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.