Dosing algorithms for warfarin incorporate clinical and genetic factors, but human intervention to overrule algorithm-based dosing may occasionally be required. The frequency and reasons for varying from algorithmic warfarin management have not been well studied.

We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics trial who were randomized to either pharmacogenetic- or clinically-guided warfarin dosing algorithms. Clinicians and participants were blinded to dose but not international normalized ratio (INR) during the first 28 days. If an issue arose that raised concern for clinicians but might not be adequately accounted for by the protocol, then clinicians contacted the unblinded medical monitor who could approve exceptions if clinically justified. All granted exceptions were logged and categorized. We analyzed the relationships between dosing exceptions and both baseline characteristics and the outcome of percentage of time in the therapeutic INR range during the first 4 weeks.

Sixteen percent of participants required at least one exception to the protocol-defined warfarin dose (15% in the genotype arm and 17% in the clinical arm). Ninety percent of dose exceptions occurred after the first 5 days of dosing. The only baseline characteristic associated with dose exceptions was congestive heart failure (odds ratio 2.12, 95% confidence interval, 1.49-3.02, P <.001). Neither study arm nor genotype was associated with dose exceptions.

Despite rigorous algorithms, human intervention is frequently employed in the early management of warfarin dosing. Congestive heart failure at baseline appears to predict early exceptions to standardized protocol management.