Pharmacogenetics-Based versus Conventional Dosing of Warfarin: A Meta-Analysis of Randomized Controlled Trials

Changcheng Shi; Wei Yan; Gang Wang; Fei Wang; Qingyu Li; Nengming Lin

doi:10.1371/journal.pone.0144511

Pharmacogenetics-Based versus Conventional Dosing of Warfarin: A Meta-Analysis of Randomized Controlled Trials

PLoS One. 2015 Dec 16;10(12):e0144511. doi: 10.1371/journal.pone.0144511. eCollection 2015.

Authors

Changcheng Shi^{1

2}, Wei Yan¹, Gang Wang¹, Fei Wang^{1

2}, Qingyu Li¹, Nengming Lin^{1

2

3

4}

Affiliations

¹ Department of Clinical Pharmacy, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, China.
² Department of Clinical Pharmacology, Hangzhou Translational Medicine Research Center, Hangzhou, Zhejiang Province, China.
³ Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, Zhejiang Province, China.
⁴ The first Affiliated Hangzhou Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.

Abstract

Background: Recently, using the patient's genotype to guide warfarin dosing has gained interest; however, whether pharmacogenetics-based dosing (PD) improves clinical outcomes compared to conventional dosing (CD) remains unclear. Thus, we performed a meta-analysis to evaluate these two strategies.

Methods: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese VIP and Chinese Wan-fang databases were searched. The Cochrane Collaboration's tool was used to assess the risk of bias in randomized controlled trials (RCTs). The primary outcome was time within the therapeutic range (TTR); the secondary end points were the time to maintenance dose and time to first therapeutic international normalized ratio (INR), an INR greater than 4, adverse events, major bleeding, thromboembolism and death from any cause.

Results: A total of 11 trials involving 2,678 patients were included in our meta-analysis. The results showed that PD did not improve the TTR compared to CD, although PD significantly shortened the time to maintenance dose (MD = -8.80; 95% CI: -11.99 to -5.60; P<0.00001) and the time to first therapeutic INR (MD = -2.80; 95% CI: -3.45 to -2.15; P<0.00001). Additionally, PD significantly reduced the risk of adverse events (RR = 0.86; 95% CI: 0.75 to 0.99; P = 0.03) and major bleeding (RR = 0.36; 95% CI: 0.15 to 0.89, P = 0.03), although it did not reduce the percentage of INR greater than 4, the risk of thromboembolic events and death from any cause. Subgroup analysis showed that PD resulted in a better improvement in the endpoints of TTR and over-anticoagulation at a fixed initial dosage rather than a non-fixed initial dosage.

Conclusions: The use of genotype testing in the management of warfarin anticoagulation was associated with significant improvements in INR-related and clinical outcomes. Thus, genotype-based regimens can be considered a reliable and accurate method to determine warfarin dosing and may be preferred over fixed-dose regimens.

Trial registration prospero: Database registration: CRD42015024127.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Anticoagulants / administration & dosage*
Anticoagulants / adverse effects
Genotype
Humans
International Normalized Ratio
Pharmacogenetics*
Publication Bias
Randomized Controlled Trials as Topic
Thromboembolism / drug therapy
Thromboembolism / etiology
Thromboembolism / mortality
Thromboembolism / prevention & control
Time Factors
Treatment Outcome
Warfarin / administration & dosage*
Warfarin / adverse effects

Substances

Anticoagulants
Warfarin

Grants and funding

The authors gratefully acknowledge financial support from Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (2010-190-4, Nengming Lin). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.