prasugrel-hydrochloride and Diabetes-Mellitus--Type-1

Diabetic patients with acute coronary syndromes (ACSs) are at a high risk for subsequent cardiovascular events but derive, at the same time, greater benefit from evidence-based therapy than non-diabetic individuals. State-of-the-art anti-thrombotic therapy includes a triple anti-platelet combination - aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa receptor inhibitors - and unfractionated heparin or enoxaparin. For low- or medium-risk individuals, a treatment based on aspirin, clopidogrel and bivalirudin is a valuable alternative. Prasugrel, a new and more potent inhibitor of the platelet P2Y(12) receptor, has to be regarded as the most promising anti-thrombotic agent for diabetic patients with ACS. This agent may replace clopidogrel - and possibly GP IIb/IIIa inhibitors - in the future. In addition to aggressive anti-thrombotic therapy, diabetic patients should undergo systematic early invasive angiography if presenting with non-ST-segment elevation ACS, and immediate percutaneous coronary intervention if presenting with ST-segment elevation myocardial infarction. Indeed, the benefit derived from these strategies appears to be more pronounced in the diabetic population than in non-diabetic individuals. Despite the benefit, multiple surveys have demonstrated that, in the setting of ACS, diabetic patients receive evidence-based therapy less frequently than non-diabetic counterparts.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Blood Glucose; Clopidogrel; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enoxaparin; Hirudins; Humans; Hypoglycemic Agents; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Recombinant Proteins; Thiophenes; Thrombosis; Ticlopidine

Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38.. We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, P(interaction)=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, P(interaction)=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, P(interaction)=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, P(interaction)=0.05).. Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.

Topics: Administration, Oral; Aged; Clopidogrel; Coronary Thrombosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; Thrombolytic Therapy; Ticlopidine; Treatment Outcome

There was an excess of new solid neoplasms (112 vs. 69), and cancer deaths (24 vs. 15) after prasugrel in the TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition). These cancers usually occur after 4 months following prasugrel, and women are especially at risk. The hypothesis has been offered that prasugrel, but not aspirin or clopidogrel, causes indirect modulation of tumor growth, and/or enhanced metastatic dissemination due to instability of platelet-tumor cell aggregates via the inability to keep cancer locally within the platelet thrombi due to excessive chronic platelet inhibition.. A 70-year old female diabetic patient underwent drug-eluting stent implantation. The patient received a loading dose of prasugrel (60 mg), followed by prasugrel 10 mg/daily as well as aspirin (81 mg/daily). After 4 months on dual antiplatelet therapy she expectorated blood when coughing. A lung X-ray and CT scan revealed numerous lung nodules later diagnosed as unclassified pleomorphic and spindle cell malignant solid neoplasm. The patient died following multiple brain metastasis.. Female gender, duration of prasugrel exposure, rare unclassified neoplasm pathology type and a tumor of a highly metastatic and aggressive nature in the index patient should be regarded with caution. The effects of novel antiplatelet agents on the onset of cancer should be tested in future mega-trials.

Topics: Aged; Aspirin; Brain Neoplasms; Carcinoma; Clinical Trials, Phase III as Topic; Clopidogrel; Colonic Neoplasms; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Drug Therapy, Combination; Drug-Eluting Stents; Fatal Outcome; Female; Humans; Lung Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Factors; Thiophenes; Ticlopidine; Time Factors

Topics: Administration, Oral; Coronary Thrombosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes

Topics: Acute Coronary Syndrome; Coronary Thrombosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes