Twice daily regimen eases aspirin resistance in diabetes



PARIS – Twice-daily dosing with aspirin worked substantially better for blocking platelet aggregation than did once-daily treatment with the same total dosage, in patients with diabetes and coronary artery disease in a single-center crossover study with 92 patients.

Patients with diabetes are often less responsive to aspirin treatment for secondary prevention of cardiovascular events than are patients without diabetes, apparently because of faster platelet turnover in patients with diabetes, Dr. Jean-Guillaume Dillinger said at the annual meeting of the European Association for Percutaneous Cardiovascular Interventions. Because aspirin levels sufficient to dampen platelet aggregation persist only for about 2 hours following a dose, faster platelet turnover leads to fewer platelets exposed to an adequate aspirin level, increased aspirin resistance, and greater thrombotic potential.

Mitchel L. Zoler/IMNG Medical Media

Dr. Jean-Guillaume Dillinger

"The results of our study offer a new option to overcome biological aspirin resistance in patients with diabetes," said Dr. Dillinger, a cardiologist at Lariboisière Hospital in Paris. But Dr. Dillinger also cautioned that "large, prospective trials are needed to test if aspirin twice daily can decrease the rate of atherothrombotic events without increasing side effects such as gastrointestinal toxicity." Another potential drawback of twice-daily dosing is that patient compliance with the regimen may be reduced.

Dr. Dillinger also stressed that his study specifically enrolled patients with diabetes with at least one additional risk factor for loss of aspirin efficacy: They were either smokers or had elevated inflammatory markers, and hence, "the results cannot be extrapolated to the whole population of patients with diabetes and coronary artery disease." But he estimated that more than half of patients with diabetes and coronary artery disease (CAD) likely have at least one of these increased-risk factors.

"The results from Dr. Dillinger’s pharmacodynamic study show that a twice-daily regimen may offer greater antiplatelet effects than once daily and are in line with the results from prior investigations," commented Dr. Dominick J. Angiolillo, director of the Cardiovascular Research and Thrombosis Research Center at the University of Florida in Jacksonville. "The data support that [a twice-daily] regimen can be an effective strategy to improve response profiles, but this was a pharmacodynamic study and no conclusions can be made from the results on its clinical efficacy of safety. Clinical studies are warranted to support a change in practice," he said in an interview.

Mitchel L. Zoler/IMNG Medical Media

Dr. Dominjick Angiolillo

Dr. Dillinger and his associates enrolled 92 patients with diabetes and angiography-confirmed CAD who were already on aspirin treatment. All patients had been first diagnosed with diabetes after they were 30 years old, and they had not received insulin as their initial diabetes treatment unless their treatment had begun during an episode of acute coronary syndrome. In addition, all enrolled patients had at least one of these additional risk factors: current smoker, a high-sensitivity C-reaction protein (hsCRP) level of more than 4 mg/L, a fibrinogen level of more than 4 g/L, or a platelet count of more than 270,000/mm3.

The patients averaged 64 years old, 85% were men, and they entered the study an average of 12 years following their diabetes diagnosis. Of the 92 patients, 48% had one high-risk marker, 30% had two, 15% had three, and 7% had all four of the high-risk markers. Forty-eight (52%) of the patients entered the study on a daily clopidogrel regimen, and that treatment continued.

Patients were randomized to receive either 150 mg aspirin once daily taken every morning for 7-14 days before blood sampling, or 75 mg of aspirin taken twice daily, once in the morning and once in the evening for 7-14 days before their blood was drawn. Following the blood draw, they immediately switched to the alternative regimen that again continued for 7-14 days before the researchers took a second blood sample.

They assessed aspirin resistance by measuring platelet aggregation of each blood specimen using light transmission aggregometry. Specimens that produced a maximum aggregation intensity of at least 20% were considered to indicate aspirin resistance.

Testing revealed aspirin resistance in 39 (42%) patients when the study group received aspirin once daily, and in 16 patients (17%) when they were on the twice-daily regimen, a statistically significant difference.

When the 39 patients who showed aspirin resistance on the once-daily dosage were switched to twice-daily, 24 became aspirin responders on the twice-daily schedule. In contrast, among the 16 patients who were aspirin resistant on twice-daily treatment, 1 patient became responsive on the once-daily regimen, Dr. Dillinger reported.

The researchers also applied a second measure of platelet function – global platelet reactivity – using a platelet function analyzer. By this measure, they found that 38 (41%) of patients had normal platelet reactivity with once-daily aspirin, compared with 27 (29%) when patients were on twice-daily treatment. Within the subgroup of 27 patients who were resistant on either of the two regimens but not the other, 19 (70%) became responders when switched to the bid regimen, with 8 (30%) becoming responders when switched to once daily, a statistically significant difference between the two regimens.


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