A hospital in London, Ontario, recently opened a warfarin clinic in which clinicians will use pharmacogenomic strategies to try to reach the right starting dose for patients prescribed the anticoagulant.
Through this effort physicians at the London Health Sciences Center – University Hospital are attempting to introduce personalized medicine to the southwestern corner of the province, and conduct research into developing a gene-based dosing algorithm for warfarin.
Patients who come to the hospital’s clinic can volunteer to participate in the research program and receive free genetic testing to see if they have the CYP2C9 and VKORC1 genetic polymorphisms that render them more at risk for serious adverse events when treated with warfarin.
However, the Canadian government does not provide public funding for gene-based warfarin dosing. Labels for warfarin sold in Canada include language on how CYP2C9 may affect dosage, but do not yet include information about VKORC1.
Although there is a growing consumer demand for genetic tests that can help tailor existing treatments, Canadians do not currently have broad access to warfarin genetic testing. Canadians can pay out of pocket for genetic tests marketed through private firms or they can participate in research programs at hospital clinics like the one at London Health Sciences Center.
By comparison, the US Food and Drug Administration updated warfarin’s label last year to highlight the increased risk for serious adverse reactions associated with CYP2C9 and VKORC1 genetic polymorphisms. The agency, however, stopped short of requiring doctors to genetically test patients prior to starting patients on the anticoagulant. Many large insurers have said that more clinical utility data is needed before they reimburse for pharmacogenetic-based warfarin dosing. However, individuals can be prescribed such tests and pay for them on their own.
Richard Kim, a clinician scientist who in 2006 moved his research team from Vanderbilt University School of Medicine in Nashville, Tenn., to London to head up the clinical investigation unit at London Health Sciences Center spoke to Pharmacogenomics Reporter this week about the goals and challenges associated with introducing personalized medicine through the hospital’s new warfarin clinic.
Below is an edited transcript of the interview with Kim.
Why did you decide to start the warfarin clinic at this time?
Warfarin is one of the few drugs that the [US] FDA issued a guideline last year saying that genetic testing for warfarin may be useful for identifying people at risk for toxicity from warfarin. … Many groups are interested in finding out how to use the genetic information in the [CYP2C9 and VKORC1] genes in terms of prescribing warfarin. Our group has been interested in how we could better prescribe warfarin for patients who are about to start warfarin therapy. This is why we have embarked on this. There is a component of this that is both research as well as patient care.
How many patients do you plan to enroll in your research effort and what is the timeline for this study?
About 300 people in total in the next 12 to 18 months.
What platform are you using to test patients?
It’s a straightforward TaqMan-based assay [made by Applied Biosystems]. The volume is such that we won’t need to handle a large number of samples. All of the subjects that are going to participate will be enrolled in to our research study as well. So, this is really research to understand warfarin response.
The FDA has said that it is working on developing a nomogram for warfarin dosing. Is that something you are working on at your clinic?
Absolutely. Our research project focuses on testing our algorithm for starting warfarin. Obviously, because people measure INR, everyone gets to the target dose in INR eventually. But in the first month or so, people struggle a little more in finding the right dose of warfarin. So, many groups are putting their effort into developing a nomogram that is genetics-guided.
Does the hospital’s surrounding population have a need for genetics-guided warfarin dosing?
Yes. We’re in southwestern Ontario. This hospital serves about 1.5 million patients, close to 2 million if you count some of the referring areas. There is a significant demand and we’re focused specifically on atrial fibrillation and warfarin use. So, we think more people who could benefit from warfarin, who have atrial fibrillation, but guiding their therapy is viewed in some ways as onerous because they have to be on chronic warfarin therapy.
What is the Canadian health regulatory authorities’ stance on genetically guided warfarin dosing?
I think a lot of people take to heart what the FDA recommends. I think it’s often viewed as a worldwide suggestion. At the Canadian regulatory equivalent, I think they feel that frequent monitoring for INR and having a warfarin clinic to monitor patients are very useful. I don’t think there is any specific guideline per se on how to use genetic information. Other than FDA’s recommendation to look for genotypes, I don’t think there are any specific guidelines in this regard in the US, as well. People don’t really know what to do with it. So, this is where most of the research is going. We need to know what algorithm works best at the beginning of therapy. Finding out what dose you need after you are stable on warfarin makes no difference in terms of genetics. I mean, genetics is helpful, but you’re already on a stable dose. The real bang for the buck is understanding the initiation of warfarin based on genotype.
In a single-payor system, does the government currently pay for this type of testing?
Oh, no. For us, the genotyping [at the clinic] will be enrolled in our research component. We will use this information as part of our studies, but this is not part of our regular standard care that the hospital pays for.
What would the regulatory health care body in Canada need to see before they start paying for this?
For any genetic test, they would need to see that it’s as good or as bad as the current standard of care. Presumably, there would need to be some sense that this is saving hospital visits and stopping bleeding incidents. There is a component of patient well being, as well as pharmacoeconomics that would have to be considered. Research in this regard is quite helpful. We’ll be able to say, ‘Well, if you understand genetic make up and have the right nomogram, to come up with a right dose from the beginning, you are likely to stay within target INR for longer duration, or stay within it much better than those that get random care, or just simple INR-based measurements.’
Does your research have a pharmacoeconomic component to it?
The pharmacoeconomic side we will try to measure, but it will take a lot longer. I don’t know if we would have a sufficient number of people. At some point, we really want to do a large trial comparing the best genotype-based algorithm against a standard nomogram that doesn’t take genetic information into account. That’s going to be an essential study to prove the safety and overall benefit [of the genetic approach]. But, right now, there is a clear sense that understanding genotype is still very useful. No one has come out and said we have the best algorithm for genotype-guided therapy.
Having introduced gene-based warfarin dosing in Canada through the hospital setting, do you think this will be adopted more broadly if these types of projects prove successful?
One advantage of the Canadian system [is that the] hospital in essence is government owned, and the government and the hospital are willing to work together to enhance safety and efficiency. Because if the hospital saves money in terms of reducing visits to the emergency room, for example, that is a significant cost saving to the hospital as well as better care for the patient.
In the US system the patient that are seen in an outpatient setting may or may not be going to the hospital that they would be going to if they had a bleeding event. There are different payors involved. In Canada, there is only one payor. The doctors here at the hospital see the healthcare system as one component, so then, it actually makes sense that if you do a better job as an outpatient clinic, you have less inpatient admissions, and thus, lessen severe bleeding events. The hospital was a very useful setting to start our clinic that would allow us to move forward with this type of research.
Are clinics like the one you’ve started at London Health Sciences Center unique in Canada?
I don’t believe there are many groups that are running both research and clinical care. I think from our side we will look after patients whether they participate in the research or not. We don’t think we should only run a clinic to enroll patients for a study. So, we do have a standard clinic that will have a nurse, doctors, and pharmacist look after people who need to have their INRs monitored and doses adjusted. And then a subset of patients may elect to enroll in the genetics-guided study. Either way, it will result in reduced emergency room visits due to warfarin-related problems.
Do you have other such clinics planned in the area of personalized medicine?
This is one of our hopes for an overall view of personalized medicine. And it’s slowly going this way. Many other drugs also have genetic variations that can be very important. There was a paper recently in the New England Journal of Medicine about a risk for muscle injury from statin drugs. The study showed that a genetic defect in the drug transporter that really brings drugs into the liver of the [organic anion–transporting polypeptide] is a major risk factor for a devastating form of statin toxicity. [The study suggests that] out of the millions of people on statins for lipid lowering, a small subset of patients may develop this form of muscle injury that can be fatal.
Our group actually identified this genetic defect seven years ago. It turns out that now it’s one of the most important markers for statin-induced muscle injury. That’s another area we think that consideration should be given to genetic testing.
Certainly, a number of cancer drugs have genetic variations in terms of drug metabolism pathways. So, [these projects in personalized medicine] are not something we would announce next month, but step-by-step, our group, the hospital, and the Department of Medicine, we have an overall vision of delivery of personalized medicine.