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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). 

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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.