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MM-WES: Genetic testing for warfarin sensitivity linked with reduction in hospitalizations
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All-cause hospital admissions were reduced by nearly one-third after early genetic testing for two genotype variations that influenced sensitivity to warfarin, results from the MM-WES study suggested.
Researchers genotyped 896 patients beginning warfarin therapy and compared them with a control group of 2,688 age- and sex-matched patients who were not genotyped. The researchers focused on specific genotype variations in the CYP2C9 and VKORC1 genes. The primary outcome was the incident hospitalization rate during the six months after the start of outpatient warfarin treatment.
The researchers reported that 29.2% of patients had normal warfarin sensitivity, 25.4% had lower-than-normal sensitivity, 12.2% had mild sensitivity and 33.2% had moderate to very high sensitivity. Patients in the intervention group had a 28% lower rate of hospitalization for any cause vs. control patients (18.5% vs. 25.5%, P<.001). Patients in the warfarin intervention group also had a 27% reduction in the risk for bleeding or thromboembolism vs. control patients (6% vs. 8.1%, P=.039). After an adjusted per-protocol analysis, patients in the intervention group showed a 33% lower rate of all-cause hospitalization (HR=0.67; 95% CI, 0.55-0.81), as well as a 43% lower rate of all-cause hospitalizations for bleeding or thromboembolism vs. control patients (HR=0.57; 95% CI, 0.39-0.83). Adjusted hospitalization rates after an intent-to-treat analysis suggested that patients in the genotyped group had 31% fewer hospitalizations overall (P<.001) and 28% fewer hospitalizations for bleeding or thromboembolism (P=.029) during six-month follow-up.
“The closer you do genotyping to the first day of therapy, the better because you could miss some of the adverse effects if you go out too far,” Robert S. Epstein, MD, chief medical officer and president of Medco Research Institute in Franklin Lakes, N.J., said in a presentation. “We also saw that physicians modified the dosing according to the direction of the genotyping report. Of course, that was prior to the new FDA labeling that gives more specificity regarding dosing based on genotype.”
Epstein R. LBCT III. Presented at: American College of Cardiology 59th Annual Scientific Sessions; March 13-16, 2010; Atlanta.
Epstein and colleagues are to be congratulated for conducting this community-based, real-world assessment of a personalized medicine tool in a critical area of therapy that we all confront. The conclusion that not only bleeding episodes and hospitalization for thromboembolism-related hospitalizations, but also that all-cause hospitalizations were impacted equally in the study, deserves consideration. Any primary outcome measure that is created as an endpoint has to not only be of relevance, which all-cause hospitalization certainly is, but it must also have some direct biological plausibility that the intervention contested. Certainly the bleeding and thromboembolism outcome is in line with what one would expect from warfarin adequacy, but certainly all-cause hospitalizations create some reservation. Whether there is a disease-modifying effect with warfarin of equal magnitude on other primary disease etiologies is left in some doubt.
If that is the case, then one has to assume that we are seeing what was alluded to in the study limitations — a Hawthorne effect — and that is that this was a population with much better and much closer follow-up. Even if we include propensity scoring, and one can only control for those baseline variables that one can see, the dynamic variables that nonetheless occur in terms of following patients with warfarin titration are not accounted for in a propensity score analytical statistical modulation. In fact, one could argue that an appropriate propensity score should have looked at dynamic variables. The control group also deserves some attention and leaves a lot to be desired. This is not a contemporaneous control. It leaves a lot of doubt about whether these patients were equally managed during the post-intervention phase. We did not see data on whether target INR was achieved or a portion of target INR achieved within the two groups. Is this the effect of genotyping that was demonstrated, or was it the effect of closer attention paid to the patient? My conclusion is that this trial design was not adequate to answer the question posed, and most definitely the use of genotyping for warfarin was not established in this study in the real world.
– Mandeep Mehra, MD
Professor of Medicine, University of Maryland School of Medicine
Chief of Cardiology, University of Maryland Medical Center, Baltimore