Comparative Effectiveness of Pharmacologic Interventions for Pulmonary Arterial Hypertension

Abstract

BACKGROUND:We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH).METHODS: MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016. Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected.RESULTS: Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA þ PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA þ PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo.CONCLUSIONS: Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy. REGISTRATION: PROSPERO CRD42016036803CHEST 2017; 151(1):90-105 KEY WORDS: comparative efficacy; network meta-analysis; pulmonary arterial hypertension ABBREVIATIONS: 6MWD = 6-min walk distance; ERA = endothelin receptor antagonist; FDA = Food and Drug Administration; GRADE = Grading of Recommendations Assessment, Development, and Education; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PDE5i = phosphodiesterase-5 inhibitor; RCT = randomized controlled trial; RR = risk ratio; SUCRA = surface under the cumulative ranking area; WHO = World Health Organization; WMD = weighted mean difference Pulmonary arterial hypertension (PAH) or World Health Organization (WHO) group 1 pulmonary hypertension is a progressive disease associated with significant morbidity and a 5% to 15% annual mortality rate. [1][2][3] In recent years, a number of drug classes to treat PAH have been approved for clinical use. These include endothelin receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE5i), parenteral and nonparenteral prostacyclins, a soluble guanylate cyclase stimulator, and a prostacyclin-receptor agonist. Although randomized ...

A focus on riociguat in the treatment of pulmonary arterial hypertension

“…When riociguat was compared with PDE‐5 inhibitors as a group (sildenafil and tadalafil), MD in 6MWD was found to be −2.51 m (95% CI: −31.93; 26.90), indicating that riociguat might not be more effective than the PDE‐5 inhibitors. It must be pointed out that results of this network meta‐analysis were based on low‐ to moderate‐quality evidence, due to differences in patient characteristics, outcome assessments and cointerventions . More trials and comparative trials are needed to determine whether one treatment is more effective than the other.…”

“…Compared to this, riociguat only showed clinical worsening in 2.8% of patients and PDE-5 inhibitors (sildenafil and tadalafil) in 5.7% of patients. 47 The point estimate for riociguat must be interpreted carefully since it is only based on the PATENT-1 study.…”

“…It must be pointed out that results of this network meta-analysis were based on low-to moderate-quality evidence, due to differences in patient characteristics, outcome assessments and cointerventions. 47 More trials and comparative trials are needed to determine whether one treatment is more effective than the other.…”

A pulmonologist's guide to understanding network meta-analysis

“…ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor. Produced from data reported in the study by JAIN et al[2].…”

The Selective Prostacyclin (Ip) Receptor Agonist Selexipag: A Promising Drug in Pediatric Pulmonary Artery Hypertension

“…The efficacy of selexipag was seen by improvements in pulmonary hemodynamics, exercise capacity, and clinical symptoms in a cohort of adult Japanese PAH patients [6]. More detailed discussion and information about selexipag use in adult PAH can be found in several recent reviews [7][8][9][10][11][12][13][14].…”