Pulmonary hypertension (PH) is characterized by an increase in pulmonary artery pressure. It can be associated with a wide range of conditions,1 the most common of which are left heart disease and lung disease, in which PH has considerable prognostic significance but no indication for specific therapy.2 The distinction between these causes and less frequent causes of PH such as pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is often challenging and always critical, since the latter have an ominous prognosis without specific treatment.3,4 Ten specific pulmonary vasodilators are currently available for PAH and there is robust evidence on the clinical benefits of pulmonary endarterectomy (PEA) for CTEPH patients.2

Despite notable advances in recent decades, rare diseases such as PAH and CTEPH still present numerous challenges. Early diagnosis is fundamental but still an unmet need. The more advanced the functional class at diagnosis, the worse the prognosis.5,6 Regarding treatment, generalization of data from clinical trials is not straightforward, as these trials’ study populations often differ from real-world patients.7 Observational data from registries and cohort studies are accordingly crucial to provide insights on epidemiology, adherence to guidelines, effectiveness of treatments, and outcomes in clinical practice. Several international registries and PH referral center cohort studies have been published.8 However, available data on PAH and CTEPH patients followed in Portugal are limited, especially in terms of long-term mortality.9–11

We studied PAH and CTEPH patients followed in a Portuguese PH referral center with the following aims: (1) to describe patients’ clinical, functional and hemodynamic profile at diagnosis; (2) to characterize the use of specific pulmonary vasodilator treatments; and (3) to examine long-term mortality and survival trends between different time periods.

This retrospective single-center study included all group 1 and group 4 PH patients followed in the Pulmonary Vascular Disease Unit of Hospital de Santo António, Centro Hospitalar do Porto (Porto, Portugal) between January 2005 and December 2016. This unit is the official referral center for the treatment of PH in the Northern region of the country, covering an adult population of 3.8 million. Demographic, clinical, hemodynamic, and treatment data were collected using dedicated PH software (PAHTool®, Inovultus Lda., Santa Maria da Feira, Portugal). Specific vasodilator treatments were collected from the last follow-up observation. All patients had incident PAH confirmed by right heart catheterization (RHC) using the criteria and PH classification from current international clinical guidelines.2 The ethics committee of Hospital de Santo António authorized the study and waived patients’ consent. Survival status (all-cause mortality) was assessed by chart review through February 1, 2017.

Demographic and clinical variables were summarized with descriptive statistics. Categorical variables were summarized as absolute frequency and percentage, and continuous variables were summarized as mean and standard deviation. Bivariate analysis was conducted using the Student's t test, Wilcoxon's test, Fisher's exact test, or chi-square tests, as appropriate. Cumulative survival was estimated using the Kaplan-Meier method. Multivariate Cox proportional hazards regression models were used to assess the unadjusted and adjusted association of PH etiology and mortality. To describe survival trends over time, patients diagnosed in two different six-year periods (2005-2010 vs. 2011-2016) were compared. A 5% significance level was employed for all analyses. The statistical analysis was performed using Stata software, version 12.1 (StataCorp LP, College Station, TX, USA).

These long-term data of PH patients followed at a Portuguese referral center illustrate the following: (1) at diagnosis most of patients were in an advanced NYHA functional class; (2) the mean age at diagnosis of I/HPAH patients is increasing over time; (3) specific treatments and survival are comparable to other registries and cohort studies; and (4) PEA and lung transplantation are underused treatments despite being associated with better survival of CTEPH and PAH patients.

Most patients, 64% of group 1 PH and 57% of CTEPH, presented in NYHA functional class III-IV at diagnosis. Over time, a reduction was observed in the proportion of patients with advanced functional incapacity only in the CTEPH subgroup (92 vs. 44%, p=0.004). Observational data from registries in the UK, France and the USA that enrolled a broad spectrum of PAH etiologies consistently showed that patients diagnosed in NYHA class I and II had lower mortality than those in NYHA class III and IV.5,12,13 The earlier detection of CTEPH in our patients in the more recent study period might be explained by clinicians’ and patients’ increased awareness of this disease due to local and international campaigns.14–16 Despite our continued efforts, more has to be done to diagnose patients earlier, particularly in group 1 PH, such as establishing screening programs in high-risk populations and raising awareness of the disease. Currently, PH care in Portugal is organized into four regional treatment centers to which patients with suspected PH should be sent for assessment. Further development of this referral network might help the early diagnosis of PH.

Changes in the demographic landscape of PAH have been consistently described by several contemporary registries.17,18 Our data corroborate the higher mean age at diagnosis of PAH, a disease classically described as affecting young women. In addition, in our study age was independently associated with prognosis. This trend may reflect increased life expectancy, the widespread availability of screening tools like transthoracic echocardiography, and growing awareness regarding PAH in the medical community.19 Irrespective of the underlying cause of this demographic shift in PAH patients, this subset of older patients poses specific clinical challenges regarding their response to pulmonary vasodilators and their potential side effects, which need to be addressed in future studies.

In line with previous studies,5,20 the PH patients with the worst prognosis were those with CTD-PAH, who presented a five-year survival of 52%. Prognosis in this subset of patients showed improvement over time (Figure 2) despite the similar functional class at diagnosis in the two periods (NYHA III-IV class: 67 vs. 68%; p=0.93). We hypothesize that a more aggressive treatment approach can, at least in part, explain this better survival. In contrast, survival of patients with I/HPAH was unexpectedly worse in the more recent study period. Given the similar aggressiveness of vasodilator treatment in this subgroup over time, we speculate that the higher percentage of vasoreactive PAH patients (36% vs. 9%) can explain the worse survival. This difference may reflect survival bias, given the better prognosis of vasoreactive PAH. The overall survival rates of this subgroup (one-year and five-year survival rates of 95% and 80%, respectively) were similar to those of other registries,21 including one recently published by another Portuguese referral center.11

At the time of death, only 20% of PAH patients were under parenteral prostanoid therapy. The underuse of parenteral prostanoids in severe PAH has been reported by others.22–24 Physicians overlooking disease progression and underestimating its severity, organizational deficiencies in the management of this complex therapy, late referral, and patients’ refusal may all contribute to the underuse of prostanoids in PAH.25 Patient refusal, particularly by older patients, and social and cultural factors hindering self-management of continuous parenteral therapy were the main obstacles we found in our clinical practice. The lung transplantation numbers in our cohort reflect the constraints on this very effective treatment for PAH in Portugal, given the low volume of lung transplantations performed, particularly for PAH patients. This is a major issue that should be dealt with in the near future, by collaborating with national surgical centers or with foreign PH expert centers in the European Reference Network on respiratory diseases (ERN-LUNG) recently approved by the European Commission.26

As in previous reports from Portugal,9,11 CHD-associated PAH represented a significant proportion of our cohort, which may be due to the limited access to corrective cardiac surgery in the past. Despite the lower age and better functional class at diagnosis, and a trend toward better survival over time, efforts should be made to enhance the prevention of PH development by early referral of these patients to the recently designated congenital heart disease expert centers network.27

Estimated one-year and five-year survival in our CTEPH patients was 95% and 81%, respectively. These outcomes are in line with those reported in other registries (one-year: 88-97%; five-year: 65-83%).9,28–31 PEA is the cornerstone treatment for CTEPH patients.2 It is potentially curative and is associated with low in-hospital mortality if performed in high-volume centers.32 Despite robust evidence of its benefits, underuse of PEA has been reported in previous registries. Escribano-Subías et al.28 showed that this underuse is particularly marked in centers without PH expertise, in which only 5% of CTEPH patients underwent PEA, compared to 48% of those treated in expert centers. Almost 40% of our CTEPH patients underwent PEA or angioplasty after referral to a European high-volume surgical center. After adjusting for age, PEA was no longer associated with better survival, suggesting that some of the observed survival differences between operated and non-operated subgroups are accounted for by patient characteristics. The low statistical power, and consequent wide confidence intervals, should also be taken into consideration when analyzing these results. The main reason for not undergoing PEA was patient refusal to undergo the procedure in a foreign center, despite the existence of a national program that covers all expenses of cross-country care in this field. The majority of non-operated patients were treated with pulmonary vasodilators, initially with an endothelin receptor antagonist and later with a soluble guanylate cyclase stimulator, recently approved for the treatment of non-operable patients and those with persistent PH after PEA.2

Our study has several limitations that should be considered. The single-center nature of our data limits the generalizability of our conclusions, as etiologies and access to PH treatments may vary significantly across different centers. The small number of patients in some of the subgroups limits wider inferences. Despite the strong signs of improvements in survival, our analysis is underpowered to detect statistically significant time trends in the survival of patients diagnosed at different periods.

Our data consistently indicate a trend toward improved survival over time of PH patients treated at a Portuguese referral PH center, except for I/HPAH. Efforts to achieve an early diagnosis, to increase use of parenteral prostanoids and to promote the delivery of surgical treatments to PH patients are needed to further improve their prognosis.

The authors have no conflicts of interest to declare.