Cynthia L. Green

Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes.

BACKGROUND The abrupt cessation of heparin and other thrombin inhibitors when used to treat acute coronary syndromes has been accompanied by a clustering of thrombotic events. It is unknown whether these events are the result of inadequate antithrombin therapy or whether they represent a rebound increase in thrombin activity. This study was designed to determine whether there is a true rebound, as defined by an increase followed by a subsequent decrease, in thrombin activity after discontinuation of intravenous heparin therapy. METHODS AND RESULTS Thirty-five patients with recent acute myocardial infarction or unstable angina who had received at least 48 hours of intravenous heparin were studied. Patients underwent ST-segment monitoring, and blood samples for determination of thrombin generation and activity were drawn at 0, 3, 6, 10, and 24 hours after heparin discontinuation. Median aPTT was 65 seconds before heparin discontinuation. Median fibrinopeptide A increased from 9.5 to 16.9 ng/mL at 3 hours (P < .0004) and returned to 10.5 by 24 hours. Prothrombin fragment 1.2 likewise transiently increased, from 0.34 to 0.51 nmol/L at 6 hours (P < .0002). Modified antithrombin III decreased over time (P < .002), and activated protein C increased from 2.3 to 4.5 ng/mL at 3 hours (P < .001). Although there were no clinical thrombotic events in the first 24 hours, 4 patients had evidence of ischemia by ST-segment monitoring at a median of 12 hours after heparin discontinuation. The degree of increase in fibrinopeptide A and prothrombin fragment 1.2 was not found to be associated with baseline diagnosis, duration of heparin therapy, baseline level of antithrombin III, or activated protein C. CONCLUSIONS This study demonstrates a transient rebound increase in thrombin activity as well as in activated protein C upon abrupt discontinuation of intravenous heparin. Clinicians should be vigilant for associated thrombotic events. Further investigation of the significance, mechanism, and possible prevention of this rebound phenomenon is needed.

Comparison of the ABC/2 Estimation Technique to Computer-Assisted Volumetric Analysis of Intraparenchymal and Subdural Hematomas Complicating the GUSTO-1 Trial

BACKGROUND AND PURPOSE The volume of an intracerebral hemorrhage has been shown to be an important independent predictor of mortality in several reports. A technique for estimating hematoma volume, known as the ABC/2 method, has been proven a reliable, simple bedside technique for the volume measurement of intraparenchymal intracerebral hemorrhage. Subdural hematomas also carry a significant mortality risk but are more amenable to surgical evacuation. A reliable, simple bedside measurement of subdural hematoma volume may prove a valuable tool in prognostication and management of patients with this entity. METHODS Computed tomographic (CT) brain scans of 244 patients suffering from intracranial hemorrhage in the GUSTO-1 trial were systematically reviewed. The volumes of 298 intraparenchymal hematomas were measured by the ABC/2 technique, and the volumes of 44 subdural hematomas were measured by an adaptation of this technique and compared to computer-assisted volumetric analysis. RESULTS Excellent correlation between the techniques were achieved for both subdural (r=0.842; slope, 0.982) and intraparenchymal hematoma volume measurements (r=0.929; slope, 1.11). CONCLUSIONS The ABC/2 method is a simple and accurate technique for the measurement of intraparenchymal hematoma volume, and a simple adaptation allows for a similarly accurate measurement of subdural hematoma volume as well.

Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

Background— KAI-9803, a &dgr;-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Methods and Results— Direct Inhibition of &dgr;-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a “first-in-human,” dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in 99mtechnetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3. Conclusions— KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.

Incidence and Clinical Relevance of the Occurrence of Bundle-Branch Block in Patients Treated With Thrombolytic Therapy

BACKGROUND Whether thrombolytic therapy alters the incidence and clinical outcome of bundle-branch block is unclear. METHODS AND RESULTS We examined the occurrence of new-onset bundle-branch block, both transient and persistent, in 681 patients with acute myocardial infarction enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction 9 and Global Utilization of Streptokinase and t-PA for Occluded Arteries 1 protocols. Each patient underwent continuous 12-lead ECG monitoring for 36 to 72 hours with the Mortara ST monitoring system. Bundle-branch block was characterized as right, left, alternating, transient, or persistent. The overall incidence of bundle-branch block was 23.6% (n = 161), with transient block in 18.4% (n = 125) and persistent block in 5.3% (n = 36). Right bundle-branch block was found in 13% (n = 89) of the population; left bundle-branch block was found in 7% (n = 48). Alternating bundle-branch block was seen in 3.5% (n = 24) of patients. Left anterior descending artery infarcts accounted for most bundles (54%, n = 79). Patients with bundle-branch block had lower ejection fractions, higher peak creatine phosphokinase levels (P < .0001), and more diseased vessels (P < .019). Mortality rates in patients with and without bundle-branch block were 8.7% and 3.5%, respectively (P < .007). A higher mortality rate was observed in the presence of persistent (19.4%) versus transient (5.6%) or no (3.5%) bundle-branch block (P < .001). CONCLUSIONS Thrombolytic therapy reduces the overall mortality rate associated with persistent bundle-branch block. However, persistent bundle-branch block remains predictive of a higher mortality rate than either transient or no bundle-branch block. Continuous 12-lead ECG monitoring provides an accurate characterization of the incidence and type of conduction disturbances after acute myocardial infarction.

Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: Results of the platelet aggregation receptor antagonist dose investigation and reperfusion gain in myocardial infarction (PARADIGM) trial

OBJECTIVES The trial was designed to assess the safety, pharmacodynamics and effects on reperfusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor lamifiban when given with thrombolysis to patients with ST segment elevation acute myocardial infarction. BACKGROUND Studies of fibrinolytic agents in acute myocardial infarction have demonstrated a direct relationship between early complete reperfusion and survival. Blockade of the platelet GP IIb/IIIa receptor complex inhibits platelet aggregation and may speed reperfusion when given in conjunction with thrombolysis to patients with acute myocardial infarction. METHODS Patients with ST segment elevation presenting within 12 h of symptom onset who were treated with either tissue-plasminogen activator or streptokinase were enrolled in this three-part Phase II dose exploration study. In Part A, all patients received the GP IIb/IIIa inhibitor lamifiban in an open-label, dose escalation scheme. Parts B and C were a randomized, double-blind comparison of a bolus plus 24-h infusion of lamifiban versus placebo with patients randomized in a 2:1 ratio. The goal was to identify a dose(s) of lamifiban that provided >85% adenosine diphosphate (ADP)-induced platelet aggregation inhibition. A composite of angiographic, continuous electrocardiographic and clinical markers of reperfusion was the primary efficacy end point, and bleeding was the primary safety end point. RESULTS Platelet aggregation was inhibited by lamifiban in a dose-dependent manner with the highest doses exceeding 85% ADP-induced platelet aggregation inhibition. There was more bleeding associated with lamifiban (transfusions in 16.1% lamifiban-treated vs. 10.3% placebo-treated patients). Lamifiban induced more rapid reperfusion as measured by all continuous electrocardiographic (ECG) parameters. CONCLUSIONS Lamifiban given with thrombolytic therapy appears to be associated with more rapid and complete reperfusion than placebo. As expected in this small sample, there were no obvious clinical benefits to lamifiban over placebo. Reconciliation of ECG monitoring with clinical outcomes will require a larger, adequately powered clinical trial.

Thrombolysis-Related Intracranial Hemorrhage A Radiographic Analysis of 244 Cases From the GUSTO-1 Trial With Clinical Correlation

BACKGROUND AND PURPOSE Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis. METHODS CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing. RESULTS Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to 13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002). CONCLUSIONS Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.

Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial

BACKGROUND Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI. METHODS The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated. RESULTS Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo. CONCLUSIONS With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI.

Results From the IQ‐CSRC Prospective Study Support Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase

The QT effects of five “QT‐positive” and one negative drug were tested to evaluate whether exposure–response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6‐fold the therapeutic dose. The study provides evidence that robust QT assessment in early‐phase clinical studies can replace the thorough QT study.

A Randomized Trial of Vascular Hemostasis Techniques to Reduce Femoral Vascular Complications After Coronary Intervention

This report details a prospectively randomized clinical trial comparing mechanical clamp compression to hand applied pressure for attaining vascular hemostasis after coronary intervention. Effectiveness was determined by comparing the incidence of femoral vascular complications resulting from each of the 2 techniques. Eligible participants included 778 consecutive patients scheduled for percutaneous coronary intervention over an 8-month period. An unselected cohort of the eligible patients (n = 592), determined by the availability of cross-trained clinicians, underwent follow-up serial physical examinations by blinded observers for the duration of their hospital stay. A second, similarly determined cohort (n = 390), underwent color-duplex ultrasonography within 24 hours of sheath removal. Baseline demographic and clinical characteristics, sheath removal parameters, and subsequent outcomes were collected prospectively. The primary end point was a composite of ultrasound-defined femoral vascular complications: femoral artery thrombosis, echogenic hematoma, pseudoaneurysm, or arteriovenous fistulae formation. Complications diagnosed by physical examination constituted the second fundamental end point and included: persistent oozing, ecchymosis, hematoma, bruit, and pulsatile mass. Compared to manual compression, mechanical clamp hemostasis reduced the primary adverse end point by 63% (p = 0.041). Physical examination detected ecchymosis, oozing, and hematomas at equally high frequencies in the two cohorts. Although 65% of the patients in both treatment groups encountered at least one of these cosmetic complications, the diagnoses made by physical examination did not correlate with ultrasound-defined pathology. Multivariable stepwise logistic regression analysis identified a relationship of advanced age and lower body weight to vascular complications. Utilization of a mechanical clamp rather than conventional hand pressure to attain vascular hemostasis significantly reduces ultrasound-defined femoral vascular pathology. Discrepancies between physical examination and ultrasound diagnoses challenge the utility of clinical assessment alone and establish ultrasound as the diagnostic modality of choice.

Impact of perioperative allogeneic and autologous blood transfusion on acute wound infection following total knee and total hip arthroplasty.

BACKGROUND Patients undergoing total hip or knee arthroplasty frequently receive blood transfusions. The relationship between transfusion and the risk of infection following total joint arthroplasty is unclear. In this study, we sought to examine the impact of allogeneic and autologous transfusion on the risk of acute infection following total hip and total knee arthroplasty. METHODS We performed a retrospective study of consecutive primary total knee arthroplasties and total hip arthroplasties. Patients who had a reoperation for suspected infection within three months after the arthroplasty were identified. Differences in risk factors were assessed across transfusion groups: no transfusion, autologous only, and allogeneic exposure (allogeneic with or without additional autologous transfusion). Backward-stepwise logistic regression analysis was used to compare reoperations (as outcomes) between cases with and those without allogeneic exposure. Prespecified covariates were body mass index, diabetes, an American Society of Anesthesiologists (ASA) score of >2, preoperative hematocrit, and total number of units transfused perioperatively. RESULTS We identified 3352 patients treated with a total hip or knee arthroplasty (1730 total knee arthroplasties and 1622 total hip arthroplasties) for inclusion in the study. Transfusion was given in 1746 cases: 836 of them had allogeneic exposure, and 910 had autologous-only transfusion. There were thirty-two reoperations (0.95%) for suspected infection. Between-group risk-factor differences were observed. The mean age and the rates of diabetes, immunosuppression, ASA scores of >2, and bilateral surgery were highest in the allogeneic group, as were estimated blood loss, surgery duration, and total number of units transfused (p < 0.001). In the unadjusted analyses, the rate of reoperations for suspected infection was higher in the cases with allogeneic exposure (1.67%) than in those without allogeneic exposure (0.72%) (p = 0.013). Autologous-only transfusion was not associated with a higher reoperation rate. However, multivariable logistic regression demonstrated that the total number of units transfused (p = 0.011) and an ASA score of >2 (p = 0.008)-but not allogeneic exposure-were significantly predictive of a reoperation. CONCLUSIONS Perioperative allogeneic transfusion was associated with a higher rate of reoperations for suspected acute infection. However, patients with allogeneic exposure had increased infection risk factors. After adjustment for the total number of units transfused and an ASA score of >2, allogeneic exposure was not significantly predictive of a reoperation for infection.