Vardeny O, Claggett B, Packer M, et al.
Eur J Heart Fail 2016;published online ahead of print

Background

In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan showed a greater risk reduction of cardiovascular (CV) death and of heart failure (HF) hospitalisation compared with enalapril, in patients with chronic HF and reduced ejection fraction [1].
The study design included a run-in period before randomisation, during which all patients were titrated to a target dose of enalapril 10 mg twice daily and then sacubitril/valsartan 200 mg twice daily, with mean achieved daily doses of 18.9 mg and 375 mg, respectively, for the majority of patients [2]. Since not all patients were maintained on target doses of study medication during the long-term follow-up, the question remains whether there is a similar benefit from the administration of sacubitril/valsartan at lower than target doses than observed for low doses of enalapril. This was evaluated in this post-hoc analysis of PARADIGM-HF data

Main results

• Out of 8399 participants, 43% of patients in the enalapril arm and 42% of patients in the sacubitril/valsartan arm had any dose reduction after randomisation (P=NS).
• The median time to dose reduction was 255 days (IQR: 70 – 516) for enalapril and 249 days (IQR: 64 - 506) for sacubitril/valsartan (P=NS).
• Of those with a dose reduction, 1332 (37.5%) subsequently returned to target study medication doses, and this occurred more frequently in patients randomised to sacubitril/valsartan than with enalapril (39.8% vs. 35.3%; P =0.005).
• In a multivariable regression model, 11 significant predictors of dose reduction were identified, including higher serum creatinine, geographic region (North America, Latin America, and Western Europe), higher NT-proBNP, higher heart rate, older age, lower systolic blood pressure, NYHA class, history of MI, history of DM, use of beta-blockers and female sex
• A history of MI was a stronger predictor of dose reduction in patients randomised to sacubitril/valsartan (OR:1.31) than in those randomised to enalapril (OR: 1.06; P for interaction=0.021).
• Any dose reduction, regardless of treatment assignment, was associated with a higher subsequent risk of the primary event (HR: 2.5; 95% CI: 2.2–2.7).
• When the primary outcome events were censored at the time of dose reduction, participants taking sacubitril/valsartan had fewer events relative to enalapril prior to dose reduction (HR: 0.79; 95% CI:0.71–0.88).
• In a landmark analysis beginning at the time of dose reduction, there was a similar magnitude of benefit for sacubitril/valsartan after dose reduction (HR: 0.80; 95% CI: 0.70–0.93), which was maintained after adjustment (HR: 0.80; 95% CI: 0.69–0.92).

Conclusion

In HF patients with reduced ejection fraction enrolled in the PARADIGM-HF study, dose reductions of the study medication were common and associated with a higher risk of primary events. The observed magnitude of benefit of lower doses of sacubitril/valsartant compared with enalapril was consistent with prior PARADIGM-HF analyses.

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References

1. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
2. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Committees and Investigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062–73.