Article Text

Concise Report
The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH
  1. Philip J Clements1,
  2. Mary Tan2,
  3. Vallerie V McLaughlin3,
  4. Ronald J Oudiz4,
  5. Victor F Tapson5,
  6. Richard N Channick6,
  7. Lewis J Rubin7,
  8. Anatoly Langer2 on behalf of the Pulmonary Arterial Hypertension Quality Enhancement Research Initiative (PAH-QuERI)Investigators
  1. 1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  2. 2Canadian Heart Research Centre, Toronto, Ontario, Canada
  3. 3Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
  4. 4Department of Medicine, LA Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA
  5. 5Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
  6. 6Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  7. 7Department of Medicine, University of California, San Diego, California, USA
  1. Correspondence to Dr Philip J Clements, Department of Medicine, David Geffen School of Medicine at UCLA, 1000 Veteran Avenue, Los Angeles, CA 90095, USA; pclements{at}


Objective The objective of this report is to compare baseline, management and survival characteristics in idiopathic pulmonary arterial hypertension (IPAH) with systemic sclerosis-associated pulmonary arterial hypertension (SSc-APAH) using data from the prospectively enrolled PAH Quality Enhancement Research Initiative.

Methods Between August 2005 and July 2007, patients with IPAH and SSc-APAH were enrolled across 60 US sites and followed up for 3 years. Data on diagnostic tests, clinical variables, pulmonary arterial hypertension (PAH) medication and outcomes were recorded.

Results With some exceptions, baseline clinical and laboratory characteristics were similar between the 279 patients with IPAH and the 228 with SSc-APAH. Patients with SSc-APAH were older at the time of PAH diagnosis, were more likely to be female and were antinuclear antibody positive. Patients with SSc-APAH had poorer spirometric results. During the 3-year follow-up, both groups were managed with prostacyclin and prostacyclin analogue treatment, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors (PDE5i) singly or in combination. At 3 years, patients with SSc-APAH were more likely to be treated with PDE5i alone or with an endothelin receptor antagonist. Patients with SSc-APAH had a significantly lower survival rate compared to patients with IPAH (60% vs 77%, p<0.0001).

Conclusions The cohort with SSc-APAH was older, was more severely ill, was more likely to be female, was managed with PDE5i and had reduced 3-year survival compared with the cohort with IPAH.

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Pulmonary arterial hypertension (PAH) is a complex, multidisciplinary disorder resulting from progressive deterioration in flow through pulmonary arterial circulation, leading to increased pulmonary vascular resistance (PVR) and, ultimately, right heart failure and death.1 2 PAH is a subgroup of pulmonary hypertension and is defined as having a mean pulmonary artery pressure (PAP) ≥25 mm Hg plus pulmonary capillary wedge pressure ≤15 mm Hg at rest and PVR >3 Wood units in the absence of left ventricular dysfunction and other causes of the disease such as hypoxemic lung disease and venous thromboembolism.1

The majority of patients with PAH have idiopathic pulmonary arterial hypertension (IPAH) disease, but PAH is also associated with other conditions such as congenital heart disease and connective tissue disease, most commonly systemic sclerosis (SSc).1 Pulmonary and pulmonary vascular involvements in SSc are the leading causes of morbidity and mortality in affected patients.3 The prevalence of pulmonary hypertension in patients with SSc ranges from 4.9% to 38% (mean, 16%).4

PAH risk factors in patients with SSc include older age, limited cutaneous SSc and elevated baseline right ventricular systolic pressure on echocardiographic examination.5 The diagnosis and management of PAH have changed dramatically over the past 30 years since the first major registry was conducted by the National Institutes of Health.6 7 However, despite advances in PAH treatment,8 the disease continues to be progressive, with a 1-year on-treatment mortality of approximately 10%–17%.9,,11 The few studies that have been undertaken suggest that patients with systemic sclerosis-associated PAH (SSc-APAH) have the worst outcomes among subgroups with PAH, significantly lower than patients with IPAH (82% vs 93%, respectively).12 The prognosis of patients with SSc-APAH remains poor; thus, strategies involving early screening and more aggressive treatment may benefit these patients, even those who present with mild symptoms.3

The PAH Quality Enhancement Research Initiative (PAH-QuERI) was set up to integrate guidelines and clinical care delivery procedures and to facilitate a guidelines-based approach to PAH treatment. PAH-QuERI has two essential components: (1) quality enhancement, which aims to define existing practice patterns and current variations from guidelines and to identify and implement interventions to improve outcomes, and (2) a research initiative, which is based on an analysis of the data monitoring the management and outcomes in real-world practice.13 This report compares the baseline characteristics, management and 3-year survival rates of patients with IPAH with patients with SSc-APAH prospectively enrolled in the PAH-QuERI registry.


Design and patients

Between August 2005 and July 2007, 60 US physicians (43 pulmonologists, 14 cardiologists and 3 rheumatologists) consecutively enrolled patients. Patients with documented or suspected PAH and available for long-term follow-up were eligible for inclusion. Participation was voluntary, and written informed consent was obtained from all subjects. Protocol approval was received from an independent central ethics review board (Western Institutional Review Board) and individual institutions prior to initiation. The electronic case report forms and electronic database were designed, maintained and supported by the Canadian Heart Research Centre (Toronto, Ontario, Canada).


For purposes of this study, the baseline was considered to be the time of enrolment in the registry. The following tests, suggested by the guidelines of the American College of Chest Physicians4 as part of routine screening and diagnosis, were performed at the baseline assessment:

  • Essential blood work (complete blood count, liver function tests, connective tissue disease screening and HIV screening)

  • Contingent blood work (genetic testing)

  • Chest x-ray and ventilation/perfusion (V/Q) lung scan

  • Pulmonary function testing, oximetry and 6 min walk distance (6MWD) test

  • ECG and two-dimensional echocardiogram

  • Right heart catheterisation (RHC)

Physicians captured the following data at baseline, at 6 months and at each annual follow-up (years 1, 2 and 3) on an electronic case report form:

  • Results of American College of Chest Physicians-recommended diagnostic tests

  • Clinical variables

  • Current medications, including PAH-specific treatments

  • Outcomes (death/survival rates)

The diagnosis of SSc was made by the primary investigator at each site; no data were accrued about the criteria used to make that diagnosis.

Statistical analyses

In this substudy, patients were grouped according to their PAH aetiology (IPAH vs SSc-APAH) to compare clinical characteristics, management and outcome. Numerical variables are summarised as median (25th percentile, 75th percentile), and categorical variables, as absolute frequency and proportion. Comparisons of categorical variables were performed using the Pearson χ2 test (or Fisher's exact test if the number of observations per cell was <5). The Wilcoxon rank-sum test was performed for comparison of numerical variables between the two groups. Probability of survival was calculated using the Kaplan–Meier method. All statistical tests were performed with a significance level of 0.05 using SAS software V.9.2.


Baseline demographics, clinical characteristics and evaluations

Of 791 total patients enrolled, 279 had IPAH, and 228 had SSc-APAH. Baseline characteristics are shown in table 1. Patients with SSc-APAH were older than patients with IPAH at the time of PAH diagnosis (57 vs 53 years old, p=0.0008) and more likely to be on immunosuppressive drugs (online supplementary table 1, 11% vs 3%; p=0.0001).

Table 1

Baseline demographics and clinical characteristics of patients with idiopathic PAH (IPAH) or systemic sclerosis-associated PAH (SSc-APAH)*

Differences were also seen in echocardiography and spirometric test results (table 2); patients with SSc-APAH had a significantly higher frequency of pericardial effusion and significantly lower lung function than patients with IPAH. Only 41% of patients (n=210/507) had data on antinuclear antibodies (ANAs) and the reported Raynaud's phenomenon (4/114 IPAH and 53/96 patients with SSc-APAH were positive for both). Patients with SSc-APAH were more likely to be ANA positive (abnormal ANA) and to have elevated brain natriuretic peptide (BNP) >140 pg/ml and a shorter 6MWD. However, they had lower mean PAP, PVR and pulmonary artery systolic pressure.

Table 2

Baseline laboratory and clinical investigations of patients with idiopathic PAH (IPAH) or systemic sclerosis-associated PAH (SSc-APAH)*

Patients with SSc-APAH were significantly more likely to undergo an RHC, a 6MWD test, a pulmonary function test and a high-resolution CT of the chest but were less likely to have a V/Q lung scan than those with IPAH. The proportions of patients undergoing other specific evaluations were similar between groups with IPAH and SSc-APAH.

A few other variables (body mass index and haemoglobin) were statistically different between the two groups, but the differences were not deemed clinically important.


Over 3 years of follow-up, both groups were managed with prostacyclin or prostacyclin analogue treatment, endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors either as monotherapy or in combination (figure 1A). During follow-up, the use of all PAH-specific treatments tended to increase. The most commonly used PAH-specific treatment in both groups was an ERA.

There were only small differences in drug regimens that were administered over the 3 years of follow-up between groups. Patients with SSc-APAH were less likely to be treated with parenteral prostanoids than patients with IPAH (19% vs 38%, p=0.0006) but were more likely to be treated with an ERA (66% vs 54%, p=0.048) or a combination of phosphodiesterase type 5 inhibitors and an ERA (25% vs 12%, p=0.003) at the 3-year follow-up. Information regarding supportive treatment is presented in online supplementary table 1.

Figure 1

Frequency of patients with idiopathic PAH (IPAH) or systemic sclerosis-associated PAH (SSc-APAH) receiving treatment at baseline and at 3-year follow-up. (B) Kaplan–Meier comparison of 3-year survival probability in patients with IPAH or SSc-APAH. ERA, endothelin receptor antagonist; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase type 5 inhibitor; PGI2, prostacyclin.


Using the Kaplan–Meier method (figure 1B), the 3-year survival probability was significantly lower in patients with SSc-APAH than in patients with IPAH (60% vs 77%, p<0.0001). Other outcomes including changes in functional class, all-cause hospitalisations and transplants are listed in online supplementary table 2.


These data support findings from previous studies in which patients with SSc-APAH have been shown to have worse outcomes than other subgroups with PAH.12 14 15 Similar patterns were also found in a UK registry investigating the survival and characteristics of patients diagnosed with connective tissue disease-associated PAH.16

There are no guidelines specific for patients with SSc-APAH, and those for PAH that specifically mention SSc-APAH suggest treating them similarly to patients with IPAH.1 2 17 18 The results from QuERI suggest that the survival is different in these two groups. These findings may warrant further considerations regarding specific guidelines for the treatment of patients with SSc-APAH.

Limitations to this registry include physician and patient enrolment bias, few patients who did not have confirmatory RHC, self-reporting of data, baseline differences, differences in reporting influenced by the data entry mechanism itself and the dynamic pattern of data collection in relation to the practice enhancement aspect of the programme (the main purpose of PAH-QuERI). It is also important to acknowledge that the study design does not allow for evaluation of a cause-and-effect relationship. Since this was a post hoc data analysis, the study was not powered to show statistically significant differences in parameters between subgroups with IPAH and SSc-APAH. It is important to note that elements of SSc diagnostic criteria (sclerodactyly, SSc-skin involvement elsewhere, digital pitting scars and interstitial changes on chest radiography) were not collected in the PAH-QuERI study. Thus, it is possible that some patients in the group with IPAH in this study had some SSc characteristics, and the extent of differences seen between the two groups in this analysis may be underestimated.

These data from PAH-QuERI indicate that patients with scleroderma represent a high-risk subgroup of patients with PAH. Significant differences in evaluation and treatment were observed between patients with SSc-APAH and IPAH. Further studies are required to evaluate clinical outcomes achieved with earlier diagnosis and more intensive treatments, particularly in patients with SSc-APAH who have poor prognoses and worse outcomes than patients with IPAH, with current conventional treatment based on functional class.


Editorial assistance was provided by Jennifer M Kulak, PhD; Tracy Harrison, BSc (Hons) and Mary Hines, BSc (Hons) of inScience Communications, a Wolters Kluwer business.


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Files in this Data Supplement:

    • Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
    • Web Only Data - This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Funding This assistance was supported by Actelion Pharmaceuticals US; PAH-QuERI was conceived, designed and coordinated by the Canadian Heart Research Centre, a federally incorporated non-profit academic research organisation. The sponsor had no role in the collection, management, analysis or interpretation of the data.

  • Competing interests PJC has received consulting fees from Gilead Sciences. MT has no competing interests. VVMcL has received consulting/speaking fees from Actelion Pharmaceuticals US, Bayer, Gilead Sciences and United Therapeutics. VVMcL has received research grants from Actelion Pharmaceuticals US, Gilead Sciences, Novartis Pharmaceuticals and United Therapeutics. RJO has received consulting fees and research grants from Actelion Pharmaceuticals US, Bayer, Gilead Sciences, LungRx, Pfizer and United Therapeutics. VFT has received research grants from Arena, Bayer, Gilead Sciences, LungRx and United Therapeutics. RNC has received consulting fees from Actelion Pharmaceuticals US and received research grants from Gilead Sciences. LJR has received research grants from Actelion Pharmaceuticals US, Gilead Sciences, Pfizer and United Therapeutics. AL has received research grants from Actelion Pharmaceuticals US.

  • Ethics approval The study was approved by Western Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.