Safety and tolerability of sacubitril/valsartan in chronic heart failure and reduced ejection fraction: Results from the open-label extension of the PARADIGM-HF study

Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), is recommended by the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guideline for heart failure (HF) in patients with HF with reduced ejection faction, New York Heart Association class II−III, and by the 2021 European Society of Cardiology (ESC) guidelines to replace angiotensin-converting enzyme inhibitors (ACEIs) for reducing HF hospitalizations and death risk.^{1, 2} These recommendations stem from the PARADIGM-HF trial, which showed sacubitril/valsartan's superiority over enalapril in reducing cardiovascular death or HF hospitalization by 20%, although long-term safety data beyond 27 months were not available.³

Despite guideline recommendations, clinical practice highlights a low adoption of recommended doses of HF therapies. In CHAMP-HF, most patients received ACEIs/angiotensin receptor blockers (ARB)/ARNI, beta-blockers, and mineralocorticoid receptor antagonists; however, only 13% of patients were prescribed ARNI, with 14% at target dose.⁴ Similarly, the ESC-HF Registry data indicate that only 30% of patients received recommended doses, often limited by adverse event (AE) concerns.^{5, 6} Patients in PARADIGM-HF largely represent the real-world HF population.^{4, 5, 7} Safety assessment of PARADIGM-HF trial over 12 months showed that sacubitril/valsartan reduced blood pressure, while enalapril increased renal impairment, hyperkalaemia, and cough incidents. The PARADIGM-HF open-label extension (OLE; NCT02226120), a single-arm follow-up study, continued safety and tolerability evaluations of sacubitril/valsartan post-trial until clinical approval (from October 2014 to December 2017) at 397 centres across 60 countries. The study enrolled patients who completed the double-blind phase of the PARADIGM-HF trial. After an initial treatment with 49/51 mg sacubitril/valsartan twice daily (BID), the dose was planned to be up-titrated to 97/103 mg, with dose adjustments based on tolerance (online supplementary Figure S1). Safety was assessed every 6 months. The primary outcome of the study was to evaluate the long-term (30 months) safety and tolerability of sacubitril/valsartan, based on the incidence of AEs, serious AEs, AEs leading to dose adjustments, and temporary or permanent discontinuations.

Adverse events were summarized by the number and percentage of patients, the severity, and its relationship to treatment. Statistical analysis was performed on the safety set, and Kaplan–Meier survival analysis was used to estimate the probability of death by study group.

Of the 8399 patients enrolled in PARADIGM-HF, 2060 patients were enrolled in the OLE study. Patients were considered eligible if they were enrolled and treated with double-blind study medication in PARADIGM-HF. Patients taking other investigational drugs at the time of enrolment or within 30 days, requiring treatment with both ACEI and ARB, having an estimated glomerular filtration rate <30 ml/min/1.73 m² at screening, or having symptomatic hypotension (systolic blood pressure <100 mmHg) were excluded. All patients provided written informed consent prior to entering the study and receiving study medication. A total of 1979 patients completed the screening phase, of which three patients were excluded as they did not receive the study medication. The safety set included 1980 patients, as four patients, who failed during screening phase, were included because their dosing records were available in the database. For the analysis, two of these four patients were excluded as one patient was counted twice during this study and the other patient was not randomized in PARADIGM-HF. Thus, data from 1978 patients were included in the analysis, of whom 52.2% of patients (n = 1033) received sacubitril/valsartan (continuation group) and 47.8% (n = 945) received enalapril (switch group) in the core study (online supplementary Figure S1B). The mean (standard deviation) interval between completing the PARADIGM-HF and starting the extension study was 547.3 (166.0) days, and patients were followed up for 504 days (2–1014 days) (median [range]). At the time of entry into the OLE (after the up-titration phase), 44.6% of patients (n = 883) were up-titrated to sacubitril/valsartan 97/103 mg BID, while 37.9% (n = 750) continued on 49/51 mg BID and 15.5% (n = 306) continued on 24/26 mg BID. Only 2% of patients (n = 39) did not receive the drug. By the end of the study, 55.5% of patients (n = 1099) were receiving sacubitril/valsartan 97/103 mg BID, while 22.9% (n = 454) were receiving 49/51 mg BID and 14.3% (n = 283) were receiving 24/26 mg BID. Only 7.3% of patients (n = 144) were no longer taking sacubitril/valsartan at the end of the study. Among all dose levels, the mean treatment exposure was highest (412.1 days) to the target dose of sacubitril/valsartan 97/103 mg BID.

Overall, 65.1% of patients (n = 1288) reported at least one AE; the majority were mild or moderate (as judged by the investigator). The most commonly reported AEs were hypotension (13.3%) and cardiac failure (10%). The incidence of AEs was similar between the continuation and switch groups (Figure 1). At least one serious AE was reported in 28.0% of patients (n = 554); the most frequent being cardiac failure (7.3%).

Figure 1

Open in figure viewerPowerPoint

Most common adverse events (safety set; ≥1%). UTI, urinary tract infection. *Treatment assignment has been considered from the core part of the study.

Overall, 7.0% of patients (n = 139) discontinued the study due to an AE; cardiac failure (1.0%, n = 19) and hypotension (0.8%, n = 16) were the leading causes of discontinuation. Serious AEs leading to permanent discontinuation during the treatment period were reported in 5.1% of patients (n = 101).

Overall, 26.4% of patients (n = 522) with AEs required or prolonged hospitalization (13.4% [n = 265] continuation group and 13.0% [n = 257] switch group). The frequency of hospitalizations due to HF or AEs was similar in both the continuation and switch groups. Most events (60.2%) did not need sacubitril/valsartan dose adjustment.

Common AEs leading to treatment discontinuation were HF (2.0%), hypotension (0.6%), and pneumonia (0.6%). Among patients with HF and AE who required prolonged hospitalization, a higher percentage of patients were receiving the target dose of 97/103 mg BID at the end of the study (38.9% [203/522] in patients with AEs and 31.8% [63/198] in patients with HF). During the study period, 9.4% of patients (n = 186) died, of which 55 patients had HF as the primary cause; no significant differences in mortality were noted between the continuation and switch groups. Most patients (108/186) were off their study medication at time of death. Kaplan–Meier analysis revealed no significant difference in mortality between the continuation and switch groups (online supplementary Figure S2).

The PARADIGM-HF OLE study aimed to provide sacubitril/valsartan to PARADIGM-HF participants until approval. It assessed long-term safety and tolerability without study-specific mandates and dosing was at investigators discretion, with 44.6% achieving the target dose at entry, increasing to 55.5% by the end. Unlike PARADIGM-HF, dose adjustments were allowed for continued medication access. The safety and tolerability profile of sacubitril/valsartan in the PARADIGM-HF OLE study was consistent with prior studies, showing no significant differences in AEs between new and switched patients.^{3, 7, 8} Common AEs were hypotension and cardiac failure, generally mild, and often managed by dose adjustment or temporary discontinuation. Most deaths during the study were among patients not on sacubitril/valsartan or on a lower dose, with the mean dose among deceased patients being lower than the overall study population. The OLE period's safety profile aligned with the randomized treatment period of PARADIGM-HF, PIONEER-HF OLE, and a systematic review of observational studies.^{3, 7, 8} The major limitation of the PARADIGM-HF OLE study is the absence of concurrent controls. Exclusion of patients intolerant to sacubitril/valsartan or enalapril, and the inclusion of survivors from the PARADIGM-HF, may bias outcomes. Open-label design and the 1.5-year gap between studies further limit the assessment of treatment effects on hospitalizations and mortality.

Sacubitril/valsartan was safe and well tolerated during the 30-month follow-up in the PARADIGM-HF OLE study. The incidence of angio-oedema remained low and appears to be unchanged over long-term use. The overall safety profile was similar between patients who had previously received either sacubitril/valsartan or enalapril in PARADIGM-HF.