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Idiopathic Pulmonary Arterial Hypertension in AsiansPulmonary Arterial Hypertension in Asians: A Long-term Study on Clinical Outcomes FREE TO VIEW

Genevieve M. Y. Tan, MD, PhD; Edgar L. Tay, MBBS; Bee-Choo Tai, PhD; James W. L. Yip, MBBS
Author and Funding Information

From the National University Heart Centre (Drs Tan, Tay, and Yip), National University Health System; and the Saw Swee Hock School of Public Health (Dr Tai) and the Yong Loo Lin School of Medicine (Dr Tai), National University of Singapore.

CORRESPONDENCE TO: Edgar L. Tay, MBBS, National University Heart Centre, NUHS Tower Block Level 9, 1E Kent Ridge Rd, Singapore 119228; e-mail: Edgar_Tay@nuhs.edu.sg


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(4):e160-e163. doi:10.1378/chest.14-2919
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Published online
To the Editor:

Pulmonary vasodilators have improved the outcomes of patients with idiopathic pulmonary arterial hypertension (IPAH) but they remain inaccessible in most developing Asian countries without medical subsidies. This letter describes the first Asian IPAH long-term follow-up study to our knowledge.

Data were prospectively collected from 2001 to 2013 from a single IPAH center. Observed survival was described using Kaplan-Meier analysis and was compared with that predicted by National Institutes of Health1 and Pulmonary Hypertension Connection (PHC) registry1 equations using χ2 analysis. All patients demonstrating a vasodilatory response received calcium channel blockers or were initiated on low-dose vasodilators with gradual escalation where indicated during subsequent 3-monthly reviews.

The mean age of the 55 patients with IPAH was 50.0 ± 20.9 years (80% women). Mean baseline right atrial pressure, pulmonary arterial pressure, and cardiac index were 12.5 ± 5.4 mm Hg, 55.9 ± 14.0 mm Hg, and 2.14 ± 0.73 L/min/m2, respectively. Median N-terminal pro-B-type natriuretic peptide levels and mean 6-min walk distance (6MWD) were 1,363 (interquartile range, 704-3,001) pg/mL and 354.6 ± 100.1 m, respectively. Fifteen patients (27.3%) demonstrated World Health Organization functional class III/IV (Table 1). Forty patients (72.7%) received monotherapy and 13 (23.6%) received combination therapy; two (3.5%) declined treatment (Table 2). Forty patients (73%) received lower-than-recommended doses (Fig 1). Mean follow-up was 4.83 (95% CI, 4.0-5.7) years, and 21.8% died at the end of follow-up, with 41.7% being cardiac-related deaths. Kaplan-Meier-observed survival rates were 96.0%, 86.4%, 79.0%, 64.8%, and 64.8% at 1, 3, 5, 7, and 9 years, respectively, and were significantly higher than mean National Institutes of Health-predicted and PHC-predicted survival (Fig 2). Of the 13 deaths, eight received monotherapy, three dual therapy, and one triple therapy.

Table Graphic Jump Location
TABLE 1 ]  Comparison of Baseline Demographics of Patients With IPAH in the NUHCS Pulmonary Hypertension Registry With Other PAH Registries

Data are presented as mean ± SD or No. (%). NIH, PHC, and Chinese Registry data are listed for comparison and are not included in any data analysis. IPAH = idiopathic pulmonary arterial hypertension; NA = not available; NIH = National Institutes of Health; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NUHCS = National University Heart Centre of Singapore; PAH = pulmonary arterial hypertension; PHC = Pulmonary Hypertension Connection; WHO FC = World Health Organization functional class.

a 

Data represent the 95% CI.

b 

Data represent No. patients (%) in WHO FC I/II.

c 

Data represent No. patients (%) in WHO FC III/IV.

Table Graphic Jump Location
TABLE 2 ]  Vasodilator Regimens for NUH Patient Cohort

eod = every other day; mane = morning; NUH = National University Hospital.

a 

Declined active treatment.

Figure Jump LinkFigure 1 –  Vasodilator therapy for patients from the National University Heart Centre of Singapore (NUHCS). PDE5 = phosphodiesterase-5.Grahic Jump Location
Figure Jump LinkFigure 2 –  Observed vs predicted survival using the PHC and NIH equations in patients with IPAH from the NUHCS. IPAH = idiopathic pulmonary arterial hypertension; KM = Kaplan-Meier; NIH = National Institutes of Health; PHC = Pulmonary Hypertension Connection. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Although most patients presented with World Health Organization functional class I/II, they exhibited hemodynamics comparable to functional class III white populations, including higher median N-terminal pro-B-type natriuretic peptide levels and shorter 6MWD compared with the Chinese population, despite receiving phosphodiesterase-5 inhibitor (PDE5I) (Table 1). This is consistent with poor prognostic and survival outcomes in patients with baseline 6MWD < 325 m in the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER)-24 study. Thus, these patients had more advanced disease despite milder presentations.

Initiating PAH therapy at lower doses is viable. Asians have smaller BMI/body surface areas relative to whites and possess a different drug metabolism with variable drug responses. Thus, they may benefit from dose adjustments according to body surface area/weight. Genetic polymorphisms5 of cytochrome P450 enzymes, common in Asians, can generate large ethnic variability in PDE5I6 and endothelin receptor antagonist6 metabolism and lower intrinsic clearances to achieve target therapeutic levels with lower doses.

Our study outcomes are compatible with published cohorts despite our low-dose PAH therapy. This presents a safe, cost-effective strategy for Asians and provides the impetus for funding agencies in developing countries to support this life-saving cause.

References

Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J. 2010;35(5):1079-1087. [CrossRef] [PubMed]
 
Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-223. [CrossRef] [PubMed]
 
Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest. 2011;140(2):301-309. [CrossRef] [PubMed]
 
Rubin LJ, Badesch DB, Fleming TR, et al; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011;140(5):1274-1283. [CrossRef] [PubMed]
 
Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84(3):347-361. [CrossRef] [PubMed]
 
Srinivas NR. Substrate-specific pharmacokinetic interaction between endothelin receptor antagonists and phosphodiesterase-5 inhibitors—assembling the clues. Br J Clin Pharmacol. 2009;67(4):475-477. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Vasodilator therapy for patients from the National University Heart Centre of Singapore (NUHCS). PDE5 = phosphodiesterase-5.Grahic Jump Location
Figure Jump LinkFigure 2 –  Observed vs predicted survival using the PHC and NIH equations in patients with IPAH from the NUHCS. IPAH = idiopathic pulmonary arterial hypertension; KM = Kaplan-Meier; NIH = National Institutes of Health; PHC = Pulmonary Hypertension Connection. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Comparison of Baseline Demographics of Patients With IPAH in the NUHCS Pulmonary Hypertension Registry With Other PAH Registries

Data are presented as mean ± SD or No. (%). NIH, PHC, and Chinese Registry data are listed for comparison and are not included in any data analysis. IPAH = idiopathic pulmonary arterial hypertension; NA = not available; NIH = National Institutes of Health; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NUHCS = National University Heart Centre of Singapore; PAH = pulmonary arterial hypertension; PHC = Pulmonary Hypertension Connection; WHO FC = World Health Organization functional class.

a 

Data represent the 95% CI.

b 

Data represent No. patients (%) in WHO FC I/II.

c 

Data represent No. patients (%) in WHO FC III/IV.

Table Graphic Jump Location
TABLE 2 ]  Vasodilator Regimens for NUH Patient Cohort

eod = every other day; mane = morning; NUH = National University Hospital.

a 

Declined active treatment.

References

Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J. 2010;35(5):1079-1087. [CrossRef] [PubMed]
 
Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-223. [CrossRef] [PubMed]
 
Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest. 2011;140(2):301-309. [CrossRef] [PubMed]
 
Rubin LJ, Badesch DB, Fleming TR, et al; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011;140(5):1274-1283. [CrossRef] [PubMed]
 
Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84(3):347-361. [CrossRef] [PubMed]
 
Srinivas NR. Substrate-specific pharmacokinetic interaction between endothelin receptor antagonists and phosphodiesterase-5 inhibitors—assembling the clues. Br J Clin Pharmacol. 2009;67(4):475-477. [CrossRef] [PubMed]
 
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