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DOAC Pharmacogenomics: Personalized Therapeutics to Avoid Bleeding and Thrombotic Complications

C. Schekel1, F. Shamoun2, M. Abdelmalek2, J. Wang2, M. Girardo2, Y. Kusne2

1Mayo Clinic, Rochester, United States, 2Mayo Clinic Arizona, Scottsdale, United States

Abstract Number: PB1719

Meeting: ISTH 2020 Congress

Theme: Platelets and Megakaryocytes » Platelet Proteomics and Genomics

Background: The direct oral anticoagulants (DOACs) have growing utility in patients with atrial fibrillation (AF) and venous thromboembolic disorders. Major bleeding and thrombotic complications occur in 1-3% of patients. A number of enzymes including CYP450 contribute to the absorption and metabolism of DOACs. CYP450 activity varies among individuals and is susceptible to inhibition and induction via drug-drug interactions. Utilizing pharmacogenomics (PGx) in DOACs dosing may lead to lower bleeding and thrombotic complications.

Aims: We evaluated the association of bleeding and thrombosis complications in subjects on DOACs with specific pharmacogenomics variations.

Methods: We analyze pharmacogenomics data of subjects enrolled in the “Right 10k Study” and on one of the DOACs.

Results: There are 10,036 patients with baseline PGx data enrolled in the Mayo Clinic “Right10k Study”. 294 patients used DOACs, mean age was 73, and 46.9% were female. 66.3 % (195/294) used apixaban, 33.7% (99/294) used rivaroxaban, and 7.1% (21/294) used dabigatran. 21 patients used more than 1 DOAC over the course of treatment for the qualifying condition. AF was the most common indication for DOAC use (71.8%). There were (46) subjects experienced bleeding and (39) have thrombotic complications. Among bleeding complications, 19 developed GI bleeding, 6 developed intracranial hemorrhage, and the remainder had clinically relevant nonmajor bleeding. Among thrombotic complications, 20 developed DVTs/PEs, 4 superficial thromboses, and the remainder were strokes/TIAs. No significant differences with respect to age, gender, DOAC, cancer history were seen between those without complication while on therapy. Chronic kidney disease (CKD) stage 3 or greater was associated with significantly higher rates of bleeding (p=0.018).

Conclusions: Patient genotype was not associated with increased risk of bleeding or thrombotic complications while on DOACs. Patients with CKD were significantly more likely to have major bleeding on DOACs.

Phenotype No complications Bleeding and Thrombotic complications Total Chi-Square P value
CYP3A4_Phenotype Normal (extensive) metabolizer 192 (86.9%) 68 (93.2%) 260 (88.4%) 0.1712
Warfarin sensitivity Phenotype 68 (30.8%) 25 (34.2%) 93 (31.6%) 0.9287
CYP2C19_Phenotype Decreased function 44 (19.9%) 17 (23.3%) 61 (20.7%) 0.2526
CYP2C9_Phenotype Normal (extensive) metabolizer 133 (60.2%) 43 (58.9%) 176 (59.9%) 0.4721
CYP1A2_Phenotype Rapid metabolizer 194 (87.8%) 66 (90.4%) 260 (88.4%) 0.6011
CYP3A5_Phenotype Poor metabolizer 192 (86.9%) 63 (86.3%) 255 (86.7%) 0.9423
CYP2D6_Phenotype Normal (extensive) metabolizer 76 (34.4%) 23 (31.5%) 99 (33.7%) 0.5665
SLCO1B1_Phenotype Decreased function 44 (19.9%) 17 (23.3%) 61 (20.7%) 0.1185
UGT1A1_Phenotype Normal (extensive) metabolizer 109 (49.3%) 32 (43.8%) 141 (48.0%) 0.0819

[DOACs Pharmacogenomics phenotype]

To cite this abstract in AMA style:

Schekel C, Shamoun F, Abdelmalek M, Wang J, Girardo M, Kusne Y. DOAC Pharmacogenomics: Personalized Therapeutics to Avoid Bleeding and Thrombotic Complications [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/doac-pharmacogenomics-personalized-therapeutics-to-avoid-bleeding-and-thrombotic-complications/. Accessed October 1, 2023.

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