Genell L. Knatterud

Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

Treatment of gram-negative bacteremia and septic shock with ha-1a human monoclonal antibody against endotoxin: A randomized, double-blind, placebo-controlled trial

BACKGROUND HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia. METHODS To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol. RESULTS Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected. CONCLUSIONS HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.

Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Improvement of Cardiac Ischemia at 1 Year After PTCA and CABG

BACKGROUND Cardiac ischemia on the ambulatory ECG (AECG) and/or on the exercise treadmill test (ETT) is associated with an increased risk of adverse outcome. Myocardial revascularization more often suppresses cardiac ischemia than does medical management alone. However, few studies have compared the effects of percutaneous transluminal coronary angioplasty (PTCA) with those of coronary artery bypass grafting (CABG) on cardiac ischemia and clinical outcome. METHODS AND RESULTS A total of 558 patients were randomly assigned to one of three treatment strategies in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study: angina-guided medical strategy (n = 184), ischemia-guided medical strategy (n = 182), or revascularization (n = 192). In patients assigned to revascularization, the choice of the procedure, PTCA or CABG, was made by the clinical unit staff and patient based on a coronary angiogram usually performed within 2 months of enrollment. CABG was selected in 78 patients and PTCA in 92 patients. At 12 weeks, ischemia on the AECG was suppressed in 70% of CABG patients versus 46% of PTCA patients (P = .002). Ischemia on the ETT was no longer present in 46% versus 23% of the patients, respectively (P = .005). Angina, within 4 weeks of the follow-up visit, was absent in 90% versus 68%, respectively (P = .001). These clinical variables remained improved in both groups at 1 year. Clinical events (myocardial infarction or repeat revascularization) occurred in 1 CABG patient versus 7 PTCA patients at 12 weeks, and in 1 versus 16 patients, respectively, at 12 months (P < .001). CONCLUSIONS Ischemia on the AECG and ETT and angina were relieved in many patients after both procedures; however, CABG was superior to PTCA, and it was associated with a lower incidence of clinical events at 1 year. These results suggest that more complete revascularization relates to better clinical outcome. However, a large trial is needed to confirm these results.

Photocoagulation Treatment of Proliferative Diabetic Retinopathy: The Second Report of Diabetic Retinopathy Study Findings

Data from the Diabetic Retinopathy Study (DRS) show that photocoagulad inhibited the progression of retinopathy. These beneficial effects were noted to some degree in all those stages of diabetic retinopathy which were included in the Study. Some deleterious effects of treatment were also found, including losses of visual acuity and constriction of peripheral visual field. The risk of these harmful effects was considered acceptable in eyes with retinopathy in the moderate or severe retinopathy in the moderate or severe proliferative stage when the risk of severe visual loss without treatment was great. In early proliferative or severe nonproliferative retinopathy, when the risk of severe visual loss without treatment was less, the risks of harmful treatment effects assumed greater importance. In these earlier stages, DRS findings have not led to a clear choice between prompt treatment and deferral of treatment unless and until progression to a more severe stage occurs.

Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Two-Year Follow-up Outcomes of Patients Randomized to Initial Strategies of Medical Therapy Versus Revascularization

BACKGROUND Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization. METHODS AND RESULTS The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia-guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (P<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (P<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (P<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison. CONCLUSIONS A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.

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.

Evidence-based behavioral medicine: What is it and how do we achieve it?

The goal of evidence-based medicine is ultimately to improve patient outcomes and quality of care. Systematic reviews of the available published evidence are required to identify interventions that lead to improvements in behavior, health, and well-being. Authoritative literature reviews depend on the quality of published research and research reports. The Consolidated Standards for Reporting Trials (CONSORT) Statement (www.consort-statement.org) was developed to improve the design and reporting of interventions involving randomized clinical trials (RCTs) in medical journals. We describe the 22 CONSORT guidelines and explain their application to behavioral medicine research and to evidence-based practice. Additional behavioral medicine-specific guidelines (e.g., treatment adherence) are also presented. Use of these guidelines by clinicians, educators, policymakers, and researchers who design, report, and evaluate or review RCTs will strengthen the research itself and accelerate efforts to apply behavioral medicine research to improve the processes and outcomes of behavioral medicine practice.

Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, Phase II, pilot and clinical trial.

In the Thrombolysis in Myocardial Infarction, Phase II pilot and clinical trial, 908 patients [326 (35.9%) in the pilot study and 582 (64.0%) in the randomized study] were treated with 150 mg recombinant tissue-type plasminogen (rt-PA) activator in combination with heparin and aspirin, and 3,016 patients [64 (2.1%) in the pilot study and 2,952 (97.9%) in the randomized study] were treated with 100 mg rt-PA in combination with heparin and aspirin. Adverse neurological events occurred in 23 patients treated with 150 mg rt-PA (2.5%) [nine cerebral infarctions (1.0%), 12 intracerebral hemorrhages (1.3%), and two subdural hematomas (0.2%)] and in 33 patients treated with 100 mg rt-PA (1.1%) [20 cerebral infarctions (0.7%), 11 intracerebral hemorrhages (0.4%), and two subdural hematomas (0.1%)]. The difference in adverse neurological events observed comparing the two rt-PA regimens was primarily due to a higher frequency of intracerebral bleeding among patients treated with 150 mg rt-PA (1.3% versus 0.4%, p less than 0.01). Patients with recent (within 6 months) histories of stroke were not eligible for the study, and patients with any history of cerebrovascular disease were declared ineligible early in the study. The small number of patients (89, or 2.3%) with any history of neurological disease, intermittent cerebral ischemic attacks, or stroke who were enrolled before the stricter eligibility criteria were imposed or on the basis of incomplete baseline information experienced an increased frequency of intracerebral hemorrhage compared with patients without such histories (3.4% versus 0.5%). Mortality at 6 weeks after presentation among 23 patients who had intracerebral hemorrhage was 47.8%. Intracerebral hemorrhage is a severe but infrequent complication of rt-PA therapy for acute myocardial infarction. The combined frequency of intracerebral hemorrhage, subdural hematoma, and cerebral infarction after treatment with 100 mg rt-PA is comparable to that observed in other trials with thrombolytic agents in acute myocardial infarction.

Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial.

The efficacy and safety of a 3 hr, 80 mg intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) were investigated in 47 patients with acute myocardial infarction. Coronary angiography, performed before the administration of rt-PA and for 90 min thereafter, demonstrated that 37 patients had total coronary occlusion before therapy. After 90 min of rt-PA (50 mg), reperfusion of the infarct-related artery was observed in 25 patients (68%). Continuous infusions of heparin for anticoagulation were administered for 8 to 10 days. Of 36 patients who underwent follow-up coronary cineangiography, 21 had initially presented with total occlusion and had experienced reperfusion at 90 min. Sustained perfusion of the infarct-related artery was observed in 14 (67%) of these 21 initially reperfused patients. Late angiography was performed in nine patients who initially demonstrated subtotal occlusion of the infarct-related artery; sustained perfusion was observed in eight (89%). Significant bleeding was observed in 15 patients (32%). A hematoma at the site of the acute catheterization accounted for most instances of significant bleeding (11/15, 73%). Administration of rt-PA resulted in a significant decline in fibrinogen and plasminogen while amounts of fibrin(ogen) degradation products rose. In no patient, however, did fibrinogen levels decline to less than 140 mg/dl. Thus, rt-PA, administered as a brief 80 mg intravenous infusion, is capable of restoring blood flow in a high proportion of patients with acute myocardial infarction due to total coronary obstruction. Declines in plasma fibrinogen and plasminogen are observed. If combined with heparin anticoagulation and invasive vascular procedures, significant bleeding is a common complication.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Effects on Clinical Outcomes of Aggressive Lowering of Low-Density Lipoprotein Cholesterol Levels and Low-Dose Anticoagulation in the Post Coronary Artery Bypass Graft Trial

Background —The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. Methods and Results —Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P =0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P =0.008 and 0.003, respectively. Conclusions —The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.