Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials

We sought to compare the risk of hemorrhage due to the low (<100 mg), moderate (100 to 200 mg), and high (>200 mg) doses of aspirin (acetylsalicylic acid [ASA]) in 192,036 patients enrolled in 31 clinical trials. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA was associated with the lowest risk, and moderate doses caused a relatively high hemorrhagic event rate, especially with regard to minor, gastrointestinal, and total bleeding, and stroke. These findings should be considered when using combination antiplatelets, anticoagulant therapy, or both, with ASA, especially with the daily dose of >100 mg.     

Monitoring of platelet function in the setting of glycoprotein IIb/IIIa inhibitor therapy

The role of the platelet in the pathogenesis of acute coronary syndromes is clearly established. In addition, the beneficial effects of oral and intravenous platelet inhibitor therapies were demonstrated in multiple, large, randomized clinical trials. However, despite these advances, current antiplatelet therapy fails to prevent coronary events in a substantial proportion of patients. One possible explanation for this phenomenon is that antiplatelet medications are administered without monitoring of the response to therapy. For example, oral antiplatelet therapy is administered as a standard dose for all patients, while intravenous inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor are dosed based on patient body weight. A major limitation of measuring platelet function has been that no practical test exists. The historic gold standard, bleeding time, was a very crude measure of platelet function with limited clinical utility. The current "gold standard," turbidimetric aggregometery, requires a central laboratory and is cumbersome to perform. Fortunately, a number of new tests with rapid turnaround time can be performed at the patient's bedside. This article discusses the details regarding the performance, advantages, disadvantages, and available data related to clinical use of each test in populations with coronary disease and patients treated with antiplatelet therapy.     

Optimal Platelet Inhibition for PCI in ACS: Pretreatment, In-laboratory, Both or Neither

The results of recent trials suggest that an aggressive antiplatelet regimen that includes a glycoprotein (GP) IIb/IIIa antagonist, in conjunction with an early revascularization strategy, may be the optimal treatment plan for patients presenting with a non-ST-elevation acute coronary syndrome (ACS). However, whether all patients presenting to the emergency room with a suspected ACS really benefit from the addition of a GP IIb/IIIa receptor inhibitor, and in those who do, the optimal time to start therapy has not yet been clearly identified. Patients with objective evidence of ischemia, especially elevated myocardial enzymes, as well as patients on chronic aspirin therapy at the time of their ACS, appear to derive the greatest benefit from the addition of a GP IIb/IIIa antagonist. Trial results strongly support the use of a GP IIb/IIIa inhibitor at the time of a percutaneous coronary intervention in this patient population, but starting therapy prior to the procedure is best supported by the data in those patients who have refractory ischemia despite good medical therapy, or patients who will be medically stabilized for greater than 24 hours.     

Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention.

OBJECTIVES: This study sought to determine the optimal timing of a 300-mg clopidogrel loading dose before percutaneous coronary intervention (PCI) in patients enrolled in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. BACKGROUND: A loading dose of clopidogrel before a PCI has become relatively commonplace, although the data supporting this practice are limited and sometimes conflicting. METHODS: Patients were randomized to receive either 300 mg clopidogrel or a matching placebo administered a minimum of 3 h and a maximum of 24 h before PCI. The primary 28-day combined end point was death, myocardial infarction, or urgent target vessel revascularization. Linear splines were used to summarize the effect of the time of pre-treatment as a continuous variable. RESULTS: A total of 1,762 patients were evaluated. For patients randomized to placebo, there was no relationship between the duration of pre-treatment and the occurrence of the primary end point, whereas longer durations of pre-treatment in patients randomized to clopidogrel were associated with improved outcomes. The event rates diverged maximally at 24 h. The difference in outcomes between placebo and clopidogrel pre-treated patients was not significant until > or =15 h pre-treatment, with a 58.8% (p = 0.028) reduction in the primary end point in patients pre-treated with clopidogrel > or =15 h compared with placebo. CONCLUSIONS: When a 300-mg loading dose of clopidogrel is used, little benefit is obtained compared with just 75 mg at the time of the PCI when the treatment duration is <12 h. In patients pre-treated for longer durations, the optimal duration seems to approach 24 h.     

Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects

Vitamin K antagonists have been the only available oral anticoagulant therapy for decades until the recent introduction of novel (new) oral anticoagulants. This breakthrough provides patients with alternative treatment choices that have predictable pharmacokinetics and do not require routine coagulation monitoring. Though more convenient from patient perspective, these drugs have distinct pharmacological properties that are particularly important to recognize when transitioning anticoagulant therapies. The following review focuses on transitioning to and from the novel oral anticoagulants, employing a practical pharmacokinetic- and pharmacodynamic-based approach.     

Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy

BACKGROUND: Despite widespread heparin use in clinical practice, the associated development of thrombocytopenia is an underrecognized and undertreated complication. METHODS: We analyzed data from consecutive hospitalized patients treated with heparin (unfractionated or low molecular weight) for 4 days or longer to determine the incidence, predictors, prognostic significance, and management of "thrombocytopenia," defined as a platelet count less than 150 x 10(9)/L, reduction in platelet count of 50% or more from the admission level, or both. RESULTS: We enrolled 2420 patients (median age, 65.2 years; 43.8% women) in 48 US hospitals. Thrombocytopenia occurred in 881 patients (36.4%; 95% confidence interval [CI], 34.5%-38.3%). Of those who developed thrombocytopenia, 5.1% died, compared with 1.6% of those without thrombocytopenia (odds ratio [OR], 3.4; 95% CI, 2.1-5.6; P< .001). Thrombocytopenia was also associated with greater risk of myocardial infarction (OR, 2.1; 95% CI, 1.5-2.8; P< .001) and congestive heart failure (OR, 1.3; 95% CI, 1.1-1.6; P= .01). After adjustment for important covariates, thrombocytopenia remained an independent predictor of thrombotic and hemorrhagic events. A relative reduction in platelet count of more than 70% was the strongest independent predictor of death (OR, 13.4; 95% CI, 6.5-27.6; P< .001), followed by a relative reduction in platelet count of 50% to 70%, worse Killip class, occurrence of thromboembolic complications, older age, and longer duration of heparin therapy. CONCLUSIONS: Thrombocytopenia occurs frequently after prolonged heparin therapy and is strongly associated with worse short-term clinical outcome. The relative reduction in platelet count is a powerful independent predictor of all-cause mortality in hospitalized patients.     

Glycoprotein IIb/IIIa receptor inhibitor-thrombolytic combination therapy for acute myocardial infarction

Over the past two decades, we have witnessed a large decrease in the death and complication rate of patients experiencing acute myocardial infarction (MI), due to our ability to restore blood flow to infarct-related arteries. Therapies include strategies to inhibit platelet function and induce fibrinolysis, and mechanical reperfusion with percutaneous intervention. Despite decreases in morbidity and mortality with thrombolytic therapy, reperfusion rates remain less than optimal. With standard fibrinolytic therapy in combination with aspirin, it is thought that thrombolyticinduced platelet activation may be an important reason for failure to induce perfusion, or maintain reperfusion in the infarct-related artery. In the past 10 years we have moved from platelet inhibition with aspirin to newer, more potent platelet inhibitors such as glycoprotein (GP) IIb/IIIa antagonists. Recent trials have evaluated the efficacy and safety of combining thrombolytic drugs with GP IIb/IIIa receptor antagonists. Future trends may use combination therapy as a part of a mechanical strategy, using these medications to induce early reperfusion as the patient is prepared for percutaneous intervention. This review summarizes recently published trials using combination thrombolytic and GP IIb/ IIIa receptor inhibitor therapy in the treatment of acute MI.