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Original Investigation |

Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues:  Meta-analysis of Randomized Clinical Trials

Kathleen Stergiopoulos, MD, PhD1; David L. Brown, MD2
[+] Author Affiliations
1Division of Cardiovascular Medicine, Stony Brook University, Stony Brook, New York
2Cardiovascular Division, Washington University School of Medicine, St Louis, Missouri
JAMA Intern Med. 2014;174(8):1330-1338. doi:10.1001/jamainternmed.2014.2368.
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Importance  Significant variations in dose requirements of warfarin and its analogues (acenocoumarol and phenprocoumon) make selecting the appropriate dose for an individual patient difficult. Genetic factors account for approximately one-third of the variation in dose requirement. The clinical usefulness of genotype-guided dosing of warfarin has been previously assessed in randomized clinical trials that were limited by lack of power and inconsistent results.

Objective  To compare genotype-guided initial dosing of warfarin and its analogues with clinical dosing protocols.

Data Sources and Study Selection  MEDLINE (inception to December 31, 2013), EMBASE (inception to December 31, 2013), and the Cochrane Library Central Register of Controlled Trials (inception to December 31, 2013) were searched for randomized clinical trials comparing genotype-guided warfarin dosing vs clinical dosing for adults with indications for anticoagulation.

Data Extraction and Synthesis  Two investigators extracted data independently on trial design, baseline characteristics, and outcomes. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up.

Main Outcomes and Measures  The outcomes analyzed included the percentage of time that the international normalized ratio (INR) was within the therapeutic range, the percentage of patients with an INR greater than 4, and the incidence of major bleeding and thromboembolic events. Summary standardized differences in means (or Mantel-Haenszel risk ratios) were obtained using a random-effects model.

Results  In 9 trials, 2812 patients were randomized to receive warfarin, acenocoumarol, or phenprocoumon according to a genotype-guided algorithm or a clinical dosing algorithm. Follow-up ranged from 4 weeks to 6 months (median, 12 weeks). The standardized difference in means of the percentage of time that the INR was within the therapeutic range was 0.14 (95% CI, −0.10 to 0.39) in the genotype-guided dosing cohort (P = .25). The risk ratio for an INR greater than 4 was 0.92 (95% CI, 0.82 to 1.05) for genotype-guided dosing vs clinical dosing. The risk ratios for major bleeding and thromboembolic events were 0.60 (95% CI, 0.29 to 1.22) and 0.97 (95% CI, 0.46 to 2.05), respectively, for genotype-guided vs clinical dosing.

Conclusions and Relevance  In this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms.

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Figure 1.
Study Selection

Flow diagram depicts the study selection for inclusion in the meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for reporting systematic reviews and meta-analyses.36a“Not original research” was defined as review articles or editorials.

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Figure 2.
Comparison of Genotype-Guided Initial Dosing of Warfarin Therapy vs Clinical Dosing in Patients With an Indication for Anticoagulation

A, Percentage of time that the international normalized ratio (INR) was within the therapeutic range. Heterogeneity: Q = 68 (P < .001) and I2 = 88%. B, INR >4. Heterogeneity: Q = 5.6 (P = .59); I2 = 0%. C, Major bleeding. Heterogeneity: Q = 3.0 (P = .81); I2 = 0%. D, Thromboembolic events. Heterogeneity: Q = 4.6 (P = .59); I2 = 0%. Point estimates of the standardized difference in means (SDM) or risk ratio (RR) and respective 95% CIs. The size of the squares denoting the point estimate in each study is proportional to the weight of the study; the size of the Caraco et al29 study was too small for indication in part A. MH indicates Mantel-Haenszel; diamonds, the overall SDM or RR and 95% CI for the outcome of interest.

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