Eighty participants were enrolled, all fully qualified senior physicians and decision-makers for initiating treatment of PAH patients. Since PAH is a complex disease impacting both the lung and the heart function, an equal number of pulmonologists (40) and cardiologists (40) was included, all working primarily in public hospitals. All participants were required to have a minimum caseload of 3 PAH patients per year (minimum to be considered a PAH treater, given the low national mean of 7.5 new patients per physician and year), and to dedicate at least 60% of their time to direct patient management (required to ensure respondents are only active clinical specialists, and dismiss healthcare professionals whose primary dedication is in research or academia). The geographic distribution of the participants was representative of the distribution of specialists across Spain, according to the latest report of the Spanish national institute of statistics (dated 31st December 2020). Around half of the clinicians were recruited in the Center and North-East of Spain (27% and 24%, respectively) and the other half were evenly distributed within the 3 other main areas (18% in the North/North-West, 16% in the South, and 15% in the East of Spain). The profile of all participants is summarized in Table 1.

Two different clinical scenarios (prior to and after a 6-month treatment) were assessed on 4 virtual patients, all currently under double-combination therapy with ERA and PDE5i/GCs, as presented in Table 2. The survey focused on FC II and FC III PAH patients with 2 different etiologies, either idiopathic (IPAH) or connective tissue disorder (CTD-associated) PAH, which are the 2 most represented groups of PAH worldwide3 and in Spain (together with congenital heart disease).4

Pilot interviews were carried out separately with one pulmonologist and one cardiologist by mean of a 60-minute videocall to assist in the design of an online survey investigating the management of PAH patients in Spain. These experts were selected using the same inclusion criteria as the main survey participating clinicians (Table 1). The aim of these interviews was to validate the pertinence of the survey with regards to PAH management and the terminology used by field experts.

Hospital-based physicians were asked to spend up to 45minutes reviewing patient cases and answering an online questionnaire. All data were collected in a period of approximately 1 month, May 21st to June 24th, 2021. The data included the participating clinicians’ profiles, caseloads (number and types of PH patients received in their clinical practice in an average year), and answers on their typical risk assessment strategy and management of mock cases scenarios based on the 4 virtual PAH patients as detailed in Table 2.

This research complied with the European general data protection regulation (GDPR).

All participating physicians signed informed consent form prior to participation, and the need for ethics approval was waived due to the study classification as Market Research and based on the Royal Decree 1090/2015 issued from the Spanish Ministry of Health, Social Services and Equality “BOE” (reference: BOE-A-2015-14082).

Statistical tests were carried out using the Gandia BarbWin analysis software (version 7.0.1614.3). Continuous variables were assessed using counts, standard deviation, and median values. Categorical variables were summarized using frequencies and percentages. Statistical tests were 2-sided, and P-values were calculated with a 95% confidence interval. P-values ≤.05 were considered statistically significant. For group comparisons, unpaired t-tests were used. Due to rounding and the multiple-choice nature of some of the retrieved results, the percentage totals on some tables and figures may not correspond to the sums of the separate percentages.

Data were compared between FC II and FC III PAH patients and between clinicians with different yearly caseloads. Three caseload categories were defined: low- (3–5 patients/year), intermediate- (6–9 patients/year) and high-caseload (over 10 patients/year).

In total, the clinicians declared receiving a median of 46 PH patients for management or consultation within their average year (Table 3). The median number of PAH patients (group 1 PH) was 7 and represented the third most frequent type of PH cases, following group 2 (PH due to left heart disease; 14 cases/year) and group 3 PH (due to respiratory disease and/or hypoxemia; 10 cases/year).

The 2 main types of PAH among their received PAH patients were idiopathic (IPAH) and/or heritable PAH, and CTD-associated PAH (CTD-PAH) with, respectively, 3 and 2 cases/year.

A poorer functional class of PAH (FC III or FC IV) was the most frequent clinical factor for drug intensification, considered by 88% of the clinicians. The 2 succeeding main criteria associated with worse prognosis and therefore pointing to treatment intensification, were hospitalization for PAH decompensation within the past 6 months and intermediate- or high-risk hemodynamic parameters (from 79% and 76% of the clinicians, respectively). In other criteria, 40% of clinicians took into account the age of the patients for patients over 65 years, 35% considered any relevant comorbidities, and 29% the male gender.

For initial risk assessment, Fig. 1A shows that most clinicians requested an echocardiography (93%), a 6MWT (85%), a BNP/NT-proBNP testing (79%), and an RHC (78%). Interestingly, clinicians from all 3 caseload categories ranked echocardiography, BNP/NT-proBNP test, 6MWT and RHC as the 4 most decisive tests for determining the risk status of PAH patients (data not shown).

Fig. 1.

Intermediate-risk parameters ranked as very and/or extremely important. (A) For initial assessment or before considering treatment intensification (N=80). (B) For risk-assessment before treatment intensification for FC II (n=160) and FC III (n=160) PAH patients (N=80). Data are given as percentage of clinicians who ranked each of the risk parameters as very and/or extremely important. 6MWT: 6-minute walk test; BNP: brain natriuretic peptide; DLCO: diffusion lung capacity for carbon monoxide; ECG: electrocardiogram; N: number of clinicians; n: total number of answers collected for each of the PAH patients; NT-proBNP: N-terminal pro-B-type natriuretic peptide; RHC: right heart catheterization. *P≤.05 with 95% confidence interval.

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Before considering treatment intensification for FC II and FC III PAH patients currently under oral double combination therapy (ERA and PDE5i/GCs), clinicians again agreed that the echocardiography, 6MWT, BNP/NT-proBNP blood tests and RHC were the main intermediate-risk criteria to be considered, although they tended to use ergospirometry and diffusing capacity for carbon monoxide less frequently (Fig. 1A). These ratings were similar for FC II and FC III PAH patients (Fig. 1B).

Our data showed that ESC/ERS color coding is by far the most commonly used tool for risk stratification (68% of clinicians) regardless of the clinician caseload, followed by REVEAL 2.0 (Fig. 2). REVEAL 2.0 was used by around a quarter of clinicians with lower (3–5 PAH patients/year) and intermediate (6–9 PAH patients/year) caseloads. Clinicians with the highest caseload (over 10 PAH patients/year) used REVEAL 2.0 and REVEAL lite 2 at similar levels, closely followed by the FPHN registry (simplified model) (Fig. 2).

Fig. 2.

Risk stratification tools used by the clinicians overall and according to their PAH caseload. The overall percentage of clinicians using each tool is shown in the center of each panel (N=80 participants). Data are presented for each stratification tool for clinicians with lower (3–5 cases/year) N=31, intermediate (6–9 cases/year) N=23 and higher caseload (≥10 cases/year) N=31. ESC/ERS: European Society of Cardiology/European Respiratory Society; FPHN: French Pulmonary Hypertension Network; N: number of clinicians.

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Overall, for FC II–III PAH patients, double-combination therapy (ERA and PDE5i/GCs) was the preferred initial treatment (Fig. 3). The addition of a third drug (either PC-receptor agonist or PC analog) was more frequently prescribed to FC III PAH patients with at least one intermediate-risk hemodynamic parameter, compared to FC II patients who presented only low-risk parameters (Fig. 3), indicating that a more severe functional class and intermediate-risk parameters advocated for a more aggressive therapy. When considering initial triple-combination therapy, the oral selective PC-receptor agonist was chosen by most clinicians. In particular for initial treatment of FC III PAH patients, around 20% of the clinicians would directly add the PC-receptor agonist to ERA and PDE5i/GCs (Fig. 3).

Fig. 3.

Initial combination therapies given in PAH mock case scenarios according to functional class. Percentage of clinicians who would prescribe double-combination therapy (ERA and PDE5i/GCs) or triple-combination therapy (adding either an oral PC-receptor agonist or a parenteral PC analog). Data are presented for FC II (n=160) and FC III (n=160) PAH patients. N=80 clinicians. n=total number of answers collected for each of the PAH patients. ERA: endothelin receptor antagonists; FC: functional class; GCs: guanylate cyclase stimulator; PAH: pulmonary arterial hypertension; PC: prostacyclin; PDE5i: phosphodiesterase type 5 inhibitors.

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Most of the clinicians (85%) chose to prescribe a PC-receptor agonist as a first choice for intensification to triple-combination therapy, for FC II–III PAH patients in absence of high-risk parameters (Fig. 4A). The choice of a third drug for intensification slightly varied according to the functional class of PAH patients, with 91% of clinicians prescribing the oral PC-receptor agonist to FC II patients compared to 79% to FC III PAH patients (P≤.05). Parenteral PC analogs were prescribed more frequently to FC III PAH patients (21% versus 9% for FC II PAH patients; P≤.05) (Fig. 4A). The clinicians rated both comfort and efficacy as the 2 main reasons for selecting either PPA as their first choice for a third additional drug (Fig. 4B), closely followed by the drug safety for PAH patients (Fig. 4B). Another reason for prescribing a PPA for around one third of clinicians was to follow the international clinical guidelines and/or their hospital's protocol (Fig. 4B).

Fig. 4.

Prescription of PPA. (A) Percentage of clinicians who would prescribe either an oral selective PC-receptor agonist or a parenteral PC analog for treatment intensification overall and according to functional class for patients presenting intermediate-risk parameters. The total percentage of clinicians using each type of PPA is shown in the center (N=80). (B) Reasons for choosing either an oral PC-receptor agonist or a parenteral PC analog according to the functional class (FC) (II or III) of the PAH patients. N: number of clinicians; FC: functional class; PAH: pulmonary arterial hypertension; PC: prostacyclin; PPA: prostacyclin pathway agents. *P≤.05 with 95% confidence interval.

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Overall, bosentan and macitentan were the most frequently prescribed ERA (86% and 80% of the clinicians, respectively) compared to ambrisentan which is used by 70% of the clinicians (Fig. 5A). The GCs riociguat was shown to be currently used by 79% of specialists (Fig. 5A). Selexipag, approved by the European Medicines Agency in 2016, was known to nearly all physicians and had already been prescribed by two-thirds (66%) of them. All physicians knew the ERA bosentan. Only 1% of the clinicians were not familiar with the ERA macitentan or the GCs riociguat and 3% with the ERA ambrisentan or the PPA selexipag (not shown). Of note, Fig. 5B shows that management of PAH patients under selexipag was rated easy or very easy by 53% of the clinicians.

Fig. 5.

Pharmacological treatments typically used in clinical practice. (A) Percentage of clinicians who regularly, occasionally, or never prescribed bosentan, ambrisentan, macitentan, riociguat, and selexipag. N=80. (B) Rating of PAH patients management under selexipag. N=80. N: number of clinicians; PAH: pulmonary arterial hypertension.

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Next, we investigated the decision-making process for treatment intensification with a third drug (either parenteral PC analog or oral selective PC-receptor agonist) for FC II and III PAH patients who were receiving the double-combination therapy ERA and PDE5i/GCs for a period of 6 months (Fig. 6). For FC II PAH patients who initially presented only low-risk hemodynamic parameters, the actual decision depended on the presence of one or more new intermediate-risk parameters. We found that for FC II patients who presented only one intermediate-risk parameter, 83% of the clinicians considered intensifying treatment with a PPA, and 92% were inclined to prescribe PPA upon the occurrence of multiple new intermediate-risk parameters (Fig. 6).

Fig. 6.

Decision pathway for triple therapy. Percentage of clinicians who would add a PPA (either an oral PC-receptor agonist or a parenteral PC analog) to ERA and PDE5i/GCs combination therapy according to functional class and new intermediate-risk parameters; N=80 clinicians. ERA: endothelin receptor antagonists; FC: functional class; GCs: guanylate cyclase stimulator; PAH: pulmonary arterial hypertension; PC: prostacyclin; PDE5i: phosphodiesterase type 5 inhibitors; PPA: parenteral or oral prostacyclin pathway agents (either PC-receptor agonist or PC analogs).

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For FC III patients who initially presented at least one intermediate-risk parameter and maintained the same risk status despite a 6-month treatment with ERA and PDE5i/GCs, 93% of the clinicians would consider prescribing PPA, and nearly all clinicians would add a PPA in sequential triple-combination therapy to FC III PAH patients with one or several new intermediate-risk parameters (97% and 99%, respectively; Fig. 6).

Risk stratification is primordial to tailor the treatment strategy according to the risk of adverse outcomes for PAH patients.7,8 We found that the hospital-based clinicians of our study mostly requested echocardiography, 6MWT, BNP-pro-NT-BNP levels and, although to a lower extent, RHC. RHC was most often used for initial risk stratification and slightly less requested for re-evaluating the patients before treatment intensification. RHC is necessary to diagnose PAH as per the European ESC/ERS guidelines.7 However, whether RHC should be used to monitor PAH patients after initial diagnosis is controversial when all other risk parameters are low or intermediate,7,11 which is the case in all the mock scenarios evaluated in our study. In addition, the clinicians may base their decision on their experience of alternative tests being more easily accepted by patients than RHC.12 The ESC/ERS guidelines advise that risk assessment should include the determination of WHO FC, at least one exercise capacity evaluation such as 6MWT, and some indication of RV function. Most of these parameters can be measured in a non-invasive and cost-effective manner. Indeed, several critical hemodynamic parameters were shown to be reliably measured by transthoracic echography and to strongly correlate with RHC results. These included right atrial pressure13 and pulmonary arterial systolic pressure.14 A retrospective analysis (from January 2001 to December 2012) showed that right ventricular systolic pressure estimated by echocardiography also reflected RHC results.14 In addition, Boucly et al.15 reported that non-invasive 6MWT and BNP/NT-proBNP plasma levels were reliable indicators of 1-year survival, together with functional class, potentially precluding the need for RHC for FC II PAH patients after initial diagnosis. More recently, Helgeson et al.16. suggested that BNP and NT-proBNP levels could also be used as an alternative to right atrial pressure for risk stratification. Accordingly, we observed a tendency to request slightly more often BNP/NT-proBNP testing than 6MWT, for risk-assessment prior to escalation to triple-combination therapy for FC II–III PAH patients. This finding was also in line with the CHEST expert consensus survey.17 Altogether, our results reflect the current trend in follow-up risk assessments to favor less invasive procedures which are shown to offer powerful and reliable prognostic value.

We found that, in addition to ESC/ERS risk assessment strategy defined in the European clinical guidelines, the American registry-based REVEAL 2.0 risk calculator was often used by the Spanish clinicians, whereas the FPHN registry was the least used model. This is in line with findings from Benza et al.18 who reported that REVEAL 2.0 showed greater risk discrimination compared to FPHN and COMPERA registry-based models, in patients enrolled in the REVEAL registry. REVEAL lite was also used, though mostly by clinicians with higher caseloads.

Of note, our study highlighted that the recently developed REVEAL Lite calculator was used mostly by clinicians who manage over 10 PAH patients/year, indicating that these specialists are more prone to consider the new tools available and to integrate them quickly into their current practice. This result may also be explained by their individual experience and, for those who are practicing in specialized PH units, the combined knowledge and expertise of their colleagues, further advocating for the referral of PAH patients to specialized PH centers.11,19

We found that dual therapy with ERA and PDE5i/GCs was prescribed by most clinicians for FC II–III patients in the absence of high-risk parameters. Indeed, initial double-combination therapy with ERA and PDE5i was shown to delay the progression of PAH20,21 and is recommended for newly diagnosed FC II–III PAH patients with intermediate-risk status.7,8,22

The decision of the Spanish clinicians to add PPA to ERA and PDE5i/GCs for FC III patients whose intermediate-risk status did not improve, and FC II–III PAH patients whose condition worsened despite 6 months dual oral therapy, follows the current guidelines. Indeed, the ESC/ERS experts advise to intensify treatment to lower risk parameters, for intermediate-risk FC II, III and IV PAH patients,7 with the objective to achieve or maintain low-risk status.22 The addition of parenteral PC analogs is the recommended strategy for high-risk FC III and IV PAH patients,7,8 whilst the selective PC-receptor agonist selexipag is recommended for treatment intensification of FC II PAH patients with intermediate-risk parameters and FC III PAH patients in the absence of high-risk parameters.8 Selexipag may also be prescribed to FC IV patients who severely suffer from side effects resulting from the implanted device administering PC analogs subcutaneously.12,20 Selexipag may be prescribed to FC II PAH patients as either mono-, double- or triple-combination therapy with ERA and/or PDE5i.7

The recommendation for selexipag in triple-combination therapy for FC II and III PAH patients whose risk status remains intermediate while receiving double-combination therapy9 was based on several clinical trials. Firstly, the GRIPHON clinical trial showed a benefit of the oral PC-receptor agonist selexipag, when added to the ERA and PDE5i combination, for FC II–III PAH patients.10,23 Comparatively, the American guidelines were not able to make a definitive recommendation on when to add selexipag to dual ERA and PDE5i therapy, because of a higher cut-off value for 6MWT set by the CHEST experts.24 Most recently, the TRITON study suggested that there was a positive trend over time to fewer morbidity and mortality events in newly diagnosed/treatment naive patients with PAH treated with initial triple oral therapy (ERA macitentan, PDE5i tadalafil, and selexipag) versus initial double oral combination therapy (macitentan and tadalafil), and both strategies showed a marked reduction of pulmonary vascular resistance. The benefit of selexipag as a third drug for treatment intensification was supported by a pooled post hoc analysis of adverse clinical outcomes in PAH patients enrolled in the GRIPHON and the TRITON clinical trials. In this latest study, Coghlan et al.25 showed that initial and early sequential (less than 6 months after diagnosis) treatment with selexipag, in addition to double-combination therapy (ERA and PDE5i), decreased the risk of disease progression by 48% compared to double-combination therapy only.

The major strengths in the design of our study interrogating clinicians on their management of virtual PAH patients, is that their decisions on risk assessment and treatment could reliably be compared, without the bias of individual variations specific to any patient, and that all answers could be collected without any missing data. Another advantage, compared to retrospective studies, was the ability to analyze the rationale behind these choices. However, we recognize that this design has several limitations. Firstly, the mock case scenarios do not represent all PAH patients received by the participants in their real-world practice, and therefore do not address all possible clinical situations. One other limitation of our survey regarding typical practice is that it did not include details on the clinical profile of the patients, such as age and comorbidities. Besides, we did not interrogate the clinicians on the type of ERA, PDE5i or PC analogs they would prescribe to the virtual patients. Finally, the interpretation of some subgroup analyses was limited by their small size.