Biomedical subjects
Publications and source records attributed to R M Califf.
In elderly patients with myocardial infarction, clinicians face a management catch-22: Mortality is increased in the absence of therapy, which is often withheld because elderly patients may succumb to its complications. What to do? Evidence from recent studies suggests that the benefits of aggressive therapy with early thrombolysis may outweigh the risks.
Understanding the clinical risks of intravenous thrombolytic therapy is critical to appropriate patient selection. The major risks can be classified into 5 major categories: intracranial hemorrhage, systemic hemorrhage, immunologic complications, hypotension, and myocardial rupture. Although theoretical concern exists about thromboembolic complications, they rarely occur. Although cardiac rhythm disturbances are somewhat more likely to occur at the time of reperfusion, the clinical significance of "reperfusion arrhythmias" is minimal. Intracranial hemorrhage, the most devastating complication, occurs in 0.2-1% of patients treated with thrombolytic therapy. Factors associated with incremental risk are now being identified from large clinical trials. Systemic hemorrhage is uncommon in patients without major vascular punctures and seldom leads to serious adverse outcomes. Immunologic complications--including anaphylaxis, which is rare, and immune complex disease, which is more common--occur only with streptokinase or agents with a streptokinase moiety, including anistreplase (anisoylated plasminogen--streptokinase activator complex, APSAC). Hypotension, which can be managed easily in most patients, is also observed much more frequently with streptokinase and anistreplase. Myocardial rupture is increasingly being recognized as a possible complication of late thrombolysis. A proper perspective on clinical risk can only be gained in the context of potential benefit of therapy. In many cases individual patients considered to be at highest risk for complications also stand to gain the most from treatment. Many of the questions raised by currently available data about bleeding risk are being addressed in the ongoing Global Utilization of t-PA and Streptokinase (GUSTO) Trial. A paradigm for considering this decision making problem is presented.
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Patients in whom early and stable reperfusion through the infarct artery fails after thrombolytic treatment might benefit from further revascularization therapy. A reliable noninvasive technique able to detect both reperfusion and reocclusion would be useful to test this hypothesis. However, no such technique presently exists. ST-segment recovery analysis using continuous digital 12-lead ST monitoring has been shown to be an accurate predictor of infarct artery patency in real time. This method was dependent on a trained clinician's analysis of the recordings on a personal computer. For optimal bedside application, salient principles of this ST-segment recovery analysis were converted into algorithms and built into the ST monitor software. The essentials of these algorithms are described in this report.
The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial is a large scale international trial of new myocardial reperfusion strategies. The primary hypothesis is that early and sustained coronary artery recanalization will be associated with a significant reduction in mortality. The four regimens that are being tested are 1) streptokinase with subcutaneous heparin; 2) streptokinase with intravenous heparin; 3) accelerated recombinant tissue-type plasminogen activator (rt-PA) with intravenous heparin; and 4) combination streptokinase, rt-PA and intravenous heparin. The planned recruitment of 41,600 patients in 1,500 sites from 15 countries is expected to be completed by December 1992 and will enable detection of a 15% reduction or 1% absolute difference in mortality compared with that associated with standard therapy (streptokinase and subcutaneous heparin). In designing the trial, two important issues were directly addressed. First, a strategy was developed to provide assurance of patient safety during large scale investigational use of an aggressive thrombolytic regimen. This includes fascimile transmission of a one-page safety summary form to the Data Coordinating Center within 24 h of death or discharge, acceptance of the concept of "net clinical benefit" and close surveillance of the trial's progress by the independent Data and Safety Monitoring Committee. Second, to avoid potential conflict of interest beyond elimination of any position of financial equity, the Steering Committee unanimously voted to prohibit any honoraria for speaking engagements, payment for consultancy or travel or reimbursement of any kind from any of the five corporate sponsors until 1 year after publication of the results. Incorporation of these approaches may facilitate the design of future large scale randomized trials in cardiovascular medicine.
OBJECTIVES: The purpose of this study is to describe the outcome in cardiogenic shock treated with aggressive reperfusion therapy and to identify factors predictive of in-hospital and long-term mortality. BACKGROUND: Cardiogenic shock is the most common cause of death in patients admitted to the coronary care unit. Although studies have reported lower mortality rates in shock treated with angioplasty, few studies have described a cohort of patients with shock who were not selected because they were most likely to benefit from reperfusion therapy. METHODS: A consecutive series of 200 patients admitted with acute myocardial infarction complicated by cardiogenic shock were studied. RESULTS: The in-hospital mortality rate was 53%. Variables with significant univariable association with in-hospital death included patency of the infarct-related artery, patient age, lowest cardiac index, highest arteriovenous oxygen difference and left main coronary artery disease. The most important independent predictors of in-hospital death were patency of the infarct-related artery, cardiac index and peak creatine kinase, MB fraction. The mortality rate in patients with patent infarct-related arteries was 33% versus 75% in those with closed arteries and 84% in those in whom arterial patency was unknown. Patients who survived to hospital discharge were followed up for a median of 2 years, with a mortality rate of 18% after 1 year. The best descriptors of the relation between these variables and postdischarge mortality included age, peak creatine kinase, ejection fraction and patency of the infarct-related artery. CONCLUSIONS: In a large consecutive series of patients with cardiogenic shock with complete follow-up, patency of the infarct-related artery was most strongly associated with in-hospital and long-term mortality. This finding supports an aggressive interventional strategy in patients with cardiogenic shock.
Monitoring coagulation parameters during thrombolytic therapy could be useful for prediction and treatment of haemorrhagic episodes. Technology based on dry reagent chemistry has been developed that allows rapid (less than 10 min) assays on small samples of whole blood. The assay principle is based on the restriction of motion of paramagnetic particles during fibrin polymerization, and subsequent liberation of particle motion during fibrinolysis. This technology was used to monitor prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels and fibrinolysis profiles during thrombolytic therapy with tissue plasminogen activator for acute myocardial infarction. The PT and aPTT obtained with the COAG-1 correlated well with conventional assays (r = 0.93 and 0.92 for PT and aPTT, respectively; p = 0.0001). Fibrinogen estimates, obtained by COAG-2 also correlated well with modified Clauss assays (r = 0.86, p = 0.0001). The rapid determination of the aPTT may improve management of adjunctive anticoagulant therapy following thrombolysis. The fibrinolysis profile may be useful during thrombolytic therapy to verify that a lytic state has been achieved, to monitor the lytic state throughout therapy, and to verify that the lytic state normalizes once therapy has been completed.
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BACKGROUND: Experimental and observational clinical studies of acute coronary occlusion have suggested that late reperfusion prevents infarct expansion and facilitates myocardial healing. The purpose of this trial was to assess whether infarct vessel patency could be achieved in late-entry patients and what benefit, if any, can be demonstrated. METHODS AND RESULTS: In a double-blind fashion, 197 patients with 6 to 24 hours of symptoms and ECG ST elevation were randomly assigned to tissue-type plasminogen activator (100 mg over 2 hours) or placebo. Coronary angiography within 24 hours was used to determine infarct vessel patency status. Patients with infarct-related occluded arteries were then eligible for a second randomization to either angioplasty (34 patients) or no angioplasty (37 patients). Ventricular function and cavity size were reassessed at 1 month by gated blood pool scintigraphy and at 6 months by repeat cardiac catheterization. The primary end point, infarct vessel patency, was 65% for plasminogen activator patients compared with 27% in the placebo group (p less than 0.0001). There were no differences between these groups in ejection fraction or infarct zone regional wall motion at 1 or 6 months. At 6 months, infarct vessel patency was 59% in both groups. In the placebo group, there was a significant increase in end-diastolic volume from acute phase of 127 ml to 159 ml at 6-month follow-up (p = 0.006) but no increase in cavity size for the plasminogen activator group patients. Coronary angioplasty was associated with an initial 81% recanalization success and improved ventricular function at 1 month, but by late follow-up no advantage could be demonstrated for this procedure, and there was a 38% spontaneous recanalization rate in the patients assigned to no angioplasty. CONCLUSIONS: The study demonstrates that it is possible to achieve infarct vessel recanalization in the majority of late-entry patients with either thrombolytic therapy or angioplasty. Thrombolytic intervention had a favorable effect on prevention of cavity dilatation and left ventricular remodeling, but there are no late benefits on systolic function after thrombolysis or coronary angioplasty. The conclusions concerning overall potential benefit of applying late reperfusion therapy will require data from large-scale trials designed to assess mortality reduction.
BACKGROUND: Work disability is common in patients with coronary artery disease and adversely affects both economic well-being and quality of life. The purpose of this study was to construct a model to predict premature departure from the work force of patients with coronary disease and to validate this model prospectively in an independent cohort of patients. METHODS AND RESULTS: We enrolled 1,252 coronary disease patients referred for diagnostic cardiac catheterization who were less than age 65, employed, and without prior coronary angioplasty or coronary bypass surgery. Medical, functional, psychological, economic, and job-related variables were measured at the time of baseline diagnostic cardiac catheterization, and all patients were followed for 1 year. Three hundred twelve patients underwent percutaneous transluminal coronary angioplasty (PTCA) within 60 days of catheterization, and 449 had coronary artery bypass graft surgery (CABG) within 60 days of catheterization. The remaining 491 patients were treated with initial medical therapy. Logistic regression was used to develop a multivariable model for predicting 1-year work status in the training sample patients (872 patients enrolled between March 1986 and February 1989). This model was then validated in the independent prospective test sample (380 patients enrolled between March 1989 and June 1990). Eight factors were independent predictors of departure from the work force: lower initial functional status (as assessed by the Duke Activity Status Index), followed by older age, black race, presence of congestive heart failure, lower education level, presence of extracardiac vascular disease, poorer psychological status, and lower job classification. Standard clinical variables provided only 20% of the total predictive information available from the model about follow-up work outcomes, whereas functional measures provided 27%, and demographic and socioeconomic measures provided 45%. In the test sample, the area under the receiver operating characteristic curve for the model predictions was 0.74, compared with 0.80 in the training sample, and model predictions agreed well with observed prevalences of return to work. After adjustment for baseline imbalances, there was no significant difference in 1-year return-to-work rates among the patients receiving initial PTCA or CABG therapy versus initial medical therapy. CONCLUSIONS: Patients with coronary disease who are at high risk for premature departure from the work force can be accurately identified from a combination of medical and nonmedical risk factors. The model developed in this study provides a tool to identify patients at high risk for premature loss from the work force. Such patients may benefit from special multidimensional intervention programs designed to preserve work status. Our data show that revascularization with either PTCA or CABG is not, by itself, sufficient to accomplish this goal.
Changes in the economic and therapeutic environment have altered the time frame in which an accurate diagnosis of acute myocardial infarction (AMI) must be made. The advent of effective reperfusion therapies and the increasing emphasis on reducing cost produce an environment in which rapid diagnosis can reduce morbidity and mortality while simultaneously reducing overall cost by avoiding unnecessary hospitalization and intervention. The first element of a diagnostic strategy remains a brief, directed history and physical examination. The orientation of this phase is to identify important causes of symptoms other than AMI, while rapidly leading to more definitive evaluation for myocardial ischemia when another diagnosis is not found. The ECG provides the most rapid definitive diagnosis, but the diagnosis remains equivocal in many patients with nondiagnostic ECGs. In this group, the use of cardiac enzyme measurements early in the course holds promise in directing intensive care at high-risk patients while avoiding unnecessary intervention in low-risk patients. A protocolized approach to patient evaluation should become a part of standard practice patterns in every hospital.
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In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.
BACKGROUND: The purpose of this study was to describe the long-term event-free survival patterns of patients with significant coronary artery disease treated medically versus patterns of those treated surgically and to evaluate the factors associated with improved event-free survival. METHODS AND RESULTS: We studied the results of 5,824 patients undergoing medical and surgical therapy for ischemic heart disease from 1969 to 1984, with follow-up to 1991. Events considered for this evaluation were nonfatal myocardial infarction or cardiovascular death. The Cox proportional hazards model was used to determine factors differentially affecting surgical event-free survival. The survival benefits previously reported for bypass surgery in this population were largely preserved when event-free survival was examined. The two factors associated with significant event-free survival benefits for surgically treated patients were more severe coronary artery disease and a more recent surgery data. Patients with more severe coronary obstruction had a greater relative improvement with surgery in event-free survival than did patients with less severe anatomic disease. Event-free survival with surgery progressively improved over the period of the study and, by 1984, was significantly better than medical therapy for most patient subgroups. Patients with poor prognosis because of risk factors such as older age, severe angina, or left ventricular dysfunction had a risk reduction with surgery proportional to their overall risk under medical therapy. CONCLUSIONS: Higher-risk patients with more severe disease (due to either coronary disease or other risk factors and age) should be considered for coronary revascularization because it is in these patients that coronary artery bypass graft surgery has the greatest impact in reducing future cardiovascular events.
Cardiopulmonary resuscitation (CPR) is often considered a contraindication to thrombolytic therapy for acute myocardial infarction. Of 708 patients involved in the first 3 Thrombolysis and Angioplasty in Myocardial Infarction trials of lytic therapy for acute infarction, 59 patients required less than 10 minutes of CPR before receiving lytic therapy (CPR greater than 10 minutes was an exclusion of the trials) or required CPR within 6 hours of treatment. The patients receiving CPR were similar to the remainder of the group with respect to baseline demographics. The indication for CPR was usually ventricular fibrillation (73%) or ventricular tachycardia (24%). The median duration of CPR was 1 minute, with twenty-fifth and seventy-fifth percentiles of 1 and 5 minutes, respectively. The median number of cardioversions/defibrillations performed was 2 (twenty-fifth and seventy-fifth percentiles of 1 and 3 minutes, respectively). Patients receiving CPR were more likely to have anterior infarctions (66 vs 39%), the left anterior descending artery as the infarct-related artery (63 vs 38%) and lower ejection fractions on the initial ventriculogram (46 +/- 11 vs 52 +/- 12%) than those not receiving CPR. In-hospital mortality was 12 vs 6% with most deaths due to pump failure (57%) or arrhythmia (29%) in the CPR group and pump failure (38%) or reinfarction (25%) in the non-CPR group. At 7 day follow-up the CPR group had a significant increase in ejection fraction (+5 +/- 9%) compared with no change in non-CPR group. There were no bleeding complications directly attributed to CPR.(ABSTRACT TRUNCATED AT 250 WORDS)
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BACKGROUND: The treadmill exercise test identifies patients with different degrees of risk of death from cardiovascular events. We devised a prognostic score, based on the results of treadmill exercise testing, that accurately predicts outcome among inpatients referred for cardiac catheterization. This study was designed to determine whether this score could also accurately predict prognosis in unselected outpatients. METHODS: We prospectively studied 613 consecutive outpatients with suspected coronary disease who were referred for exercise testing between 1983 and 1985. Follow-up was 98 percent complete at four years. The treadmill score was calculated as follows: duration of exercise in minutes--(5 x the maximal ST-segment deviation during or after exercise, in millimeters)--(4 x the treadmill angina index). The numerical treadmill angina index was 0 for no angina, 1 for nonlimiting angina, and 2 for exercise-limiting angina. Treadmill scores ranged from -25 (indicating the highest risk) to +15 (indicating the lowest risk). RESULTS: Predicted outcomes for the outpatients, based on their treadmill scores, agreed closely with the observed outcomes. The score accurately separated patients who subsequently died from those who lived for four years (area under the receiver-operating-characteristic curve = 0.849). The treadmill score was a better discriminator than the clinical data and was even more useful for outpatients than it had been for inpatients. Approximately two thirds of the outpatients had treadmill scores indicating low risk (greater than or equal to +5), reflecting longer exercise times and little or no ST-segment deviation, and their four-year survival rate was 99 percent (average annual mortality rate, 0.25 percent). Four percent of the outpatients had scores indicating high risk (less than -10), reflecting shorter exercise times and more severe ST-segment deviation; their four-year survival rate was 79 percent (average annual mortality rate, 5 percent). CONCLUSIONS: The treadmill score is a useful and valid tool that can help clinicians determine prognosis and decide whether to refer outpatients with suspected coronary disease for cardiac catheterization. In this study, it was a better predictor of outcome than the clinical assessment.