DOI: 10.1097/FTD.0b013e3181e1a665
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PMID: 20498559
Issn Print: 0163-4356
Publication Date: 2010/06/01
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Excerpt
The short duration of the trial means the ability to use genomic information to examine stability of warfarin dosing over time is limited. Two weeks of warfarin therapy is unlikely sufficient to judge the overall occurrence of adverse effects from the drug, particularly those that occur with longer anticoagulation periods (post-DVT for example). This is a major limitation in determining the utility of gene-based dosing but is appropriately discussed in the accompanying paper. An important finding from this paper is that it may be that the lack of genetic markers means more aggressive therapy to achieve a therapeutic INR is made more possible and safer.
Much remains to be understood in pharmacogenetic applications. More work is necessary to fully characterize genetic variants including the contribution of at risk alleles and whether there are additive or even synergistic effects with greater numbers of these alleles. It is also unknown which variants are most predictive of serious adverse outcome versus milder reactions that can be easily managed clinically. This information may also come with future clinical research.
The best use of warfarin pharmacogenetics may be instead as a tool to help understand warfarin sensitivity in patients with gene variants-patients who are quicker to therapeutic concentrations, have more rapid or sustained occurrences of bleeding and other ADRs. Much of this will require further work in gene sequencing to determine if all risk alleles that are relevant have been discovered. The utility of pharmacogenetics may ultimately be quite different from the expectations that once surrounded, say, pharmacokinetics, where we all hoped for better ways to ensure effective drug therapy. In the name of pharmacogenetics, can we improve our predictions of in whom the most serious adverse drug reactions are likely? This would be a significant advance in therapeutic drug monitoring.
One key consideration for warfarin pharmacogenetics and even other drug genetics is which clinicians will most benefit from these additional drug therapy monitoring and management tools. Pharmacist-run anticoagulation clinics, for example, have been demonstrated to provide more effective and safer anticoagulation services than without them. Specialist monitoring teams may therefore derive less benefit from pharmacogenetic testing than non-specialist teams since they are likely more experienced at empiric dosing and therapeutic monitoring. We know that monitoring itself is an important factor in warfarin use outcomes. The use of an experienced anticoagulation team in this study means the comparison of gene/non-gene approaches was somewhat negated. The better comparison would be in non-experts who of course number in the thousands in the clinical ranks and may be responsible for much more drug-induced harm. But according to the US Centers for Medicare and Medicaid Services in 2008, only 20% of patients are managed through an anticoagulation service, less than 5% of patients are managed by self-testing, and more than 75% are managed by a physician or other health care provider.
Maybe this is a time to rethink drug monitoring in the outpatient realm-do we need new drugs or new ways of monitoring and managing the current therapeutic armamentarium? We need both of course. Paradigm shifts are not easy nor necessary if there isn't a new place to go. Perhaps the evolution of clinical genotyping coupled with vastly improved clinical phenotyping will play a large role in helping to answer these difficult questions.
