ABSTRACT
AIMS: At the time of the design of the Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study in 1996, oral hormone therapy (HT) was assumed to reduce cardiovascular risk. The evidence mainly came from the effects of combined conjugated equine oestrogens plus medroxyprogesterone acetate (CEE/MPA) therapy. Other HT regimes had not been studied widely. Tibolone, a selective tissue oestrogenic activity regulator, has several effects on cardiovascular risk factors, one of which is HDL lowering. Because the overall effect of tibolone on cardiovascular risk was unknown, the OPAL study was designed. METHODS AND RESULTS: The OPAL study was a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone (2.5 mg daily) and of CEE/MPA (0.625/2.5 mg daily) over 3 years on progression of carotid intima-media thickness (CIMT) in 866 healthy post-menopausal women. The women were recruited from six US and five European centres. The primary outcome was change in mean common CIMT. Annual common CIMT progression rates in the tibolone and CEE/MPA groups were higher than in the placebo group: 0.0077 mm [95% confidence interval (CI) 0.0051-0.0103] in the tibolone group, 0.0074 mm (0.0048-0.0099) in the CEE/MPA group, and 0.0035 mm (0.009-0.0061) in the placebo group. The differences with placebo (0.0042 mm/year for tibolone and 0.0039 mm/year for CEE/MPA) were statistically significant. HDL cholesterol increased in CEE/MPA group and was lowered in the tibolone group. CONCLUSION: Both tibolone and CEE/MPA showed increased progression of common CIMT. Translation of the increased common CIMT progression of the CEE/MPA group into cardiovascular disease risk could not fully explain the observed increased cardiovascular risk as observed in the Women's Health Initiative study. This suggests that the net effect of tibolone and CEE/MPA on cardiovascular events may depend on the combined effects on the arterial wall, clotting factors, and possibly inflammation.
Subject(s)
Atherosclerosis/chemically induced , Estrogen Receptor Modulators/adverse effects , Estrogens, Conjugated (USP)/adverse effects , Medroxyprogesterone Acetate/adverse effects , Norpregnenes/adverse effects , Osteoporosis/prevention & control , Aged , Double-Blind Method , Estrogen Receptor Modulators/therapeutic use , Estrogens, Conjugated (USP)/administration & dosage , Female , Humans , Medroxyprogesterone Acetate/therapeutic use , Middle Aged , Norpregnenes/therapeutic use , Treatment Outcome , Tunica Intima/drug effects , Tunica Media/drug effectsABSTRACT
The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) trial is a three-arm, randomized, placebo-controlled, double-blind study to determine the effect of tibolone 2.5 mg (Org OD 14) and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate (0.625 mg/2.5 mg respectively) on progression of intima-media thickness of the carotid arteries and bone mineral density of the lumbar vertebrae and proximal femur in postmenopausal women. A total of 866 healthy postmenopausal women were recruited in six U.S. centers and five European centers. Duplicate carotid ultrasound examinations of the common carotid artery, the carotid bifurcation, and the internal carotid artery were performed at baseline. Single measurements of bone mineral density of the lumbar vertebrae and proximal femur were obtained at baseline. After randomization, ultrasound examinations were repeated every 6 months for 36 months following baseline, with a duplicate examination at the end of the study. Bone mineral density was measured every 12 months throughout the trial. The primary outcome is change in mean common carotid intima-media thickness (CIMT), defined as the average of the intima-media thickness measurements performed circumferentially at predefined angles for the near and far wall of 10-mm segments of the right and left distal common carotid arteries. Unique new features of the OPAL study are the specifically developed OPAL ultrasound protocol, yielding highly reproducible CIMT measurements, and the use of two experienced core laboratories for CIMT readings (one in the United States and one in Europe) with one common quality assurance and control program. The OPAL study is a large, placebo-controlled trial evaluating the effects of tibolone, as well as one of the first large randomized studies to determine the effects of continuous combined estrogen-progestin therapy on carotid atherosclerosis in healthy postmenopausal women. The OPAL study results are expected to complement other studies on atherosclerosis progression in healthy postmenopausal women.
