Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension.
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.


CONCLUSIONS
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.
Langleben
David
D
Jewish General Hospital, McGill University, Montreal, Quebec, Canada. david.langleben@mcgill.ca
Christman
Brian W
BW
Barst
Robyn J
RJ
Dias
Virgil C
VC
Galiè
Nazzareno
N
Higenbottam
Timothy W
TW
Kneussl
Meinhard
M
Korducki
Larry
L
Naeije
Robert
R
Riedel
Axel
A
Simonneau
Gerald
G
Hirsch
Andrew M
AM
Rich
Stuart
S
Robbins
Ivan M
IM
Oudiz
Ronald
R
McGoon
Michael D
MD
Badesch
David B
DB
Levy
Robert D
RD
Mehta
Sanjay
S
Seeger
Werner
W
Solèr
Markus
M
D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D016138:Walking
D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C112331:terbogrel; D013930:Thromboxane-A Synthase