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Drug Watch: Prostacyclin in primary pulmonary hypertension

Primary pulmonary hypertension is a rare disease, affecting about one person in 150,000 at any one time. Its cause is not known. Blood vessels in the lungs become diseased leading to a rise in blood pressure in them, and in arteries leading to the lungs. In its milder form it can be managed with familiar drugs such as calcium antagonists and anti-coagulants, but it is often progressive, in which case treatment with prostacyclin (epoprostenol, PGI2) is sometimes used.

Patients with severe disease may be offered heart-lung transplantation. Prostacyclin is licensed as an anticoagulant for use during renal dialysis, but not for primary pulmonary hypertension. There is no evidence that the drug alters the progress of the disease; it acts as an inhibitor of platelet aggregation and may prevent pulmonary thrombosis, an important complication of the disease.

Is prostacyclin treatment effective?

Only three controlled studies comparing prostacyclin with conventional treatment which report the impact of this drug on clinical outcomes have been published. Two reported randomised trials. The first [1] showed an improvement in haemodynamic variables and symptoms, but was too short to examine survival. The second [2] showed that the addition of prostacyclin improved walking distance, quality of life and survival to twelve weeks (0/41 versus 8/40, p=0.0029). This second study is published only in abstract, making thorough appraisal impossible.

A third paper [3] investigated 44 patients at a British hospital; in 25 the decision to purchase prostacyclin treatment was made by the patients' health authority, and in 19 the decision was not to purchase, so the treatment decision was not randomised. A group of historical controls from the Mayo Clinic comprised patients studied before the drug was available. In terms of prognosis at outset the historical controls were in a more favourable position than the British patients, while the untreated British controls may have had a slightly better outlook than the treated patients.

The British patients (together) had a relative risk of death of 0.56 (95% confidence interval 0.31 to 1.00) compared with historical untreated controls from the Mayo Clinic. Among the British cohort, prostacyclin doubled the time on the waiting list for heart-lung transplantation or to death (from 8 to 17 months). Deaths differed little between groups (9/25 compared with 9/19); prostacyclin apparently increased the chances of transplantation but the numbers were very small (7/25 compared with 3/19) and the difference was not significant.

The total number of patients on prostacyclin in all these studies was 149, and the results can only be regarded as preliminary. It is not clear how the patients who were treated differed from those who were not, but such differences may explain differences in outcome. There is an obvious need for a much larger, adequately reported randomised controlled trial of prostacyclin, since random allocation is the only way to exclude differences between groups of patients. Postponing transplantation is not necessarily desirable since it leaves the patient symptomatic for longer and defers rather than removes the need for transplantation surgery, thus only helping match supply and demand of donor organs in the short term.

How much does prostacyclin cost?

A vial of prostacyclin contains 0.5 mg and costs £103. The drug is infused continuously into a central vein and the minimum requirement is two vials a day. This costs £75,800 a year. As patients deteriorate their requirement rises, sometimes up to 12 or 15 vials per day, costing up to £500,000 per year. Nearly all these costs are for patients treated outside hospital. At the moment, specialist units using prostacyclin estimate that about one patient per health authority will be recommended to receive prostacyclin at any one time. Nearly all of these are assessed for transplant, but those doing well on prostacyclin are not considered urgent cases for transplantation.

What should purchasers do?

This is a very expensive treatment for a rare but often fatal disease. The evidence of efficacy is scanty and at the moment the drug can only be used experimentally rather than as part of evaluated and accepted routine clinical practice. However, the number of patients is very small and unlikely to rise.

Purchasers should encourage the entry of patients into a large randomised controlled trial. In the meantime prostacyclin for primary pulmonary hypertension should not be purchased.

Dr Tom Dent
Senior Registrar in Public Health Medicine
Cambridge and Huntingdon Health Commission

References:

  1. LJ Rubin, J Mendoza, M Hood et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Annals of Internal Medicine 1990 112: 485-91.
  2. W Long, L Rubin, R Barst et al. Randomized trial of conventional therapy alone vs. conventional therapy plus continuous infusion of prostacyclin in primary pulmonary hypertension. American Review of Respiratory Disease 1993 149: A538.
  3. TW Higgenbottam, D Spiegelhalter, JP Scott et al. The value of prostacyclin (epoprostenol) and heart-lung transplantation for severe pulmonary hypertension. British Heart Journal 1993 70: 366-70.

Questions to be answered

Q: What need is met by this treatment?
A: Possibly increasing life span, and chance of transplantation in a group of patients with a rare disease.
Q: What happens at present?
A: Prostacyclin is only given by specialist units.
Q: What is the revenue cost per case?
A: From £75,000 to £500,000 per year per case.
Q: Will this increase effectiveness or quality.
A: On present evidence this is unlikely.
Q: Is more information needed?
A: Yes. RCT with appropriate numbers is needed.

Advice to health authorities and GP fundholders

  • Will not increase quality or effectiveness.
  • Will increase total cost of care.
  • Patients treated should be part of a well-organised RCT.




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