The U.S. Food and Drug Administration (FDA) has updated the label information for the commonly used anti-clotting medication Plavix® (clopidogrel) to stress to physicians that patients carrying certain genetic variations may not receive the full benefit from the drug.

Plavix reduces the chance a harmful clot will develop by preventing blood cells called platelets from sticking together. Usually prescribed in combination with aspirin, Plavix has been shown to help reduce the risk of subsequent heart attacks or strokes in people who have already suffered from a cardiovascular event. Plavix also reduces the risk of heart attack and stroke in people diagnosed with peripheral artery disease.  The drug is also is used to lower the risk of blood clots in people with unstable angina (chest pain) caused by partially blocked arteries and in those who have had a stent implanted to help keep their arteries open.

Once inside the body, Plavix is absorbed in the intestines and then converted into its active form by enzymes in the liver. But some people have genetic variations that reduce the activity of one of the most critical enzymes — CYP2C19. This, in turn, reduces the amount of active drug in the bloodstream and its effectiveness in preventing clots.

The FDA first added information about poor metabolizers of Plavix to the drug label in May 2009. Additional data has prompted them to add the boxed warning to further caution physicians that some of their patients may be at risk, inform them that testing for CYP2C19 variations is available (although no test is FDA-approved specifically for determining Plavix efficacy), and recommend that other medications or increased dosages of Plavix be used in patients identified as poor metabolizers.

“We want to highlight this warning to make sure health care professionals use the best information possible to treat their patients,” said Mary Ross Southworth, Pharm.D., a clinical analyst in the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research, in a press release.

A recently approved drug, Effient® (prasugrel), may be an alternative for some patients identified as poor metabolizers. Like Plavix, Effient prevents platelets from forming blood clots. The advantage is that the conversion of Effient to its active form can take place in the presence of the genetic variations that affect Plavix. Studies have shown that Effient is effective at preventing heart attacks, strokes and stent-blocking clots.  The risk of dangerous bleeding, however, is higher with this drug.

23andMe Health Edition and Complete Edition customers can view their data for genetic variations in CYP2C19 in the Clopidogrel (Plavix) Efficacy Drug Response Report.

A downloadable PDF version of the Clopidogrel (Plavix) Efficacy report is available to help customers share their results with their doctors.

Only a physician can determine whether Plavix is the right medication for a particular patient and at what dosage it should be given.  The information contained in 23andMe Drug Response reports should not be used to independently establish a drug regimen or abolish or adjust an existing course of treatment.  If you are concerned about Plavix, talk to a health professional.

• Read more about the Plavix label update here and here.
• Just last month the FDA updated the label on another anti-clotting medication, warfarin, to include more information on the effects of genetic variations.  Read more here in the Spittoon.

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Medco Health Solutions, Inc., announced this week that it will conduct a clinical trial to assess whether clopidogrel bisulfate (Plavix®, Bristol-Myers Squibb and Sanofi-aventis) is just as effective as the newer drug prasugrel (Effient™, Eli Lilly and Company) in people who lack a genetic variation that inhibits their metabolism of clopidogrel. This new research has important implications for both patient safety and health care costs.

Both clopidogrel and prasugrel are anti-platelet medications that reduce the ability of blood to form clots. The drugs are used to reduce the risk of a heart attack and stroke in people who have suffered from a recent cardiovascular event, and in those who have peripheral artery disease, unstable angina or a stent.

Variations in the CYP2C19 gene that prevent clopidogrel from being converted into its active form in the body have been shown to prevent patients from receiving the drug’s full benefit. People with these gene variations who are taking clopidogrel may be at a higher risk for heart attacks, strokes and death from cardiovascular causes than those whose genetics allow them to metabolize the drug.

(Prasugrel is metabolized through a different biological pathway than clopidogrel, and is not affected by CYP2C19 variants.)

23andMe customers can see their data for several important CYP2C19 variations in the ‘Clopidogrel (Plavix®) Efficacy’ Clinical Report.

Medco’s study will assess patients’ rates of nonfatal heart attacks, nonfatal strokes and cardiovascular deaths after six months of treatment with either clopidogrel or prasugrel. Researchers will be looking to see if there is any difference between those patients who are taking clopidogrel, and whose genetics predict that they should be able to metabolize it—and those patients who are taking prasugrel.

“Plavix is going generic in 2011 and if found to be equally effective as Effient for patients who have a normally functioning version of the CYP2C19 gene, the study provides the evidence that would allow these patients to opt for a lower cost treatment,” said Medco’s chief medical officer Dr. Robert Epstein in a press release.

Former U.S. Secretary of Health and Human Services Michael O. Leavitt was quoted in the Medco press release as saying, “Studies like this are necessary to show how innovation can derive greater value from what we spend on health care.  A simple test can identify a drug’s ability to work for a particular patient or point them to another one that could provide a better outcome. Personalized medicine is the new frontier in making medication safer and more effective. What we learn from this study, and others like it, will save lives and money.”

Patients aren’t the only ones who would save if Medco’s research shows that the soon-to-be generic clopidogrel is an effective choice for them. An Associated Press story notes that generic drugs are more profitable for Medco than higher-priced brand name products.

Comparative effectiveness research has received a lot of attention in the United States health care debate lately.  Some worry that it will result in policies that are not in patients’ best interests.

“We need to be mindful of the goal of comparative effectiveness research and not lose all that we have gained in understanding how individuals differ and how that could be factored into better diagnostics and preventive strategies,” said National Institutes of Health (NIH) director Francis Collins, speaking at a recent American Association for the Advancement of Science forum on personalized medicine.

Collins recommended that genetic factors be included in comparative effectiveness research (as is the case in Medco’s study), to make sure that treatments that work for specific groups of patients are not “lost in the wash by considering everybody equivalent.”

The Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study (GeCCO) is part of Medco’s “Genetics for Generics” program and is registered with the NIH.

Related Spittoon Posts:
More Evidence that Genetics Can Reduce the Efficacy of Anti-Clotting Medication Clopidogrel
SNPwatch: Genetic Variants May Reduce Ability of Anti-Clotting Drug Clopidogrel to Prevent a Second Heart Attack

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A new report in the Journal of the American Medical Association adds to the mounting evidence that genetic variations impact the efficacy of clopidogrel (Plavix®), a drug used to prevent blood clots in people who have had a heart attack or stroke and also those with peripheral artery disease and unstable angina.

Previous research has shown that certain variations in the CYP2C19 gene prevent the body from converting clopidogrel into its active form. That reduces the amount of anti-clotting effect people get from the medication, increasing their risk for heart attacks, strokes and death from cardiovascular causes.

(23ndMe customers can learn how their data fits in with this research in a previous Spittoon post or in the Clopidogrel Efficacy Drug Response Report.)

The researchers, led by Alan Shuldiner of the University of Maryland School of Medicine, determined that BMI, lipid levels and age account for about 10% of the variation in clopidogrel’s ability to prevent blood clotting. Variation in the CYP2C19 gene accounted for another 12%, meaning that other factors, probably both genetic and non-genetic, are also at work.

For patients whose genetics may reduce the benefits of clopidogrel treatment, there are other options. Prasugrel (Effient®) was recently approved by the FDA and appears not to be affected by the same variations that impact clopidogrel efficacy, although there are some concerns about bleeding caused by this drug.  Several other drugs (ticagrelor, cangrelor, elinogrel) that could be used for clotting reduction in place of clopidogrel are currently in clinical trials.

Clinical trials have not yet been conducted to show if identifying people with variants of the CYP2C19 before prescribing clopidogrel actually improves health outcomes.  If such studies do show a benefit and this type of testing becomes routine, people with these variants might be steered away from clopidogrel by their doctors, which would seem to be a boon for the makers of newer medications.

But in an editorial accompanying the study in JAMA, Deepak Bhatt suggests that testing for these variations would also allow physicians to know for whom clopidogrel will work (probably). This would be an important piece of information considering that the patent on clopidogrel is set to expire in 2011, so cheaper generic forms of the drug will be available then.

“Although such testing currently is expensive, the cost will decrease and hopefully will coincide with supportive data.  Furthermore, if such testing allowed use of a less expensive generic anitplatelet drug, the test might essentially pay for itself,” he writes.

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Every year, about half of the more than one million people in the United States who have a heart attack survive. But because the first heart attack increases their risk for another one, these people must make major adjustments in their lives to keep their hearts healthy in the future.

In addition to adopting a healthy diet, quitting smoking and losing weight, most people who’ve had a heart attack take medications to help further reduce their risk. Clopidogrel — sold under the trade names Plavix, Iscover, Clopilet and Ceruvin — is a drug commonly prescribed (often in combination with aspirin) to help prevent platelets in the blood from forming clots that can block blood flow to the heart.

Clopidogrel is converted into its active form once it is inside the body. But some people carry genetic variants that reduce the activity of an enzyme central to this conversion process, which in turn reduces the amount of active clopidogrel in the bloodstream and the effectiveness of the drug in preventing clots. Three reports published online this week – two in the New England Journal of Medicine and one in The Lancet – show that these genetic variants can increase the chances that a patient will suffer a second major cardiovascular event.

Jessica Mega and co-workers from Brigham and Women’s Hospital and Harvard Medical School in Boston tracked 1,477 subjects who had had unstable angina or a heart attack and were taking clopidogrel.

Their results, published in NEJM, showed that those people who carried one or more copies of a function-reducing variation in the CYP2C19 gene that (referred to as *2, *3, *4 and *5) had 1.53 times the risk of having a heart attack, stroke or dying from cardiovascular causes compared to non-carriers. The risk of a stent-blocking clot (in those patients who had stents implanted during angioplasty to keep their arteries open) was increased three-fold.

The second NEJM report, from researchers at several Paris hospitals led by Tabassome Simon, showed that in a group of 2,208 heart attack patients taking clopidogrel, carrying two CYP2C19 variants (any combination of *2, *3, *4, or *5) led to a 1.98 times increased risk of heart attack, stroke or death from any cause. Among the 1,535 patients who underwent angioplasty while in the hospital, having two function-reducing CYP2C19 variants increased the risk of cardiovascular events by 3.58 times.

Unlike the study from Mega et al, Simon and colleagues did not see an increased risk in those people with only one copy of a CYP2C19 function-reducing variant.

Finally, Jean-Philippe Collet and colleagues (also from Paris, France) followed the outcomes for 259 young (< 45 years old) heart attack patients taking clopidogrel. Their results, published in The Lancet, showed that having one or two copies of the CYP2C19*2 variant increased the risk of a second heart attack by 4.54 times. The risk of a stent-blocking clot increased 6.02 times.

Collet et al did not investigate the other CYP2C19 variants included in the other reports.

(23andMe customers can check whether they carry any of the CYP2C19 variants mentioned in these reports, except for CYP2C19*5, using the Browse Raw Data feature. See the table at the end of this post for more information.)

Although the magnitude of the effect of CYP2C19 variants was different in each report, all three did show that versions of the CYP2C19 gene that reduce its ability to activate clopidogrel also increased the risk of a second cardiovascular event in those patients who have already suffered one. Based on these results, both Simon et al and Collet et al suggest that genotyping patients might be a good alternative to the current practice of monitoring their platelet response to clopidogrel.

But in a commentary accompanying the report in The Lancet, Dr. Robert Storey of the Cardiovascular Research Unit at the University of Sheffield School of Medicine, UK, argues that testing platelet function in patients is faster than genotyping, and has the added benefit of finding patients who are not responding to clopidogrel due to factors other than CYP2C19 variants, such as age, diabetes, renal failure and cardiac failure.

“Genotyping of patients with acute coronary syndrome is not necessarily the appropriate solution without further work to validate such an approach,” he writes.

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