Dabigatran and Vorapaxar: Interaction Details

a) A drug interaction study demonstrated that coadministration of dabigatran 110 mg twice daily with ticagrelor 90 mg twice daily increased the AUC and Cmax of dabigatran by 26% and 29%, respectively, while coadministration with a loading dose of ticagrelor 180 mg, the levels increased by 49% and 65%, respectively. However, ticagrelor 180 mg loading dose when given 2 hours after dabigatran only increased the AUC and Cmax of dabigatran by 27% and 24%, respectively ¹.

b) A 76-year-old woman taking dabigatran 150 mg twice daily for bilateral lower extremity DVTs and low-dose quiNIDine (10 mg twice daily) for an unknown indication was admitted from a nursing home with abdominal pain and rectal bleeding. On admission she was found to have anemia (Hb, 4.9 g/dL) and coagulopathy (thrombin time (TT) greater than 60 seconds), with acute kidney injury (SCr of 2 mg/dL; baseline 0.8 mg/dL), and an elevated BUN at 90 mg/dL. She was diagnosed with acute blood loss anemia secondary to lower GI bleeding likely related to dabigatran use. Bleeding risk associated with catheter placement precluded initiation of hemodialysis. Transfusion measures and treatment with idaruCIZUmab initially normalized the patient's Hb (8.2 g/dL) and TT (14.3 seconds), but she experienced rebleeding, and the TT returned to greater than 60 seconds when rechecked approximately 20 hours after administration of idaruCIZUmab. A 10-day hospitalization for persistent coagulopathy, rectal bleeding, and renal impairment was necessary, and the patient received 2 additional doses of idaruCIZUmab on hospital days 2 and 4, with each treatment providing only temporary normalization of coagulation parameters. The patient continued to have rectal bleeding until day 5 at which point it began to improve, however TT remained elevated until hospital day 9. While renal impairment may have contributed to reduced dabigatran clearance in this case, quiNIDine (a P-gp inhibitor), was thought to have contributed to the initial suspected supratherapeutic levels of dabigatran ⁴.

c) In a comparative effectiveness study of patients with nonvalvular atrial fibrillation and normal kidney function, the overall bleeding rate was 52% higher (244.9 vs 158.4 per 1000 person-years; HR, 1.52; 95% CI, 1.05 to 2.2) with coadministration of dabigatran and verapamil or dilTIAZem (n=750) compared with coadministration with amLODIPine (n=1316), and 43% higher (291.3 vs 199.7 per 1000 patient-years; HR, 1.43; 95% CI, 1.02 to 2) with dabigatran and verapamil or dilTIAZem (n=764) compared with metoprolol (n=1334). Additionally, overall gastrointestinal (GI) bleeding (HR, 2.16; 95% CI, 1.3 to 3.6), minor bleeding (HR, 1.56; 95% CI, 1.07 to 2.27) and GI minor bleeding (HR, 2.16; 95% CI, 1.29 to 3.63) were also significantly increased with dabigatran and verapamil or dilTIAZem compared with amLODIPine, and overall GI bleeding (HR, 2.32; 95% CI, 1.42 to 3.79), major/moderate bleeding (HR, 3.32; 1.54 to 7.16), major/moderate GI bleeding (HR, 5.49; 95% CI, 1.67 to 18.03), and GI minor bleeding (HR, 2.33; 95% CI, 1.42 to 3.82) were significantly increased with dabigatran and verapamil or dilTIAZem compared with metoprolol. Patients received dabigatran 150 mg twice daily. Caution may be necessary with coadministration of dabigatran with verapamil and dilTIAZem, and possibly other moderate to strong P-gp inhibitors, regardless of kidney function ³.

d) Concomitant use of dabigatran and simvastatin (n=502) or lovastatin (n=27), both P-gp inhibitors, significantly increased the risk of major hemorrhage by 46% compared with other statins not implicated in P-gp inhibition (atorvastatin, pravastatin, fluvastatin or rosuvastatin) in a study of patients 66 years or older (median, 82 years) with major hemorrhage (n=1117 cases and 4465 controls). Simvastatin itself was associated with a significant 44% increased risk of major hemorrhage, while lovastatin itself had a nonsignificant 90% increased risk compared with other statins ².

e) Concomitant use of direct oral anticoagulant (DOAC) and antiplatelet therapy (APT; n=78) compared to DOAC therapy alone (n=329) did not significantly alter the incidence of major bleeding (1.3% vs 1.2%) or clinically relevant non-major bleeding (10.2% vs 6.4%) over 6 months of treatment in a retrospective study. Patients were primarily Caucasian men with a mean age of 63.7 years. Patients receiving concurrent APT had significantly higher mean body mass index (30.7 vs 28.4), mean CHA2DS2-VASc score (4.28 vs 3.85), and were more likely to have diabetes (26.9% vs 17.3%) compared with those prescribed DOAC monotherapy. DOACs were prescribed for VTE treatment or atrial fibrillation, and included apixaban (58.5%), rivaroxaban (38.1%), and dabigatran (3.4%). Single antiplatelet therapy was utilized in 94.9% (74 patients), with aspirin 81 mg once daily as the most common regimen (69 patients). Other APT regimens included aspirin 81 mg twice daily (3 patients), aspirin 325 mg daily (1 patient), clopidogrel 75 mg daily (1 patient), and dual APT with aspirin 81 mg and clopidogrel 75 mg daily (4 patients) ⁵.

f) In a retrospective study of patients 65 years or older who received a coronary artery stent (N=70,900), coadministration of direct oral anticoagulant (DOAC; dabigatran or rivaroxaban) and prescription antiplatelet therapy (predominantly clopidogrel) significantly increased the risk of major hemorrhagic events compared with antiplatelet therapy alone (HR, 2.36; 95% CI, 1.91 to 2.93) over 12 months following stent placement; this risk was similar to coadministration of warfarin and antiplatelets (HR, 2; 95% CI, 1.83 to 2.18). When patients were stratified by index atrial fibrillation (AF) status, the risk of major hemorrhagic events was also significantly increased with coadministration of DOAC and antiplatelet therapy for both AF (HR, 1.94; 95% CI, 1.48 to 2.54; n=10,238) and non-AF groups (HR, 3.09; 95% CI, 2.15 to 4.46; n=60,662). Hemorrhages in the first 30 days after stenting were considered periprocedural morbidity and excluded. The average observation period was 11.5 months, with 24.470,270 person-days of exposure; antiplatelet only therapy accounted for 73.8% of person-days of exposure, antiplatelets plus DOACs for 0.6%, and antiplatelets plus warfarin for 4.7% ⁶.