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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This Monday acting Surgeon General Steven K. Galson issued a Call to Action to reduce the number of people in the United States affected by two serious blood clotting conditions: deep vein thrombosis and pulmonary embolism.

Deep vein thrombosis (DVT), sometimes called “economy class syndrome” is the formation of a blood clot in a vein deep within the body, usually in the legs. Pulmonary embolism (PE) occurs if the clot breaks free and travels through the circulatory system to the lungs. Together these two conditions affect an estimated 350,000 to 600,000 Americans each year and contribute to at least 100,000 deaths.

“Deep vein thrombosis and pulmonary embolisms are often ’silent’ conditions — they can occur suddenly and without symptoms,” Galson said in a statement. “But we have made a lot of progress in understanding how these disorders develop and how to prevent, diagnose, and treat them. It’s time to put this knowledge into action.”

Researchers have found that DVT and PE usually develop in response to a triggering event – being hospitalized or confined to bed rest, having major surgery, suffering a trauma, or traveling for several hours — in people who either have an inherited predisposition to blood clotting disorders or another risk factor.

23andMe customers have access to their data for the two most common genetic risk factors for DVT and PE (collectively known as Venous Thromboembolism).

Having the riskier version of one or both of the SNPs 23andMe reports data for (Factor V Leiden and Prothrombin 20210) significantly increases the risk of developing DVT or PE. An estimated 15 to 20 percent of DVT/PE patients have the Factor V Leiden mutation, while 6 percent have the Prothrombin 20210 mutation.

The average risk of DVT/PE in people between the ages of 40 and 59 (anyone can be afflicted, but risk does increase with age) is 2.5%. But in those people in this age group who inherit a copy of the Factor V Leiden mutation, the risk jumps to 11%. Having one copy of the Prothrombin 20210 mutation raises the risk to 8.8%. In the unlucky few who have one copy of each of these mutations, the risk is a 32%. And in the extremely rare case that someone inherits two copies of both mutations, the risk of DVT/PE is 69%.

(This information applies only to those with European ancestry. Average risk numbers are different for other groups, and the genetic risk factors discussed here are not usually found in people with African or Asian ancestry.)

Other risk factors for DVT and PE include being overweight or obese, cancer and its treatment, pregnancy and childbirth, use of hormones for birth control or menopause, and smoking.

“We want to increase the awareness and knowledge of these potentially deadly conditions and encourage patients and health care providers to take the steps to prevent them,” Galson said.

For more information:

• Surgeon General’s Fact Sheet on Deep Vein Thrombosis and Pulmonary Embolism
• The Coalition to Prevent Deep-Vein Thrombosis
• Patient and Provider Guides from the Agency for Healthcare Research and Quality (also available in Spanish)

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