Temporal trends in pulmonary arterial hypertension: results from the COMPERA registry
Marius M. Hoeper,Christine Pausch, Ekkehard Grünig, Gerd Staehler, Doerte Huscher, David Pittrow, Karen M. Olsson, Carmine Dario Vizza, Henning Gall, Oliver Distler, Christian Opitz, J. Simon R. Gibbs, Marion Delcroix, H. Ardeschir Ghofrani, Stephan Rosenkranz, Da-Hee Park, Ralf Ewert, Harald Kaemmerer, Tobias J. Lange, Hans-Joachim Kabitz, Dirk Skowasch, Andris Skride, Martin Claussen, Juergen Behr, Katrin Milger, Michael Halank, Heinrike Wilkens, Hans-Jürgen Seyfarth, Matthias Held, Daniel Dumitrescu, Iraklis Tsangaris, Anton Vonk-Noordegraaf, Silvia Ulrich, Hans Klose
European Respiratory Journal 2022 59: 2102024; DOI: 10.1183/13993003.02024-2021
Background Since 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.
Methods We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.
Results A total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).
Conclusions The use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.
In this analysis of temporal trends in PAH treatment patterns and survival in 2010–2019, this study found an increase in the use of targeted combination therapies but only a slight, nonsignificant trend towards improved survival 3 years after diagnosis https://bit.ly/3FExlK5
The term pulmonary arterial hypertension (PAH) describes a potentially fatal pulmonary vasculopathy characterised by a progressive increase in pulmonary vascular resistance (PVR) that may lead to right-sided heart failure. The most common form of PAH is idiopathic (IPAH), but there are also heritable (HPAH) and drug-associated (DPAH) forms as well as disease manifestation associated with various conditions, such as connective tissue disease (CTD), HIV infection, portal (porto-pulmonary) hypertension and congenital heart disease (CHD) .
Before targeted treatments became available, the outlook for patients with PAH was grim. A US registry study published in 1991 found a median survival of patients with IPAH (at that time called primary pulmonary hypertension) of 2.8 years after diagnosis . Over the ensuing 30 years, various treatments have been developed which improve haemodynamics, exercise tolerance and worsening-free survival. Life expectancy of patients with PAH has also increased, with median survival after diagnosis now exceeding 5 years. However, for most of the currently approved therapies, no effect on mortality has been demonstrated in randomised clinical trials (except for i.v. epoprostenol, which improved survival in a randomised, open-label study done at a time when no other treatments were available).
Over the years, with more PAH drugs becoming available, treatment strategies have evolved. In the 2004 European pulmonary hypertension guidelines, monotherapy was recommended for almost all patients and all disease stages, with combination therapy receiving a “may be considered” recommendation as a last resort. In the 2009 European pulmonary hypertension guidelines, initial monotherapy remained the recommended strategy for most patients, with initial combination therapy to be considered for patients presenting in World Health Organization Functional Class IV and sequential combination therapy in case of an insufficient response to monotherapy . In 2015, the results of the AMBITION (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension) study were published showing markedly better treatment outcomes in terms of exercise tolerance and disease progression with initial combination therapy with ambrisentan (an endothelin receptor antagonist (ERA)) and tadalafil (a phosphodiesterase-5 inhibitor (PDE5i)) compared with monotherapy with these compounds. Like other studies in the field, AMBITION was not designed to detect and did not show a survival benefit at the end of the study. Still, the revised European pulmonary hypertension guidelines published in 2015 recommended for the first time to use initial combination therapy in most patients with newly diagnosed PAH.
Concurrently with the evolution of PAH therapies, there have been changes in patient phenotypes, particularly in countries with an ageing population. While the disease was originally seen mostly in young, otherwise healthy females, a diagnosis of PAH is nowadays made predominantly in male and female patients of older age. In several recent registries, median age at PAH diagnosis was >60 years and many of the older patients presented with numerous cardiopulmonary comorbidities. Such patients were not well represented in the clinical trials that led to the approval of PAH medications. The aforementioned AMBITION study had a small (n=105) subset of older (mean age 62 years) patients with multiple comorbidities that were analysed separately and in whom no clear benefit from combination therapy could be demonstrated. According to registry data, older patients, compared with younger patients, tend to be treated less aggressively, respond less well to PAH medications, have a higher likelihood to discontinue their PAH medications and have a higher mortality risk.
It is unclear how the introduction of new treatments and new treatment strategies for PAH and the demographic changes observed in this patient population have affected treatment patterns and survival over time. Here, we present data from COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension). The objective of the present analysis was to describe temporal trends in treatment patterns and survival of patients diagnosed with PAH between 2010 and 2019, i.e. over a 10-year period.
Details of COMPERA (www.COMPERA.org; ClinicalTrials.gov: NCT01347216) have been reported previously. In brief, COMPERA is an ongoing web-based pulmonary hypertension registry launched in 2007 that prospectively collects baseline, follow-up and outcome data of patients who receive targeted therapies for pulmonary hypertension. Originally, COMPERA was initiated as a registry for patients with PAH who were treated with ERA, but in June 2009, COMPERA evolved into a comprehensive pulmonary hypertension registry enrolling patients with all forms of pulmonary hypertension who receive medical therapy with any drug approved for PAH. Centres must enter their patients within 6 months after the pulmonary hypertension diagnosis to ensure inclusion of newly diagnosed patients. Pulmonary hypertension centres from various European countries participate (Austria, Belgium, Germany, Greece, Hungary, Italy, Latvia, Lithuania, Netherlands, Slovakia, Switzerland and the UK), with ∼80% of the enrolled patients coming from German pulmonary hypertension centres.
COMPERA has been approved by the ethics committees of all participating centres and all patients provide written, informed consent prior to inclusion.
For the present analysis, patients were selected from the COMPERA database by the following criteria: 1) treatment-naïve patients aged ≥18 years newly diagnosed with any form of PAH between 1 January 2010 and 31 December 2019, 2) at least one follow-up available, and 3) resting mean pulmonary arterial pressure ≥25 mmHg and mean pulmonary arterial wedge pressure ≤15 mmHg at baseline. Patients with suspected or confirmed pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosis were excluded, as were patients with other forms of pulmonary hypertension.
This was a post hoc analysis of prospectively collected variables. Continuous data are presented as mean with standard deviation or as median (interquartile range). Categorical data are presented as number (percentage). The dataset as of 1 September 2021 was analysed. Annualised data on the use of monotherapy and combination therapy within 3 months after diagnosis, also termed early combination therapy in this article, and after 1 year (±6 months) were shown based on the year of diagnosis. Ascertainment of vital status was done by on-site visits or phone calls to the patients or their caregivers. Patients who underwent lung transplantation and patients who were lost to follow-up were censored at the date of the last contact. Survival was evaluated using Kaplan–Meier analysis and the log-rank test. Estimated survival probability at 1 and 3 years was shown with 95% confidence intervals for each year of diagnosis. All trends were visualised in figures without formal statistical testing. The 1-year survival analyses were performed for all patients diagnosed between 2010 and 2019, while the 3-year survival analysis was done only for patients diagnosed between 2010 and 2018. All analyses were done for the entire cohort, for subgroups of patients divided by age (<65 versus ≥65 years), for subgroups of patients with I/H/D-PAH and CTD-PAH, and for a subgroup of patients with I/H/D-PAH who had no comorbidities and a diffusing capacity of the lung for carbon monoxide (DLCO) >45% predicted. In addition, we compared the cumulative survival rates of patients diagnosed between 2010 and 2014 with those of patients diagnosed between 2015 and 2019.
All statistical analyses were performed using R version 3.5.2 (www.r-project.org).
Patient characteristics, treatment and survival of the entire cohort
A total of 2531 patients were included in the present analysis (figure 1). The patients’ baseline characteristics, including those of the subgroups of patients with I/H/D-PAH and CTD-PAH, are shown in table 1. The baseline characteristics of the patient cohorts <65 years (n=1031 (40.7%)), ≥65 years (n=1500 (59.3%)), and I/H/D-PAH without comorbidities and DLCO >45% predicted (n=128 (5.1%)) are shown in supplementary table S1a–c. The annualised baseline characteristics did not suggest temporal trends in patient demographics or disease severity over time (supplementary table S2 and supplementary figure S1).
STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) diagram showing eligibility for analysis. PAH: pulmonary arterial hypertension; mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure. #: more than one reason for exclusion could apply.
Baseline characteristics of patients newly diagnosed with pulmonary arterial hypertension (PAH) between 2010 and 2019
The use of PAH medications, cumulated over the entire enrolment period, is shown in table 2 for the entire group and in supplementary table S3a–e for the subgroups. Overall, 19.6% of the patients received combination therapy within 3 months after diagnosis, 42.9% after 1 year and 49.8% after 3 years. In patients who received combination therapy, ERA and PDE5i were used in about two-thirds of the cases. Other combination therapies were used less frequently, and triple combination therapy including i.v. or s.c. prostacyclin analogues (PCAs) was used in 0.9% of the patients at entry and in 3.5% of the patients during follow-up. The median dosages of PAH medications at 3 months and 1 year are shown in supplementary table S4.