Personalized Anticoagulation

Abstract

Background Clinical trials testing pharmacogenomic-guided (PG-guided) warfarin dosing for patients with atrial fibrillation(AF) have demonstrated conflicting results. Non-vitamin K antagonist oral anticoagulants (NOACs) are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need. Methods and Results Characteristics from 14,206 patients with AF were integrated into a validated warfarin clinical trial simulation framework using iterative Bayesian network modeling and a pharmacokinetic–pharmacodynamic model. Individual dose response for patients was simulated for five warfarin protocols – a fixed-dose protocol, a clinically guided protocol and three increasingly complex PG-guided protocols. For each protocol a complexity score was calculated using the variables predicting warfarin dose and the number of predefined INR thresholds for each adjusted dose. Study outcomes included optimal time in therapeutic range (TTR) ≥65% and clinical events. A combination of age and genotype identified different optimal protocols for various subpopulations. A fixed-dose protocol provided well-controlled INR only in normal responders ≥65, while for normal responders <65 years old, a clinically guided protocol was necessary to achieve well-controlled INR. Sensitive responders ≥65 and <65 and highly sensitive responders ≥65 years old required PG-guided protocols to achieve well-controlled INR. However, highly sensitive responders <65 years old, did not achieve well-controlled INR and had higher associated clinical events rates than other subpopulations. Conclusions Under the assumptions of this simulation, patients with AF can be triaged to an optimal warfarin therapy protocol by age and genotype. Clinicians should consider alternative anticoagulation therapy for patients with suboptimal outcomes under any warfarin protocol.

Advancing treatment of retinal disease through in silico trials

“…Drug-based ISCTs often revolve around testing differing dosing strategies either through having complex multi-arm ISCTs as is the case when studying optimal warfarin dosing [238], or through developing optimal control algorithms and testing those algorithms in an ISCT as with insulin control models [161]. Models have also been developed to look at treating rare bone conditions in children using agent-based models [56] and simulating the response of haemodialysis patients to treatment for anaemia with ODEs [110], as well as predicting the cardiotoxicity of drugs [224].…”

“…Whilst there are no regulatory approved ISCTs at this phase, the examples given earlier can be extrapolated straightforwardly to this phase. Examples of ISCTs that have attempted to model phase 3 trials include an ISCT comparing two drugs for attention-deficit/hyperactivity-disorder [123] and a multi-arm trial of warfarin dosage [238]. Others have attempted to augment phase 3 trials only through the control arm, avoiding the complexity of simulating disease and intervention yet still improving the power of trials [101,292].…”

“…Running ISCTs requires a close collaboration between experimentalist, modellers and clinicians (see figures 2 and 9). Other medical disciplines such as oncology and cardiology have already benefited from in silico trials [43,238]. Ophthalmology can also benefit from such trials which require large amounts of data.…”

Warfarin in nonvalvular atrial fibrillation—Time for a change?

“…In addition, there is up to a 20-fold interindividual variation in therapeutic dose. 7 As a result, patients often have INR values that are above and below the therapeutic range.…”