Abstract
BackgroundPulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients.MethodsWe performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy.ResultsTen RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 ± 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%.ConclusionWhen applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.
Highlights
Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade
Articles were selected that described hemodynamic changes from baseline and considered trials among patients with idiopathic PAH (iPAH), or PAH associated with connective tissue diseases (CTD), congenital heart disease (CHD) or Human Immunodeficiency Virus (HIV)
Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil
Summary
Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. With the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients. A number of drug classes have been approved for this indication on the basis of randomized controlled trials (RCTs), namely prostanoids (epoprostenol and iloprost), a phosphodiesterase-5-inhibitor (sildenafil), and endothelin (ET)-. Given the paucity of data on which to differentiate the available therapies, there are continuing discussions as to the prognostic accuracy of surrogate endpoints such as cardiopulmonary hemodynamics. The authors developed a predictive equation based on mean right atrial pressure (mRAP), mean pulmonary artery pressure (mPAP) and cardiac index (CI). The accuracy of the equation and predictive nature of the three hemodynamic variables were subsequently validated by several authors [5,6,7]
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