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. 2022 Jun 2;59(6):2101552.
doi: 10.1183/13993003.01552-2021. Print 2022 Jun.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era

Jason G E Zelt  1   2 , Jordan Sugarman  3 , Jason Weatherald  4   5 , Arun C R Partridge  6 , Jiaming Calvin Liang  1 , John Swiston  7 , Nathan Brunner  8 , George Chandy  2   9 , Duncan J Stewart  1   2   10 , Vladimir Contreras-Dominguez  9 , Mitesh Thakrar  4 , Doug Helmersen  4 , Rhea Varughese  4   11 , Naushad Hirani  4 , Fraz Umar  2 , Rosemary Dunne  2 , Caroyln Doyle-Cox  2 , Julia Foxall  2 , Lisa Mielniczuk  12   2
Affiliations

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era

Jason G E Zelt et al. Eur Respir J. .

Abstract

Background: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH.

Methods: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy).

Results: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53).

Conclusions: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

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Conflict of interest statement

Conflict of interest: J.G.E. Zelt has nothing to disclose. Conflict of interest: J. Sugarman has nothing to disclose. Conflict of interest: J. Weatherald reports grants, personal fees and nonfinancial support from Janssen Inc. and Actelion, personal fees and nonfinancial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: A.C.R. Partridge has nothing to disclose. Conflict of interest: J. Liang has nothing to disclose. Conflict of interest: J. Swiston reports personal fees from Janssen J&J, outside the submitted work. Conflict of interest: N. Brunner reports personal fees from Janssen Pharmaceuticals, outside the submitted work. Conflict of interest: G. Chandy reports personal fees for advisory board work and consultancy from Bayer Pharmaceuticals, personal fees for advisory board work, lectures and consultancy from Janssen Pharmaceuticals, personal fees for advisory board work from Apotex, during the conduct of the study. Conflict of interest: D.J. Stewart reports other (equity) from Northern Therapeutics, outside the submitted work. Conflict of interest: V. Contreras-Dominguez has nothing to disclose. Conflict of interest: M. Thakrar reports grants from Reata Pharmaceuticals, outside the submitted work; and advisory board work for Janssen Pharmaceuticals. Conflict of interest: D. Helmersen reports grants from Gilead, Janssen and United Therapeutics, outside the submitted work. Conflict of interest: R. Varughese has nothing to disclose. Conflict of interest: N. Hirani reports grants (paid to institution) from Bayer, United Therapeutics and Northern Therapeutics, grants (paid to institution) and other (advisory board membership) from Actelion/Janssen, outside the submitted work. Conflict of interest: F. Umar has nothing to disclose. Conflict of interest: R. Dunne has nothing to disclose. Conflict of interest: C. Doyle-Cox has nothing to disclose. Conflict of interest: J. Foxall has nothing to disclose. Conflict of interest: L. Mielniczuk reports grants and personal fees for lectures from Janssen, grants from Bayer, outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Kaplan–Meier curves for baseline a) New York Heart Association (NYHA) Functional Class (FC) and c) European Society of Cardiology/European Respiratory Society (ESC/ERS)-based risk assessment, and b, d) the associating proportion of patients per ESC/ERS guideline iteration.
FIGURE 2
FIGURE 2
a) Class of initial and follow-up pulmonary arterial hypertension (PAH) therapy per European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline iteration. This was further divided according to b) PAH-specific agents and c) New York Heart Association (NYHA) Functional Class (FC). ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase type 5 inhibitor; sGC: soluble guanylate cyclase; IP: prostacyclin.
FIGURE 3
FIGURE 3
European Society of Cardiology/European Respiratory Society (ESC/ERS) treatment era (2009–2015 and after 2015) and survival in pulmonary arterial hypertension patients: a) 1-year and b) 5-year post-diagnosis survival was not different before and after publication of the 2015 ESC/ERS guidelines.
FIGURE 4
FIGURE 4
Survival of incident patients in historical and contemporary pulmonary arterial hypertension (PAH) registries: 1-, 3- and 5- year survival rates are displayed with registries placed in chronological order. NIH: National Institutes of Health Pulmonary Hypertension Registry [3]; USA: McLaughlin et al. [4]; FPHN: French Pulmonary Hypertension Registry [26]; US-PHC: Pulmonary Hypertension Connection database [27]; REHAP-Spain: Spanish Registry of PAH [28]; UK: UK PAH Registry [29]; REVEAL: Registry to Evaluate Early And Long-term PAH Disease Management [30]; Swiss: Swiss PAH Registry [31]; COMPERA: European PAH Registry (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) [32]; Swedish: Swedish PAH Registry [33]; EXPERT: Exposure Registry Riociguat in Patients with Pulmonary Hypertension [34]. #: data from our Canadian PAH cohort of treatment-naïve Group 1 PAH patients.
FIGURE 5
FIGURE 5
Survival and initial drug therapy: a) 1-year and b) 5-year post-diagnosis survival according to initial treatment with a single agent (mono), dual or triple therapy. PDE5i: phosphodiesterase type 5 inhibitor; sGCs: soluble guanylate cyclase stimulator; ERA: endothelin receptor antagonist; PCA: prostacyclin analogue.
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