A Meta-Analysis of RCTls in Pulmonary Arterial Hypertension
A Meta-Analysis of RCTls in Pulmonary Arterial Hypertension
Aims: There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. The effect on survival of these compounds has not been appropriately assessed in individual trials because of small sample size and short duration. We performed a meta-analysis of all randomized controlled trials with drugs published in this condition.
Methods and Results: Trials were searched in the Medline database from January 1990 to October 2008. The primary analysis included only studies with a placebo comparator arm, the sensitivity analysis also included studies comparing two active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35-0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39-1.00; P = 0.048).
Conclusion: The results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension.
Pulmonary arterial hypertension is a devastating, progressive disease with increasingly debilitating symptoms. Increased pulmonary vascular resistance owing to obstructive proliferative changes in the lung microcirculation results in extensive heart structural changes, limits patients exercise capacity, and eventually leads to right heart failure and premature death.
The pathogenesis of pulmonary arterial hypertension is poorly understood, but an imbalance between vasoconstrictor/proliferative agents (e.g. endothelin) and vasodilator/antiproliferative substances (e.g. prostacyclin and nitric oxide) have been identified in the lung vasculature.
There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and the phosphodiesterase type-5 inhibitors. These therapies improve symptoms, exercise capacity, haemodynamics, and outcome but the clinical relevance of these effects have been recently challenged. The main criticisms include the limited improvements observed on the exercise capacity and the short duration and the small sample size of the individual studies which have precluded any insight on the prognostic relevance of the treatments.
A meta-analysis on 16 randomized controlled trials (RCTs) performed in pulmonary arterial hypertension concluded that the treatments 'produced limited benefits in clinical endpoints and failed to support a significant survival advantage.' However, the meta-analysis did not consider six RCTs published before its submission, included both acute and long-term studies and included one study on patients with lung fibrosis.
We present the data of a meta-analysis on 23 RCTs with drugs performed exclusively in pulmonary arterial hypertension patients (only in one study a minority of patients with inoperable chronic thrombo-embolic pulmonary hypertension was included) published as of October 2008. We excluded acute studies assessing only haemodynamic variables.
Abstract and Introduction
Abstract
Aims: There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. The effect on survival of these compounds has not been appropriately assessed in individual trials because of small sample size and short duration. We performed a meta-analysis of all randomized controlled trials with drugs published in this condition.
Methods and Results: Trials were searched in the Medline database from January 1990 to October 2008. The primary analysis included only studies with a placebo comparator arm, the sensitivity analysis also included studies comparing two active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35-0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39-1.00; P = 0.048).
Conclusion: The results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension.
Introduction
Pulmonary arterial hypertension is a devastating, progressive disease with increasingly debilitating symptoms. Increased pulmonary vascular resistance owing to obstructive proliferative changes in the lung microcirculation results in extensive heart structural changes, limits patients exercise capacity, and eventually leads to right heart failure and premature death.
The pathogenesis of pulmonary arterial hypertension is poorly understood, but an imbalance between vasoconstrictor/proliferative agents (e.g. endothelin) and vasodilator/antiproliferative substances (e.g. prostacyclin and nitric oxide) have been identified in the lung vasculature.
There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and the phosphodiesterase type-5 inhibitors. These therapies improve symptoms, exercise capacity, haemodynamics, and outcome but the clinical relevance of these effects have been recently challenged. The main criticisms include the limited improvements observed on the exercise capacity and the short duration and the small sample size of the individual studies which have precluded any insight on the prognostic relevance of the treatments.
A meta-analysis on 16 randomized controlled trials (RCTs) performed in pulmonary arterial hypertension concluded that the treatments 'produced limited benefits in clinical endpoints and failed to support a significant survival advantage.' However, the meta-analysis did not consider six RCTs published before its submission, included both acute and long-term studies and included one study on patients with lung fibrosis.
We present the data of a meta-analysis on 23 RCTs with drugs performed exclusively in pulmonary arterial hypertension patients (only in one study a minority of patients with inoperable chronic thrombo-embolic pulmonary hypertension was included) published as of October 2008. We excluded acute studies assessing only haemodynamic variables.
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