March 16, 2010 (Atlanta, Georgia) — Genotyping warfarin patients resulted in a 30% reduction in all-cause hospitalizations and hospitalizations for bleeds/thromboemboli, a new study suggests.

Presenting the Medco-Mayo Warfarin Effectiveness Study (MM-WES) at the American College of Cardiology (ACC) 2010 Scientific Sessions today, Dr Robert Epstein (Medco Research Institute, Franklin Lakes, NJ) said: "Our study shows that genetic testing is a tool clinicians can use to more accurately predict the best warfarin dose early on. Patients may get to a stable dose more quickly and therefore have a lower risk of negative outcomes."

Discussant Critical

But discussant of the study at the late-breaking trials session, Dr Mandeep Mehra (University of Maryland School of Medicine, Baltimore), was deeply critical of the trial on several levels. He argued that the design of the trial was far from ideal and that the question of whether genotyping warfarin patients actually reduces hospitalizations has not been answered by this study. "The control group in this study leaves a lot to be desired, in my opinion, and leaves doubt as to whether the reduction in hospitalization seen in the genotyping group was actually due to the genotyping results or just that the doctor paid closer attention to these patients."

He also suggested that the primary end point--all-cause hospitalization--was not the best measure to use, as it was not directly clinically relevant to warfarin.

Epstein said Mehra made too many comments to be able to address each one, but on the main issue, Epstein responded: "If genotyping does make the physician pay closer attention, then I think that's a good thing."

Is It the Genotyping or Just the Extra Attention?

But challenged at the ACC press conference on whether genotyping, at a cost of $200 to 400 per test, was actually just a very expensive way of making physicians manage their warfarin patients more closely, Epstein said: "Regardless of whether it is the genotyping or it is just extra attention paid to these patients, if we can reduce hospitalizations in the numbers we showed, it would be more than cost-saving." He added: "Warfarin has been in use for 50 years, and we have been taking about how to achieve better control for all that time, but we still have a 22% hospitalization rate within six months of starting treatment. So if we have a new technology that brings more precision to dosing, then that's got to be good."

Cardiologists present at the press conference who were not part of the warfarin study tended to agree with this line.

Chair of the conference, Dr James McClurken (Temple University, Philadelphia, PA), said: "I think the genotyping is a good thing. [The more] tools we can utilize to improve management of these patients, the better. I would consider using it myself."

Dr Scott Solomon (Brigham and Women's Hospital, Boston, MA) made the point that the cost of the test would be spread over the often very long time period that the patient will be taking this drug, so $200 to $400 wasn't really very much in that context. Dr Chris O'Connor (Duke Clinical Research Institute, Durham, NC) agreed, saying: "This is an important advance. Having this genotype knowledge will make patients and physicians more careful, which must be a good thing."

I think the genotyping is a good thing. [The more] tools we can utilize to improve management of these patients, the better.

Epstein reported that MM-WES was the first national, prospective, comparative effectiveness study to evaluate the role of genetic testing in assisting physicians to gauge the best warfarin dose and monitor intensity during the early dose-adjustment phase of treatment.

For the study, researchers recruited 896 patients who were beginning warfarin therapy between 2007 and 2009. All study participants were members of a prescription benefits plan managed by Medco Health Solutions. They came from 49 of 50 states and a variety of practice settings. Shortly after starting warfarin therapy, patients gave a blood sample or buccal swab, which was analyzed for the genetic expression of two genes, CYP2C9 and VKORC1, polymorphisms in either of which can signal the need for higher or lower doses of warfarin. Results and their interpretation were sent to the doctors treating the individual patients, who had the option to adjust warfarin dosing based on the patient's genotype test results.

Hospitalization rates for these patients were compared with rates for a historical control group of similar patients who were new to warfarin treatment but began treatment during the preceding year. The principal comparison was the difference in event-free time during the first six months after treatment onset. To allow for any other changes that might have occurred between the different times that the intervention and control groups were recruited, there were two additional external control groups--one beginning warfarin therapy during the same time period as the intervention group and one starting warfarin treatment during the prior year.

Epstein reported that physicians did adjust their warfarin prescribing after the genotype results were received and that 75% went on to adopt the genotyping practice. Results of the study showed that, compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the six-month follow-up period. During the same period, there was no difference in outcomes between the two external control groups.

Adjusted Hazard Ratios for Hospitalizations With Genotyping vs Historical Controls

Outcome Hazard ratio 95% CI p
All-cause hospitalization 0.69 0.58–0.82 <0.001
Hospitalization for bleeding/thromboembolism 0.72 0.53–0.97 0.029

Epstein reported that the hospitalization curves started to diverge at about 40 days after the start of warfarin treatment and that the whole process of genotyping and getting the results to the doctors/patients took between 11 and 60 days. It was found that the earlier the results were attained, the more outcomes improved.

This study is also in press at the Journal of the American College of Cardiology and is expected to be published shortly.

Medco provided funding for genotyping and data collection. Epstein is an employee of Medco.