Low thrombin generation in postmenopausal women using estetrol

Figures & data

Table 1. Baseline characteristics by treatment group of all participants who received at least one dose of oral estetrol (E4) or placebo.

		Placebo	E4 2.5 mg	E4 5 mg	E4 10 mg	E4 15 mg
Parameter	Statistic	(n = 31)	(n = 42)	(n = 29)	(n = 34)	(n = 32)	p-Value
Age (years)	Mean (SD)	54.00 (4.70)	54.17 (4.56)	52.97 (4.32)	54.09 (4.35)	54.78 (3.92)	0.6121^a
	Median (minimum, maximum)	54 (45, 63)	54 (43, 64)	53 (46, 61)	53 (45, 64)	54 (47, 62)
Body mass index (BMI) (kg/m^2)	Mean (SD)	26.36 (3.79)	25.60 (3.69)	25.07 (3.95)	26.65 (3.72)	26.38 (4.37)	0.4653^a
	Median (minimum, maximum)	25.70 (19.90,33.60)	25.50 (19.90,34.20)	24.40 (18.90,34.30)	26.85 (19.80,35.00)	26.80 (18.30,34.50)
Smoking		7 (23%)	5 (12%)	3 (10%)	8 (24%)	2 (6%)	0.1914^b
Number of pregnancies	Mean (SD)	2.13 (0.99)	2.17 (1.31)	2.31 (1.26)	2.76 (1.16)	2.06 (1.56)
	Median (minimum, maximum)	2 (0, 4)	2 (0, 5)	2 (0, 5)	3 (0, 5)	2 (0, 8)	0.0512^c
Time since menopause (years)	Mean (SD)	5.20 (4.77)	5.21 (5.29)	3.46 (2.36)	4.61 (4.31)	4.17 (3.72)	0.5930^c
	Median	4 (1, 21)	4 (1, 28)	3 (1, 10)	3 (1, 22)	3 (1, 12)
FSH (IU/ml)	Mean (SD)	94.50 (32.14)	88.16 (29.75)	86.57 (28.11)	85.81 (21.86)	97.31 (26.43)
	Median (minimum, maximum)	81.00 (43.00,180.20)	77.60 (40.70,168.00)	84.90 (44.00,154.70)	87.90 (43.70,143.80)	95.70 (49.90,159.90)	0.3315^c
E2 (pg/ml)	n^d	13	24	13	17	17
	Mean (SD)	36.26 (27.27)	36.56 (28.65)	29.69 (21.04)	36.72 (39.13)	20.49 (9.64)
	Median (minimum, maximum)	22.40 (11.80,95.40)	21.85 (11.80,99.10)	19.10 (11.80,69.70)	23.60 (11.80,172.50)	17.00 (11.80,43.30)
Hysterectomized	All, n (%)	3 (19%)	7 (28%)	2 (15%)	4 (20%)	7 (37%)	0.5921^b
	Complete hysterectomy	1 (33%)	3 (43%)	0	2 (50%)	4 (57%)
	Partial hysterectomy	2 (67%)	1 (14%)	1 (50%)	0	2 (29%)
	Other hysterectomy	0	3 (43%)	1 (50%)	2 (50%)	1 (14%)
Selected medical history	Diabetes mellitus	0	0	1	0	1
	Hyperlipidemia	11	6	3	7	5
	Hypertension	6	6	3	6	4
	Thyroid disorders	6	10	3	3	6
Concomitant medication	All, n (%)	15 (48%)	14 (33%)	9 (31%)	16 (47%)	12 (38%)	0.4882^b
	Antidiabetics	0	0	1	0	1
	Cholesterol lowering drugs	7	8	3	9	5
	Antihypertensive drugs	9	5	3	8	5
	Thyroid therapy	6	7	3	2	5

FSH, follicle stimulating hormone; SD, standard deviation.

^aOne-way analysis of variance; ^bChi-square test; ^cKruskal-Wallis test; ^dEstradiol (E2) was only measured for participants who had their last menstruation within the last 6 and 12 months.

Figure 1. Mean (2.5th–97.5th percentile) thrombogram of the entire baseline cohort (n = 168) and mean thrombograms (95% confidence interval [CI] of the mean) after 12 weeks of treatment. Mean thrombogram of the entire baseline cohort is represented by the yellow line and 2.5th–97.5th percentiles, indicating reference ranges, are represented by yellow dotted lines. Women treated with placebo or E4 2.5 mg, 5.0 mg, 10 mg and 15 mg are represented in blue, red, orange, pink and purple, respectively. None of the mean thrombograms were outside the reference range established at baseline, demonstrating the low impact of estetrol (E4) on the entire coagulation process.

Figure 2. Spaghetti plot of individual data comparing the baseline endogenous thrombin potential (ETP), peak and mean velocity rate index (mVRI) and absolute changes from baseline versus week 12 (visit 4). Changes from baseline were assessed using ordinary one-way analysis of variance with a Dunnett’s multiple comparison test. Only differences versus placebo are reported. E4, estetrol.

Figure 3. Spaghetti plot of individual data comparing baseline lag time and time to peak and absolute changes from baseline versus week 12 (visit 4). Changes from baseline were assessed using ordinary one-way analysis of variance with a Dunnett’s multiple comparison test. Only differences versus placebo are reported. E4, estetrol.

Table 2. Thrombin generation parameters with different doses of estetrol (E4) (from 2.5 mg to 15 mg once daily) at baseline and after 12 weeks of treatment.

Parameter	Baseline	Week 12	Change from baseline
			Absolute difference	Relative difference (%)
ETP (nM*min)
E4 2.5 mg	1456 ± 219	1452 ± 234	−4 ± 160	0.18 ± 10.85
E4 5.0 mg	1405 ± 208	1450 ± 239	45 ± 186^a	3.77 ± 13.62
E4 10 mg	1387 ± 203	1428 ± 204	40 ± 143^a	3.54 ± 11.18
E4 15 mg	1457 ± 214	1558 ± 290	101 ± 145^a	6.70 ± 9.61
Placebo	1532 ± 224	1447 ± 219	−86 ± 156	−5.16 ± 10.51
Peak height (nM)
E4 2.5 mg	257 ± 54	259 ± 64	3 ± 53	2.27 ± 21. 45
E4 5.0 mg	252 ± 65	273 ± 75	21 ± 54^a	9.38 ± 22.07
E4 10 mg	243 ± 69^a	261 ± 66	17 ± 63^a	11.78 ± 30.40
E4 15 mg	259 ± 50	306 ± 63	47 ± 63^a	19.37 ± 18.18
Placebo	293 ± 66	268 ± 69	−26 ± 71	−6.90 ± 25.13
Lag time (min)
E4 2.5 mg	2.95 ± 0.41	2.80 ± 0.62	−0.15 ± 0.60	−4.28 ± 19.67
E4 5.0 mg	2.97 ± 0.49	2.75 ± 0.46	−0.22 ± 0.46^a	−6.27 ± 16.38
E4 10 mg	3.17 ± 0.59	2.82 ± 0.50	−0.34 ± 0.48^a	−9.71 ± 14.11
E4 15 mg	3.10 ± 0.63	2.72 ± 0.40	−0.38 ± 0.50^a	−10.10 ± 15.91
Placebo	2.91 ± 0.35	3.05 ± 0.69	0.14 ± 0.57	4.66 ± 19.14
Time to peak (min)
E4 2.5 mg	6.11 ± 0.86	5.94 ± 1.15	−0.17 ± 1.10	−2.00 ± 17.97
E4 5.0 mg	6.19 ± 1.07	5.77 ± 1.17	−0.42 ± 0.90 ^a	−6.14 ± 15.72
E4 10 mg	6.48 ± 1.33	5.87 ± 1.11	−0.61 ± 1.10^a	−7.77 ± 16.52
E4 15 mg	6.27 ± 1.17	5.40 ± 0.80^a	−0.87 ± 0.92^a	−11.99 ± 15.93
Placebo	5.78 ± 0.84	6.12 ± 1.41	0.36 ± 1.30	6.96 ± 21.99
mVRI (nM/min)
E4 2.5 mg	86.2 ± 33.2	90.3 ± 42.9	4.2 ± 36.4	9.44 ± 45.67
E4 5.0 mg	86.5 ± 40.0	102.1 ± 49.1	15.6 ± 35.7^a	22.81 ± 44.35
E4 10 mg	83.5 ± 44.6^a	95.1 ± 44.9	11.6 ± 44.4^a	31.19 ± 65.17
E4 15 mg	88.3 ± 37.5	121.0 ± 47.2	32.7 ± 41.3^a	46.18 ± 47.45
Placebo	110.7 ± 43.2	96.6 ± 43.0	−15.3 ± 45.6	−5.14 ± 46.46

Mean values ± standard deviations are reported. Absolute and relative changes from baseline for each treatment group are reported. Absolute changes from baseline were used for statistical evaluation of treatment effect on thrombin generation assay (TGA) parameters. ETP, endogenous thrombin potential; mVRI, mean velocity rate index.

^aDifferent from placebo, the p value had been estimated using ordinary one-way analysis of variance. A Tukey’s multiple comparisons test with a single pooled variance was run to assess the difference between the groups. p < 0.05 considered statistically significant.

Table 3. Reference intervals (2.5th–97.5th percentile of entire baseline cohort) of thrombin generation parameters and out-of-range results after 12 weeks of treatment.

Treatment	Lag time (min)	Time to peak (min)	Peak (nM)	ETP (nM*min)	mVRI (nM/min)
Reference interval (2.5th–97.5th percentile of entire baseline cohort)
Reference range (n = 168)	2.1–4.3	4.3–8.8	146–399	1013–1893	32.5–201.0
Out of reference range^a after 12 weeks of treatment, n (%)
Placebo (n = 31)	1 (3%)	1 (3%)	1 (3%)	1 (3%)	0 (0%)
E4 2.5 mg (n = 42)	5 (12%)	4 (10%)	0 (0%)	2 (5%)	1 (2%)
E4 5 mg (n = 29)	3 (10%)	2 (7%)	0 (0%)	2 (7%)	0 (0%)
E4 10 mg (n = 34)	4 (12%)	2 (6%)	1 (3%)	0 (0%)	1 (3%)
E4 15 mg (n = 32)	2 (6%)	3 (9%)	4 (13%)	3 (9%)	2 (6%)

E4, estetrol; ETP, endogenous thrombin potential; mVRI, mean velocity rate index.

^aEither 2.5th or 97.5th percentile.

Figure 4. Comparison of thrombin generation assay (TGA) parameters after 12 weeks of treatment.