Sildinafil in Pulmonary Hypertension-Rheumatic Chronic Valvular Disease(RCT) (SERIES)

Efficacy of Sildenafil in Severe Pulmonary Hypertension Secondary to Rheumatic Chronic Valvular Disease: A Double-Blinded Placebo Randomized Control Trial

Pulmonary hypertension secondary to left heart disease is associated with increased morbidity and mortality, particularly in patients with rheumatic chronic valvular heart disease, which remains highly prevalent in low- and middle-income countries. These patients often present late with severe pulmonary hypertension, limiting surgical options and worsening outcomes. Sildenafil, a phosphodiesterase-5 inhibitor, has demonstrated benefit in various forms of pulmonary hypertension; however, its role in pulmonary hypertension secondary to rheumatic valvular disease remains inadequately studied.

This double-blind, placebo-controlled randomized clinical trial aims to evaluate the efficacy and safety of sildenafil as an adjunct to standard medical therapy in patients with severe pulmonary hypertension due to rheumatic chronic valvular heart disease. Eligible participants will be randomized in a 1:1 ratio to receive either sildenafil (25 mg three times daily) or placebo for six weeks. The primary outcome is change in six-minute walk distance, while secondary outcomes include changes in right ventricular function and dimensions, systolic pulmonary artery pressure, NYHA functional class, and hospitalization rates. The study seeks to generate evidence to support medical optimization and bridging therapy in this high-risk population awaiting definitive surgical intervention.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Hypertension; Rheumatic Valvular Heart Disease
• Intervention / Treatment: Drug: Sildenafil 25 MG; Drug: Placebo

Detailed Description

Pulmonary hypertension (PH) secondary to left heart disease represents the most common form of pulmonary hypertension and is associated with significantly increased morbidity and mortality. In low- and middle-income countries, rheumatic chronic valvular heart disease remains a major contributor to left heart disease, with many patients presenting late with severe pulmonary hypertension and advanced right ventricular dysfunction. Severe pulmonary hypertension in this population complicates surgical decision-making, increases perioperative risk, and limits therapeutic options while patients await corrective valve surgery.

Sildenafil, a selective phosphodiesterase-5 inhibitor, increases cyclic guanosine monophosphate levels in the pulmonary vasculature, resulting in pulmonary vasodilation and improved right ventricular-pulmonary arterial coupling. While sildenafil has demonstrated efficacy in pulmonary arterial hypertension and selected forms of secondary pulmonary hypertension, evidence supporting its use in patients with pulmonary hypertension secondary to rheumatic valvular heart disease is limited. This randomized controlled trial is designed to evaluate the efficacy of sildenafil as an adjunct to standard medical therapy in patients with severe pulmonary hypertension due to rheumatic chronic valvular disease.

This study is a double-blind, placebo-controlled, randomized clinical trial conducted at the adult cardiology and cardiac surgery departments of the National Institute of Cardiovascular Disease (NICVD), Karachi and Hyderabad, Pakistan. Eligible patients aged 18 to 80 years with diagnosed rheumatic chronic valvular heart disease and severe pulmonary hypertension (defined as systolic pulmonary artery pressure ≥60 mmHg on echocardiography) will be enrolled. Participants will be randomized in a 1:1 ratio using permuted block randomization to receive either sildenafil 25 mg three times daily or matching placebo, in addition to standard guideline-directed medical therapy, for a duration of six weeks.

Randomization concealment will be ensured through an electronic allocation system, and outcome assessments will be performed by an independent team blinded to treatment allocation. Standard medical therapy will include rheumatic fever prophylaxis, diuretics, and guideline-directed therapy for heart failure where indicated. Patients undergoing corrective cardiac surgery within six weeks, those with contraindications to sildenafil, unstable cardiovascular conditions, or recent major cardiovascular events will be excluded.

The primary efficacy outcome is the change in six-minute walk distance from baseline to six weeks. Secondary outcomes include changes in right ventricular function and dimensions assessed by echocardiography, systolic pulmonary artery pressure, New York Heart Association functional class, and number of hospitalizations during the study period. Safety monitoring will include regular telephonic follow-up to assess medication adherence and adverse events, with predefined criteria for treatment discontinuation and trial termination in the event of significant harm.

The results of this trial are expected to provide evidence regarding the role of sildenafil in improving functional capacity and hemodynamic parameters in patients with severe pulmonary hypertension secondary to rheumatic chronic valvular heart disease and may inform medical optimization strategies for patients awaiting definitive surgical intervention.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Dr Aamir Khuwaja; Phone Number: 03323594539; Email: khuwaja.aamir91@gmail.com
• Study Contact Backup: Name: Dr Raheela Khowaja; Phone Number: 03312273977; Email: drraheela.allahbux@gmail.com

Study Locations

• Pakistan
  • Sindh
    • Hyderābād, Sindh, Pakistan
      • Recruiting
      • Sindh Institute of Cardiovascular Diseases
      • Contact: Dr Aamir Khuwaja; Phone Number: 03323594539

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient with diagnosed rheumatic valvular heart disease
2. Age between 18-> 80 years
3. Severe pulmonary hypertension

Exclusion Criteria:

1. Patient undergoing corrective surgery within 6 weeks
2. Uncontrolled hypertension (>170/110mmHg)
3. Hypotension (Blood pressure of < 90/50mmHg)
4. Heart Failure or Coronary Arterial Diseases with Unstable Angina
5. Hypersensitivity to sildenafil or any component of the formulation of sildenafil
6. Prior episode of non-arteritic anterior ischemic neuropathy
7. Stroke in last 6 months
8. Life-threatening arrhythmias
9. MI in last 6 months
10. Patient takes nitrates as essential drug therapy
11. Patient doesn't have a plan for corrective surgery within 6 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Participants receive oral sildenafil 25 mg three times daily for 6 weeks in addition to standard guideline-directed medical therapy for rheumatic chronic valvular heart disease and associated conditions.	Drug: Sildenafil 25 MG; Thrice a day
Placebo Comparator: Placebo Group; Participants receive matching placebo three times daily for 6 weeks in addition to standard guideline-directed medical therapy.	Drug: Placebo; Thrice a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6-Minute Walk Distance (6MWD)	Change in distance walked during the 6-minute walk test from baseline to 6 weeks after randomization.	Baseline to 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Right Ventricular Function Description:	Change in right ventricular systolic function assessed by echocardiographic parameters (including tricuspid annular plane systolic excursion [TAPSE] and/or other standard RV functional indices) from baseline to 6 weeks.	Baseline to 6 weeks
Change in Right Ventricular Dimensions	Change in right ventricular dimensions measured by transthoracic echocardiography from baseline to 6 weeks.	Baseline to 6 weeks
Change in Systolic Pulmonary Artery Pressure	Change in systolic pulmonary artery pressure estimated by echocardiography from baseline to 6 weeks.	Baseline to 6 weeks
Change in New York Heart Association (NYHA) Functional Class	Change in NYHA functional class from baseline to 6 weeks.	Baseline to 6 weeks
Number of Hospitalizations	Number of hospitalizations for cardiovascular causes during the 6-week study period.	Up to 6 weeks

Collaborators and Investigators

• Sponsor: Sindh Institute of Cardiovascular Diseases
• Collaborators: National Institute of Cardiovascular Diseases
• Investigators: Study Director: Dr Jawaid Akbar Sial, Sindh Institute of Cardiovascular Diseases

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Six minutes walk
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; Purines; Sulfonamides; Sulfones; Piperazines; Sildenafil Citrate
• Other Study ID Numbers: ERC-44/2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No