INTRODUCTION: 

• Warfarin is the primary cause of medication-related emergency visits in older patients 
• Differences in SNPs can impact metabolism of warfarin and consequent dose requirements  
• Previous studies are inconclusive as to benefits of genotype-guided dosing  
• Gage et al. (JAMA, 2017) sought to determine whether genotype-guided warfarin dosing improves the safety of warfarin administration 

METHODS: 

• Double-blind randomized clinical trial (RCT) 
• Patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty  
• Patients were genotyped for DNA polymorphisms related to warfarin metabolism 
  • VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M 
• Patients were randomized into: 
  • Genotype-guided warfarin dosing on day 1 through 11 
  • Clinically-guided warfarin dosing on day 1 through 11 
• Patients also received a target INR of either 1.8 or 2.5 
• Primary outcome was the composite of major bleeding, INR ≥ 4, VTE, or death 

RESULTS: 

• 1650 patients were randomized 
  • 63.6% were female 
  • 91.0% were white  
  • Mean age 72.1 years (SD 5.4) 
• 1597 (96.8%) completed the trial  
  • N= 808 in genotype-guided group  
  • N= 789 in clinically guided group 
• In the genotype group there were fewer cases of  
  • Major bleeding (2 vs 8); Relative risk [RR], 0.24; 95%CI, 0.05-1.15 
  • INR ≥ 4 (56 vs 77) RR, 0.71; 95%CI, 0.51-0.99 
  • Venous thromboembolism (33 vs 38) RR, 0.85; 95%CI, 0.54-1.34 
• There were no deaths 
• When looking at a composite of the above adverse events 
  • Fewer patients in the genotype group (10.8%) met at least one of the adverse event end points compared to the clinical (14.7%)  
  • Absolute difference, 3.9% (95%CI, 0.7%-7.2%, P = .02) 
  • RR 0.73 (95%CI, 0.56-0.95) 

CONCLUSION: 

• Among patients ≥ 65 undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing significantly reduced composite serious adverse events  
• The main driver for reducing the composite adverse outcomes was INR ≥ 4 
• Genotyping may be more helpful at non-academic/low volume hospitals which may have higher adverse events  
• Cost-effectiveness was not addressed in this study 

Learn More – Primary Sources: 

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty 

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