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 common genetic variation may influence how well a person recovers from heart surgery, a study published online yesterday in the Journal of the American Society of Nephrology suggests.

Coronary artery bypass surgery, which involves using blood vessels from elsewhere in the body to reroute blood around clogged arteries feeding the heart, increases the risk of low blood pressure and shock.  Norepinephrine can be used to bring blood pressure back up to acceptable levels, but a variation in the gene for an enzyme critical to the metabolism of this drug, COMT, may make some people less responsive.

Researchers studied 260 people who had had bypass surgery and found that those who carried an A at both copies of rs4680 went into shock more often compared to those with other genotypes (69% vs. 57% in AG people and 46.6% in GG people). The A version of rs4680 produces a less efficient version of the COMT enzyme.

Prolonged shock, lasting more than 48 hours, was also more frequent in people with two As (25% vs. 13% for AG and 6.8% for GG). Because the body responds to shock by restricting blood flow to the kidneys, people with two As at rs4680 also had greater frequency of acute kidney injury.

The median hospital stay after bypass surgery was longer for people with two As at rs4680: nine days vs. eight days for AG and seven days for GG.

(23andMe customers can check their data for rs4680 using the Browse Raw Data feature.)

More research on the effects of the COMT variation investigated in this study and variations in other genes that could also affect recovery after bypass surgery will be needed.  But if confirmed, the researchers suggest that their findings could help tailor drug regimens and lead to better outcomes.

“If confirmed in larger trials, preoperative COMT genotyping together with known clinical risk factors could aid in preoperative risk stratification to anticipate occurrence of circulatory and renal dysfunction, and prolonged recovery.  Patients thus identified may benefit from an individualized treatment…” the authors conclude.

• Having two As at rs4680 in the COMT gene has been associated with a number of conditions, ranging from neuropsychiatric and hormonal disorders to cardiovascular diseases. 23andMe customers can read about how this SNP interacts with tea drinking to affect breast cancer risk in the Breast Cancer Risk Modifiers Research Report.  There is also a Research Report about another SNP in the COMT gene and its effects on pain sensitivity.

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Each beat of your heart is the result of a highly coordinated electrical system.  An impulse that starts in a few tiny cells spreads throughout the whole organ, causing cardiac cells to contract, pumping your blood in the never-ending circuit that courses through your body.

The “QT interval”, a measurement made from electrocardiogram recordings of the heart’s electrical activity, reflects the amount of time it takes for cells to reset after a contraction.  If this interval is abnormally long or short, it can scramble the electrical system of the heart, causing an erratic beat and limiting the heart’s ability to supply the body with enough newly oxygenated blood.  This can lead to fainting and, in some cases, sudden cardiac death.

Several genetic mutations that cause long and short QT intervals are known to run in families.  But these mutations don’t account for all cases of sudden cardiac death, nor do they explain the normal variation in QT interval seen in the population.  To learn more about the genetics of heartbeat regulation, two independent research teams (QTGEN and QTSCD) looked for genetic variants associated with natural variation in QT interval in more than 28,000 people.  The results, published online yesterday in the journal Nature Genetics, identify a total of 14 SNPs that can now be used as the basis of future research aimed at understanding susceptibility to QT interval-related irregular heart beat and sudden cardiac death.

“The reason people die from this cardiovascular disorder is because we know nothing about the antecedents,” said Aravinda Chakravarti, QTSCD study senior investigator, in a statement.  “It’s like a truck barreling down a slope: there’s no way to stop it.  The only way out is to understand the science of this in a deep, meaningful way.  If we know, we can begin to intervene.”

More than half of the variants identified by the researchers are located in genes already known to be involved in heart cell regulation, some of which are also mutated in familial syndromes characterized by long QT intervals.  But five of the SNPs are in genes not previously recognized as players in the electrical activity of the heart.  These findings open up new avenues for cardiovascular research.

According to the authors of one study (QTGEN), the variants found in these studies together explain more of the variation in QT interval seen in the population than any other factor except for heart rate.  But they warn that more research is still needed to determine whether the variants actually contribute to the risk for sudden cardiac death in addition to lengthening QT intervals.

The following table lists the variations reported in the studies discussed above.  SNPs available to 23andMe customers are linked to the Browse Raw Data feature.  Note that the individual changes in QT interval attributable to each individual SNP are very small compared to the normal range of 300 to 450 milliseconds (ms). THESE SNPS CANNOT BE USED TO DIAGNOSE OR PREDICT LONG OR SHORT QT SYNDROME.

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One of the much-heralded claims of the post-genomic era is that personal genetic information may allow medical treatments to be tailored to an individual’s genetic makeup. While we are not there yet, a trio of new studies on heart disease may just have brought us one step closer. The studies were the product of a collaboration between researchers at Harvard Medical School and Celera (the company that helped spur completion of the public Human Genome Project).

In the first study of over 25,000 women, those with the GG or AG genotypes at the SNP rs20455 were found to have a slightly increased chance of having a heart attack—about 34% higher than those with the AA genotype. (This study confirmed at least two other preliminary findings that this SNP, which is in the gene KIF6, is associated with heart disease.)

A second study of about 3,000 subjects further confirmed the first finding, and also examined whether the SNP was associated with the outcome of treatment with the cholesterol-lowering drug pravastatin. As other studies have reported, those with the GG or AG genotypes were found to be at higher risk of having a heart attack than those with the AA genotype. But when treated with pravastatin, the risk of heart attack for people with GG or AG was substantially reduced—approximately equal to that of the lower-risk AA group. (Pravastatin treatment had little or no effect on those with the AA genotype.)

Lastly, a third study of about 4,000 subjects compared how rs20455 affected differences in outcomes for people given the standard-dose pravastatin therapy versus high-dose treatment with atorvastatin, another anti-cholesterol drug. Those with the AA genotype saw no additional benefit of receiving the more intense atorvastatin treatment compared to the standard pravastatin treatment. But people in the study with GG or AG did see a significant reduction in their risk of having a heart attack, cutting their risk by about 40% over two years.

23andMe customers may examine their genotype at rs20455 in the Genome Explorer (now called Browse Raw Data) and compare their genetic data to that of the studies in this article. Keep in mind, however, the points made in the introduction to this SNPwatch article.

In addition to the SNPwatch reminder, remember that genetics are only one factor that physicians may consider when prescribing preventive medications for heart disease or any condition. If you have concerns or questions about what you learn through 23andMe, you should contact your physician or other appropriate professional.

Update [2008/01/24]: Although our Gene Journal article on heart attacks (now called Health and Traits) does not currently cover this SNP, we believe that this association has been replicated sufficiently enough to include in the article–we’ll get to it as soon as we can!

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