Ticlopidine versus aspirin after myocardial infarction (STAMI) trial.

OBJECTIVES: We sought to compare the efficacy of aspirin and ticlopidine in survivors of acute myocardial infarction (AMI) treated with thrombolysis. BACKGROUND: The role of ticlopidine in secondary prevention after AMI has not yet been explored. METHODS: Of 4,696 patients with AMI treated with thrombolysis who were screened, 261 died in the hospital (5.6%) and 1,470 were enrolled in this randomized, double-blind, multicenter trial and allocated to treatment with either aspirin (160 mg/day) or ticlopidine (500 mg/day). The most frequent reasons for exclusion were refusal to give informed consent, planned myocardial revascularization, risk of noncompliance with study procedures, need for anticoagulant therapy and contraindications to the study treatments. The primary end point was the first occurrence of any of the following events during the six-month follow-up: fatal and nonfatal AMI, fatal and nonfatal stroke, angina with objective evidence of myocardial ischemia, vascular death or death due to any other cause. RESULTS: The primary end point was recorded in 59 (8.0%) of the 736 aspirin-treated and 59 (8.0%) of the 734 ticlopidine-treated patients (p = 0.966). Vascular death was the first event in five patients taking aspirin and in six patients taking ticlopidine (0.7% vs. 0.8%; p = NS); nonfatal AMI in 18 and 8 (2.4% vs. 1.1%; p = 0.049); nonfatal stroke in 3 and 4 (0.4% vs. 0.5%; p = NS); and angina in 33 and 40 (4.5% vs. 5.4%; p = NS), respectively. The frequency of adverse reactions was not significantly different between the two groups. CONCLUSIONS: No difference was found between the ticlopidine and aspirin groups in the rate of the primary combined end point of death, recurrent AMI, stroke and angina.

Early administration of verapamil after thrombolysis in acute anterior myocardial infarction. Effect on left ventricular remodeling and clinical outcome. VAMI Study Group. Verapamil Acute Myocardial Infarction.

BACKGROUND: The administration of verapamil during the reperfusion phase of acute myocardial infarction can reduce the extent and severity of microvessel damage and limit myocardial dysfunction. We aimed at investigating the effect of early verapamil administration on left ventricular remodeling and the clinical evolution after myocardial infarction. METHODS: Eighty-eight patients with first acute anterior myocardial infarction thrombolysed < 4 hours from symptom onset were enrolled in a multicenter, randomized, double-blind, controlled study of verapamil administration (5 mg i.v. + 2 microg/kg/min over 24 hours). Echocardiographic end-diastolic (EDV) and end-systolic (ESV) left ventricular volumes were assessed by biplane Simpson's rule. RESULTS: At 90 days, EDV in the verapamil and placebo groups was respectively 88.9 +/- 27.8 and 95.8 +/- 30.7 ml (p = 0.11), ESV was 52.6 +/- 22.7 and 57.7 +/- 25.4 ml (p = 0.18). There was no change over time in the verapamil group (day 3 vs day 90: EDV 85.0 +/- 17.7 vs 88.9 +/- 27.8 ml, p = NS; ESV 48.7 +/- 14.1 vs 52.6 +/- 22.7 ml, p = NS) while left ventricular volume increased in the placebo group (day 3 vs day 90: EDV 87.6 +/- 21.1 vs 95.8 +/- 30.7 ml, p = 0.03; ESV 52.0 +/- 16.9 vs 57.7 +/- 25.4 ml, p = 0.08). NYHA functional classes were differently distributed at 30 and 90 days (chi2 = 0.009 and 0.07), with a lower prevalence of classes II and III in the verapamil group (p = 0.03). CONCLUSIONS: The early intravenous administration of verapamil in thrombolysed patients can reduce left ventricular remodeling and NYHA functional class after acute anterior myocardial infarction.

Low-dose dobutamine responsiveness in idiopathic dilated cardiomyopathy: relation to exercise capacity and clinical outcome.

AIMS: To evaluate myocardial contractile reserve using low-dose dobutamine echocardiography in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy stratified by peak exercise oxygen consumption (VO(2)). METHODS AND RESULTS: Sixty clinically stable patients (56+/-11 years; 45 males) with idiopathic cardiomyopathy and NYHA class I to III symptoms of heart failure were studied and followed-up for 13+/-3 months. All patients underwent cardiopulmonary exercise testing and low-dose dobutamine. The dobutamine infusion protocol consisted of an initial dose of 2.5 micro. kg(-1)per 3 min, increasing by 2.5 micro. kg(-1)per min every 3 min; the maximal dose was 10 micro. kg(-1)per min. The end-systolic volume index, left ventricular ejection fraction and cardiac output were measured at baseline and peak dobutamine dose and their change calculated as ((peak dose value-baseline value)/baseline value]x100. Ten normal subjects with normal left ventricular function and no coronary artery lesions served as a control group to compare low-dose dobutamine results. All analysed echocardiographic variables either at baseline or following dobutamine infusion were significantly lower in patients with chronic heart failure as a whole compared to the control group. When the patients were grouped according to Weber's classification, a statistically significant decrease in percentange changes in end-systolic volume index (rho=-0.77;P<0.0001), left ventricular ejection fraction (rho=-0.72;P<0.0001) and cardiac output (rho=-0. 82;P<0.0001) from class A to class C was observed. The mean percentage decrease in end-systolic volume index following the dobutamine infusion was 28.7+/-9% in class A (peak VO(2)>20 ml. kg(-1). min(-1)), 18.6+/-8% in class B (peak VO(2)between 16 and 20 ml. kg. min(-1)), and only 6.4+/-6% in class C (peak VO(2)between 10 and 16 ml. kg(-1). min(-1)) patient groups. At multivariate analysis, only the percentage change in end-systolic volume index was significantly associated with a peak VO(2)<15 ml. kg(-1). min(-1)(P=0.006). During the follow-up, 17 patients had events (15 readmissions for worsening heart failure and two deaths). At multivariate analysis, only the percentage change in end-systolic volume index was significantly associated with the occurrence of events (P=0.003). The area under the receiver operating characteristic curve for percentage change in end-systolic volume index was not significantly different from that for peak VO(2)(0. 86+/-0.04 vs 0.80+/-0.06;P:ns). CONCLUSION: This study indicates that in patients with chronic heart failure secondary to idiopathic cardiomyopathy, the cardiac response to low-dose dobutamine, as assessed by echocardiography, is correlated with peak VO(2), an objective and accurate measure of the severity of the disease and clinical outcome.

Percent achieved of predicted peak exercise oxygen uptake and kinetics of recovery of oxygen uptake after exercise for risk stratification in chronic heart failure.

To investigate whether percent achieved of predicted peak exercise oxygen uptake (%VO2max) and recovery of oxygen consumption after exercise may provide prognostic information in chronic heart failure (CHF), we prospectively studied 196 patients with mild to moderate CHF. The following variables were examined: age, etiology of CHF, functional class, ejection fraction (EF), peak exercise oxygen uptake normalized for body weight (VO2max), %VO2max, time to reach 50% of the peak oxygen uptake after exercise (T1/2VO2max), presence of nonsustained ventricular tachycardia (NSVT) and inability to take ACE-inhibitors. VO2max was the most powerful predictor of cardiac death (P<0.0001). Other independent predictors of death were EF, T1/2VO2max, NSVT and inability to take ACE-inhibitors. The discriminatory accuracy of VO2max for cardiac death was not significantly greater than that of %VO2max. In conclusion, the determination of %VO2max does not enhance risk stratification in CHF whereas the kinetics of oxygen consumption after exercise can provide prognostic information.

[Value of peak oxygen consumption during exercise for the prognostic stratification of patients with severe systolic dysfunction of the left ventricle]. / Valore del consumo massimo di ossigeno durante esercizio per la stratificazione prognostica di pazienti con severa disfunzione sistolica del ventricolo sinistro.

We sought to assess the prognostic value of peak exercise oxygen consumption (peak VO2) in patients with severe left ventricular systolic dysfunction and mild to moderate symptoms of chronic heart failure. We focused on 1-year mortality. We prospectively studied 77 patients with left ventricular ejection fraction (EF) < or = 25% and NYHA functional class I/II (61%) or III (39%). All patients underwent cardiopulmonary exercise test, two-dimensional echocardiography and 24-hour Holter monitoring. Examined variables were age, etiology, NYHA functional class, EF, peak VO2, and presence of nonsustained ventricular tachycardia. Overall 1-year mortality rate was 23%. At univariate analysis, age > or = 60 years, ischemic etiology, and peak VO2 < 14 ml/kg/min were significantly associated with mortality. At multivariate analysis, peak VO2 was the most powerful predictor of death (p = 0.0001). In the subgroup of patients with a peak VO2 < 14 ml/kg/min, the actuarial 1-year mortality rate was 56%. One additional patient underwent heart transplantation because of severe hemodynamic deterioration. By contrast, in the subgroup of patient with a peak VO2 > 14 ml/kg/min, 1-year mortality rate was 11%. This study provides evidence that patients with severe left ventricular dysfunction and mild to moderate symptoms of chronic heart failure can be accurately stratified into subgroups with strikingly divergent prognosis by an objective criteria such as peak VO2.

Sleep suppression of ventricular arrhythmias: a predictor of beta-blocker efficacy.

It has been reported that the frequency of premature ventricular contractions in some patients tend to decrease during the hours of sleep when modifications in autonomic tone and bradycardia occur. The aim of this study was to evaluate whether the phenomenon of sleep suppression may be a sensitive and specific parameter for predicting the antiarrhythmic effect of beta-blockers on premature ventricular contractions. The presence of sleep suppression was evaluated in 45 patients (mean age 50 +/- 17 years) with frequent premature ventricular contractions at two baseline Holter recordings. Sleep suppression was defined as > 50% reduction in the number of nighttime as opposed to day-time premature ventricular contractions. Three groups of patients were identified: those with sleep suppression at both Holter recordings (group 1); those with sleep suppression at only one Holter recording (group 2); and those without sleep suppression at either Holter recording (group 3). A third Holter was performed 5 days after nadolol administration. In group 1, nadolol led to a mean reduction in the number of premature ventricular contractions of 90% (> 70% in 21/23 patients). In group 2, the mean reduction was 76% (> 70% in three out of six patients). In group 3, there was a mean increase in the number of premature ventricular contractions of 33%. The positive predictive accuracy of sleep suppression in relation to the antiarrhythmic efficacy of nadolol is very high (88%) when sleep suppression is present during two baseline Holter recordings. Sleep suppression is a sensitive parameter for identifying the premature ventricular contractions likely to benefit from beta-blocker administration.

Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial.

OBJECTIVES: This study was performed to evaluate the effects of L-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. BACKGROUND: Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. METHODS: The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or L-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or L-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. RESULTS: A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6- and 12-month evaluation was significantly reduced in the L-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the L-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients. CONCLUSIONS: L-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event.

Transient myocardial ischemia in patients with chronic angina: relation to heart rate changes and variability in exercise threshold. BAY r 1999 in Chronic Angina Study Group.

This study was undertaken to assess the relation of ambulatory myocardial ischemia to heart rate changes and variability in exercise threshold in patients with chronic angina. The study involved 118 patients with chronic angina and proven coronary artery disease who had a 'positive' exercise test result. All patients underwent a first exercise test followed by a 48-h period of ambulatory electrocardiographic monitoring. A second exercise test was performed 4 days later. A total of 101 ischemic episodes were recorded in 35 patients. The heart rate at the appearance of 1-mm ST segment depression during ambulatory electrocardiographic monitoring was > or = 20 beats/min lower than that during exercise testing in 58 ischemic episodes (57%, Group A), 10-19 beats/min lower in 26 (26%, Group B), and < or = 9 beats/min lower or higher in 17 (17%, Group C). Thirty-five percent of the Group A ischemic episodes, 69% of Group B, and 71% of Group C were preceded by an increase in heart rate of > or = 10 beats/min. Thirty patients showed a variable exercise threshold. The prevalence of Group A and B ischemic episodes was not significantly different in patients with fixed or variable exercise threshold, whereas that of Group C episodes was 22% in the former and 0% in the latter (P = 0.036). These results suggest that increased coronary tone may be one of the mechanisms contributing to modulate the occurrence of transient myocardial ischemia in most patients with chronic angina and transient myocardial ischemia at ambulatory electrocardiographic monitoring. This occurs regardless of whether the patients have a variable or fixed exercise threshold.

Prediction of mortality in mild to moderately symptomatic patients with left ventricular dysfunction. The role of the New York Heart Association classification, cardiopulmonary exercise testing, two-dimensional echocardiography and Holter monitoring.

In order to investigate the value of peak oxygen consumption (peak VO2) in predicting mortality in mild to moderately symptomatic patients with left ventricular dysfunction, we studied 103 NYHA II/III class patients with a left ventricular ejection fraction (LVEF) < or = 40%. Heart failure was due to coronary artery disease (CAD) in 39 patients, idiopathic dilated cardiomyopathy in 54, hypertension in eight and surgically corrected valvular disease in two. The following variables were analysed: age, cause of heart failure (CAD vs no CAD), NYHA class, peak VO2, LVEF, left ventricular end-systolic volume index (LVESVI), ventricular tachycardia (VT) on Holter monitoring and the use of antiarrhythmic drugs. Statistical analysis was performed by Cox's proportional-hazards regression model. During a mean follow-up period of 20 months, there were 25 deaths. The estimated cumulative probabilities of survival were 88%, 73% and 58% at 1, 2 and 3 years, respectively. Cox's model identified CAD (P = 0.01), NYHA III class (P = 0.04) and LVEF (P = 0.02) as independent, statistically significant predictors of mortality. Peak VO2 had only a marginal statistical significance (P = 0.07). Age, LVESVI, VT on Holter monitoring and use of antiarrhythmic drugs were not related to mortality. These data can be important in patient clinical management and clinical trial design.

[The Italian contribution to the application of high-technology methods to clinical trials]. / Il contributo italiano nell'applicazione di metodiche ad alta tecnologia nei trial clinici.

Clinical trials are important research tools currently used in assessing new drugs and therapeutic strategies, which are unable to produce large effects evaluable in small series of patients. We describe methodological principles of clinical trials and significant advantages in their implementation produced by using a computer network for long-distance modem transmission of echocardiographic images and clinical data. This network has been recently developed in Italy and is operative at the University of Bari and the Associazione per la Ricerca in Cardiologia. Several clinical participating centers of the CEDIM Study and PHASE Study are connected in real time to a data center via modem by a special telephone network (RFD) of the Italian State Telephone Company (SIP). We describe the configuration, main features and applicative potential of such a powerful research tool in modem clinical trial methodology.

A digital network for long-distance echocardiographic image and data transmission in clinical trials: the CEDIM (Carnitina, Ecocardiografia Digitalizzata, Infarto Miocardico) study experience.

A special computer network has been specifically designed and realized to connect 36 Italian cardiological institutions to a central core laboratory. This network, which has been created to run the CEDIM Multicenter Trial (effects of L-carnitine on left ventricular function in patients with myocardial infarction assessed by digital echocardiography), enables automatic verification, via computer, 24 hours a day, of patient eligibility criteria, randomization, transmission, and filing of real-time left ventricular echocardiographic examinations. All the investigators participating in the CEDIM trial underwent several training courses as well as dummy run procedures to achieve optimal performance of all the operational procedures required for the network to function smoothly and correctly. This paper describes the aims of this special network, its technical characteristics, and the investigator training and dummy run procedures.

Propionyl-L-carnitine: a new compound in the metabolic approach to the treatment of effort angina.

The effects of propionyl-L-carnitine on exercise tolerance of 12 patients with stable exertional angina were assessed in a double-blind, placebo-controlled, cross-over protocol using serial exercise tests. Compared to placebo, propionyl-L-carnitine significantly increased total work from 514 +/- 199 to 600 +/- 209 W (P less than 0.05) (17%) and prolonged exercise time and time to ischemic threshold from 515 +/- 115 to 565 +/- 109 sec (P less than 0.05) (10%) and from 375 +/- 102 to 427 +/- 93 sec (P less than 0.01) (14%), respectively. ST segment depression at the highest common work level was significantly reduced from 0.19 +/- 0.08 to 0.15 +/- 0.08 mV (P less than 0.05) (21%). No significant changes in heart rate, systolic blood pressure, and rate-pressure product at rest, at the highest common work level, on appearance of the ischemic threshold, or at peak exercise were observed after propionyl-L-carnitine treatment. No side effects were observed under propionyl-L-carnitine treatment. This study shows that propionyl-L-carnitine can significantly improve exercise tolerance in patients with stable angina. Our data seem to confirm that propionyl-L-carnitine most likely exerts its protective action via the metabolic pathway.

Ticlopidine treatment for patients with unstable angina at rest. A further analysis of the study of ticlopidine in unstable angina. Studio della Ticlopidina nell'Angina Instabile Group.

Data collected to investigate the effects of ticlopidine in a subset of 489 patients with angina at rest accompanied by transient ischaemic electrocardiographic changes have been analysed. Of the 489 patients, 255 received conventional treatment including beta-blockers, nitrates, or calcium antagonists (control group); 234 received conventional treatment plus ticlopidine 250 mg b.i.d. (ticlopidine group). The predefined end-points were vascular death and acute myocardial infarction (AMI). The incidence of end-points was assessed according to the intention-to-treat principle. The post-hoc estimated statistical power was 80%. The rate of death or AMI in the 6-month follow-up period was reduced from 14.9 to 6.8% (-54.4%) (odds ratio: 0.42; confidence intervals: 0.22, 0.80). The incidence of fatal or nonfatal AMI was reduced from 12.2 to 4.3% (-65%) (odds ratio: 0.32; confidence intervals: 0.14, 0.70) and of nonfatal AMI from 10.2 to 3.8% (-63%) (odds ratio: 0.35; confidence intervals: 0.15, 0.80). Nineteen patients died; 12 in the control group (4.7%) and seven in the ticlopidine group (83%) (-36%) (odds ratio: 0.62; confidence intervals: 0.21, 1.74); five patients in the control group and only one in the ticlopidine group died of an AMI. The post-hoc estimated statistical power was 80%. However, we cannot draw definitive conclusions about the clinical effect of ticlopidine treatment in the patients with angina at rest accompanied by transient ischaemic electrocardiographic changes because the subgroup analysis was not planned a priori. Nevertheless, this report strongly suggests that such patients can benefit from antiplatelet treatment with ticlopidine; the benefit mainly depends on the protective effect against myocardial infarction.

Efficacy and duration of the effect of gallopamil sustained release in patients with chronic stable effort angina.

This double-blind, placebo-controlled, cross-over study was designed to evaluate the effects and duration of action of gallopamil sustained release (SR) in patients with stable effort angina. Exercise tests were performed 3, 8, and 12 hours after the last administration of placebo or gallopamil SR. Blood samples for plasma gallopamil concentration were taken just before each exercise test. Statistical analysis was performed using an analysis of variance for multiple comparisons with evaluation of interaction between sequence and period according to a cross-over design. Compared to placebo, gallopamil SR significantly prolonged exercise time from 412 +/- 100 to 481 +/- 71 s (p less than 0.02; 17%), from 416 +/- 88 to 484 +/- 67 s (p less than 0.01; 16%), and from 364 +/- 88 to 440 +/- 85 s (p less than 0.02; 21%) at 3, 8 and 12 hours respectively after administration. Time to -1 mm ST segment depression was also significantly prolonged from 263 +/- 56 to 336 +/- 76 s (p less than 0.001; 28%), from 262 +/- 81 to 356 +/- 70 s (p less than 0.001; 36%), from 231 +/- 65 to 291 +/- 76 s (p less than 0.001; 26%), respectively. No significant relationship between plasma levels and anti-ischemic activity was observed. In conclusion, our data show that gallopamil slow-release is effective in improving exercise tolerance of patients with chronic angina and that its therapeutic effect persists, substantially unchanged, up to 12 hours after administration.

Thrombolysis in unstable angina: results of clinical studies.

Ample evidence exists to support the major role of intracoronary thrombosis superimposed on a disrupted plaque in unstable angina. Consequently, thrombolytic treatment, already established to be highly beneficial in patients with acute myocardial infarction, might also be indicated in patients with unstable angina. The clinical response to thrombolytic treatment has been evaluated in several small-sized studies with inconsistent and somewhat deceiving results. Thus, the role of thrombolysis in the treatment of unstable angina is still controversial. Two ongoing large-scale, randomized, controlled trials, the Third Thrombolysis in Myocardial Infarction (TIMI III) in the United States testing recombinant tissue-type plasminogen activator and UNASEM in Europe testing anisoylated plasminogen-streptokinase activator complex will, it is hoped, solve the debate. At present, early thrombolysis might be considered for the treatment of the subset of patients with severe rest angina associated with transient ST-T ischemic changes.

Evaluation of pentisomide on stable ventricular premature beats. Comparison with placebo.

Pentisomide, a new class I anti-arrhythmic drug, was compared to placebo in 50 hospitalized patients with frequent (greater than 30 h-1) and stable ventricular premature beats (VPB) (variation less than 50% between two preliminary and one placebo 24-h Holter recordings). All patients underwent a single-dose acute oral testing followed by a short-term testing with 300 mg t.i.d. for 4 days and then by a 4-day placebo period. For the studied population, a 56.4% reduction of simple VPB and a 98.8% decrease of couplets and runs were the minimum required to define the drug efficacy and to exclude spontaneous variability, using the linear regression analysis. Pentisomide was found effective in 27 (54%) of the 50 patients after the acute test and in 23 (46%) after the short-term test. The drug induced a mild increase of PR and QRS intervals, while QTc, heart rate, blood pressure and ejection fraction showed no significant variations. Subjective tolerability was excellent.