Preventive aspirin inflames opinions

Aspirin's long-standing role in cardiovascular health does not resolve its precise benefit in terms of cardiovascular prevention, specifically in patients who haven't had a myocardial infarction or stroke.

Despite aspirin's long-standing role in easing inflammation and its antiplatelet effects, its precise benefit in terms of cardiovascular prevention, specifically in patients who haven't had a myocardial infarction or stroke, remains an unresolved question.

That uncertainty presents a dilemma for doctors who must treat patients with a mixed bag of risk factors, both gastrointestinal and cardiovascular. By 2003, at least one-third of American adults ages 35 and older, as well as 4 out of every 5 with cardiovascular disease, were taking aspirin daily or every other day, according to federal survey data published in 2006 in the American Journal of Preventive Medicine.

Illustration by David Cutler
Illustration by David Cutler

For secondary prevention, the evidence has proven consistent and convincing that daily low-dose aspirin reduces the likelihood of further cardiovascular events in patients who have already had a heart attack or a stroke, said Richard Becker, MD, chief of cardiology at the University of Cincinnati College of Medicine and a spokesperson for the American Heart Association. Moreover, that beneficial effect holds true for a variety of scenarios, including whether the patient has had a stent implanted or not, he said.

But over the last decade, published guidelines have been dialing back their emphasis on aspirin for primary prevention. One concern has been the risk of bleeding. Some recent studies also have called into question to what degree aspirin prevents cardiovascular episodes, particularly as statin use has become more widespread.

“I think that the case for aspirin in primary prevention is becoming more and more controversial these days,” said Ravi Hira, MD, an interventional cardiology fellow at Houston's Baylor College of Medicine and the author of a recent study looking at inappropriate aspirin use.

In 2014, officials at the Food and Drug Administration denied an application by Bayer HealthCare to market aspirin for primary heart attack prevention, stating that the agency's research review didn't find sufficient evidence to support aspirin use for primary prevention of heart attack or stroke. Dr. Hira also pointed to the results of a randomized study published last December, which found that daily low-dose aspirin consumption didn't significantly reduce cardiovascular death and nonfatal stroke or heart attack in nearly 14,500 Japanese adults ages 60 and older with cardiovascular risk factors.

Several studies, including A Study of Cardiovascular Events in Diabetes (ASCEND) and Aspirin in Reducing Events in the Elderly (ASPREE), are expected to publish findings in the next few years that will hopefully better clarify the extent of aspirin's protective benefit. The U.S. Preventive Services Task Force, which last published aspirin guidance in 2009, is in the process of revisiting and updating its recommendations.

Until more information becomes available, doctors must strive to strike a balance for each patient, assessing cardiovascular risk against the potential for bleeding, Dr. Becker said. Even so, he acknowledged, there are challenges facing clinicians, such as when a patient has a high cardiovascular risk and a notable vulnerability to bleeding.

“I believe that clinicians, whether they be primary care physicians or cardiologists, still struggle with getting that risk-benefit equation right,” said Dr. Becker, who puts himself into that group as well. “Additional guidance for optimal decision making is expected from ASCEND and ASPREE.”

A secondary buffer

Among patients who have already experienced a stroke or heart attack, though, aspirin continues to be recommended to lower future risk, according to an update on secondary cardiovascular risk reduction strategies from the American Heart Association and the American College of Cardiology, published in 2011 in Circulation.

Besides recommending aspirin in all patients with coronary artery disease unless contraindicated, the guidelines suggested starting patients on the antiplatelet medication after an acute coronary syndrome or an angioplasty involving a stent, as well as heart bypass surgery. Aspirin alone or clopidogrel alone also was advised for patients following an ischemic stroke or transient ischemic attack or for patients with peripheral artery disease.

The 2011 guidelines provided a range for aspirin dosing regimens depending on the underlying cardiovascular condition, most frequently 75 to 325 mg daily. Subsequent recommendations published in 2013 in Circulation scaled back the maintenance dosage following a heart attack, stating that 81 mg daily was preferred.

But an analysis of aspirin prescribing practices in 221,199 heart attack patients following hospital discharge highlighted considerable room for improvement, said Sandeep Das, MD, associate professor of internal medicine at University of Texas Southwestern Medical Center in Dallas. That analysis, which Dr. Das co-authored, focused on aspirin dosing from January 2007 and March 2011 prior to the newer guidance on 81-mg doses.

Still, Dr. Das noted that 56.7% of patients who had experienced a major bleeding episode while in the hospital were discharged on the higher dose of 325 mg, according to the findings, published last year in Circulation: Cardiovascular Quality and Outcomes.

“The bottom line is that it's likely that current practice patterns are exposing patients to undue risk of bleeding,” Dr. Das said. “And that a simple adjustment, simply questioning whether this patient could be appropriately managed with a low-dose aspirin, may significantly improve bleeding while providing the same cardiac outcome.”

Mary Ann Bauman, MD, an internist in Oklahoma City, said that she might recommend aspirin for secondary prevention, depending on the underlying source of bleeding. If there's any indication that her patient has previously had a hemorrhagic stroke, Dr. Bauman will consult with a neurologist before moving forward. In cases where a patient has a prior, but distant, history of gastrointestinal bleeding, she said that she would likely suggest low-dose aspirin. But she would also prescribe a proton-pump inhibitor and monitor that patient closely.

“I'm very cautious, telling them that I want to know if they are beginning to have any GI upset with it, if they are having any black stools—those types of things to watch for,” she said.

The primary uncertainty

Baylor's Dr. Hira decided to delve into how frequently patients take aspirin for primary prevention, and whether their use is appropriate, after encountering a patient who struck him as not an optimal candidate. The man, who was in his early 40s, didn't have any risk factors other than a family history of heart disease and had started the drug on his own after a friend had suffered a heart attack.

Once Dr. Hira started looking at the various clinical guidelines, he was surprised to discover that the cardiovascular risk benchmark, the level of risk at which aspirin might be deemed beneficial, varied to some degree. Depending on the specific guideline, that cutoff ranged from a 10-year coronary and stroke risk of more than 6% to more than 10%.

For the purposes of his study, Dr. Hira conservatively defined patients with a 10-year cardiovascular risk of below 6% as at low risk and thus not good candidates for aspirin. Based on that benchmark, 11.6% of the 68,808 patients studied were not taking the drug appropriately, according to the findings published Jan. 20 in the Journal of the American College of Cardiology. (The data were self-reported, and it's not clear how often the over-the-counter drug was initiated by the patient or the doctor.) The rate of inappropriate use was higher in women than in men, 16.6% versus 5.3%.

Another complication for physicians is that there are now several methodologies to calculate cardiovascular risk. In addition to the calculator associated with the Framingham Heart Study, there's a newer methodology, the American Heart Association/American College of Cardiology Foundation CV Risk Calculator, linked to the organizations' new cholesterol recommendations issued in 2013. (With that calculator, statins are recommended when an individual's 10-year cardiovascular risk exceeds 7.5%.)

Darren McGuire, MD, a cardiologist and diabetes expert at University of Texas Southwestern Medical Center, described the statin-related calculator as a step forward, given that it incorporates diabetes risk. For patients with known diabetes, Dr. McGuire recommended the U.K. Prospective Diabetes Study (UKPDS) risk engine, which is tailored to that population.

But aspirin recommendations for primary prevention in diabetic patients also have been shifting in recent years, said Dr. McGuire, who is the Dallas Heart Ball Chair for Research on Heart Disease in Women at UT Southwestern. The turning point was the publication of 2 studies in 2008, which both looked at the role of low-dose aspirin in preventing cardiovascular events in people with type 2 diabetes but no known cardiovascular disease.

“Both of them were effectively negative in terms of cardiovascular prevention,” Dr. McGuire said. Those findings, he said, “really tempered the enthusiasm for aspirin across the world. This was a global shift in thinking.”

Weighing risks

In recent years, Dr. McGuire said, the Europeans have been ahead of American medical groups in moderating their enthusiasm over aspirin, first by emphasizing low-dose aspirin and more recently by discouraging its use in primary prevention for adults at low cardiovascular risk.

In his own practice, Dr. McGuire has adopted a middle-ground approach, saying that he typically does not recommend low-dose aspirin until a patient's 10-year cardiovascular risk exceeds 15% or 16%, and then only if there are no prohibitive worries about bleeding. To that end, he looks into whether the patient has any history of peptic ulcer disease, gastrointestinal bleeding, or intracranial hemorrhage.

For doctors, one of today's greatest challenges is that there's no calculator to quantify bleeding risk as there is for cardiovascular risk, Dr. Becker said. Thus, doctors need to make time to ask some specific questions in order to capture a broader picture of bleeding vulnerability. Among them: Have patients ever had blood in their stool or experienced an ulcer? Do any family members have bleeding disorders? Has a blood transfusion ever been necessary? Did taking aspirin previously result in unusual patterns of bruising or a bloody nose?

Doctors also should think twice about adding aspirin to warfarin, as data don't indicate that the combination works any better in preventing heart attack than either medication alone, Dr. Becker said. Combining aspirin with nonsteroidal anti-inflammatory drugs should similarly be approached with caution, he said.

Moving forward, Dr. Hira questions to what extent more widespread use of statins will alter the aspirin primary prevention equation. For example, in a randomized study involving nearly 14,500 Japanese adults published in December 2014 in the Journal of the American Medical Association, participants took 100 mg of aspirin in addition to other ongoing medications.

As statin use becomes more common, particularly in the wake of the new cholesterol guidelines, “the incremental value of preventing a heart attack or preventing a stroke by using aspirin has probably gone down,” Dr. Hira said.

But researchers haven't given up on unraveling the cardiovascular benefits of the anti-inflammatory drug, including the optimal patient candidates or dosing regimens, Dr. McGuire said. He noted that simply typing “aspirin and diabetes” into the federal database finds evidence of some 100 studies in various stages.

One intriguing line of research is looking at whether twice-daily dosing might be more effective in people with diabetes, given that they clear aspirin more quickly than those without the disease and thus fewer platelets are exposed to adequate aspirin levels, Dr. McGuire said. “Although we've not been successful, I think it's clear that the scientific community has not yet abandoned the possibility that aspirin may be beneficial in this population,” he said.