Table 2.
Association between serious bleeding events and treatment with P‐gp/CYP3A4 inhibitors in DOAC‐treated patients, Clalit, 2010‐2020
|
Controls (N = 29,764) |
Cases with serious bleeding (N = 1,587) |
OR (95% CI) | P value | Adjusted OR a (95% CI) | P value | |
|---|---|---|---|---|---|---|
| P‐gp/CYP3A4 inhibitors | ||||||
| Any P‐gp/CYP3A4 inhibitor | 1,977 (6.6) | 132 (8.3) | 1.41 (1.15–1.73) | 0.001 | 1.32 (1.07–1.61) | 0.008 |
| Amiodarone | 1,507 (5.1) | 96 (6.0) | 1.31 (1.04–1.64) | 0.021 | 1.21 (0.96–1.52) | 0.101 |
| Verapamil | 310 (1.0) | 25 (1.6) | 1.61(1.06–2.46) | 0.026 | 1.56 (1.02–2.39) | 0.037 |
| Dronedarone | 77 (0.3) | 6 (0.4) | 1.51 (0.65–3.50) | 0.337 | 1.48 (0.64–3.43) | 0.367 |
| Diltiazem | 72 (0.2) | 4 (0.3) | 1.1 (0.40–3.01) | 0.860 | 1.02 (0.37–2.82) | 0.964 |
| Clarithromycin | 30 (0.1) | 4 (0.3) | 2.67 (0.94–7.57) | 0.065 | 2.51 (0.88–7.18) | 0.086 |
| Any P‐gp/CYP3A4 inhibitor by DOAC type b | ||||||
| Dabigatran | 440 (8.1) | 31 (9.8) | 1.43 (0.94–2.17) | 0.098 | 1.33 (0.87–2.04) | 0.184 |
| Rivaroxaban | 576 (5.6) | 47 (8.5) | 1.89 (1.33–2.70) | < 0.0001 | 1.78 (1.24–2.54) | 0.002 |
| Apixaban | 961 (6.8) | 54 (7.5) | 1.15 (0.84–1.56) | 0.381 | 1.06 (0.78–1.44) | 0.716 |
| Verapamil by DOAC type b | ||||||
| Dabigatran | 87 (1.6) | 10 (3.2) | 2.35 (1.17–4.74) | 0.017 | 2.29 (1.13–4.62) | 0.021 |
| Rivaroxaban | 82 (0.8) | 9 (1.6) | 2.25 (1.11–4.55) | 0.025 | 2.18 (1.07–4.44) | 0.031 |
| Apixaban | 141 (1.0) | 6 (0.8) | 0.84 (0.37–1.92) | 0.676 | 0.81 (0.36–1.86) | 0.627 |
| Amiodarone by DOAC type b | ||||||
| Dabigatran | 325 (6) | 17 (5.4) | 0.97 (0.57–1.65) | 0.918 | 0.90 (0.53–1.53) | 0.687 |
| Rivaroxaban | 438 (4.3) | 35 (6.4) | 1.78 (1.20–2.63) | 0.004 | 1.66 (1.12–2.46) | 0.012 |
| Apixaban | 744 (5.3) | 44 (6.1) | 1.21 (0.87–1.69) | 0.259 | 1.11 (0.79–1.55) | 0.543 |
| A potential CYP3A4 inhibitor | ||||||
| Bisoporolol | 14,405 (48.4) | 819 (51.6) | 1.17 (1.05–1.29) | 0.004 | 1.15 (1.04–1.28) | 0.007 |
| Bisoprolol by DOAC type: b | ||||||
| Dabigatran | 2,344 (43.3) | 160 (50.6) | 1.36 (1.08–1.72) | 0.009 | 1.35 (1.07–1.71) | 0.012 |
| Rivaroxaban | 5,097 (49.5) | 266 (48.4) | 0.99 (0.83–1.17) | 0.873 | 0.98 (0.83–1.17) | 0.735 |
| Apixaban | 6,964 (49.6) | 393 (54.5) | 1.24 (1.06–1.45) | 0.006 | 1.22 (1.05–1.42) | 0.011 |
| P‐gp inhibitor | ||||||
| Amlodipine | 1,999 (6.7) | 88 (5.5) | 0.82 (0.65–1.04) | 0.097 | 0.80 (0.64–1.01) | 0.064 |
| Amlodipine by DOAC type b | ||||||
| Dabigatran | 451 (8.3) | 14 (4.4) | 0.52 (0.29–0.91) | 0.023 | 0.53 (0.30–0.93) | 0.027 |
| Rivaroxaban | 600 (5.8) | 25 (4.5) | 0.77 (0.50–1.19) | 0.237 | 0.76 (0.49–1.18) | 0.217 |
| Apixaban | 948 (6.7) | 49 (6.8) | 1.02 (0.74–1.39) | 0.917 | 0.97 (0.71–1.33) | 0.836 |
| Active comparators to the P‐gp/CYP3A4 inhibitors | ||||||
| Any active comparator to P‐gp/CYP3A4 inhibitors | 9,474 (31.8) | 475 (29.9) | 0.92 (0.82–1.03) | 0.149 | 0.92 (0.82–1.03) | 0.133 |
| Atenolol | 4,271 (14.3) | 217 (13.7) | 0.95 (0.82–1.10) | 0.457 | 0.94 (0.81–1.10) | 0.449 |
| Metoprolol | 1,557 (5.2) | 86 (5.4) | 1.04 (0.83–1.31) | 0.723 | 1.04 (0.83–1.30) | 0.725 |
| Carvedilol | 1,150 (3.9) | 69 (4.3) | 1.15 (0.89–1.48) | 0.283 | 1.14 (0.89–1.47) | 0.284 |
| Propranolol | 456 (1.5) | 29 (1.8) | 1.20 (0.82–1.76) | 0.353 | 1.20 (0.82–1.76) | 0.353 |
| Sotalol | 420 (1.4) | 13 (0.8) | 0.57 (0.33–1.00) | 0.050 | 0.57 (0.32–1.00) | 0.050 |
| Propafenone | 1,735 (5.8) | 62 (3.9) | 0.67 (0.52–0.87) | 0.002 | 0.67 (0.52–0.87) | 0.002 |
| Tetracyclines | 404 (1.4) | 21 (1.3) | 0.99 (0.64–1.55) | 0.970 | 0.95 (0.61–1.48) | 0.804 |
| Azithromycin | 116 (0.4) | 9 (0.6) | 1.48 (0.75–2.92) | 0.265 | 1.4 (0.71–2.78) | 0.332 |
Use of erythromycin, fluconazole, and itraconazole (0,3; 1,17; 0,2; respectively, in cases and controls); and of labetalol (1, 19) was low, and did not permit separate analysis. There was no use within cases neither controls of the strong inhibitors ketoconazole, voriconazole, ritonavir, nor of pindolol.
Within strong CYP3A4 inhibitors only clarithromycin could be evaluated and seemed to be associated with the highest risk (with large CI due to low number of cases). Verapamil, diltiazem, erythromycin, and fluconazole are known as moderate inhibitors. Amiodarone exact strength of inhibition is still "yet to‐be‐determined" in the published lists. 14 Bisporolol, is known to be metabolized partly by CYP3A4 (and partly by CYP2D6). 57 , 58 , 59 , 60 Amlodipine had been shown to affect P‐gp mediated transport, and is not a CYP3A4 inhibitor. 31 , 32
CI, confidence interval; DOAC, direct oral anticoagulant; OR, odds ratio.
Adjusted for the propensity score to receive a drug from the group.
Dabigatran: 5,411 controls, 316 cases; Rivaroxaban: 10,305 controls, 550 cases; Apixaban: 14,048 controls, 721 cases.