1-Medicine - IJMPS - Hemodynamic - Burabha P - Dual - IJCCM - Thailand - Paid

International Journal of Medicine and Pharmaceutical Sciences (IJPMPS) ISSN 2250-0049 Vol.2, Issue 2, Sep 2012 1-9 © TJPRC Pvt. Ltd.,

HEMODYNAMIC EFFICACY OF BERAPROST THERAPY IN SYSTEMIC SCLEROSIS-RELATED PULMONARY ARTERY HYPERTENSION 1

BURABHA PUSSADHAMMA, 2PYATAT TATSANAVIVAT, 3RATANAVADEE NANAGARA, 4 AJANEE MAHAKKANUKRAUH & 5SONGSAK KIATCHOOSAKUN

1,2,5

3,4

Division of Cardiology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand

Division of Allergy and Rheumatology, Department of Medicine, Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand

ABSTRACT Backgrounds: Systemic sclerosis-related pulmonary artery hypertension (SSc-PAH) is a poor prognostic condition. Beraprost, an oral prostacyclin analogue, is the only PAH-specific drug in the National list of Essential Drugs (NLED) available for medicare in Thailand. However, the efficacy of beraprost in treating SSc-PAH has never been established.

Objective: To evaluate the short term hemodynamic efficacy of beraprost therapy in SSc-PAH. Methods: A study was conducted in functional class (FC) II-III SSc-PAH patients. Beraprost was administered in up-titration strategy to the maximum or maximally-tolerated dose. Right heart catheterization (RHC), symptoms, and N-terminal pro B-type natriuretic peptide (NT-proBNP) were evaluated at baseline and end of study. Primary end point was hemodynamic changes. Secondary end point was non-hemodynamic changes (symptoms and NT-proBNP).

Results: A total of 21 patients were enrolled, 14 patients were completely evaluated (2 denied reevaluation, 2 were dead from infection during study period, 2 had severe comorbidity, and 1 was loss to follow up). The mean age was 49.6 years, 57% were female, 71% were in FC II, and 64% were diffuse SSc. The mean dose of beraprost was 201.4 µg/day and mean study duration was 13.7 weeks. Beraprost had a trend but not significantly improve hemodynamic changes. Mean pulmonary artery pressure (mPAP) was reduced from 35.1 mmHg to 32.5 mmHg (p = 0.096, 95% CI, -0.54 to 5.83), mean right atrial pressure (mRAP) was reduced from 8.3 mmHg to 7.3 mmHg (p = 0.428, 95% CI, -1.64 to 3.64), pulmonary vascular resistance (PVR) was reduced from 6.35 Wood units to 6.07 Wood units (p = 0.639, 95% CI, -0.95 to 1.50), and cardiac index (CI) was increased from 3.13 l/min/m2 to 3.16 l/min/m2 (p = 0.927, 95% CI, -0.69 to 0.63). There was also a trend to improve according to secondary end point. FC was improve in 5 patients and stable in 8 patients, mean NT-proBNP was reduced from 1129 pg/ml to 1050 pg/ml (p = 0.771, 95% CI, -496.54 to 654.68). Heart failure was developed in 3 patients and no any syncopal event happen.

2

Burabha Pussadhamma,Pyatat Tatsanavivat, Ratanavadee Nanagara, Ajanee Mahakkanukrauh & Songsak Kiatchoosakun

KEYWORDS: Hemodynamic Efficacy, Beraprost Therapy, Systemic Sclerosis, Pulmonary Artery Hypertension.

INTRODUCTION Systemic sclerosis (SSc) is one of a rare connective tissue disease. In Thailand, it is more common among the northeastern related to genetic background (HLA-DQB1*0501 and DRBQ*1502).

Data from the Department of Registry and Biostatistics revealed 100 new cases per year averagely presented at scleroderma clinic at Srinagarind hospital, Khon Kaen University. The prevalence of Systemic sclerosis-related pulmonary artery hypertension (SSc-PAH) was ranged from 4.9 to 35% depended on the diagnostic strategy.1-12 The echocardiography-diagnosed prevalence was 59.1% of SSc patients who had abnormal cardiorespiratory complaints.13 SSc-PAH was well recognized for being a poor prognostic condition, its mortality was higher than other subgroups of either SSc or pulmonary hypertension (PH).6,14 Although the guidelines for the diagnosis and treatment of pulmonary hypertension has recommended the PAH-specific drugs management strategy for the group 1 pulmonary hypertension which already included SSc-PAH,15 but the evidences were derived mostly from idiopathic pulmonary artery hypertension (IPAH) and limited type of SSc without pulmonary fibrosis. SSc found in Thai patients was diffused subtype which is more severe skin involvement with high incidence of internal organ involvement including pulmonary fibrosis. Prognosis of PAH related to diffused-SSc with pulmonary fibrosis is even worse than limited-SSc with isolated PAH.16,17 Standard PAH-specific therapy has never been established in this type of SSc. Evidence of PAH-specific drugs therapy in diffuse subtype of SSc is very limited. One short term randomized controlled trial (RCT) of continuous intravenous epoprostenol, a prostacyclin analogue, in SSc-PAH patients demonstrated a significant improvement in exercise capacity and hemodynamic, but no effect in survival.18 And to the best of our knowledge, there was no study using Beraprost therapy undertaken in this patient subgroup, even it is the only PAH-specific drug available in the National List of Essential Drugs (NLED) for Universal Coverage Medicare for Thai patients. We conducted a prospective uncontrolled clinical interventional study to evaluate the short term efficacy of beraprost, an oral prostacyclin analogue, in this high risk condition.

METHODS Study Patients and Oversight Patients were enrolled since July 2010 to December 2010 from scleroderma clinic or in-patient department of Srinagarind hospital, Khon Kaen University, Thailand. The inclusion criteria were systemic sclerosis patients who were age ≥ 15 year-old, World Health Organization functional class (WHO FC) II or III, and right heart catheterization (RHC)-diagnosed PAH (mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg). Patients who were hypotension (mean arterial pressure (MAP) ≤ 60 mmHg), had severe comorbidity, and refused

Hemodynamic Efficacy of Beraprost Therapy in Systemic Sclerosis-Related Pulmonary Artery Hypertension

3

evaluation were excluded. The protocol was approved by the Khon Kaen University ethics committee for human research. All patients provided written informed consent before enrollment.

Study Protocol SSc patients with age ≥ 15 year-old, WHO FC II or III, and echocardiographic suspected PH (tricuspid regurgitation maximum velocity (TRVmax ≥ 2.9 m/s, right ventricular (RV) dilatation, hypertrophy, or systolic dysfunction) were further evaluated for other possible causes of PH and informed to undertaken RHC. The eligible cases were classified by RHC-diagnosed PAH and were enrolled. The baseline symptoms and N-terminal pro B-type natriuretic peptide (NT-proBNP) were also evaluated and beraprost was initially administered at a dose of 20 µg qid. Clinical monitoring and beraprost dose up-titration was made every 2-4 weeks. Target dose of beraprost was maximal dose at 320 µg/day or maximal tolerated dose. The reevaluation study was performed at 12-16 weeks for symptoms, WHO FC, NT-proBNP, and hemodynamic parameters from RHC. All symptoms and WHO FC evaluation were done by first author, and RHC procedures were done mostly by first author with coeditor supervised.

End points The primary end point was hemodynamic achievement, which composed of mPAP, mean right atrial pressure (mRAP), pulmonary vascular resistance (PVR), and cardiac index (CI) changes. The secondary end point was non-hemodynamic achievement, which composed of symptoms (heart failure, syncope), WHO FC, and NT-proBNP changes.

Statistical analysis By the two related group study formula (N = (Zα/2 + Zβ)2σ2/d2). We choose the type I error of 0.05 and type II error of 0.1. The σ2 = σ12 + σ22-2rσ1σ2, by which r = 0 and according to the previous relevant study,19 σ1 = 4.8, σ2 = 3.2, and d = 5, then the estimated sample size was 15. The continuous variables were described using mean and standard variation, and categorical variables were using percentage or proportion. For comparisons, continuous variable were analyzed by pair student t-test, and categorical variable were analyzed by Mc-Nemar chi squar test. P valve ≤ 0.05 was considered statistical significant.

Results Overall, 34 patients underwent RHC. Of these, 21 met the diagnostic criteria and were enrolled into the study, with the aim of 15 complete follow-up cases. 14 patients completed the study, 2 patients were dead during study period due to sepsis (unrelated to the investigational procedure), 2 patients were excluded due to severe comorbidity, 2 patients denied the re-evaluation, 1 patient loss to follow up, and 1 patient developed sudden death shortly after complete the reevaluation study. The flow of the study was as figure 1.

4

Burabha Pussadhamma,Pyatat Tatsanavivat, Ratanavadee Nanagara, Ajanee Mahakkanukrauh & Songsak Kiatchoosakun

Table 1 demonstrated demographic data of 14 patients who had completed the study. The mean age was 49.6 years, 57% were female, 71% were in FC II, and 64% were diffuse SSc. The mean dose of beraprost was 201.4 Âľg/day and mean study duration was 13.7 weeks.

Table 2 showed the primary end point of hemodynamic changes. The mean changes of all hemodynamic parameters were statistically insignificant. mPAP was 2.6 mmHg lower after treatment (from 35.1 to 32.5 mmHg, p = 0.096, 95% CI, -0.54 to 5.83), mRAP was 1.0 mmHg lower after treatment (from 8.3 to 7.3 mmHg, p = 0.428, 95% CI, -1.64 to 3.64), PVR was 0.28 WUs lower after treatment (from 6.35 to 6.07 WUs, p = 0.639, 95% CI, -0.95 to 1.50), and CI was 0.03 l/min/m2 increase after treatment (from 3.13 to 3.16 l/min/m2, p = 0.927, 95% CI, -0.69 to 0.63).

Table 3 showed the secondary end point of non-hemodynamic changes. Ten patients were initially in WHO FC II and three were initially in WHO FC III. In initially WHO FC II group, one patient was progress to WHO FC III while the others were in stable condition at the end of study (4 patients were in WHO FC I and 5 patients were in FC II). In initially WHO FC III group, all patients remained in the same WHO FC at the end of study. Two patients developed new heart failure (1 from initially WHO FC II and another from initially WHO FC III) and one patient had recurrent heart failure during the study. No syncopal event was reported. Mean NT-proBNP change was also statistical insignificant, 79 pg/ml lower after treatment (from 1129 to 1050 pg/ml, p = 0.771, 95% CI, -496.54 to 654.68).

According to the poor clinical outcomes; death and heart failure, there were 5 accumulative events within the study period (2 dead events and 3 heart failure events). And one patient with heart failure also developed sudden death shortly after the end of the study. Between the group with and without poor clinical outcomes, the mean NT-proBNP level was significantly different, which was 2548.8 pg/ml in the prior and 471.8 in the later group.

DISCUSSIONS This is the first study ever evaluated the efficacy of beraprost therapy specifically in SSc-PAH patients. We found a trend to improve both hemodynamic and non-hemodynamic parameters from beraprost in short term, though the overall improvements were statistically insignificant.

In the ALPHABET study.20 Beraprost of the median dose 320 Âľg a day improved the exercise capacity by 6-minute walk test (6-MWT) and symptoms compared to placebo in short term duration (12 weeks), but had small improvement of hemodynamic parameters without statistical significant detected.

Even though most populations in ALPHABET study were idiopathic pulmonary artery hypertension and they considered worsen according to disease severity, i.e., they had nearly equal number of WHO FC II and III and they initially had severe hemodynamic parameters (mRAP 8.5 mmHg, mPAP 60 mmHg, mean PVR index 23 U/m2, and mean CI 2.4 l/min/m2) compared to our study which most patients were initially in WHO FC II (71%) and they had less severe hemodynamic parameters initially (mRAP 8.3 mmHg, mPAP 35.1 mmHg, mean PVR 6.35 WUs, and mean CI 3.13 l/min/m2). The results from these 2

Hemodynamic Efficacy of Beraprost Therapy in Systemic Sclerosis-Related Pulmonary Artery Hypertension

5

studies supported the short term efficacy of beraprost therapy in broad range of population and disease severity.

However, regarding to the long term result, beraprost failed to achieve its efficacy. According to the study of Barst et al.21 which most patients were idiopathic pulmonary artery hypertension, beraprost could not significantly reduce disease progression and improve 6-minute walk distance at one year.

Anyway, there is still no study evaluating long term efficacy of beraprost therapy specifically in SScPAH patients until now.

As the clinical course of SSc patients is progressive and become rapidly deteriorating in symptoms and physical limitations, especially after pulmonary artery hypertension, this limited improvement in both hemodynamic and non-hemodynamic parameters in our uncontrolled clinical trial could be also due to the counter effects of the deteriorating effects of the disease itself.

For non-hemodynamic parameters, WHO FC and NT-proBNP, we observed that the initial level of WHO FC or NT-proBNP may be able to predict the therapeutic response trend. In whom with initial WHO FC III or NT-proBNP > 500 pg/ml, they seemed to developed a poor clinical events, such as death or heart failure, while in whom with initial WHO FC II or NT-proBNP < 500 pg/ml, they seemed to achieved the satisfactory and stable condition.

Therefore, from those findings, it may be appropriate to conduct a randomized double blind placebo-controlled trial to assess the potential long term benefit of beraprost therapy in proper-selected, mild degree of SSc-PAH patients, e.g., initially WHO FC II, NT-proBNP < 500 pg/ml, and neither prior heart failure nor syncope, to evaluate the long term efficacy of such therapy Though the 6-MWT was the most used parameter to evaluated the efficacy of PAH-specific therapy, but due to its musculoskeletal and pain limitation in SSc-PAH,22 hence we decided not to use this parameter for the efficacy evaluation.

This study had clearly limitation due to being single center, single operator, and small sample size, even with regards to the careful conduct of the study. The unavoidable bias was present and caused the studyâ&#x20AC;&#x2122;s limitation.

Conclusion In this high risk group of pulmonary hypertension, beraprost had a trend in short term to improve both hemodynamic and non-hemodynamic parameters and it could be considered as an optional therapy. Further long term study of beraprost therapy in mild, well-selected cases of SSc-PAH is suggested.

CONCLUSIONS In this high risk group of pulmonary hypertension, beraprost had a trend in short term to improve both hemodynamic and non-hemodynamic parameters.

6

Burabha Pussadhamma,Pyatat Tatsanavivat, Ratanavadee Nanagara, Ajanee Mahakkanukrauh & Songsak Kiatchoosakun

REFERENCES 1.

Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis

associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088-93.

2.

MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk

factors for progression and consequences for survival. Rheumatology (Oxford) 2001;40:453-9.

3.

Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and

diffuse scleroderma. Chest 1996;110:1515-9.

4.

Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary

hypertension and interstitial lung disease. J Rheumatol 2003;30:2398-405.

5.

Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in

systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792800.

6.

Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an

analysis of 17 patients. Br J Rheumatol 1996;35:989-93.

7.

Launay D, Mouthon L, Hachulla E, et al. Prevalence and characteristics of moderate to severe

pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol 2007;34:1005-11.

8.

Murata I, Takenaka K, Yoshinoya S, et al. Clinical evaluation of pulmonary hypertension in

systemic sclerosis and related disorders. A Doppler echocardiographic study of 135 Japanese patients.

Chest 1997;111:36-43.

9.

Plastiras SC, Karadimitrakis SP, Kampolis C, Moutsopoulos HM, Tzelepis GE. Determinants of

pulmonary arterial hypertension in scleroderma. Semin Arthritis Rheum 2007;36:392-6.

10.

Pope JE, Lee P, Baron M, et al. Prevalence of elevated pulmonary arterial pressures measured

by echocardiography in a multicenter study of patients with systemic sclerosis. J Rheumatol 2005;32:1273-8.

11.

Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial

hypertension in progressive systemic sclerosis. Am J Med 1983;75:65-74.

12.

Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of

undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 2005;52:2125-32.

Hemodynamic Efficacy of Beraprost Therapy in Systemic Sclerosis-Related Pulmonary Artery Hypertension

13.

7

Wangkaew S, Kasitanon N, Phrommintikul A, Sukitawut W, Wichainun R, Louthrenoo W.

Pulmonary arterial hypertension in Thai patients with systemic sclerosis. J Med Assoc Thai 2008;91:16672.

14.

Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Hemodynamics and

survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123:344-50.

15.

Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of

pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537 16.

Denton CP, Pope JE, Peter H-H, et al. Long-term effects of bosentan on quality of life, survival,

safety and tolerability in pulmonary arterial hypertension related to connective tissue disease. Ann Rheum Dis 2008;67:1222-28 17.

Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease-associated pulmonary

arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179:151-57 18.

Badesch 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;132:425â&#x20AC;&#x201C;434.

19.

Yoshiaki Okano, Takao Yoshioka, Akito Shimouchi, et al. Orally active prostacyclin analogue

in primary pulmonary hypertension. Lancet 1997;349:1365.

20.

Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin

analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebocontrolled trial. J Am Coll Cardiol 2002;39:1496-502.

21.

Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial

hypertension. J Am Coll Cardiol 2003;41:2119-25 22.

Garin MC, Highland KB, Silver RM, et al. Limitations to the 6-minute walk test in interstitial

lung disease and pulmonary hypertension in scleroderma. J Rheumatol 2009;36:330â&#x20AC;&#x201C;6.

8

Burabha Pussadhamma,Pyatat Tatsanavivat, Ratanavadee Nanagara, Ajanee Mahakkanukrauh & Songsak Kiatchoosakun

APPENDICES

Figure 1. Flow of study

Table 1. demographic data of 14 patients Patient

Age (years)

Sex

SSc type

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean

52 58 60 51 54 48 46 55 65 17 40 38 57 53 49.6

F M M F F F M F F F M M M F

L D D D D D D L D L L D D L

Initial WHO FC 3 2 3 2 2 2 2 2 3 2 2 2 3 2

Maximal dose (Âľg/day) 20 240 320 120 180 240 100 240 240 240 160 240 240 240 201

Study duration (weeks) 11 15.3 12.9 15 16 14 13 13 12.6 15 14 15 13.6 12 13.7

Hemodynamic Efficacy of Beraprost Therapy in Systemic Sclerosis-Related Pulmonary Artery Hypertension

Table 2. Primary end point changes (represented by mean) Parameters

Baseline

Posttherapy

Mean change

P value

95% CI

mPAP (mmHg)

35.1

32.5

-2.6

0.096

-6.37

mRAP (mmHg)

8.3

7.3

-1

0.428

-5.28

PVR (WU)

6.35

6.07

-0.28

0.639

-2.45

CI (l/min/m2)

3.13

3.16

0.03

0.927

-1.32

Table 3. Secondary endpoint changes (represented by mean and absolute numbers)

Parameters

Baseline

Posttherapy

FC I (no.)

-

4

FC II (no.)

10

6

FC III (no.)

4

4

FC IV (no.)

-

-

NT-proBNP (pg/ml)

1129

1050

Mean change

P value

95% CI

-79

0.771

1151.22

9