New Statement Urges Caution for Primary-Prevention Aspirin in Diabetics

June 03, 2010

June 3, 2010 (Chapel Hill, North Carolina) — A new scientific statement on the use of aspirin for the primary prevention of cardiovascular disease in patients with diabetes recommends that low-dose aspirin is "reasonable" in those with no history of vascular disease but who are at an increased 10-year risk of cardiovascular events [1].

The new recommendations, from a joint statement of the American Diabetes Association (ADA), the American Heart Association (AHA), and the American College of Cardiology (ACC), essentially call for tighter criteria for aspirin use in the diabetic population. The organizations state that only men older than 50 and women older than 60 who have one or more additional major risk factors should be treated with aspirin for primary prevention of cardiovascular events.

"The guidelines are more conservative, or there is less of a general recommendation for aspirin than there used to be, and this is based on some of the newer studies that have come out," Dr Sue Kirkman (ADA, Alexandria, VA), a member of the writing committee, told heartwire . "The previous recommendations had been that pretty much anybody with diabetes over the age of 40 should be on aspirin."

The group recommends low-dose aspirin, 75 mg/d to 162 mg/d, for adults with diabetes and no history of cardiovascular disease but who are at an increased risk based on age and at least one additional cardiovascular disease risk factor, such as smoking, dyslipidemia, hypertension, family history of disease, and albuminuria. It is a class IIa recommendation with a level of evidence B.

Aspirin is not recommended for high-risk diabetic patients who are also at risk for bleeding and is not recommended for individuals at low risk of cardiovascular events. For those at intermediate risk, the use of aspirin can be "considered" until further research is available.

JPAD and POPADAD Showed No Benefit

The new joint statement, with writing committee chair Dr Michael Pignone (University of North Carolina, Chapel Hill), is published May 27, 2010 in Circulation, Diabetes Care, and the Journal of the American College of Cardiology. The recommendations of the group are based on an analysis of the available evidence with aspirin in primary prevention of cardiovascular disease for diabetic patients.

This is not a one-size-fits-all approach simply because a patient has diabetes.

With no single study providing definitive results, the writing committee attempted to reconcile the findings by examining existing meta-analyses, such as the one performed by the Oxford Antithrombotic Treatment Trialists' (ATT) collaboration [2]. With the ATT meta-analysis, one that included 4000 diabetic patients from six clinical trials, the researchers found that aspirin reduced the risk of vascular events 12%, with the largest reduction in nonfatal MI.

Two of the newer primary-prevention trials, however, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) and the Prevention of Progression of Arterial Disease and Disease (POPADAD), included diabetic patients only, and both failed to show any benefit of aspirin therapy in the primary prevention of cardiovascular events of diabetic patients. When JPAD, POPADAD, and the Early Treatment of Diabetic Retinopathy Study (ETDRS) were included with the six trials from the ATT collaboration, aspirin was associated with a 9% nonsignificant reduction in coronary heart disease events.

In light of the summary of the existing literature and the more conservative recommendations, Kirkman said that doctors should use clinical judgment when treating a patient with diabetes. "The main thing is to think about the individual patient, in terms of trying to assess their particular risk for cardiovascular events, and whether it's high enough to warrant aspirin therapy," she told heartwire . "This is not a one-size-fits-all approach simply because a patient has diabetes."

The ADA, AHA, and ACC recommend various risk-assessment tools that can be used in patients with diabetes, including the UKPDS Risk Engine, the ARIC Coronary Heart Disease Risk Calculator, and the ADA Risk Assessment Tool.

To heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), who was not part of the writing committee, agreed that the recommendations are conservative but said they are still based on a risk-assessment approach, even though past studies, including POPADAD and JPAD, did not show a relationship between the 10-year coronary heart disease risk and treatment effect.

"The recommendations make sense, it's intuitive, but it's not borne out by the evidence," said Kaul. He added that the recommendations are weak, as reflected by the class IIa and III recommendation, with low- or moderate-quality evidence.

Aspirin Therapy Not Unlike Glucose Lowering

Also commenting on the new recommendations, Dr Steven Marso (Mid America Heart Institute, Kansas City, MO) said that during the past decade a number of professional societies have scaled back their recommendations for aspirin use in primary prevention. Several studies have also warned against aspirin use in some of the key primary-prevention populations, such as diabetics, but also patients with asymptomatic atherosclerosis and peripheral artery disease. The ATT investigators, for example, concluded their recent meta-analysis by stating the results "do not seem to justify general guidelines advocating the routine use of aspirin in all healthy individuals above a moderate level of risk for coronary heart disease."

In some of the earliest studies of aspirin in primary prevention, said Marso, the percentage of patients with diabetes ranged from 1% or 2% to 22%, while cardiovascular event rates were very high. As a result, in contemporary studies, where event rates are much lower because of improvements in overall therapy, it is difficult to assess the benefit of aspirin in primary prevention because there is only a modest reduction in events with treatment.

"The challenge is the risk of developing bleeding," said Marso, a cardiologist with expertise in diabetes. "There is about a 10% relative risk reduction with aspirin, but you have to balance this with the risk of bleeding. Also, if you look at lipid control, aspirin therapy is nowhere near as good. Aspirin therapy kind of falls in line with glucose lowering; they both, without a doubt, reduce events, but it's mild."

Regarding the recommendations, Marso said they are as good as one could expect given the level of evidence that is out there. He mentioned, however, that in addition to age and one additional cardiovascular disease risk factor, which qualifies as individual as high risk, physicians should also be aware of the patient's "duration" of diabetes. Data from other studies, including the Framingham Health Study, have shown that having diabetes for more than 10 years is a cardiovascular disease risk equivalent, he said.

Diet and Lifestyle Rather Than Aspirin

To heartwire , Kaul said his priority with diabetic patients is to get them to implement a healthy lifestyle, with diet and exercise, and to ensure that blood pressure and cholesterol levels are controlled. He said that he's more likely to add a statin and control blood pressure before starting a patient on aspirin for primary prevention.

"The guidelines still continue to recommend aspirin in primary prevention, but the evidence is changing," he said. "The recommendations were based on a pooled analysis of older trials that were done in a noncontemporary era where statins were not so widely used and risk factors not so closely controlled. When you look at the contemporary trials like JPAD and POPADAD, statin use has gone up compared with previous trials and risk factors modified to a greater degree."

Two studies assessing the safety and benefit of aspirin for the prevention of cardiovascular events among patients with diabetes are ongoing. Those trials, A Study of Cardiovascular Events in Diabetes (ASCEND) and Aspirin and Simvastatin Combination for CV Events Prevention Trial in Diabetes (ACCEPT-D), are still some years away from completion.

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