Effect of tramadol and DOACs with special attention to dabigatran on concomitant use, on the risk of mayor bleeding using BIFAP database in Spain

Abstract

Background Tramadol, a weak opioid, inhibits the reuptake of serotonin, a key feature on vascular homeostasis. A suspected interaction exists between dabigatran and tramadol, which might trigger an excess on risk of bleeding however, there is a gap in knowledge on this topic. Purpose To estimate the effects of tramadol, dabigatran and concomitant use on the risk of hospitalized major bleeds (Gastrointestinal bleeding and intra‐extracranial bleeds). Methods Among a validated established cohort of new users of oral anticoagulants for non‐valvular atrial fibrillation (NVAF) aged 18 years or older, we identified all hospitalized bleed episodes (GIB and extra/intracranial bleeds) within 2008–2015. A nested case–control analysis was conducted using conditional logistic regression. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for dabigatran, tramadol, and concomitant use. Several sensitivity analyses were carried out. Results aORs (95%CIs) for current use of only dabigatran, only tramadol and concomitant users were 1.73 (1.37–2.18) and 1.38 (1.13–1.67) and 2.04 (0.74–5.67) compared with non‐users of both drugs (>365 days). aORs for current continuers and non‐continuer users of dabigatran were 1.36 (1.00–1.86) and 2.19 (1.61–2.98), respectively. For the latter, non‐continuer users with a short duration of dabigatran cumulated the highest risk (3.36 [1.88–5.99]). There also was an increased risk with concomitant use of tramadol and rivaroxaban (2.24 [1.19–4.21]), or antagonist of vitamin K (1.30 [1.00–1.69]). Conclusion There was a trend towards and increased risk of excess bleeds when using concomitantly with dabigatran. The effect decreases with a narrower definition of current use.

Suspected Hematuria: Adverse Effects of Rivaroxaban in Older Adult Treated for Atrial Fibrillation

“…Increased rivaroxaban drug levels are observed in patients with reduced kidney function who are treated with diltiazem, a moderate CYP3A4 inhibitor, and P-gp substrates. The concomitant application of rivaroxaban with P-gp and strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and phenobarbital should be avoided according to the recommendations listed on the FDA label [36,37].…”

Use of tramadol and the risk of bleeding complications in patients on oral anticoagulants: a systematic review and meta-analysis

“…The other cohort study had an aRR of 2.37 [95% CI: 0.93 to 6.01] [32]. The 2 case-control studies reached a NOS score of 9 stars [30] and 6 stars [14] and the 2 cohort studies a score of 9 stars [31] and 8 stars [32] (Supplementary Tables 4 and 5).…”

“…The search process and reasons for exclusion are depicted in the PRISMA flow diagram (Figure 1). Of the 17 included studies, 1 was a case series [17], 12 were case reports [18][19][20][21][22][23][24][25][26][27][28][29], 1 was a case-control study nested in a cohort study [30], 1 was a case-control study [14], and 2 were cohort studies [31,32].…”

“…Characteristics of case-control and cohort studies are presented in Table 1 and their results in Table 2. Anticoagulants prescribed concurrently with tramadol were warfarin in one cohort study and the case-control study [14,32], phenprocoumon or acenocoumarol in the other cohort study [31], and dabigatran, rivaroxaban or VKAs in the nested case-control study [30]. The nested case-control study found no statistically significant increase in the risk of bleeding in patients with atrial fibrillation taking tramadol + dabigatran (aOR: 2.04 [95% CI: 0.74 to 5.67]), compared to patients with atrial fibrillation taking neither tramadol nor dabigatran, but possibly taking another anticoagulant [30].…”

“…Anticoagulants prescribed concurrently with tramadol were warfarin in one cohort study and the case-control study [14,32], phenprocoumon or acenocoumarol in the other cohort study [31], and dabigatran, rivaroxaban or VKAs in the nested case-control study [30]. The nested case-control study found no statistically significant increase in the risk of bleeding in patients with atrial fibrillation taking tramadol + dabigatran (aOR: 2.04 [95% CI: 0.74 to 5.67]), compared to patients with atrial fibrillation taking neither tramadol nor dabigatran, but possibly taking another anticoagulant [30]. In the same study, associations with bleeding were also not statistically significant for tramadol + rivaroxaban (aOR: 2.24 [95% CI: 1.19 to 4.21]) and tramadol + VKAs (aOR: 1.30 [95% CI: 1.00 to 1.79]).…”