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Biomedical subjects

R M Califf

Publications and source records attributed to R M Califf.

At least 19 recordsLinked to original sources
PubMed1992

Mechanism of benefit of combination thrombolytic therapy for acute myocardial infarction: a quantitative angiographic and hematologic study.

OBJECTIVES: The goal of this study was to lend insight into the mechanisms responsible for the beneficial effects of combination thrombolytic therapy. BACKGROUND: Combination thrombolytic therapy for acute myocardial infarction has been associated with less reocclusion and fewer in-hospital clinical events than has monotherapy. METHODS: Infarct-related quantitative coronary dimensions and hemostatic protein levels were evaluated in 287 patients with acute myocardial infarction during the early (90-min) and convalescent (7-day) phases after administration of recombinant tissue-type plasminogen activator (rt-PA), urokinase or combination rt-PA and urokinase. RESULTS: Minimal lumen diameter was similar in the 90-min and 7-day phases after treatment with rt-PA, urokinase and combination rt-PA and urokinase (0.72 +/- 0.45 mm, 0.62 +/- 0.53 mm and 0.75 +/- 0.58 mm, respectively, at 90 min, p = 0.16; and 1.05 +/- 0.56 mm, 1.12 +/- 0.72 mm and 0.94 +/- 0.54 mm, respectively, at 7 days, p = 0.22). In-hospital clinical event and reocclusion rates were less frequent in patients receiving combination therapy than in those receiving monotherapy (25% vs. 38% and 32% for rt-PA and urokinase, respectively, p = 0.084; and 3% vs. 13% and 9% for rt-PA and urokinase, respectively, p = 0.03), but these events were unrelated to early or late coronary dimensions. Patients receiving combination therapy or urokinase monotherapy had significantly higher peak fibrin degradation products (1,307 +/- 860 and 1,285 +/- 898 micrograms/ml vs. 435 +/- 717 micrograms/ml, respectively, p < 0.0001) and lower nadir fibrinogen levels (0.85 +/- 1.00 and 0.75 +/- 0.53 g/liter vs. 1.90 +/- 0.86 g/liter, respectively, p < 0.0001) than did those receiving rt-PA monotherapy. Peak fibrinogen degradation products indirectly correlated (p = 0.004) and baseline (p = 0.026) and nadir (p = 0.089) fibrinogen levels directly correlated with reocclusion. CONCLUSIONS: Lower in-hospital clinical event and reocclusion rates observed with combination thrombolytic therapy may relate to systemic hematologic factors rather than to the residual lumen obstruction after thrombolysis.

Blood Proteins↗
PubMed1992

Outcome of patients sustaining acute ischemic mitral regurgitation during myocardial infarction.

OBJECTIVE: To describe outcomes of patients sustaining an acute myocardial infarction complicated by mitral regurgitation managed with contemporary reperfusion therapies. DESIGN: Inception cohort case study. Long-term follow-up was obtained in 99% of all patients. SETTING: University referral center. PATIENTS: A series of 1,480 consecutive patients presenting between April 1986 and March 1989 who had emergency cardiac catheterization within 6 hours of infarction. Fifty patients were found to have moderately severe or severe mitral regurgitation. OUTCOME MEASURES: Mortality; follow-up cardiac catheterization in patients with regurgitation. RESULTS: Acute ischemic moderately severe to severe (3+ or 4+) mitral regurgitation was associated with a mortality of 24% at 30 days (95% CI, 12% to 36%), 42% at 6 months (CI, 28% to 56%), and 52% at 1 year (CI, 38% to 66%); multivariable analysis identified 3+ or 4+ mitral regurgitation as a possible independent predictor of mortality (P = 0.06). Patients with mitral regurgitation tended to be female, older, and to have cerebrovascular disease, diabetes, and preexisting symptomatic coronary artery disease. A physical examination did not identify 50% of patients with moderately severe to severe regurgitation. Acute reperfusion with thrombolysis or angioplasty did not reliably reverse valvular incompetence. In this observational study, the greatest in-hospital and 1-year mortalities were seen in patients reperfused with emergency balloon angioplasty, whereas patients managed medically or with coronary bypass surgery had lower mortalities. CONCLUSIONS: Moderately severe to severe (3+ or 4+) mitral regurgitation complicating acute myocardial infarction portends a grave prognosis. Acute reperfusion does not reduce mortality to levels experienced by patients with lesser degrees of mitral regurgitation nor does it reliably restore valvular competence.

Acute Disease↗
PubMed1992

Referral patterns for coronary artery disease treatment: gender bias or good clinical judgment?

OBJECTIVE: To determine whether a gender bias exists in referral for coronary bypass graft surgery among patients with catheterization-documented coronary artery disease. DESIGN: Historical cohort study (1969 to 1984). SETTING: A referral medical center. PATIENTS: A total of 5795 patients with catheterization-documented coronary artery disease. MEASUREMENTS: Surgical referral patterns of men and women grouped by risk for cardiac death and by treatment effectiveness. Time trends were evaluated for three periods: 1969 to 1974, 1975 to 1979, and 1980 to 1984. RESULTS: Overall, when no adjustment was made for baseline risk for cardiac death, no statistical difference was found between men and women regarding referral for surgery (46% compared with 44%, respectively). When an adjustment was made for such risk, the male-to-female odds ratio for surgical referral was 1.28 (95% Cl, 1.05 to 1.58) among patients with a low risk for cardiac death. This effect was most evident in the 1980 to 1984 period (odds ratio, 1.73; Cl, 1.29 to 2.31). In the high-risk group, the odds ratio was 0.84 (Cl, 0.68 to 1.04), with little change occurring during the study. Men were more likely to be referred for surgery when surgery offered the least survival benefit relative to medical therapy (odds ratio, 1.29; Cl, 1.08 to 1.54). This effect was most pronounced in the 1980 to 1984 period (odds ratio, 1.63; Cl, 1.27 to 2.10). CONCLUSIONS: Women are less likely than men to be referred for coronary bypass graft surgery among patients with a low risk for cardiac death, in whom surgery offers little or no survival benefit over medical treatment. Women are at least as likely as men to be referred for bypass surgery among more symptomatic and more severely diseased patients, in whom surgery offers the greatest survival benefits. These trends were most prominent in the recent years of the study. Based on surgical survival benefits, these referral patterns may represent more appropriate treatment referral for women than men.

Coronary Artery Bypass↗
PubMed1992

Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis.

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

Anticoagulants↗
PubMed1992

Accelerated plasminogen activator dose regimens for coronary thrombolysis. The TAMI-7 Study Group.

To determine the clinical profile and efficacy of accelerated recombinant tissue-type plasminogen activator (rt-PA) dose regimens, five different strategies of thrombolytic therapy in a total of 232 patients were systematically evaluated in the setting of acute myocardial infarction. The fifth strategy involved a combination of accelerated rt-PA and intravenous urokinase (regimen E). A weight-adjusted dose of 1.25 mg/kg body weight of tissue plasminogen activator over 90 min (regimen C) yielded the highest coronary patency rate (83%) at acute angiography. The associated in-hospital reocclusion rate for this regimen was low (4%). An exaggerated (60-min) dosage regimen yielded an inferior coronary patency rate (63%). Combination therapy (regimen E) was associated with a 72% patency rate and 3% reocclusion rate. Marginal improvement in global ejection fraction and regional wall function was demonstrated with all strategies by predischarge catheterization. Bleeding complications were most common at the periaccess site and were not different from those in previous experiences reported with conventional 3-h dosing regimens. Measurements of baseline, 30-min and 3-h levels of tissue plasminogen activator, fibrinogen and fibrin(ogen) degradation products were obtained. At 3 h, fibrinogen levels of less than 1 g/liter were demonstrated with combination therapy (regimen E) as well as with regimen C. Major clinical outcomes including death, reocclusion and reinfarction also showed a tendency to be less common with regimen C. Therefore, although accelerated dose regimens of rt-PA do not reliably yield acute coronary patency rates greater than 85%, an acute coronary patency rate of approximately 85% can be approached.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Aggressive therapy of acute MI in the elderly.

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.

Aged↗
PubMed1992

Clinical risks of thrombolytic therapy.

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.

Anistreplase↗
PubMed1992

Evolution of an automated ST-segment analysis program for dynamic real-time, noninvasive detection of coronary occlusion and reperfusion.

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.

Electrocardiography↗
PubMed1992

Confronting the issues of patient safety and investigator conflict of interest in an international clinical trial of myocardial reperfusion. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) Steering Committee.

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.

Biomedical Research↗
PubMed1992

Prognosis in cardiogenic shock after acute myocardial infarction in the interventional era.

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.

Academic Medical Centers↗
PubMed1992

Exploration of rapid bedside monitoring of coagulation and fibrinolysis parameters during thrombolytic therapy.

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.

Blood Coagulation↗
PubMed1992

A randomized trial of late reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction-6 Study Group.

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.

Angioplasty, Balloon, Coronary↗
PubMed1992

Identification of patients with coronary disease at high risk for loss of employment. A prospective validation study.

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.

Angioplasty, Balloon, Coronary↗