Dropouts during the PARADIGM-HF run-in period did not affect superiority of ARNI over ACEiDesai AS et al., Circ Heart Fail. 2016
Factors Associated With Noncompletion During the Run-In Period Before Randomization and Influence on the Estimated Benefit of LCZ696 in the PARADIGM-HF Trial
Desai AS, Solomon S, Claggett B, et al.
Circ Heart Fail 2016;9:e003116
BackgroundThe results of the PARADIGM-HF trial (Prospective Comparison of ARNI With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial) showed superiority of sacubitril/valsartan (LCZ696) over the ACE inhibitor enalapril . In this trial, HF patients were randomised after a run-in period, to ensure short-term tolerability of LCZ696/enalapril target doses. However, a proportion of patients did not complete this run-in period.
This study was performed to analyse patient characteristics that were associated with run-in noncompletion and the implications of these exclusions for the initial observed study result. These insights might help understand the applicability of the PARADIGM-HF results to a less selected population.
The first run-in period corresponded to 2 weeks enalapril 10 mg twice daily, and the second run-in period consisted of an initial twice daily 100 mg LCZ696 dose, for 1-2 weeks for patients who tolerated enalapril, continued by uptitration to 200 mg twice daily for 2-4 weeks. Those who tolerated both drugs were double-blindly randomised to either 10 mg enalapril twice daily or LCZ696 200 mg twice daily.
- 19.8% of patients discontinued the study before randomisation: 10.5% failed to complete the enalapril run-in phase and 9.3% failed to complete the LCZ696 run-in phase.
- In about two-thirds of cases, exclusion during the run-in was due to adverse events (mainly hypotension, hyperkalaemia, worsening renal function) or abnormal test results.
- Cough and hyperkalaemia occurred significantly more often during the enalapril run-in phase, whereas hypotension and worsening of renal function were more related to the LCZ696 run-in phase.
- Baseline patient characteristic that predicted drop-out were, after multivariable adjustment: lower systolic blood pressure (OR: 1.11, 95%CI: 1.07-1.14, Z value: 6.56), higher N-terminal pro-BNP levels (OR: 1.20, 95%CI: 1.14-1.26, Z value: 7.18 per log increment), eGFR<60 mL/min per 1.73 m2 (OR: 1.49, 95%CI: 1.35-1.65, Z-value: 7.72), ischemic cause of HF (OR: 1.25, 95%CI: 1.13-1.39, Z value: 4.20) and region of enrolment (Central/Eastern Europe vs. elsewhere: OR: 0.68, 95%CI: 0.60-0.76, Z value: -6.64).
- Except for cause of HF, which was associated only with the enalapril run-in phase, all predictors were applicable to both run-in phases.
- Using inverse probability weighting, it was determined that the HR favouring LCZ696 over enalapril did not alter with regard to the primary outcome of CV death or HF hospitalisation (HR 0.80; 95% CI: 0.73-0.87, P<0.001), nor for key additional end points of CV death (HR 0.80; 95% CI: 0.71-0.89, p<0.001) and all-cause mortality (HR 0.84; 95% CI: 0.76-0.92, p<0.001).
- Estimates of the treatment benefit in the full-screened population when assuming a neutral effect of randomised treatment for those who failed to complete the run-in period were largely consistent for the primary end point (HR 0.84; 95% CI: 0.78-0.91, P<0.001).
ConclusionThe magnitude of the treatment benefit of LCZ696 compared to enalapril for any of the key outcomes in PARADIGM-HF was not affected by the exclusion of patients during the run-in period before randomisation. Predictors for discontinuation during the run-in period for both drugs were low blood pressure, low eGFR and more advanced HF. Patients with these characteristics should be monitored more closely during uptitration of these drugs or during the conversion of patients from enalapril to LCZ696 in clinical practice. However, the successful inclusion for many of these patients in the PARADIGM-HF trial, highlights the difficulty in predicting drug intolerance.
Find this article online at Circulation Heart Failure
1. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGMHF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077.