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A common variation in a gene may modify the cardiovascular benefit of aspirin

A new study, "Polymorphisms in Catechol-O-Methyltransferase Modify Treatment Effects of Aspirin on Risk of Cardiovascular Disease," appearing online July 17, 2014 in the journal Arteriosclerosis, Thrombosis and Vascular Biology suggests that a common genetic variation in the COMT gene may modify the cardiovascular benefit of aspirin, and in some people, may confer slight harm. That means if you have certain mutations in a gene, aspirin may not be the right solution for your individual needs.

A common variation in a gene may modify the cardiovascular benefit of aspirin.
Photo by Andreas Rentz/Getty Images

Aspirin is the gold standard for antiplatelet therapy and a daily low-dose aspirin is widely prescribed for the prevention of cardiovascular disease. Now, a new study suggests that common genetic variation in the gene for catechol-O-methyltransferase (COMT) may modify the cardiovascular benefit of aspirin, and in some people, may confer slight harm. The findings, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital (BWH) appear online in the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology.

"This is one of the few cases where you can identify a single genetic polymorphism which has a significant interaction with aspirin such that it affects whether or not it protects against cardiovascular disease," says first author Kathryn Hall, PhD, MPH, an investigator in the Division of General Medicine and Primary Care at BIDMC and Research Fellow at Harvard Medical School.

COMT is a key enzyme in the metabolism of catecholamines, a group of hormones that include epinephrine, norepinephrine, and dopamine. "These hormones are implicated in a broad spectrum of disorders, including hypertension," explains Hall, "We were initially interested in finding out if the COMT gene affected people's susceptibility to incident cardiovascular disease such as myocardial infarction or ischemic stroke." Knowing that aspirin is commonly prescribed for the prevention of incident cardiovascular disease, the investigators also wanted to learn if genetic variation in COMT would influence aspirin's potential benefit.

To answer these questions, the researchers used data from the Women's Genome Health Study, a cohort of over 23,000 women who were followed for 10 years in a randomized double-blind, placebo-controlled trial of low-dose aspirin or vitamin E for the primary prevention of incident cardiovascular disease. Their analysis focused on val158met, a common variant in the COMT gene: Individuals who are homozygous for the enzyme's high-activity valine form, the "val/vals," have been shown to have lower levels of catecholamines compared to individuals who are homozygous for the enzyme's low-activity methionine form, the "met/mets,". The val/met heterozygotes are in between.

"When we examined women in the placebo arm of the trial, we found that the 23 percent of the women who were 'val/vals' were naturally protected against incident cardiovascular disease," explains senior author Daniel I. Chasman, PhD, according to the July 18, 2014 news release, "Genetic variations may modify cardiovascular benefit of aspirin." Chasman is a genetic epidemiologist in the Division of Preventive Medicine at Brigham and Women's Hospital and Associate Professor of Medicine at Harvard Medical School. "This finding, which was replicated in two other population-based studies, was in itself of significant interest." But, he adds, the investigation further revealed the surprising discovery that when the women with the val/val polymorphism were allocated to aspirin, this natural protection was eliminated.

"As we continued to look at the effects of drug allocation, we found that val/val women who were randomly assigned to aspirin had more cardiovascular events than the val/vals who were assigned to placebo," says Chasman, according to the news release. Among the 28 percent of women who were met/met, the opposite was true, and these women had fewer cardiovascular events when assigned to aspirin compared to placebo. The benefit of aspirin compared to placebo allocation for met/mets amounted to reduction of one case of incident cardiovascular disease for 91 treated women over 10 years of study follow-up. By contrast, the harm of aspirin compared to placebo allocation for the val/val women was an increase of one case per 91 treated.

The researchers further found that rates of cardiovascular disease were also reduced in met/met women assigned to vitamin E compared to those assigned to placebo

The authors stress that the findings will require further research and replication to understand their potential for clinical impact. Nonetheless they note that given that aspirin is preventively prescribed to millions of individuals and the COMT genetic variant is extremely common, this study underscores the potential importance of individualizing therapies based on genetic profiles.

"What this study suggests is that we can be smarter about the groups of patients that would most likely benefit from aspirin," says study coauthor Joseph Loscalzo, MD, PhD, according to the news release. Loscalzo is Chairman of the Department of Medicine and Physician-in-Chief at BWH. "Rather than give aspirin to all patients with risk factors for heart disease, we need to use modern genomics and genetics to identify those individuals for whom aspirin has the greatest benefit and the lowest risk of adverse effects."

One possible reason for the val/val protection could lie in COMT's role in the breakdown of epinephrine, the "fight or flight" hormone which is tightly linked to regulation of the cardiovascular system. "When epinephrine levels rise in response to stress, blood pressure goes up and high blood pressure is a precursor to heart disease," explains Hall, according to the news release.

"One possibility is that val/val individuals have less epinephrine than met/met individuals because their COMT is more efficient at breaking it down. This might help to naturally protect them against cardiovascular disease – that's our working hypothesis. It's harder to explain why the effect is modified by aspirin and that's what we're in the lab aggressively trying to figure out."

In addition to Hall, Chasman and Loscalzo, coauthors include Roger B. Davis, Irving Kirsch, Ted J. Kaptchuk and Murray Mittleman from BIDMC; Julie E. Buring and Paul M Ridker from BWH; and Christopher P. Nelson and Nilesh J. Samani from the University of Leicester, UK.

The Women's Genome Health Study is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute. This study was also supported by NIH grants from the National Center for Complementary and Alternative Medicine (T32A5000051; R01AT004662; K24AT004095; R21AT002860; 3R01AT004662-02S1.)

Notice how few news stories appear about reversal diets that work for those who are using them

There are more news stories in the mainstream media and in some scientific journals about drugs as compared to specific types of diets, perhaps because there's no money in reminding people to eat their vegetables or more raw vegan foods to help clean out the soft plaque from their arteries, if they have the genes that allow plaque to quickly fill up their vascular system and organs. Remember how many times you heard on the news or from doctors (in general) to take an aspirin a day to prevent a heart attack? Often, over the years, doctors and/or the ads said, "a low-dose aspirin." Now the FDA says not to take that daily aspirin unless you already had a heart attack. You may wish to check out the article, "FDA Says Not To Take A Daily Aspirin If You Haven't Had A Heart Attack."

Or you can peruse the latest ScienceWorld Report, "Daily Dose of Aspirin may not be Safe for Everyone: FDA," appearing online May 7, 2014. Or see the May 5, 2014 article appearing on FDA's Consumer Updates page, which features the latest on all FDA-regulated products. The news appears in a variety of publications. The moral of this story is science changes with the times. A lot of money has been made selling daily aspirins to adults, especially the low-dose aspirins. The issue is now, whether or not you need aspirin, actually depends.

In the meantime, the FDA, US Food and Drug Administration's latest press release in its Consumer Updates section, "Can an Aspirin a Day Help Prevent a Heart Attack?" says that depends. Scientific evidence shows that taking an aspirin daily can help prevent a heart attack or stroke in some people, but not in everyone. It also can cause unwanted side effects.

Notice, you won't hear the government advising you to take other blood thinners found in food ingredients or supplements such as cod liver oil, resveratrol, vitamin E (all 8 parts), ginko biloba, aged garlic extract, or any other blood-thinning supplement or food extract. The FDA generally speaks for the majority of the public who don't read nutrition studies or books on which foods have medicinal qualities, but find the word 'aspirin' familiar from childhood or constant advertising as in the old adage attributed to doctors in the past "take two aspirin and call me in the morning." How different is that familiar saying from hearing "take one baby aspirin daily, if your doctors tells you to," heard repeatedly on TV, radio, and in print advertising for at least the past decade.

So whether a aspirin a day helps you ward off a heart attack or stroke depends on whether you already had a stroke or heart attack. And what kind of a stroke, an ischemic stroke from a blood clot or piece of broken-off plaque? Or is your blood so thin already that the stroke you had was caused by bleeding in the brain, a different type of stroke not caused by blood that's too thick? The answer the FDA has is that depends.

According to Robert Temple, M.D., deputy director for clinical science at the Food and Drug Administration (FDA), one thing is certain: You should use daily aspirin therapy only after first talking to your health care professional, who can weigh the benefits and risks. The only issue consumers may have with that is whether their doctors are trained in alternative foods and supplements that affect the blood in different ways, whether to thin or thicken.

Who Can Benefit?

"Since the 1990s, clinical data have shown that in people who have experienced a heart attack, stroke or who have a disease of the blood vessels in the heart, a daily low dose of aspirin can help prevent a reoccurrence," Temple says, according to the FDA's news release. (A dose ranges from the 80 milligrams (mg) in a low-dose tablet to the 325 mg in a regular strength tablet.) This use is known as "secondary prevention." However, after carefully examining scientific data from major studies, FDA has concluded that the data do not support the use of aspirin as a preventive medication by people who have not had a heart attack, stroke or cardiovascular problems, a use that is called "primary prevention." In such people, the benefit has not been established but risks—such as dangerous bleeding into the brain or stomach—are still present.

Caution Needed With Other Blood Thinners

When you have a heart attack, it's because one of the coronary arteries (which provide blood to the heart), has developed a clot that obstructs the flow of blood and oxygen to the heart. Aspirin works by interfering with your blood's clotting action. Care is needed when using aspirin with other blood thinners, such as warfarin, dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixiban (Eliquis).

What about people who have not had heart problems or a stroke but who, due to family history or showing other evidence of arterial disease are at increased risk? Is an aspirin a day a safe and effective strategy for them? Again, Temple emphasizes, the clinical data do not show a benefit in such people. He adds, however, that there are a number of ongoing, large-scale clinical studies continuing to investigate the use of aspirin in primary prevention of heart attack or stroke. FDA is monitoring these studies and will continue to examine the evidence as it emerges.

In the Meantime

The bottom line is that in people who have had a heart attack, stroke or cardiovascular problems, daily aspirin therapy is worth considering. And if you're thinking of using aspirin therapy, you should first talk to your health care professional to get an informed opinion, Temple says, according to the FDA's news release.

Finally, how much aspirin you take matters. It's important to your health and safety that the dose you use and how often you take it is right for you. Your health care professional can tell you the dose and frequency that will provide the greatest benefit with the least side effects.

If your health care professional recommends daily aspirin to lower the risk of a heart attack and clot-related stroke, read the labels carefully to make sure you have the right product. Some drugs combine aspirin with other pain relievers or other ingredients, and should not be used for long-term aspirin therapy. If you're older than 65, there's the chance aspirin could cause stomach bleeding.

That's why it's necessary to find out what is the best solution for you and your health condition. For more information, check out articles such as, Before Using Aspirin to Lower Your Risk of Heart Attack or Stroke, Here is What You Should Know, Use of Aspirin for Primary Prevention of Heart Attack and Stroke, or Aspirin for Reducing Your Risk of Heart Attack and Stroke: Know the Facts. If most HMO doctors are telling patients for years to take a daily aspirin, and suddenly the FDA says don't take a daily aspirin unless you already had a heart attack or stroke, you have to know what type of stroke: one caused by bleeding and too-thin blood?

Or a blood clot or too thick blood or unstable plaque moving around? And with a heart attack, did you already have one? If so, what caused it, hardened arteries, a blood clot, or an emotional experience on whistle-clean arteries? You need to know where you stand before you take any type of medicine.

On the other hand, you'll find because food is uncontrolled when used as medicine, you'll rarely hear about diet, holistic health alternatives, or how to use food or supplements as medicine. Then again, there's more money in medicine than in foods and various extracts, and some of them can lead to too much bleeding in people with naturally thin blood. That's why you need to find out where your health stands.

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