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Pulmonary Arterial Hypertension Treatment
Quick Takes
- Drugs targeting the three traditional treatment pathways (nitric oxide, endothelin, and prostacyclin) significantly increased 6-minute walk distance (6MWD) and reduced the likelihood of clinical worsening compared to placebo in patients with PAH.
- Combination therapy targeting both the nitric oxide and endothelin pathway was associated with the greatest benefit in terms of 6MWD, time to clinical worsening, mortality, and NT-proBNP, compared with single therapy targeting the nitric oxide, endothelin, or prostacyclin pathways.
- Treatment heterogeneity was appreciated between treatment pathways and comorbidities: There was significant interaction between treatment pathway and age and diabetes for change in 6MWD, and between treatment pathway and age, hypertension, and coronary artery disease for the clinical worsening outcome.
Study Questions:
What is the comparative effectiveness of therapies targeting the different treatment pathways in pulmonary arterial hypertension (PAH)?
Methods:
This was an individual patient data (IPD) meta-analysis that included randomized controlled trials (RCTs) of PAH therapy that were submitted to the US Food and Drug Administration, which provided the IPD from these RCTs. The study sample consisted of PAH patients in phase 3 RCTs of approved PAH drugs. The individual drugs were grouped into treatment pathways based on their mechanism of action: ambrisentan, bosentan, macitentan, and sitaxentan were considered “endothelin pathway”; sildenafil, tadalafil, and riociguat were considered “nitric oxide pathway”; and iloprost, selexipag, treprostinil, and epoprostenol were considered “prostacyclin pathway.” The prostacyclin pathway drugs were stratified into oral/inhaled (PO/Inh) and intravenous/subcutaneous (IV/Sc) routes of administration.
The primary outcome was change in 6-minute walk distance (6MWD) from baseline to 12 or 16 weeks and time to clinical worsening. Clinical worsening was defined as any one of the following: all-cause death, hospitalization for worsening PAH, lung transplantation, atrial septostomy, discontinuation of study treatment (or study withdrawal) for worsening PAH, initiation of parenteral prostanoid therapy, or a decrease of ≥15% in 6MWD from baseline combined with either a worsening of World Health Organization (WHO) functional class from baseline or the addition of an approved PAH treatment. The IV/Sc prostacyclin pathway group was not assessed for the clinical worsening outcome because the epoprostenol trials did not capture most clinical worsening events, and the initiation of parenteral prostanoid therapy, which is a clinical worsening event, was the intervention in this group.
Results:
Of the 23 available RCTs, 20 phase 3 RCTs with 6,811 PAH patients were included in this analysis. There were 306 patients in the endothelin + nitric oxide pathway combination group, 999 in the nitric oxide pathway group, 1,414 in the endothelin pathway group, 1,321 in the PO/Inh prostacyclin pathway group, and 330 in the IV/Sc prostacyclin pathway group. The mean age was 49.2 ± 15.4 years, 78.4% were females, 69.3% were white, and 59.7% had idiopathic PAH.
At 12- or 16-week follow-up, 6MWD increased by 4.7 m in the placebo group, 46.6 m in the endothelin + nitric oxide pathway combination group, 33.7 m in the nitric oxide pathway group, 29.4 m in the endothelin pathway group, 23.1 m in the PO/Inh prostacyclin pathway group, and 31.1 m in the IV/Sc prostacyclin pathway group. After covariate adjustment, treatments targeting all three pathways significantly increased 6MWD at 12 or 16 weeks compared to placebo.
A total of 356 per 1,000 person-years had at least one clinical worsening event in the placebo group, 120 per 1,000 person-years in the endothelin + nitric oxide pathway combination group, 212 per 1,000 person-years in the nitric oxide pathway group, 215 per 1,000 person-years in the endothelin pathway group, and 238 per 1,000 person-years in the PO/Inh prostacyclin pathway group, respectively. After covariate adjustment, all treatment pathways significantly reduced the likelihood of having a clinical worsening event compared with placebo. The endothelin + nitric oxide pathway combination therapy significantly improved the primary outcomes compared with the single treatment pathways (except the IV/Sc prostacyclin pathway for the 6MWD outcome).
Interactions of the treatment pathways with potential effect modifiers were noted. There were significant interactions between treatment pathway and age and diabetes for the change in 6MWD outcome, and between treatment pathway and age, body mass index (BMI), hypertension, and coronary artery disease for the clinical worsening outcome. Treatment effects decreased with increasing age for all treatment pathways (except the IV/Sc prostacyclin pathway), with the nitric oxide pathway having the greatest decline. For the clinical worsening outcome, the treatment effect of the endothelin pathway did not vary by BMI. The treatment effect of the nitric oxide pathway decreased with increasing BMI, while the treatment effect of the PO/Inh prostacyclin pathway was greater with increasing BMI.
Conclusions:
Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH. Combination therapy targeting the endothelin and nitric oxide pathways was associated with the greatest benefit in terms of 6MWD and time to clinical worsening compared with single therapy targeting the nitric oxide, endothelin, or prostacyclin pathways. PAH therapy may be less effective in patients with some comorbidities, including older age, obesity, systemic hypertension, diabetes, and coronary artery disease.
Perspective:
The treatment of PAH has evolved significantly in the past decades with several PAH-specific medical therapies now available, encompassing three major pathways (nitric oxide, endothelin, and prostacyclin pathways). Their benefits have been shown in RCTs and have exhibited improvements in symptoms, exercise capacity, and a reduction in clinical worsening events. However, comparing the different therapies for PAH is a challenging task, in part due to the rarity of the disease. Although previous meta-analyses have compared the effectiveness of PAH therapies, these included study-level aggregate data rather than IPD. The use of IPD from multiple trials enables adjustment for confounders and provides more power to detect treatment-covariate interactions.
The current study complements the already available data of PAH medical therapy showing that all three pathways significantly improve outcomes when compared to placebo. The fact that combination therapy targeting the nitric oxide and endothelin pathways was associated with the greatest clinical benefit than any other single pathway therapy is relevant for clinical practice and further supports the Class I recommendation made by the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension on initial combination treatment for low- and intermediate-risk PAH patients. The treatment heterogeneity found is of important significance as well, as it may assist clinicians in shared decision making with patients when discussing selection of medical therapy. One should be cautious on the interpretation of the IV/Sc prostacyclin pathway group results given the historical epoprostenol trials included did not have the comprehensive data of other trials and these are currently used in clinical practice at higher doses, in faster up-titration, and in combination with other therapies.
Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension, Prevention
Keywords: Pulmonary Arterial Hypertension, Treatment Outcome
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