Clinical Investigations: AHJ Online Exclusive
Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension
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Abstract

Background Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH). Methods To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied. Results Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites. Conclusion Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered. (Am Heart J 2002;143:e4)

Section snippets

Study design

The study was approved by the Institutional Research Ethics Review Boards of each participating institution. It used a multicenter, randomized, double-blind, placebo-controlled protocol structured to evaluate the safety and efficacy of 12 weeks of oral terbogrel therapy in 135 patients with New York Heart Association (NYHA) functional classification II and III PPH, at doses of 0 mg twice a day (bid; placebo), 100 mg bid, or 200 mg bid (45 patients per group). The primary efficacy endpoint was

Study termination and patient enrollment

The Data Safety Monitoring Board performed an interim analysis after approximately one third of the patients had completed the trial. They recommended stopping enrollment on the basis of the incidence of the significant side effect of leg pain. They also recommended that an analysis be conducted to explore the efficacy of terbogrel to determine whether to continue the study or terminate it prematurely. This analysis was conducted by the Steering Committee, which recommended premature

Discussion

With examination from an intention-to-treat perspective, with all enrolled patients included, terbogrel was ineffective as a therapeutic agent in PPH. However, the primary endpoint was a change in 6-minute walk distance, and this endpoint was greatly confounded by the unanticipated problem of leg pain. Moreover, many of the patients who remained in the study for the entire 12 weeks had at least temporarily reduced or interrupted their terbogrel intake at some time because of leg pain. This may

Acknowledgements

We thank Patricia Price and Terri Hagan for assistance with the prostaglandin assays. David Langleben, MD, is a Chercheur Boursier Clinicien (Research Scholar) of the Fonds de la Recherche en Sante du Quebec.

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Conflict of interest: Drs Langleben, Christman, Barst, Galie, Higgenbottam, Kneussl, Naeije, Simonneau, Rich, Robbins, Oudiz, McGoon, Badesch, Levy, Mehta, Seeger, and Soler were principal investigators or members of the Steering Committee of the study and, as such, received indirect support from Boehringer Ingelheim, Inc. Drs Dias and Riedel and Mr Korducki are employees of Boehringer Ingelheim, Inc.

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Reprint requests: D. Langleben, MD, Jewish General Hospital, 3755 Cote Ste, Catherine, Montreal, Quebec, Canada H3T 1E2.

E-mail: [email protected]

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