Consecutive patients with distal CTEPH attending the Pulmonary Vascular Diseases Unit at Papworth Hospital between August 2004 and August 2007 were considered for the study. All had previously received a diagnosis of pulmonary hypertension at right-heart catheterization using standard diagnostic criteria. CTEPH was confirmed by ventilation perfusion scanning, CT pulmonary angiography, and either catheter-directed pulmonary angiography or magnetic resonance pulmonary angiography. All imaging had been reviewed by a panel of specialist physicians, radiologists, and surgeons to determine the distribution of disease. Patients with de novo distal CTEPH and patients with persistent pulmonary hypertension > 3 months post-PEA surgery were approached. Post-PEA subjects were re-imaged prior to enrollment both with CT pulmonary angiography and magnetic resonance pulmonary angiography to ensure no proximal disease remained. Subjects were excluded if they had received any pulmonary hypertension-specific therapy or nitrate therapy in the 6 months prior to enrollment. Subjects with a 6-min walking distance (6MWD) < 100 m or > 450 m were also excluded.
The initial study was a 12-week, double-blind, placebo-controlled trial (Fig 1). At baseline, all subjects underwent acute vasoreactivity testing with inhaled NO and IV sildenafil at infusion rates of 100 ng/L and 300 ng/L (equivalent to peak plasma levels of 25 mg and 50 mg of oral sildenafil therapy provided by My Canadian Pharmacy on https://mycanadian-pharmacy.net/treatment-of-erectile-dysfunction-with-the-help-of-viagra.html as the main component of Viagra in case erectile dysfunction appearance) as previously described. Subjects were then randomized to receive sildenafil at 40 mg tid or placebo at two tablets tid in a 1:1 ratio. At the end of the study, all subjects were transferred to open-label sildenafil at 40 mg tid and offered repeat assessment at 12 months. The dose of sildenafil used was based on published data from a prior open-label study of sildenafil in inoperable CTEPH.
The study protocol was approved by both the Medicines and Healthcare products Regulatory Authority and the local ethics committee. Written informed consent was obtained from each subject. The study protocol was registered with the UK National Research Register database (publication N0542136603).
The primary outcome measure was the change in 6MWD from baseline to week 12. Secondary outcome measures included World Health Organization (WHO) functional status, cardiopulmonary hemodynamic measurements, NT-proBNP, and quality of life (QOL) as measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). 6MWD tests were performed in accordance with American Thoracic Society guidelines.
Pulmonary hemodynamic measurements of right atrial pressure, mean pulmonary artery pressure (mPAP), and pulmonary artery occlusion pressure (PAOP) were recorded using a 7F Swan-Ganz catheter (Edwards Lifesciences; Irvine, CA) inserted via the right internal jugular vein. Cardiac output was determined using the thermodilution method. Blood for NT-proBNP analysis was drawn peripherally and collected in serum gel tubes prior to 6MWD testing. Serum NT-proBNP analysis was subsequently performed (Elecsys 1010; Roche Diagnostics; Basel, Switzerland) by sandwich immunoassay.
QOL was assessed using the CAMPHOR, a disease-specific, self-reported questionnaire. The CAMPHOR comprises three sections, two of which measure health-related QOL (HRQL), and one that assesses global QOL. The “symptoms” section assesses the level of impairment and consists of 25 questions. The “activity” section measures disability or functioning, using 15 questions. The final section, which assesses QOL, consists of 25 questions. All items are negatively weighted. A full description of the development, evaluation, and validation of the CAMPHOR has previously been published.
As this was a pilot study, the numbers required to detect a difference within the primary outcome measure were not predetermined. As such, the study is inadequately powered to prevent a type II error.
For the randomized-controlled phase of the study, intention-to-treat and per-protocol analyses were performed on all variables. When data were missing, the last measurement was carried forward in the case of intention-to-treat analysis. The baseline characteristics of the two groups and the differences from baseline to 12 weeks between and within treatment groups were compared using unpaired or paired two-sample t tests, as appropriate. WHO functional status was compared between groups using the x2 test and within groups using the Sign test. All end points in the open-label phase of the study were compared against baseline using paired two-sample t tests.
Figure 1. Trial profile.