Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study.

BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.

Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3.

OBJECTIVES: We sought to determine trends in the treatment of myocardial infarction from 1990 through 1999 in the U.S. and to relate these trends to current guidelines. BACKGROUND: Limited data are available to show how recent clinical trials and clinical guidelines have impacted treatment of myocardial infarction. METHODS: Temporal trends in myocardial infarction treatment and outcome were assessed by using data from 1,514,292 patients in the National Registry of Myocardial Infarction (NRMI) 1, 2 and 3 from 1990 through 1999. RESULTS: During this interval, the use of intravenous thrombolytic therapy declined from 34.3% to 20.8%, but the use of primary angioplasty increased from 2.4% to 7.3% (both p = 0.0001). The median "door-to-drug" time among thrombolytic therapy recipients fell from 61.8 to 37.8 min (p = 0.0001), primarily owing to shorter "door-to-data" and "data-to-decision" times. The prevalence of non-Q wave infarctions increased from 45% in 1994 to 63% in 1999 (p = 0.0001). From 1994 through 1999, there was increased usage of beta-blockers, aspirin and angiotensin-converting inhibitors, both during the first 24 h after admission and on hospital discharge (all p = 0.0001). Between 1990 and 1999, the median duration of hospital stay fell from 8.3 to 4.3 days, and hospital mortality declined from 11.2% to 9.4% (both p = 0.0001). CONCLUSIONS: The NRMI data from 1990 through 1999 demonstrate that the recommendations of recent clinical trials and published guidelines are being implemented, resulting in more rapid administration of intravenous thrombolytic therapy, increasing use of primary angioplasty and more frequent use of adjunctive therapies known to reduce mortality, and may be contributing to the higher prevalence of non-Q wave infarctions, shorter hospital stays and lower hospital mortality.

ACC policy statement. Recommended guidelines for training in adult clinical cardiac electrophysiology. Electrophysiology/ Electrocardiography Subcommittee, American College of Cardiology.

Training in clinical cardiac electrophysiology should take place in an Accreditation Council for Graduate Medical Education accredited cardiology program, and the electrophysiology training program itself should be accredited by the Council. Each trainee must be eligible for board certification in Internal Medicine and either eligible for certification in Cardiovascular Diseases or in a program leading to eligibility. Training faculty should be certified in clinical cardiac electrophysiology or demonstrate equivalent credentials. At least two training faculty members are preferred. The faculty must be dedicated to teaching, active in performing or promoting research and must spend a substantial portion of their time in research, teaching and practice of clinical electrophysiology. A curriculum of training should be established. Faculty experts in the related basic sciences should be available and involved in teaching. The institution should have a fully equipped clinical electrophysiology laboratory and complete noninvasive capabilities. A close working relation with a cardiac surgery faculty member skilled in surgical treatment of arrhythmias is required. Training in application of pharmacologic and all current nonpharmacologic therapies, in the outpatient and inpatient setting, is necessary. The clinical exposure must include all facets of arrhythmia diagnosis and treatment and must be quantitatively sufficient to allow the trainee to develop proficiency. The period of training should not be less than one year in addition to the period of cardiology fellowship required by the ABIM for board eligibility. A continuous period of training is preferred.

Factors influencing the time to thrombolysis in acute myocardial infarction. Time to Thrombolysis Substudy of the National Registry of Myocardial Infarction-1.

BACKGROUND: The Time to Thrombolysis Substudy of the National Registry for Myocardial Infarction provided the opportunity to identify factors that delay thrombolytic treatment of patients with ST-segment elevation acute myocardial infarction. PARTICIPANTS: Forty-two participating registry hospitals volunteered for the Time to Thrombolysis Substudy. METHODS: A case report form was developed to collect time points for emergency department arrival (door), recording of the electrocardiogram (ECG) (data), entry of the order to give a thrombolytic drug (decision), and initiation of the thrombolytic infusion (drug) as defined by the National Heart Attack Alert Program. The impact of mode of transportation to the hospital, sex, policy-driven cardiology consultation and/or contact of the primary care physician on door-to-drug time, and each component interval were determined in 1755 patients who were treated with recombinant tissue-type plasminogen activator (A1-teplase). The t test was used for comparison of means and the nonparametric sign test was used for medians. RESULTS: A minority of patients arrived at the hospital by ambulance, although more women (49.6%) arrived by ambulance than men (40.9%). However, women arrived at hospitals significantly later after onset of symptoms than men. It took half as long for patients arriving by ambulance to be seen by the physician than those who transported themselves to the hospital. It took longer for women to have the initial 12-lead ECG recorded than men. The decision to order a thrombolytic agent was delayed by 22 minutes and median door-to-drug time by 21 minutes in those patients who had a cardiac consultation over those in whom the drug was ordered and infusion was initiated by the emergency physician. Although the initial 12-lead ECG showed ST-segment elevation in 86% of patients who received the thrombolytic drugs, with no difference between men and women and no difference in the rate of cardiology consultation between men and women (77%), door-to-decision time and door-to-drug time were substantially longer for women having consultation than men. There was no significant difference in door-to-decision time between men and women when no consultation was performed, but it still took longer for a drug infusion to be initiated in women. Contacting the primary care physician delayed the decision to give a thrombolytic drug by 18 minutes and the administration of the drug by 20 minutes, but there were no differences between men and women. Preparation of the drug in the pharmacy resulted in significant delay compared with mixing it in the emergency department. CONCLUSIONS: Hospital practices and policies, including contacting the primary care physician prior to the initiation of a lytic drug, cardiology consultation, and preparation of the drug in the pharmacy rather than in the emergency department, significantly delay the goal of early treatment of patients with ST segment elevation acute myocardial infarction. Delays in hospital arrival for women are compounded by delays in the decision to treat them with a thrombolytic drug and initiation of the drug therapy in those women who receive consultation compared with men. Other delays in acquiring the first ECG and initiating the drug infusion in women are not explained.

Consultation before thrombolytic therapy in acute myocardial infarction. Second National Registry of Myocardial Infarction (NRMI 2) Investigators.

Among 57,398 thrombolytic recipients in the National Registry of Myocardial Infarction 2, consultation with another physician was sought in 64% before initiating lytic therapy, although presenting features were typical, rather than atypical, in most patients. Consultation significantly delayed the administration of lytic therapy and was associated with increased hospital mortality.

Differences between men and women in the management of unstable angina pectoris (The GUARANTEE Registry). The GUARANTEE Investigators.

Few data are available in prospectively collected cohorts of patients with unstable angina pectoris or on the use of appropriate medications or interventions. Accordingly, we evaluated 2,948 consecutive patients with unstable angina admitted to 35 hospitals in the United States in 1996, and comparing men and women (39% of the patients were women). Differences were seen in coronary risk profiles with a higher incidence of systemic hypertension, diabetes mellitus, and a family history of coronary disease in women. Women were less likely to receive Agency for Health Care Policy Research (AHCPR) recommended pharmacologic treatment than men. Cardiac catheterization, coronary angioplasty, and bypass was performed less often in women compared with men (44% vs. 53%, p = 0.002; 12% vs. 18%, p = 0.02; 7% vs. 10%, p = 0.001, respectively). At catheterization, women were more likely to have no significant coronary artery disease (25% vs. 14%, p = 0.001). Although fewer women than men fulfilled the AHCPR criteria for cardiac catheterization (54% vs. 64%, p = 0.001), a similar rate of men and women with positive criteria underwent catheterization and angioplasty. However, fewer women with positive criteria underwent bypass surgery (36% vs. 46%, p = 0.03). More men "ruled-in" for a myocardial infarction at admission (13% vs. 8%, p = 0.001), but there was no difference in recurrent angina, in-hospital myocardial infarction, or death. Despite different epidemiologic profiles and less evidence of coronary artery disease by noninvasive and invasive tests, women and men had similar outcomes.

Evaluation of physician skills in cardiopulmonary resuscitation.

Thirty-five physicians at various levels of postgraduate training in internal medicine were evaluated for performance skills in cardiopulmonary resuscitation (CPR) according to standards of the American Heart Association. They were given instruction in only the cognitive knowledge related to CPR through lectures and a demonstration of the technique, without supervised manikin practice. Only 22% (8) of the physicians tested were able to adequately compress and ventilate the manikin in a simulated cardiac arrest. Although physicians are proficient in the use of drugs during resuscitative efforts, it is also imperative that they be able to perform basic CPR.

A noninvasive method of predicting pulmonary-capillary wedge pressure.

BACKGROUND: The noninvasive prediction of pulmonary-capillary wedge pressure (PCWP) is important for the recognition and treatment of a variety of cardiovascular disorders. The response of the arterial pressure to the Valsalva maneuver has been shown to correlate with the PCWP. We therefore devised a noninvasive method to measure this pressure response at the bedside and correlated these measurements with the PCWP measured directly with a pulmonary-artery catheter. METHODS: Simultaneous, blinded, noninvasive measurements of the ratio of the final amplitude to the initial amplitude of the pulse wave form during the stress phase of the Valsalva maneuver (pulse-amplitude ratio) and direct measurements of the PCWP were obtained in 20 clinically stable patients and in 14 clinically unstable patients who were receiving vasoactive agents, 12 of whom also had endotracheal tubes in place. RESULTS: Using linear regression analysis, we found that the pulse-amplitude ratio strongly correlated with the measured PCWP over a range of base-line values from 4 to 32 mm Hg for the 20 clinically stable patients (R2 = 0.80) and the 14 clinically unstable patients (R2 = 0.85). The method also correctly predicted changes in the PCWP after the administration of nitroglycerin or furosemide and after expansion of the intravascular volume (R2 = 0.79). CONCLUSIONS: These preliminary data indicate that a simple noninvasive method can accurately predict the PCWP and changes in the PCWP in response to medical therapy.

Effects of PEEP and of increased frequency of ventilation during CPR.

Previous reports have attributed increased carotid blood flow to lung ventilation during CPR. This study was undertaken to determine whether PEEP (20 torr airway pressure) or increased frequency of ventilation (3:1) improved arterial pressure, flow, and blood gases. Thirty-three domestic pigs were studied using three protocols (standard 5:1 CPR, 5:1 CPR plus PEEP, 3:1 CPR) distributed such that comparisons could be made between groups as well as within the same pig. For intrapig comparisons, PO2 was significantly improve (p less than 0.05) by PEEP (delta PO2 = 9.7 +/- 13.0 torr). PCO2 was significantly less (p less than 0.005) for 3:1 compared to 5:1 (delta PCO2 = -4.7 +/- 2.1 torr). For group comparisons, PO2 was 55.5 +/- 12.9 torr without and 70.1 +/- 16.3 torr with PEEP (p less than 0.025). For 3:1, PO2 was 66.3 +/- 11.6 torr that was greater (p less than 0.10) than for 5:1. When ventilation was temporarily halted, phasic changes in flow with ventilation were replaced by nearly constant flow approximately equal to maximal flow when ventilation was provided. PEEP and more frequent ventilation improved blood oxygenation but at the expense of carotid blood flow.

Changing physician behavior in ordering digoxin assays.

OBJECTIVE: To assess the ability to modify physicians' use of serum digoxin assays in a sustained fashion through (1) an educational intervention by a clinical pharmacist, and (2) changes in the computerized medical information system. DESIGN: A before/after methodology was used to compare test use by hospital staff physicians in two phases. Phase 1 was an educational intervention conducted by a clinical pharmacist with an 8-month follow-up. Phase 2 was a medical information system intervention with a 12-month follow-up. PATIENTS: Adult inpatients from July 1990 through December 1993 who received either digoxin therapy or at least one serum digoxin assay. MAIN OUTCOME MEASURE: Digoxin assays per patient day while receiving digoxin (assays/digoxin day), in-hospital mortality, and length of stay were compared before and after implementation of the interventions. RESULTS: A total of 9468 patients received a digoxin and/or serum digoxin assay. Baseline use of serum digoxin assays was 0.178 assays/digoxin day. Following phase 1, the educational intervention, use declined 20.2% to 0.142 assays/digoxin day (p < 0.03). After phase 2, the implementation of changes in the medical information system, digoxin assay use was maintained at 16.3% less than that at baseline (p < 0.03). Patient mortality was unaffected. CONCLUSIONS: A low-intensity educational intervention by a clinical pharmacist supplemented by medical information system modification resulted in an important decrease in the use of digoxin assays. The change in physician behavior was sustained for more than 18 months. The model presented is not labor intensive, does not require continuous maintenance by healthcare personnel for a sustained effect, and may be widely applicable to healthcare providers.

Correlated measurement of platelet release and aggregation in whole blood.

We have used a technique for the simultaneous measurement of platelet activation and aggregation in whole blood using two-color immunofluorescence and flow cytometry to study the relationship between the release reaction and aggregation. A monoclonal antibody specific for the alpha granule membrane protein GMP-140 was used to measure the release reaction, and a monoclonal antibody specific for platelet membrane glycoprotein Ib (GPIb) was used to identify platelets and platelet aggregates. Aggregates were identified as particles expressing both levels of GPIb and size larger than that of resting single platelets. Anticoagulated whole blood was incubated with platelet agonists. At various times samples of the blood were removed and immediately fixed with paraformaldehyde. Blood that had been anticoagulated with ethylenediamine tetraacetic acid showed progressive release of platelets but little or no aggregation. However, blood anticoagulated with citrate or heparin showed correlated release and aggregation. The degree of aggregation was greater in heparin than in citrate. The expression of GPIb and GMP-140 increased in direct proportion to the size of the aggregates. Aggregates were observed varying in apparent diameter up to approximately 20 microns. During prolonged incubation there was progressive disaggregation of adenosine diphosphate (ADP)-induced aggregates. After disaggregation the proportion of GMP-140 negative single platelets increased, indicating that both released and nonreleased platelets participated in the aggregation. There was little or no disaggregation of phorbol myristate acetate (PMA)-induced aggregates. The relatively small size and reversibility of platelet aggregates that we have observed in whole blood may be relevant to phenomena occurring in vivo and in extracorporeal circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Expediting the early hospital care of the adult patient with nontraumatic chest pain: impact of a modified ED triage protocol.

A prospective study that compared a traditional emergency department (ED) triage protocol with an expedited protocol was conducted to determine if minimizing the subjectivity of nursing triage would result in more efficient management of adult patients presenting with nontraumatic chest pain. The traditional protocol triaged 382 patients into 1 of 5 categories of acuity. The expedited study group (418 patients) were triaged as usual but subsequently were treated as if they were triage category 1 or 2 (medical evaluation within 15 minutes of arrival). Traditional triage led to 40% of acute myocardial infarction (AMI) patients being triaged into inappropriately low-acuity categories. The expedited protocol resulted in significant improvement in the following intervals: ED arrival to triage, triage to cubicle, ED arrival to cubicle, ED arrival to electrocardiogram (ECG) ordered, ED arrival to ECG available, ED arrival to physician evaluation, and ED arrival to decision to thrombolyse. Study patients with non-AMI cardiac chest pain and AMI cardiac chest pain were evaluated by a physician an average of 12 minutes and 8 minutes after ED arrival, respectively. Delays in interdepartmental processes, such as ECG-technician responsiveness, thrombolysis protocol fulfillment and thrombolytic agent delivery, negated benefits derived from improvements in internal processes. Effective coordination of the numerous processes involved in the initial ED management of adult patients with nontraumatic chest pain is required to make thrombolytic therapy for AMI within 30 minutes of patient arrival a routinely achievable goal.

Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study.

In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality.

Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial.

OBJECTIVES: To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events. DESIGN: A multicenter, randomized, controlled trial. SETTING: Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II). INTERVENTIONS: Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy. MEASUREMENTS: Patients were monitored for hemorrhagic events during hospitalization. MAIN RESULTS: In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose. CONCLUSIONS: Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.