Survival in pulmonary hypertension in Spain: insights from the Spanish registry

Study population

Initially 1,162 patients were enrolled. However, 134 patients were removed because they did not meet all the inclusion criteria, yielding a final total of 1,028 patients. It should be noted that 61% of the patients included in the registry were reported by three centres. Clinical and haemodynamic data at the time of diagnosis are shown in table 1.

In incident cases, the delay between the onset of symptoms and diagnosis was 2.2 yrs, whereas in previously diagnosed cases it was 3.7 yrs. Most of the patients had severe symptoms at the time of diagnosis, with 69% of them in World Health Organization (WHO) functional class (FC) III or IV in the PAH group and 77% in the CTEPH group. Only 30% of patients with CTEPH underwent pulmonary endarterectomy (PEA).

The mean 6-min walk distance and haemodynamic data were related to FC in both the PAH and CTEPH groups (table 2).

Acute vasodilator testing was carried out on 643 patients with PAH (75%) and 91 with CTEPH (52%). A positive response was observed in 12% of patients from the PAH incident group, whereas in previously diagnosed PAH it was reported to be positive in 21%.

Subgroups of PAH

The distribution and characteristics of patients across the various types of PAH are shown in table 3. Among patients with PAH associated with connective tissue diseases (CTDs), systemic sclerosis (61%) was the most common diagnosis.

In PAH associated with congenital heart disease (CHD) (167 patients), simple type defects were the most frequent forms (69%). It is noteworthy that 30% of patients had PAH after corrective cardiac surgery.

24 (2.3%) patients displayed two coexisting conditions known to be associated with PAH: HIV infection and portal hypertension were the most common coexisting conditions (n=8).

The clinical and haemodynamic data at diagnosis for each PAH subgroup and CTEPH are displayed in table 3.

Incident versus previously diagnosed cases of PH

Between July 1, 2007 and June 30, 2008, 167 (16.2%) patients were newly diagnosed (incident cases), whereas the remaining had been diagnosed before the establishment of the registry.

In previously diagnosed cases, we differentiated between those patients who were alive on July 1, 2007 (prevalent cases) and those who died before that date. The clinical and haemodynamic data at diagnosis for incident and previously diagnosed cases of PH are summarised in table S1. Incident cases were slightly older with a lower P_pa.

Prevalence and incidence

The overall estimated prevalence of PH in Spain is 19.2 cases per million adult inhabitants (MAI), based on the 715 cases that were alive between July 1, 2007 and June 30, 2008. The estimated prevalence of PAH was 16 cases per MAI, while the prevalence of CTEPH was 3.2 cases per MAI. Among patients with PAH, the estimated prevalence of IPAH, CHD, CTD and PAH associated with toxic oil syndrome (TOS) were 5.6, 3, 2.5 and 0.5 cases per MAI, respectively.

In this period, the low estimated incidence of PH was 4.6 cases per MAI per year (PAH 3.7 and CTEPH 0.9 cases per MAI per year). As regards the PAH group, the low estimated incidence of IPAH was 1.2 cases per MAI per year.

Survival

Over a mean follow-up of 3.7±4.2 yrs, 331 (32%) patients died, while 101 (9.8%) were lost to follow-up. For survival analysis, the latter were censored at the time of their last visit or observation.

The 1-, 3- and 5-yr survival rates in the different PH groups are shown in table 4. Kaplan–Meier survival curves according to different aetiologies are shown in figure 1.

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Figure 1–

Kaplan–Meier estimates of 5-yr survival from time of diagnosis in different pulmonary hypertension subtypes. IPAH: idiopathic pulmonary arterial hypertension; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; PoPH: portopulmonary hypertension; PVOD: pulmonary veno-occlusive disease. The p-value for the overall comparison is <0.001. ^#: compared with IPAH.

In the subgroup of patients with idiopathic, anorexigen-induced or heritable PAH (n=314), those who showed a positive response (n=70) in the acute vasodilator test were excluded from the survival analysis, to prevent potential bias. Figure 2a shows predicted survival using the NIH and the PHC Registry equations in the IPAH nonresponders population.

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Figure 2–

a) Observed and estimated survival (National Institutes of Health (NIH) and Pulmonary Hypertension Connection (PHC) equations) of idiopathic pulmonary arterial hypertension (IPAH) nonresponders in the Spanish Registry of Pulmonary Arterial Hypertension (REHAP) registry. b) Observed and estimated survival (French equations) of IPAH cases diagnosed <48 months before June 30, 2008 in the REHAP registry.

In order to test the applicability of the French registry equation to estimate survival in our cohort, we restricted the analysis to patients with IPAH diagnosed up to 48 months before June 30, 2008 (45 incident and 104 diagnosed in the 36 months previous). Figure 2b shows both the observed and the estimated survival curves. Survival predicted by the equation derived from the French registry slightly infra-estimated the actual survival of the REHAP cohort the first 2 yrs (p=0.019).

Furthermore, we also considered the applicability of the REVEAL equation to estimate the 1-yr survival. In order to achieve comparable populations, we excluded from the analysis those patients with TOS (n=33), pulmonary veno-occlusive disease (PVOD) (n=15), and also patients with fewer than seven factors contained in the REVEAL formula (n=108), which is the minimum necessary to maintain the reliability of the results. The 1-yr survival in the 713 remaining patients with PAH estimated by the REVEAL equation was 92%, whereas the observed survival (number at risk 686) was significantly lower (88%, 95% CI 85–91%; p=0.001). However, when the REVEAL risk equation was applied exclusively in the incident group predicted survival was 93%, whereas observed 1-yr survival (number at risk=118) was only slightly lower, without significant difference (88%, 95% CI 82–94%; p=0.157).

In the univariate analysis, age, male sex, WHO FC III–IV, pericardial effusion, reduced exercise capacity, increased right atrial pressure (P_ra), PVR, heart rate, reduced % predicted carbon monoxide diffusing capacity, cardiac index and cardiac output were all associated with an increased risk of death. However, time since diagnosis and blood pressure were not associated with an increased risk. Among subtypes of PAH, PAH associated with CTD, portal hypertension and PVOD were all associated with an increased risk of death. In contrast, PAH associated with CHD was associated with a lesser risk of death when compared with IPAH (table S2).

In the multivariate analysis (table 5), only male sex, WHO FC, P_ra and cardiac index remained independent predictors of death in PAH. With regard to PAH subtypes, PAH associated with CTD, portal hypertension or PVOD also remained as independent predictors of death.

Epidemiology of PH in Spain

The observed incidence and prevalence of IPAH in REHAP are similar to those observed in the French registry [4] and clearly lower than those described in the Scottish registry [5]. Methodological differences in the criteria used to include cases may account for these differences. Presumably, both the French and the current registry may underestimate these figures in their respective countries.

The incidence and prevalence of PAH associated with other conditions varies enormously between registries, mainly due to registry design and PAH subtypes that are included, particularly with respect to the number of cases of PAH associated with CHD. In the majority of registries published to date, the number of patients with CHD is relatively low, probably reflecting a lack of interaction between physicians caring for patients with CHD and PH units. In the recently published Belgian registry on CHD [15], the estimated prevalence of Eisenmenger’s syndrome was 11 cases per MAI, clearly higher than the prevalence observed in the REHAP (2.9 cases per MAI), even after taking into account the fact that patients with PAH after corrective surgery were not included in the Belgian registry.

Pulmonary veno-occlusive disease

The true incidence and prevalence of PVOD is unknown and probably underestimated, because many cases might be misclassified as IPAH. There is no information about the epidemiology of PVOD in any PH registry. Prevalence in the current registry was 0.16 cases per MAI, representing 1.5% of all PH subtypes. Patients with PVOD had more severe hypoxaemia, lower carbon monoxide diffusion capacity, absence of vasodilator response and the worst survival compared with patients with IPAH, which is in line with previous reports [16].

PH associated with TOS

PH associated with TOS is a particular subtype of PAH related to an epidemic produced by the ingestion of rapeseed oil that had been denatured for industrial use, which took place in Spain in May, 1981 and affected >20,000 people. PH developed in ∼20% of the patients, although in most of them it regressed spontaneously. Nevertheless, in a small number of patients (0.2%) it progressed to a malignant course, leading rapidly to death in the following years. A small group of patients (n=33) not initially diagnosed with severe PAH developed the disease after a latency period of 15–20 yrs. They all share common characteristics: all of them belong to the registered TOS population group (official Spanish census), approximately half of them had mild PAH in the acute phase of the disease and, in general, they had a good quality of life until the diagnosis of severe PAH (some females had successful full-term pregnancies during this period). The last diagnosis of a patient with TOS-associated PAH was in 2007 (26 yrs after the epidemic). In contrast with other registries [4, 6], PAH induced by anorexigen use appears to be extremely rare in Spain.

CTEPH

Information about the incidence and prevalence of CTEPH is sparse and we have only an indirect estimate carried out by Condliffe et al. [10], where the estimated incidence was 1.75 cases per MAI. In the REHAP registry, the incidence was 0.9 cases per MAI per year (clearly lower than the UK results), and the prevalence was 3.2 cases per MAI, which is the only reported figure to date.

Factors affecting survival

All recent registries [4–6, 14] and the current registry show that PAH is still detected late in the course of the disease.

In our registry, among patients with PAH, male sex, lower cardiac index and higher P_ra were independent predictors of death. Regarding the aetiology of PH, three subtypes remain as independent predictors of outcome: portopulmonary hypertension, PVOD and CTD. The importance of the haemodynamic values has been previously published [17, 18]. However, the more negative prognosis associated with male sex, a finding that has also been reported in the REVEAL [7] and French registries [8], does not have any clear explanation.

In our cohort, portopulmonary hypertension was found to be an independent predictor of death, as it has also been reported in the REVEAL registry [7]. In contrast, no difference in mortality between IPAH and porto-pulmonary hypertension was observed in the French registry [19]. One potential explanation for such difference might be related to the severity of underlying hepatic disease, which unfortunately is not reported in PAH registries.

CTD was also found to be an independent risk factor for mortality, in agreement with all previous registries [7, 14, 19, 20].

Survival prediction

In our cohort of patients with IPAH, observed survival was 89% and 77% at 1 and 3 yrs, respectively. These findings are similar to those observed in the recent USA PHC registry [9] and are better than those reported >20 yrs ago in the NIH registry [2]. Likewise, the 3-yr survival rate of IPAH nonresponders to the vasodilator test in the REHAP registry matches perfectly with the predicted survival using the PHC equation [9]. Although some degree of improvement in survival compared with historical cohorts can be expected due to advances in general patient care and improved living circumstances, the magnitude seen here suggests an effect derived from specific PH therapy.

The overall survival of patients with PAH in REHAP was similar to that of the PHC, REVEAL and French registries (table S3).

However, differences in registry design might influence the potential applicability of a given survival prediction equation to populations different from those where the equation was derived. The REHAP registry included 1,028 consecutive patients diagnosed in Spain over one decade (1998–2008). As mentioned, observed survival in this cohort fits quite well with that predicted from the PHC registry equation [9], which also covers a broad time span (1991–2007). In contrast, survival in the REHAP registry, restricted to patients with IPAH diagnosed <48 months before June 30, 2008, was slightly better in the first 2 yrs than that predicted using the French registry equation [8]. Presumably, this could be explained because patients in the REHAP were diagnosed between 2004 and 2008, and had less severe disease at diagnosis than patients in the French registry, who were diagnosed between 1999 and 2003 [19]. Such differences in the time of diagnosis could be important in PAH, where the therapeutic approach has been refined in the past 5 yrs, as PH units have gained more experience. Currently, treatment is started at a less severe disease stage and therapeutic goals are more ambitious [21]. All these factors could explain the observed differences in survival.

Regarding the equation derived from the REVEAL registry [7], the 1-yr survival observed in the REHAP registry for all PAH cases was significantly lower than that predicted by this equation. This fact may be related to differences in population selection: whereas the REVEAL registry included 85% of prevalent cases, in the REHAP registry sequentially diagnosed patients were enrolled, including both alive (prevalent) and deceased patients, over a long period of time. Moreover, the REHAP registry extends back to 1998, whereas the REVEAL registry only extends back to 2003. This is important because prior to 2003 the only treatments that were available were epoprostenil and treprostinil. Presumably, these differences could explain the observed differences when the whole REHAP cohort is considered, whereas 1-yr survival of incident cases in the REHAP registry fits quite well with that predicted by the REVEAL equation. All in all, these observations suggest a beneficial impact on PAH survival of contemporary therapeutic strategy.

Survival in CTEPH

Until recently it was thought that CTEPH had a better prognosis than IPAH, partly due to the fact that it is the only potentially curable form of PH. The overlap in the survival curves of CTEPH and IPAH observed in our study was unanticipated. Survival of the CTEPH cohort, of which only 30% underwent PEA, was similar to that reported in the Swiss registry [22] (10% PEA) and only slightly lower than that experienced in the UK (50% PEA) [10]. However, the 5-yr survival after PEA of patients who survived up to 3 months after surgery was 90%, with a remarkable improvement in functional capacity and haemodynamic profile, which was markedly better than that of non-surgical patients [23–25]. Thus, continued efforts to consider PEA in CTEPH treatment are needed.

Several limitations should be considered when interpreting data from our study. This is an observational and voluntary registry with a large number of patients entered retrospectively; this can lead to missing or inconclusive data for analysis. However, these limitations could be minimised, as two-thirds of the patients included in REHAP had been prospectively collected in local databases, which were included in the registry database. In addition, although all PH centres included patients in the registry, we cannot rule out that patients with PH treated in small hospitals were not reported to the registry, which works on a voluntary basis. However, since all PH centres were included, the REHAP population is representative of the whole Spanish PAH population. Furthermore, it should be also taken into consideration that these problems are unavoidable when doing a multicentre national registry.

The Spanish PH registry covers a long period of time, almost a decade. The management of the disease has changed considerably over the course of these years. Initially, the time between the onset of symptoms and diagnosis was >3 yrs. Accordingly, some of the most aggressive cases may have died before being diagnosed, and therefore before being included in the registry. This may have led to an underestimate of mortality.

In summary, the present study shows striking similarities in PAH epidemiology, as well as in evolution and survival, between patients in Spain and those reported in recent European and American registries. Results of the REHAP registry confirm significant survival improvement with current treatment strategies and provide evidence on the applicability of recently reported survival prediction equations to different populations, although differences intrinsic to registry design should be taken into account. Overall, our results support the validity of multicentre international clinical trials and indicate that, despite differences in health systems and populations, the evolution of the disease is quite homogeneous when access to advanced specific therapies is guaranteed.