Sacubitril–Valsartan for Heart Failure: From Devil's Advocate to Evidence-Based Medicine

The article by Yandrapalli et al1 discusses 8 main limitations of LCZ696 (sacubitril/valsartan) in the management of patients with heart failure with reduced ejection fraction (HFrEF), based on the results of the PARADIGM-HF trial.2 Although these limitations are important to be known by the clinician, I have some comments based on the most recent secondary analyses of this trial, and also based on the “real-life” studies. Maximum recommended dose of enalapril for the treatment of HFrEF, 40 mg/d, was not used in this trial. However, in clinical practice, according to the European Society of Cardiology Heart Failure Long-Term Registry, less than 30% of patients received the target dose of angiotensin converting enzyme (ACE) inhibitors.3 The mean daily enalapril dose achieved in PARADIGM-HF, 18.9 mg, was higher than doses used in SOLVD-T (16.6 mg) and CONSENSUS (18.4 mg), respectively.2 In comparison with this dose of enalapril, LCZ696 reduced primary end point of cardiovascular death or hospitalization for heart failure (HF) by 20%, cardiovascular death by 20%, all-cause death by 16%, sudden cardiac death by 20%, first hospitalization for worsening HF by 21%, and readmission for HF during the first 30 days (“vulnerable phase”) by 38%, all these results being highly statistically significant and clinically relevant.2,4,5 Moreover, an indirect comparison versus putative placebo from SOLVD-T trial showed a 43% relative risk reduction of the primary end point of cardiovascular death or hospitalization for HF with LCZ696.6 Main reasons for not reaching the target dose of ACE inhibitors in real life are symptomatic hypotension, worsening renal function, hyperkalaemia, and cough.3 Interestingly, in PARADIGM-HF trial, apart from symptomatic hypotension which had a higher rate with LCZ696 compared with enalapril (14.0% vs. 9.2%, P < 0.001), worsening renal function, hyperkalaemia, and cough had a lower rate with LCZ696, compared with enalapril.2 Consequently, fewer patients on LCZ696 than on enalapril stopped their study medication because of an adverse event (10.7% vs. 12.3%; P = 0.03), suggesting that LCZ696 is better tolerated than the 10 mg twice daily dose of enalapril. Moreover, among patients treated with mineralocorticoid receptor antagonists (MRAs), severe hyperkalaemia was more likely during treatment with enalapril than with LCZ696 (3.1 vs. 2.2 per 100 patient-years; hazard ratio = 1.37; 95% confidence interval, 1.06–1.76; P = 0.02), suggesting that LCZ696 might attenuate the risk of hyperkalaemia when combined with MRA in patients with HFrEF.7 In the PARADIGM-HF trial, a run-in phase was used to test the tolerability of both LCZ696 and enalapril.2 Although, during this run-in phase, LCZ696 was up-titrated to its target dose of 200 mg twice daily, enalapril dose of 10 mg twice daily was maintained stable, numerically lower proportion of patients on LCZ696 (9.3%) discontinued the study during the run-in phase, in comparison with enalapril (10.5%).2 By multivariable model, patients with low blood pressure, low estimated glomerular filtration rate, and more advanced HF were associated with higher risk for run-in noncompletion,8 suggesting that these patients should undergo closer monitoring during the up-titration of LCZ696 or the conversion of patients from enalapril to LCZ696. Weighted analysis of key study outcomes accounting for the effect of run-in noncompletion did not affect the magnitude of the treatment benefit of LCZ696 over enalapril.8 Run-in phases have been part of the design of many HF trials, such as SOLVD-Treatment trial, MERIT-HF trial, and US Carvedilol Heart Failure Study Group. In nearly all of these cases, subsequent analyses affirmed the validity of the primary study results, suggesting that this study design did not introduce significant data distortions.8 Moreover, medications recommended in HF, such as beta-blockers, ACE inhibitors, and ivabradine, are all up-titrated in clinical practice, during a run-in period. This up-titration is obviously necessary for LCZ696 and, as proved by the PARADIGM-HF trial, it is possible in approximately 80% of the patients.2,8 Neprilysin, the enzyme inhibited by sacubitril (one of the 2 compounds of LCZ696), is also one of the many enzymatic and nonenzymatic pathways clearing amyloid-β peptides from the central nervous system.9 Accumulation of certain amyloid-β peptides is considered a pathognomonic feature of Alzheimer type dementia.9 Therefore, there is a theoretical concern about the long-term effects of LCZ696 on cognition and memory. A recent study analyzed dementia-related adverse events in PARADIGM-HF trial and placed these findings in the context of other 3 HF trials (Val-HeFT, ATMOSPHERE, and CORONA).10 The age-adjusted annual rates of dementia-related events in both treatment groups in PARADIGM-HF were similar (0.95 vs. 0.98 per 100 patient-years, for LCZ696 and enalapril, respectively) and were also similar to those in the 3 others HF trials.10 These findings do not support the concerns about adverse cognitive effects of LCZ696, although longer follow-up may be necessary in further studies. Finally, although there are some subgroups poorly represented into the PARADIGM-HF trial (ie, black patients), so far this is the largest published trial in HFrEF, with 8399 patients randomly assigned to medication.2 The European Society of Cardiology HF guidelines recommend the use of LCZ696 as a replacement for an ACE inhibitor in ambulatory patients with HFrEF, who remain symptomatic, despite optimal treatment with an ACE inhibitor, a beta-blocker, and an MRA (class 1, level B of recommendation).11 In addition, patients should have elevated natriuretic peptides (plasma B-type Natriuretic Peptide BNP ≥150 pg/mL or plasma N-terminal-proBNP ≥600 pg/mL; if patient was hospitalized for HF within the last 12 months, plasma BNP ≥100 pg/mL or plasma N-terminal-proBNP ≥400 pg/mL), and patients should tolerate enalapril 10 mg twice daily. To minimize the risk of angioedema caused by overlapping ACE and neprilysin inhibition, the ACE inhibitor should be with held for at least 36 hours before initiating LCZ696.