Relative value of clinical variables, bicycle ergometry, rest radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring at discharge to predict 1 year survival after myocardial infarction.

The relative value of predischarge clinical variables, bicycle ergometry, radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring for predicting survival during the first year in 351 hospital survivors of acute myocardial infarction was assessed. Discriminant function analysis showed that in patients eligible for stress testing the extent of blood pressure increase during exercise slightly improved the predictive accuracy beyond that of simple clinical variables (history of previous myocardial infarction, persistent heart failure after the acute phase of infarction and use of digitalis at discharge), whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring did not. The predictive value for mortality was 12% with clinical variables alone and 15% with the stress test added. Radionuclide ventriculography and 24 hour electrocardiographic monitoring were slightly additive to clinical information in the whole group of patients independent of the eligibility for stress testing (predictive value for mortality 24% with clinical variables alone and 26% with radionuclide ejection fraction and 24 hour electrocardiographic monitoring added). It is concluded that the appropriate use of simple clinical variables and stress testing is sufficient for risk stratification in postinfarction patients, whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring should be limited to patients not eligible for stress testing.

Prediction of mortality during the first year after acute myocardial infarction from clinical variables and stress test at hospital discharge.

The predictive value of a predischarge symptom-limited stress test was studied in 405 consecutive survivors of acute myocardial infarction (AMI). Three hundred patients performed bicycle ergometry; 105 could not perform it. Among these latter 105 patients, the stress test was contraindicated in 43 because of angina or heart failure and in 62 because of noncardiac limitations. One-year survival was 44% in the "cardiac-limited" group (19 of 43) and 92% in the "non-cardiac-limited" group (57 of 62). One-year survival among the patients who performed an exercise test at discharge was 93% (280 out of 300). The best stress test predictor of mortality by univariate analysis was the extent of blood pressure (BP) increase: 42 +/- 24 mm Hg in 280 survivors vs 21 +/- 14 mm Hg in 20 nonsurvivors (p less than 0.001). Among the 212 patients in whom BP increased 30 mm Hg or more, mortality was 3% (n = 6), while it was 16% (n = 14) among the 88 patients in whom BP increased less than 30 mm Hg. Angina, ST changes and arrhythmias were not as predictive. Stepwise discriminant function analysis showed inadequate BP increase to be an independent predictor of mortality. A high-risk group can be identified at discharge on clinical grounds in patients unable to perform a stress test, whereas intermediate- and low-risk groups can be identified by the extent of BP increase during exercise.

Comparison of peak serum C-reactive protein and hydroxybutyrate dehydrogenase levels in patients with acute myocardial infarction treated with alteplase and streptokinase.

Peak serum C-reactive protein concentrations were measured in 146 patients randomized to receive streptokinase, alteplase, or a combination of streptokinase and alteplase in the GUSTO-I trial. Those receiving alteplase treatment had lower values than those receiving streptokinase or the combination treatment. Irrespective of treatment, complete reperfusion of the infarct-related artery (TIMI grade 3 flow) was associated with low peak serum C-reactive protein values.

Four-year prognostic value of exercise-induced angina and painless ST segment depression early after myocardial infarction.

The aim of this study was to establish if angina pectoris and silent ST segment depression during pre-discharge exercise tests are predictive of 4 years survival after myocardial infarction. Accordingly, 377 consecutive hospital survivors of myocardial infarction underwent symptom-limited bicycle ergometry at hospital discharge. Sixty-eight patients had angina during exercise, 124 patients had silent ST segment depression and 184 had neither angina nor ST depression. The baseline demographic profile, exercise capacity during ergometry and radionuclide left ventricular ejection fraction were comparable in the three groups. The total mortality within 4 years in the three groups was 15%, 21% and 22%, and mortality due to reinfarction or sudden death was 10%, 17% and 14%. When patients on digitalis were excluded, the incidence of mortality due to reinfarction or sudden death in the group with painless ST segment depression was 11%. Coronary artery bypass grafting or percutaneous transluminal coronary angioplasty due to recurrent symptoms was performed in 41%, 20% and 18% respectively of the three groups. It is concluded that conditional upon modern treatment, including secondary prevention with beta-blockers and revascularization procedures in selected patients with symptoms refractory to medical therapy, exercise-induced angina and painless ST segment depression do not identify a group of patients at higher risk of sudden death or fatal reinfarction during the 4 years after myocardial infarction.

Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation.

The aim of this study was to assess the social fate (work resumption) and long-term (four years) survival in 141 patients who completed a cardiac rehabilitation programme after a recent myocardial infarction. Out of the 100 patients who had been working up to recently before the myocardial infarction, 58 resumed their work. Of the predischarge evaluation (clinical data, resting radionuclide ventriculography, bicycle ergometry and 24-h ambulatory ECG monitoring) and bicycle ergometry after the rehabilitation, the only significant predictor of work resumption was a better exercise tolerance at discharge (P less than 0.02). Work was resumed by 68% of white-collar workers and by 52% of blue-collar workers. The four-year cardiac mortality in patients who completed the rehabilitation was 8.5% (N = 12). Four patients died during the first year. Clinical, ventriculographic and ergometric variables collected at hospital discharge, which were related to left ventricular dysfunction, were predictive of survival, while ventricular arrhythmias and markers of myocardial ischaemia were less predictive. The exercise testing performed after the rehabilitation programme was not useful for risk assessment. It is concluded that markers of left-ventricular dysfunction are predictive of a poor outcome; however, due to the low risk of patients who were referred to our rehabilitation unit and completed the rehabilitation programme, it seems reasonable for return to work to be based primarily on clinical information, exercise tolerance, and on psychological and social grounds. An additional extensive cardiological evaluation should be individually tailored for patients with specific symptoms.

Incidence and prognostic implications of repetitive ventricular complexes during pre-discharge bicycle ergometry after myocardial infarction.

The clinical significance of repetitive ventricular complexes (RVCs) during pre-discharge bicycle ergometry after acute myocardial infarction has been assessed in 408 consecutive patients. RVCs occurred in 32 patients (8%). When compared to patients without RVCs, those with RVCs had a larger infarction, a higher prevalence of heart failure and late sustained ventricular tachycardia or fibrillation, a lower radionuclide ejection fraction and more frequent RVCs during pre-discharge 24-hour electrocardiographic monitoring. During a follow-up 30 patients died, 17 suddenly. Mortality was 15% (N = 5) in patients with RVCs during exercise test and 7% (N = 25) in those without RVCs. Sudden death occurred in only one patient with RVCs. When multivariate analysis was applied to clinical and exercise test data, RVCs during exercise did not predict cardiac mortality independent of variables related to left ventricular function, such as a history of previous myocardial infarction, persistence of heart failure in the late hospital phase and the extent of blood pressure rise during exercise test.

Prediction of 1-year outcome after complicated and uncomplicated myocardial infarction: Bayesian analysis of predischarge exercise test results in 300 patients.

After myocardial infarction (MI), the additive prognostic value of exercise variables to clinical variables has been questioned. The merits of a symptom-limited predischarge exercise test were therefore evaluated in clinically defined subgroups of patients. Exercise tests were consecutively performed by 208 survivors of uncomplicated MI (no heart failure, postinfarction angina, recurrent infarction, or late arrhythmias) and by 92 survivors of complicated MI. After uncomplicated MI (1-year mortality rate 4%), an achieved workload greater than 70% of age-predicted maximum identified 145 patients at very low risk (predictive value for survival 98%). After complicated MI (1-year mortality rate 13%), an exaggerated heart rate response was the best predictor of outcome, but had low (92%) predictive value of survival at 155 bpm. It is concluded that stress testing has only limited value after complicated MI. After uncomplicated MI, exercise variables are extremely helpful in identifying patients at very low risk in whom further investigations are not warranted.

Ineligibility for predischarge exercise testing after myocardial infarction in the elderly: implications for prognosis.

This study describes the clinical profile and prognosis of elderly patients not eligible for predischarge exercise testing. The database consisted of 133 patients 55-64 years of age, and 111 patients older than 64 years of age who survived an acute myocardial infarction. Follow-up was one year. In the younger age group, 24 (18%) patients were unable to perform the test, in contrast to 63 (57%) of the elderly subjects. In these two groups, one-year mortality rates were 13% and 37%, compared with 6% and 4% for the respective patients eligible for stress testing. Clinical profile and radionuclide ejection fraction between ineligible patients in both age groups were similar. Ejection fraction measurement was the best predictor of late mortality in those patients who did not have an exercise test. It is concluded that ineligibility for predischarge exercise test identifies a high-risk group, especially in patients older than 64 years of age.

Changes in plasma lipoproteins after cardiac rehabilitation in patients not on lipid-lowering drugs.

The extent to which a conventional cardiac rehabilitation programme can influence plasma lipoproteins was investigated in a prospective study. The relationship between changes in plasma lipoproteins and baseline characteristics, as well as variables related to the physical training and to dietary habits were assessed in 77 cardiac patients. All patients participated in a physical training programme, including general dietary advice. Patients who received lipid-lowering drugs were excluded from this study. Total plasma cholesterol decreased from 7.1 +/- 1.6 to 6.8 +/- 1.2 mmol l-1 (P less than 0.05), but it remained high in many patients, 61% having a level above 6.5 mmol l-1. The high- and low-density lipoprotein fractions (HDL- and LDL-cholesterol), and the ratio of total cholesterol to HDL-cholesterol, did not change significantly. The change in total plasma cholesterol was greatest (P less than 0.05) in patients who changed their diet in the recommended direction, and was poorly related to the change in maximal workload. It is concluded that a combination of general dietary advice and moderate physical exercise training is followed by a small reduction in total plasma cholesterol levels without changing HDL-cholesterol, and that cardiac rehabilitation should include strict programmes for the reduction of elevated plasma cholesterol.

Differential effects of tissue plasminogen activator and streptokinase on infarct size and on rate of enzyme release: influence of early infarct related artery patency. The GUSTO Enzyme Substudy.

BACKGROUND: The recent international GUSTO trial of 41,021 patients with acute myocardial infarction demonstrated improved 90-min infarct related artery patency as well as reduced mortality in patients treated with an accelerated regimen of tissue plasminogen activator, compared to patients treated with streptokinase. A regimen combining tissue plasminogen activator and streptokinase yielded intermediate results. The present study investigated the effects of treatment on infarct size and enzyme release kinetics in a subgroup of these patients. METHODS: A total of 553 patients from 15 hospitals were enrolled in the study. Four thrombolytic strategies were compared: streptokinase with subcutaneous heparin, streptokinase with intravenous (i.v.) heparin, tissue plasminogen activator with i.v. heparin, and streptokinase plus tissue plasminogen activator with i.v. heparin. The activity of alpha-hydroxybutyrate dehydrogenase (HBDH) in plasma was centrally analysed and infarct size was defined as cumulative HBDH release per litre of plasma within 72 h of the first symptoms (Q(72)). Patency of the infarct-related vessel was determined by angiography in 159 patients, 90 min after treatment. RESULTS: Infarct size was 3.72 g-eq.1(-1) in patients with adequate coronary perfusion (TIMI-3) at the 90 min angiogram and larger in patients with TIMI-2 (4.35 g-eq.1(-1) or TIMI 0-1 (5.07 g-eq.1(-1) flow (P = 0.024). In this subset of the GUSTO angiographic study, early coronary patency rates (TIMI 2 + 3) were similar in the two streptokinase groups (53 and 46%). Higher, but similar, patency rates were observed in the tissue plasminogen activator and combination therapy groups (87 and 90%). Median infarct size for the four treatment groups, expressed in gram-equivalents (g-eq) of myocardium, was 4.4, 4.5, 3.9 and 3.9 g-eq per litre of plasma (P = 0.04 for streptokinase vs tissue plasminogen activator). Six hours after the first symptoms, respectively 5.3, 6.6, 14.0 and 13.6% of total HBDH release was complete (P < 0.0001 for streptokinase vs tissue plasminogen activator). CONCLUSIONS: Rapid and complete coronary reperfusion salvages myocardial tissue, resulting in limitation of infarct size and accelerated release of proteins from the myocardium. Treatment with tissue plasminogen activator, resulting in earlier reperfusion was more effective in reducing infarct size than the streptokinase regimens, which contributes to the differences in survival between treatment groups in the GUSTO trial.

Value of predischarge data for the prediction of exercise capacity after cardiac rehabilitation in patients with recent myocardial infarction.

The aim of this study was to assess whether data related to predischarge clinical examinations, resting radionuclide ventriculography and symptom-limited bicycle ergometry can predict the achievement of a normal exercise capacity after a rehabilitation program in patients with a recent myocardial infarction. The study population consists of 141 consecutive patients who completed a 3-month training program. Patients with heart failure and/or severe angina were excluded. The rehabilitation program included two training sessions weekly during the 3 months. Working capacity (WC) increased from 79 +/- 17% at hospital discharge to 105 +/- 21% of normal values after rehabilitation (P less than 0.001), by 33% on average. Ninety-five patients achieved a normal WC. Conventional predischarge clinical evaluation, resting left ventricular ejection fraction, exercise induced angina, or ST segment depression were not predictive of normal WC after rehabilitation. Predischarge WC was the single best predictor of a normal WC after rehabilitation compared to those with a persistently low WC (84 +/- 15% in patients with normal WC vs 69 +/- 14% in those with persistently low WC, P less than 0.001). Nevertheless, 49% of patients with a baseline WC of less than 80% achieved a normal WC after rehabilitation. No correlation was found between the change of WC after rehabilitation and predischarge WC or ejection fraction. Therefore, the selection of patients for cardiac rehabilitation after a myocardial infarction should be based primarily on clinical grounds. Exclusion based on exercise induced angina, ST segment depression or low resting ejection fraction at hospital discharge or at entry in the rehabilitation program is not justified.

Pharmacodynamics and safety of lefradafiban, an oral platelet glycoprotein IIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty.

OBJECTIVE: Lefradafiban is the orally active prodrug of fradafiban, a glycoprotein IIb/IIIa receptor antagonist. The present phase II study aimed to determine the dose of lefradafiban that provides 80% blockade of the glycoprotein IIb/IIIa receptors by fradafiban, and to study the pharmacodynamics and safety of different doses in patients with stable angina undergoing angioplasty. DESIGN: A double blind, placebo controlled, dose finding study. SETTING: Four academic and community hospitals in the Netherlands. PATIENTS: 64 patients with stable coronary artery disease undergoing elective percutaneous transluminal coronary angioplasty. INTERVENTIONS: 30 mg, 45 mg, and 60 mg of lefradafiban three times daily or placebo was given for 48 hours. MAIN OUTCOME MEASURES: The primary safety end point was the occurrence of bleeding, classified as major, minor, or insignificant according to the thrombolysis in myocardial infarction (TIMI) criteria. Efficacy indices included per cent fibrinogen receptor occupancy (FRO), ex vivo platelet aggregation, and plasma concentrations of fradafiban. RESULTS: Administration of lefradafiban 30, 45, and 60 mg three times daily resulted in a dose dependent increase in median FRO levels of 71%, 85%, and 88%, respectively. Inhibition of platelet aggregation was closely related to FRO. There were no major bleeding events. The 60 mg lefradafiban group had a high (71%) incidence of minor and insignificant bleeding. The incidence of bleeding was 44% in the 30 mg and 45 mg groups, compared with 9% in placebo patients. Puncture site bleeding was the most common event. The odds of bleeding increased by 3% for every 1% increase in FRO. CONCLUSIONS: Lefradafiban is an effective oral glycoprotein IIb/IIIa receptor blocker. The clinical effectiveness of doses up to 45 mg three times daily should be investigated.

Safety and preliminary efficacy of one month glycoprotein IIb/IIIa inhibition with lefradafiban in patients with acute coronary syndromes without ST-elevation; a phase II study.

AIMS: Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients with acute coronary syndromes. We assessed the safety and preliminary efficacy of 1 month treatment with three dose levels of the oral GP IIb/IIIa blocker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation. METHODS: The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a dose-escalation trial with 20, 30 and 45 mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefradafiban or placebo in a double-blind manner. Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and recurrent angina. Safety was evaluated by the occurrence of bleeding classified according to the TIMI criteria and by measuring clinical laboratory parameters. RESULTS: There was a trend towards a reduction in cardiac events with lefradafiban 30 mg when compared with placebo and lefradafiban 20 mg. The benefit was particularly apparent in patients with a positive (> or = O.1 ng. ml(-1)) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac event rate decreased with increasing minimal levels of fibrinogen receptor occupancy. There was a dose-dependent increase in the incidence of bleeding: the composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20 mg and in 7% of patients receiving 30 mg, with an excessive risk (15%) in the 45 mg group which resulted in early discontinuation of this dose level. Gingival and arterial or venous puncture site bleedings were most common and accounted for more than 60% of all haemorrhagic events. There was an increased incidence of neutropenia (neutrophils <1. 5 x 10(9)/l) in the lefradafiban groups (5.2% vs 1.5% in the placebo group), which did not result from bone marrow depression but rather from a reversible redistribution of neutrophils by margination or clustering. CONCLUSION: One month's treatment with the oral glycoprotein IIb/IIIa inhibitor lefradafiban in patients with unstable angina and myocardial infarction without persistent ST elevation resulted in a decrease in cardiac events with lefradafiban 30 mg and a dose-dependent increase in haemorrhagic events. The observed favourable trend towards a reduction in cardiac events in patients with elevated troponin levels requires confirmation in a large clinical trial.

Continuous ST-segment monitoring associated with infarct size and left ventricular function in the GUSTO-I trial.

BACKGROUND: The aim of this study was to evaluate whether in patients with myocardial infarction, the intensity and duration of myocardial ischemia as measured by continuous ST monitoring are associated with infarct size and residual left ventricular function. METHODS AND RESULTS: The analyses included patients with myocardial infarction, receiving thrombolytic therapy, who were enrolled in the electrocardiographic substudy of GUSTO-I, monitored by a vector-derived 12-lead electrocardiographic recording system, and in whom either infarct size (defined as cumulative release of alpha-hydroxybutyrate dehydrogenase activity per liter of plasma over a 72-hour period [Q(72)]) or left ventricular ejection fraction (LVEF) was determined. With the use of linear regression analysis, we investigated the association of various ST-trend characteristics with Q(72) (206 patients) and with LVEF (180 patients). A higher area under the ST trend since thrombolysis until 50% ST recovery and a higher area under recurrent ischemic episodes (ST reelevations) were significantly associated with a higher Q(72), whereas only a higher area under recurrent ischemic episodes was significantly associated with a lower LVEF. These associations remained after adjusting for other patient characteristics such as age, sex, infarct location, and time to treatment. CONCLUSIONS: These findings support the physiologic hypothesis that both the intensity and duration of myocardial ischemia (both reflected by the estimated areas under the ST-trend curve) determine myocardial damage and thus are associated with infarct size and ejection fraction in patients with acute myocardial infarction who receive thrombolytic therapy.