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.
Until now, the only evidence that vasoactive therapy may be beneficial in distal CTEPH, was derived from open-label and/or uncontrolled studies. Although the randomized controlled Aerosolized Ilo-prost Randomization study included 57 subjects with CTEPH, retrospective subgroup analysis failed to show any significant advantages from inhaled iloprost on either exercise capacity or hemodynamics in this patient cohort. Recently, however, more placebo-controlled data regarding the use of bosen-tan, an endothelin receptor antagonist, has become available courtesy of the Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension study. This 16-week study demonstrated advantages with bosentan use in terms of pulmonary vascular resistance (PVR) and N-terminal pro brain natriuretic peptide (NT-proBNP) levels, although it also failed to show any improvement in exercise capacity. As such, the exact role of medical therapy in inoperable CTEPH is still unclear.
Sildenafil, a selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase-5, has proven efficacy in IPAH. It enhances nitric oxide (NO)-mediated vasodilatation and may have additional beneficial effects on platelet activation, pulmonary vascular remodeling, and cardiac function. There is evidence that patients with distal CTEPH show a partial response to acute administration of inhaled NO.- Furthermore, two small open-label studies- have demonstrated sustained benefits from long-term sildenafil therapy. Therefore, the objective of this randomized, double-blind, placebo-controlled pilot study is to examine the efficacy and tolerability of sildenafil therapy in distal CTEPH.