We designed a single-center, prospective cohort study based on incident cases of PAH. PAH was defined as per guidelines14: right heart catheterization (RHC)-confirmed precapillary pulmonary hypertension (PH) in the absence of other etiologies for PH (left heart disease, lung disease, chronic thromboembolic PH). Precapillary PH was defined as a mean pulmonary arterial pressure (mPAP) of ≥25mmHg and a pulmonary arterial occlusion pressure (PAOP) of ≤15mmHg. PAH was classified into six different groups based on etiology, based on the latest guidelines14: IPAH, HPAH, DPAH, PAH-CHD, PAH-CTD, PoPH, and PVOD (group 1′). Patients were ineligible if they were aged under 18 years at enrollment.

For purposes of analysis, we divided the groups into two major diagnostic subgroups: PAH-CHD patients (Eisenmenger syndrome in non-corrected systemic to pulmonary shunts and PAH after shunt correction) and non-PAH-CHD patients (IPAH, HPAH, DPAH, PAH-CTD and PoPH). IPAH, HPAP and DPAH were combined into one group to simplify survival analysis. We also stratified the population according to age and gender to perform subgroup survival analysis.

We collected information regarding demographics, clinical and laboratorial parameters at presentation, namely 6-minute walking distance (6MWD), B-type natriuretic peptide (BNP) and hemodynamics from the diagnostic, baseline RHC.

All follow-up visits were conducted at our institution and managed by a small group of PH specialists (G.C., R.B. and A.M.S.). Follow-up intervals and initiation of relevant therapy were determined at the physician's discretion. Because of changes in therapy, availability, and recommendations throughout the time period, treatment is registered as the latest administration on last visit.

The primary endpoint of our study was all-cause mortality. The secondary endpoint was a combination of all-cause mortality and admission for decompensated heart failure. Survival time was estimated from the date of the diagnostic RHC. At the end of the study, on November 12, 2015, vital status was obtained by access to the National Health Data Platform (Plataforma Nacional de Dados de Saúde). We also registered all hospital admissions for decompensated heart failure after the first hospital admission. No patient was lost to follow-up.

Continuous variables were reported as means±SD or as medians with interquartile range (IQR) where appropriate. Categorical variables were reported as absolute frequencies and percentages. Survival analysis was performed using Kaplan–Meier curves, with the date of entry into the study defined as the date of the first diagnostic RHC or the first visit to the PH clinic for those patients that did not undergo any initial RHC. Patients that did not die were censored at the end of the study. The log-rank test was used for comparison between groups.

Univariate Cox's proportional hazards analysis was used to assess the relationship between PAH and outcomes. Co-linearity between variables was examined. Significant variables on the univariate analysis along with those variables previously reported to be related with mortality, were included in a forward stepwise multivariate Cox's proportional hazards model in order to identify independent predictors of outcomes in the overall PAH population.

We conducted three subgroup analysis, investigating the interaction between PAH etiology (PAH-CHD vs. non-PAH-CHD), age, gender and prognosis. We also conducted an exploratory analysis including the IPAH, HPAP and DPAH groups in which the actual survival was compared with the historical survival from the NIH cohort,10 using the prognostic equation as follows15: P(t)=H(t)A(x,y,z); H(t)=0.88–0.14t+0.01t2, where t=time in years; A(x,y,z)=e(0.007325x+0.0526y−0.3275z), where x=mean pulmonary artery pressure; y=mean right-sided atrial pressure; and z=cardiac index. The calculated survival was visually compared with the observed survival at the same time points with 95% CI. A P value (two-sided) below 0.05 was considered statistically significant. STATA software (STATA IC for Windows, ver. 13, Lakeway Drive, TX, USA) was used for statistical analysis.

A total of 65 patients were consecutively enrolled in our study; their clinical and hemodynamic characteristics at the time of diagnosis are shown in Table 1. The mean age was 48 (±19.2) years and the majority of patients were female (68%, n=44). The most common PAH subgroup was PAH-CHD (n=31; 48%), followed by PAH-CTD (n=16; 25%), IPAH (n=8; 12%), PoPH (n=8; 12%) and HPAH (n=1; 1.5%). On admission, the mean 6MWD was 399 (±113.9)m and the median BNP was 79 [IQR 36–138]pgdL−1. Most patients had severe hemodynamics at diagnosis, characterized by high indexed pulmonary vascular resistance (7.5±5.2Woodunitsm−2) and low cardiac index (2.7±1.3Lmin−1m−2). On the last follow-up visit, regarding pulmonary vasodilator therapy, about half (n=37) of the patients were on monotherapy and one-third (n=22) were on combination therapy (Table 2).

Over a median follow-up period of 3.1 [IQR 1.7–5.4] years, 17 patients (26%) died. The Kaplan–Meier survival curve for the total cohort is illustrated in Figs. 1 and 2 shows the estimated survival according to the different etiologies. Survival was numerically better in patients with PAH-CHD than in patients without PAH-CHD, although it did not achieve statistical significance (log-rank P=0.06). No significant difference was observed in estimated survival between male and female patients (log-rank P=0.07) or among different age groups (log-rank P=0.14). However, higher BNP values at diagnosis were significantly associated with increased mortality (log-rank P<0.001) (see Fig. S1 in the Supplementary Material Online).

Figure 1.

Kaplan–Meier curves for all-cause mortality. (A) Global cohort of patients with pulmonary arterial hypertension (PAH) (n=65). (B) PAH cohort stratified by the different etiologies of PAH. IPAH+HPAH: idiopathic and hereditable PAH; PAH-CTD: connective tissue disease-associated PAH; PAH-CHD: congenital heart disease-associated PAH and PoPH: portopulmonary hypertension.

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Figure 2.

Kaplan–Meier curve for the secondary, combined endpoint of all-cause mortality and admission for decompensated heart failure. Global cohort of patients with pulmonary arterial hypertension (PAH) (n=65).

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Kaplan–Meier curve for the secondary endpoint is represented in Fig. 3. Older age (log-rank P=0.010), higher BNP levels at diagnosis (log-rank P=0.003) and non-CHD-PAH (log-rank P=0.017) were associated with worse prognosis, regarding all-cause death and admission for heart failure decompensation) (see Fig. S2 in the Supplementary Material Online).

Figure 3.

Kaplan–Meier estimates with 95% confidence intervals and predicted survival using the NIH equation10,15 for the IPAH, HPAH and DPAH cohort (n=9). At the 1-year time-point, there is a numerically difference of survival. At the latter time-points, the 95% confidence interval includes the observed survival. ---: observed survival; ––: predicted survival.

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In a Cox proportional hazards model, BNP, age and male gender were independently associated with the primary and secondary endpoints (Table 3, see also Table S1 in the Supplementary Material Online). We generated and compared two subgroups from the main cohort, concerning BNP levels and gender: females with BNP levels lower than the median and males with BNP levels over the median. The rates of death [OR 8.5 (95% CI 1.4–51.5), P=0.02] and combined endpoint of death and admission for decompensated heart failure [OR 11.2 (95% CI 1.2–104), P=0.03) were significantly higher in the latter group.

We conducted an exploratory analysis using the NIH prognostic equation10,15 to calculate the expected survival of our incident IPAH, DPAH and HPAH cohort at 1 and 3 years. The 1- and 3-year expected survival was 75%, and 55%, respectively; the observed survival was numerically higher (100% and 76%), although not statistically significant (Fig. 3).

The French17 and the REVEAL16 studies comprised a large percentage of prevalent cases, with a significantly worse survival for incident cases than for prevalent cases. This can be explained by inclusion of long-term survivors in the prevalent cohorts. The difference in 1-year survival between these two studies is minimal (88% vs. 85%). However, these survival rates are numerically lower than the ones in our cohort, with a 1-year survival of 95%. In terms of long-term outcomes, our cohort had a 3-year survival rate of 77%, higher than the 65–68% reported in previous studies16,17; and a 5-year survival of 71% also numerically higher than the 57% reported in the REVEAL study.16 The survival estimates presented in our population are from an incident cohort, usually displaying lower survival rates than cohorts including prevalent cases. Reasons for a higher survival rate in our cohort than in other cohorts reflect, but may be not limited to, a larger population of PAH-CHD patients, usually with better overall prognosis. Also, the availability of all drugs to treat PAH patients may help to promote survival in this group of patients.

PAH mortality has been associated with male sex, right ventricular hemodynamic function and exercise limitation (6MWD) in the REVEAL,16 French17 and Spanish6 registries. In our study, male sex and higher BNP values were independent predictors of death and hospitalization for decompensated heart failure. Although reported in several studies, there is no clear explanation for the association of male sex and mortality.5,9,17 Additionally, no significant difference was observed in survival times between male and female patients. An improved understanding of the influence of gender on PAH outcomes is, therefore, of critical importance.5,17 Higher BNP values at diagnosis were associated with increased mortality, as also described in previous studies.25–27 This probably reflects the impact of right ventricular failure in determining the prognosis. In our registry, hemodynamic parameters did not achieve statistical significance as predictors of mortality, which can be explained by the lack of statistical power of our study population.

The major limitation of our study is the small sample size, which did not allow us to identify other predictors of mortality. Our study is underpowered due to the small number of patients and events. Taking into consideration an expected mortality reduction of 43%,28 we calculated that 106 events would be necessary in order to identify a mortality reduction against placebo (i.e. the NIH patients). This number is even more limitative as we could only include IPAH, HPAH and DPAH in our NIH-comparative analysis. However, although underpowered, our analysis reflects the totality of our patients since 2009, having true value as real world data in our country. The direct comparison of the Kaplan–Meier curves of our IPAH, HPAP and DPAH subgroups against the expected survival predicted by the NIH curve has several limitations, as (i) the NIH equation was extrapolated from a mixed cohort of incident and prevalent cases, (ii) it only comprised 3 hemodynamic variables, (iii) the patients were younger with a different demographic distribution and (iv) from a cohort living 30 years ago. Although limited, this analysis is of interest as the simple observation of the curves gives a clear signal of the difference that is the actuarial survival gain with a contemporary approach. Finally, comparisons with other studies must be made with caution, given the disparity of the population size and characteristics, such as a larger cohort of PAH-CHD, which might result in overly optimistic survival estimates. The external validity of the sample is limited to centers with similar medical and pharmacological resources available.

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that no patient data appear in this article.

The authors declare that no patient data appear in this article.