Prophylactic aspirin: To take or not to take?

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Not long ago, aspirin was viewed primarily as a means of providing relief from minor aches, pains, and fevers. But as evidence mounted in support of aspirin's preventive powers, this medicine-chest mainstay morphed into an inexpensive “miracle” drug, touted as a prophylactic against serious health conditions ranging from heart disease and stroke to cancer.

Despite aspirin's impressive powers, however, its steady, long-term use can create serious health risks. Sorting through the risks and benefits as well as the research can be challenging since findings have not been consistent. This summary of the best evidence will provide clarification for primary-care clinicians who wish to convey prudent patient recommendations.

Cardiovascular and cerebrovascular disease

Aspirin's benefits in maintaining healthy vascular systems are clear-cut. Along with a number of other nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin inhibits the aggregation of platelets, thereby preventing circulating blood from becoming “sticky.” This anticlotting power is significant in patients with atherosclerotic plaque, who are vulnerable to clot formation when chunks of the plaque dislodge from arterial walls. Without an anticlotting agent, arterial blockage and oxygen deprivation can occur, leading to an MI, stroke, or peripheral arterial disease.

According to Henry Cohen, PharmD, who teaches pharmacy at Long Island University in Brookville, N.Y., and is chief pharmacotherapy officer at Kingsbrook Jewish Medical Center in Brooklyn, N.Y., aspirin's anticoagulation powers are superior to other drugs in its class. “Unlike other NSAIDs that merely inhibit platelet aggregation temporarily—for 6-12 hours at a time —aspirin acts to destroy platelets for their entire seven-day life span, thereby conferring superior and constant protection against platelet aggregation and dangerous clot formation,” Dr. Cohen states. One or two 81-mg baby aspirin taken daily is believed to be sufficient to provide anticlotting benefits.

However, due to individual variations in genetic predisposition, patients may respond differently to aspirin. “Many people on 81 mg may simply never respond, but [unless they're tested] we'll never know,” Dr. Cohen says. He believes that routine efficacy testing via bleeding-time assessment—though not routinely done in most laboratories and not reimbursable by most insurance companies—would eliminate the uncertainty and ensure that patients receive adequate, customized dosing.

What are the risks?

While aspirin's physiologic benefits are clear, so are its risks. Even at the low doses recommended for cardiovascular and cerebrovascular therapy, chronic use of aspirin is associated with increased bleeding (potentially into the abdomen) and hemorrhagic stroke. According to Dr. Cohen, patients on 81 mg daily increase their risk of peptic ulcer disease 2.3-fold; those taking 325 mg (a standard adult pill) experience a fourfold increase in risk. Proton-pump inhibitors can be prescribed to lessen gastric side effects in patients with risk factors (e.g., age older than 60, concurrent use of other NSAIDs or steroids, history of peptic ulcer disease, etc.).

Given the side effects, a patient's cardiovascular and cerebrovascular health and risk profile must be considered before recommending long-term use. Presently, it is widely believed that patients—both men and women of any age—who have already suffered a heart attack, stroke, or peripheral arterial disease, or who have undergone bypass surgery or angioplasty, will benefit from daily aspirin, taken at low doses, for the secondary prevention of future episodes. Research indicates that a range of aspirin doses—from 75 to 1,500 mg/day—provide considerable benefit in terms of mortality, MI, and stroke in both men and women with previously established disease.1

“For people with heart disease, the primary approach is aspirin,” says Leslie Cho, MD, director of the Women's Cardiovascular Center and medical director of preventive cardiology at the Cleveland Clinic. The situation is less clear, however, with regard to primary prevention—or whether to use aspirin to prevent the onset of cardiovascular disease (CVD) in patients considered at high-risk for developing the condition. Moreover, research indicates that both men and women in this category may receive different benefits from long-term use. A 2006 analysis of randomized controlled trials concluded that aspirin decreases the risk of MI—but not stroke—in men without a history of clinical atherosclerotic CVD, while it lowers the risk of stroke—but not MI—in women with similar health profiles.2

Conflicting results from two major long-term studies have added to the confusion over the advantages aspirin provides for women without previously diagnosed CVD. When researchers at Massachusetts General Hospital and Harvard Medical School in Boston recently analyzed the Nurses' Health Study, conducted among 80,000 women from 1976 through 2004, they found that participants who took 1-14 standard tablets of aspirin a week had a 25% reduced risk of death from any cause and a 38% reduced risk of death from CVD. Cardiovascular benefits were achieved within the first five years.3

These results differ from the 2005 findings of the 11-year Women's Health Study, a primary prevention clinical trial that reported no reduced risk of cardiovascular or other death associated with low-dose aspirin therapy (100 mg on alternate days) in the 40,000 participants.4

Inconsistent research results have led to differing recommendations regarding aspirin therapy for primary prevention. Based on current data, the Cleveland Clinic's Dr. Cho recommends low-dose (81 mg/day) prophylactic aspirin for primary prevention of heart attack and stroke in men over age 45 and women over age 65 who possess risk factors such as hypertension, high cholesterol, hyperlipidemia, family history, smoking, and diabetes. Yet Dr. Cho cautions, “Each case is judged individually. Because the risks are not trivial, we have to do the risk/benefit assessment and then apply medicines accordingly. Generally, therapy should be considered for those whose risk factors for heart disease or stroke are significant enough to make it worth risking possible aspirin side effects.”

Despite its widespread use for CVD prevention, Dr. Cho says aspirin may be contraindicated in some patients, such as those with bleeding risks (including recent brain bleeds or surgeries) or ulcers and in patients concurrently taking blood thinners or ibuprofen (which can negate aspirin's therapeutic effect). Even though aspirin-allergic patients may ultimately need to avoid aspirin, Dr. Cho attempts to desensitize them whenever possible to make aspirin therapy feasible. “That's how important we think aspirin is,” she says. Dr. Cho adds that the more potent, prescription anticlotting agent, clopidogrel (Plavix)—though associated with more potent side effects—represents an alternative, second-line therapy for patients diagnosed with CVD who cannot tolerate aspirin.

Aspirin resistance may build up over time in a significant number of patients. At the recent International Stroke Conference in San Francisco, a team of British researchers led by George Krasopoulos, MD, PhD, Royal Brompton Hospital in London, shared findings from an analysis of 19 trials of 2,700 patients taking prophylactic aspirin for heart disease and stroke prevention. More than 25% of patients developed aspirin resistance (as measured by various platelet function assays), leaving them vulnerable to higher rates of stroke, MI, unstable angina, or graft failure, with men appearing to be 65% more likely to be resistant than women. “Clinicians should screen for aspirin resistance,” and “prescribe other antiplatelet medications if necessary,” says Dr. Krasopoulos.

Cancer prevention

In addition to its anticlotting powers, several studies indicate that aspirin can also help prevent cancer—most notably, colon cancer. According to Dr. Cohen, aspirin retards carcinogenesis in the colon by inhibiting the enzyme cyclooxygenase, resulting in increased cancer cell death. Early studies indicated that the 81-mg daily dose frequently recommended for heart disease prevention is also sufficient to interfere with the formation of precancerous colorectal polyps.

However, subsequent research showed that higher aspirin doses (325 mg) are necessary for colon cancer prevention. Ned Calonge, MD, MPH, chairman of the U.S. Preventive Services Task Force, explains that based on a review of risks of these higher doses vs. cancer prevention benefits, the current recommendation is not to use aspirin or other NSAIDs to reduce colorectal cancer risk in average-risk individuals. “Somewhere around one and two regular-dose aspirin a day did reduce colon cancer, but at that higher dose, you start accruing more negative impact, like GI bleeds, hemorrhagic stroke, and the renal impairment associated with other NSAIDs. We looked at all the risks and harms caused by higher-dose aspirin or NSAID therapy and concluded that the net benefit is zero—or maybe even harmful,” states Dr. Calonge.

Dr. Calonge points out that the risks of chemoprophylaxis for colon cancer should also be viewed in the context of the existence of a safe alternative: screening. “Periodic colonoscopy provides a very effective strategy for colon screening and treatment. We wouldn't want people to rely on polyp suppression with aspirin and NSAIDs when we have this other method,” he states. “Yet people at extreme higher risk should discuss the pros and cons of these agents with their clinicians.”

Other cancers

New data from the American Cancer Society point to the possibility of additional connections between long-term aspirin use and cancer prevention. A study of nearly 70,000 men and 76,000 women showed that daily use of adult-strength aspirin (325 mg) for at least five years may be associated with an approximately 15% reduction in overall cancer incidence (though not statistically significant in women), along with a 20% reduction in prostate cancer risk, and a non-statistically significant lower risk of female breast cancer. A 30% lower risk of colon cancer in men and women was also detected. No effect was seen on the risk levels of other cancers examined, including those of the lung, bladder, pancreas, and kidney; melanoma; leukemia; and non-Hodgkin's lymphoma.5

Study authors acknowledge that these results do not have immediate clinical implications but that confirmation from randomized trials should be sought. Again, adverse effects of relatively high-dose aspirin must be kept in mind.

Alzheimer's disease

The jury is still out on aspirin's efficacy against Alzheimer's disease. Results on the effects of aspirin and other NSAIDs on protecting memory and preventing dementia have been mixed.

Some studies may have suggested slight cognitive benefits, but a long-term, 11-year trial conducted at Brigham and Women's Hospital in Boston and Johns Hopkins School of Medicine in Baltimore indicates that low-dose aspirin (along with other NSAIDs tested) offered no protection against cognitive decline or Alzheimer's, as measured by a battery of memory tests. Additional research is warranted, based on some evidence of improved maintenance of verbal fluency in women taking long-term aspirin. n Ms. Levy is a freelance medical writer in New York City.

References

1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.

2. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295:306-313.

3. Chan AT, Manson JE, Feskanich D, et al. Long-term aspirin use and mortality in women. Arch Intern Med. 2007;167:562-572.

4. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-1304.

5. Jacobs EJ, Thun MJ, Bain EB, et al. A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst. 2007;99:608-615.

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