Cardiovascular conditions are the leading cause of death worldwide.A. MASSEE/SPL
Posted on 08/22/2009 12:03:18 AM PDT by neverdem
Gene-association studies hint at better ways of treating the leading cause of death, but capitalizing on them is proving to be a slow and difficult process. Erika Check Hayden reports.
Cardiovascular conditions are the leading cause of death worldwide.As personalized cancer treatment edges into the clinic, doctors and scientists are hoping that cardiovascular disease — the world's top killer — will be next to benefit from genomics.
An avalanche of studies has linked genetic variants to various cardiovascular conditions and to patients' responses to commonly prescribed drugs. First up could be genetic guidance for the anti-clotting agents warfarin and clopidogrel, followed by testing for genetic variants responsible for conditions such as atrial fibrillation, a heart-rhythm abnormality that is a leading cause of stroke.
Doctors caution that there is a long way to go before the hints raised by gene-association studies translate into solid evidence that genetic variants can improve clinical practice. "I would hope that cardiovascular disease would be one of the next leading areas of personalized medicine, because it has such an enormous impact on public health," says Christopher Granger, a cardiologist at Duke University Medical Center in Durham, North Carolina. But "we're at a primitive stage right now", he says.
Warfarin exemplifies some of the promise and pitfalls of personalized medicine. The drug is commonly used to prevent clotting in patients who have atrial fibrillation and other conditions, yet the dose needed varies from patient to patient; if it's not precisely right, it can trigger fatal haemorrhaging. In 2007, after studies found that variants in two genes, CYP2C9 and VKORC1, account for up to half of the reason why patient response differed, the US Food and Drug Administration (FDA) changed the labelling to suggest that doctors consider using genetic tests to guide dosing.
Yet studies have failed to show that such tests help improve patient outcomes. In 2007, for instance, a trial of 206 people reported that using information about a patient's genetic variants to guide their dosing regimens didn't lessen the risk that patients on warfarin would develop unsafe levels of clotting proteins1. And this January, another group reported that genetic testing wouldn't save money if done in all patients prescribed the drug, partly because it still costs hundreds of dollars to determine the genetic variants of each patient2.
The US National Heart, Lung and Blood Institute in Bethesda, Maryland, is now sponsoring a larger clinical trial to test the usefulness of genetically guided warfarin dosing. But as Eric Topol, director of the Scripps Translational Science Institute in La Jolla, California, says: "Warfarin was kind of the poster adult for pharmacogenomics, but it's really lost favour."
He and other doctors now see greater potential instead for clopidogrel, marketed by Bristol-Myers Squibb of New York and Sanofi-Aventis of Paris as Plavix. Clopidogrel is given to fight clotting, including in patients who have already had a stroke or heart attack. The drug, second in the world in global sales, is converted in the body into an active form that inhibits the pro-clotting protein P2Y12. But it, too, can cause haemorrhages.
In December, three groups reported that variations in the CYP2C19 gene were associated with an increased risk of cardiovascular events in patients on clopidogrel3,4,5, and a poor ability to convert clopidogrel into its active form4.
And last month, the FDA approved a new drug, prasugrel, which is a more potent inhibitor of P2Y12 but also carries a higher risk of bleeding. It is conceivable that patients who have the genetic variants associated with poor response to clopidogrel might instead be treated with prasugrel, says Matthew Price, an interventional cardiologist at Scripps Clinic/Green Hospital in La Jolla.
Predicting the overall risk of cardiovascular diseases is proving even more complicated than treating them with genetically targeted drugs. Many genome-wide association studies have been done, but few have uncovered variants that, on their own, boost the risk of cardiovascular disease very much. And taken together, the variants discovered so far still don't explain most of the genetic risk of various diseases.
For instance, last January, US researchers aimed to improve risk prediction of cardiovascular disease by adding information about a genetic variant associated with coronary artery disease and diabetes to other risk factors, such as smoking, cholesterol levels and family history of heart attack.The variant, found on chromosome 9, had formed the basis of a genetic test sold by deCODE Genetics in Reykjavik, Iceland. The team found that genotyping the variant did not improve the ability to predict whether the 22,129 women in the study would develop heart disease6. "Our study didn't show very much change [in risk-prediction ability], especially over the risk score that had family history in it already," says Nina Paynter, team leader and an epidemiologist at Brigham and Women's. "I was a little bit disappointed."
Since Paynter's study began, however, many more genetic associations with cardiac risk have been reported, and companies such as deCode, Navigenics of Foster City, California, and 23andMe of Mountain View, California, now sell tests that purport to assess heart-disease risk using combinations of these variants. Paynter's group is evaluating multi-variant genomic tests, as is the independent Evaluation of Genomic Applications in Practice and Prevention initiative set up by the US Centers for Disease Control and Prevention in 2004, which is expected to issue recommendations on their use this autumn.
“I would hope that cardiovascular disease would be one of the next leading areas of personalized medicine.”
Other groups have already examined genomic tests for diabetes, which greatly increases the risk of heart disease and stroke. Last year, for instance, three groups published studies examining whether a number of variants associated with diabetes could predict a person's risk of developing this disease7,8,9. All found that the variants added little to the predictive value of known diabetes risk factors, such as obesity, smoking and family history.
In addition, the way these genomics tests are reported can be confusing to consumers. Companies update consumers' risk profiles as new variants are discovered, but because each new variant changes a person's risk so little, variants added to a risk profile can cancel out previous ones.
A team led by Cecile Janssens of Erasmus Medical College in Rotterdam, the Netherlands, showed this by studying the same diabetes-associated variants analysed in the 2008 risk-prediction studies10. When genotypes of 17 of these variants were added to an existing risk profile based on variants of TCF7L2 — a gene whose variants confer a substantial increase in risk of common forms of diabetes — 34% of the patients' risk profiles changed, for example, from high to low or low to high. When data about patients' age, sex and body mass index were added to the profiles, 29% changed risk categories, and 11% of the participants reverted to their initial risk category.
Patients hoping to use their genotyping results to motivate healthy lifestyle changes might thus be confused when their disease risk changes multiple times without any action on their part, Janssens says: "Our studies show that these products are not ready for prime time."
Cardiologists hope that will change, and see some promise on the horizon in specific cardiovascular diseases.
Last month, for instance, two research teams published studies that linked variants in the ZFHX3 gene to atrial fibrillation11,12. Two years ago one of the same groups published variants adjacent to a separate gene, PITX2, that almost doubles the risk of atrial fibrillation13. Drugs and monitoring can be used to treat the condition, and might help prevent the roughly one-third of strokes that have no known cause. So atrial fibrillation could serve as an early example of genomic risk prediction, Topol says.
"To be able to zoom in on the probable cause of a stroke by genomics, and then institute a much more intensive heart-rhythm monitoring programme, would be a whole new path that we didn't have months or even a year ago," he says.
But even if the tests are proven useful, they may still have a limited impact on patient care — at least at first. Granger says that doctors already have various risk-prediction tools that work, but don't use them effectively. For instance, patients with higher levels of the protein complex troponin, an indicator of heart-muscle damage, do better on certain treatment strategies. But, Granger says, they are no more likely to get those drugs for various reasons, including that family doctors are not as familiar with the cardiac literature. "Part of our challenge is that we've already got some information that could help us better customize medicine to patient risk, and we tend not to be doing that in practice."
Remedying that problem will require more physician education — and some knockout examples of genetic profiling aiding medicine, as seems to be happening in cancer. "Maybe we need a couple of major success stories of the benefit of using genetic variants for treatment of disease, and I think we're getting some of those," Granger says. Cancer drugs may be blazing the trail for personalized medicine, but cardiovascular drugs may not be far behind.
The experts know less than they care to admit.
I know one thing - I would never let anyone roto-rooter my blood vessels. Angioplasty and bypass surgery are no more effective in the long term (5 years +) than drug therapy. The risks are real; the benefits highly questionable.
Don’t expect a cardiologist to agree. Their knee-jerk resonse is to fiddle with your arteries and heart, in spite of the evidence showing it is not the safest or best treatment option.
Yes, there are many other procedures that are questionable by other Doctors... the problem is who to listen to.
My gosh, in the last few years, what use to be know bad for you is now good and visa versa... It only goes to show that sometimes medicine and other fields are varying...ie, they don’t always know what they are talking about, (Reminds me of other scientific fields).
It’s kind of like a jig-saw puzzle...you have to fit the pieces together yourself.
In the end, you have to go with you you feel you know and hope for the best. Most of what we know today will be gibberish in the future anyway...
Completely agree.
Cardiologists are second only to general surgeons in their absolutely unjustified arrogance.
I would argue a bit about that statement, at least in my specific case.
In 1974 I had a massive heart attack (LAD blocked) and was left with nothing but angina and a miserable existence. Medicine did little or nothing to help, and the future looked awfully bleak.
Then in 1981 I had 6 coronary bypasses, and it was as if the surgeons had passed a miracle. No more angina, no more coronary pain. I could walk 5 or 6 miles at a semi-trot without angina.
The surgery was 28 years ago, and the bypasses are still open. I live an active life. And that's thanks to CAGB.
You are so full of it.
If you ever have to go to an ER with a heart attack in progress, I bet you change your mind.
No, I don’t think so. I still believe drug treatment is as good or better than angioplasty, stents, bypass, or any other kind of violence that cardiologists are wont to do to one’s blood vessels. The benefit does not justify the risk involved, and the outcomes are better in the long run for drug treatment. The studies supporting this view are beginning to appear, but don’t expect all the hospitals dedicated to invasive cardiology to give up their preconceived notions easily.
I refer you to the books by Dr. Nortin Hadler, MD. His most recent is Worried Sick and is probably at your local library.
I’m very glad to hear it. We need all our Freepers! :-)
I agree completely! What is good one day is bad the next. Part of the problem is the way epidemiology has been stretched to try to provide explanations for every disease and malady we experience. Some things just cannot be studied accurately. Most of the studies that purport to say eating or not eating various foods, for example, are based on asking large groups of diverse people to remember what they ate over the course of a year. How absurd!
You have to take everything with a grain of salt and make the best decisions you can with what you know.
Bingo...right on...
Exercise beats angioplasty for some heart patients
By MARIA CHENG AP Medical Writer
Published: 8/30/2009 2:21 PM
BARCELONA, Spain — Working up a sweat may be even better than angioplasty for some heart patients, experts say.
Studies have shown heart patients benefit from exercise, and some have even shown it works better than surgical procedures. At a meeting of the European Society of Cardiology on Sunday, several experts said doctors should focus more on persuading their patients to exercise rather than simply doing angioplasties.
Angioplasty is the top treatment for people having a heart attack or hospitalized with worsening symptoms. It involves using a tiny balloon to flatten a blockage and propping the heart artery open with a mesh tube called a stent. Most angioplasties are done on a nonemergency basis, to relieve chest pain caused by clogged arteries cutting off the heart’s blood supply.
“It’s difficult to convince people to exercise instead of having an angioplasty, but it works,” said Rainer Hambrecht of Klinikum Links der Weser in Bremen, Germany.
Hambrecht published a study in 2004 that found that nearly 90 percent of heart patients who rode bikes regularly were free of heart problems one year after they started their exercise regimen. Among patients who had an angioplasty instead, only 70 percent were problem-free after a year.
Hambrecht is now conducting a similar trial, which he expects to confirm his initial findings: that for some heart patients, exercise is more effective than a surgical procedure.
Other experts agreed that would likely be the case.
An angioplasty “only opens up one vessel blockage,” said Dr. Christopher
Cannon, an associate professor of medicine at Harvard University and spokesman for the American College of Cardiology. He was not linked to Hambrecht’s research. “Exercise does a lot more than fixing one little problem.”
Among other benefits, exercise lowers bad cholesterol while raising good cholesterol, helps the body process sugar better, improves the lining of the blood vessels and gets rid of waste material faster. Exercise also lowers blood pressure and prevents plaque buildup in the arteries.
Previous research has estimated one third of heart disease and stroke could be prevented if patients did two-and-a-half hours of brisk walking every week. In the U.S., that would mean 280,000 fewer heart-related deaths every year.
Joep Perk, a professor of health sciences at Sweden’s Kalmar University and spokesman for the European Society of Cardiology, said two thirds of heart patients in line for an angioplasty could probably get better benefits by regularly working up a sweat.
Experts say less than 20 percent of heart patients get the recommended amount of exercise — about 30 minutes of moderate activity five times a week.
Perk said doctors who performed angioplasties on their patients without asking them to change their lifestyles were ignoring the fundamental problem. “It would be like getting rid of the most troubled rust spots on a car without doing anything to stop more rust from appearing tomorrow.”
Still, doctors admitted that persuading patients to exercise instead of simply going in for an angioplasty, which can take less than a day, would be a tough sell.
“Most patients want the quick fix,” Cannon said. Exercise may improve patients’ hearts better than an angioplasty, but it may also take months or even longer for patients to feel the benefits. “It’s a lot easier to get your artery fixed than it is to exercise every day.”
From the article:
Angioplasty is the top treatment for people having a heart attack or hospitalized with worsening symptoms. It involves using a tiny balloon to flatten a blockage and propping the heart artery open with a mesh tube called a stent. Most angioplasties are done on a nonemergency basis, to relieve chest pain caused by clogged arteries cutting off the heart’s blood supply.If it's an emergency or you're getting worse in the hospital, get one. If it's a non-emergency, consider the exercise.
thanks, bfl
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