Idiopathic pulmonary arterial hypertension (PAH) is usually associated with a poor outcome but the prognosis with other forms of PAH is not well-described. Advances in therapy have furthered clouded the disease course. We sought to determine the baseline indicators of prognosis in patients with PAH. We reviewed the records of patients with PAH followed up at our institution to identify those who died within 2 years (reduced survival group; n = 21) and those who survived >5 years (long survival group; n = 60). The groups were compared for prognostic significance of the baseline clinical parameters. The reduced survival group were older (p = 0.001) and more likely to have scleroderma-associated PAH (p = 0.01), have pericardial effusion (p = 0.01), have a shorter 6-minute walk test (6MWT) distance (p = 0.001), to require oxygen during 6MWT (p = 0.02), have a worse World Health Organization functional class (p <0.001), and have greater serum brain natriuretic peptide levels (p = 0.01). Regression analysis showed age, World Health Organization functional class, 6MWT distance, the need for oxygen during the 6MWT, and renal disease to be independently associated with a poor prognosis. In conclusion, age, PAH etiology, World Health Organization functional class, pericardial effusion, 6MWT distance, the need for oxygen during the 6MWT, and brain natriuretic peptide are predictors of prognosis in patients PAH receiving specific therapy and might help identify a group that could benefit from aggressive upfront therapy.
Exercise capacity, hemodynamics, Doppler echocardiography, and biomarkers have been studied extensively and found to be clinically useful in assessing the disease severity and prognosis of pulmonary arterial hypertension (PAH). Recent publications have focused on developing prediction equations that incorporate several baseline measures. Although these prediction models might prove to be very accurate after additional validation, these are typically rather complex and might not be applicable to most physician practices, where most patients with PAH are likely to receive care. There is clearly a need to identify predictors of prognosis that are accurate but easier to apply. We sought to study the baseline markers of prognosis in PAH in the current era of disease-specific therapy to determine the indicators of reduced survival (≤2 years, RS group) and those associated with long survival (≥5-years, LS group).
Methods
PAH was defined as a mean pulmonary artery pressure of ≥25 mm Hg at rest with a pulmonary capillary wedge pressure of ≤15 mm Hg using right heart catheterization. To not bias our analysis, patients with a pulmonary capillary wedge pressure >15 mm Hg were included when the patient had PAH in the opinion of the treating clinician and the pulmonary capillary wedge pressure was thought to be inaccurate or due to underdiuresis. These included patients with left ventricular end-diastolic pressure of ≤15 mm Hg and/or no evidence of left-sided cardiac disease on Doppler echocardiogram. We reviewed the medical records of consecutive patients with PAH who underwent diagnostic right heart catheterization at our institution from February 1996 to January 2006. During this period, 21 patients died within 2 years of the baseline right heart catheterization and formed the RS group and 60 patients lived for ≥5 years and were included in the LS group. These groups were compared for demographics, co-morbidities, PAH etiology, baseline hemodynamics, functional measures, and initial PAH-specific therapy. Pulmonary function testing and the 6-minute walk test (6MWT) were performed according to American Thoracic Society/European Respiratory Society criteria. The echocardiographic variables studied included the right atrial area (measured by planimetry in the 4-chamber view), left ventricular ejection fraction (measured by Simpson’s rule), right ventricular size and function (estimated qualitatively), right ventricular systolic pressure (calculated by tricuspid regurgitant velocity), collapse of the inferior vena cava (defined as >50% collapse during inspiration), and the presence of pericardial effusion.
In addition to continuous and categorical variables, various cutoffs of selected variables were chosen based on the published data or clinical relevance ( Supplementary Appendix 1 ) and were included in the survival modeling. Our institutional review board approved the study protocol.
Categorical variables are summarized as the frequency and percentage and quantitative variables as the mean ± SD. For comparisons of the 2 prognostic groups with respect to the quantitative and ordinal variables, the associations were assessed using the Wilcoxon rank sum test. Associations between categorical variables were performed using Fisher’s exact test or chi-square test. Logistic regression analysis was used to estimate the odds ratio and 95% confidence intervals of belonging to the poor prognosis group. Multivariate regression analysis was performed for prognostic groups using forward stepwise selection of variables with a Wald p value cutoff of 0.10.
Results
The etiology of PAH was idiopathic in 72%, connective tissue disease in 24% (with scleroderma representing 19%), congenital heart disease in 2 patients, portal hypertension in 1 patient, and drug related in 1 patient. Co-morbidities included hypertension (26%), diabetes mellitus (14%), chronic kidney disease (10%), obstructive ventilatory defect on spirometry (12%), and obstructive sleep apnea (17%). The initial therapy for PAH included prostanoid analogs (65%) and endothelin receptor antagonists (27%). Six patients were acutely vasodilator responsive and were prescribed calcium channel blockers. All 6 of these patients were in the LS group.
Compared to the LS group ( Table 1 ), the patients in the RS group were older (p = 0.001) and were more likely to have scleroderma-associated PAH (p = 0.01) and chronic kidney disease (24% vs 5%, p = 0.03). The groups were not significantly different in terms of other co-morbid conditions. Among the serum markers, compared to the LS group, the patients in the RS group had higher brain natriuretic peptide (BNP) (p = 0.01) and a trend toward higher blood urea nitrogen (p = 0.07) and creatinine (p = 0.09).
| Variable | Overall (n = 81) | Survival ≥5 years (n = 60) | Survival ≤2 years (n = 21) | p Value |
|---|---|---|---|---|
| Age (years) | 49 ± 14 | 46 ± 14 | 59 ± 11 | 0.001 |
| Women | 70 (86.4%) | 52 (87%) | 18 (86%) | 1.0 |
| White | 68 (85%) | 50 (83%) | 18 (90%) | 0.8 |
| Body mass index (kg/m 2 ) | 31 ± 7 | 31 ± 7 | 31 ± 7 | 1.0 |
| Cause of PAH | ||||
| Idiopathic | 58 (72%) | 48 (80%) | 10 (48%) | 0.01 |
| Scleroderma | 14 (19%) | 6 (11%) | 8 (44%) | 0.01 |
| Initial PAH medication | ||||
| Epoprostenol | 47 (58%) | 38 (63%) | 9 (43%) | 0.1 |
| Other prostanoids | 6 (7%) | 3 (5%) | 3 (14%) | 0.2 |
| Bosentan | 22 (27%) | 13 (21%) | 9 (43%) | 0.07 |
| Calcium channel blocker | 6 (7%) | 6 (10%) | 0 | 0.3 |
| World Health Organization functional class | ||||
| Overall | 2.9 ± 0.6 | 2.7 ± 0.5 | 3.4 ± 0.5 | 0.001 |
| II | 19 (24%) | 19 (32%) | 0 | |
| III | 53 (65%) | 40 (67%) | 13 (62%) | |
| IV | 9 (11%) | 1 (2) | 8 (38) | |
| 6-Minute walk test | ||||
| Distance (m) | 323 (277, 413) | 346 (298, 426) | 244 (183, 300) | 0.001 |
| Percentage of predicted | 62 ± 19 | 64 ± 17 | 52 ± 24 | 0.08 |
| Distance ≤332 m | 40 (53%) | 26 (44%) | 14 (82%) | 0.01 |
| Distance ≤250 m | 16 (21%) | 7 (12%) | 9 (53%) | 0.001 |
| Oxygen needed during test | 33 (43%) | 21 (36%) | 12 (71%) | 0.05 |
| Distance saturation product (m%) | 329 (271, 405) | 343 (294, 408) | 176 (82, 310) | 0.01 |
| Borg dyspnea | 4.5 ± 2.6 | 4.2 ± 2.6 | 5.6 ± 2.4 | 0.04 |
| Heart rate at rest (beats/min) | 86 ± 14 | 87 ± 13 | 82 ± 17 | 0.4 |
| Heart rate end of test (beats/min) | 120 ± 18 | 123 ± 17 | 107 ± 18 | 0.003 |
| Heart rate delta (beats/min) | 34 ± 17 | 37 ± 16 | 25 ± 18 | 0.02 |
| Pulmonary function | ||||
| Forced expiratory vital capacity (% predicted) | 69 ± 16 | 71 ± 16 | 63 ± 18 | 0.3 |
| Forced expiratory lung volume in 1 s (% predicted) | 69 ± 18 | 70 ± 16 | 66 ± 24 | 0.9 |
| Total lung capacity (% predicted) | 83 ± 14 | 84 ± 14 | 75 ± 12 | 0.06 |
| Carbon monoxide diffusion capacity (% predicted) | 58 ± 29 | 61 ± 28 | 32 ± 28 | 0.2 |
| Blood tests | ||||
| Sodium (mEq/L) | 139 ± 3 | 140 ± 3 | 138 ± 3 | 0.1 |
| Sodium ≤136 mEq/L | 12 (14.8%) | 8 (13.3%) | 4 (19.0%) | 0.5 |
| Blood urea nitrogen (mEq/L) | 19.9 ± 13.8 | 18.0 ± 9.0 | 25.5 ± 21.9 | 0.07 |
| Creatinine (mEq/L) | 1.1 ± 1.0 | 0.9 ± 0.2 | 1.5 ± 1.8 | 0.09 |
| Brain natriuretic peptide (pg/ml) | 114 (42, 364) | 104 (29, 281) | 364 (116, 852) | 0.01 |
| Brain natriuretic peptide >100 pg/ml | 45 (58%) | 30 (52%) | 15 (79%) | 0.04 |
Patients in the RS group had a worse baseline World Health Organization (WHO) functional class (p = 0.001), worse Borg dyspnea score (p = 0.05), and shorter 6MWT distance (p = 0.001), were more likely to need oxygen during the 6MWT (p = 0.05), and had a worse distance saturation product (p = 0.01) compared to patients in the LS group ( Table 1 ). The patients in the RS group also had a lower carbon monoxide diffusion capacity but the difference was not statistically significant (p = 0.2).
Patients in the RS group were significantly more likely to have a pericardial effusion compared to the LS group (p = 0.01), and a trend was seen toward a higher Doppler estimated right ventricular systolic pressure (p = 0.09) and a larger right atrial area ( Table 2 ). No statistically significant differences were identified in the baseline invasive hemodynamics between the 2 groups.
| Variable | Overall (n = 81) | Survival ≥5 Years (n = 60) | Survival ≤2 Years (n = 21) | p Value |
|---|---|---|---|---|
| Transthoracic echocardiographic variables | ||||
| Left ventricular ejection fraction | 56 ± 7 | 56 ± 8 | 55 ± 4 | 0.3 |
| Severe right ventricular dilation | 19 (27%) | 14 (29%) | 5 (24%) | 0.7 |
| Severe right ventricular dysfunction | 25 (34%) | 18 (35%) | 7 (33%) | 0.8 |
| Right atrial area (cm 2 ) | 25 ± 8 | 23 ± 7 | 28 ± 9 | 0.1 |
| Right ventricular systolic pressure (mm Hg) | 75 ±25 | 72 ± 26 | 84 ± 20 | 0.09 |
| No inferior vena cava collapse | 19 (37%) | 13 (37%) | 6 (38%) | 0.9 |
| Pericardial effusion | 12 (17%) | 5 (10%) | 7 (39%) | 0.01 |
| Hemodynamics | ||||
| Mean right atrial pressure (mm Hg) | 12 ± 9 | 12 ± 10 | 11 ± 6 | 1.0 |
| Mean right atrial pressure ≥12 mm Hg | 28 (41%) | 20 (41%) | 8 (40%) | 0.8 |
| Mean pulmonary artery pressure (mm Hg) | 55 ± 17 | 56 ± 19 | 51 ± 10 | 0.3 |
| Systolic pulmonary artery pressure (mm Hg) | 83 ± 23 | 84 ± 26 | 81 ± 17 | 0.4 |
| Pulmonary artery pulse pressure (mm Hg) | 48 ± 16 | 48 ± 17 | 49 ± 14 | 0.6 |
| Stroke volume (ml) | 50 ± 18 | 52 ± 18 | 46 ± 18 | 0.2 |
| Pulmonary capillary wedge pressure (mm Hg) | 12 ± 10 | 13 ± 11 | 12 ± 6 | 0.6 |
| Pulmonary vascular resistance (Wood units) | 11 ± 6 | 11 ± 7 | 11 ± 5 | 0.5 |
| Cardiac output (L/min) | 4.6 ± 2.1 | 4.7 ± 2.2 | 4.4 ± 1.9 | 0.5 |
| Cardiac index (L/min/m 2 ) | 2.4 ± 1.0 | 2.5 ± 1.0 | 2.3 ± 1.0 | 0.6 |
| Cardiac index ≤1.8 L/min/m 2 | 18 (30%) | 12 (29%) | 6 (33%) | 0.9 |
In our study, the patients with scleroderma were older than those with idiopathic PAH (IPAH). Patients with scleroderma had worse WHO functional class, a lower 6MWT distance, had worse renal function, had higher BNP, and were more likely to have pericardial effusion on the Doppler echocardiogram compared to patients with IPAH. No statistically significant differences were found in hemodynamics ( Table 3 ).
| Variable | IPAH (n = 58) | Scleroderma (n = 14) | p Value |
|---|---|---|---|
| Age (years) | 47 ± 15 | 58 ± 8 | 0.001 |
| Women | 50 (86%) | 12 (86%) | 1 |
| World Health Organization functional class | 2.8 ± 0.6 | 3.1 ± 0.4 | 0.03 |
| Forced vital capacity (% predicted) | 73 ± 14 | 62 ± 19 | 0.2 |
| 6-Minute walk distance (m) | 337 (288, 430) | 284 (183, 336) | 0.01 |
| 6-Minute walk distance ≤250 m | 7 (13) | 5 (42) | 0.03 |
| Need for oxygen during 6-minute walk test | 36% | 33% | 0.1 |
| Blood urea nitrogen (mEq/L) | 17 ± 10 | 24 ± 11 | 0.007 |
| Creatinine (mEq/L) | 0.9 ± 0.3 | 1.1 ± 0.4 | 0.04 |
| Brain natriuretic peptide (pg/ml) | 103 (26, 256) | 364 (105, 560) | 0.01 |
| Mean right atrial pressure (mm Hg) | 12 ± 9 | 10 ± 6 | 0.6 |
| Mean right atrial pressure ≥12 mm Hg | 68% | 57% | 0.5 |
| Mean pulmonary artery pressure (mm Hg) | 58 ± 19 | 49 ± 12 | 0.1 |
| Mean pulmonary artery pressure ≥50 mm Hg | 64% | 43% | 0.1 |
| Cardiac index (L/min/m 2 ) | 2.3 ± 0.9 | 2.7 ± 1.0 | 0.2 |
| Cardiac index ≤1.8 L/min/m 2 | 32% | 21% | 0.7 |
| Pulmonary vascular resistance (Wood units) | 12 ± 7 | 11 ± 7 | 0.5 |
| Pericardial effusion on echocardiogram | 4 (8%) | 7 (54%) | 0.001 |
| Epoprostenol therapy | 35 (60%) | 7 (50%) | 0.2 |
| Dead within 2 years | 10 (17%) | 8 (57%) | 0.004 |
Patients receiving epoprostenol had similar demographics, functional characteristics, BNP, and renal function compared to those not receiving epoprostenol ( Table 4 ). Although patients receiving epoprostenol had worse baseline pulmonary hemodynamics, these differences did not reach statistical significance.
| Epoprostenol Therapy | p Value | ||
|---|---|---|---|
| No (n = 34) | Yes (n = 47) | ||
| Age (years) | 51 ± 13 | 48 ± 15 | 0.3 |
| Women | 31 (91%) | 39 (83%) | 0.3 |
| World Health Organization functional class | 2.9 ± 0.6 | 2.8 ± 0.5 | 0.4 |
| Connective tissue disease | 23% | 23% | 1.0 |
| 6-Minute walk distance (m) | 321 (280, 403) | 328 (264, 419) | 0.6 |
| Blood urea nitrogen (mEq/L) | 21 ± 18 | 19 ± 10 | 0.7 |
| Creatinine (mEq/L) | 1.2 ± 1.4 | 1.0 ± 0.3 | 0.3 |
| Mean right atrial pressure (mm Hg) | 10 ± 6 | 13 ± 10 | 0.2 |
| Mean right atrial pressure ≥12 mm Hg | 36% | 45% | 0.3 |
| Mean pulmonary artery pressure (mm Hg) | 53 ± 17 | 57 ± 18 | 0.2 |
| Mean pulmonary artery pressure ≥50 mm Hg | 50% | 64% | 0.2 |
| Cardiac index (L/min/m 2 ) | 2.6 ± 1.1 | 2.3 ± 0.8 | 0.3 |
| Cardiac index ≤1.8 L/min/m 2 | 27% | 33% | 0.6 |
| Pulmonary vascular resistance (Wood units) | 10 ±6 | 12 ±6 | 0.3 |
| Pulmonary capacitance (L/mm Hg) | 1.4 ±1.0 | 1.1 ±1.0 | 0.2 |
| Pericardial effusion on echocardiogram | 4 (14%) | 8 (20%) | 0.8 |
| Dead within 2 years | 12 (35%) | 9 (19%) | 0.1 |
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