Keith Fox

A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease

BACKGROUND Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring. METHODS In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days. RESULTS At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P=0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P=0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001), primarily because of ecchymoses at injection sites. CONCLUSIONS Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding.

Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention. The Global Registry of Acute Coronary Events.

Objective: Treatment delays may result in different clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy vs primary percutaneous coronary intervention (PCI). The aim of this analysis was to examine how treatment delays relate to 6-month mortality in reperfusion-treated patients enrolled in the Global Registry of Acute Coronary Events (GRACE). Design: Prospective, observational cohort study. Setting: 106 hospitals in 14 countries. Patients: 3959 patients who presented with STEMI within 6 h of symptom onset and received reperfusion with either a fibrin-specific fibrinolytic drug or primary PCI. Main outcome measures: 6-month mortality. Methods: Multivariable logistic regression was used to assess the relationship between outcomes and treatment delay separately in each cohort, with time modelled with a quadratic term after adjusting for covariates from the GRACE risk score. Results: A total of 1786 (45.1%) patients received fibrinolytic therapy, and 2173 (54.9%) underwent primary PCI. After multivariable adjustment, longer treatment delays were associated with a higher 6-month mortality in both fibrinolytic therapy and primary PCI patients (p<0.001 for both cohorts). For patients who received fibrinolytic therapy, 6-month mortality increased by 0.30% per 10-min delay in door-to-needle time between 30 and 60 min compared with 0.18% per 10-min delay in door-to-balloon time between 90 and 150 min for patients undergoing primary PCI. Conclusions: Treatment delays in reperfusion therapy are associated with higher 6-month mortality, but this relationship may be even more critical in patients receiving fibrinolytic therapy.

Coronary thrombolysis with intravenously administered human tissue-type plasminogen activator produced by recombinant DNA technology.

Coronary thrombolysis was induced by intravenous infusion of human tissue-type plasminogen activator (recombinant human t-PA or rt-PA) obtained by expression of the cloned gene in a mammalian cell system. Thrombolysis was detected by the appearance of reperfusion arrhythmia and confirmed by repeat angiography in anesthetized dogs with 1-hr-old thrombi of the left anterior descending coronary artery that were induced with a copper coil. Infusion of 1000 IU (10 micrograms)/kg/min intravenous rt-PA (n = 9) elicited reperfusion within 13.7 +/- 1.9 min (mean +/- SE) without producing systemic fibrinolysis or distal coronary embolization. Infusion of urokinase at the same rate elicited thrombolysis in seven of 10 dogs within an average of 19.3 +/- 2.2 min. However, distal coronary embolization occurred in two dogs and systemic fibrinolysis was observed in all. In three dogs treated with urokinase thrombolysis was obtained only with subsequent intracoronary infusion. Restoration of myocardial perfusion and metabolism assessed with positron-emission tomography was consistently noted in dogs treated with rt-PA. Thus, rt-PA, a clot-selective thrombolytic agent that does not activate the fibrinolytic system systemically and that is potentially available in large quantities, in view of its synthesis by recombinant DNA technology, offers a promising practical approach for coronary thrombolysis in patients with acute myocardial infarction.

IMPACT OF SMOKING STATUS ON CLINICAL OUTCOMES WITH PRASUGREL VERSUS CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES MANAGED WITHOUT revascularization: INSIGHTS FROM THE TRILOGY ACS TRIAL

Active smoking is associated with increased thrombosis risk and enhanced efficacy of clopidogrel therapy vs placebo. Prasugrel metabolism is not influenced by smoking and has superior pharmacodynamic efficacy, but its relationship to clinical outcomes has not been evaluated in medically managed ACS

Time-Varying Effects of Prasugrel Versus Clopidogrel on the Long-Term Risks of Stroke After Acute Coronary Syndromes: Results From the TRILOGY ACS Trial.

Background and Purpose— The role of more intense, sustained platelet inhibition in preventing stroke after acute coronary syndrome (ACS) is unclear. We observed a signal for reduced stroke risk in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial after 12 months of treatment with prasugrel versus clopidogrel in medically managed patients with ACS. Methods— We examined 7243 patients with ACS, aged <75 years and without prior stroke, analyzing differences in baseline characteristics between patients with and without a stroke event through 30 months with a Cox proportional hazards model. We also assessed the effect of prasugrel versus clopidogrel (plus aspirin) on risk of all stroke events and ischemic stroke over time with an extended Cox proportional hazards model. Results— Stroke events were infrequent through 30 months (ischemic stroke=62; hemorrhagic stroke=15). Patients with stroke were older, had more comorbidities, and had a higher Global Registry of Acute Coronary Events (GRACE) risk score. There was a trend for a lower unadjusted frequency of all stroke events through 30 months for prasugrel versus clopidogrel: 31 (1.5%) versus 46 (2.2%); P=0.08. There was a significant treatment-by-time interaction for those with ischemic stroke (P=0.03), consistent with the 12-month landmarked Kaplan–Meier log-rank test showing a reduced hazard of ischemic stroke after 12 months with prasugrel (P=0.04). No significant interactions between treatment effect of prasugrel versus clopidogrel and time were observed for all stroke events. Conclusions— We observed a potential late treatment effect for prasugrel versus clopidogrel for a reduced risk of ischemic stroke in medically managed patients with ACS aged <75 years. These hypothesis-generating findings suggest that longer duration and more potent platelet inhibition with prasugrel may be associated with lower risk of ischemic stroke after 12 months. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998.

USE AND OUTCOMES OF ANTIARRHYTHMIC THERAPY IN PATIENTS WITH ATRIAL FIBRILLATION RECEIVING ORAL ANTICOAGULATION: RESULTS FROM THE ROCKET AF TRIAL

Antiarrhythmic drug (AAD) therapy and oral anticoagulation are mainstays of atrial fibrillation (AF) treatment. We studied the use and outcomes of AADs in patients anticoagulated for stroke prophylaxis. Patients randomized in the ROCKET AF trial (n=14,264) were grouped by AAD use at baseline:

OUTCOMES OF TEMPORARY INTERRUPTIONS OF RIVAROXABAN OR WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION IN THE ROCKET AF TRIAL

Temporary interruption (TI) of oral anticoagulation (OAC) is common in patients with atrial fibrillation (AF). The characteristics of patients with TI and association of TI with clinical events are not well understood. We evaluated baseline characteristics, management, and outcomes from 3 days post

Prospective use of platelet glycoprotein IIb/IIIa receptor blockers in the emergency department setting.

Platelets play a pivotal role in the pathophysiology of acute coronary syndromes (ACS) and thus are logical therapeutic targets for treatment of this disease process. Platelet glycoprotein (GP IIb/IIIa receptor antagonists, which interrupt the final common pathway of platelet aggregation, have been proven to reduce the 30-day incidence of death, acute myocardial infarction (MI), and urgent revascularization in both high-risk and low-risk patients undergoing percutaneous intervention procedures. Three-year follow-up has indicated that these benefits appear durable. Recent large-scale randomized trials have demonstrated the value of GP IIb/IIIa receptor inhibitors in reducing the risk of death and MI in unstable angina/non-Q-wave MI patients receiving pharmacologic management. And, emerging evidence suggests a future role for GP IIb/IIIa receptor inhibitors as an adjunct to low-dose fibrinolytic therapy in patients with acute MI. As the list of indications for GP IIb/IIIa receptor antagonists expands to encompass the full spectrum of ACS, there is increasing interest in the potential use of these agents in the emergency department setting. The integration of GP IIb/IIIa receptor inhibitors into emergency department protocols will ultimately depend largely on whether these drugs prove to be safe and effective regardless of the direction of ST-segment deviation, and irrespective of whether definitive therapy will be invasive or conservative.

THROMBOLYTIC THERAPY IN ANTICOAGULATED PATIENTS: CASE SERIES FROM RIVAROXABAN VERSUS WARFARIN IN NONVALVULAR ATRIAL FIBRILLATION (ROCKET AF)

Background: Rivaroxaban is widely used for stroke prevention in patients with atrial fibrillation, yet the safety of thrombolysis in anticoagulated patients is uncertain. Methods: We analyzed the characteristics, indications, and 30-day rates of stroke, mortality, and bleeding in patients who

SAFETY AND EFFICACY OF RIVAROXABAN IN PATIENTS WITH CARDIAC IMPLANTABLE ELECTRONIC DEVICES: OBSERVATIONS FROM THE ROCKET AF TRIAL

Patients with atrial fibrillation (AF) may require cardiac implantable electronic devices (CIEDs). However, limited data are available on the use of oral factor Xa inhibitors in patients receiving CIEDs. ROCKET AF randomized 14,264 patients with nonvalvular AF to warfarin or rivaroxaban. We