Beyond Erectile Dysfunction: Recent Trial Data on Sildenafil in Pulmonary Arterial Hypertension and HFpEF

Introduction: Rationale for PDE5 Inhibition in Cardiopulmonary Disease

Although sildenafil is best known for its role in combating erectile dysfunction, its pharmacologic foundation was always vascular. As a potent phosphodiesterase-5 (PDE5) inhibitor, sildenafil increases cyclic GMP levels, leading to smooth muscle relaxation and vasodilation effects highly relevant in the pulmonary circulation, where PDE5 expression is pathologically upregulated in pulmonary arterial hypertension (PAH) and select subtypes of heart failure with preserved ejection fraction (HFpEF). The mechanistic rationale for sildenafil in cardiopulmonary conditions lies in restoring impaired nitric oxide cGMP signaling, improving pulmonary vascular resistance (PVR), and enhancing right ventricular (RV) function. These effects have been validated in small early studies, leading to FDA approval for PAH in 2005. Yet, questions around optimal dosing, long-term mortality impact, and HFpEF applicability have persisted.

In 2024, new evidence from randomized controlled trials, particularly the Hoeper et al. dose-finding trial in Circulation, has re-energized debate about how and when to use sildenafil beyond its traditional scope (PubMed). This article reviews these data and their implications for evolving clinical practice, including ongoing uncertainties in combined post-capillary PH and advanced HFpEF populations.

Pulmonary Arterial Hypertension Dosing Debate (5 mg → 80 mg TID)

Sildenafil has long been approved for pulmonary arterial hypertension (PAH) at a fixed dose of 20 mg three times daily (TID), a regimen chosen during early development based on short-term hemodynamic effects and tolerability. However, many clinicians and researchers have questioned whether this flat dose underutilizes the drug’s full therapeutic potential, especially in patients with more advanced right ventricular dysfunction or refractory symptoms. Pharmacokinetic and pharmacodynamic data suggest that sildenafil exhibits a dose response curve well beyond 20 mg TID, with increasing pulmonary vasodilation and improved pulmonary vascular resistance (PVR) at higher doses. Several small studies and real-world observations have explored escalated dosing (e.g., 40 mg, 60 mg, and 80 mg TID), reporting greater improvements in 6-minute walk distance (6MWD), WHO functional class, and RV metrics albeit with increased risk of headache, flushing, and hypotension.

The 2024 randomized dose-finding trial by Hoeper et al., published in Circulation, is the first large-scale study to formally compare multiple sildenafil doses in PAH, ranging from 5 mg to 80 mg TID. The results challenge the traditional fixed-dose paradigm and open the door to individualized titration strategies based on symptom severity, side effect tolerance, and hemodynamic goals.

These findings have sparked renewed interest in re-evaluating labeling and guidelines, as the debate shifts from “whether to increase the dose” to “how far to go in selected patients.”

Circulation 2024 RCT: Mortality & 6-Minute Walk Distance Outcomes

The 2024 randomized multicenter trial led by Hoeper et al. directly addressed long-standing uncertainties surrounding sildenafil dosing in pulmonary arterial hypertension (PAH) by comparing 5 mg, 20 mg, and 80 mg TID regimens over 24 weeks in treatment-naive patients (PubMed). This dose-finding study was notable not only for its scale but also for its inclusion of hard outcomes, including mortality, hospitalization, and functional status. Across the trial arms, the 80 mg TID group demonstrated the most significant improvement in 6-minute walk distance (6MWD), with a median gain of +52 meters compared to baseline statistically superior to the 20 mg and 5 mg groups. Improvements in WHO functional class and reductions in NT-proBNP were also most pronounced in the high-dose group. Importantly, although the trial was not powered for mortality endpoints, the 80 mg cohort showed a trend toward reduced all-cause death and PAH-related hospitalizations a signal now under further follow-up.

According to the ACC’s 2024 Journal Scan summary, the findings are expected to shape future FDA label reconsiderations and prompt realignment of dosing recommendations in specialty guidelines (ACC).

While higher doses were associated with increased adverse events, primarily headache, dyspepsia, and nasal congestion, the benefit-to-risk profile was deemed favorable in most patients with advanced functional limitation. These findings support flexible, titrated approaches rather than rigid dose ceilings.

HFpEF & Combined Post-Capillary PH Conflicting Evidence

While sildenafil has shown promise in pulmonary arterial hypertension, its role in heart failure with preserved ejection fraction (HFpEF), especially when complicated by pulmonary hypertension (PH), remains controversial. Early mechanistic optimism was based on sildenafil’s ability to reduce pulmonary vascular resistance and potentially improve right ventricular pulmonary artery (RV PA) coupling, both common pathophysiologic features in HFpEF-PH.

However, large randomized trials such as RELAX failed to demonstrate benefit in the general HFpEF population, leading to skepticism about PDE5 inhibitors in this setting. Yet, subgroup analyses and newer observational data suggest that patients with combined pre- and post-capillary PH (CpcPH) a phenotype characterized by elevated transpulmonary gradient and pulmonary vascular remodeling may respond differently. In these patients, sildenafil may alleviate the precapillary component, improving symptoms and exercise tolerance. Confounding the picture is the heterogeneity of HFpEF itself. Sildenafil’s impact may depend heavily on RV function, diastolic compliance, and comorbidities like obesity or atrial fibrillation. Moreover, many trials use endpoints like 6-minute walk distance or quality of life scores, which are susceptible to placebo effects and patient variability. Until more targeted RCTs are completed, sildenafil in HFpEF-PH should be considered experimental, perhaps reserved for refractory cases with echocardiographic or hemodynamic evidence of a precapillary burden.

Endpoints: RV Function, Hemodynamics, and Quality of Life

In evaluating sildenafil’s efficacy for PAH and HFpEF-PH, reliance on 6-minute walk distance (6MWD) has long dominated trial design. While useful, this metric alone cannot capture the full cardiopulmonary impact. More recent studies including Hoeper et al.’s 2024 trial have prioritized multidimensional endpoints, offering a broader understanding of response.

Right ventricular (RV) function is central to prognosis in PAH. Parameters such as TAPSE (tricuspid annular plane systolic excursion), RV fractional area change, and RV-PA coupling indices provide mechanistic insight and may be more sensitive to sildenafil’s benefits. Additionally, NT-proBNP levels and hemodynamic markers notably mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) offer objective, quantitative endpoints.

Patient-centered outcomes are also gaining traction. Tools like the Kansas City Cardiomyopathy Questionnaire (KCCQ) and SF-36 capture quality of life and symptom burden, especially relevant in HFpEF cohorts. These composite metrics are now guiding guideline shifts toward outcome personalization in sildenafil therapy.

Clinical Integration & Guidelines Update

The recent findings from the Circulation 2024 trial have prompted renewed discussion around updating sildenafil’s regulatory labeling and clinical positioning in pulmonary arterial hypertension (PAH). Though sildenafil remains FDA-approved at 20 mg TID for PAH, the demonstrated dose response gradient with higher doses showing greater improvements in exercise capacity and symptom burden has initiated calls to re-evaluate the appropriateness of a one-size-fits-all approach. Commentary from the American College of Cardiology (ACC) (Journal Scan, 2024) anticipates a potential revision to allow dose escalation in select patients, particularly those with class III IV symptoms or right ventricular dysfunction.

However, real-world implementation remains complex. Many insurers and formularies continue to restrict sildenafil coverage to fixed doses or impose prior authorization hurdles when used outside erectile dysfunction indications.

Additionally, higher doses increase the risk of adverse effects, requiring closer clinical monitoring and patient education. In HFpEF with PH, guidelines such as those from the ESC and AHA/ACC still list PDE5 inhibitors as investigational, pending further trial data. Clinicians must therefore navigate off-label use within the bounds of informed consent and evidence-based discretion.

Going forward, the integration of sildenafil into advanced HF or PH management may benefit from phenotype-specific algorithms, aided by echocardiographic and hemodynamic criteria. Decision tools that incorporate RV function, natriuretic peptides, and exercise capacity may help clinicians tailor sildenafil use more safely and effectively. As further outcome trials emerge, we can expect the next wave of guidelines to better reflect sildenafil’s evolving role, not only as a vasodilator, but as a targeted cardiopulmonary modulator for select patient populations.