Abstract
Initial versus sequential combination therapy in PAH, that is the question: a robust comparison of these two strategies is needed (initial oral combination versus monotherapy followed by sequential combination therapy when treatment goals are not met) https://bit.ly/35BxQXB
1-year estimated risk of mortality is a key information supporting treatment management in patients with pulmonary arterial hypertension (PAH) [1–3]. Thus, risk stratification instruments are of major importance to guide first-line therapy, determine treatment goals and refine treatment strategy at follow-up (unchanged, sequential combination therapy, switch, listing for lung transplantation, etc.). In treatment-naïve patients at low or intermediate risk, initial treatment with an oral PAH drug is recommended, either dual combination therapy of an endothelin-receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE-5i), or monotherapy (ERA or a PDE-5i), especially in patients with cardio-pulmonary comorbidities or mild PAH [1–3]. As a result, there is a trend for an increased use of initial dual oral combination therapy in newly diagnosed PAH patients [1, 2]. However, contemporary PAH registries still reveal that the majority of patients are initiated with a single oral PAH drug, despite an increasing use of initial combination therapy [4–6].
The evidence for the superiority of initial dual oral combination therapy over monotherapy is based on the results of the single randomised controlled trial (RCT) AMBITION (AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION) [7]. This event-driven study showed a 50% reduction in the primary end-point of time to a clinical failure event (defined as the first occurrence of a composite end-point of death, hospitalisation for PAH worsening, disease progression, or unsatisfactory long-term clinical response) in patients initiated with ambrisentan and tadalafil compared to those receiving monotherapy with ambrisentan or tadalafil [7]. In addition, change from baseline in 6-min walking distance and in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasma levels also showed a superiority of initial combination therapy [7].
If the AMBITION trial didn't provide haemodynamic insights, other studies have convincingly shown that initial combination therapy with an ERA and a PDE-5i leads to marked haemodynamic improvement [8–10]. The OPTIMA trial was a prospective, multicentre, single-arm, open-label, phase 4 study exploring the efficacy and safety of macitentan administered as initial oral combination therapy with tadalafil, in newly diagnosed treatment-naïve PAH patients. The study showed a 47% reduction of pulmonary vascular resistance (PVR) at 16 weeks, together with a 68% reduction in the NT-proBNP levels [8]. The recent TRITON RCT compared efficacy and safety of initial triple (macitentan, tadalafil and selexipag) versus initial dual oral combination therapy (macitentan, tadalafil and placebo). A 52% reduction in PVR with initial dual combination therapy was observed, quite similar to the effect of initial triple combination (54% reduction) [9]. Interestingly, such results have been shown in an observational study from the French registry focusing on initial oral dual PAH therapy (ERA and PDE-5i): irrespective of the initial treatment regimen (bosentan or ambrisentan combined with sildenafil or tadalafil), a marked haemodynamic improvement was observed at first follow-up (45% PVR reduction at 4 months) and was sustained in the long term (median of 2 years) [10].
With regard to long-term outcomes, no survival benefit of initial dual combination therapy over monotherapy could be shown at the end of study in AMBITION [11]. However, this study was not powered to show survival benefits. In addition, AMBITION compared initial dual oral combination therapy versus monotherapy, and there was no predefined analysis of sequential combination therapy when treatment goals were not met. As of today, no RCT has ever shown a survival benefit of initial oral combination therapy over monotherapy. Only observational studies from registries have studied the putative superiority on survival of initial dual oral combination therapy over initial monotherapy followed by timely guideline-supported sequential combination therapy, if appropriate.
Two manuscripts published in the current issue of the European Respiratory Journal have analysed whether change in treatment paradigm proposed in the latest guidelines were followed by incremental improvements in long-term survival [5, 6]. The first article studied temporal trends in the use of combination therapy and survival of newly diagnosed PAH patients from the COMPERA registry [5]. A large population of more than 2500 patients included in the registry between 2010 and 2019 was analysed. According to temporal guidelines, the use of initial combination therapy increased from 10% to 25% during the study period. Despite this change in initial therapy, survival rates remain similar before and after the publication of the 2015 European guidelines (2010–2014 and 2015–2019 periods). 3-year survival was 65% (95% CI 58.8–71.8%) in 2010–2014 versus 75.3% (95% CI 69.9–81.2%) in 2015–2019 [5]. Although 96% of the elderly patients (≥65 years old) presented with intermediate or high risk at the time of PAH diagnosis, only a minority of patients were started with combination therapy (4.1% and 18.6%, respectively). Of note, patients less than 65 years old (who presented with less advanced PAH at first diagnosis than their elderly counterparts) were more likely to receive initial combination therapy in recent years (up to 46%). 1 year after PAH diagnosis, almost two thirds of patients younger than 65 years old received combination therapy, compared to only one third among the elderly patients [5].
The second manuscript reports Canadian experience of PAH therapy since 2006 in 435 incident patients [6]. As in the COMPERA registry, the use of initial combination therapy increased since 2015 from 0% to 36%. Despite the increase in combination therapy, no improvement in survival was observed in the recent period with 3- and 5-year survival rates of 75% and 57%, respectively [6]. There was a nonsignificant difference in 5-year survival in patients who received initial monotherapy (53.8%) or initial dual combination therapy (59.2%) (p=0.37). Finally, there was no difference in survival between patients receiving sequential combination therapy, when compared to those started on dual combination therapy (p=0.45) [6].
At follow-up, the proportion of sequential treatment escalation has increased in both registries: from 28% to 46% 1 year after PAH diagnosis in COMPERA [5] and from 16% to 57% 2 years after PAH diagnosis in the Canadian report [6]. These data highlight the increasing use of both initial and sequential combination therapy in Europe and Canada since the dissemination of the 2015 European guidelines. The lack of improved survival questions the value of initial oral combination therapy on hard outcomes.
Results of these two studies are consistent with the recent French retrospective study aiming to determine the impact of initial treatment strategy on long-term survival in PAH [4]. Among the 1611 incident patients with idiopathic, heritable or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry between 2006 and 2018, 984 were initiated on monotherapy, 551 received initial dual therapy, and 76 were initiated on triple therapy including a parenteral prostacyclin. No difference was observed in terms of survival in patients initiated on monotherapy or dual therapy (61% at 5 years) [4]. The rapid treatment escalation (average of 9 months) of half of the patients receiving monotherapy may explain at least in part these results. However, among intermediate-risk patients at the time of PAH diagnosis, survival of those initiated on dual combination therapy was better than that of those receiving initial monotherapy, whereas no difference was observed between initial monotherapy and initial dual combination therapy in patients at low risk [4]. Unlike the COMPERA and Canadian studies, the French cohort included a large subgroup of patients initiated on triple combination therapy including a parenteral prostacyclin. Despite their initial severity, the 5-year survival rate of this subset of patients was much better than that of patients initiated with monotherapy or dual combination therapy (91% versus 61% at 5 years) [4].
Despite improved survival in recent years, large PAH registry studies (COMPERA, and those conducted in France and Canada) did not show survival benefit with the use of initial oral combination therapy [4–6]. This could be partly explained by the timely treatment escalation in patients receiving initial monotherapy and not meeting predefined treatment goals at early follow-up. One must however acknowledge that registry data suffer from important limitations and should remain hypothesis-generating.
“To be or not to be”, said Hamlet in the famous William Shakespeare play. Inspired by this line, we would state that “Initial versus sequential combination therapy, that is the question.” To robustly demonstrate the potential superiority of initial oral combination over monotherapy (followed by guideline-supported sequential combination therapy when treatment goals are not met), a RCT should be considered, comparing these two treatment strategies in low- to intermediate-risk PAH patients, as depicted in figure 1. In order to further improve the quality of evidence supporting initial PAH therapy, the PAH community has now the responsibility to support this strategy trial.
Shareable PDF
Supplementary Material
This one-page PDF can be shared freely online.
Shareable PDF ERJ-00390-2022.Shareable
Footnotes
Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; consulting fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; and participation on advisory boards for Acceleron, Janssen and MSD, all outside the submitted work. A. Boucly reports lecture honoraria from Janssen and MSD, outside the submitted work. M. Humbert reports grants and consulting fees from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; and participation on advisory boards for Acceleron, Janssen, Merck and United Therapeutics, all outside the submitted work.
- Received February 20, 2022.
- Accepted February 21, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org