In this single-center, randomized, double-blind, placebo-controlled pilot study, sildenafil significantly improved WHO functional class and PVR in subjects with distal CTEPH over 12 weeks. Although failing to achieve its primary outcome measure, this study presents further controlled data to support the use of medical therapy in inoperable CTEPH. Furthermore, the sustained improvements in 6MWD, symptom scores, activity scores, hemodynamics, and NT-proBNP levels seen at 12 months suggest that sildenafil may favorably alter the natural history of the disease.
The 6MWD is a well-established assessment tool in PAH and has also been proposed as an appropriate end point in CTEPH. Although improvements were seen in 6MWD and Borg dyspnea score in the sildenafil group at 12 weeks, neither changes achieved statistical significance. This likely reflects the pilot and hence the underpowered nature of the study. In addition, the 6MWD achieved by the placebo group may have been confounded by the high proportion of post-PEA subjects within this group. Evidence suggests that although hemodynamic improvements typically peak within 3 months of PEA, further improvements in functional performance occur beyond this, presumably as a result of ongoing improvements in fitness and conditioning. As four placebo subjects were recruited just 3 months after PEA, this issue may have positively influenced the 6MWD achieved by this group.
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Of 21 subjects recruited, 19 subjects fulfilled inclusion criteria and were randomly assigned to receive either sildenafil at 40 mg tid (9 subjects) or placebo at two tablets tid (10 subjects). Baseline characteristics are shown in Table 1. Despite randomization, there were significant differences between the two groups with respect to baseline WHO functional status, CAMPHOR scores, and proportion of post-PEA subjects.
An extensive urticarial rash developed in one subject in the sildenafil arm, who was thus withdrawn from the study. No other code break took place before the 12-week assessment.
Acute Vasoreactivity Testing
The results of acute vasoreactivity testing with inhaled NO and IV sildenafil have been previously described elsewhere.
Outcome Measures: 12 Weeks
The changes from baseline in 6MWD (Fig 2) and Borg dyspnoea scale did not differ significantly between the sildenafil and placebo groups. Significant improvements were demonstrated however in WHO functional status and PVR (Table 2). The improvement in PVR remained significant even after results were adjusted for baseline differences. The difference in mPAP was not significant by intention-to-treat analysis (— 6.2 mm Hg; p = 0.052; 95% confidence interval [CI], — 12.4 to 0.1) but was significant when per-protocol analysis was applied (— 6.9 mm Hg; p = 0.04; 95% CI, — 13.4 to — 0.4). Furthermore, the change in mPAP within the sildenafil group was also significant when compared with baseline (— 6.5 mm Hg; p = 0.026; 95% CI, — 12.0 to — 1.1). Similarly, there was a significant improvement in the activity component of the CAMPHOR score within subjects receiving sildenafil (— 2.9; p = 0.008; 95% CI, — 4.7 to — 1.0).
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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.
Continue reading “My Canadian Pharmacy: Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension”
Chronic thromboembolic pulmonary hypertension (CTEPH) represents an uncommon consequence of acute pulmonary embolic disease. Untreated, it leads to progressive right ventricular dysfunction and death. In patients with predominantly “proximal” disease, surgical intervention (pulmonary endarterectomy [PEA]) can be effective. However, when hemodynamic compromise is disproportionate to the degree of surgically accessible disease, surgery is often inappropriate. In addition, a proportion of surgical patients have persistent pulmonary hypertension postoperatively as a result of residual inaccessible disease. Both groups of patients have “distal” disease, in which the majority of the disease lies beyond the subsegmental level.
There are currently no licensed therapies for these patients, and thus their long-term outcomes are typically poor.
Conversely, in idiopathic pulmonary arterial hypertension (IPAH), a range of licensed vasoactive therapies is available that significantly improves morbidity and mortality. Histopathologic studies suggest that the small-vessel changes seen in IPAH may also be common to CTEPH, coexisting with the more classically described obstructive lesions. These vasculopathic changes have predominantly been described in unobstructed beds and may represent a maladaptive response to elevated pressure and shear stress. Given this shared vasculopathic morphology, there has been considerable interest in using IPAH-specific vasoactive therapies in patients with distal CTEPH.
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