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Long Term Treatment of Pulmonary Arterial Hypertension with Beraprost, an Oral Prostacyclin Heart: First Published As 10.1136/Heart.86.6.661 on 1 December 2001

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Long Term Treatment of Pulmonary Arterial Hypertension with Beraprost, an Oral Prostacyclin Heart: First Published As 10.1136/Heart.86.6.661 on 1 December 2001 Heart 2001;86:661–665 661 Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin Heart: first published as 10.1136/heart.86.6.661 on 1 December 2001. Downloaded from analogue C D Vizza, S Sciomer, S Morelli, C Lavalle, P Di Marzio, D Padovani, R Badagliacca, A R Vestri, R Naeije, F Fedele Abstract Objective—To evaluate the eVects of one year’s treatment with beraprost, an orally active prostacyclin analogue, in patients with severe pulmonary hypertension. Patients—13 patients with severe pulmonary hypertension. This was primary in nine, thrombo- embolic in three, and caused by Eisenmenger syndrome in one. Methods—All patients underwent right heart catheterisation. Mean (SD) right atrial pressure was 5 (3) mm Hg, mean pulmonary artery pressure was 48 (12) mm Hg, cardiac index was 2.6 (0.8) l/min/m2, and mixed venous oxygen saturation was 68 (7)%. Beraprost was started at the dose of 20 µg three to four times a day (1 µg/kg/day), increasing after one month to 40 µg three to four times a day (2 µg/kg/day), with further increases of 20 µg three to four times a day in case of clinical deterioration. Main outcome measures—New York Heart Association (NYHA) functional class, exercise capacity measured by distance walked in six minutes, and systolic pulmonary pressure (by echo- cardiography) were evaluated at baseline, after one month’s treatment, and then every three months for a year. Results—After the first month of treatment, NYHA class decreased from 3.4 (0.7) to 2.9 (0.7) (p < 0.05), the six minute walking distance increased from 213 (64) to 276 (101) m (p < 0.05), and systolic pulmonary artery pressure decreased from 93 (15) to 85 (18) mm Hg (NS). One patient died after 40 days from refractory right heart failure, and another was lost for follow up at six months. The 11 remaining patients had persistent improvements in functional class and exer- cise capacity and a significant decrease in systolic pulmonary artery pressure in the period from 1–12 months. Side eVects were minor. Conclusions—Oral administration of beraprost may result in long lasting clinical and haemody- namic improvements in patients with severe pulmonary hypertension. (Heart 2001;86:661–665) Keywords: pulmonary arterial hypertension; prostacyclin; beraprost http://heart.bmj.com/ Continuous intravenous epoprostenol (prosta- therefore been raised by preliminary Japanese cyclin) has been shown to improve the func- studies reporting beneficial eVects of the oral Department of tional state, exercise capacity, pulmonary prostacyclin analogue beraprost in patients Cardiovascular and 13–15 Respiratory Sciences, haemodynamics, and survival in patients with with primary pulmonary hypertension. University La primary pulmonary hypertension.1–6 Similar We here report our experience of 13 patients Sapienza, Rome, Italy with severe pulmonary hypertension treated clinical eVects of intravenous epoprostenol on October 2, 2021 by guest. Protected copyright. C D Vizza treatment have been reported in patients with with oral beraprost and followed for one year. S Sciomer Satisfactory clinical improvement was ob- C Lavalle pulmonary hypertension secondary to connec- 78 910 D Padovani tive tissue disease, congenital heart defects, served in 11 of these patients. R Badagliacca and peripheral chronic thromboembolism.10 A R Vestri However, chronic intravenous epoprostenol F Fedele Methods requires a permanently implanted central STUDY PATIENTS Institute of Internal venous catheter and a portable infusion pump, Thirteen consecutive patients with severe pul- Medicine, University which exposes the patient to a series of compli- monary hypertension (four male and nine La Sapienza cations including catheter related thrombosis, female), aged between 11 and 62 years (mean S Morelli infection, and delivery system malfunction age 45 years), gave their informed consent to the P Di Marzio resulting in rapid underdosing or overdosing of study, which had been approved by the local a drug with a very short half life.1–10 Because of Department of ethics committee. They were referred to our Pathophysiology, these drawbacks, alternative modes of adminis- centre between January 1998 and January 2000, Erasme University tration and longer acting prostacyclin deriva- at a time when intravenous epoprostenol treat- Hospital, Erasme tives are currently under investigation. ment was not yet available in Italy. The patients Campus CP 604, 808 Favourable results have been reported in were diagnosed as having either primary (nine Lennik Road, B-1070 patients with primary and secondary severe pul- Brussels, Belgium patients), peripheral thromboembolic (three), or R Naeije monary hypertension treated with nebulised ilo- congenital heart disease associated (one patient) prost. However, the relatively short half life of pulmonary hypertension. Dyspnoea was the Correspondence to: this prostacyclin analogue imposes the need main symptom in all patients, while six had chest Dr Naeije for up to 12 inhalations a day, each of which pain and seven syncope. The duration of symp- [email protected] lasts up to 15 minutes,11 12 while the use of toms ranged from 1–36 months, mean (SD) 14 Accepted 12 July 2001 aerosol nebulisers is cumbersome. Hopes have (10) months. All the patients had severe www.heartjnl.com 662 Vizza, Sciomer, Morelli, et al functional limitation as assessed by the New Table 1 Baseline haemodynamics and six minute walk York Heart Association (NYHA) classification: distance six were in class IV, six others in class III, and Heart: first published as 10.1136/heart.86.6.661 on 1 December 2001. Downloaded from Variable Mean (SD) only one in class II. The diagnosis of primary pulmonary hyper- Distance (m) 213 (64) Right atrial pressure (mm Hg) 5 (3) tension relied on right heart catheterisation Pulmonary artery pressure (mm Hg) 48 (12) showing a mean pulmonary artery pressure Paop (mm Hg) 7 (4) higher than 25 mm Hg, and the use of an algo- Cardiac index (l/min/m2) 2.6 (0.8) Pulmonary vascular resistance (Wood units) 14.0 (7.6) rithm incorporating a mandatory chest x ray, Mixed venous oxygen saturation (%) 68 (7) respiratory function tests, a perfusion lung scan, an echocardiogram, arterial blood gas Paop, pulmonary artery occluded pressure analysis, and the results of the right heart cath- Table 2 Concomitant treatment eterisation to exclude secondary causes.16 The diagnosis of chronic peripheral inoperable Number of patients thromboembolic pulmonary hypertension was Drug treated Daily dose based on significant perfusion abnormalities on Digoxin 13/13 0.125–0.25 mg a ventilation/perfusion lung scan, and con- Frusemide 13/13 25–125 mg 17 Warfarin 11/13 4–6 mg firmed by a pulmonary angiogram. The diag- Nifedipine 3/13 40–60 mg nosis of ventricular septal defect was made by Enalapril 2/13 5 mg Nitrates 2/13 60–80 mg echocardiography. Amiodarone 1/13 200 mg STUDY PROTOCOL After the diagnostic right heart catheterisation, variance was applied to the series of monthly which included an acute vasodilator challenge measurements, with a correction for the with 20–60 ppm inhaled nitric oxide, the missing data in the patient who died after 40 patients were managed with conventional days and the patient who left the study after the treatment including digitalis, diuretics, ni- six month visit.21 Modified t tests (that is, t tests trates, oral anticoagulants, and nifedipine when with the residual variance of the analysis of indicated.18 Conventional treatment was ti- variance) were used to compare follow up trated in 3–4 weeks in order to obtain the measurements with the baseline when the F maximum clinical eVect. ratio of the analysis of variance reached a criti- At the end of this period, the patients had a cal value of p < 0.05.21 clinical evaluation, a Doppler echocardiogram, and two, six minute walk tests (on successive days). The best of the two walking tests was Results used as the baseline result. Beraprost was then The initial values for invasive haemodynamic added to the standard treatment, starting at a measurements are shown in table 1. The dose of 20 µg three to four times a day patients all had severe pulmonary hypertension (1 µg/kg/day) and progressively increasing to a with a low cardiac output and on average nor- http://heart.bmj.com/ maximum dose of 2 µg/kg/day, or as tolerated. mal right and left heart filling pressures. The The patients were followed up with a clinical right atrial pressure was above 10 mm Hg in examination, a six minute walk test, and an three patients. echocardiogram at 1, 3, 6, 9, and 12 months. In The baseline conventional treatment after addition, telephone contact was made at least the one month run in period is summarised in twice a month. table 2. Three patients were given nifedipine on The dose of beraprost was increased if there the basis of > 30% reversibility of pulmonary was clinical deterioration, in increments of vascular resistance on acute reversibility testing on October 2, 2021 by guest. Protected copyright. 5–10–µg three to four times a day until with inhaled nitric oxide. Two patients did not improvement occurred or until there were receive anticoagulant treatment because of adverse eVects. If hypotension occurred, the previous gastrointestinal bleeding. One patient other vasodilators were reduced or stopped was on prophylactic amiodarone because of before considering a stepwise reduction in the recurrent atrial fibrillation. There was no beraprost dose. The dose of diuretics was change in the clinical state of the patients dur- increased if there was weight gain and clinical ing the one month run in period. signs of right heart failure. During the The individual daily beraprost doses at one treatment period, all measurements were per- month and 12 months of treatment are shown formed 3–4 hours after the last dose of berap- in table 3.
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