Pulmonary arterial hypertension (PAH) remains a disease with significant morbidity and mortality despite a plethora of modern medications with known mechanisms of action and an active search for novel therapeutic targets and approaches.1Galie N. Humbert M. Vachiery J.-L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)., 2Galie N. Channick R.N. Frantz R.P. et al.Risk stratification and medical therapy of pulmonary arterial hypertension., 3Mercurio V. Bianco A. Campi G. et al.New drugs, therapeutic strategies, and future direction for the treatment of pulmonary arterial hypertension. Based on several large clinical trials (eg, the AMBITION, SERAPHIN, and GRIPHON trials), it is now clear that combination therapy (whether upfront, such as in AMBITION, or sequential) is the best current approach for these patients.4Galie N. Barbera J.A. Frost A.E. et al.Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension., 5Pulido T. Adzerikho I. Channick R.N. et al.Macitentan and morbidity and mortality in pulmonary arterial hypertension., 6Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension., 7Sitbon O. Cottin V. Canuet M. et al.Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension., 8Vonk Noordegraaf A. Chin K.M. Haddad F. et al.Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. However, timing of treatment initiation and drug choice remain critical in tackling a disease with unacceptably high morbidity and mortality.3Mercurio V. Bianco A. Campi G. et al.New drugs, therapeutic strategies, and future direction for the treatment of pulmonary arterial hypertension.In this issue of CHEST, Gaine and colleagues9Gaine S. Sitbon O. Channick R.N. et al.Relationship between time from diagnosis and morbidity/mortality in pulmonary arterial hypertension: results from the phase III GRIPHON study. addressed an interesting question, whether early is better than delayed treatment with, in this case, selexipag, an oral prostacyclin receptor (IP receptor) agonist. In a post hoc analysis of one of the largest randomized controlled clinical trials in PAH to date, GRIPHON,6Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension. the authors investigated the impact of time from diagnosis to selexipag initiation on morbidity and mortality. Patients were dichotomized based on their time from PAH diagnosis to the date of study randomization, using a 6-month threshold (ie, lesser or greater than 6 months). Hazard ratios were calculated for the primary endpoint of morbidity and mortality events using Cox proportional hazard models. The results indicated that most patients (65.1%) in this trial received selexipag 6 months after the time of PAH diagnosis. Newly diagnosed patients (less than 6 months from the time of diagnosis) had poorer long-term outcomes when on placebo (50% reaching the primary outcome compared with 37% of patients with longer PAH diagnosis). Compared with placebo, selexipag reduced the outcome in both groups, however, with a more pronounced effect, 55% vs 26%, in newly diagnosed (6 months) from diagnosis. The authors conclude that newly diagnosed patients have a worse prognosis compared with patients with a longer time from diagnosis, but a better outcome in response to selexipag. There was an equal distribution of patients in the low-, intermediate-, and high-risk groups, when sorted according to the European Society of Cardiology and the European Respiratory Society risk stratification guidelines1Galie N. Humbert M. Vachiery J.-L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). for both groups. Although there were some geographical differences (a higher proportion of patients from Asia and Eastern Europe for newly diagnosed patients) and a higher proportion of patients receiving background double combination in the longer time from diagnosis group, these factors, we are told, did not significantly influence the results.The methods used for this post hoc analysis appear, in general, to be sound. However, some caveats related to the interpretation of the results are noteworthy. First, the 6-month cutoff chosen for this study was based on previous studies and conventional agreement5Pulido T. Adzerikho I. Channick R.N. et al.Macitentan and morbidity and mortality in pulmonary arterial hypertension.,10Simonneau G. Channick R.N. Delcroix M. et al.Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN. of time from diagnosis defining incident vs prevalent patients. This is an important point, considering the potential for an arbitrary cutoff as chosen post hoc. One would hope that the latter was not decided based on results producing the most meaningful difference between the “incident” and “prevalent” patients.

The effects of background therapy are also worth discussing, because they are not easily interpretable. The authors suggest that the results related to worse outcomes in incident patients are not explained by the fact that these patients were less likely, compared with prevalent patients, to be on background therapy at time of enrollment. However, as noted in the results, a low interaction P value “suggested a more pronounced treatment effect in newly diagnosed patients.” This could have potentially been statistically significant had the numbers been larger. In addition, as is now known from multiple registries, incident patients are more likely to die than prevalent patients (survivor bias). Therefore, one could easily attribute the overall effect of selexipag being more pronounced (ie, causing improved outcomes) in incident patients on the fact that, being recently diagnosed, these patients are clearly more at risk of untoward outcome, compounded with the additional fact that they were less likely to be on background therapy. Therefore, they are the group most likely to benefit from addition of therapy.

The differential treatment responses relating to time from diagnosis and whether treatment started early (in this case with selexipag), as reported by the authors, support prior research findings and observations.4Galie N. Barbera J.A. Frost A.E. et al.Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension.,7Sitbon O. Cottin V. Canuet M. et al.Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension.,10Simonneau G. Channick R.N. Delcroix M. et al.Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.,11Humbert M. Sitbon O. Yaici A. et al.Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Whether this improved outcome is implicitly associated with initiating prostacyclin treatment or, for that matter, any other PAH drug early in the disease course, is unclear, however. Although upfront combination therapy has not been compared with combined therapy provided in a sequential manner, it is now widely accepted that starting PAH therapy early, and starting with upfront combined therapy, is the recommended strategy in PAH.1Galie N. Humbert M. Vachiery J.-L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Whether initial treatment has to include a prostacyclin analog remains, however, an open debate.12Barnes H. Yeoh H.L. Fothergill T. Burns A. Humbert M. Williams T. Prostacyclin for pulmonary arterial hypertension.In summary, this is a clearly valuable and provocative post hoc analysis by Gaine et al9Gaine S. Sitbon O. Channick R.N. et al.Relationship between time from diagnosis and morbidity/mortality in pulmonary arterial hypertension: results from the phase III GRIPHON study. of the large landmark GRIPHON trial investigating the impact of time from diagnosis to initiation of selexipag on morbidity and mortality. The authors’ conclusions are consistent with prior reports that incident PAH patients have worse long-term outcomes compared with prevalent patients and that starting a PAH drug early, in this case, selexipag (whether in incident or prevalent patients), positively affects long-term outcomes. The data confirm current “best practice” in PAH therapy. Whether improved outcomes, when treatment is given early, are specific to a prostacyclin analog (with the clear advantage of oral administration in the case of selexipag) or any upfront combination therapy from the three currently targeted PAH pathways, needs further clarification.ReferencesGalie N. Humbert M. Vachiery J.-L. et al.

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Cochrane Database Syst Rev. 5: CD012785Article InfoFootnotes

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: P. M. H. has served on a scientific advisory board for MSK, an activity unrelated to the current work. None declared (M. N.).

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DOI: https://doi.org/10.1016/j.chest.2021.02.009

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© 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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