Platelet FcγRIIa as a Marker of Cardiovascular Risk After Myocardial Infarction.

Background: A previous single-center study of patients with myocardial infarction (MI) showed that platelet FcγRIIa (pFCG) can distinguish patients at higher and lower risk of subsequent MI, stroke, and death.

Objectives: The authors performed an 800-patient 25-center study to validate the prognostic implications of pFCG.

Methods: Patients with type 1 MI (ST-segment elevation and non-ST-segment elevation) were enrolled in a prospective noninterventional trial during their index hospitalization.

Assessing prognosis by quantifying FcγRIIa on fixed platelets.

FcγRIIa amplifies platelet activation and higher platelet FcγRIIa identifies patients at greater risk of subsequent cardiovascular events. We report the accuracy and precision of a modified test to quantify FcγRIIa on previously fixed platelets (pFCG test). An antibody clone (5G1) was developed after exposure of mice to formaldehyde treated FcγRIIa.

Exploring the potential cost-effectiveness of a novel platelet assay for guiding dual antiplatelet therapy duration in acute coronary syndrome patients following percutaneous coronary intervention.

Objective: Duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) influences ischemic and bleeding events. Platelet expression of constant fragment of immunoglobulin, low affinity IIa, receptor (FcγRIIa) independently predicts risk of ischemic complications and is proposed as a tool to guide individualized care.

Methods: We used a Markov model to predict lifetime ischemic and bleeding events and healthcare costs in acute myocardial infarction (MI) patients treated with PCI and DAPT and to project cost-effectiveness of platelet FcγRIIa-assay-guided care (30:3 months DAPT for patients at high: low ischemic risk) versus current standard care (12 months DAPT) from the perspective of the US healthcare system.

Incidence rate of hospitalization and mortality in the first year following initial diagnosis of cardiac amyloidosis in the US claims databases.

Objective: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases.

Methods: Three administrative claims databases, IBM MarketScan Commercial Claims and Encounters (CCAE), IBM MarketScan Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease.

Randomized phase 2 trial comparing JNJ-9375, a thrombin-directed antibody, with apixaban for prevention of venous thrombosis.

Background: JNJ-9375 is an antibody against exosite 1 on thrombin, inhibits substrate binding but not catalytic activity.

Objective: To examine the possibility that JNJ-9375 attenuates thrombosis without affecting hemostasis, we compared the efficacy and safety of JNJ-9375 and apixaban.

Methods: In this double-blind, double-dummy phase 2 trial, 308 patients undergoing knee arthroplasty were randomized to receive either a single postoperative intravenous infusion of JNJ-9375 in doses ranging from 0.

Benefit-risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty.

Purpose: Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit-risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) randomized clinical studies of rivaroxaban versus enoxaparin after total hip (THA) or knee (TKA) arthroplasty generally used pooled THA and TKA results, counted fatal bleeding as both an efficacy and a safety event, and included the active and placebo-controlled portions of RECORD2, which might confound benefit-risk assessments.

Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis-mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins.

Effects on platelet function of a direct acting antagonist of coagulation factor Xa.

Because novel direct acting anticoagulants are being tested in the secondary prevention of cardiovascular events, we assessed potential effects of a direct acting antagonist of Factor Xa on platelet function. Blood from patients with known coronary artery disease who were treated with aspirin but no other antithrombotic agent was spiked in vitro with rivaroxaban alone or in combination with a direct acting P2Y12 antagonist (cangrelor). To limit cofounding effects of anticoagulants and to enable interaction between coagulation factors, blood was anticoagulated only with a specific inhibitor of Factor XIIa, corn trypsin inhibitor.

Cardiovascular safety profile of dapoxetine during the premarketing evaluation.

The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses.

A Comparison of Cardiovascular Biomarkers in Patients Treated for Three Months with Etoricoxib, Celecoxib, Ibuprofen, and Placebo.

OBJECTIVES: Selective cyclooxygenase (COX)-2 inhibitors are effective analgesic and anti-inflammatory agents with improved gastrointestinal safety and tolerability compared with traditional NSAIDs. However, data from long-term, placebo-controlled studies have shown an increased risk of thrombotic cardiovascular (CV) events for COX-2 inhibitors. Changes in levels of CV biomarkers are potentially useful surrogate measures of pathologic changes associated with CV risk.

Outcome of patients with acute coronary syndrome admitted to hospitals with or without onsite cardiac catheterization laboratory: a TACTICS-TIMI 18 substudy.

In the TACTICS-TIMI-18 trial, patients with acute coronary syndrome were treated with aspirin, heparin, and tirofiban and were randomized to an invasive strategy with routine catheterization or to a conservative strategy with catheterization (only if the patient had objective evidence of ischemia). Eighty-two of 2,220 patients were treated in 13 peripheral hospitals without an onsite catheterization laboratory. Tirofiban was administered to the peripheral hospital group (which was treated invasively) for 28.

Early invasive strategy improves outcomes in patients with acute coronary syndrome with previous coronary artery bypass graft surgery: a report from TACTICS-TIMI 18.

Background: Patients with previous coronary artery bypass graft surgery (CABG) have been classified as a high-risk subset of patients who experience non-ST elevation acute coronary syndrome (ACS). Recent studies suggest that an early invasive strategy is beneficial in moderate- and high-risk patients with non-ST elevation ACS. We hypothesized that an early invasive strategy is associated with improved outcomes in patients with non-ST elevation ACS with prior CABG.

Are statins being underdosed in clinical practice? Data from TACTICS-TIMI 18.

Background: Although clinical trials in the 1990s have found significant reductions in cardiovascular events with fixed doses of statins, specifically 40 mg of simvastatin or pravastatin, in clinical practice, treatment is usually initiated at lower doses. It is not clear, however, if the doses are then titrated upward after the initial dosing.

Methods: We examined the dosing for patients receiving statins at the time of entry and at 6 months follow-up in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI) 18 trial, and their relationship to the measured low-density lipoprotein cholesterol (LDL-C) on admission.

Greater benefit of early invasive strategy for unstable angina and non-ST elevation myocardial infarction in United States compared with non-United States patients: a TACTICS-TIMI 18 substudy.

Background: The TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial Infarction 18) trial compared routine invasive to conservative care for the management of patients with unstable angina and non ST-elevation myocardial infarction, and included the routine use of the platelet glycoprotein IIb/IIIa inhibitor tirofiban in the initial medical stabilization of all patients.

Methods: Because previous trials utilizing IIb/IIIa inhibition for acute coronary syndrome (ACS) patients have demonstrated different outcomes in non-US and US patients, the authors sought to determine whether differences in baseline characteristics and practice patterns between 1844 US and 376 non-US patients and physicians would affect outcomes in the TACTICS-TIMI 18 trial. Event rates were stratified by treatment strategy and adjusted for baseline and treatment differences between cohorts.

The relationship of obesity to ischemic outcomes following coronary stent placement in contemporary practice.

Objectives: We analyzed the relationship of obesity, determined by body mass index (BMI), to short- and long-term outcomes in the TARGET trial.

Background: : Previous studies have conflicting findings regarding the relationship of BMI to outcomes following percutaneous coronary intervention (PCI).

Methods: The TARGET trial studied the use of glycoprotein (GP) IIb/IIIa inhibition in patients undergoing planned coronary stent placement.

The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: the do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial.

Background: Renal function significantly impacts morbidity and mortality after a percutaneous coronary intervention. Platelet glycoprotein (GP) IIb/IIIa inhibitors reduce ischemic complications during percutaneous coronary intervention; little is known of whether their safety and efficacy are influenced by renal function. In particular, whether outcome differences exist between agents that are renally excreted (tirofiban) or not (abciximab) in patients with mild renal impairment is not known.

Correlation between the TIMI risk score and high-risk angiographic findings in non-ST-elevation acute coronary syndromes: observations from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial.

Background: The TIMI risk score for unstable angina and non-ST elevation myocardial infarction is an effective tool for predicting the risk of death and ischemic events among patients with non-ST elevation acute coronary syndromes, as well as for identifying those who are likely to benefit most from low-molecular-weight heparin and glycoprotein IIb/IIIa inhibition.

Methods: To explore the pathobiologic basis for this interaction, we evaluated the relationship between the risk score, assessed at presentation, and angiographic findings among patients with non-ST elevation acute coronary syndromes. Angiographic data regarding thrombus, epicardial flow, and lesion severity were available for 1491 patients from the angiographic substudy of PRISM-PLUS.

Analysis of bleeding complications associated with glycoprotein IIb/IIIa receptors blockade in patients with high-risk acute coronary syndromes: insights from the PRISM-PLUS study.

We aim to characterize the hemorrhagic complications and predictors of increased bleeding risk in a population of patients with high-risk acute coronary syndromes (ACS), enrolled in the PRISM-PLUS study. Patients treated with heparin plus tirofiban had more bleeding events compared to patients treated with heparin alone. No significant increase in major bleeding, thrombocytopenia, blood loss and blood products transfusions was observed among the patients who received the combination therapy.

Does clopidogrel increase the degree of platelet inhibition when a platelet glycoprotein IIb/IIIa inhibitor has been given? Insights from an optical platelet aggregometry study.

Introduction: While the CURE trial demonstrated the benefits of clopidogrel in acute coronary syndromes, patients receiving glycoprotein IIb/IIIa antagonists were excluded. Given the frequent coadministration of these two medications, we sought to examine their interaction and their combined effect on platelet inhibition.

Methods: Ten patients admitted to the hospital with stable or unstable angina underwent phlebotomy prior to, three hours and six hours after administration of a standard oral loading dose of clopidogrel.

Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy.

Objectives: The purpose of this study is to determine whether there is clinical significance to elevated troponin I in patients with suspected acute coronary syndromes (ACS) with non-critical angiographic coronary stenosis.

Background: Elevation of troponin in patients admitted with ACS symptoms with non-critical coronary artery disease (CAD) may result from coronary atherothrombosis not evident using standard angiography or from other ischemic and non-ischemic causes that may confer increased risk for future events.

Methods: Patients with ACS enrolled in the Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI)-18 were included.

Safety of stress testing during the evolution of unstable angina pectoris or non-ST-elevation myocardial infarction.

Patients (n = 1,106) were chosen from the conservative arm of the Treat Angina with aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI) 18 trial. Only 1 patient had a myocardial infarction and another died on the day of stress testing (mortality 0.12%).

Association of elevated B-type natriuretic peptide levels with angiographic findings among patients with unstable angina and non-ST-segment elevation myocardial infarction.

Objectives: We hypothesized that elevated B-type natriuretic peptide (BNP) levels would be associated with a greater severity of angiographic disease and a greater extent of myocardium at risk.

Background: Elevations of BNP have been associated with increased risk of adverse outcomes in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI).

Methods: Of the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction-18 (TACTICS-TIMI-18) trial, 276 randomized to the invasive arm had both baseline BNP levels and angiographic core laboratory data.

Association between duration of tirofiban therapy before percutaneous intervention and tissue level perfusion (a TACTICS-TIMI 18 substudy).

In the setting of acute coronary syndromes, thrombotic embolization and activation of platelets with release of vasoconstrictors into the downstream microvasculature may occur before cardiac catheterization. In the Treat Angina with tirofiban and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial angiographic substudy, a shorter duration of tirofiban infusion before percutaneous coronary intervention was associated with impaired myocardial perfusion before and after intervention.

A risk score to estimate the likelihood of coronary artery bypass surgery during the index hospitalization among patients with unstable angina and non-ST-segment elevation myocardial infarction.

Objectives: A simple risk score on admission to estimate the likelihood of in-hospital coronary artery bypass graft surgery (CABG) might be useful in selecting patients for early clopidogrel therapy.

Background: Routine early use of clopidogrel in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) is associated with increased risk of bleeding in patients who undergo early CABG.

Methods: The test cohort utilized to derive the score was the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction-18 (TACTICS-TIMI-18) trial.