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Original Research Pulmonary Vascular Disease
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Pulmonary Arterial Hypertension in the Southern Hemisphere Results From a Registry of Incident Brazilian Cases Jose Leonidas Alves Jr, MD; Francisca Gavilanes, MD; Carlos Jardim, MD, PhD, FCCP; Caio Julio Cesar dos Santos Fernandes, MD, PhD; Luciana Tamie Kato Morinaga, MD; Bruno Dias, MD, PhD; Susana Hoette, MD, PhD; Marc Humbert, MD, PhD; and Rogerio Souza, MD, PhD
Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of patients with PAH, although data coming from the Southern Hemisphere remain scarce. The objective of this study was to describe a cohort of incident patients with PAH from a large reference center in Brazil.
BACKGROUND:
All consecutive patients who received a diagnosis of PAH by right-sided heart catheterization between 2008 and 2013 were included in the study.
METHODS:
A total of 178 patients with newly diagnosed PAH were enrolled in the study (mean age, 46 years; female/male ratio, 3.3:1; 45.5% in New York Heart Association functional class III or IV). Idiopathic PAH (IPAH), connective tissue disease (CTD), and schistosomiasisassociated PAH (Sch-PAH) accounted for 28.7%, 25.8%, and 19.7% of all cases, respectively. The patients were treated with phosphodiesterase type 5 inhibitors (66%), endothelin receptor antagonists (27%), or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the patients with CTD was worse than that for the patients with IPAH and Sch-PAH (P 5 .03).
RESULTS:
The distribution of PAH causes and the baseline characteristics in our registry clearly differ from the previously published European and US-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials.
CONCLUSIONS:
CHEST 2015; 147(2):495-501
Manuscript received April 28, 2014; revision accepted August 20, 2014; originally published Online First October 9, 2014. ABBREVIATIONS: CTD 5 connective tissue disease; FC 5 functional class; IPAH 5 idiopathic pulmonary arterial hypertension; mPAP 5 mean pulmonary arterial pressure; PAH 5 pulmonary arterial hypertension; PVR 5 pulmonary vascular resistance; REVEAL Registry 5 Registry to Evaluate Early and Long-term PAH Disease Management; Sch-PAH 5 schistosomiasis-associated pulmonary arterial hypertension AFFILIATIONS: From the Pulmonary Department (Drs Alves, Gavilanes, Jardim, Fernandes, Morinaga, Dias, Hoette, and Souza), Heart Institute, University of São Paulo Medical School, São Paulo, Brazil; and the University Paris-Sud (Dr Humbert), Inserm UMR_S 999, Service de
journal.publications.chestnet.org
Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Rogerio Souza, MD, PhD, Pulmonary Department, Heart Institute, University of São Paulo Medical School, Av Dr Eneas de Carvalho Aguiar, 44, São Paulo, Brazil 05403-000; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1036
495
Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature.1,2 The disease is associated with various underlying causes but is diagnosed by the presence of an elevated mean pulmonary arterial pressure (mPAP) and normal pulmonary occlusion arterial pressure at rest, in the absence of significant lung or left-sided heart disease.3,4 The past decade has witnessed an increasing interest in the worldwide characteristics of PAH. Data from national registries have been published and have contributed to the understanding of regional characteristics regarding the epidemiology, demographics, etiology, clinical course, hemodynamics, disease management, and treatment outcomes.5-12 Nevertheless, data remain scarce
Materials and Methods From January 2008 to December 2013, a total of 178 consecutive patients with PAH, diagnosed according to the Nice classification,15 were enrolled in this study. PAH diagnosis was established in accordance with current international guidelines.4 The date of the first rightsided heart catheterization was defined as the date of diagnosis.9 Other causes of pulmonary hypertension were excluded by echocardiography, pulmonary function testing, chest CT scans, and ventilation-perfusion scans. The investigators who enrolled the subjects into the registry classified the subjects into the PAH subgroups based both on laboratory tests and their impressions of the most likely causes of the PAH. Baseline clinical, functional, and hemodynamic data were collected, and
Results A total of 178 patients with PAH were included in the study. Figure 1 shows the proportion of the patients in each PAH subgroup. IPAH, connective tissue disease (CTD), and schistosomiasis-associated PAH (Sch-PAH) represented the most prevalent subgroups, accounting for 28.7%, 25.8%, and 19.7% of all cases, respectively. From the 46 patients with CTD-PAH, 23 patients had systemic sclerosis, 14 patients had systemic lupus erythematosus, five patients had mixed CTD, and the remaining four patients had other CTD. The clinical and hemodynamic data at diagnosis for the main subgroups of PAH are displayed in Table 1. Although pulmonary vascular resistance (PVR) was not used as part of the definition of PAH, only three patients with PVR , 3 Wood units were included in the cohort, all presenting portopulmonary hypertension (PVR of 2.8, 2.5, and 2.2 Wood units for each one of the individuals). The mean age of all patients enrolled in the cohort was 46 years, and the female to male ratio was 3.3:1. At diagnosis, 45.5% of the patients were classified as New York Heart Association functional class (FC) III or IV. 496 Original Research
with respect to such aspects for the population living in the Southern Hemisphere. Most pulmonary hypertension registries enroll a mixed population of patients, including both prevalent and incident cases. “Prevalent” indicates those who have already been diagnosed and treated at the time the registry is started, whereas “incident” designates those diagnosed and treated during the generation of the registry (“newly diagnosed cases”). This distinction is relevant because prevalent patients have a better prognosis compared with incident patients and may be overrepresented in registries.13,14 The objective of this study was to describe the epidemiology, baseline characteristics, and outcomes of a population of incident patients with PAH in Brazil with respect to the underlying causes.
all patients were followed until December 2013. Data collection was approved by the institutional review board of the University of Sao Paulo Clinical Hospital (approval number 0832/07). The continuous variables were expressed as mean values and SDs and were compared using paired t tests. One-way analysis of variance with Bonferroni correction for multiple comparisons was used to identify differences among the patient groups. The categorical variables were expressed as proportions and compared using the x2 test or Fisher exact test, as appropriate. The survival was described using Kaplan-Meier curves; the log-rank test was used for curve comparison. The predicted survival according to the French equation13 was also calculated for the idiopathic PAH (IPAH) patient group. A P value of .05 was considered to be significant.
Compared with the subjects with Sch-PAH and IPAH, patients with CTD presented with a worse FC, despite
Figure 1 – The proportion of patients in each subgroup of pulmonary arterial hypertension (PAH) by cause.
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TABLE 1
] Clinical and Hemodynamic Data at Diagnosis
Characteristic
IPAH
Subjects, No. (%)
51 (28.7)
Sex, female (male)
3.3 (1) 39.8 ⫾ 14.8a
Age, y
CTD
Sch-PAH
46 (25.8)
Others
35 (19.7)
10.5 (1)
19 (10.7)
1.7 (1)
48.4 ⫾ 15.1
Total 178 (100)
1.1 (1)
48.3 ⫾ 15.4
3.3 (1)
49.8 ⫾ 11.4
46.0 ⫾ 15.0
RAP, mm Hg
11 ⫾ 5
10 ⫾ 5
10 ⫾ 5
11 ⫾ 8
10 ⫾ 5
mPAP, mm Hg
61 ⫾ 20
44 ⫾ 14a
52 ⫾ 19
49 ⫾ 12
52 ⫾ 18
11 ⫾ 4
PAOP, mm Hg CO, L/min
11 ⫾ 4
4.1 ⫾ 1.3
13 ⫾ 5
4.2 ⫾ 1.1
13.5 ⫾ 9.8
4.7 ⫾ 1.5
11 ⫾ 4
5.9 ⫾ 2.0
4.8 ⫾ 1.5
7.0 ⫾ 3.1
10.4 ⫾ 6.1
PVR, Wood units
13.5 ⫾ 6.4a
8.7 ⫾ 5.1
9.7 ⫾ 6.1
FC III or IV, %
52.9 (27)
54.3 (25)
31.4 (11)
36.8 (7)
45.5 (81)
BNP, pg/mL
205 ⫾ 262
274 ⫾ 361
123 ⫾ 174
146 ⫾ 216
208 ⫾ 292
6MWD, m
398 ⫾ 152
366 ⫾ 117
366 ⫾ 200
408 ⫾ 139
383 ⫾ 152
Data are given as mean 6 SD unless otherwise indicated. 6MWD 5 6-min walk distance; BNP 5 B-type natriuretic peptide; CO 5 cardiac output; CTD 5 connective tissue disease; FC 5 functional class (New York Heart Association); IPAH 5 idiopathic pulmonary arterial hypertension; mPAP 5 mean pulmonary arterial pressure; PAOP 5 pulmonary artery occlusion pressure; PVR 5 pulmonary vascular resistance; RAP 5 right atrial pressure; Sch-PAH 5 schistosomiasis-associated pulmonary arterial hypertension. aP , .05 for the comparison between IPAH, CTD, and Sch-PAH.
lower mPAP values, lower PVR, and similar cardiac output (Table 1). The patients with IPAH were younger at diagnosis, with a mean age of 39 years. Table 2 provides the baseline characteristics of patients enrolled in the French,7 Spanish,6 Chinese,8 UK,14 and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry)5 registries. Despite simTABLE 2
ilar hemodynamic profiles, fewer patients in our study presented with FC III and IV. Interestingly, the 6-min walk distance for the patients with most severe disease in our study was different from that of the other cohorts: Patients with FC III in our study walked . 400 m (Fig 2). Sildenafil and bosentan were the only available therapies for PAH in Brazil during the period of the study. Sildenafil
] Demographic, Clinical, and Hemodynamic Characteristics of Published Registries
Characteristic
Brazilian
Subjects, No.
178
Spanish6 866
REVEAL Registry5 2,525
French7 674
Chinese8,
a
72
UK14,
b
482
Age, y PAH
46 ⫾ 15
45 ⫾ 17
53 ⫾ 14
50 ⫾ 15
N/A
N/A
IPAH
39.8 ⫾ 14.8
46 ⫾ 18
53 ⫾ 14
52 ⫾ 15
36 ⫾ 12
50 ⫾ 17
Patients with IPAH, %
28.7
36.2
46.2
39.2
Women, %
77
71
79.5
65.3
FC III-IV, %
69.9
45.5
69 363 ⫾ 120
FC I/II
438 ⫾ 31
442 ⫾ 97
…
415 ⫾ 86
…
…
FC III
419 ⫾ 34
343 ⫾ 111
…
319 ⫾ 92
…
…
FC IV
294 ⫾ 83
255 ⫾ 98
…
192 ⫾ 96
Cardiac index, L/min
2.6 ⫾ 0.8
2.6 ⫾ 0.9
PVR, Wood units
10 ⫾ 5 10.4 ⫾ 6.1
mPAP, mm Hg
52 ⫾ 18
9⫾5
2.4 ⫾ 0.8
329 ⫾ 109
2.5 ⫾ 0.8
9.3 ⫾ 5.6
8⫾5
12 ⫾ 6
21.1 ⫾ 12.5d
20.5 ⫾ 10.2d
54 ⫾ 16
50.7 ⫾ 13.6
55 ⫾ 15
61
100
383 ⫾ 152
366 ⫾ 126
75
70.8
6MWD, m
RAP, mm Hg
55.6
100
400 ⫾ 126c
84 292 ⫾ 123
…
…
2.9 ⫾ 1.4c
2.1 ⫾ 0.7
13 ⫾ 6
10 ⫾ 6
20.4 ⫾ 8
13 ⫾ 6
64 ⫾ 17
54 ⫾ 14
Data are given as mean 6 SD unless otherwise indicated. N/A 5 not available. See Table 1 legend for expansion of other abbreviations. The Chinese registry includes only idiopathic and familial PAH. bThe UK registry includes idiopathic, heritable, and anorexigen-induced PAH. cData available for only 12 cases of IPAH. dIndexed values. a
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Figure 2 – Functional and hemodynamic parameters according to functional class. A, 6MWD. B, BNP. C, Cardiac output. D, Right atrial pressure. E, Pulmonary vascular resistance. F, Pulmonary vascular compliance. 6MWD 5 6-min walk distance; BNP 5 B-type natriuretic peptide.
was used as the first-line therapy by 66% of patients, whereas 27% used bosentan and 5% began with the combination therapy. The survival rates for the PAH group as a whole at 1, 2, and 3 years after diagnosis were 92.7%, 79.6%, and 73.9%, respectively. Considering only the three most prevalent causes, the prognosis for the 498 Original Research
patients with CTD, who had a 3-year survival of 63.6%, was considerably worse than in IPAH and Sch-PAH groups (Fig 3) (P 5 .03). For IPAH, the survival rates at 1, 2, and 3 years were 97%, 91%, and 87%, respectively, higher than those estimated by the French equation (92%, 90%, and 80% at 1, 2, and 3 years, respectively).
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evaluating PAH therapies. Although some evidence of specific treatment efficacy in Sch-PAH exists,21 not a single randomized clinical trial included patients with Sch-PAH, preventing any direct extrapolation of their results to support the widespread use of targeted therapies in this subgroup of patients. The prevalence of CTD-PAH in the present study is notably increased compared with the data published in 2006.18 In that retrospective cohort, CTD characterized approximately 10% of all patients with PAH; CTD-PAH now accounts for 25% of all patients. This result is a clear reflection of a better referral process, which began after and as a consequence of the previous report. This improvement reinforces the role of regional registries11 in changing health care for specific clinical conditions.
Figure 3 – Survival according to PAH cause. See Figure 1 legend for expansion of other abbreviation.
Discussion To our knowledge, the present study represents the first prospective registry including only incident cases of PAH in Brazil. Data coming from the Southern Hemisphere are scarce, making it difficult to compare these data directly to the published registries from the United States and Europe.5-10,12,14,16,17 Our study allowed the comparison not only in terms of baseline characteristics but also in terms of long-term prognosis. Our study confirmed that schistosomiasis is an important associated condition for the development of PAH, as suggested by a retrospective study published approximately 1 decade ago.18 In our center, approximately 20% of all patients with PAH presented with Sch-PAH, representing the third most important form, following IPAH and CTD-PAH. This is a clear characteristic of a developing country, because schistosomiasis is a disease closely associated with poor sanitary conditions.19 Schistosomiasis may be one of the main causes of PAH in the world. The World Health Organization estimates that schistosomiasis affects . 200 million people worldwide,20 although most cases remain undiagnosed. The fact that Sch-PAH accounts for a significant proportion of all PAH cases at our center clearly underscores the need to develop treatment policies for rare diseases based on unique regional PAH profiles. Furthermore, these regional characteristics have to be taken into account when interpreting the results of clinical trials
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The predominance of women and the mean age of the patients in the present study are similar to those of other registries in developed5-7,10 or developing countries.8 Nevertheless, if IPAH is considered separately, the mean age found in our study (39 years) is much closer to that described in the first National Institutes of Health registry2 (36 years), published in the late 1980s and to the Chinese registry8 (35 years) than to the European and American registries.5-7,14 This shift from younger to older patients was clearly described in the American population by the comparison of patients with IPAH from the REVEAL Registry with the data from the National Institutes of Health registry.22 Within the UK registry,14 an increasing rate of comorbidities has also been recognized, supporting the concept of a new phenotype in PAH, whereas in developing countries a purer pulmonary vascular disease would still be present, as supported by our results and the data from the Chinese registry.8 The reason for this difference is not clear, nor is its impact on long-term outcome. It may be a result of different levels of disease awareness or the availability of different treatment options or even a consequence of accessibility to health care within the country, changing the diagnostic approach instead. A future evaluation of the baseline characteristics in our patient population might provide valuable information regarding a real change in PAH phenotype over time, from a pure form of PAH to a form with multiple comorbidities or simply a change in disease recognition and management. Nevertheless, this coexistence of multiple diseases and PAH imposes a new challenge in terms of treatment approach. The presence of comorbidities might have a significant impact in the long-term prognosis of patients with PAH, mainly considering that older age has been 499
consistently associated with worse prognosis.7,14,16 Furthermore, the effect of the targeted therapies or its magnitude might be different in the presence of multiple comorbidities. Future global clinical trials should account for these regional differences in the PAH populations, from a more pure disease to a clinical profile with multiple comorbidities, by stratifying enrollment or by predefining secondary analysis of results according to more homogeneous subgroups. Although the mean 6-min walk distance in our registry is similar to values reported previously, the differences in the mean values found in patients with FC III disease are interesting. In the French and Spanish registries, the mean distance walked by patients with FC III was between 319 and 343 m,6,7 but patients with FC III in our study walked . 400 m. This difference could not be explained by their hemodynamic profiles, which were similar in the three studies. Moreover, B-type natriuretic peptide levels found in our study, according to the FC, are also consistent with previously published data.23 It is difficult to speculate how much of this finding could be the result of an intrinsic characteristic of the patients or of an environmental factor associated with the socioeconomic conditions that might influence the level of daily activity for the patients. Our group previously reported that patients with Sch-PAH present with a less severe hemodynamic profile24 compared with the patients with IPAH, as observed in the current study. In the present cohort, the patients with CTD presented with less pronounced hemodynamic impairment, as indicated by a significantly lower PVR. However, these patients demonstrated a more severe clinical manifestation, as shown by the higher proportions of the patients with FC III and IV. Moreover, the survival rate for each of these groups was much more consistent with the clinical profile than with the hemodynamic impairment, with the patients with CTD demonstrating worse survival at 1, 2, and 3 years, when compared with patients with IPAH and Sch-PAH, both presenting similar long-term survival. This finding highlights the importance of establishing more aggressive screening programs for CTD, which would allow earlier diagnosis and intervention with the aim of potentially improving the outcomes.25
500 Original Research
One of the important aspects of our study was the inclusion of only incident patients with PAH. The inclusion of prevalent patients in registries leads not only to overestimation of survival13 but also to biased evaluation of disease severity at baseline. The REVEAL Registry is a clear example of the impact of mixing incident and prevalent patients. Although the proportion of patients with FC III and IV was 55.6% in the overall population, if only incident cases are considered, this proportion rises to 73.6%,26 suggesting a population with much more severe disease. Considering these aspects, our results are expected to be more realistic in terms of long-term prognosis. If only IPAH is considered, allowing a better comparison without the influence of Sch-PAH, our 3-year survival is similar to the one described in the UK registry,14 even considering the different treatment approaches, because prostanoids are not available in Brazil. Again, the impact of comorbidities in long-term prognosis could be speculated to explain these findings; however, only a direct comparison between the two cohorts would allow any definite conclusion. Our study has some limitations that need to be acknowledged. The single-center nature of our study may be considered to be a limitation. However, our center is the largest reference center for PAH in Brazil and receives patients from all other regions of the country due to greater treatment availability in our region. This factor decreases the potential impact of this limitation. Along with the progress in therapeutics, the clinical outcomes of patients with PAH have significantly improved in recent years. The recognition of regional characteristics might allow the adaptation of clinical guidelines for diagnosis and management of PAH. Our study showed some similarities to recent European and American registries, but there were also some remarkable differences. Even considering only IPAH, our results raise questions regarding the need to balance the enrollment of patients in clinical trials accordingly, as a way to account for the potential differences in patients’ characteristics as well as their access to medical care and the availability of a broad range of medical therapies.
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Acknowledgments Author contributions: R. S. takes full responsibility for the whole content of the manuscript. J. L. A., F. G., C. J., C. J. C. d. S. F., L. T. K. M., B. D., and S. H. collected the data; J. L. A., F. G., M. H., and R. S. analyzed the data and drafted the manuscript; and M. H. and R. S. planned the study. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Souza has received lecture fees and/or has participated in advisory boards for Bayer AG, GlaxoSmithKline, Actelion Pharmaceuticals Ltd, and Bristol-Myers Squibb. Drs Alves, Gavilanes, Jardim, Fernandes, Morinaga, Dias, Hoette, and Humbert have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
References 1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336(2): 111-117. 2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-223. 3. Hoette S, Jardim C, Souza Rd. Diagnosis and treatment of pulmonary hypertension: an update. J Bras Pneumol. 2010;36(6): 795-811. 4. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl 25):D42-D50. 5. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387. 6. Escribano-Subias P, Blanco I, LópezMeseguer M, et al; REHAP investigators. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J. 2012;40(3):596-603. 7. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in
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France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9): 1023-1030. Jing ZC, Xu XQ, Han ZY, et al. Registry and survival study in Chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest. 2007;132(2):373-379. McGoon MD, Benza RL, EscribanoSubias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013;62(suppl 25):D51-D59. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30(1): 104-109. Souza R, Jardim C, Carvalho C. The need for national registries in rare diseases. Am J Respir Crit Care Med. 2006; 174(2):228. Fischler M, Speich R, Dorschner L, et al; Swiss Society for Pulmonary Hypertension. Pulmonary hypertension in Switzerland: treatment and clinical course. Swiss Med Wkly. 2008;138(25-26):371-378. Humbert M, Sitbon O, Yaïci A, et al; French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010; 36(3):549-555. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186(8): 790-796. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl 25):D34-D41. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol. 2013;168(2):871-880.
17. Thenappan T, Shah SJ, Rich S, GombergMaitland M. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J. 2007;30(6): 1103-1110. 18. Lapa MS, Ferreira EV, Jardim C, Martins BdoC, Arakaki JS, Souza R. Clinical characteristics of pulmonary hypertension patients in two reference centers in the city of Sao Paulo [in Portuguese]. Rev Assoc Med Bras. 2006;52(3):139-143. 19. Hovnanian A, Hoette S, Fernandes CJ, Jardim C, Souza R. Schistosomiasis associated pulmonary hypertension. Int J Clin Pract Suppl. 2010;64(165):25-28. 20. Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation. 2009;119(11):1518-1523. 21. Fernandes CJ, Dias BA, Jardim CV, et al. The role of target therapies in schistosomiasis-associated pulmonary arterial hypertension. Chest. 2012; 141(4):923-928. 22. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US contemporary registries. Chest. 2011;139(1):128-137. 23. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102(8):865-870. 24. dos Santos Fernandes CJ, Jardim CV, Hovnanian A, et al. Survival in schistosomiasis-associated pulmonary arterial hypertension. J Am Coll Cardiol. 2010;56(9):715-720. 25. Humbert M, Yaici A, de Groote P, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522-3530. 26. McGoon MD, Miller DP. REVEAL: a contemporary US pulmonary arterial hypertension registry. Eur Respir Rev. 2012;21(123):8-18.
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Pulmonary Arterial Hypertension in the Southern Hemisphere Results From a Registry of Incident Brazilian Cases Jose Leonidas Alves Jr, MD; Francisca Gavilanes, MD; Carlos Jardim, MD, PhD, FCCP; Caio Julio Cesar dos Santos Fernandes, MD, PhD; Luciana Tamie Kato Morinaga, MD; Bruno Dias, MD, PhD; Susana Hoette, MD, PhD; Marc Humbert, MD, PhD; and Rogerio Souza, MD, PhD
Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of patients with PAH, although data coming from the Southern Hemisphere remain scarce. The objective of this study was to describe a cohort of incident patients with PAH from a large reference center in Brazil.
BACKGROUND:
All consecutive patients who received a diagnosis of PAH by right-sided heart catheterization between 2008 and 2013 were included in the study.
METHODS:
A total of 178 patients with newly diagnosed PAH were enrolled in the study (mean age, 46 years; female/male ratio, 3.3:1; 45.5% in New York Heart Association functional class III or IV). Idiopathic PAH (IPAH), connective tissue disease (CTD), and schistosomiasisassociated PAH (Sch-PAH) accounted for 28.7%, 25.8%, and 19.7% of all cases, respectively. The patients were treated with phosphodiesterase type 5 inhibitors (66%), endothelin receptor antagonists (27%), or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the patients with CTD was worse than that for the patients with IPAH and Sch-PAH (P 5 .03).
RESULTS:
The distribution of PAH causes and the baseline characteristics in our registry clearly differ from the previously published European and US-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials.
CONCLUSIONS:
CHEST 2015; 147(2):495-501
Manuscript received April 28, 2014; revision accepted August 20, 2014; originally published Online First October 9, 2014. ABBREVIATIONS: CTD 5 connective tissue disease; FC 5 functional class; IPAH 5 idiopathic pulmonary arterial hypertension; mPAP 5 mean pulmonary arterial pressure; PAH 5 pulmonary arterial hypertension; PVR 5 pulmonary vascular resistance; REVEAL Registry 5 Registry to Evaluate Early and Long-term PAH Disease Management; Sch-PAH 5 schistosomiasis-associated pulmonary arterial hypertension AFFILIATIONS: From the Pulmonary Department (Drs Alves, Gavilanes, Jardim, Fernandes, Morinaga, Dias, Hoette, and Souza), Heart Institute, University of São Paulo Medical School, São Paulo, Brazil; and the University Paris-Sud (Dr Humbert), Inserm UMR_S 999, Service de
journal.publications.chestnet.org
Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Rogerio Souza, MD, PhD, Pulmonary Department, Heart Institute, University of São Paulo Medical School, Av Dr Eneas de Carvalho Aguiar, 44, São Paulo, Brazil 05403-000; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1036
495
Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature.1,2 The disease is associated with various underlying causes but is diagnosed by the presence of an elevated mean pulmonary arterial pressure (mPAP) and normal pulmonary occlusion arterial pressure at rest, in the absence of significant lung or left-sided heart disease.3,4 The past decade has witnessed an increasing interest in the worldwide characteristics of PAH. Data from national registries have been published and have contributed to the understanding of regional characteristics regarding the epidemiology, demographics, etiology, clinical course, hemodynamics, disease management, and treatment outcomes.5-12 Nevertheless, data remain scarce
Materials and Methods From January 2008 to December 2013, a total of 178 consecutive patients with PAH, diagnosed according to the Nice classification,15 were enrolled in this study. PAH diagnosis was established in accordance with current international guidelines.4 The date of the first rightsided heart catheterization was defined as the date of diagnosis.9 Other causes of pulmonary hypertension were excluded by echocardiography, pulmonary function testing, chest CT scans, and ventilation-perfusion scans. The investigators who enrolled the subjects into the registry classified the subjects into the PAH subgroups based both on laboratory tests and their impressions of the most likely causes of the PAH. Baseline clinical, functional, and hemodynamic data were collected, and
Results A total of 178 patients with PAH were included in the study. Figure 1 shows the proportion of the patients in each PAH subgroup. IPAH, connective tissue disease (CTD), and schistosomiasis-associated PAH (Sch-PAH) represented the most prevalent subgroups, accounting for 28.7%, 25.8%, and 19.7% of all cases, respectively. From the 46 patients with CTD-PAH, 23 patients had systemic sclerosis, 14 patients had systemic lupus erythematosus, five patients had mixed CTD, and the remaining four patients had other CTD. The clinical and hemodynamic data at diagnosis for the main subgroups of PAH are displayed in Table 1. Although pulmonary vascular resistance (PVR) was not used as part of the definition of PAH, only three patients with PVR , 3 Wood units were included in the cohort, all presenting portopulmonary hypertension (PVR of 2.8, 2.5, and 2.2 Wood units for each one of the individuals). The mean age of all patients enrolled in the cohort was 46 years, and the female to male ratio was 3.3:1. At diagnosis, 45.5% of the patients were classified as New York Heart Association functional class (FC) III or IV. 496 Original Research
with respect to such aspects for the population living in the Southern Hemisphere. Most pulmonary hypertension registries enroll a mixed population of patients, including both prevalent and incident cases. “Prevalent” indicates those who have already been diagnosed and treated at the time the registry is started, whereas “incident” designates those diagnosed and treated during the generation of the registry (“newly diagnosed cases”). This distinction is relevant because prevalent patients have a better prognosis compared with incident patients and may be overrepresented in registries.13,14 The objective of this study was to describe the epidemiology, baseline characteristics, and outcomes of a population of incident patients with PAH in Brazil with respect to the underlying causes.
all patients were followed until December 2013. Data collection was approved by the institutional review board of the University of Sao Paulo Clinical Hospital (approval number 0832/07). The continuous variables were expressed as mean values and SDs and were compared using paired t tests. One-way analysis of variance with Bonferroni correction for multiple comparisons was used to identify differences among the patient groups. The categorical variables were expressed as proportions and compared using the x2 test or Fisher exact test, as appropriate. The survival was described using Kaplan-Meier curves; the log-rank test was used for curve comparison. The predicted survival according to the French equation13 was also calculated for the idiopathic PAH (IPAH) patient group. A P value of .05 was considered to be significant.
Compared with the subjects with Sch-PAH and IPAH, patients with CTD presented with a worse FC, despite
Figure 1 – The proportion of patients in each subgroup of pulmonary arterial hypertension (PAH) by cause.
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TABLE 1
] Clinical and Hemodynamic Data at Diagnosis
Characteristic
IPAH
Subjects, No. (%)
51 (28.7)
Sex, female (male)
3.3 (1) 39.8 ⫾ 14.8a
Age, y
CTD
Sch-PAH
46 (25.8)
Others
35 (19.7)
10.5 (1)
19 (10.7)
1.7 (1)
48.4 ⫾ 15.1
Total 178 (100)
1.1 (1)
48.3 ⫾ 15.4
3.3 (1)
49.8 ⫾ 11.4
46.0 ⫾ 15.0
RAP, mm Hg
11 ⫾ 5
10 ⫾ 5
10 ⫾ 5
11 ⫾ 8
10 ⫾ 5
mPAP, mm Hg
61 ⫾ 20
44 ⫾ 14a
52 ⫾ 19
49 ⫾ 12
52 ⫾ 18
11 ⫾ 4
PAOP, mm Hg CO, L/min
11 ⫾ 4
4.1 ⫾ 1.3
13 ⫾ 5
4.2 ⫾ 1.1
13.5 ⫾ 9.8
4.7 ⫾ 1.5
11 ⫾ 4
5.9 ⫾ 2.0
4.8 ⫾ 1.5
7.0 ⫾ 3.1
10.4 ⫾ 6.1
PVR, Wood units
13.5 ⫾ 6.4a
8.7 ⫾ 5.1
9.7 ⫾ 6.1
FC III or IV, %
52.9 (27)
54.3 (25)
31.4 (11)
36.8 (7)
45.5 (81)
BNP, pg/mL
205 ⫾ 262
274 ⫾ 361
123 ⫾ 174
146 ⫾ 216
208 ⫾ 292
6MWD, m
398 ⫾ 152
366 ⫾ 117
366 ⫾ 200
408 ⫾ 139
383 ⫾ 152
Data are given as mean 6 SD unless otherwise indicated. 6MWD 5 6-min walk distance; BNP 5 B-type natriuretic peptide; CO 5 cardiac output; CTD 5 connective tissue disease; FC 5 functional class (New York Heart Association); IPAH 5 idiopathic pulmonary arterial hypertension; mPAP 5 mean pulmonary arterial pressure; PAOP 5 pulmonary artery occlusion pressure; PVR 5 pulmonary vascular resistance; RAP 5 right atrial pressure; Sch-PAH 5 schistosomiasis-associated pulmonary arterial hypertension. aP , .05 for the comparison between IPAH, CTD, and Sch-PAH.
lower mPAP values, lower PVR, and similar cardiac output (Table 1). The patients with IPAH were younger at diagnosis, with a mean age of 39 years. Table 2 provides the baseline characteristics of patients enrolled in the French,7 Spanish,6 Chinese,8 UK,14 and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry)5 registries. Despite simTABLE 2
ilar hemodynamic profiles, fewer patients in our study presented with FC III and IV. Interestingly, the 6-min walk distance for the patients with most severe disease in our study was different from that of the other cohorts: Patients with FC III in our study walked . 400 m (Fig 2). Sildenafil and bosentan were the only available therapies for PAH in Brazil during the period of the study. Sildenafil
] Demographic, Clinical, and Hemodynamic Characteristics of Published Registries
Characteristic
Brazilian
Subjects, No.
178
Spanish6 866
REVEAL Registry5 2,525
French7 674
Chinese8,
a
72
UK14,
b
482
Age, y PAH
46 ⫾ 15
45 ⫾ 17
53 ⫾ 14
50 ⫾ 15
N/A
N/A
IPAH
39.8 ⫾ 14.8
46 ⫾ 18
53 ⫾ 14
52 ⫾ 15
36 ⫾ 12
50 ⫾ 17
Patients with IPAH, %
28.7
36.2
46.2
39.2
Women, %
77
71
79.5
65.3
FC III-IV, %
69.9
45.5
69 363 ⫾ 120
FC I/II
438 ⫾ 31
442 ⫾ 97
…
415 ⫾ 86
…
…
FC III
419 ⫾ 34
343 ⫾ 111
…
319 ⫾ 92
…
…
FC IV
294 ⫾ 83
255 ⫾ 98
…
192 ⫾ 96
Cardiac index, L/min
2.6 ⫾ 0.8
2.6 ⫾ 0.9
PVR, Wood units
10 ⫾ 5 10.4 ⫾ 6.1
mPAP, mm Hg
52 ⫾ 18
9⫾5
2.4 ⫾ 0.8
329 ⫾ 109
2.5 ⫾ 0.8
9.3 ⫾ 5.6
8⫾5
12 ⫾ 6
21.1 ⫾ 12.5d
20.5 ⫾ 10.2d
54 ⫾ 16
50.7 ⫾ 13.6
55 ⫾ 15
61
100
383 ⫾ 152
366 ⫾ 126
75
70.8
6MWD, m
RAP, mm Hg
55.6
100
400 ⫾ 126c
84 292 ⫾ 123
…
…
2.9 ⫾ 1.4c
2.1 ⫾ 0.7
13 ⫾ 6
10 ⫾ 6
20.4 ⫾ 8
13 ⫾ 6
64 ⫾ 17
54 ⫾ 14
Data are given as mean 6 SD unless otherwise indicated. N/A 5 not available. See Table 1 legend for expansion of other abbreviations. The Chinese registry includes only idiopathic and familial PAH. bThe UK registry includes idiopathic, heritable, and anorexigen-induced PAH. cData available for only 12 cases of IPAH. dIndexed values. a
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Figure 2 – Functional and hemodynamic parameters according to functional class. A, 6MWD. B, BNP. C, Cardiac output. D, Right atrial pressure. E, Pulmonary vascular resistance. F, Pulmonary vascular compliance. 6MWD 5 6-min walk distance; BNP 5 B-type natriuretic peptide.
was used as the first-line therapy by 66% of patients, whereas 27% used bosentan and 5% began with the combination therapy. The survival rates for the PAH group as a whole at 1, 2, and 3 years after diagnosis were 92.7%, 79.6%, and 73.9%, respectively. Considering only the three most prevalent causes, the prognosis for the 498 Original Research
patients with CTD, who had a 3-year survival of 63.6%, was considerably worse than in IPAH and Sch-PAH groups (Fig 3) (P 5 .03). For IPAH, the survival rates at 1, 2, and 3 years were 97%, 91%, and 87%, respectively, higher than those estimated by the French equation (92%, 90%, and 80% at 1, 2, and 3 years, respectively).
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evaluating PAH therapies. Although some evidence of specific treatment efficacy in Sch-PAH exists,21 not a single randomized clinical trial included patients with Sch-PAH, preventing any direct extrapolation of their results to support the widespread use of targeted therapies in this subgroup of patients. The prevalence of CTD-PAH in the present study is notably increased compared with the data published in 2006.18 In that retrospective cohort, CTD characterized approximately 10% of all patients with PAH; CTD-PAH now accounts for 25% of all patients. This result is a clear reflection of a better referral process, which began after and as a consequence of the previous report. This improvement reinforces the role of regional registries11 in changing health care for specific clinical conditions.
Figure 3 – Survival according to PAH cause. See Figure 1 legend for expansion of other abbreviation.
Discussion To our knowledge, the present study represents the first prospective registry including only incident cases of PAH in Brazil. Data coming from the Southern Hemisphere are scarce, making it difficult to compare these data directly to the published registries from the United States and Europe.5-10,12,14,16,17 Our study allowed the comparison not only in terms of baseline characteristics but also in terms of long-term prognosis. Our study confirmed that schistosomiasis is an important associated condition for the development of PAH, as suggested by a retrospective study published approximately 1 decade ago.18 In our center, approximately 20% of all patients with PAH presented with Sch-PAH, representing the third most important form, following IPAH and CTD-PAH. This is a clear characteristic of a developing country, because schistosomiasis is a disease closely associated with poor sanitary conditions.19 Schistosomiasis may be one of the main causes of PAH in the world. The World Health Organization estimates that schistosomiasis affects . 200 million people worldwide,20 although most cases remain undiagnosed. The fact that Sch-PAH accounts for a significant proportion of all PAH cases at our center clearly underscores the need to develop treatment policies for rare diseases based on unique regional PAH profiles. Furthermore, these regional characteristics have to be taken into account when interpreting the results of clinical trials
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The predominance of women and the mean age of the patients in the present study are similar to those of other registries in developed5-7,10 or developing countries.8 Nevertheless, if IPAH is considered separately, the mean age found in our study (39 years) is much closer to that described in the first National Institutes of Health registry2 (36 years), published in the late 1980s and to the Chinese registry8 (35 years) than to the European and American registries.5-7,14 This shift from younger to older patients was clearly described in the American population by the comparison of patients with IPAH from the REVEAL Registry with the data from the National Institutes of Health registry.22 Within the UK registry,14 an increasing rate of comorbidities has also been recognized, supporting the concept of a new phenotype in PAH, whereas in developing countries a purer pulmonary vascular disease would still be present, as supported by our results and the data from the Chinese registry.8 The reason for this difference is not clear, nor is its impact on long-term outcome. It may be a result of different levels of disease awareness or the availability of different treatment options or even a consequence of accessibility to health care within the country, changing the diagnostic approach instead. A future evaluation of the baseline characteristics in our patient population might provide valuable information regarding a real change in PAH phenotype over time, from a pure form of PAH to a form with multiple comorbidities or simply a change in disease recognition and management. Nevertheless, this coexistence of multiple diseases and PAH imposes a new challenge in terms of treatment approach. The presence of comorbidities might have a significant impact in the long-term prognosis of patients with PAH, mainly considering that older age has been 499
consistently associated with worse prognosis.7,14,16 Furthermore, the effect of the targeted therapies or its magnitude might be different in the presence of multiple comorbidities. Future global clinical trials should account for these regional differences in the PAH populations, from a more pure disease to a clinical profile with multiple comorbidities, by stratifying enrollment or by predefining secondary analysis of results according to more homogeneous subgroups. Although the mean 6-min walk distance in our registry is similar to values reported previously, the differences in the mean values found in patients with FC III disease are interesting. In the French and Spanish registries, the mean distance walked by patients with FC III was between 319 and 343 m,6,7 but patients with FC III in our study walked . 400 m. This difference could not be explained by their hemodynamic profiles, which were similar in the three studies. Moreover, B-type natriuretic peptide levels found in our study, according to the FC, are also consistent with previously published data.23 It is difficult to speculate how much of this finding could be the result of an intrinsic characteristic of the patients or of an environmental factor associated with the socioeconomic conditions that might influence the level of daily activity for the patients. Our group previously reported that patients with Sch-PAH present with a less severe hemodynamic profile24 compared with the patients with IPAH, as observed in the current study. In the present cohort, the patients with CTD presented with less pronounced hemodynamic impairment, as indicated by a significantly lower PVR. However, these patients demonstrated a more severe clinical manifestation, as shown by the higher proportions of the patients with FC III and IV. Moreover, the survival rate for each of these groups was much more consistent with the clinical profile than with the hemodynamic impairment, with the patients with CTD demonstrating worse survival at 1, 2, and 3 years, when compared with patients with IPAH and Sch-PAH, both presenting similar long-term survival. This finding highlights the importance of establishing more aggressive screening programs for CTD, which would allow earlier diagnosis and intervention with the aim of potentially improving the outcomes.25
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One of the important aspects of our study was the inclusion of only incident patients with PAH. The inclusion of prevalent patients in registries leads not only to overestimation of survival13 but also to biased evaluation of disease severity at baseline. The REVEAL Registry is a clear example of the impact of mixing incident and prevalent patients. Although the proportion of patients with FC III and IV was 55.6% in the overall population, if only incident cases are considered, this proportion rises to 73.6%,26 suggesting a population with much more severe disease. Considering these aspects, our results are expected to be more realistic in terms of long-term prognosis. If only IPAH is considered, allowing a better comparison without the influence of Sch-PAH, our 3-year survival is similar to the one described in the UK registry,14 even considering the different treatment approaches, because prostanoids are not available in Brazil. Again, the impact of comorbidities in long-term prognosis could be speculated to explain these findings; however, only a direct comparison between the two cohorts would allow any definite conclusion. Our study has some limitations that need to be acknowledged. The single-center nature of our study may be considered to be a limitation. However, our center is the largest reference center for PAH in Brazil and receives patients from all other regions of the country due to greater treatment availability in our region. This factor decreases the potential impact of this limitation. Along with the progress in therapeutics, the clinical outcomes of patients with PAH have significantly improved in recent years. The recognition of regional characteristics might allow the adaptation of clinical guidelines for diagnosis and management of PAH. Our study showed some similarities to recent European and American registries, but there were also some remarkable differences. Even considering only IPAH, our results raise questions regarding the need to balance the enrollment of patients in clinical trials accordingly, as a way to account for the potential differences in patients’ characteristics as well as their access to medical care and the availability of a broad range of medical therapies.
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Acknowledgments Author contributions: R. S. takes full responsibility for the whole content of the manuscript. J. L. A., F. G., C. J., C. J. C. d. S. F., L. T. K. M., B. D., and S. H. collected the data; J. L. A., F. G., M. H., and R. S. analyzed the data and drafted the manuscript; and M. H. and R. S. planned the study. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Souza has received lecture fees and/or has participated in advisory boards for Bayer AG, GlaxoSmithKline, Actelion Pharmaceuticals Ltd, and Bristol-Myers Squibb. Drs Alves, Gavilanes, Jardim, Fernandes, Morinaga, Dias, Hoette, and Humbert have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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