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Prostacyclin

From Dr Tim Higenbottam,
Regional Pulmonary Physiology Laboratory
Papworth Hospital

Re: DrugWatch - Prostacyclin (PGI2)

I read with interest the article by Dr Tom Dent who questioned the evidence that intravenous PGI2 is an effective treatment for primary pulmonary hypertension (PPH). He encourages purchasers to enter patients into a large randomised controlled trial. The evidence of efficacy is scanty he states, and the drug at the moment can only be used experimentally. Perhaps an alternative view comes closer to reality.

How common is PPH?

Each year in England & Wales, perhaps only 40 patients are diagnosed as having PPH, not the 400 patients reported by Dr Dent. Of these only a small fraction can be identified from physiological measurements as having sufficiently poor prognosis to merit consideration for heart-lung transplantation. In this group of patients PGI2 appears to be effective. Some seven years have been required to undertake the studies Dr Dent reported on a total of 149 patients, recruitment taking place both in the USA and the UK.

Large scale studies are therefore out of the question. This particular difficulty of studying a rare and fatal disease is emphasised by the fact that efficacies of the other current treatments for PPH have not yet been tested by randomised controlled trials. This includes the milder forms of treatment such as calcium antagonists and anticoagulants or invasive treatments such as transplant surgery.

What then can be concluded from our present state of understanding about the effects of PGI2 in PPH patients?

Is prostacyclin an effective treatment for PPH patients?

Randomised studies over three months comparing PGI2 with a therapy of calcium antagonists and anticoagulants showed that a physiological improvement occurred only in PGI2-treated patients [1,2]. Of interest to clinicians caring for these greatly disabled patients quality of life also improved only in those treated with PGI2. For those patients whose survival is limited it can be argued that PGI2 lessens the suffering.

Does the use of PGI2 improve survival? Dr Dent argues that differences between patients could account for the improved survival seen with PGI2 in the British study [3]. There were, however, no significant differences in the prognostic physiological measurements between the control group and the group receiving PGI2.

Other workers more recently have compared survival of PGI2-treated PPH patients with the survival of PPH patients recruited in the NIH registry study [4]. They found a substantive improvement of survival in like patients, 63% in PGI2-treated patients at 3 years compared with 41% in an historical control group (hazard ratio 2.9, CI 1.0-8.0, P=0.045 [5]). Similar historical comparisons have been used to test efficacy of transplant surgery. Why in a rare disease such as PPH should it not be equally appropriate to use this type of analytical approach to test efficacy of PGI2?

How expensive is prostacyclin?

Dr Dent reports the cost of PGI2 at £103 per vial. The cost to users of continuously infused drug is half this cost. Similar costs are also offered to clinicians in France to treat PPH patients. Initial costs are £25-35,000 a year, but may increase 10-fold in patients who have survived five to ten years. Such survival times would not have been predicted if the patients were not receiving the drug - perhaps a measurement of its efficacy in itself.

Who should then receive PGI2?

By comparison with the other treatments for PPH the evidence for efficacy of PGI2 is far from scanty, and surely can no longer be regarded as experimental. In those patients with PPH diagnosed using established criteria [4] and when physiological measurements predict a survival of less than one year, PGI2 can lessen symptoms and improve quality of life. There is also growing evidence of the efficacy of PGI2 in lengthening survival in these patients.

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. randomised trial of conventional therapy alone vs conventional therapy plus continuous infusion of prostacyclin in primary pulmonary hypertension. American Review of Respiratory Disease 1993 149:A535.
  3. TW Higenbottam, 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.
  4. GE D'Alonso, RJ Barst, SM Ayers et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Annals of Internal Medicine 1991 107: 343-49.
  5. RJ Barst, LJ Rubin, MD McGoon et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Annals of Internal Medicine 1994 121: 409-15.



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