONSENSUS Trial Study Group. N Engl J Med. 1987; 316;1429-35.

14. MERIT-HF Study Group. Lancet. 1999; 353:2001-7.

15. Pfeffer MA, McMurray JJV, Velazquez EJ, et al., for the Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med. 2003; 349:1893-906.

Authors do not have any conflicts to disclose.