Title:

Sex differences in spontaneous reports on adverse bleeding events of antithrombotic treatment

Journal:

European Journal of Clinical Pharmacology

Authors:Diana M Rydberg, MD1,2, Lennart Holm, RN2,9, Stefan Mejyr, RN2, DesiréeLoikas, MSc Pharm5,8, Karin Schenck-Gustafsson, MD, PhD3,4, Mia von Euler, MD, PhD2,3,6,7, BjörnWettermark, MScPharm, PhD5,8, Rickard E Malmström MD, PhD1,2

Author Affiliations: 1Clinical Pharmacology, Department of Medicine Solna, KarolinskaInstitutet;2Clinical Pharmacology, Drug Safety and Evaluation Sector, Karolinska University Hospital Solna; 3Centre for Gender Medicine, KarolinskaInstitutet; 4Department of Medicine Solna, Cardiology Unit, KarolinskaInstitutet; 5Public Healthcare Services Committee, Stockholm County Council; 6Karolinska Institutet Stroke Research Network at Södersjukhuset 7Department of Clinical Science and Education, Södersjukhuset, KarolinskaInstitutet; 8Centre for Pharmacoepidemiology (CPE), Department of Medicine Solna, Clinical Epidemiology Unit, KarolinskaInstitutet, Stockholm;9Department of Rational Use of Medicine, Medical Products Agency, Uppsala, Sweden.

Corresponding author’s email:

Appendix

Suppl. table 1. Reports and exposure data for clopidogrel (DDDs)

Number of 100 DDDs / Total reports with bleeding events1 / RR adjusted for nr of 100 DDDs2 (CI3) / Serious reports with bleeding events / RR adjusted for nr of 100 DDDs2 (CI3)
1999-2010
Total / 2274 322 / 219 / 194
Women / 940 348 / 93 / 78
Men / 1 332 685 / 126 / 116
RR2 / 1.05
(0.80-1.37) / 0.95
(0.72-1.27)
2005-2010
Total / 694 690 / 139 / 120
Women / 279 728 / 64 / 53
Men / 414 962 / 75 / 67
RR2 / 1.27
(0.91-1.77) / 1.17
(0.82-1.68)

1 For details on reported events, see Table 4.

2 RR women vs men

30.95 Confidence Interval

Suppl. table 2. Reports and exposure data for low-dose aspirin (DDDs)

Number of 100 DDDs / Total reports with bleeding events1 / RR adjusted for nr of 100 DDDs2 (CI3) / Serious reports with bleeding events / RR adjusted for nr of 100 DDDs2 (CI3)
1999-2010
Total / 50 490 145 / 676 / 625
Women / 23957 367 / 293 / 270
Men / 26508 732 / 383 / 355
RR2 / 0.85
(0.73-0.99) / 0.84
(0.72-0.99)
2005-2010
Total / 12919 585 / 417 / 372
Women / 6108 704 / 178 / 156
Men / 6810 881 / 239 / 216
RR2 / 0.83
(0.68-1.01) / 0.81
(0.66-0.99)

1 For details on reported events, see Table 5.

2 RR women vs men

30.95 Confidence Interval

Suppl. table 3. Reports and exposure data for warfarin (DDDs)

Number of 100 DDDs / Total reports with bleeding events1 / RR adjusted for nr of 100 DDDs2 (CI3) / Serious reports with bleeding events / RR adjusted for nr of 100 DDDs2 (CI3)
1999-2010
Total / 5785 407 / 1386 / 1334
Women / 2188 131 / 618 / 598
Men / 3593 086 / 768 / 736
RR2 / 1.32
(1.19-1.47) / 1.33
(1.20-1.49)
2005-2010
Total / 1 561 255 / 717 / 677
Women / 583 431 / 302 / 290
Men / 977 824 / 415 / 387
RR2 / 1.22
(1.05-1.41) / 1.26
(1.08-1.46)

1 For details on reported events, see Table 6.

2 RR women vs men

30.95 Confidence Interval

Suppl. table 4. Clopidogrel and co-medication in reports with bleeding events 20050701-2010

Total reports / Serious reports
Women / Men / RR6 / Women / Men / RR6
Clopidogrel / 64 / 75 / NA / 53 / 67 / NA
Co-medication / Low-dose aspirin / 38 (59%) / 52 (69%) / 0.86
(0.67-1.10) / 32 (60%) / 45 (67%) / 0.90
(0.68-1.18)
Heparin/LMWH1 / 24 (38%) / 27 (36%) / 1.04
(0.67-1.61) / 21 (40%) / 23 (34%) / 1.15
(0.72-1.85)
Warfarin / 5 (8%) / 10 (13%) / 0.59
(0.21-1.63) / 4 (8%) / 8 (12%) / 0.63
(0.20-1.99)
Other antithrombotics2 / 7 (11%) / 9 (12%) / 0.91
(0.36-2.31) / 5 (9%) / 9 (13%) / 0.70
(0.25-1.97)
NSAIDs3 / 3 (5%) / 5 (7%) / 0.70
(0.17-2.83) / 3 (6%) / 5 (7%) / 0.76
(0.17-2.83)
Antidepressants4 / 4 (6%) / 2 (3%) / 2.34
(0.44-12.38) / 4 (8%) / 1 (2%) / 5.06
(0.58-43.91)
Corticosteroids5 / 0 / 1 (1%) / NA / 0 / 0 / NA

1ATC-code B01AB. Reports included: heparin and LMWH (Low Molecular Weight Heparin);enoxaparin, dalteparin, tinzaparin

2 ATC-code B01A. Reports included:fondaparinux, abciximab, eptifibatide, tirofiban, tenecteplase, reteplase, alteplase and ATC-code N02BA01; high-dose aspirin

3ATC-code M01A (excl. M01AX05). Reports included:diclofenac, diclofenacin combination, ibuprofen, naproxen, etoricoxib, sulindac

4ATC-codes N06AA, N06AB, N06AX. Reports included: citalopram, duloxetine, sertraline

5ATC-code H02A. Report included:prednisolone

6RR women vs men (0.95 Confidence Interval)

Suppl. table 5. Low-dose aspirin and co-medication in reports with bleeding events 20050701-2010

Total reports / Serious reports
Women / Men / RR6 / Women / Men / RR6
Low-dose aspirin / 178 / 239 / NA / 156 / 216 / NA
Co-medication / Clopidogrel / 38 (21%) / 52 (22%) / 0.98
(0.68-1.42) / 32 (21%) / 45 (21%) / 0.98
(0.66-1.47)
Heparin/LMWH1 / 31 (17%) / 34 (14%) / 1.22
(0.78-1.91) / 29 (19%) / 27 (13%) / 1.49
(0.92-2.41)
Warfarin / 24 (13%) / 49 (21%) / 0.66
(0.42-1.03) / 22 (14%) / 44 (20%) / 0.69
(0.43-1.11)
Other antithrombotics2 / 8 (4%) / 17 (7%) / 0.63
(0.28-1.43) / 7 (4%) / 16 (7%) / 0.61
(0.26-1.44)
NSAIDs3 / 30 (17%) / 19 (8%) / 2.12
(1.23-3.64) / 27 (17%) / 18 (8%) / 2.08
(1.19-3.64)
Antidepressants4 / 20 (11%) / 7 (3%) / 3.84
(1.66-8.87) / 19 (12%) / 6 (3%) / 4.38
(1.79-10.72)
Corticosteroids5 / 8 (4%) / 7 (3%) / 1.53
(0.57-4.15) / 8 (5%) / 6 (3%) / 1.85
(0.65-5.21)

1 ATC-code B01AB. Reports included: LMWH (Low Molecular Weight Heparin);enoxaparin, dalteparin, tinzaparin

2 ATC-code B01A. Reports included: dipyridamole, prasugrel, fondaparinux,dabigatran,abciximab, eptifibatide, tirofiban, tenecteplase, reteplase, alteplase and ATC-code N02BA01; high-dose aspirin and ATC-code N02BA51; high-dose aspirin in combination

3ATC-code M01A (excl. M01AX05). Reports included: naproxen, etoricoxib, diclofenac, diclofenac in combination, celecoxib, nabumetone, ketoprofen, ibuprofen, indometacin, sulindac

4ATC-codes N06AA, N06AB, N06AX. Reports included:citalopram, duloxetine, sertraline, clomipramine

5ATC-code H02A. Reports included:prednisolone, betamethasone

6RR women vs men (0.95 Confidence Interval)

Suppl. table 6. Warfarin and co-medication in reports with bleeding events 20050701-2010

Total reports / Serious reports
Women / Men / RR8 / Women / Men / RR8
Warfarin / 302 / 415 / NA / 290 / 387 / NA
Co-medication / Low-dose aspirin / 23 (8%) / 49 (12%) / 0.65
(0.40-1.03) / 21 (7%) / 44 (11%) / 0.64
(0.39-1.05)
Heparin/LMWH1 / 14 (5%) / 22 (5%) / 0.87
(0.45-1.68) / 14 (5%) / 16 (4%) / 1.2
(0.60-2.43)
Clopidogrel / 5 (2%) / 10 (2%) / 0.69
(0.24-1.99) / 4 (1%) / 8 (2%) / 0.67
(0.21-2.19)
Other antithrombotics2 / 2 (<1%) / 0 (0%) / NA / 1 (<1%) / 0 (0%) / NA
NSAIDs3 / 4 (1%) / 6 (1%) / 0.92
(0.26-3.22) / 4 (1%) / 6 (2%) / 0.89
(0.25-3.12)
Antidepressants4 / 12 (4%) / 8 (2%) / 2.06
(0.85-4.98) / 11 (4%) / 7 (2%) / 2.10
(0.82-5.34)
Corticosteroids5 / 3 (<1%) / 2 (<1%) / 2.06
(0.35-12.26) / 3 (1%) / 1 (<1%) / 4.00
(0.42-38.29)
Cotrimoxazole6 / 1 (<1%) / 1 (<1%) / 1.37
(0.09-21.88) / 1 (<1%) / 1 (<1%) / 1.33
(0.08-21.25)
PPIs7 / 1 (<1%) / 1 (<1%) / 1.37
(0.09-21.88) / 1 (<1%) / 1 (<1%) / 1.33
(0.08-21.25)

1 ATC-code B01AB. Reports included: heparin and LMWH (Low Molecular Weight Heparin);enoxaparin, dalteparin, tinzaparin

2 ATC-code B01A. Reports included: fondaparinux and ATC-code N02BA01; high-dose aspirin

3ATC-code M01A (excl. M01AX05). Reports included:diclofenac, ibuprofen, nabumetone, naproxen, celecoxib

4ATC-codes N06AA, N06AB, N06AX. Reports included:citalopram, clomipramine, duloxetine, sertraline, venlafaxine, mirtazapine

5ATC-code H02A. Reports included:prednisolone, methylprednisolone

6ATC-code J01E. Reports included:trimethoprim, trimethoprim-sulfamethoxazole

7ATC-code A02BC, A02BD. Reports included: omeprazole, esomeprazole in combination

8RR women vs men (0.95 Confidence Interval)

Suppl. table 7a

Number of patients that, at least once during July 2005-December 2010, dispensed clopidogrel and the proportion of these patients with warfarin or low-dose aspirin or heparin/LMWH or any other antithrombotic agent the same day or within six months

Clopidogrel / Clopidogrel and warfarin / Clopidogrel and low-dose aspirin / Clopidogrel and heparin/LMWH / Clopidogrel and any antithrombotic agent1
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 157 179 / 2840
(1.8 %) / 12281
(8.2 %) / 91116
(58 %) / 131786
(84 %) / 2262
(1.4 %) / 9630
(6.1 %) / 94 087
(60 %) / 137806
(88 %)
Women / 59495 / 729
(1.2 %) / 4137
(7.0 %) / 30351
(51 %) / 46703
(79 %) / 802
(1.3 %) / 3769
(6.3 %) / 31 443
(53 %) / 49508
(83 %)
Men / 97684 / 2111
(2.2 %) / 8684
(8.9 %) / 60765
(62 %) / 85083
(87 %) / 1460
(1.5 %) / 5861
(6.0 %) / 62 644
(64 %) / 88298
(90 %)
RR2 / NA / 0.57 / 0.78 / 0.82 / 0.90 / 0.90 / 1.10 / 0.82 / 0.92
CI3 / NA / 0.52-0.62 / 0.75-0.81 / 0.81-0.83 / 0.90-0.91 / 0.83-0.98 / 1.01-1.10 / 0.82-0.83 / 0.92-0.92

1Clopidogrel, low-dose aspirin, warfarin or any other antithrombotic agent with ATC-code B01A

2Women vs men

30.95 Confidence Interval of the RRs

Suppl. table 7b

Number of patients that, at least once during July 2005-December 2010, dispensed clopidogrel and the proportion of these patients with NSAIDs or antidepressants or corticosteroids or PPIs the same day or within six months

Clopidogrel / Clopidogrel and NSAIDs1 / Clopidogrel and antidepressants2 / Clopidogrel and corticosteroids3 / Clopidogrel and PPI4
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 157 179 / 7 624
(4.9 %) / 37 804
(24 %) / 16 262
(10 %) / 32 051
(20 %) / 7 288
(4.6 %) / 23 630
(15 %) / 34 373
(22 %) / 63508
(40 %)
Women / 59495 / 3193
(5.4 %) / 15 204
(26 %) / 8 763
(15 %) / 16 623
(28 %) / 3 761
(6.3 %) / 11 231
(19 %) / 15250
(26 %) / 27758
(47 %)
Men / 97684 / 4 431
(4.5 %) / 22 600
(23 %) / 7 499
(7.7 %) / 15 428
(16 %) / 3 527
(3.6 %) / 12 399
(13 %) / 19 123
(20 %) / 35750
(37 %)
RR5 / NA / 1.18 / 1.10 / 1.92 / 1.77 / 1.75 / 1.49 / 1.31 / 1.27
CI6 / NA / 1.13-1.24 / 1.09-1.12 / 1.86-1.98 / 1.74-1.80 / 1.67-1.83 / 1.45-1.52 / 1.29-1.33 / 1.26-1.29

1ATC-code M01A (excl. M01AX05)

2 ATC-codes N06AA, N06AB, N06AX

3ATC-code H02A

4ATC-code A02BC, A02BD

5Women vs men

60.95 Confidence Interval of the RRs

Suppl. table 8a

Number of patients that, at least once during July 2005 – December 2010, dispensed low-dose aspirin and the proportion of these patients with warfarin or clopidogrel or heparin/LMWH or any other antithrombotic agent the same day or within six months

Low-dose aspirin / Low-dose aspirin and warfarin / Low-dose aspirin and clopidogrel / Low-dose aspirin and heparin/LMWH / Low-dose aspirin and any antithrombotic agent1
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 1082 352 / 17888
(1.7 %) / 107957
(10 %) / 91116
(8.4 %) / 131786
(12 %) / 14448
(1.3 %) / 87948
(8.1 %) / 155161
(14 %) / 323806
(30 %)
Women / 521201 / 5292
(1.0 %) / 44008
(8.4 %) / 30351
(5.8 %) / 46703
(9.0 %) / 7767
(1.5 %) / 44472
(8.5 %) / 57815
(11 %) / 136 802 (8.5 %)
Men / 561151 / 12596
(2.2 %) / 63949
(11 %) / 60765
(11 %) / 85083
(15 %) / 6681
(1.2 %) / 43476
(7.7 %) / 97346
(17 %) / 187 004 (7.7 %)
RR2 / NA / 0.45 / 0.74 / 0.54 / 0.59 / 1.25 / 1.10 / 0.64 / 0.79
CI3 / NA / 0.44-0.47 / 0.73-0.75 / 0.53-0.54 / 0.58-0.60 / 1.21-1.29 / 1.09-1.12 / 0.63-0.65 / 0.78-0.79

1Low-dose aspirin, warfarin, clopidogrel or any other antithrombotic agent with ATC-code B01A

2Women vs men

30.95 Confidence Interval of the RRs

Suppl. table 8b

Number of patients that, at least once during July 2005-December 2010, dispensed low-dose aspirin and the proportion of these patients with NSAIDs or antidepressants or corticosteroids or PPI the same day or within six months

Low-dose aspirin / Low-dose aspirin and NSAIDs1 / Low-dose aspirin and antidepressants2 / Low-dose aspirin and corticosteroids3 / Low-dose aspirin and PPIs4
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 1082 352 / 159 042
(15 %) / 396 688
(37 %) / 204 253
(19 %) / 276 863
(26 %) / 80 546
(7.4 %) / 187 531
(17 %) / 258354
(24 %) / 389298
(35 %)
Women / 521201 / 81158
(16 %) / 194 705
(37 %) / 124 525
(24 %) / 165 035
(32 %) / 44 702
(8.6 %) / 99 135
(19 %) / 135331
(26 %) / 202379
(39 %)
Men / 561151 / 77 884
(14 %) / 201 983
(36 %) / 79 728
(14 %) / 111 828
(20 %) / 35 844
(6.4 %) / 88 396
(16 %) / 123023
(22 %) / 186919
(33 %)
RR5 / NA / 1.12 / 1.04 / 1.68 / 1.59 / 1.34 / 1.21 / 1.18 / 1.17
CI6 / NA / 1.11-1.13 / 1.03-1.04 / 1.67-1.70 / 1.58-1.60 / 1.32-1.39 / 1.20-1.22 / 1.18-1.19 / 1.16-1.17

1ATC-code M01A (excl. M01AX05)

2 ATC-codes N06AA, N06AB, N06AX

3ATC-code H02A

4ATC-code A02BC, A02BD

5Women vs men

60.95 Confidence Interval of the RRs

Suppl. table 9a

Number of patients that, at least once during July 2005 – December 2010, dispensed warfarin and the proportion of these patients with clopidogrel or low-dose aspirin or heparin/LMWH or any other antithrombotic agent the same day or within six months

Warfarin / Warfarin and clopidogrel / Warfarin and low-dose aspirin / Warfarin and heparin/LMWH / Warfarin and any antithrombotic agent1
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 271 003 / 2840
(1.0 %) / 12821
(4.7 %) / 17 888
(8.4 %) / 107957
(40 %) / 48537
(18 %) / 101151
(37 %) / 65946
(24 %) / 179644
(66 %)
Women / 113 627 / 729
(0.6 %) / 4137
(3.6 %) / 5 292
(4.7 %) / 44008
(39 %) / 20759
(18 %) / 42360
(37 %) / 25982
(23 %) / 74846
(66 %)
Men / 157 376 / 2111
(1.3 %) / 8684
(5.5 %) / 12596
(11 %) / 63949
(41 %) / 27778
(18 %) / 58791
(37 %) / 39964
(25 %) / 104798
(67 %)
RR2 / NA / 0.48 / 0.66 / 0.58 / 0.95 / 1.04 / 1.00 / 0.90 / 0.99
CI3 / NA / 0.44-0.52 / 0.64-0.68 / 0.56-0.60 / 0.94-0.96 / 1.02-1.05 / 0.99-1.01 / 0.89-0.91 / 0.98-0.99

1Warfarin, clopidogrel, low-dose aspirin or any other antithrombotic agent with ATC-code B01A

2Women vs men

30.95 Confidence Interval of the RRs

Suppl. table 9b

Number of patients that, at least once during July 2005-December 2010, dispensed warfarin and the proportion of these patients with NSAIDs or antidepressants or corticosteroids or cotrimoxazole or PPIs the same day or within six months

Warfarin and NSAIDs1 / Warfarin and antidepressants2 / Warfarin and corticosteroids3 / Warfarin and cotrimoxazole4 / Warfarin and PPIs5
Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months / Same
day / Six
months
Total Rx / 11 171
(4.1 %) / 59 457
(22 %) / 32 797
(12 %) / 55 337
(20 %) / 21 009
(7.8 %) / 54 827
(20 %) / 3 143
(1.2 %) / 27 009
(10 %) / 45701
(17 %) / 85136
(31 %)
Women / 4 374
(3.8 %) / 24 961
(22 %) / 18 314
(16 %) / 30 319
(27 %) / 10 286
(9.1 %) / 25 538
(22 %) / 1 817
(1.6 %) / 15 376
(14 %) / 21360
(19 %) / 40030
(35 %)
Men / 6 797
(4.3 %) / 34 496
(22 %) / 14 483
(9.2 %) / 25 018
(16 %) / 10 723
(6.8 %) / 29 289
(19 %) / 1 326
(0.8 %) / 11 633
(7.4 %) / 24341
(15 %) / 45106
(29 %)
RR6 / 0.89 / 1.00 / 1.75 / 1.68 / 1.33 / 1.21 / 1.90 / 1.83 / 1.22 / 1.23
CI7 / 0.86-0.93 / 0.99-1.02 / 1.72-1.79 / 1.65-1.70 / 1.29-1.36 / 1.19-1.23 / 1.77-2.04 / 1.79-1.87 / 1.20-1.24 / 1.22-1.24

1ATC-code M01A (excl. M01AX05)

2 ATC-codes N06AA, N06AB, N06AX

3ATC-code H02A

4ATC-code J01E

5ATC-code A02BC, A02BD

6Women vs men

70.95 Confidence Interval of the RRs