Effects of short term and long term danazol treatment on lipoproteins, coagulation, and progression of atherosclerosis: two clinical trials in healthy volunteers and patients with hereditary angioedema.
BACKGROUND Danazol is a synthetic androgen derivative frequently used as prophylaxis in patients with hereditary angioedema (HAE) due to complement 1 esterase inhibitor deficiency. However, danazol has been reported to decrease high density lipoprotein cholesterol (HDL C) levels and to adversely affect coagulation parameters, which are considered to be proatherothrombotic. OBJECTIVE The short and long term effects of danazol were evaluated on proatherogenic intermediate end points in healthy volunteers and patients with HAE. METHODS Short term effects were evaluated in healthy men randomly assigned to 200 mg/d of danazol or placebo for 4 weeks in a crossover trial with no washout period. Long term effects of danazol on lipoproteins, coagulation, and carotid intima media thickness (CIMT) were evaluated in a cross sectional study in which patients with HAE treated with danazol, a mean dose of 170 mg/d for >or=2 years, were compared with healthy controls matched for age, sex, and body mass index (BMI) Drug tolerability was assessed by questionnaires and adherence was measured by pill count when drug bottles were returned after every study visit. RESULTS Patients in the short term study were 15 men with a mean (SD) age of 32.6 (6.9) years and BMI of 24.3 (4.1) kg/m(2) In the long term study, patients with HAE were 10 women and 7 men with a mean (SD) age of 41.1 (12.9) years and BMI of 25.4 (2.6) kg/m(2) the 17 matched controls had a mean (SD) age of 39.8 (11.8) years and BMI of 25.4 (2.6) kg/m(2) Short term danazol treatment was associated with a decrease from baseline in apolipoprotein A I of 21% and in HDL C of 23% Flow mediated dilation and coagulation parameters were unaffected after 4 weeks. Longterm danazol treatment did not adversely affect HDL C concentration (1.1 [0.5] vs baseline, 1.2 [0.5] pmol/L) HDL related transfer proteins such as paraoxonase 1 activity (92 [62] vs 80 [40] U/mM) cholesteryl ester transfer protein mass (1.5 [0.4] vs 2.2 [0.6] microg/mL) lecithin cholesterol acyltransferase activity (21.2 [4.5] vs 32.1 [7.2] nmol CE mL( 1) h( 1) plasma phospholipid transfer protein activity (15.4 [1.5] vs 14.9 [1.2] AU) and apolipoproteins between patients with HAE and controls. The mean (SD) CIMT was similar between patients with HAE and controls (0.62 [0.09] vs 0.59 [0.08] mm; P NS) However, HAE patients using danazol had increased coagulation activation when compared with controls (prothrombin fragments, 286 [119] vs 164 [57] pmol/L, P 0.002; thrombinantithrombin complex, 3.9 [1.4] vs 2.6 [1.1] microg/L, P 0.01) CONCLUSIONS Short term danazol treatment in healthy volunteers was associated with a reduction in HDL C levels without a significant effect on endothelial function or coagulation parameters. In contrast, patients with HAE treated for >2 years with danazol had increased activation of coagulation, but there were no significant differences in HDL C or CIMT compared with matched healthy controls.
Clinical therapeutics