Scripps Starts Routine Genetic Testing for Clopidogrel Responsiveness

October 15, 2009

October 15, 2009 (San Diego, California)In what is believed to be a first for a health system in the US, Scripps Health has announced that it is now offering patients undergoing elective stenting a test for the gene variants associated with an inability to convert clopidogrel to its active metabolite, so that antiplatelet therapy can be "individualized" [1].

The reduced-function CYP2C19 allele is present in around 30% of people of European ancestry and more than 40% of those of African or Asian ancestry. Dr Eric Topol, chief academic officer of Scripps Health, explained to heartwire that many different studies have now shown that people with these gene variants carry double or triple the risk of death, MI, or stroke, compared with people with the normal metabolism alleles. Under the new program at Scripps Health, these people will be identified and will have their treatment adjusted as the treating physician sees fit.

The physician could choose to just treat with the normal 75-mg dose of clopidogrel and watch carefully; increase the dose of clopidogrel to 150 mg daily; or use the new antiplatelet drug prasugrel or, in the future, ticagrelor.

Scripps physicians will initially offer the genetic tests at Scripps Green Hospital, but Scripps may eventually extend the offering to its other facilities across San Diego County. Scripps has partnered with Quest Diagnostics for this initiative. Quest will perform the CYP2C19 testing for Scripps patients at its Quest Diagnostics Nichols Institute laboratory, in San Juan Capistrano, CA. The results will be transmitted to the treating physician, and treatment choice can be modified based on the patient's risk for lack of clopidogrel effect, with respect to the coronary anatomy and bleeding risk.

The increased risk of patients with this gene variant is incontrovertible. We can't just do nothing and leave them like sitting ducks.

"Knowing a patient's individualized risk has a tremendous impact on treatment decisions," said Dr Paul Teirstein, head of interventional cardiology at Scripps Green Hospital and Scripps Clinic, in a press release from Scripps Health. "The point is to do everything we can to give patients the best possible outcomes. This kind of genomic screening gives us critical information we need to help patients."

Topol commented to heartwire : "The increased risk of patients with this gene variant is incontrovertible. We can't just do nothing and leave them like sitting ducks. The biology is clear. The only thing that isn't clear is what you do for that individual patient. But it is too difficult to study that in a randomized trial, as there are too many factors that have to be taken into account, such as bleeding risk on prasugrel, risk status of coronary anatomy, cardiac function, etc. This is individualized medicine on two levels--ascertaining the genotype of each patient, and using this to guide therapy choices based on each individual patient's characteristics." He added that these patients will be tracked and a comprehensive database maintained, thus generating new data to work with in the future.

Is It Ready for Prime Time?

But some other experts are cautious about such an approach, suggesting that it might be too early to justify routine screening at present and there are too many outstanding questions. One of these is Dr Peter Berger (Geisinger Health, Danville, PA): "I am reluctant to disagree with Eric, because he has a long history of being ahead of the curve and ultimately being proven right. But on this issue, I am not so sure," Berger told heartwire .

"First, the genetic substudy from CHARISMA (on which I was a coinvestigator) raised questions about whether this loss-of-function polymorphism is associated with a worse outcome independent of the antiplatelet drug(s) a patient is on. Only about half of patients who have it are hyporesponders to clopidogrel, and in almost all examples I am aware of, phenotype trumps genotype. Furthermore, I am not even sure how hyporesponsiveness should be measured--with what device, using which cutoff, and how, or even if, it should be used to guide an individual patient's therapy," Berger added.

Dr Robert Harrington (Duke University, Durham, NC) thinks the Scripps approach is a good idea as a research tool, but he also questioned whether genetic testing for clopidogrel response is ready for routine implementation. "This is certainly very forward thinking, as we would expect of Eric Topol. As a research tool, the proposed plan is interesting and has great merit. I'm assuming that they will be following these patients to track outcomes, etc. In that case, it makes some sense to embark on something like this at a place like Scripps. I don't believe that the available data support wide-scale testing and adapting of therapy based on that testing. We don't have enough good data about the second step (ie, adapting the choice of antiplatelet therapy as a response to the genetic test).

Dr Shaun Goodman (St Michael's Hospital, Toronto, ON) holds similar views: "I believe this is an exciting research opportunity, and Dr Topol and Scripps Health are the ideal group to pursue this. However, I don't believe that the current published data support routine genetic testing in patients undergoing stenting."

He points to the recent controversy over the association between proton-pump inhibitor (PPI) use and clopidogrel. "As we have been recently reminded . . . we should be cautious about distinguishing between association (eg, identifying patients at increased risk for stent thrombosis based on their genetic profile) and cause and effect (ie, modification of treatment to produce a better outcome) before considering implementation of a 'screening test' in routine clinical practice. They may indeed be on the right track and ahead of the curve, but I believe that this should still be considered an open question requiring additional research before it's ready for 'prime-time' utilization," Goodman said.

Topol: Randomized Trial Not Possible

But Topol responds that these views do not acknowledge the "critical importance" of the genomewide association study performed in the Amish [2]. And he adds that the PPI story is completely different from the work that has been done to nail down the importance and risk of CYP2C19 loss-of-function alleles. "To say we need to wait for more studies is backward thinking," Topol told heartwire . "That kind of thinking is what holds up progress in medicine."

There are times when you have to take biologically valuable information and extrapolate that and take care of patients better, and that's where we are now.

He added: "There are already too many studies showing striking findings of elevated risk of stent thrombosis, stroke, and death in these patients. There is no question that something else needs to be done for these patients. There has to be an effect of using more potent antiplatelet regimens in this group. The question is, 'What is the optimum therapy?' and there is no optimal therapy for all patients. It has to be worked out on the individual patient level. There is no randomized trial that could possibly study all the logical ways to individualize the approach for each patient who carries unequivocal heightened risk for stent thrombosis. The data show that high-dose clopidogrel has clearly been shown to be more effective than the conventional dose and that prasugrel does not seem to be affected by this cytochrome. In fact, it may be that the benefit of prasugrel and ticagrelor over clopidogrel may be accounted for by this group of patients who do not respond well to clopidogrel. There are times when you have to take biologically valuable information and extrapolate that and take care of patients better, and that's where we are now."

Topol notes that in a recent [industry-supported] panel recorded for, he asked several experts in the antiplatelet field if they would want their genotype assessed if they themselves were undergoing stent implantation, and all said absolutely yes. "Well, if it's good enough for them, then why isn't it being done for every patient?" he asks.

What About GRAVITAS?

Berger also raised the point that this announcement might harm the GRAVITAS study, which is testing a higher dose of clopidogrel in 2800 patients shown to have high platelet reactivity on the standard dose, with cardiovascular events as the main outcome. Both Berger and Topol are on the steering committee of this trial. "It seems to me that the GRAVITAS study is ideally designed to address some of these questions that have not yet, in my opinion, been definitively answered," Berger commented to heartwire .

But Topol responded: "I respectfully disagree with Peter regarding GRAVITAS, which will not assess the relationship between genotype and the various strategies that one can implement for individuals who carry at least one risk allele of CYP2C19."

Use With Platelet-Function Testing?

Others believe that such gene testing needs to be done alongside platelet-function tests. One to have such an opinion is Dr Bernard Gersh (Mayo Clinic, Rochester, MN). He commented to heartwire : "The bottom line is that this is really an interesting and also logical approach but probably should be done in conjunction with some analysis of platelet responsiveness." He also suggested that the genome findings need to be validated in other clinical trials done in a prospective manner before justifying the widespread use of genotyping for CYP2C19 variants to guide clopidogrel therapy and justify the cost of more expensive alternatives, especially if clopidogrel becomes generic soon. "The cost benefit may have to be then carefully analyzed in the context of cardiovascular-related hospitalizations and lives saved," he said.

Topol responds that he has no problem with adding platelet-function testing into the mix. "That might well be helpful," he commented, but he pointed out that platelet function has the drawback of varying at different time points. "The problem with platelet-function testing is that it is dynamic. You may have to test the patient several times to get an accurate picture. But genotyping is fixed. It is not going to change. It is the real deal," he argued.

Topol adds: "The genomewide study showed that CYP2C19 was the most common cause of loss of function, but it is not the only cause. Certain individuals may have something going on in their P2Y12 receptor, or other cytochromes may come into play in others. So there is variability. It isn't that straightforward. If a patient has a CYPC219 loss-of-function allele but still shows good platelet inhibition on clopidogrel, then that is comforting, and 75-mg clopidogrel is probably okay for that patient. But relying on platelet-function tests alone is not the best strategy, as there is too much noise. You could be misled by one single result. You need several measurements.

"With genotyping, one test can give you a pretty good idea of whether a patient will respond to the normal clopidogrel dose or not. Also, it is relatively inexpensive to do--it costs less than measuring platelet function. It provides consistent, important information. Yes, you can add to that by measuring platelet function, but if you want just one test to give the most information, I would go for genotyping every time," he said.

Results in Two Days

Topol explained that the results of the gene test take about two days to come in. "In some patients, yes, we could get the results before the stenting procedure, but this won't be possible for all patients at present, as many patients are referred in. It doesn't have to be done beforehand, because they are on this drug for a year. At the moment, we send the blood out and the results are back in two days. But it will probably get down to a matter of hours in the next year or so."

He added: "There is already an iPhone application for your genetic data, so anyone who has had a genomewide scan, which you can do for a few hundred dollars, will know their CYP2C19 status, and someday this will be a consumer-driven story. You will be able walk into your doctor's and say. 'Don't give me that drug, or give me high dose or low dose' or whatever, based on your genetic data. We're not there yet, but that's where we're going. But for now, we are doing single genotype tests."

Topol is editor-in chief of He has served as a consultant to Sanofi-Aventis and Daiichi-Sankyo. Berger  has served as a consultant to Accumetrics, the Medicines Company, Eli Lilly/Daiichi-Sankyo, AstraZeneca, and Novartis/Portola (each for less than $10 000) and has received research funding from Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, the Medicines Company, Corgenix/Aspirinworks, and Lilly/Daiichi-Sankyo. Goodman receives research grant support and speaker/consulting honoraria from Sanofi-Aventis/Bristol-Myers Squibb (clopidogrel), Eli Lilly/Daiichi-Sankyo (prasugrel), and AstraZeneca (ticagrelor).  Harrington is director of the Duke Clinical Research Institute, which has research contracts with manufacturers of all the oral antiplatelet agents. Gersh serves on the advisory board for Boston Scientific, Bristol-Myers Squibb, and AstraZeneca.