Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials

JAMA Intern Med. 2014 Aug;174(8):1330-8. doi: 10.1001/jamainternmed.2014.2368.


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.

Publication types

  • Meta-Analysis

MeSH terms

  • Acenocoumarol / administration & dosage*
  • Acenocoumarol / metabolism
  • Algorithms*
  • Anticoagulants / administration & dosage*
  • Anticoagulants / metabolism
  • Cytochrome P-450 CYP2C9 / genetics*
  • Genotype*
  • Humans
  • International Normalized Ratio
  • Phenprocoumon / administration & dosage*
  • Phenprocoumon / metabolism
  • Polymorphism, Single Nucleotide
  • Randomized Controlled Trials as Topic
  • Vitamin K Epoxide Reductases / genetics*
  • Warfarin / administration & dosage*
  • Warfarin / metabolism


  • Anticoagulants
  • Warfarin
  • Cytochrome P-450 CYP2C9
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • Acenocoumarol
  • Phenprocoumon