Diabetes — A Benefit from Targeted Therapy with Prasugrel in ACS

Abstract & Commentary

By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

Source: Wiviott SD, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in Myocardial Infarction 38. Circulation. 2008;118:1626-1636.

Prasugrel, a novel third-generation oral thienopyridine (following ticlopidine and clopidogrel), has recently been shown to provide clinically important platelet inhibition in acute coronary syndromes (ACS), with decreased ischemic events compared to clopidogrel in the TRITON-TIMI 38 trial of almost 14,000 ACS patients undergoing PCI. The benefits of reduced cardiovascular (CV) death, non-fatal MI, and non-fatal stroke were greater in diabetics randomized to prasugrel. However, more bleeding was seen in the prasugrel-treated subjects. Overall, diabetics had a greater benefit than non-diabetics with prasugrel, with a gradient of increased benefit in insulin-dependent subjects; thus, greater efficacy with prasugrel was confirmed in the diabetic cohort, who also experienced a considerably increased risk of ischemic events. The study compared prasugrel to clopidogrel in ACS patients undergoing percutaneous interventions (PCI); a pre-specified analysis of the primary endpoints in diabetics is the subject of this report. As of this writing, prasugrel has not yet received final FDA approval. This drug, an irreversible antagonist of the platelet (ADP) PDY12 receptor, has a faster onset of action, less inter-individual variability of effect, and greater potency than clopidogrel.

TRITON-TIMI: 38 Study — Important Data

• In the total cohort of 13,608 subjects with ACS, there were 3,146 diabetics (776 on insulin). Study patients were moderate- to high-risk unstable angina or non-ST elevation myocardial infarction (UA/NSTEMI) or post medical treatment for STEMI patients with a planned PCI. (Increased bleeding risk or recent clopidogrel use subjects were excluded.)

• The primary endpoint was a composite of CV death, non-fatal MI, non-fatal stroke, or TIMI major bleeding unrelated to CABG.

• The results showed a 19% reduction in the primary endpoint with prasugrel compared to clopidogrel.

• Overall, diabetics were more likely to have UA or STEMI, older age, more CABG, be women, and have higher BMI, compared to non diabetics.

• Thrombotic events were higher in diabetics, 14.6% vs 9.9% without diabetes. Insulin-treated patients had the worst outcomes (p = < 0.0001).

• MI occurred in 8% without diabetes mellitus (DM) and 10.7% with DM.

• Stent thrombosis, but also net clinical benefit, was higher in diabetics.

• Major bleeding rates were similar between non-diabetics and diabetics: 2.6% vs 2.0%, p < 0.08; any bleeding 4.8% vs 4.9%, p = NS.

• Prasugrel compared to clopidogrel in diabetic patients.

• A 14% reduction in the primary endpoint in subjects without DM, and a 30% reduction with DM by prasugrel, p < 0.001 (mostly due to a decrease in MI).

• Diabetics had a > 40% decrease in MI; stent thrombosis was decreased with prasugrel independent of diabetic status.

• MI rates were decreased with prasugrel by 18% in non-diabetics, (p = 0.006) compared to a > 40% decrease in diabetics (p = 0.001).

• Bleeding in non-diabetics was seen in 4.9% on prasugrel vs 3.6% in the clopidogrel group, and 5.3% prasugrel vs 4.3% clopidogrel in diabetics (NS) (p = 0.13).

• Diabetics had a greater reduction in ischemic events without an increase in major bleeding (no DM 8%, DM 26%), resulting in a "greater" net clinical benefit for prasugrel among subjects with DM.

• Large benefits in all major endpoints were seen in diabetics, including ischemic events, with greatest effectiveness in insulin-treated DM subjects.

• The authors concluded that in prasugrel-treated ACS patients, clinical outcomes were benefited vs clopridogrel. More intensive anti-platelet therapy is key, especially in diabetics who have variable and less effective anti-platelet action and a less predictable benefit from clopidogrel.

Commentary

This study confirms enhanced efficacy with this third generation antiplatelet drug. The authors conclude, "... more intrusive and consistent anti-platelet therapy ... with prasugrel resulted in a reduction in ischemic events compared with standard dual anti-platelet therapy, but with more bleeding ... on balance an improved net clinical benefit." And subsequently, "prasugrel was especially efficacious in patients with DM." Net clinical benefits were more with prasugrel vs clopidogrel, but bleeding rates were increased. Platelet reactivity is increased in ACS, worse in insulin-treated diabetics, and "treatment with insulin may identify a group of subjects at particular risk for a poor response to clopidogrel." The authors emphasize that clopidogrel is less than ideal vs prasugrel, particularly in high-risk patients. Studies with different doses of prasugrel and clopidogrel hopefully will ultimately support a safer dose regimen for both drugs. At present, prasugrel is a drug to be closely watched — hopefully a positive nod from the FDA may be forthcoming, particularly if safer dosage regimens can be achieved without loss of efficacy, but with less bleeding potential.