The Effect of Additive On-Demand Sildenafil vs. Dextrose Candy on Maximum Exercise Capacity in Pulmonary Arterial Hypertension

This study is a prospective, randomized, cross-over trial evaluating the effects of additive 20 mg sildenafil versus placebo/sham dextrose candy on exercise capacity in patients with previously diagnosed pulmonary arterial hypertension (PAH).

PAH is a progressive and debilitating disease characterized by increased mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), leading to right ventricular overload, and ultimately right heart failure. Despite advancements in pharmacological therapy, treatment options remain limited and optimizing individualized approaches to improve exercise capacity and manage symptom burden remains a challenge.

Phosphodiesterase type 5 inhibitors, such as sildenafil, are cornerstones of PAH treatment, enhancing pulmonary vasodilation and improving haemodynamics. While three times daily dosing is standard with three time 20-80mg daily. On-demand additive sildenafil use before exercise has not been studied, but as recent trials have shown that dosing up to three times 80mg is as safe as 20mg, there is a potential that additive therapy may be beneficial. Given sildenafil's rapid onset of action with peak effects after 30-120 minutes, it may offer acute functional benefits regarding maximum workload (Wmax) when administered shortly beforehand, in the terms of a "pill-in-the pocket" intake.

After providing informed consent, eligible participants (aged 18 - 80 years, with PAH diagnosed according to the ESC/ERS 2022/2019 guidelines) will be randomly assigned to receive either 20 mg sildenafil or dextrose candy (Dextro Energy). 45 minutes post-intake, they will undergo incremental spiroergometry (10-20 W increases) and right heart focused stress-echocardiography on a cycle ergometer until exhaustion. After a rest phase of 30 minutes, patients will perform CWRET at 75% of achieved Wmax until exhaustion. Then, after a washout period of minimum 24 hours up to 12 weeks, participants will cross over to the opposite treatment, repeating the same protocol.

In case of a beneficial result, our study could support the use of an additive pill-in-the-pocket therapy strategy which may allow treatment to be tailored to the individual activity demands of patients.

Inclusion criteria

• Signed Informed consent
• Age 18 - 80 years (both sexes)
• Pulmonary hypertension (PH) class I (PAH) previously diagnosed according to ESC/ERS 2022/2019 guidelines (mPAP ≥ 20 mmHg, PVR ≥ 2 WU, PAWP ≤ 15 mmHg) during diagnostic right-heart catheterization.
• Stable condition, on the same PH-medication for >4 weeks

Exclusion criteria

• Severe resting hypoxia (PaO2 <7.3 kPa)
• Moderate-to-severe chronic obstructive or restrictive pulmonary disease (FEV1 ≤ 60% predicted, FVC ≤ 60% predicted)
• Women with known pregnancy or breast feeding
• Other clinically significant concomitant disease states (e.g., severe renal or hepatic disease, unstable cardiovascular disease, etc.)
• Concurrent medication with:

• Nitric oxide donors (molsidomine, nicrorandil, etc.)
• Soluble guanylate cyclase stimulators (riociguat)
• Potent CYP3A4 inhibitors (azoles, clarithromycin, protease inhibitors)
• History of anterior ischemic optic neuropathy or hereditary retinal disease
• Participation in another study with investigational drug with potential influence the study data within the 30 days preceding and during the present study.
• Known allergies or hypersensitivity to sildenafil 20mg (Revatio 20mg) or dextrose candy (Dextroenergy) including any of its components