Meta-analysis of genotype-guided warfarin trials yields disappointing results
A meta-analysis of randomized clinical trials found that genotype-guided dosing of warfarin, acenocoumarol, or phenprocoumon did not result in a greater percentage of patients with international normalized ratio (INR) in therapeutic range, fewer patients with INR greater than 4, or fewer major bleeding or thromboembolic events than use of clinical dosing protocols.
Warfarin is widely used to prevent thromboembolic events associated with atrial fibrillation, thrombosis, pulmonary embolism, and prosthetic heart valves. Although genetic variability in CYP2C9 and VKORC1 has been shown to influence warfarin dosage requirements, studies investigating the impact of this variability on clinical endpoints have had conflicting results.
Stergiopoulos and colleagues conducted a meta-analysis of randomized clinical trials that compared genotype-guided dosing of warfarin, acenocoumarol, or phenprocoumon for anticoagulation with clinical dosing protocols in adults. Investigators identified prospective, randomized trials indexed in MEDLINE, Cochrane, BioMed Central, and PubMed databases through December 2013. References for retrieved articles and prior reviews were also searched for relevant studies. The primary endpoint was percentage of time that INR was within the therapeutic range; secondary endpoints included percentage of patients with INR greater than 4 and incidence of major bleeding and thromboembolic events.
A total of 9 trials including 2,812 patients were identified with follow-up periods ranging from 4 weeks to 6 months. Six of these studies used CYP2C9 and VKORC1 testing, 2 studies used CYP2C9 testing only, and 1 study used CYP2C9, VKORC1, and CYP4F2 testing. Genotype-guided dosing was used on warfarin initiation, with subsequent dosing adjustments made according to a clinical protocol.
The difference in means of the percentage of time that INR was in the therapeutic range was 0.14 (95% CI -0.10–0.39) greater for individuals receiving genotype-guided warfarin than patients in the clinically-based dosing cohort (P = 0.25). Risk ratios (RRs) for an INR greater than 4 (RR = 0.92; 95% CI 0.82–1.05), major bleeding events (RR = 0.60; 95% CI 0.29–1.22), or major thromboembolic events (RR = 0.97; 95% CI 0.46–2.05) did not differ significantly between groups.
Study findings are notable as previous meta-analyses of genotype-guided dosing of warfarin are limited. Based on study findings, authors concluded that a personalized medicine approach “does not appear to offer incremental benefit over clinical dosing of warfarin alone in patients with indications for oral anticoagulation.”
However, authors offered important caveats to these conclusions based on study and data limitations. First, genotype-guided dosing was employed only for dosage initiation and not subsequent dose modifications in all analyzed studies. Second, the protocol-based dosing and aggressive INR monitoring used for control group patients are not consistent with the current standard of care, and therefore conclusions based on these comparisons may be limited. Third, there was significant heterogeneity for the percentage of time that the INR was within range across all studies. Additional limitations included variable dosing strategies, patient populations, length of follow up, outcome measures, and clinical endpoints among analyzed studies and a small number of overall clinical events.
Authors of an accompanying commentary echoed these sentiments, but also noted that many challenges face routine adoption of personalized medicine. “The journey to a world of personalized medicine is exciting but bumpy,” commentary authors wrote.
The current articles join other recently published expert interpretations of warfarin pharmacogenomics clinical trials available in the New England Journal of Medicine and Clinical Pharmacology and Therapeutics. More information about these studies and genotype-guided warfarin dosing is available through the Pharmacogenomics Knowledgebase.
Stergiopoulos K et al. Genotype-guided versus clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med. 2014 [Epub ahead of print].
Kazi DS et al. Warfarin, genes, and the (health care) environment [Commentary]. JAMA Intern Med. 2024 [Epub ahead of print].