Author + information
- aRespiratory Department, Hospital Ramón y Cajal and Universidad de Alcalá (IRYCIS), Madrid, Spain
- bCardiology Department, Hospital Universitario Doce de Octubre, Madrid, Spain
- ↵∗Address for correspondence:
Dr. David Jiménez, Respiratory Department and Medicine Department, Hospital Ramón y Cajal and Universidad de Alcala (IRYCIS), 28034 Madrid, Spain.
Pulmonary arterial hypertension (PAH) still has a poor prognosis despite the advances in treatment options that have occurred over the past 2 decades (1). The World Health Organization (WHO) functional (disease severity) classification for PAH strongly predicts mortality (2). A 2015 clinical practice guideline proposed a goal-oriented PAH treatment strategy based on a comprehensive risk stratification that includes assessments of WHO functional class, clinical signs of right heart failure, exercise capacity (e.g., 6-min walking test [6MWT] or cardiopulmonary exercise testing), and right ventricular function (brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, or echocardiography) (3). Using the guideline’s risk definitions, investigators recently used the SPAHR registry (Swedish PAH Registry) to explore the potential prognostic advantage of moving from a non–low-risk profile to a low-risk profile (4). Of the 530 registry patients, 383 completed a 1-year follow-up assessment. The 54 patients who improved from non-low risk to low risk had similar 1-, 3-, and 5-year survival (98%, 96%, and 96%) compared with the 57 patients who remained in the low-risk subgroup at baseline and during follow-up (100%, 98%, and 89%) (4). Because the study also showed that the 59 patients who deteriorated in risk category (i.e., from low- to intermediate- or high-risk categories) had worse survival, it provided the rationale for an aggressive treatment strategy that aims to have patients who have a non-low risk profile to improve to a low-risk profile.
During the last 2 decades, a number of randomized controlled trials have evaluated the efficacy and safety of targeted therapies for PAH, that included prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and a soluble guanylate cyclase stimulator (5). Debate has occurred over the decades regarding the most appropriate efficacy and safety outcomes that PAH trials should use. Most of the PAH drugs obtained regulatory approvals on the basis of short-term studies that mainly demonstrated improvements in exercise capacity (e.g., improvement in the 6MWT). Alternatively, more recent long-term, event-driven trials for novel drugs used morbidity and mortality endpoints, which might represent a more robust assessment of efficacy (6,7). However, studies have not strongly demonstrated the validity of PAH-related morbidity as a surrogate outcome measure.
In this issue of the Journal, McLaughlin et al. (8) reported their assessment of the prognostic relevance of PAH-related morbidity in the setting of a randomized controlled trial. They analyzed data from 2 global, double-blind, randomized, placebo-controlled, event-driven phase III trials, SERAPHIN (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension) and GRIPHON (Selexipag [ACT-293987] in Pulmonary Arterial Hypertension). In the SERAPHIN trial, pre-specified, independently adjudicated, morbidity events included worsening of PAH (i.e., decrease in the 6MWT, worsening of symptoms, or the need of additional treatment for PAH), initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy. The GRIPHON trial used slightly different pre-specified, independently adjudicated, morbidity events that included disease progression (i.e., 15% decrease in the 6MWT and either worsening in WHO functional class or need for additional PAH therapy) and worsening of PAH (i.e., hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, lung transplantation, or balloon atrial septostomy). In the combined total cohorts from both studies, the patients who experienced a morbidity event tended to have worse impairment, defined by a higher WHO functional class status and a shorter 6MWT, compared with those who did not have an event. After adjustment for randomized treatment, 6MWT distance, and WHO functional class, the randomized patients (intention to treat) who experienced a PAH-related nonfatal morbidity event within the first 3 months of follow-up had a 2.3-fold increased risk of death in the SERAPHIN trial, and a 3.1-fold increased risk of death in the GRIPHON study in comparison with the patients who did not have such a morbidity event. Analyses based on the 6-month and 12-month landmarks yielded similar findings (i.e., an association between morbidity events and increased risk of death) for both studies, and the results indicated no heterogeneity of the effect of morbidity between the treatment arms (p value for interaction = 0.30 in the SERAPHIN trial; p value for interaction = 0.15 in the GRIPHON study). The study did not address whether the number of nonfatal morbidity events experienced by the patients would modify the magnitude of the association between morbidity and mortality.
The McLaughlin et al. (8) study demonstrates an association between morbidity events and survival in patients who have PAH. This study provides indirect evidence that supports the consideration of using specific PAH augmentation therapy for clinical deterioration. Though this study did not provide strong evidence for widespread implementation of such a strategy, clinicians should use the results to bolster their clinical decision making until further data emerge. Future studies should determine the effects of augmented PAH therapy on morbidity events, and the relationship between the morbidity event rates and survival (9).
Recognition of the importance of worsening PAH as a clinical event should lead to the concept that new drugs for patients with PAH might exert beneficial effects by maintaining clinical stability through a reduction in the risk of morbidity. Similar to published heart failure trials, future PAH trials might consider a hierarchical clinically relevant composite outcome that combines nonfatal morbidity events and mortality. The composite outcome might rank relevant measures and outcomes according to clinical priority (10). We encourage investigators to incorporate clinically important PAH-related morbidity events (e.g., worsening of PAH and disease progression) into clinical trial primary outcome assessments.
Until well-designed trials demonstrate that the intervention’s effects on PAH-related morbidity have an association with its effect on mortality, clinicians may pursue treatment regimens that prevent deterioration of patients who have PAH.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Stępnowska E.,
- Lewicka E.,
- Dąbrowska-Kugacka A.,
- Miękus P.,
- Raczak G.
- Galie N.,
- Humbert M.,
- Vachiery J.L.,
- et al.
- Kylhammar D.,
- Kjellstrom B.,
- Hjalmarsson C.,
- et al.
- Badlam J.B.,
- Bull T.M.
- McLaughlin V.V.,
- Hoeper M.M.,
- Channick R.N.,
- et al.
- Califf R.M.