Prognosis of Pulmonary Arterial Hypertension*
2004; Elsevier BV; Volume: 126; Issue: 1 Linguagem: Inglês
10.1378/chest.126.1_suppl.78s
ISSN1931-3543
AutoresVallerie V. McLaughlin, Kenneth W. Presberg, Ramona L. Doyle, Steven H. Abman, Douglas C McCrory, Terry Fortin, Gregory S. Ahearn,
Tópico(s)Cardiovascular Issues in Pregnancy
ResumoAlthough idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH. Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH. Although idiopathic pulmonary arterial hypertension (IPAH) is perceived as a progressive disease, usually with a poor outcome, the natural history of the disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well described. Over the past decade, advances in medical therapies have changed the course of the disease and have made decisions regarding transplantation more complicated. The objective of this chapter is to answer two questions: what is the expected survival of patients with PAH, and what are the clinical factors associated with survival in patients with PAH? We conducted a computerized search of the MEDLINE bibliographic database from 1992 to October 2002. We searched using the term hypertension, pulmonary. The search was limited to articles concerning human subjects that were published in the English language and accompanied by an abstract. In addition, we searched the reference lists of included studies, practice guidelines, systematic reviews, and meta-analysis, and consulted with clinical experts to identify relevant studies missed by the search strategy or published before 1992. We selected studies that described survival over time and considered studies among patients with known or suspected IPAH or PAH associated with connective tissue diseases, chronic liver disease with portal hypertension, congenital heart disease (CHD) and Eisenmenger syndrome, HIV infection, and chronic thromboembolic disease. We excluded studies of pulmonary hypertension associated with COPD, other parenchymal lung disease, high altitude, or cardiac disease (eg, left-heart failure or valvular heart disease) except CHD. We also excluded studies of neonates and case series with < 10 subjects. Two physicians (one with methodologic expertise and one with content area expertise) reviewed the abstracts of candidate articles and selected a subset to review in full text. Full-text articles were again reviewed by two physicians to determine whether they were study reports or review articles, and were pertinent to the key questions. The studies were further reviewed and classified according to primary diagnosis (IPAH vs PAH associated with another disease), treatment strategy, survival rates, risk factors, and type of analysis done. As the vast majority of studies included patients with IPAH, the bulk of this chapter will focus on IPAH. Comments regarding PAH associated with other diagnosis and pediatric considerations are also discussed. The natural history of IPAH has been well described. The National Institutes of Health (NIH) Registry followed up 194 patients with IPAH enrolled at 32 clinical centers from 1981 to 1985.1D'Alonzo GE Barst RJ Ayres SM et al.Survival in patients with primary pulmonary hypertension: results from a national prospective registry.Ann Intern Med. 1991; 115: 343-349Crossref PubMed Scopus (3056) Google Scholar The estimated median survival was 2.8 years, with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34%, respectively. Other series have studied the natural history of IPAH with similar results. Among a cohort of 61 IPAH patients followed up in Mexico, the mean survival was 25.9 ± 20.7 months (± SD]).2Sandoval J Bauerele O Palomar A et al.Survival in primary pulmonary hypertension: validation of a prognostic equation.Circulation. 1994; 89: 1733-1744Crossref PubMed Scopus (321) Google Scholar The median survival was 33 months among a cohort of 223 patients followed up in Japan.3Okada O Tanabe N Yasuda J et al.Prediction of life expectancy in patients with primary pulmonary hypertension: a retrospective nationwide survey from 1980–1990.Intern Med. 1999; 38: 12-16Crossref PubMed Scopus (44) Google Scholar In a single-center, uncontrolled case series4Rajasekhar D Balakrishnan KG Venkitachalam CG et al.Primary pulmonary hypertension: natural history and prognostic factors.Indian Heart J. 1994; 46: 165-170PubMed Google Scholar from India, the median survival was 22 months, with 2-year, 5-year, and 10-year survival rates of 48%, 32%, and 12%, respectively. Table 1summarizes survival for the entire data set, including all etiologies of PAH and all therapies.Table 1Survival in PAH*Data are presented as unweighted and unadjusted averages of entire data set.DiagnosisYear 1Year 2Year 3Year 4Year 5CHD0.92 (2)0.885 (2)0.77 (1)0.77 (1)Collagen vascular disease0.67 (3)0.405 (2)0.37 (2)HIV0.58 (1)0.39 (2)0.21 (1)Primary pulmonary hypertension0.79 (21)0.66 (12)0.59 (14)0.28 (3)0.48 (14)Portopulmonary hypertension0.64 (1)* Data are presented as unweighted and unadjusted averages of entire data set. Open table in a new tab Although survival curves have been most well described for IPAH, it is clear that the underlying diagnosis associated with PAH influences outcome. Early series have suggested that the prognosis in patients with PAH associated with the scleroderma spectrum of diseases may even be worse than those with IPAH. In a retrospective, single-center, uncontrolled series, Stupi et al5Stupi AM Steen VD Owens GR et al.Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis.Arthritis Rheum. 1986; 29: 515-524Crossref PubMed Scopus (354) Google Scholar identified 673 patients with systemic sclerosis between 1963 and 1983. Of these, 59 patients (9%) had PAH, 30 of whom had isolated PAH, and 20 of whom underwent cardiac catheterization. Among the patients with isolated PAH, the 2-year survival rate was 40%. It has also been suggested that even with epoprostenol therapy, patients with PAH related to the scleroderma spectrum of diseases have a less favorable outcome. In a series6Kuhn KP Byrne DW Arbogast PG et al.Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol.Am J Respir Crit Care Med. 2003; 167: 580-586Crossref PubMed Scopus (206) Google Scholar of 91 patients with PAH treated with epoprostenol therapy, those with a diagnosis of scleroderma spectrum of disease had a worse outcome (hazard ratio [HR] for death, 2.32; 95% confidence interval, 1.08 to 4.99). Similarly, Kawut et al7Kawut SM Taichman DB Archer-Chicko CL et al.Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis.Chest. 2003; 123: 344-350Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar compared the survival of 33 patients with IPAH and 22 patients with PAH related to the scleroderma spectrum of diseases at a single center. Patients underwent initial cardiac catheterization between January 1997 and June 2001, and were treated with usual medical therapies including digoxin, warfarin, and continuous IV epoprostenol. The risk of death was higher in the patients with the scleroderma spectrum of diseases than in IPAH (unadjusted HR, 2.9; confidence interval, 1.1 to 7.8; p = 0.03). This increased risk persisted after adjustment for a variety of demographic, hemodynamic, and treatment variables. Survival in patients with HIV-associated PAH appears similar to the IPAH population. Opravil et al8Opravil M Pechere M Speich R et al.HIV-associated primary pulmonary hypertension: a case control study; Swiss HIV Cohort Study.Am J Respir Crit Care Med. 1997; 155: 990-995Crossref PubMed Scopus (257) Google Scholar performed a prospective, case-controlled, single-center study in 19 patients with PAH associated with HIV. The probability of surviving was significantly decreased in patients with PAH compared with the control subjects (median survival, 1.3 years vs 2.6 years; p < 0.005). In a retrospective, uncontrolled, single-center study, Petitpretz and coworkers9Petitpretz P Brenot F Azarian R et al.Pulmonary hypertension in patients with human immunodeficiency virus infection: comparison with primary pulmonary hypertension.Circulation. 1994; 89: 2722-2727Crossref PubMed Scopus (217) Google Scholar identified 20 patients with HIV-associated PAH and compared their outcome to that of 93 patients with IPAH identified between 1987 and 1992. Overall survival was poor and not significantly different between HIV-associated PAH and IPAH, with 46% and 53% survival rates, respectively, at 2 years. Notably, most of the deaths in the HIV group were related to PAH. Although no studies have directly compared patients with PAH related to CHD with other types of PAH, observations suggest that those with CHD have a better prognosis. Hopkins et al10Hopkins WE Ochoa LL Richardson GW et al.Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome.J Heart Lung Transplant. 1996; 15: 100-105PubMed Google Scholar evaluated 100 adults with severe PAH, 37 of whom had Eisenmenger syndrome and 6 of whom had previously repaired congenital heart defects, who were followed up in a transplantation or adult CHD clinic. Hopkins et al19Rich S Kaufmann E Levy PS The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N Engl J Med. 1992; 327: 76-81Crossref PubMed Scopus (1421) Google Scholar described an actuarial survival of patients who did not receive transplantation of 97%, 89%, and 77% at 1 year, 2 years, and 3 years, respectively, for the patients with Eisenmenger syndrome compared with 77%, 69%, and 35% at 1 year, 2 years, and 3 years, for patients with IPAH. Similarly, in a cohort of patients with PAH treated with epoprostenol, survival was greater for those with CHD than for IPAH.6Kuhn KP Byrne DW Arbogast PG et al.Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol.Am J Respir Crit Care Med. 2003; 167: 580-586Crossref PubMed Scopus (206) Google ScholarFigure 1summarizes the mean survival of patients with PAH based on etiology. The rationale for, and effects of epoprostenol therapy in IPAH is extensively discussed by Badesch et al (see section on Medical Therapy for Pulmonary Arterial Hypertension in this Supplement). To date, six series have demonstrated the positive impact of epoprostenol on survival in IPAH. Patients who had previously participated in a randomized controlled trial (RCT) of epoprostenol were followed up over a period of 37 to 69 months.11Barst RJ Rubin LJ McGoon MD et al.Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin.Ann Intern Med. 1994; 121: 409-415Crossref PubMed Scopus (520) Google Scholar The observed survival rates at 1 year, 2 years, 3 years, and 5 years were 87%, 72%, 63%, and 54%, respectively, while the survival rates of 31 historical control subjects from the NIH Registry1D'Alonzo GE Barst RJ Ayres SM et al.Survival in patients with primary pulmonary hypertension: results from a national prospective registry.Ann Intern Med. 1991; 115: 343-349Crossref PubMed Scopus (3056) Google Scholar were 77%, 52%, 41%, and 27%; the survival with epoprostenol was greater than control (HR, 2.9; 95% confidence interval, 1.0 to 8.0; p = 0.045). In an open-label RCT12Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar of 81 patients with IPAH, 8 of 40 patients randomized to conventional therapy alone died over the 12-week study period, while none of the 41 patients randomized to epoprostenol plus conventional therapy died over the study period. While this difference was statistically significant (p = 0.003), it is important to note that the conventional therapy group appeared more ill from the onset, with a mean baseline 6-min walk test (6MWT) distance of 272 ± 23 m, while the epoprostenol group had a mean baseline 6MWT distance of 316 ± 18 m (± SD]). All of the patients who died in the conventional therapy group had a baseline 6MWT distance of < 150 m. 6MWT distance at baseline was an independent predictor of survival (p < 0.05). With the publication of this trial12Barst RJ Rubin LJ Long WA et al.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group.N Engl J Med. 1996; 334: 296-302Crossref PubMed Scopus (0) Google Scholar demonstrating a mortality benefit in patients with IPAH treated with epoprostenol in 1996, subsequent series evaluating survival have used either historical controls or projections based on the NIH Registry equation rather than concurrent subjects receiving conventional therapy. Shapiro et al13Shapiro SM Oudiz RJ Cao T et al.Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion.Am Coll Cardiol. 1997; 30: 343-349Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar reported a series of 69 patients with IPAH treated with epoprostenol, of whom 18 patients were followed up for > 330 days. The 1-year, 2-year, and 3-year survival rates for these epoprostenol-treated patients were 80%, 76%, and 49%, respectively, while the 10-month, 20-month, and 30-month survival rates of historical control patients from the NIH Registry were 88%, 56%, and 47%. Serial exercise and cardiac catheterization data were not reported. Although the mean duration of therapy is not reported in this article, the number of patients at risk declines substantially after 1 year, making conclusions about long-term survival benefit with epoprostenol suspect in this series. More recently, three large series have demonstrated a survival benefit in IPAH patients treated with epoprostenol therapy. Sitbon and colleagues14Sitbon O Humbert M Nunes H et al.Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival.Am Coll Cardiol. 2002; 40: 780-788Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar followed up 178 patients with IPAH over a mean of 26 ± 21 months (range, 0.5 to 98 months) [± SD]. The survival rates at 1 year, 2 years, 3 years, and 5 years were 85%, 70%, 63%, and 55%. This survival curve compared favorably to the survival curve of historical control subjects at the same institution. There were also significant improvements in New York Heart Association functional class (NYHA-FC), exercise tolerance as measured by the 6MWT, and hemodynamics as measured at cardiac catheterization after 3 months of therapy. Baseline variables associated with a poor outcome on univariate analysis included the following: history of right-heart failure, NYHA-FC IV, 6MWT distance less than the median of 250 m, mean right arterial pressure (mRAP) ≥ 12 mm Hg, and mean pulmonary artery pressure (mPAP) < 65 mm Hg. On multivariate analysis including both baseline variables and those measured after 3 months of epoprostenol treatment, a history of right-heart failure, persistence of NYHA-FC III or IV at 3 months, and absence of a fall in total pulmonary resistance (TPR) of > 30% compared to baseline were associated with a poor survival. Another large series15McLaughlin VV Shillington A Rich S Survival in primary pulmonary hypertension: the impact of epoprostenol therapy.Circulation. 2002; 106: 1477-1482Crossref PubMed Scopus (1009) Google Scholar of 162 consecutive patients with IPAH treated with epoprostenol and followed up for a mean of 36.3 ± 27.1 months (range, 1 to 122 months) [± SD] reported similar results. The observed survival rates at 1 year, 2 years, 3 years, 4 years, and 5 years were 88%, 76%, 63%, 56%, and 47%, respectively. The predicted survival rates based on the NIH Registry equation at 1 year, 2 years, and 3 years were 59%, 46%, and 35% (p < 0.001 at all time points by χ2 analysis). Significant improvements in NYHA-FC, exercise tolerance as assessed by low-level treadmill test, and hemodynamics as assessed by serial cardiac catheterization were also reported. Baseline predictors of survival included NYHA-FC; exercise time, as assessed by low-level treadmill test; mRAP; and vasodilator response to adenosine. Predictors of survival after 1 year of therapy included NYHA-FC and change in exercise time, cardiac index (CI), and mPAP. In a series6Kuhn KP Byrne DW Arbogast PG et al.Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol.Am J Respir Crit Care Med. 2003; 167: 580-586Crossref PubMed Scopus (206) Google Scholar of 91 patients with PAH treated with epoprostenol and followed up for a mean of 2.4 ± 1.8 years (± SD), 49 patients with IPAH had 1-year, 2-year, and 3-year survival rates of 85%, 76%, and 65%, respectively. The expected survival rates based on the NIH Registry equation were 62%, 49%, and 39%, at 1 year, 2 years, and 3 years, respectively. Also reported were significant improvements in exercise tolerance as measured by the 6MWT and hemodynamics measured at cardiac catheterization. They did not find any baseline or follow-up hemodynamic variables as predictors of survival. As noted previously, patients with PAH related to scleroderma had a worse survival than those with other forms of PAH. In a 12-week RCT16Badesch DB Tapson VF McGoon MD et al.Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial.Ann Intern Med. 2000; 132: 425-434Crossref PubMed Scopus (1006) Google Scholar in PAH related to the scleroderma spectrum of diseases, epoprostenol did not affect survival. The impact that epoprostenol has made on survival in IPAH is displayed in Figure 2. Less data evaluating the impact of medical therapies other than epoprostenol on survival in PAH are available. One small retrospective series17Nagaya N Uematsu M Okano Y et al.Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension.J Am Coll Cardiol. 1999; 34: 1188-1192Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar evaluated survival in 24 patients with IPAH treated with the oral prostacyclin analog beraprost compared to that of 34 patients treated with conventional therapy. Kaplan-Meier survival curves demonstrated that the 1-year, 2-year, and 3-year survival rates for the patients receiving beraprost were 96%, 86%, and 76%, respectively, while the survival rates were 77%, 47%, and 44% in the conventional therapy group (log-rank test, p < 0.05). A serious concern in this study is the much shorter duration of observation in the beraprost group as opposed to the conventional therapy group, in addition to the relatively small sample size. Three series have demonstrated that anticoagulation therapy has a favorable influence on survival, two series in IPAH and one series in anorectic drug-induced pulmonary hypertension. Fuster et al18Fuster V Steele PM Edwards WD et al.Primary pulmonary hypertension: natural history and the importance of thrombosis.Circulation. 1984; 70: 580-587Crossref PubMed Scopus (926) Google Scholar evaluated 120 patients in a retrospective, uncontrolled, single-center study. This study, published in 1984, was performed before the widespread use of the ventilation-perfusion scanning in the setting of suspected IPAH, and 32 of 56 subjects in whom lung tissue was evaluated at autopsy had thromboembolic disease. The median time from diagnosis to death was 1.9 years; on multivariate analysis, treatment with anticoagulation was predictive of a better outcome. In a prospective, single-center study, Rich et al19Rich S Kaufmann E Levy PS The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N Engl J Med. 1992; 327: 76-81Crossref PubMed Scopus (1421) Google Scholar described a better outcome among patients treated with warfarin who were not calcium-channel blocker responders. The 1-year, 3-year, and 5-year survival rates in those treated with warfarin were 91%, 62%, and 47%, respectively, compared to 52%, 31%, and 31% in those not treated with warfarin (p = 0.025). In a retrospective study of 173 patients, 104 of whom received the anorexigen aminorex, Frank et al20Frank H Mlczoch J Huber K et al.The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension.Chest. 1997; 112: 714-721Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar also demonstrated a survival benefit in those receiving warfarin anticoagulation. As discussed by Badesch et al (see page 000), in a select patient group, calcium-channel blocker therapy may favorably influence survival. Calcium-channel blockers may favorably influence survival in a small proportion of patients with IPAH who demonstrate a significant vasodilator response when tested with a short-acting agent. The definition of a positive vasodilator response, and the long-term outcome with calcium-channel blocker therapy in patients with IPAH has been extensively reviewed by Badesch et al. There are no data on which to make conclusions regarding the use of calcium-channel blockers in other forms of PAH. As in adults, the prognosis in children with PAH is closely linked with its underlying etiology. The spectrum of diseases associated with PAH in children is broadly similar to adults, but there are several unique diseases and key features that distinguish pediatric PAH from adult PAH. Neonatal disorders such as persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, congenital diaphragmatic hernia, primary lung hypoplasia, and alveolar capillary dysplasia are beyond the scope of this text. As observed in adults, pulmonary hypertension can accompany other childhood disorders, including obstructive sleep apnea, cystic fibrosis, sickle-cell disease, liver disease, clotting disorders, connective tissue disease, and others. Data on the prognosis in these settings are extremely limited, and mostly consist of case reports or small patient series. Pulmonary vascular disease in children with interstitial lung disease is particularly associated with high mortality.21Sondheimer HM Lung MC Brugman SM et al.Pulmonary vascular disorders masquerading as interstitial lung disease.Pediatr Pulmonol. 1995; 20: 284-288Crossref PubMed Scopus (38) Google Scholar PAH complicates the course of children with CHD, and represents the most important determinant of morbidity and mortality in these patients. An estimated 30% of patients with CHD acquire significant PAH without early surgical repair. The age at which lesions with left-to-right shunting causes significant pulmonary vascular disease is variable, but is rare after repair in the first 2 years of life. Long-term prostacyclin therapy improves prognosis and quality of life in patients with PAH associated with CHD,22Rosenzweig EB Kerstein D Barst RJ Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects.Circulation. 1999; 99: 1858-1865Crossref PubMed Scopus (446) Google Scholar but few studies have addressed long-term prognosis or the effects of pharmacologic therapy. IPAH can present during early infancy, within the first months of life, or later in childhood. Although uniformly fatal in the recent past, children with IPAH are now treated with similar strategies as adults, and the outlook has improved with advances in medical therapies. Barst and colleagues23Barst RJ Maislin G Fishman AP Vasodilator therapy for PPH in children.Circulation. 1999; 99: 1197-1208Crossref PubMed Google Scholar demonstrated that young children tend to demonstrate greater acute pulmonary vascular reactivity to vasodilators during cardiac catheterization (40% in children vs 20% in adults). In addition, treatment of children with either calcium-channel blockade (if reactive) or long-term prostacyclin infusion seemed to improve survival to a similar degree as reported in adults.23Barst RJ Maislin G Fishman AP Vasodilator therapy for PPH in children.Circulation. 1999; 99: 1197-1208Crossref PubMed Google Scholar24Sandoval J Bauerle O Gomez A et al.Primary pulmonary hypertension in children: clinical characterization and survival.J Am Coll Cardiol. 1995; 25: 466-474Abstract Full Text PDF PubMed Scopus (120) Google Scholar Data regarding the prognostic implications of demographic variables such as age, gender, and time of onset of symptoms to diagnosis are inconsistent. The NIH Registry was the first large-scale evaluation of prognostic factors in IPAH. Age, time from onset of symptoms to diagnosis, and gender were not predictive of survival.1D'Alonzo GE Barst RJ Ayres SM et al.Survival in patients with primary pulmonary hypertension: results from a national prospective registry.Ann Intern Med. 1991; 115: 343-349Crossref PubMed Scopus (3056) Google Scholar In a retrospective, single center, uncontrolled case series4Rajasekhar D Balakrishnan KG Venkitachalam CG et al.Primary pulmonary hypertension: natural history and prognostic factors.Indian Heart J. 1994; 46: 165-170PubMed Google Scholar of 61 patients with IPAH from India, younger age was associated with a worse prognosis. It should be noted that this population was younger than that included in the NIH Registry (mean age, 24.6 ± 11.8 years as compared to 36 ± 15 years [± SD]). In a study6Kuhn KP Byrne DW Arbogast PG et al.Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol.Am J Respir Crit Care Med. 2003; 167: 580-586Crossref PubMed Scopus (206) Google Scholar that included patients with many etiologies of PAH who were treated with epoprostenol, older age at diagnosis indicated a worse prognosis (HR, 3.20; 95% confidence interval, 1.32 to 7.76) for those above the median. This, however, may be confounded by the inclusion of patients with the scleroderma spectrum of disease who tend to be older and also had a worse prognosis. A national survey of IPAH was conducted in Israel from 1988 to 1997 and identified 44 patients with a mean age of 43 ± 13 years (± SD).25Appelbaum L Yigla M Bendayan D et al.Primary pulmonary hypertension in Israel: a national survey.Chest. 2001; 119: 1801-1806Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Although they did not find age to be a prognostic variable, longer time of onset from symptoms to diagnosis was associated with a worse prognosis. That hemodynamics are predictive of outcome in IPAH seems intuitive. The NIH Registry was the first large-scale evaluation of prognostic factors in IPAH.1D'Alonzo GE Barst RJ Ayres SM et al.Survival in patients with primary pulmonary hypertension: results from a national prospective registry.Ann Intern Med. 1991; 115: 343-349Crossref PubMed Scopus (3056) Google Scholar In this registry, three measured hemodynamic variables were associated with an increased risk of death by univariate analysis: increased mPAP (odds ratio, 1.16; confidence interval [CI], 1.05 to 1.28), increased mRAP (odds ratio, 1.99; CI, 1.47 to 2.69), and decreased CI (odds ratio, 0.62; CI, 0.46 to 0.82). In a multivariate analysis, these three hemodynamic variables were also predictive. In fact, data from the NIH Registry was used to formulate a regression equation in which these three hemodynamic variables were used to estimate survival. Sandoval et al2Sandoval J Bauerele O Palomar A et al.Survival in primary pulmonary hypertension: validation of a prognostic equation.Circulation. 1994; 89: 1733-1744Crossref PubMed Scopus (321) Google Scholar conducted a prospective dynamic cohort study of 61 patients with IPAH at a single center in Mexico referred between 1977 and 1991. The mean age was 22.6 ± 11 years, and the mean survival was 25.9 ± 20.7 months (± SD]). In a univariate analysis, three measured hemodynamic variables were predictive of survival: increased mRAP (HR, 3.87 [1.59–9.44]; p = 0.004), decreased CI (HR, 4.2 [1.18–14.9]; p = 0.027), and decreased mixed venous oxygen saturation (MVo2) [HR, 4.28; CI, 1.57 to 11.6; p = 0.005]. Interestingly, mPAP was not predictive of survival. In a multivariate analysis, both increased mRAP and decreased CI remained significant predictors of survival. One of the major objectives of this series was to analyze the usefulness of the NIH equation. Despite the highly variable clinical course of the disease, positive predictive values of the NIH equation in this patient population at 1 year, 2 years, and 3 years were 87%, 91%, and 89%, respectively. In a retrospective nationwide survey3Okada O Tanabe N Yasuda J et al.Prediction of life expecta
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