Correspondence

Intravenous Epoprostenol for Primary Pulmonary Hypertension

N Engl J Med 1996; 334:1477-1478May 30, 1996

Article

To the Editor:

Barst et al. (Feb. 1 issue)1 report better clinical improvement and survival in 41 patients with primary pulmonary hypertension treated with a 12-week continuous intravenous infusion of epoprostenol (no deaths) than in 40 patients receiving conventional therapy (20 percent mortality). We wish to comment on the possible risks of treatment and the treatment strategy in this study.

The placement of a permanent catheter may lead to life-threatening complications, such as catheter-induced sepsis or thromboembolism (a total of five such events in this study). Selective pulmonary application of inhaled vasodilators may offer an attractive alternative, preventing the above complications of intravenous application and systemic side effects.2

The authors did not discuss whether the reaction of pulmonary vascular resistance to epoprostenol during the initial short-term infusion had any value in predicting the outcome in this study. It may be that the marked clinical improvement associated with the epoprostenol infusion occurred in a subgroup of patients in whom the pulmonary vascular resistance reacted during the initial short-term infusion and then profited overproportionally from the long-term treatment. Rich et al.3 used the reaction of pulmonary vascular resistance during a short-term infusion of calcium antagonists to assign patients with primary pulmonary hypertension to treatment with calcium-channel blockers or conventional therapy. Likewise, in pulmonary hypertension caused by intracardiac shunting defects, the detailed examination of pulmonary vascular resistance with various vasodilators has a considerable effect on decisions about surgery versus conservative management.4

We believe that cautious examination of pulmonary vascular resistance in patients with pulmonary hypertension should be used as a guide to any specific long-term therapy. Such a study design should provide important information about whether the reaction of pulmonary vascular resistance to specific vasodilators has any predictive value in determining the long-term reaction and outcome, especially since initially ineffective substances may have an effect under other circumstances.5

Finally, the identification of subgroups of patients who may not profit from a specific substance would improve overall care and prevent unnecessary treatment complications.

Ingram Schulze-Neick, M.D.
Peter E. Lange, M.D., Ph.D.
Nikolaus A. Haas, M.D.
Deutsches Herzzentrum Berlin, 13353 Berlin, Germany

5 References

1. 1

   Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301
   Full Text | Web of Science | Medline

2. 2

   Olschewski H, Walmrath D, Schermuly R, Ghofrany H, Grimminger F, Seeger W. Aerolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med (in press).
   

3. 3

   Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81
   Full Text | Web of Science | Medline

4. 4

   Schulze-Neick I, Rossaint R, Berger F, et al. Inhaled nitric oxide and intra-venous prostacyclin for pre-operative evaluation of pulmonary vascular resistance in patients with congenital heart disease. Eur Heart J 1994;15:Suppl:524-524 abstract.
   

5. 5

   Haas NA, Schulze-Neick I, Lange PE. Intratracheal prostacyclin for resuscitation in primary pulmonary hypertension. Lancet 1995;346:643-643
   CrossRef | Web of Science | Medline

To the Editor:

In the randomized, controlled trial of intravenous epoprostenol for the treatment of primary pulmonary hypertension, the infusion of epoprostenol appears to have been effective not only in enhancing survival but also in improving symptoms. These observations are not new, however. Use of a continuous intravenous infusion of epoprostenol for the treatment of primary pulmonary hypertension was first described 12 years ago.1 The relief of symptoms2 and improved survival3 have also been reported previously.

Tim Higenbottam, M.D.
University of Sheffield, Sheffield S10 2RX, United Kingdom

3 References

1. 1

   Higenbottam T, Wheeldon D, Wells F, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984;1:1046-1047
   CrossRef | Web of Science | Medline

2. 2

   Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension with intravenous epoprostenol (prostacyclin). Br Heart J 1987;57:270-278
   CrossRef | Web of Science | Medline

3. 3

   Higenbottam TW, Spiegelhalter D, Scott JP, et al. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993;70:366-370
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Professor Higenbottam deserves credit for first treating primary pulmonary hypertension with continuous intravenous epoprostenol, and we apologize for our oversight.

In response to Dr. Schulze-Neick et al.: there is no uniform agreement regarding the criteria for a response based solely on the change in pulmonary vascular resistance. According to the National Institutes of Health Registry's definition of a short-term response (more than a 20 percent decrease in total pulmonary resistance), there was no significant difference between the numbers of responders and nonresponders with the short-term epoprostenol infusion (9 nonresponders in the epoprostenol group and 15 in the conventional-therapy group, P>0.05). Furthermore, significant improvements in exercise capacity and survival were observed in the epoprostenol-treated patients, even in the absence of a short-term hemodynamic response (as defined above). In addition, we found no differences between the two treatment groups in any of the hemodynamic measurements that have been shown to predict survival in patients with primary pulmonary hypertension (mean pulmonary arterial pressure, mean right atrial pressure, cardiac index, and mixed venous oxygen saturation, as shown in Table 2 of our article) in response to the short-term infusion of epoprostenol. Thus, unlike the situation with calcium-channel–blocker therapy in which short-term responses are predictive of the long-term response,1 the absence of a short-term response to epoprostenol does not preclude long-term improvement with continuous intravenous treatment.2-4

Aerosolized epoprostenol and inhaled nitric oxide offer theoretical advantages that may reduce the complications of continuous intravenous epoprostenol therapy. To date, there have been several reports demonstrating the short-term safety and efficacy of nebulized epoprostenol and inhaled nitric oxide, and there is one case report of long-term nitric oxide inhalation used as a bridge to transplantation.5 Considering the published experience and the potential risks and benefits, however, we currently recommend therapy with continuous intravenous epoprostenol for patients with severe primary pulmonary hypertension that is refractory to conventional medical therapy.

Robyn J. Barst, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032

Lewis J. Rubin, M.D.
University of Maryland, Baltimore, MD 21201

5 References

1. 1

   Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81
   Full Text | Web of Science | Medline

2. 2

   Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med 1990;112:485-491
   Web of Science | Medline

3. 3

   Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409-415
   Web of Science | Medline

4. 4

   Butt AY, Cremona G, Takao M, Higenbottam TW. Acute vasodilatory responsiveness in severe pulmonary hypertension (SPH) and treatment with continuous prostacyclin (PGI₂) infusion. J Am Coll Cardiol 1994;23:375A-375A abstract.
   

5. 5

   Snell GI, Salamonsen RF, Bergin P, Esmore DS, Khan S, Williams TJ. Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1263-1266
   Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Zeenat Safdar. (2011) Treatment of pulmonary arterial hypertension: The role of prostacyclin and prostaglandin analogs. Respiratory Medicine 105:6, 818-827
   CrossRef

2. 2

   Meredith E Pugh, Anna R Hemnes. (2010) Pulmonary hypertension in women. Expert Review of Cardiovascular Therapy 8:11, 1549-1558
   CrossRef

3. 3

   Robert Tulloh. (2006) Management and therapeutic options in pediatric pulmonary hypertension. Expert Review of Cardiovascular Therapy 4:3, 361-374
   CrossRef

4. 4

   Robert M.R. Tulloh. (2005) Congenital heart disease in relation to pulmonary hypertension in paediatric practice. Paediatric Respiratory Reviews 6:3, 174-180
   CrossRef