A Letter to the Editor of JACC-HF, which was Rejected

Sensible Medicine is proud to publish a brilliant critical appraisal that was sent as a letter to the editor but rejected.

Sensible Medicine is excited to publish this rejected letter to the editor of the journal JACC-HF. Our excitement comes from a) the specific lessons about the design of clinical trials, and b) we love being a place where strongly argued but contrary viewpoints can be read.

The specifics concern Chagas cardiomyopathy, which is caused by Trypanosoma cruzi infection. Chagas remains a serious health problem affecting about 6 million people, mainly in Latin America but is spreading around the world due to migration of infected patients to North America, Europe and Asia and Australia. Cardiomyopathy is the most serious complication of Chagas disease, occurring in 20-40% of infections during long-term follow-up. The cardiomyopathy is characterized by myocarditis that can involve all areas of the heart and conduction system.

JACC-HF has published the rationale and design of a Novartis-sponsored trial called PARACHUTE-HF, which compares sacubitril/valsartan (Entresto) vs enalapril. Regular readers here will recognize the similarity to the seminal PARADIGM-HF trial in patients with heart failure. Vinay Prasad authored this important critical appraisal of PARADIGM-HF.

The three Brazilian authors take issue with the design of this new trial. Editors at JACC-HF rejected their arguments. We find the letter to be well-argued. Dr Rassi is one of the world’s experts on Chagas cardiomyopathy. Here is a NEJM publication describing a risk score that he and colleagues developed for Chagas. JMM

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It is our pleasure to submit a letter to the editor regarding the very important manuscript recently published in JACC Heart Failure entitled: “Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial” by Bocchi EA, Echeverria LE, Demacq C, et al. August 1, 2024 JACC: Heart Failure | Vol. 12 No. 8

Title of the letter to the editor:

The Holes in PARACHUTE: A Study Falling Short

Authors: Anis Rassi Jr,¹ MD, PhD, FACC, FACP, FAHA; Luis Claudio L Correia,² MD, MPH; José Antonio Marin-Neto,³ MD, PhD, FACC

• ¹Division of Cardiology, Hospital do Coração Anis Rassi, Goiania, Brazil

• ²Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GE, USA

• ³Interventional Cardiology Unit, Division of Cardiology, Medical School of Ribeirao Preto, University of Sao Paulo, Brazil. Corresponding author: Anis Rassi Jr, MD, PhD, FACC, FACP, FAHA, Division of Cardiology, Hospital do Coração Anis Rassi

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Letter to the Editor: The Holes in PARACHUTE: A Study Falling Short

The PARACHUTE-HF trial¹ raises significant concerns by comparing sacubitril/valsartan to enalapril in patients with Chagas cardiomyopathy. The study's design violates a fundamental principle of causal inference: the consistency of treatment. While targeting the maximum dose of sacubitril/valsartan (200 mg twice daily), it uses only half the maximum approved dose of enalapril (20 mg/day instead of 40 mg/day), creating an uneven comparison that potentially favors sacubitril/valsartan.

The authors cite previous ACE-I placebo-controlled trials to justify their enalapril dosing, but this rationale is inadequate for active-treatment comparisons, where dose equivalence is crucial. Pointing to mean enalapril doses of 15-17 mg/day in those trials overlooks the fact that these studies capped dosing at 20 mg/day. Moreover, evidence from the HEDS study² demonstrated that NYHA class II-IV patients tolerated significantly higher enalapril doses, achieving a mean of 42.5 mg/day when targeting 60 mg/day. This suggests that higher enalapril doses could be feasible in PARACHUTE-HF.

With a target dose of 40 mg/day, citing the achieved mean enalapril dose of 18.4 mg/day in the CONSENSUS trial is misleading because that trial included only NYHA class IV patients. In contrast, the PARACHUTE-HF trial focuses on NYHA class II-III patients, who would likely tolerate higher doses of enalapril.

The key question remains: are the observed differences due to the addition of sacubitril to vasodilation therapy, or merely a result of unequal dosing.

Meta-analyses support the importance of equivalent dosing. A recent study showed that sacubitril/valsartan's superiority is evident only when compared to sub-equivalent doses of ACEIs or ARBs, not when doses are matched.³ Another meta-analysis in HF patients indicated that higher doses of ACEIs and ARBs, compared to lower doses, significantly improved outcomes.⁴

The study's open-label design increases the risk of differential misclassification of outcomes and performance biases. In addition, the use of win ratio analysis, which includes NT-proBNP reduction, further emphasizes the need for maximum doses in both groups, as NT-proBNP levels are dose-dependent on enalapril.⁵

While the protocol states that academic members of an executive committee designed the study in collaboration with Novartis, the authors' disclosures raise questions about the balance between academic and industry interests in its design.

References

1.         Bocchi EA, Echeverria LE, Demacq C, et al. Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial. JACC Heart Fail. 2024;12(8):1473-1486.

2.         Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al. Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. High Enalapril Dose Study Group. J Am Coll Cardiol. 2000;36(7):2090-2095.

3.         Rindone JP, Mellen CK. Sacubitril/valsartan compared to equivalent/sub-equivalent dose angiotensin receptor blocker or angiotensin-converting enzyme inhibitor in heart failure with reduced ejection fraction: a meta-analysis of randomized trials. Eur J Clin Pharmacol. 2024;80(8):1113-1120.

4.         Khan MS, Fonarow GC, Ahmed A, et al. Dose of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Outcomes in Heart Failure: A Meta-Analysis. Circ Heart Fail. 2017;10(8):e003956.

5.         Brunner-La Rocca HP, Weilenmann D, Kiowski W, Maly FE, Candinas R, Follath F. Within-patient comparison of effects of different dosages of enalapril on functional capacity and neurohormone levels in patients with chronic heart failure. Am Heart J. 1999;138(4 Pt 1):654-662.

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