Pulmonary hypertension (PH) is an heterogeneous condition associated with various underlying disorders, which is defined as at rest mean pulmonary arterial pressure (mPAP) ≥25mmHg confirmed by right heart catheterisation (RHC).1 The pathophysiological processes associated with the development of PH are complex and more than likely multifactorial, why explains why several types of classification have been proposed over the years. The most recent international consensus from the 5th World Symposium held in Nice in 2013, classifies PH according to five general groups of aetiologies.2 Group 1 PH refers to pulmonary arterial hypertension (PAH) and includes idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension (HPAH), and drugs and toxin induced; PH associated with diseases such as connective tissue disease (CTD), HIV infection, portal hypertension, congenital heart disease (CHD) and schistosomiasis are also included in Group 1. Group 1′ and Group 1″ refer to pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis and persistent pulmonary hypertension of the newborn, respectively. Group 2 PH includes PH due to left heart disease (LHD). Group 3 refers to PH due to lung diseases or hypoxia, such as chronic obstructive pulmonary disease (COPD) or interstitial lung disease. Group 4 PH includes chronic thromboembolic pulmonary hypertension (CTEPH) and other pulmonary artery obstructions. Group 5 refers to PH with unclear and/or multifactorial mechanisms.

Group 1 (PAH) aetiologies, except schistosomiasis associated PAH, are considered rare diseases; IPAH being an exclusion diagnosis, is the most studied form of PAH and the model for clinical management of PAH forms which are indicated for targeted therapy.3,4 Treatment of PH involves both conventional, symptom-based therapy and targeted therapy, which is indicated for specific PH aetiologies. Conventional treatment involves the use of digoxin to improve right ventricular function, diuretics to reduce peripheral oedema, supplemental oxygen, and in specific cases anticoagulants.3 Calcium channel blockers (CCBs) can be used to lower PAP, but their use is restricted to a small percentage of patients (3–5%) showing positive response to acute pulmonary vasodilator (ARVT) challenge.5,6 Targeted therapy includes the use of endothelin-1 receptor antagonists (ERA),7–9 phosphodiesterase-5 inhibitors (PDE-5I),10,11 soluble guanylate cyclase (sGC) stimulators,12,13 and prostacyclin analogues or receptor agonists,14–19 surgical treatment, like lung or heart-lung transplantation is reserved to refractory cases of PAH; pulmonary angioplasty and pulmonary endarterectomy is reserved to CTEPH patients.

The proliferation of studies assessing long-term prognosis of PH has helped identify considerably different patients and disease characteristics both over time and for populations in different geographical regions.20 These findings suggest the need for specific regional data, to fully characterise local disease populations, inform clinical practice, and to help define local/regional political strategies.

In Portugal, a national PH registry has been, but given its recent implementation, only short-term data have been published.21 Recently, another study characterised the survival over a longer follow-up period but the sample size remained relatively small (n=66).22

This study aims to provide long-term data for the Portuguese PH population, by characterising the clinical presentation, evolution, and outcomes of PH patients in a specialised referral centre in Portugal.

This study provides long-term data for patient phenotypes, clinical evolution, and survival in PAH and CTEPH of a Portuguese PH population. These results build on previous findings21,24 and together they characterise the impact of this life-threatening disease in Portugal. The present study enrolled only patients with pcPH due to the substantially different disease characteristics and treatment approaches that could bias the results and ultimately hinder comparisons with other cohorts published over the years. Unlike previous studies, here we included patients with all types of PH, except for left heart disease, to provide a more accurate picture of pcPH as a whole. Left heart disease was the only PH group excluded from the analysis.

The PH dedicated software developed by the centre allowed the implementation of a mandatory case report form (CRF) with automatic alerts to avoid missing data in our clinical records. This methodology allowed us to build a true real-world cohort of PH patients from our region and following the most recent Nice recommendations.25 This is particularly relevant because PAHTool® is currently licenced for implementation in several PH centres worldwide, and its widespread use is envisioned to allow the generation of relevant real-world data, which is badly needed in the context of this non-frequent condition but rapidly evolving field.

According to existing registries, some aetiologies are underrepresented in our cohort (particularly drugs and toxins induced PH, HIV and portal hypertension associated PH), which is most likely due to low physician awareness about PH.21,26–36 CHD (36.3% of PAH group) contributed with a comparatively higher proportion of cases, which can be explained by the past low levels of detection and correction of heart defects in infancy in our country and by the fact that our centre was for a long time the only one to provide targeted therapy for PAH in the region. CTEPH was the most frequent aetiology after PAH, confirming the high prevalence of this frequently forgotten condition and in line with studies that included this subgroup of patients.21,34,37–39

Comparing our data with the most important registries in the field, we found that CTEPH age at diagnosis in our population is consistent with these registries38–40; although the mean age at diagnosis for our overall population is similar to the majority of PAH registries26,29,32 the mean age for I/HPAH is clearly lower and near the pioneer registries35,41 and those coming from the developing world,42,43 but still in line with national data.21 Female gender (66%) predominance is also in line with the majority of PH registries and cohorts.21,26–35

Baseline clinical characteristics at presentation indicate some delay in diagnosis, with most patients presenting with intermediate or high risk of mortality indicated by high NYHA FC, low 6MWD and high NT-proBNP according to risk assessment guidelines3; increased RAP (11.1±5.3mmHg) and PVR (8.1±4.8WU) are also consistent with these findings. The proportion of patients presenting with intermediate or high risk explains why the great majority of patients were treated with combination therapy: I/HPAH (88.9%), CTD (54.5%) and CHD (55.0%). These findings are, however, above what has been reported in recent European studies, as well as national data.21,30,32,34,44 There is a particularly high proportion of I/HPAH (61.1%) patients under triple therapy, which is probably the result of the close follow-up adopted and continuous risk evaluation with early step up of the therapy. ERAs and PDE-5I were the most widely used drugs, which is in accordance with previous reports.21,30,32,34,44 Still, they were used far more frequently in combination than what has been reported, which is in line with the most recent recommendations for the early use of sequential or upfront double combination therapy.3,45

Although pulmonary endarterectomy surgery is not routinely available in our country, patients are fully reimbursed by the Portuguese Public National Health Service if surgery is performed abroad. Despite limitations associated with the need for a cross-border, high risk procedure, 42% of CTEPH patients had the operation in a foreign centre, thanks to a protocol for surgical treatment of PH established in 2000. Non-operable patients, patients refusing pulmonary endarterectomy, or patients with residual persistent PH after pulmonary endarterectomy were predominantly treated with monotherapy (57.7%) and specially with ERAs (46.2%), as per previous studies.39,40

In terms of clinical outcomes during the period of the study, WHO FC, 6MWD, mPAP and PVR significantly improved for the overall population, which is in line with the accumulating evidence of substantial gains in long-term prognosis obtained over recent decades, following the introduction of several therapeutic alternatives.3,30,32,34

Although usual bias for survival estimates were eliminated in this study (including mixed population of incident/prevalent cases and “immortal” bias), survival estimates should still be considered with caution since there were substantial changes in treatment strategies during the course of the study. Nonetheless, survival estimates found for the total cohort and PAH follow the trends of the most relevant international registries26–28,30,32,35; the 1-year survival among CTEPH patients (81.5%) was considerably below estimates from other studies (88–97%),37–40 which could be connected to difficulties of access to PEA surgery.

This study had several limitations. First, its single-centre nature might affect the representativeness of the findings for the overall Portuguese population, however, the study was conducted at one of the largest PH centres in the country, serving the northern region, with an ample and diverse group of patients currently being followed. Second, the relatively small sample size impaired the ability to perform more in-depth statistical analysis such as predictors of survival, however, in the context of a non-frequent disease the data provided by this study gives highly relevant insight to inform clinical practice. Third, the enrolment period for this study was long, which is associated with highly variable follow-up times and variable treatment approaches over time. Still, the low incidence of PH and the country/region dimension make enrolment over reduced periods difficult.

This study provides long-term, real-world data for the management of PH in Portugal. It also demonstrates the potential of a dedicated information system for PAH in generating high-quality real-world data aimed at characterising PH in present clinical practice conditions. Patients presented mostly with intermediate or high risk of mortality which might be indicative of delay in diagnosis and highlights the need to increase awareness and early referral to expert centres for this condition among clinicians.

Abílio Reis is co-proprietary of the dedicated pulmonary hypertension software PAHTool®. The remaining authors have no conflicts of interests to disclose.