EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer’s Dementia—Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Study Medication
2.3. Study Design
2.4. Blood Coagulation and Bleeding Time Tests
2.5. Statistical Analyses
- (1)
- Those taking neither ASA nor warfarin as concomitant medication;
- (2)
- Those taking ASA concomitantly;
- (3)
- Those taking warfarin concomitantly.
3. Results
3.1. Group Comparison without Concomitant Use of Anticoagulants
3.2. Group Comparison per Concomitant Intake of ASA or Warfarin
3.3. Bleeding as an Adverse Event
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Dropouts | Female | Age [Years] | Weight [kg] | Height [cm] | Body Mass Index [kg/m2] | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Group | Treatment Groups | ITT [n] | [n] | [%] | [n] | [%] | Mean | SD | Mean | SD | Mean | SD | Mean | SD |
Neither ASA nor warfarin | Placebo | 99 | 24 | 24.2 | 57 | 57.6 | 77.0 | 7.9 | 67.6 | 13.5 | 164.1 | 9.8 | 25.0 | 4.2 |
EGb 761® 120 mg | 107 | 23 | 21.5 | 54 | 50.5 | 78.1 | 6.8 | 68.6 | 13.8 | 165.1 | 10.7 | 25.1 | 4.1 | |
EGb 761® 240 mg | 119 | 20 | 16.8 | 75 | 63.0 | 78.1 | 6.8 | 65.6 | 13.9 | 162.2 | 9.7 | 24.8 | 4.1 | |
ASA | Placebo | 68 * | 13 | 19.1 | 30 | 44.1 | 78.2 | 6.7 | 72.0 | 13.0 | 166.3 | 10.6 | 26.0 | 3.9 |
EGb 761® 120 mg | 57 | 10 | 17.5 | 29 | 50.9 | 79.4 | 7.0 | 69.4 | 16.1 | 162.5 | 10.8 | 26.2 | 5.1 | |
EGb 761® 240 mg | 48 ** | 10 # | 20.8 | 21 | 43.8 | 78.0 | 7.6 | 72.6 | 13.9 | 166.1 | 9.4 | 26.2 | 3.8 | |
Warfarin | Placebo | 9 * | 2 | 22.2 | 3 | 33.3 | 78.6 | 7.2 | 73.2 | 10.4 | 171.2 | 7.9 | 24.9 | 2.6 |
EGb 761® 120 mg | 5 | 1 | 20.0 | 1 | 20.0 | 81.0 | 9.3 | 72.6 | 18.6 | 173.2 | 11.5 | 24.1 | 5.0 | |
EGb 761® 240 mg | 4 ** | 1 # | 25.0 | 1 | 25.0 | 80.0 | 8.3 | 82.5 | 14.1 | 172.0 | 11.5 | 27.8 | 3.2 |
95% CI | Difference Placebo–EGb | Difference EGb 120 mg–EGb 240 mg | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Visit | Treatment | N | Mean | SD | LL | UL | Min | Max | Mean | SD | p | Mean | SD | p |
PT [s] | ||||||||||||||
Baseline | Placebo | 93 | 10.50 | 0.81 | 10.33 | 10.67 | 9.20 | 13.50 | ||||||
EGb 761® 120 mg | 105 | 10.51 | 0.73 | 10.37 | 10.65 | 9.20 | 12.80 | −0.01 | 0.77 | 0.917 | ||||
EGb 761® 240 mg | 116 | 10.44 | 0.63 | 10.33 | 10.56 | 8.20 | 11.80 | 0.06 | 0.72 | 0.580 | 0.07 | 0.68 | 0.466 | |
Week 6 | Placebo | 85 | 10.59 | 0.75 | 10.43 | 10.75 | 8.70 | 13.80 | ||||||
EGb 761® 120 mg | 99 | 10.54 | 0.63 | 10.41 | 10.66 | 9.20 | 12.40 | 0.05 | 0.69 | 0.617 | ||||
EGb 761® 240 mg | 109 | 10.39 | 0.63 | 10.27 | 10.51 | 8.60 | 12.10 | 0.20 | 0.69 | 0.041 | 0.15 | 0.63 | 0.083 | |
Week 26 | Placebo | 82 | 10.46 | 0.87 | 10.27 | 10.65 | 8.80 | 13.80 | ||||||
EGb 761® 120 mg | 95 | 10.41 | 0.93 | 10.22 | 10.60 | 8.80 | 16.70 | 0.05 | 0.91 | 0.701 | ||||
EGb 761® 240 mg | 106 | 10.33 | 0.77 | 10.19 | 10.48 | 7.00 | 12.40 | 0.13 | 0.81 | 0.289 | 0.07 | 0.85 | 0.536 | |
INR | ||||||||||||||
Baseline | Placebo | 93 | 1.02 | 0.08 | 1.00 | 1.04 | 0.90 | 1.30 | ||||||
EGb 761® 120 mg | 105 | 1.02 | 0.07 | 1.00 | 1.03 | 0.90 | 1.20 | 0.00 | 0.08 | 0.768 | ||||
EGb 761® 240 mg | 116 | 1.01 | 0.06 | 1.00 | 1.02 | 0.80 | 1.10 | 0.01 | 0.07 | 0.410 | 0.00 | 0.07 | 0.580 | |
Week 6 | Placebo | 85 | 1.03 | 0.07 | 1.01 | 1.04 | 0.80 | 1.30 | ||||||
EGb 761® 120 mg | 99 | 1.02 | 0.07 | 1.01 | 1.04 | 0.90 | 1.20 | 0.00 | 0.07 | 0.721 | ||||
EGb 761® 240 mg | 109 | 1.01 | 0.07 | 0.99 | 1.02 | 0.80 | 1.20 | 0.02 | 0.07 | 0.057 | 0.02 | 0.07 | 0.093 | |
Week 26 | Placebo | 82 | 1.02 | 0.09 | 1.00 | 1.03 | 0.90 | 1.30 | ||||||
EGb 761® 120 mg | 95 | 1.01 | 0.09 | 1.00 | 1.03 | 0.90 | 1.60 | 0.00 | 0.09 | 0.934 | ||||
EGb 761® 240 mg | 106 | 1.00 | 0.08 | 0.99 | 1.02 | 0.70 | 1.20 | 0.01 | 0.08 | 0.216 | 0.01 | 0.08 | 0.251 | |
APTT [s] | ||||||||||||||
Baseline | Placebo | 95 | 27.03 | 2.85 | 26.45 | 27.61 | 22.00 | 36.00 | ||||||
EGb 761® 120 mg | 105 | 27.45 | 2.69 | 26.93 | 27.97 | 23.00 | 39.00 | −0.42 | 2.77 | 0.290 | ||||
EGb 761® 240 mg | 116 | 27.58 | 3.18 | 26.99 | 28.16 | 19.00 | 41.00 | −0.55 | 3.04 | 0.195 | −0.13 | 2.96 | 0.745 | |
Week 6 | Placebo | 85 | 27.72 | 2.81 | 27.11 | 28.32 | 20.00 | 36.00 | ||||||
EGb 761® 120 mg | 99 | 27.37 | 2.23 | 26.93 | 27.82 | 23.00 | 33.00 | 0.34 | 2.52 | 0.357 | ||||
EGb 761® 240 mg | 110 | 27.91 | 2.97 | 27.35 | 28.47 | 22.00 | 35.00 | −0.19 | 2.90 | 0.649 | −0.54 | 2.65 | 0.146 | |
Week 26 | Placebo | 82 | 27.43 | 2.65 | 26.84 | 28.01 | 21.00 | 33.00 | ||||||
EGb 761® 120 mg | 95 | 27.72 | 2.72 | 27.16 | 28.27 | 22.00 | 40.00 | −0.29 | 2.69 | 0.477 | ||||
EGb 761® 240 mg | 106 | 27.51 | 2.95 | 26.94 | 28.08 | 21.00 | 35.00 | −0.08 | 2.83 | 0.843 | 0.21 | 2.85 | 0.609 | |
Bleeding time [min] | ||||||||||||||
Baseline | Placebo | 56 | 4.28 | 2.03 | 3.74 | 4.82 | 0.40 | 10.00 | ||||||
EGb 761® 120 mg | 61 | 4.40 | 1.62 | 3.99 | 4.82 | 0.50 | 8.00 | −0.12 | 1.82 | 0.717 | ||||
EGb 761® 240 mg | 58 | 4.82 | 1.91 | 4.32 | 5.33 | 1.30 | 9.50 | −0.54 | 1.97 | 0.145 | −0.42 | 1.77 | 0.199 | |
Week 6 | Placebo | 50 | 3.95 | 1.91 | 3.41 | 4.49 | 0.30 | 10.50 | ||||||
EGb 761® 120 mg | 59 | 4.41 | 1.49 | 4.03 | 4.80 | 2.00 | 8.00 | −0.47 | 1.69 | 0.156 | ||||
EGb 761® 240 mg | 56 | 4.45 | 1.55 | 4.03 | 4.87 | 2.00 | 9.50 | −0.50 | 1.73 | 0.139 | −0.04 | 1.52 | 0.898 | |
Week 26 | Placebo | 47 | 4.30 | 1.55 | 3.84 | 4.76 | 0.90 | 7.30 | ||||||
EGb 761® 120 mg | 59 | 3.98 | 1.76 | 3.52 | 4.44 | 0.30 | 11.00 | 0.32 | 1.67 | 0.327 | ||||
EGb 761® 240 mg | 44 | 4.45 | 1.97 | 3.85 | 5.04 | 1.00 | 9.30 | −0.15 | 1.77 | 0.696 | −0.47 | 1.85 | 0.208 |
95% CI | Difference Placebo–EGb 761 | Difference EGb 120 mg–EGb 240 mg | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Visit | Treatment | N | Mean | SD | LL | UL | MIN | MAX | Mean | SD | p | Mean | SD | p |
PT [s] | ||||||||||||||
Baseline | Placebo | 67 | 11.42 | 5.30 | 10.13 | 12.72 | 9.40 | 44.20 | ||||||
EGb 761® 120 mg | 53 | 10.51 | 0.74 | 10.31 | 10.71 | 8.40 | 12.00 | 0.91 | 3.99 | 0.215 | ||||
EGb 761® 240 mg | 48 | 10.63 | 0.66 | 10.44 | 10.82 | 9.30 | 13.00 | 0.79 | 4.07 | 0.304 | −0.12 | 0.70 | 0.392 | |
Week 6 | Placebo | 62 | 10.83 | 2.14 | 10.29 | 11.38 | 9.10 | 26.20 | ||||||
EGb 761® 120 mg | 50 | 10.52 | 0.71 | 10.32 | 10.72 | 9.10 | 12.50 | 0.31 | 1.66 | 0.323 | ||||
EGb 761® 240 mg | 46 | 10.79 | 0.61 | 10.61 | 10.97 | 9.40 | 12.30 | 0.04 | 1.67 | 0.896 | −0.27 | 0.67 | 0.049 | |
Week 26 | Placebo | 57 | 10.93 | 2.70 | 10.22 | 11.65 | 8.90 | 26.20 | ||||||
EGb 761® 120 mg | 49 | 10.41 | 0.75 | 10.19 | 10.62 | 8.10 | 11.90 | 0.53 | 2.05 | 0.189 | ||||
EGb 761® 240 mg | 46 | 10.58 | 0.76 | 10.36 | 10.81 | 9.10 | 13.40 | 0.35 | 2.07 | 0.395 | −0.18 | 0.75 | 0.256 | |
INR | ||||||||||||||
Baseline | Placebo | 67 | 1.12 | 0.52 | 0.99 | 1.24 | 0.90 | 4.30 | ||||||
EGb 761® 120 mg | 53 | 1.02 | 0.08 | 1.00 | 1.04 | 0.80 | 1.20 | 0.10 | 0.39 | 0.162 | ||||
EGb 761® 240 mg | 48 | 1.02 | 0.07 | 1.00 | 1.04 | 0.90 | 1.30 | 0.10 | 0.40 | 0.200 | −0.00 | 0.07 | 0.789 | |
Week 6 | Placebo | 61 | 1.05 | 0.20 | 1.00 | 1.10 | 0.90 | 2.50 | ||||||
EGb 761® 120 mg | 50 | 1.02 | 0.07 | 1.00 | 1.04 | 0.90 | 1.20 | 0.03 | 0.16 | 0.254 | ||||
EGb 761® 240 mg | 46 | 1.05 | 0.06 | 1.03 | 1.06 | 0.90 | 1.20 | 0.01 | 0.16 | 0.868 | −0.03 | 0.07 | 0.037 | |
Week 26 | Placebo | 57 | 1.06 | 0.25 | 0.99 | 1.13 | 0.90 | 2.50 | ||||||
EGb 761® 120 mg | 49 | 1.01 | 0.07 | 0.99 | 1.03 | 0.80 | 1.10 | 0.05 | 0.19 | 0.207 | ||||
EGb 761® 240 mg | 46 | 1.03 | 0.07 | 1.00 | 1.05 | 0.90 | 1.30 | 0.03 | 0.20 | 0.414 | −0.02 | 0.07 | 0.291 | |
APTT [s] | ||||||||||||||
Baseline | Placebo | 67 | 28.78 | 5.54 | 27.43 | 30.13 | 22.00 | 61.00 | ||||||
EGb 761® 120 mg | 53 | 27.68 | 2.96 | 26.86 | 28.50 | 23.00 | 37.00 | 1.10 | 4.58 | 0.196 | ||||
EGb 761® 240 mg | 48 | 27.29 | 3.00 | 26.42 | 28.16 | 22.00 | 41.00 | 1.48 | 4.65 | 0.094 | 0.39 | 2.98 | 0.515 | |
Week 6 | Placebo | 62 | 28.18 | 3.01 | 27.41 | 28.94 | 23.00 | 42.00 | ||||||
EGb 761® 120 mg | 50 | 27.38 | 3.33 | 26.43 | 28.33 | 24.00 | 42.00 | 0.80 | 3.15 | 0.186 | ||||
EGb 761® 240 mg | 46 | 27.85 | 3.15 | 26.91 | 28.78 | 23.00 | 41.00 | 0.33 | 3.07 | 0.582 | −0.47 | 3.24 | 0.482 | |
Week 26 | Placebo | 57 | 28.61 | 3.36 | 27.72 | 29.51 | 24.00 | 42.00 | ||||||
EGb 761® 120 mg | 49 | 27.55 | 2.82 | 26.74 | 28.36 | 23.00 | 36.00 | 1.06 | 3.12 | 0.083 | ||||
EGb 761® 240 mg | 46 | 27.59 | 3.37 | 26.59 | 28.59 | 21.00 | 42.00 | 1.03 | 3.36 | 0.127 | −0.04 | 3.10 | 0.955 | |
Bleeding time [min] | ||||||||||||||
Baseline | Placebo | 37 | 5.13 | 2.23 | 4.39 | 5.87 | 1.50 | 13.00 | ||||||
EGb 761® 120 mg | 32 | 4.71 | 2.78 | 3.71 | 5.71 | 1.40 | 15.00 | 0.42 | 2.50 | 0.489 | ||||
EGb 761® 240 mg | 29 | 5.12 | 1.71 | 4.47 | 5.78 | 2.10 | 9.00 | 0.01 | 2.02 | 0.991 | −0.41 | 2.34 | 0.491 | |
Week 6 | Placebo | 33 | 4.61 | 1.88 | 3.95 | 5.28 | 1.50 | 9.00 | ||||||
EGb 761® 120 mg | 31 | 4.05 | 1.89 | 3.35 | 4.74 | 1.00 | 8.00 | 0.57 | 1.89 | 0.234 | ||||
EGb 761® 240 mg | 28 | 5.55 | 2.15 | 4.72 | 6.38 | 2.50 | 10.00 | −0.94 | 2.01 | 0.074 | −1.50 | 2.02 | 0.006 | |
Week 26 | Placebo | 31 | 4.57 | 2.70 | 3.58 | 5.56 | 0.90 | 16.00 | ||||||
EGb 761® 120 mg | 28 | 4.73 | 2.02 | 3.95 | 5.52 | 2.20 | 9.50 | −0.16 | 2.40 | 0.794 | ||||
EGb 761® 240 mg | 26 | 5.14 | 2.81 | 4.00 | 6.27 | 1.50 | 12.00 | −0.57 | 2.75 | 0.438 | −0.41 | 2.43 | 0.542 |
Placebo | EGb 761 120 mg | EGb 761 240 mg | Comparison EGb (Both Doses) vs. Placebo | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Visit | N | Mean [Median] | (SD) | N | Mean [Median] | (SD) | N | Mean [Median] | (SD) | p-Value | |
PT [s] | Baseline | 9 | 26.8 [19.8] | (15.8) | 5 | 24.1 [21.9] | (11.1) | 4 | 16.9 [16.7] | (4.9) | 0.346 |
Week 26 | 7 | 24.1 [26.1] | (5.1) | 4 | 23.2 [23.1] | (2.4) | 4 | 17.4 [16.8] | (3.8) | 0.136 | |
APTT [s] | Baseline | 9 | 40.4 [36.0] | (11.3) | 5 | 34.6 [32.0] | (6.1) | 4 | 35.5 [33.5] | (6.1) | 0.216 |
Week 26 | 7 | 38.7 [40.0] | (7.0) | 4 | 34.5 [35.0] | (3.0) | 4 | 36.5 [37.0] | (5.5) | 0.174 | |
INR | Baseline | 9 | 2.56 [1.90] | (1.47) | 5 | 2.34 [2.10] | (1.09) | 4 | 1.63 [1.65] | (0.46) | 0.367 |
Week 26 | 7 | 2.26 [2.40] | (0.46) | 4 | 2.20 [2.25] | (0.22) | 4 | 1.65 [1.609] | (0.34) | 0.157 |
Placebo | EGb 761 120 mg | EGb 761 240 mg | Total | |
---|---|---|---|---|
Ecchymosis | 9 | 4 | 7 | 20 |
Epistaxis | 5 | 0 | 1 | 6 |
Faecal occult blood positive | 0 | 0 | 1 | 1 |
Gastric ulcer haemorrhage | 0 | 0 | 1 | 1 |
Haematuria present | 0 | 1 | 2 | 3 |
Rectal bleeding | 0 | 4 | 1 | 5 |
Retinal haemorrhage | 0 | 1 | 0 | 1 |
Total | 14 | 10 | 13 | 37 |
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Kloft, C.; Hoerr, R. EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer’s Dementia—Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial. Healthcare 2021, 9, 1678. https://doi.org/10.3390/healthcare9121678
Kloft C, Hoerr R. EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer’s Dementia—Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial. Healthcare. 2021; 9(12):1678. https://doi.org/10.3390/healthcare9121678
Chicago/Turabian StyleKloft, Charlotte, and Robert Hoerr. 2021. "EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer’s Dementia—Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial" Healthcare 9, no. 12: 1678. https://doi.org/10.3390/healthcare9121678