Doziranje varfarina prema farmakogenetičkom algoritmu u bolesnika s fibrilacijom atrija, plućnom embolijom i dubokom venskom trombozom

master's thesis

• Title (english): Warfarin dosing according to the genotype-guided algorithm is most beneficial in patients with atrial fibrillation: a randomized parallel group trial
• Author: Kristina Krželj
• Mentor: Martina Lovrić Benčić (mentor)
• Committee member: Boško Skorić (predsjednik povjerenstva)
• Committee member: Jasenka Markeljević (član povjerenstva)
• Committee member: Martina Lovrić Benčić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2018-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Clinical Pharmacology and Toxicology

Abstract

UVOD: Opservacijske studije su pokazale potencijalnu korist doziranja varfarina prema rezultatima genotipizacije za CYP2C9 i VKORC1 gene, no dosadašnji randomizirani klinički pokusi još uvijek donose oprječne rezultate. Jedan od uzroka kontradiktornih rezultata je zanemarivanje razlika u indikacijama za primjenu varfarina. Cilj ove studije jest odrediti učinkovitost i sigurnost doziranja varfarina prema farmakogenetičkom i kliničkom algoritmu u pacijenata s fibrilacijom atrija (FA), plućnom embolijom (PE) i dubokom venskom trombozom (DVT) unutar prvih pet dana nakon započinjanja terapije. ----- ISPITANICI I METODE: Provedena je randomizirana, jednostruko slijepa studija jednog centra. Analizirano je 205 pacijenata obaju spolova, starijih od 18 godina s dijagnozom FA, PE ili DVT. Ispitanici su podijeljeni u dvije skupine. Jednoj skupini varfarin je doziran prema nalazima genotipizacije (PHG skupina), dok je drugoj skupini varfarin doziran prema kliničkim parametrima (NPHG skupina). Genotipizacija je provedena metodom lančane reakcije polimeraze u stvarnom vremenu (Real-Time PCR). Primarni ishodi bili su vrijeme unutar terapijskog raspona međunarodnog normaliziranog omjera INR (od engl. international normalized ratio) (2,0-3,0) i postotak pacijenata koji su postigli stabilnu antikoagulaciju definiranu kao INR između 2,0 i 3,0 u najmanje dva uzastopna mjerenja. ----- REZULTATI: U pacijenata s FA postotak vremena provedenog u terapijskom rasponu INR-a bio je veći u PHG skupini (medijan=26% (SD 25,0)), nego u NPHG skupini (medijan=14% (SD 18,6)), (delta=12; 95% interval pouzdanosti (CI) 0-23; p=0,040). Nije pronađena statistički značajna razlika u drugim indikacijama za terapiju varfarinom. Stabilne doze varfarina postignute su u statistički značajno većeg broja pacijenata u PHG skupini 14/30 (43%), nego u NPHG skupini 7/32 (22%) (OR=3,13, 95% CI 0,92-10,98; p=0,039). ----- ZAKLJUČAK: Doziranje varfarina prema rezultatima genotipizacije za CYP2C9 i VKORC1 gene djelotvornije je u pacijenata s FA. Nema dokaza za takav zaključak u pacijenata s PE i DVT.

Abstract (english)

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 the efficacy and safety of genotype- and clinically-guided dosing of warfarin in atrial fibrillation (AF), deepvein thrombosis (DVT), and pulmonary embolism (PE) within the first five days after the introduction of therapy. ----- PATIENTS AND METHODS: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotypeguided
(PHG), and where it was adjusted according to the clinical parameters (NPHG). Genotyping of CYP2C9*2, *3 and KORC1 was performed using the Real-Time PCR 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 two 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 (CI) 0-23; p=0.040). There was no significant difference in the other two 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%) (OR=3.13, 95% CI 0.92-10.98; p=0.039). ----- CONCLUSION: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with atrial fibrillation. There is no evidence for such a conclusion in patients with DVT and PE.

• Keywords: varfarin; fibrilacija atrija; CYP2C9; VKORC1; međunarodni normalizirani omjer (INR)
• Keywords (english): warfarin; atrial fibrillation; CYP2C9; VKORC1; international normalized ratio (INR)
• Language: croatian
• URN:NBN: urn:nbn:hr:105:504064
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-03-13 09:08:19