A meta-analysis of 23 RCTs in PAH revealed distinct toxicity profiles, with ERAs increasing edema risk (RR 1.46; 95% CI 1.25-1.72) and PDE5i/sGC stimulators increasing hypotension (RR 1.31).
Meta-Analysis (n=5,800)
Do different classes of PAH pharmacotherapy have distinct safety profiles in adults with WHO Group 1 PAH?
Distinct toxicity signatures define each PAH drug pathway, enabling individualized, risk-adjusted therapy selection and informing the use of multidrug regimens.
Abstract Rationale The combination of drugs with different mechanistic actions have enabled management Pulmonary Arterial Hypertension (PAH) effectively by targeting vasodilatory, antiproliferative, and anti-remodeling pathways. Despite this understanding, the literature documenting safety data across different classes is limited; current research investigates individual drug classes without accounting for combination patterns, overlapping toxicities, or patient comorbidity profiles. As this approach standardized in medical practice, it becomes increasingly important to evaluate drug interactions. We integrated randomized trial data spanning five mechanistic pathways, endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE5i), prostacyclin-pathway agents, soluble guanylate cyclase (sGC) stimulators, and activin-pathway agents to delineate safety landscape of PAH pharmacotherapy. We compared adverse-event (AE) profiles across PAH drug classes, quantified class-level differences in AE frequency and severity, and identified emerging toxicity trends in combination-therapy. Method We identified 23 randomized controlled trials enrolling adults with WHO Group 1 PAH and reporting safety outcomes through PubMed, Embase, and ClinicalTrials.gov (1996-2024). Data were extracted for peripheral edema, anemia, hepatic enzyme elevation, hypotension or syncope, bleeding, infection, and AE-related discontinuation. Risk ratios (RRs) with 95 % confidence intervals (CIs) were pooled using a random-effects (DerSimonian-Laird) model. Between-class heterogeneity was quantified with I² and p-heterogeneity tests. Forest plots and a black-and-white heatmap summarized class-specific AE risks. Results Across 23 RCTs (n ≈ 5,800), peripheral edema (≈ 19 %), anemia (≈ 8 %), hypotension/syncope (≈ 6 %), and AE-related discontinuation (≈ 5 %) were most common. ERAs showed the highest pooled risk for edema (RR 1.46 95 % CI 1.25-1.72) and hepatic enzyme elevation (RR 2.05 1.40-3.00). PDE5i and sGC stimulators increased hypotension or syncope (RR 1.31 1.08-1.60) but had favorable hepatic safety. Prostacyclin-pathway agents produced more gastrointestinal and headache AEs but fewer hepatic events. Activin-pathway agents demonstrated dose-dependent anemia (RR 1.35 1.10-1.68) and mild bleeding tendency. Overall class-level heterogeneity was significant (p 0.01), and the composite heatmap revealed clustering of ERA-related fluid retention, PDE5i/sGC-related hypotension, and activin-related cytopenia. Conclusion This cross-mechanistic investigation confirms that toxicity signatures define each PAH drug pathway. ERAs remain the leading cause of fluid retention and hepatic enzyme elevation, whereas PDE5i and sGC agents more often induce hypotension. Activin-pathway therapies introduce hematologic toxicity considerations that may shape monitoring. Recognizing these patterns enables individualized, risk-adjusted therapy selection and inform use of multidrug regimens. By integrating all mechanistic classes under a unified analytic framework, this meta-analysis provides first comprehensive safety map of PAH pharmacotherapy and a foundation for treatment optimization. This abstract is funded by: None
Abdullah et al. (Fri,) conducted a meta-analysis in Pulmonary Arterial Hypertension (n=5,800). PAH pharmacotherapy (ERAs, PDE5i, prostacyclin-pathway agents, sGC stimulators, activin-pathway agents) was evaluated on Adverse-event (AE) profiles across PAH drug classes. A meta-analysis of 23 RCTs in PAH revealed distinct toxicity profiles, with ERAs increasing edema risk (RR 1.46; 95% CI 1.25-1.72) and PDE5i/sGC stimulators increasing hypotension (RR 1.31).
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