We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?


Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

12 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles

Users' Guides to the Medical Literature
Assessing the Strength of Recommendations: The GRADE Approach

Users' Guides to the Medical Literature
Are the Results Valid?