Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis

Abstract

Background: Previous meta-analyses of treatments for pulmonary arterial hypertension (PAH) have not shown mortality benefit from any individual class of medication.

Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through November 2009 for randomized trials that evaluated any pharmacotherapy in the treatment of PAH. Reference lists from included articles and recent review articles were also searched. Analysis included randomized placebo controlled trials of at least eight weeks duration and studies comparing intravenous medication to an unblinded control group.

Results: 1541 unique studies were identified and twenty-four articles with 3758 patients were included in the meta-analysis. Studies were reviewed and data extracted regarding study characteristics and outcomes. Data was pooled for three classes of medication: prostanoids, endothelin-receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for mortality, 6-minute walk distance, dyspnea scores, hemodynamic parameters, and adverse effects. Mortality in the control arms was a combined 4.2% over the mean study length of 14.9 weeks. There was significant mortality benefit with prostanoid treatment (RR 0.49, CI 0.29 to 0.82), particularly comparing intravenous agents to control (RR 0.30, CI 0.14 to 0.63). Mortality benefit was not observed for ERAs (RR 0.58, CI 0.21 to 1.60) or PDE5 inhibitors (RR 0.30, CI 0.08 to 1.08). All three classes of medication improved other clinical and hemodynamic endpoints. Adverse effects that were increased in treatment arms include jaw pain, diarrhea, peripheral edema, headache, and nausea in prostanoids; and visual disturbance, dyspepsia, flushing, headache, and limb pain in PDE5 inhibitors. No adverse events were significantly associated with ERA treatment.

Conclusions: Treatment of PAH with prostanoids reduces mortality and improves multiple other clinical and hemodynamic outcomes. ERAs and PDE5 inhibitors improve clinical and hemodynamic outcomes, but have no proven effect on mortality. The long-term effects of all PAH treatment requires further study.

Figure 1

Study selection. PAH, pulmonary arterial hypertension.

Figure 2

Effects of prostanoids on mortality during treatment of PAH. CI, confidence interval; M-H, Mantel-Haenszel method.

Figure 3

Relationship between mortality rate and functional class severity in individual trials. Relationship between the relative risk of mortality with prostanoid treatment compared to placebo and the proportion of patients in each trial with functional class III or IV symptoms (weighted linear regression). Studies with a greater proportion of functional class III or IV patients showed a greater reduction in mortality (R² = 0.5093). Shaded circles represent studies of intravenous prostanoids.

Figure 4

Effects of ERAs on mortality during treatment of PAH. CI, confidence interval; ERA, endothelin receptor antagonist; M-H, Mantel-Haenszel method.

Figure 5

Effects of PDE5 inhibitors on mortality during treatment of PAH. CI, confidence interval; PDE5, phosphodiesterase type 5; M-H, Mantel-Haenszel method.