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Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial

Makar-Aušperger, Ksenija, MD, PhD*; Krželj, Kristina,; Lovrić Benčić, Martina, MD, PhD; Radačić Aumiler, Matea, MD, PhD*; Erdeljić Turk, Viktorija, MD, PhD*; Božina, Nada, MD, PhD§,¶

doi: 10.1097/FTD.0000000000000501
Original Article

Background: Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy.

Methods: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, and diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided pharmacogenetics guided (PHG), and where it was adjusted according to the clinical parameters non pharmacogenetics guided (NPHG). Genotyping of CYP2C9*2, *3, and VKORC1 was performed using the real-time polymerase chain reaction method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0–3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0–3.0) range in at least 2 consecutive measurements.

Results: In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group [mean = 26% (SD 25.0)] than in the NPHG group [mean = 14% (SD 18.6)], [Δ = 12; 95% confidence interval, 0–23; P = 0.040]. There was no significant difference in other 2 indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%) than in the NPHG group 7/32 (22%) (odds ratio = 3.13, 95% confidence interval, 0.92–10.98; P = 0.039).

Conclusions: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with AF. There is no evidence for such conclusion in patients with DVT and PE.

*Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia;

University of Zagreb School of Medicine, Zagreb, Croatia;

Department of Cardiovascular Diseases, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia;

§Department for Pharmacogenomics and Therapy Individualization, University Hospital Center Zagreb, Zagreb, Croatia; and

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

Correspondence: Nada Božina, MD, PhD, Department of Pharmacogenomics and Therapy Individualization, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia (e-mail:

The authors declare no conflict of interest.

Received December 18, 2017

Accepted February 21, 2018

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