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Survival in Primary Pulmonary Hypertension with Long-Term Continuous Intravenous Prostacyclin

Robyn J. Barst, MD; Lewis J. Rubin, MD; Michael D. McGoon, MD; Edgar J. Caldwell, MD; Walker A. Long, MD; and Paul S. Levy, ScD
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From the Columbia University College of Physicians and Surgeons, New York, New York; the University of Maryland Medical System, Baltimore, Maryland; Mayo Clinic, Rochester, Minnesota; Maine Medical Center, Portland, Maine; Burroughs Wellcome Co., Research Triangle Park, North Carolina; University of Illinois, Chicago, Illinois. Requests for Reprints: Robyn J. Barst, MD, Columbia University College of Physicians and Surgeons, Division of Pediatric Cardiology, 3959 Broadway, New York, NY 10032. Acknowledgments: The authors thank Jillian Kirkpatrick, Michele Hood, Lori Hartle, Cathy Severson, and Beth Vogel for technical assistance. Grant Support: In part by a grant from Burroughs Wellcome Co., Research Triangle Park, North Carolina. Dr. Rubin is the recipient of an Academic Award in Vascular Disease from the National Heart, Lung, and Blood Institute, National Institutes of Health.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(6):409-415. doi:10.7326/0003-4819-121-6-199409150-00003
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Objective: To evaluate the effects of long-term intravenous infusion of prostacyclin on exercise capacity, hemodynamics, and survival in patients with primary pulmonary hypertension.

Design: Open, multicenter, uncontrolled trial.

Setting: Four referral centers.

Patients: 18 patients with primary pulmonary hypertension: 1 New York Heart Association (NYHA) class II patient, 13 NYHA class III patients, and 4 NYHA class IV patients.

Interventions: Continuous intravenous prostacyclin administered by portable infusion pumps. All patients were treated with anticoagulant agents.

Measurements and Main Results: With the 6-minute walk used to evaluate exercise capacity, patients could walk on average more than 100 meters farther after prostacyclin therapy was initiated (distance at 6 months, 370 ± 119 meters compared with 264 ± 160 meters at baseline; P < 0.001; distance at 18 months, 408 ± 138 meters; P = 0.02 compared with baseline). Hemodynamics were improved at 6 months: The cardiac index increased 18% (95% CI, 0.1% to 36.7%; P = 0.02), and mean pulmonary artery pressure and total pulmonary resistance decreased 9% (CI, 1.4% to 15.7%; P = 0.03) and 26% (CI, 6.1% to 46.3%; P = 0.02), respectively, compared with baseline. The improvements in cardiac index and total pulmonary resistance were maintained at 12 months (27% increase [CI, 1.3% to 51.9%; P = 0.05] and 32% decrease [CI, 9.7% to 53.6%; P = 0.02] compared with baseline, respectively). Survival was improved in NYHA class III and IV patients who received continuous prostacyclin (n = 17; follow-up, 37 to 69 months) when compared with historical controls who received standard therapy (National Institutes of Health Primary Pulmonary Hypertension Registry, n = 31, P = 0.045). Kaplan-Meier estimates of 1-, 2-, and 3-year survival rates for the patients treated with prostacyclin were 86.9%, 72.4%, and 63.3%, respectively, compared with 77.4%, 51.6%, and 40.6% for the historical control group (hazard ratio, 2.9 [CI, 1.0 to 8.0; P = 0.045]). Serious complications attributable to the drug and delivery system included two deaths and seven episodes of nonfatal sepsis in three patients.

Conclusions: Continuous intravenous prostacyclin resulted in sustained clinical and hemodynamic improvement and probably in improved survival in patients with severe primary pulmonary hypertension. Despite potentially serious complications, long-term prostacyclin may be especially helpful in seriously ill patients awaiting transplantation.


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Figure 1.
Effect of prostacyclin on exercise capacity.PP

Exercise capacity was evaluated on the basis of the 6-minute walk test. Baseline values are distances walked before starting therapy with continuous prostacyclin. Data are presented as the mean ± SD; < 0.001 at 6 months and = 0.02 at 18 months compared with baseline.

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Figure 2.
Individual patient treatment outcome while receiving long-term therapy with continuous intravenous prostacyclin.

All eight patients listed for transplantation did have transplantation. Four patients (patients 2, 3, 5, and 6) had a heart and lung transplantation, 3 patients (patients 9, 12, and 16) had single lung transplantation and 1 patient (patient 11) had bilateral lung transplantation. Two of the 4 patients who died while receiving continuous prostacyclin infusion (patients 1 and 13) declined transplantation.

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Figure 3.
Comparison of survival probabilities between patients treated with prostacyclin and historical controls.nnP

Kaplan-Meier observed survival probability curves for NYHA class III and IV patients treated with prostacyclin ( = 17) and historical controls from the NIH Registry (NYHA class III and IV patients receiving standard therapy including anticoagulant agents, = 31). Survival function was calculated at 6-month intervals for 5 years. Survival was significantly improved in the patients treated with prostacyclin ( = 0.045). The 1-, 2-, and 3-year predicted survival rates estimated by the NIH Primary Pulmonary Hypertension Registry Equation for the patients treated with prostacyclin were 63.2%, 50.4%, and 41.1%, respectively; for the historical controls, the predicted survival rates were 65.2%, 52.1% and 42.4%, respectively.

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