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Tadalafil for Combined Post-/Precapillary PH Treatment in HFpEF
Quick Takes
- PASSION was a randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of tadalafil in patients with heart failure with preserved ejection fraction (HFpEF) and combined postcapillary and precapillary pulmonary hypertension. The study was terminated prematurely because of drug supply issues.
- The available data did not support a significant impact on the composite primary endpoint of HF hospitalizations or death. All-cause mortality was higher in the tadalafil group compared to the placebo group.
Study Questions:
What is the safety and efficacy of tadalafil in patients with heart failure with preserved ejection fraction (HFpEF) and combined postcapillary and precapillary pulmonary hypertension (CpcPH)?
Methods:
PASSION (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension) was an investigator-initiated, randomized, placebo-controlled, double-blind, parallel-group, event-driven, multicenter, phase III trial funded by the German Federal Ministry of Education and Research and performed in Germany. Eligible patients had a confirmed diagnosis of HFpEF-CpcPH with New York Heart Association functional class (NYHA FC) III or IV symptoms or NYHA FC II symptoms with a history of ≥1 heart failure (HF)-associated hospitalization within the past 12 months before screening. Selected inclusion criteria included echocardiogram with a left ventricular ejection fraction ≥50% and right heart catheterization before screening with mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance (PVR) >3 WU. The target recruitment goal was 372 patients.
Patients were randomly assigned in a 1:1 fashion to tadalafil or placebo. Tadalafil was started at 20 mg qd and increased to 40 mg qd after 4 weeks. Patients who did not tolerate tadalafil 40 mg qd were allowed to down-titrate to 20 mg qd. The primary endpoint was event-free survival, which was the time to first event, defined as HF-related hospitalization or death resulting from any cause, whichever occurred first.
Results:
The first patient was randomized on March 12, 2019. The study was stopped on June 21, 2022 because of drug production issues in the manufacturing of tadalafil. Because of potential contamination, health authorities recalled all charges of tadalafil produced at that time. Because it was not possible to find appropriate replacement in a reasonable time frame, the steering committee decided to terminate the study.
At the time of study termination, a total of 125 patients had been randomized to receive tadalafil (n = 62) or placebo (n = 63). The primary endpoint events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil. Eleven patients died during the study: 2 of 63 (3%) in the placebo group and 9 of 62 (15%) in the tadalafil group. The risk of all-cause death was higher in patients assigned to tadalafil than in patients assigned to placebo (hazard ratio [HR], 5.10; 95% confidence interval [CI], 1.10–23.69; p= 0.04). Primary endpoint analyses in prespecified subgroups of patients with a diastolic pressure gradient ≥7 mm Hg or a pulmonary arterial compliance ≤2.3 mL/mm Hg also showed no significant differences between the two treatment arms. In a post hoc sensitivity analysis restricted to patients with a pulmonary vascular resistance (PVR) >5 WU (n = 59), 12 patients in the placebo group (19%) and 11 in the tadalafil group (18%) had a primary endpoint event (HR, 0.72; 95% CI, 0.29–1.75; p = 0.46).
Conclusions:
The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with HFpEF with CpcPH. There was a possible signal for increased all-cause mortality in the tadalafil group.
Perspective:
HFpEF patients who develop PH due to elevated left-sided filling pressures with an associated pulmonary vascular component—CpcPH—are at higher risk for morbidity and mortality compared to those with isolated postcapillary PH. The mainstream treatment for these patients has been the optimal medical management of HFpEF and its associated comorbidities, as there is no convincing evidence that pulmonary vasodilators offer a clear clinical benefit.
The recent European Society of Cardiology/European Respiratory Society (ESC/ERS) 2022 guidelines did not recommend the use of PH-specific medications for PH associated with left heart disease (group 2 PH) but could not give a specific recommendation in particular for or against the use of phosphodiesterase inhibitors in patients with HFpEF with CpcPH. Despite this, phosphodiesterase inhibitors are sometimes prescribed in clinical practice, possibly due to a notion of low risk for adverse effects and potential clinical benefit. Hence, clinical trials in this specific population are of great importance. Although it is unfortunate that the PASSION study was prematurely terminated, the available data are valuable in growing the understanding of how PH-specific medications may affect patients with HFpEF and CpcPH. The authors must be commended for the investigator-initiated effort to explore this population with still unmet needs and for presenting the available data concisely.
The results from this study showing no observed benefit do not support the routine use of tadalafil in HFpEF-CpcPH. Moreover, the potential safety concerns with higher all-cause death in the tadalafil compared to placebo group should give added pause to considering this intervention even when a significantly elevated PVR is present. Of note, a subgroup analysis looking at patients with significant pulmonary vascular disease (diastolic pressure gradient >7 mm Hg or PVR >5 WU) did not show a difference between groups. These results should further encourage physicians to discuss participation in ongoing clinical trials for patients with HFpEF-CpcPH.
Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Pulmonary Hypertension, Hypertension
Keywords: Hypertension, Pulmonary, Heart Failure, Preserved Ejection Fraction
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