Angiotensin receptor-neprilysin inhibitor vs. placebo in congenital systemic right ventricular heart failure: the PARACYS-RV trial

Introduction

Systemic right ventricular (sRV) dysfunction is highly prevalent and is associated with substantial morbidity and mortality in patients with complete transposition of the great arteries with atrial switch surgery (D-TGA/AS) and in those with congenitally corrected transposition of the great arteries (ccTGA).^1–3 There is no recommended evidence-based therapy proven to halt disease progression or improve survival for sRV dysfunction. Recent open-label studies support the safety of sacubitril combined with valsartan in this setting,^4,5 and highlight the need for randomized trials.

Herein, we present the results of the Prospective comparison of Angiotensin Receptor-neprilysin inhibitor vs. plAcebo in patients with Congenital sYStemic Right Ventricular heart failure (PARACYS-RV) trial. This randomized, double-blind, placebo-controlled, crossover trial was designed to compare sacubitril/valsartan to placebo in adults (≥18 years) with moderate to severe sRV dysfunction, biventricular physiology, and New York Heart Association (NYHA) functional class II to III symptoms. The study protocol (NCT05117736) was previously published.⁶ The trial was prematurely terminated due to safety concerns.

Results

Study population

At the time of study termination, 15 patients aged 48.5 ± 7.3 years, were enrolled, 14 with D-TGA/AS and 1 with ccTGA. Eleven (73.3%) patients had their angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) discontinued at the beginning of the run-in phase, with a 48-h washout period. The trial was terminated when one patient was in the run-in phase, whereas a second withdrew consent shortly after. Among the remaining 13 patients, 7 were randomized to placebo followed by crossover to sacubitril/valsartan and 6 to the alternate sequence. Six patients completed the first arm. There was no difference in follow-up duration in patients initially randomized to sacubitril/valsartan vs. placebo (110.5 ± 88.3 vs. 123 ± 81.7 days, P = .94).

Primary efficacy outcomes

Figure 1A and B depict changes in the two primary efficacy endpoints, i.e. sub-maximal total exercise duration (SmTED) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, between baseline and end of the 24-week treatment phase. Although the limited number of patients precluded formal statistical testing, SmTED decreased in all three patients randomized to placebo, whereas it increased by 100% and by 141% in two of three patients randomized to sacubitril/valsartan. In the third patient randomized to sacubitril/valsartan in whom no increase in SmTED was observed, the exercise test was terminated due to musculoskeletal pain. Similarly, NT-proBNP levels trended toward an increase in patients randomized to placebo, in contrast to a decrease in those receiving sacubitril/valsartan.

Figure 1.

Summary of principal findings of the PARACYS-RV trial. (A) Comparison of sub-maximal total exercise duration between baseline and end of the first arm for the six patients who completed the first arm. Red and green lines represent patients initially randomized to sacubitril/valsartan and placebo, respectively. The red asterisk (*) indicates results from a patient in whom the test was terminated due to musculoskeletal pain. This patient had an 11.6% reduction in N-terminal pro-B-type natriuretic peptide level. (B) Comparison of N-terminal pro-B-type natriuretic peptide levels between baseline and end of the first arm for the six patients who completed the first arm. Red and green lines represent patients initially randomized to sacubitril/valsartan and placebo, respectively. (C) The proportion of patients with heart failure events requiring diuretics during the first arm in sacubitril–valsartan (red) and placebo (green) groups. Discrete variables were compared using Fisher exact tests, with two-tailed P-values <.05 considered statistically significant. (D) Clinical events in the six patients who completed the first arm. The first three patients (first arm in red) were randomized to receive sacubitril/valsartan first, whereas the following three patients (first arm in green) were randomized to receive placebo first. COVID-19 may potentially have contributed to worsening heart failure in Patients 4 and 5. The dotted line represents the time when the study ended for each patient and the red circles indicate the timing of adverse events

Safety monitoring and concerns

During the 6-week open active run-in phase designed to determine the maximum tolerated dose of sacubitril/valsartan, one patient experienced syncope due to orthostatic hypotension following a dose increase. Other adverse events (each in one patient) included mild orthostatic hypotension, erectile dysfunction, increased photosensitivity, vertigo, headache, diarrhoea, and insomnia. No significant changes were observed in creatinine, urea, or potassium levels.

The trial was prematurely interrupted upon a unanimous decision by the steering committee owing to the high rate of worsening heart failure events. Analysis of unblinded data revealed a clear association between these events and interruption of sacubitril/valsartan, either after the run-in phase was followed by placebo or during the 2-week sacubitril/valsartan washout period prior to crossover to placebo. More specifically, during the first treatment arm, 5 of 7 (71.4%) patients initially randomized to placebo vs. 0 of 6 (0%) randomized to sacubitril/valsartan experienced worsening heart failure requiring diuretics (P = .021; Figure 1C and D). Two patients initially randomized to sacubitril/valsartan who were event-free during the first arm developed acute heart failure requiring diuretics 4–5 days into the washout phase before crossing over to placebo (Figure 1D). There were no hospitalizations or deaths.

Post-end of study

Following trial termination, all patients were promptly seen for treatment optimization. Ten of 14 (71.4%) patients were prescribed sacubitril/valsartan, 2 (14.3%) were continued on the ARB received prior to the trial, and an ARB was initiated in 2 (14.3%) patients. After a follow-up of 15 days to 1 month, NT-proBNP levels in the 10 patients prescribed sacubitril/valsartan decreased by an average of 23%, from a median of 943 [interquartile range (IQR) 488–2428] to 726 (IQR 372–726) ng/mL (P = .0039).

Discussion

Recognizing the urgent need for high-quality data to inform the management of patients with a failing sRV, it is with a heavy heart that the PARACYS-RV steering committee concluded, after careful deliberation, that it was in the best interests of study participants to terminate the trial prematurely. Nevertheless, valuable insights were gained. Firstly, all worsening heart failure events occurred after the washout of sacubitril/valsartan, either following the run-in phase or prior to crossover to placebo. It should, therefore, be noted that interrupting sacubitril/valsartan in patients with a sRV could have deleterious consequences. All patients who had worsening heart failure events after the sacubitril/valsartan run-in phase had also received an ACEi or ARB prior to trial participation, as is common in real-world clinical practice. The study design prevented distinctions between potential harmful effects of sacubitril/valsartan washout vs. ACEi/ARB discontinuation. Thus, despite the absence of conclusive evidence to support beneficial effects of ACEi/ARB in patients with sRV dysfunction,⁷ sudden withdrawal of this therapy could potentially result in worsening heart failure in vulnerable patients.

Lessons learned from PARACYS-RV have important implications for the design of future trials. Crossover trials carry the advantage of removing inter-subject variability from group comparisons since each subject serves as their own control. This maximizes study power and statistical efficiency, which are particularly attractive features in the study of rare diseases. However, crossover trials require adequate washout periods to minimize carryover effects. As the PARACYS-RV trial demonstrates, these washout periods can have adverse effects, particularly in high-risk populations.

Finally, premature interruption of PARACYS-RV precludes firm conclusions regarding the efficacy of sacubitril/valsartan in patients with sRV dysfunction and NYHA Class II to III symptoms. Despite the small sample size, sacubitril/valsartan was associated with favourable trends regarding the two primary outcomes (i.e. SmTED and NT-proBNP). These promising results, along with encouraging observational studies,⁴ support the need for conclusive trials. Future trials should avoid crossovers to placebo and discontinuation of ACEi/ARB without substitution, such as a head-to-head comparison of sacubitril/valsartan vs. an ACEi/ARB.

Declarations

Disclosure of Interest

The trial was funded by an investigator-initiated grant from Novartis. Other than source of funding, the authors have no other potential conflicts of interest to disclose.

Data Availability

The data that support the findings of this study are available from the authors upon reasonable request.

Funding

The trial was funded by an investigator-initiated grant from Novartis. The sponsor provided feedback on the study design and manuscript but had no role in data collection, analysis, interpretation, writing of papers, and decisions to submit manuscripts for publication. A clinician research scholarship from the Fonds de recherche du Québec—Santé (FRQS) to M.A.C.; the André Chagnon research chair in electrophysiology and congenital heart disease to P.K.

Ethical Approval

The protocol was approved by the Ethics Committee/Institutional Review Board affiliated with the Montreal Heart Institute and by Health Canada. All subjects provided written informed consent to participate in the trial.

Pre-registered Clinical Trial Number

The trial was registered on Clinicaltrials.gov, NCT05117736.