Table 3.
Association between new CVA/systemic embolism and treatment with P‐gp/CYP3A4 inducers in DOAC‐treated patients, Clalit, 2010–2020
|
Controls (N = 21,685) |
Cases with CVA/SE (N = 1,116) |
OR (95% CI) | P value | Adjusted OR a (95% CI) | P value | |
|---|---|---|---|---|---|---|
| P‐gp/CYP3A4 inducers | ||||||
| Any P‐gp/CYP3A4 inducer | 344 (1.6) | 39 (3.5) | 2.27 (1.62–3.18) | < 0.0001 | 2.18 (1.55–3.06) | < 0.0001 |
| Carbamazepine | 80 (0.4) | 9 (0.8) | 2.19 (1.10–4.39) | 0.027 | 2.15 (1.07–4.30) | 0.031 |
| Phenytoin | 57 (0.3) | 14 (1.3) | 4.76 (2.64–8.61) | < 0.0001 | 4.46 (2.46–8.08) | < 0.0001 |
| Phenobarbital | 19 (0.1) | 2 (0.2) | 2.11 (0.49–9.04) | 0.317 | 1.91 (0.44–8.22) | 0.386 |
| Primidone | 75 (0.3) | 6 (0.5) | 1.60 (0.70–3.68) | 0.269 | 1.51 (0.65–3.48) | 0.336 |
| Topiramate | 32 (0.1) | 2 (0.2) | 1.21 (0.29–5.07) | 0.794 | 1.21 (0.29–5.08) | 0.792 |
| Hyperici herba | 84 (0.4) | 6 (0.5) | 1.43 (0.62–3.28) | 0.399 | 1.37 (0.60–3.13) | 0.463 |
| Rifampicin | 4 (0.02) | 1 (0.1) | 5.00 (0.56–44.73) | 0.150 | 5.23 (0.58–46.83) | 0.139 |
| Any P‐gp/CYP3A4 inducer by DOAC type: b | ||||||
| Dabigatran | 99 (2.3) | 14 (6.0) | 2.77 (1.55–4.95) | 0.001 | 2.59 (1.44–4.65) | 0.001 |
| Rivaroxaban | 124 (1.8) | 13 (3.7) | 2.13 (1.19–3.82) | 0.011 | 2.02 (1.12–3.62) | 0.019 |
| Apixaban | 121 (1.2) | 12 (2.3) | 2.0 (1.10–3.64) | 0.023 | 1.99 (1.10–3.63) | 0.024 |
| Other antiepileptics of interest | ||||||
| Valproic acid | 109 (0.5) | 15 (1.3) | 2.58 (1.50–4.45) | 0.001 | 2.38 (1.37–4.12) | 0.002 |
| Levetiracetam | 74 (0.3) | 9 (0.8) | 2.38 (1.19–4.75) | 0.014 | 2.26 (1.13–4.54) | 0.021 |
| Active comparators to the P‐gp/CYP3A4 inducers | ||||||
| Any active comparator to P‐gp/CYP3A4 inducers | 1,238 (5.7) | 75 (6.7) | 1.19 (0.94–1.52) | 0.152 | 1.15 (0.90–1.47) | 0.267 |
| Lamotrigine | 109 (0.5) | 8 (0.7) | 1.46 (0.71–3.01) | 0.305 | 1.39 (0.67–2.86) | 0.378 |
| Clonazepam | 555 (2.6) | 32 (2.9) | 1.13 (0.79–1.62) | 0.509 | 1.08 (0.75–1.55) | 0.680 |
| Gabapentin | 178 (0.8) | 13 (1.2) | 1.39 (0.78–2.46) | 0.266 | 1.36 (0.77–2.41) | 0.294 |
| Valerianae radix | 450 (2.1) | 26 (2.3) | 1.14 (0.76–1.70) | 0.525 | 1.10 (0.74–1.65) | 0.640 |
Use of Oxcarbazepine (0,5 in cases and controls, respectively) was low, and did not permit separate analysis.
CI, confidence interval; CVA/SE, cerebrovascular accident/systemic emboli; DOAC, direct oral anticoagulant.
a
Adjusted for the propensity score to receive a drug from the group.
b
Dabigatran: 4,359 controls, 234 cases; Rivaroxaban: 6,920 controls, 356 cases; Apixaban: 10,406 controls, 526 cases.