The Patient Registry for the Characterization of Primary Pulmonary Hypertension was the first national registry [5]. This landmark registry, sponsored by the NIH, began in 1981 and prospectively collected clinical data on 194 patients from 32 centers in the United States with primary pulmonary hypertension (corresponding to idiopathic PAH in recent classification schemes), familial PAH (now heritable PAH), or anorexigen-induced PAH. Prior to the registry, there were many questions regarding the epidemiology and natural history of the disease. Data were collected on patients prospectively according to standardized protocol from July 1981 to Sept 1985 and patients were followed through August 1988. The registry did not address prevalence of PAH. Pulmonary hypertension was defined by catheterization as a mean pulmonary arterial pressure of >25 mmHg at rest or >30 mmHg with exercise. Primary pulmonary hypertension was only diagnosed after exclusion of other potential causes of pulmonary hypertension, including collagen vascular disease and elevated left-sided filling pressures, defined as pulmonary capillary wedge pressure >12 mmHg. Demographic data, hemodynamic measures, pulmonary function, and gas exchange variables were obtained at baseline and assessed at 6-month intervals.

There were 187 patients with mean age of 36 ± 15 years with a female to male ratio of 1.7:1. Five percent had a history of appetite suppressant use and 6 % were familial pulmonary hypertension. Female patients tended to have more severe symptoms at presentation with 75 % being in New York Heart Association (NYHA) functional class III or IV compared with 64 % of male patients. The median time from onset of symptoms to diagnosis was 2.0 ± 4.9 years (median 1.27). This landmark registry helped correlate hemodynamic findings to severity of symptoms and survival. As expected, patients with NYHA functional class III or IV symptoms had higher mean pulmonary artery pressures, higher right atrial pressures and lower cardiac indices compared to less symptomatic patients. By the time of diagnosis, the clinical and hemodynamic findings were advanced in most cases.

The NIH registry also characterized mortality and identified factors associated with survival for this select group of PAH patients. Because only incident cases were recruited and catheterizations were part of the initial evaluation, the date of diagnostic catheterization served as the baseline from which survival was measured. The estimated median survival was 2.8 years [19]. Variables associated with poor survival included NYHA functional class III or IV, presence of Raynaud’s phenomenon, elevated right atrial pressure (RAP), elevated mean pulmonary artery pressure (PAP), decreased cardiac index (CI) and decreased diffusing capacity (of the lung) for carbon monoxide (DLCO) (Table 20.3). Estimated survival rates at 1-, 3- and 5-years were 68 %, 48 % and 34 % respectively. By the end of the registry, 106 of the 194 patients had died, including 26 % with sudden or unexpected death and 47 % from right ventricular failure. Symptom duration did not correlate with disease severity implying that disease progression differs among patients. Of the 36 patients (19 %) receiving long-term (non PAH-specific) medication at study entry, there was no significant difference in survival time compared with patients not receiving therapy. However, the design of the study did not allow for valid assessment of differences in therapeutic interventions. This study certainly confirmed the poor prognosis of patients with pulmonary arterial hypertension.

The NIH registry gave the first national characterization of a rare disease with detailed evaluation of symptoms, laboratory, imaging and hemodynamic findings as well as providing prognostic indicators. This registry provided the foundation for subsequent studies of PAH.

The French National Registry is considered the first PAH registry in the modern treatment era. Disease-specific therapies were absent at the time of the NIH registry and the classification of pulmonary hypertension had changed since the late 1980s. In the nearly two decades since the NIH registry, prostanoids, endothelin receptor antagonists (ERA) and phosphodiesterase-5 (PDE5) inhibitors became specifically available for PAH. Despite these significant advances, there had not been a large-scale, national-level registry to update clinical and hemodynamic parameters of patients, prevalence of the disease or estimates of survival.

The prospective registry included 17 university hospitals with a total of 674 patients (121 incidence cases, 553 prevalent cases) through the French Network on PAH with 3-year follow-up [10]. Adult PAH patients, including idiopathic, familial, anorexigen-induced, or PAH associated with CTDs, congenital heart diseases (CHD), portal hypertension and HIV were seen between October 2002 and October 2003. Diagnosis was considered to be the time of RHC, which was a pre-requisite for enrollment. Because prevalent cases were catheterized before study entry, Humbert et al. accounted for immortal time bias by using survival estimates and a Cox proportional hazards model from the time of diagnosis. In addition, prevalent cases were entered into the risk set in delayed fashion (i.e. left truncation), by the same amount of time that had elapsed between diagnostic catheterization and registry entry. For example, if 12 months had elapsed between an individual’s diagnostic catheterization and recruitment into the registry, that individual’s subsequent time alive in the registry and contribution to the cohort’s survival estimate did not begin until the 12 month point of the cohort’s survival curve and was not included in the first 12 months. There were also 121 incident cases (newly diagnosed), who were patients diagnosed during the registry’s recruitment phase and none of these patients were lost to follow-up.

Mean age was 50 ± 15 years, much older than in the NIH registry due to a more diverse group of enrolled PAH patients; female to male ratio was 1.9. The delay between the onset of symptoms and diagnosis was still 27 months. At diagnosis, 75 % of patients had NYHA functional class III or IV symptoms. Hemodynamic evaluation demonstrated severe compromise with RAP 8 ± 5 mmHg, mean PAP 55 ± 15 mmHg and pulmonary vascular resistance index 20.5 ± 10.2 WU · m² with correlation to the NYHA functional class. IPAH comprised 39.2 % of patients and familial cases represented 3.9 % of the population. At that time, epoprostenol, bosentan, iloprost and sildenafil were the available approved therapies. No mandatory specific treatment algorithm was used; thus, use of PAH targeted therapies was at the discretion of the treating physician.

Prevalence in France was calculated to be 15.0 cases per million adults, although a significant range (5–25 cases per million population) was noted across regions of the country. Unfortunately, this registry identified that despite the increased awareness of PAH since the NIH registry 20 years prior, patients were still being diagnosed with clinical impairment as severe as during the time of the NIH registry.

The French PAH network followed patients for 3 years after study entry and demonstrated 1-, 2- and 3- year survival of 87 %, 76 % and 67 %, respectively in the overall cohort [20]. In a combined incident and prevalence (i.e. diagnosed <3 years from study entry) cohort of idiopathic, familial and anorexigen-associated PAH cases, survival for 1-, 2-, and 3-year survival rates were slightly lower, 83 %, 67 % and 58 % respectively, but still considerably better than NIH registry’s estimates [19]. The prevalent patients with idiopathic, familial and anorexigen associated PAH had higher survival rates than incident patients. Even though the registry made efforts to eliminate survivor bias (as described earlier), this finding may still reflect such a bias. There was better 3-years survival rate in patients with congenital heart disease, but poorer survival in CTD; these observations were subsequently confirmed by the REVEAL registry [21]. Multivariate analysis identified female sex, higher six minute walk distances, and higher cardiac output at time of diagnosis as independent prognostic factors for survival (Table 20.3).

The Pulmonary Hypertension Connection registry (PHC) was a large U.S. based registry conducted at three sites by essentially one group of researchers. From 1982 to 2006, 578 patients with WHO Group 1 Pulmonary Arterial Hypertension were included [8]. The goal was to define clinical characteristics and prognosis of WHO Group 1 PAH patients and compare groups by etiology and across treatment eras.

Patients were segregated into prevalent (1982–2004) versus incident (2004–2006) groups, with only the latter group’s data being collected prospectively. Patients were also compared by treatment era: pre-1996 (before approved therapies), 1996–2002 (only IV epoprostenol) and post-2002 (IV, subcutaneous or inhalational prostacyclins, ERAs and PDE5 inhibitors). Seventy-seven percent of the PHC cohort was female, confirming again the female predominance of PAH; the only subgroup without female predominance was Human Immunodeficiency Virus (HIV) -associated PAH. The PHC registry again recognized that patients with PAH are referred to specialty centers far into the disease course, as 80 % of patients had NYHA functional class III or IV symptoms at presentation.

PHC included all types of Group 1 PAH patients, including 44 % idiopathic, 4 % heritable PAH (HPAH) and 3 % anorexigen, along with several associated PAH groups – 30 % CTD, 11 % CHD, 7 % porto-pulmonary hypertension and 1 % HIV-associated PAH. These frequencies were similar to the French registry, but differed from the NIH registry which only included IPAH, HPAH and anorexigen-related PAH. Compared with other subgroups, patients with connective tissue disease (CTD) had more severe disease: poorer exercise capacity, a worse functional class, a higher mean PAP, higher pulmonary vascular resistance (PVR) and lower CI. Meanwhile, higher functional class, better exercise capacity, lower mean PAP, lowered PVR and higher CI were seen with porto-pulmonary hypertension and congenital heart disease (CHD) -associated PAH.

For the entire cohort, median survival time was 3.6 years. The 1-, 3-, and 5- year survival rates were 84 %, 67 % and 58 %, respectively. The 1-year survival for the incident cohort was 85 %, which is similar to the French registry (88 % 1 year survival) but improved from NIH registry [10, 19]. Using Cox proportional hazards analysis, increasing age, CTD as the etiology for PAH, higher functional class, higher RAP and lower CI were identified as significant and independent predictors of mortality (Table 20.3) [22]. In essence, PHC confirmed some of the NIH findings but once again highlighted how advancements in care had improved survival.

The Scottish registry described the epidemiologic features of PAH in a population over a prolonged period of time (1986–2001), by reporting data from the Scottish Morbidity Record (SMR) and the Scottish Pulmonary Vascular Unit (SPVU) [11]. This retrospective population cohort study used records from a national hospitalization database for Scotland; the SMR relied on systematic coding of hospital admissions and assembled a cohort of 374 incident patients, aged 16–65 years with diagnosis of IPAH, CTD-PAH or CHD-PAH. The overall population prevalence was 52 cases per million. The median survival of incident patients with IPAH was 3.8 years in females and 5.6 years in males, which is contrary to the poorer survival in male patients in the NIH, French, PHC and REVEAL registries [8, 19, 20, 23]. These lengthier survival times cast doubt on the PAH diagnosis in some of the patients from the SMR group.

The incidence and prevalence was also examined from the SPVU (1997–2005), which is a national specialist center for PAH management and is responsible for diagnosis and treatment of all cases of PAH in Scotland. All patients with PAH were diagnosed by standardized protocol, including RHC. The prevalence was 26 cases per million adult inhabitants.

The Scottish registry collected epidemiologic data from two perspectives. The SMR identified patients simply by ICD-9 code. The accuracy of the diagnosis was not confirmed by standardized protocol, like the SPVU data. As a result, there was a lower prevalence of PAH from the SPVU than from the SMR analysis (52 versus 26 cases per million adult inhabitants). Even though the data from SMR represents a survey of inexpert diagnoses, it still suggests that registries conducted at specialized centers may underestimate prevalence rates due to numerous challenges precluding some individuals from being evaluated at distant expert-based referral centers. In addition, the lower prevalence rate from SPVU is still significantly higher than the French National Registry (26 versus 15 cases per million) [10]. Considering these two large national experiences, differences in prevalence likely exist in various regions of the world, but also depend on the method of case identification and data collection [24].

The Spanish Registry of Pulmonary Arterial Hypertension (REHAP) examined the prevalence, incidence and survival of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain from January 1998 to June 2008 [12]. One of its objectives was to assess the applicability of recently developed predictive equations (for survival). Demographic, functional and hemodynamic variables were evaluated in 866 PAH and 162 patients with CTEPH. Patients were diagnosed as incident if diagnostic RHC took placed within 6 months of the Registry’s inception. PAH prevalence was estimated to be 16 cases per million. The prevalence for CTEPH was only 3.2 cases per million. With incident PAH cases, the delay between the onset of symptoms and diagnosis was 2.2 years and in previously diagnosed patients was 3.7 years, possibly suggesting some improvement in disease awareness over the period of the recruitment. Sixty-nine percent of patients in the PAH group were in WHO functional class III or IV, which was similar to the 77 % of the CTEPH group. Interestingly, only 30 % of CTEPH patients underwent pulmonary thromboendarterectomy, the treatment of choice for CTEPH. This was also the first registry to describe pulmonary veno-occlusive disease (PVOD) within a larger PAH cohort. PVOD only made up 1.5 % of the cohort and prevalence was estimated to be 0.16 cases per million adults; but the authors speculated an underestimation of true prevalence. Patients with PVOD had more severe hypoxemia, lower DLCO, absence of vasodilator response and poorer survival compared with patients with IPAH.

Observed survival at 1- and 3- years was 87 % and 75 %, respectively with no significant differences between the PAH and CTEPH cohorts. Corresponding survival in IPAH patients was 89 % and 77 % at 1- and 3- years respectively. In multivariate analysis, PAH associated with connective tissue disease, portal hypertension and pulmonary veno-occlusive disease were independently associated with death. Again, males, higher WHO functional class, higher mean RAP and lower CI were also independent predictors of death in PAH (Table 20.3). As defined in their objectives, Spanish investigators explored the accuracy of predictive equations from NIH, PHC, French National and REVEAL. While estimates from the PHC equation fit fairly well with the REHAP observations, significant differences between projected and observed survival were noted with the NIH, French, and REVEAL equations.