A multicenter observational study on the management of hyperglycemia in patients with acute coronary syndrome.

AIM: To assess the prevalence, risk and management of hyperglycemia in patients with acute coronary syndrome (ACS). DESIGN: a multicenter prospective observational study of a representative sample of patients with ACS consecutively admitted to intensive cardiac care units (ICCU). SETTING: 31 out of 61 ICCUs in Lombardy, the most heavily populated Italian region. From May 2009 to April 2010 1260 patients (69.4% male; mean age 68 ± 13 years) were included in the study: 301 (23.9%) were known diabetic patients (D) and 265 (21.0%) had hyperglycemia (H) (blood glucose >180 mg/dL) at hospital admission, 174 with a history of diabetes (D+H+) and 91 without (D-H+). On the first day after admission intravenous insulin infusion was prescribed to 72 D+H+ (41.4%) and 10 D-H+ (11.0%), according to different protocols. Approximately one third of D+H+ patients (59) and one fifth (17) of D-H+ maintained mean blood glucose higher than 180 mg/dL during the first day in the ICCU. Patients with diabetes or hyperglycemia had a higher incidence of major adverse cardiovascular events or death in hospital. However, at multivariable analysis neither diabetes nor blood glucose at admission was associated with a poor prognosis whereas mean blood glucose on the first day was an independent negative prognostic predictor (OR 1.010, 95% CI 1.002-1.018, p = 0.016). CONCLUSION: Hyperglycemia is frequent in patients with ACS and is independently associated with a poor in-hospital prognosis if it persists in first day. Unfortunately, however, this condition is still poorly treated, with far from optimal blood glucose control.

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

OBJECTIVE: we evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF). BACKGROUND: predicting long-term maintenance of sinus rhythm in patients with AF is difficult. METHODS: plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models. RESULTS: mean patient age was 68 ± 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR-proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06). CONCLUSION: circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study.

OBJECTIVES: This study was conducted to determine the role of insulin-dependent and noninsulin-dependent diabetes in the prognosis of patients after myocardial infarction and treatment with fibrinolytic agents. BACKGROUND: Several studies have shown that diabetic patients have a high mortality rate after acute myocardial infarction. However, the impact of diabetes on survival in patients treated with fibrinolytic agents is still undefined. It is also not known whether the type of diabetes or gender affects prognosis. METHODS: We analyzed prevalence and prognostic significance of a history of diabetes in patients enrolled in the GISSI-2 study, all of whom received fibrinolytic agents. The incidence of deaths in the hospital and at 6 months after study entry was computed for patients without diabetes and for insulin-dependent and noninsulin-dependent diabetic patients; relative risks were evaluated by univariate and multivariate analysis. RESULTS: Information on diabetic status was available for 11,667 patients, 94.2% of those randomized in the GISSI-2 study. The prevalence of diabetes was higher in women than in men (8.75% vs. 1.85%, p < 0.01 for insulin-dependent and 23.7% vs. 13.8%, p < 0.01 for noninsulin-dependent diabetic patients). The type of fibrinolytic agent did not affect mortality rates; the increase in in-hospital mortality of diabetic patients was moderate and similar for men with insulin- and noninsulin-dependent diabetes (8.7% and 10.1%, respectively, vs. 5.8% in nondiabetic patients); in women, mortality was markedly higher for insulin-dependent and only slightly higher for noninsulin-dependent diabetic patients (24.0% and 15.8%, respectively, vs. 13.9% for nondiabetic patients). The adjusted relative risks were 1.9 (95% confidence interval 1.2 to 2.9) for insulin-dependent diabetic women and 1.4 (95% confidence interval 1.1 to 1.8) for noninsulin-dependent diabetic men. The mortality rate after discharge showed a similar gender difference, and in insulin-dependent diabetic women, prognosis was ominous even in the absence of left ventricular damage before discharge. CONCLUSIONS: A history of diabetes is associated with a worse prognosis after myocardial infarction, even in patients treated with fibrinolytic agents. Gender and type of diabetes appear to be critical in affecting survival. In men, both insulin-dependent and noninsulin-dependent diabetes are associated with a moderately higher mortality rate; in women, insulin-dependent diabetes is, in itself, a strong risk factor for death after myocardial infarction.

A simple electrocardiographic predictor of the outcome of patients with acute myocardial infarction treated with a thrombolytic agent. A Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2)-Derived Analysis.

OBJECTIVES: This analysis aimed to evaluate in a large patient cohort the relation between ST segment alterations after fibrinolytic therapy for acute myocardial infarction and 1) the combined end point of in-hospital mortality plus clinical congestive heart failure or extensive left ventricular damage, and 2) mortality 30 and 180 days after randomization. BACKGROUND: Angina relief, enzyme release acceleration and ST segment normalization are related to coronary artery reperfusion and prognosis. Electrocardiographic (ECG) evaluation before and after fibrinolytic drug administration has been used to predict short- and long-term clinical outcome in acute myocardial infarction. METHODS: Patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial underwent a standard ECG on admission and after 4 h of alteplase or streptokinase therapy; 7,426 recordings were suitable for ST segment analysis. A decrease > or = 50% in the sum of ST segment elevation in all ECG leads was adopted as the cutoff for predicting coronary artery patency. Recanalization was deemed to have occurred in 4,951 patients (group A) versus 2,475 patients without reperfusion (group B). RESULTS: Group A patients experienced a lower incidence of the combined end point than did group B patients (16.2% vs. 22.9%, respectively), as well as of all its components (death, clinical heart failure, ejection fraction < 35%, injured myocardial segment > 45%, QRS score > 10). Thirty- and 180-day mortality rates were lower in group A than group B (3.5% and 5.7% vs. 7.4% and 9.9%, respectively); relative risk (Cox) was 0.46 (95% confidence interval [CI] 0.37 to 0.57) for 30-day and 0.58 (95% CI 0.48 to 0.70) for 180-day mortality. Patients in group A had significantly less ventricular fibrillation and sustained ventricular tachycardia but more ischemic episodes (early recurrent angina plus myocardial infarction recurrence). CONCLUSIONS: A simple, inexpensive instrumental evaluation, unaffected by different epidemiologic and clinical characteristics of the population analyzed, can allow early assessment of the effectiveness of fibrinolytic treatment with respect to the main clinical outcomes.

Predictors of nonfatal reinfarction in survivors of myocardial infarction after thrombolysis. Results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) Data Base.

OBJECTIVES: This study was designed to reassess the prediction of recurrent nonfatal myocardial infarction in patients recovering from acute myocardial infarction after thrombolysis. BACKGROUND: Recurrent nonfatal myocardial infarction is a strong and independent predictor of subsequent mortality. Current knowledge of risk factors for nonfatal reinfarction is still largely based on data gathered before the advent of thrombolysis. Thus, this prospective study was planned to identify harbinger of nonfatal reinfarction in the postinfarction patients of the multicenter Grouppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial. METHODS: Predictors of nonfatal reinfarction at 6 months were analyzed by multivariate technique (Cox model) in 8,907 GISSI-2 survivors of myocardial infarction with clinical follow-up, relying on a set of prespecified variables reflecting residual ischemia, left ventricular failure or dysfunction, complex ventricular arrhythmias, comorbidity as well as demographic and historical factors. RESULTS: The postdischarge to 6-month incidence rate of nonfatal reinfarction was 2.5%. Independent predictors of nonfatal reinfarction were cardiac ineligibility for exercise test (relative risk 2.97, 95% confidence interval [CI] 1.98 to 4.45), previous myocardial infarction (relative risk 1.70, 95% CI 1.22 to 2.36) and angina at follow-up (relative risk 1.50, 95% CI 1.10 to 2.04). On further multivariate analysis, performed in 6,580 patients with both echocardiographic and electrocardiographic monitoring data available, a history of angina emerged as an additional risk predictor (relative risk 1.58, 95% CI 1.10 to 2.25). CONCLUSIONS: The 6-month incidence of nonfatal reinfarction is rather low in survivors of myocardial infarction after thrombolysis. Cardiac ineligibility for exercise testing and a history of coronary artery disease are risk predictors. Recurrent nonfatal infarction is not predictable by qualitative variables reflecting residual ischemia, except by postdischarge angina. Prediction of nonfatal reinfarction appears less accurate than prediction of mortality, as almost 50% of reinfarctions occur in patients without any of the identified risk factors.

Frequency of predischarge ventricular arrhythmias in postmyocardial infarction patients depends on residual left ventricular pump performance and is independent of the occurrence of acute reperfusion. The GISSI-2 Investigators.

OBJECTIVES: To test whether acute reperfusion of the infarct-related vessel after an acute myocardial infarction is associated with a subsequent reduction in spontaneous ventricular arrhythmias that is independent of ventricular ejection fraction, 1,944 patients from the GISSI-2 study population were studied. The patients were selected on the basis of a first myocardial infarction and the availability of two-dimensional echocardiographic ejection fraction and data on the number of premature ventricular contractions per hour on Holter monitoring. BACKGROUND: It has been suggested that postthrombolytic reperfusion of the culprit vessel may be associated with an increased electrical stability of the infarcted heart, irrespective of its residual pump performance. METHODS: The predischarge relation between ejection fraction and number of premature ventricular contractions per hour was plotted according to the occurrence (1,309 patients) or not (635 patients) of acute reperfusion, identified noninvasively according to the modifications of the ST segment in serial electrocardiograms obtained in the first 24 h after infarction. RESULTS: The frequency of premature ventricular contractions increased in a linear fashion with decreasing ejection fraction in both cohorts (p < 0.005 and p < 0.0001); however, there was no significant difference between the slopes and the intercepts of the two regression lines, so that the relation between ejection fraction and number of premature ventricular contractions per hour could be adequately described by a single equation: y (number of premature ventricular contractions) = 33.0-0.42x (ejection fraction) (r = -0.107, p < 0.0001). The results were the same even when differences between group characteristics were accounted for in a multiple regression model. CONCLUSIONS: It is concluded that 1) the number of premature ventricular contractions per hour after an acute myocardial infarction is dependent in a linear, inverse fashion on the residual ventricular ejection fraction, and 2) this relation is independent of the occurrence of reperfusion in the acute phase of infarction.

Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.

OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outcomes were changed by concomitant ASA use. CONCLUSIONS: Both ASA and ACEi are beneficial in acute MI. The present results support the early use of ACEi in acute MI, irrespective of whether or not ASA is being given.

Antiarrhythmic drug prescription in patients after myocardial infarction in the last decade. Experience of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI).

BACKGROUND: Recent clinical trials have shown increased, rather than decreased, mortality in patients treated with antiarrhythmic drugs after acute myocardial infarction. OBJECTIVE: To determine whether these findings had an impact on prescription of antiarrhythmic drugs after acute myocardial infarction. METHODS: We retrospectively analyzed the class I and III antiarrhythmic prescription data of 38,072 patients with acute myocardial infarction enrolled in three large randomized clinical trials endorsed by a highly representative sample (about 75%) of Italian coronary care units during the last 10 years. The first study was conducted in 1984 to 1985; the second, in 1988 to 1989; the pilot for the third, in 1991; and the third, in 1991 to 1994. RESULTS: Total class I and III antiarrhythmic prescriptions after acute myocardial infarction was halved during the last decade, from 11.9% at discharge and 14.4% at follow-up in 1984 to 1985 to 5.8% and 5.8%, respectively, in 1991 to 1994. The trend was independent of the different distributions in the three studies of the patients' characteristics associated with antiarrhythmic use (ie, age > or = 70 years, anterior acute myocardial infarction, ventricular fibrillation during hospitalization, and Killip class > or = 2 at randomization). The same decreasing trend was observed for each antiarrhythmic drug. The drug most widely used was amiodarone, accounting for about half of the antiarrhythmic prescriptions, followed by mexiletine hydrochloride and propafenone hydrochloride; flecainide acetate was dropped from the prescription list after the publication of the Cardiac Arrhythmia Suppression Trial results. CONCLUSION: The negative results of the recent clinical trials on class I antiarrhythmic drug use after acute myocardial infarction have been rapidly transferred into routine clinical practice in Italy, since the proportion of patients who received class I and III antiarrhythmic drugs after acute myocardial infarction was halved from the early 1980s to the early 1990s.

Prognostic value of a history of hypertension in 11,483 patients with acute myocardial infarction treated with thrombolysis. GISSI-2 Investigators. Gruppo Italiano per lo Studio della, Sopravvivena nell'Infarto Miocardico.

OBJECTIVE: To assess the prognostic value of a history of hypertension in patients with acute myocardial infarction (AMI) treated with thrombolysis. DESIGN: Retrospective adjusted analysis of outcome data of patients with AMI randomly allocated to treatment in a controlled study of alteplase versus streptokinase and heparin versus no heparin. SETTING: A highly representative sample (about 90%) of Italian Coronary Care Units. PATIENTS: Patients with (n = 3306) and without (n = 7406) a history of treated hypertension. MAIN OUTCOME MEASURES: Morbidity and mortality during hospital stay and the next 6 months. RESULTS: Patients with a history of hypertension had a significantly higher mortality, both in hospital and during the next 6 months. The difference persisted also after a multivariate analysis including all major prognostic factors for in-hospital and 6-month mortality, respectively. Left ventricular failure and recurrent ischaemic events (angina and re-infarction) were also significantly more frequent in hypertensives both during their hospital stay and during follow-up study. CONCLUSIONS: A history of hypertension is a negative independent prognostic factor after acute myocardial infarction treated with thrombolysis.

One-year prognosis of primary ventricular fibrillation complicating acute myocardial infarction. The GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto miocardico) investigators.

The 1-year prognosis of 293 patients discharged alive from the hospital after acute myocardial infarction (AMI), who experienced primary ventricular fibrillation (VF) in the acute phase, was compared with that of a reference group of 6,337 patients identified from the same population included in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto miocardico (GISSI) trial. There was no difference in the 6- and 12-month mortality between the patients with primary VF and the reference group (3.7 vs 2.7% and 4.1 vs 4.2%, respectively). Survival of the 2 groups was also similar when patients were stratified according to infarct site (anterior and posterior), and whether or not they received treatment with streptokinase during AMI. Thus, long-term mortality of patients discharged alive after AMI complicated by primary VF is low and is not influenced by previous fibrinolytic therapy or by infarct site. The excess mortality of patients with primary VF is confined to the hospital phase, after which survivors represent a low-risk subgroup.

Trends and determinants of calcium antagonist usage after acute myocardial infarction (the GISSI experience).

In the last decade, several clinical trials in patients with, or recovering from, acute myocardial infarction (AMI) have evaluated the role of calcium antagonists in affecting patients' prognosis. Results have been disparate, with evidence of possible harm, no effect, or some benefit, depending on the agent used. We evaluated how the evidence from these trials has influenced the pattern of prescription of calcium antagonists and assessed the important determinants of use of these agents in patients after AMI. We analyzed retrospectively the prescription of calcium antagonists at discharge in all patients recovering from AMI enrolled in 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto-1 [GISSI-1], GISSI-2, and GISSI-3) during the last 10 years. A progressive decrease in prescriptions for calcium antagonists was evident, from 47.2% in GISSI-1 to 35.1% in GISSI-2 to 19.0% in GISSI-3 (p<0.001). The presence of post AMI angina, history of hypertension, and occurrence of reinfarction were associated with a higher usage of calcium antagonists, whereas the use of beta blockers at discharge was a major independent negative determinant. Use of calcium antagonists for secondary prevention after AMI (i.e., without specific clinical indications for their use) decreased by approximately 60% (from 26.1% to 10.3%). The data indicate that the usage of calcium antagonists in GISSI studies has been strongly affected by the results of other large multicenter trials evaluating calcium antagonists. These agents are now prescribed in patients after AMI almost exclusively in the presence of specific indications such as systemic hypertension or angina.

Coffee consumption and risk of acute myocardial infarction in Italian males. GISSI-EFRIM. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto, Epidemiologia dei Fattori di Rischio del'Infarto Miocardico.

The relationship between coffee consumption and acute myocardial infarction (AMI) was analyzed using data from a case-control study conducted in 1988 to 1989 within the framework of the GISSI-2 trial on streptokinase versus alteplase and heparin versus no heparin in the treatment of AMI. A total of 801 male patients with AMI and 792 control subjects who were hospitalized in several Italian regions for diseases unrelated to known or potential risk factors for cardiovascular diseases were included. Compared with coffee nondrinkers, the multivariate relative risks (RRs), after allowance for age, education, body mass index, smoking habits, alcohol consumption, family history of AMI, cholesterol level, history of diabetes, and hypertension, were 0.8 (95% confidence interval (CI), 0.5 to 1.2) for consumption of one cup/d, 1.3 (95% CI, 0.9 to 2.0) for two cups/d, 1.8 (95% CI, 1.1 to 2.7) for three cups, 2.5 (95% CI, 1.5 to 4.1) for four cups, and 2.6 (95% CI, 1.6 to 4.2) for five cups or more. The trend in risk with dose was statistically significant (P < 0.001). Duration of coffee consumption was not associated with the risk of AMI. The RRs for daily coffee consumption were elevated across strata of various covariates, including age, smoking habits, cholesterol level, diabetes, and hypertension, with a particularly elevated (although not significantly heterogeneous) estimate in patients younger than 50 years (RR, 5.7; 95% CI, 3.0 to 10.9 for four or more cups/d). The RR in patients who drank four or more cups of coffee per day and were current smokers was 8.1 (95% CI, 5.1 to 13.0), suggesting an unfavorable effect on the combination of cigarette smoking and high coffee intake on the risk of AMI.

GISSI update. Which patients with myocardial infarction should receive thrombolysis?

Large-scale, randomized clinical trials have produced over the last few years a wide consensus about the role of thrombolysis in the treatment of acute myocardial infarction (AMI). It has been estimated from the trials with broader inclusion criteria that about 40% of the patients admitted to coronary care units with AMI are eligible for fibrinolytic therapy and can benefit from it. On the other hand, drug utilization data suggest that only a fraction of eligible patients actually receive thrombolysis. A reason for this dissociation between knowledge and practice lies in the widespread assumption that thrombolysis is inefficacious in particular population subsets, as well as in the setting of a number of contraindications based on controversial evidence. Age per se does not represent a contraindication to thrombolysis, which could display a lifesaving potential two or three times that estimated for the general population of patients with AMI. Although it has been shown that the sooner thrombolytic treatment is provided after the onset of symptoms the more effective it is, the available evidence seems to indicate that the effect could well extend up to 12 h from the onset of symptoms. Patients with an inferior myocardial infarction should also receive thrombolytic treatment on the basis of the results of a meta-analysis carried out on 12,000 patients. Very misleading recommendations for practice can be produced by adjusting the main results so as to conveniently allow for subgroup findings, regardless of their degree of epidemiologic, biologic, and pathophysiologic consistency. For all categories of patients included in the population trials (with the exception of those with ST depression), thrombolysis should be considered a recommended treatment. From an epidemiologic perspective, the extension of the benefits of thrombolytic therapy to all AMI patients for whom the drug is not clearly contraindicated is a goal of primary importance.

Thrombolysis in acute myocardial infarction.

The 1980s has been a critical decade for the management of acute myocardial infarction (MI) because of the concentration in a very short time span of innovative results produced by a new generation of trials, in which thrombolysis has been the preeminent topic. The message coming from the results in the more than 50,000 patients included in the five key trials is simple and clear: thrombolysis, of any type, is the cornerstone of acute treatment of MI, and it works well to produce a very favorable epidemiologic picture. In the GISSI-2 trial, the nationwide adoption of a package of recommended treatments centered on thrombolysis for the overall population of patients with an acute MI has produced a relevant modification of the natural history of the disease, reducing the in-hospital mortality by about 40% in few years (from 13% to 8.8%). In particular, in the great majority of cases (patients aged less than 70 years in Killip class I with a first acute MI), the mortality has gone down to 3%, making a further reduction very hard to obtain with new drugs or strategies. In this context, we will discuss the concept of the relevance for clinical practice of obtaining even greater patency rates with new thrombolytic agents (hopefully more efficient and safe) or with new combinations of traditional agents.

GISSI trials in acute myocardial infarction. Rationale, design, and results.

The first Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto (GISSI) study showed striking evidence of the effectiveness and safety of intravenous thrombolytic treatment in acute myocardial infarction (MI). Since publication in The Lancet, the original report has become a reference work for every paper which deals with thrombolysis. In addition to GISSI's scientific value, these studies applied formal research to routine clinical practice outside of referral centers. Nearly all Italian CCUs took part in the GISSI projects, so that the results provide a profile of the patient who seeks care for acute MI in Italy. This wide data base allowed GISSI investigators to look into some relevant clinical events, eg, primary ventricular fibrillation, stroke, and in-hospital reinfarction. The GISSI-2 trial followed the GISSI-1 philosophy. The package of treatments recommended after extensive discussion with all the investigators (beta-blocker, aspirin, nitrates) was widely adopted. Now, only five years after the start of the GISSI-1, the overall mortality of Italian patients with acute MI has decreased from 13.0 percent to about 9 percent, and the number of patients with acute MI arriving in hospital within 1 h of the onset of symptoms has increased 50 percent. It is the wish of the GISSI investigators that this approach to treating acute MI will be regarded and acknowledged as their major contribution to the problem.

Is anticoagulation therapy underused in elderly patients with atrial fibrillation?

Atrial fibrillation (AF) is found in 0.4% of the adult population and is a common condition in the elderly. Its prevalence increases with age to affect 5 to 14% of those over 74 years. Recent evidence indicates that, compared with sinus rhythm, AF is associated with a 4-to 7-fold increase in the risk of stroke. However, there is strong evidence from randomised trials that full anticoagulation with warfarin substantially reduces the risk of stroke. Elderly patients are among those at higher risk and stand to gain the most from such treatment. They are also at higher risk for complications related to anticoagulant therapy and this sometimes makes clinical decisions difficult. There is a strong rationale for prescribing warfarin for all patients with AF who are over 65 years and free of contraindications. Some concerns exist about the benefit: risk ratio of warfarin in patients aged > 75 years. The answer is probably to use low intensity anticoagulant therapy (international normalised ratio 2.0 to 3.0), which is safer but no less effective than higher intensity regimens. Few data are available in the literature on physicians' attitudes to anticoagulation in elderly patients with AF. Although the results of randomised clinical trials in AF seem to suggest that anticoagulants and/or aspirin (acetylsalicylic acid) are underused in the elderly, over 90% of the patients initially screened were excluded from randomisation, making the sample highly selected. Compared with randomised controlled trials, some observational studies seem to indicate a higher likelihood of using anticoagulation and have targeted the intensity of anticoagulation according to age and clinical scenario.

Cost-effectiveness analysis of n-3 polyunsaturated fatty acids (PUFA) after myocardial infarction: results from Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione Trial.

OBJECTIVE: To estimate the cost effectiveness of treatment with n-3 polyunsaturated fatty acids (PUFA) for secondary prevention after myocardial infarction (MI). DESIGN AND SETTING: The cost-effectiveness analysis of n-3 PUFA treatment after MI was based on morbidity and mortality data and the use of resources obtained prospectively during the 3.5 year follow-up period of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione study. The cost-effectiveness analysis took into account the incremental number of life-years gained and the incremental costs for hospital admissions, diagnostic tests and drugs, applying a 5% discount rate. The value for money of n-3 PUFA treatment was assessed using the cost-effectiveness ratio and the number needed to treat (NNT) approach. PERSPECTIVE: Third-party payer. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratio for n-3 PUFA in the basecase scenario was 24,603 euro (EUR, 1999 values) per life-year gained (95% confidence interval: 22,646 to 26,930). Sensitivity analysis included the analysis of extremes, producing estimates varying from EUR15,721 to EUR52,524 per life-year gained. 172 patients would need to be treated per year with n-3 PUFA, at an annual cost of EUR68,000, in order to save 1 patient. This is comparable with the NNT value, and associated annual cost for simvastatin, but less costly than that for pravastatin. CONCLUSIONS: The cost effectiveness of long term treatment with n-3 PUFA is comparable with other drugs recently introduced in the routine care of secondary prevention after MI. Since the clinical benefit provided by n-3 PUFA is additive, this therapy should be added to the established routine practice, with additive costs.

Cost-effectiveness analysis of early lisinopril use in patients with acute myocardial infarction. Results from GISSI-3 trial.

The cost effectiveness of early treatment with lisinopril in acute myocardial infarction (MI) was estimated using survival and cost data gathered prospectively during the hospitalisation of the overall population of patients enrolled in the third study of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI-3), which assessed the efficacy of early (within 24 hours) treatment with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for 6 weeks in a group of 19,394 relatively unselected patients with acute MI. A statistically significant reduction in 6-week mortality was achieved among patients treated with lisinopril when compared with patients allocated to the control group (absolute reduction in mortality: 7.5 +/- 3.6 lives saved per 1000 treated patients). The comparative cost-effectiveness ratio for the use of lisinopril, expressed as cost per additional survivor among patients randomised to receive lisinopril, was $US2080 per life saved (1993 values). The sensitivity analysis conducted to examine the effects of varying the estimated absolute reduction in mortality throughout its 95% confidence interval, which ranged from 14.6 to 0.4 lives saved per 1000 treated patients, showed that the cost-effectiveness ratios consequently vary from $US1121 to $US40,910 per life saved. The cost effectiveness of early treatment with lisinopril of a relatively unselected population of patients with acute MI compares very favourably with that of other therapies judged to be worthwhile by the medical community.

The GISSI-2 trial: premises, results, epidemiological (and other) implications. Gruppo Italiano per lo Studio delia Sopravvivenza nell'Infarto Miocardico.

Population trials on myocardial infarction have produced significant advances in therapeutic results. The first clearly stated aim of the GISSI-2 protocol was the assessment of the overall benefit to a population attributable to the application of a package of pharmacological treatments (thrombolysis, intravenous beta blockade, and oral aspirin) shown effective in reducing mortality in large-scale randomized clinical trials. At variance with the classical concept of trials, a clinical epidemiological interest came first: The comparison between drugs was considered a main target of the investigation only within that broader framework, and was explicitly formulated as the direct confrontation between two concepts or two generations of thrombolysis. A selective, highly efficient, and specific new thrombolytic agent, tissue plasminogen activator (tPA), is compared with streptokinase with the expectation that the more selective approach could enhance the benefits of specificity, drastically limiting the systemic risks aspects (hemorrhagic complications). The main results of GISSI-2 are summarized. GISSI-2 may be considered a reliable window on the epidemiology of AMI in a whole country. There are implications for the transfer of these clinical findings into public health applications and for the choice of future research priorities.