This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tavazzi, L. Articles by Volpi, A. Search for Related Content PubMed PubMed Citation Articles by Tavazzi, L. Articles by Volpi, A.

(Circulation. 1997;95:1341-1345.)
© 1997 American Heart Association, Inc.

Articles

Remarks About Postinfarction Prognosis in Light of the Experience With the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI) Trials

Luigi Tavazzi, MD; Alberto Volpi, MD; for the GISSI Investigators

the Fondazione Salvatore Maugeri IRCCS (L.T.), Centro Medico di Montescano, Divisione di Cardiologia, 27040 Montescano (Pavia); and Ospedale Civile Fornaroli (A.V.), Divisione di Cardiologia, 20013 Magenta (Milano), Italy.

Correspondence to Prof Luigi Tavazzi, Fondazione Salvatore Maugeri, Via P Azzario 19, 27100 Pavia, Italy.

Key Words: myocardial infarction • prognosis • thrombolysis

	Introduction

Top Introduction The Changing Early and... Outcome Predictors Revised Unpredictability of Ischemic... References

 
The contribution of large-scale trials to the impressive therapeutic advances that have occurred over the past 10 years in the area of acute myocardial infarction (AMI) is universally acknowledged. A less frequently considered aspect of trials on AMI is their capacity of acting as "new-generation" data bases providing real-time updated prognostic information. This aspect seems to apply specifically to the case of the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI) trials.^{1 2 3} Indeed, their open design, the absence of age limits in the enrollment criteria, and the countrywide coverage of the recruitment appear to be crucial for close mimicking of routine conditions of care. Moreover, the very large number of patients enrolled (>40 000 in three trials) and the prospective collection of clinical and laboratory data of prognostic relevance provide a privileged perspective for evaluation of postinfarction prognosis. Last, but not least, the observed low frequency of coronary revascularization procedures (8%) limits the workup bias. Therefore, the purpose of this report is to propose a view of postinfarction prognosis in the light of the experience of the GISSI trials. Accordingly, emphasis is placed on questions that have been specifically addressed by GISSI trial investigators.

	The Changing Early and Late Prognoses of AMI

Top Introduction The Changing Early and... Outcome Predictors Revised Unpredictability of Ischemic... References

 
The establishment of a new therapeutic standard for AMI that is centered on thrombolytics and aspirin in addition to intravenous ß-blockers has led to a substantial reduction in early mortality after the acute coronary event.

Although doubts have been cast as to whether the survival benefit documented in large-scale trials can actually be transferred to routine clinical practice, in view of the underutilization of recommended treatments in some countries, including the United States and Canada,^{4 5 6 7} it is worth noting that a >70% use of thrombolytic drugs has been reported in the multinational ISIS-4 and Italian GISSI-3 trials.^{3 8} Moreover, in these trials, nearly 90% of the patients received aspirin or other antiplatelet agents. This improvement in management policies is mirrored by overall estimates of short-term outcome for patients with suspected AMI who were admitted to coronary care units in Italy (Figure). A striking decline in the in-hospital death rates from 12.6% in 1984 through 1985 to 9.1% in 1991 through 1993 was observed for patients admitted to the coronary care units participating in the GISSI trials. This reduction in mortality refers to both randomized and nonrandomized patients, thereby indicating a general improvement in survival not restricted to specific subsets of patients.

View larger version (17K): [in this window] [in a new window]   Figure 1. Bar graph showing in-hospital total mortality for patients with suspected AMI (randomized and not randomized) admitted to the coronary care units participating in the first three GISSI trials.

It is also being increasingly realized that the outcome of patients recovering from AMI has improved even over the past decade. A few studies have already reported a reduction in 1-year postdischarge mortality rate for cohorts of patients studied in the 1970s through the early 1980s.^{9 10} More recently, a decline in postdischarge mortality has been observed in patients who have undergone fibrinolytic therapy. Indeed, GISSI-2 hospital survivors exhibited a lower 6-month death rate (3.5%) than that observed in both the GISSI-2–like cohort of the GISSI-1 trial (4.6%) and the intervention arm of the ASSET study (4.6%).^{11 12} Similarly, low mortality rates (<4% by 6 months) have been seen in large and relatively unselected populations enrolled in megatrials of the use of ACE inhibitors.^{3 8} Mechanisms underlying this relatively low overall risk profile of hospital survivors are complex, but they appear to largely reflect both a global improvement in early therapeutic interventions¹³ and a wider application of effective secondary prophylactic measures such as risk factor modification and the use of ß-blockers, antithrombotic drugs, ACE inhibitors, and, more recently, statins.¹⁴

An indirect confirmation of the late protection conferred by the package of acute phase treatments via a limitation of myocardial damage comes from the echocardiographic data gathered in the GISSI-3 study.¹⁵ In >11 000 patients, segmental left ventricular wall motion was analyzed with the use of two-dimensional echocardiography near the time of hospital discharge to generate an approximate indicator of ischemic damage expressed as the percentage of akinetic or dyskinetic segments. The mean value of this index was 15%, with more than two thirds of patients exhibiting values of 18%. This indicates that relatively small infarcts were frequently observed among GISSI-3 patients recovering from AMI. Notably, the observed percentage of wall motion asynergy was smaller than that seen in the GISSI-1 echocardiographic substudy, ranging from 20% in the treatment group to 24% in the control group,¹⁶ and tended to decrease during follow-up, as demonstrated by the 6-month echocardiographic data. This tendency, independent of randomized treatments, suggests late recovery of reversibly dysfunctional myocardium and thus implies the presence of an even smaller proportion of irreversible myocardial damage in the baseline predischarge echocardiograms.

The aforementioned better survival probabilities in the year after AMI are paralleled by relatively low reinfarction rates. Previously reported event rates of 6% to 10%¹⁷ have no longer been observed in more recent data base studies regardless of whether there is a history of fibrinolytic therapy. In aggregate, available data suggest rates of nonfatal reinfarction of <4% by 6 months and 5% by 1 year.^{18 19 20} Thus, a growing body of data suggests a changing natural history of AMI with a declining risk of in-hospital and short-term fatal outcomes and a rather low postdischarge event rate. Such considerations should prompt the reassessment of current diagnostic and prognostic schemes and related therapeutic attitudes.

	Outcome Predictors Revised

Top Introduction The Changing Early and... Outcome Predictors Revised Unpredictability of Ischemic... References

 
One major question raised in recent years is related to whether postinfarction risk predictors identified in prethrombolytic studies are still valid for patients who have undergone thrombolysis. The evidence from the GISSI-2 data base indicates that on the whole, these predictors of mortality retain their value for risk stratification^{21 22} (Table 1).

View this table: [in this window] [in a new window]   Table 1. Ranked Independent Predictors of 6-Month Mortality Among 10 219 Hospital Survivors Based on the Cox Model

It is noticeable that among GISSI-2 hospital survivors, those without any indicator of left ventricular failure or dysfunction who were younger than 70 years had a mortality as low as 1.2% by 6 months. This low-risk category comprised >60% of the overall population. For these patients, it would be unrealistic to assume that aggressive diagnostic and therapeutic strategies may improve outcome, once severe ischemia has been ruled out by noninvasive stress testing. Consequently, the more logical approach should be a conservative one based on prophylactic pharmacological interventions and risk factor modification.

Contrasting sharply with the favorable outlook of this low-risk subpopulation is the outcome of patients whose infarction was complicated by clinical heart failure or echocardiographically determined left ventricular dysfunction. In these risk categories, 6-month mortality figures approaching or exceeding 10% were observed. Contrary to expectations,²³ the ejection fraction/mortality curve of postinfarction patients who have undergone thrombolysis still exhibits a hyperbolic trend. This curve slope implies an upturn in mortality once ejection fraction falls below 40%, with a 6-month death rate of 15% for patients exhibiting values of <30%. Moreover, the cumulative risk resulting from overlapping markers of left ventricular dysfunction is highlighted by the 19% mortality rate of GISSI-2 patients who had both clinical evidence of heart failure and an ejection fraction of <40%.²⁴ In addition to the short- to mid term risk of mortality of patients with severe postinfarction left ventricular dysfunction, progressive remodeling of the left ventricle ultimately leading to symptomatic heart failure represents a continuing source of risk of adverse outcome for those patients who exhibit a sizable degree of myocardial damage.²⁵

For these high-risk patient subsets, the therapeutic role of ACE inhibitors has been established.²⁶ In addition, the evidence from the GISSI-3 study indicates that the early administration of ACE inhibitors can prevent left ventricular dysfunction. The analysis of echocardiographic data collected in this trial shows both a reduced frequency of severely depressed ejection fraction by 6 weeks after the index infarction and smaller left ventricular volumes by 6 months in patients randomized to lisinopril.^{3 21} These changes in left ventricular volumes are small, but statistically and clinically significant, as evidenced by the observation of a lower risk of heart failure by 6 months.²¹ However, over and above the benefit accrued from ACE inhibition therapy, postinfarction patients with left ventricular dysfunction, whether symptomatic or asymptomatic, should be the target of thorough investigation to assess the viability of dysfunctional myocardial regions.

Data from the GISSI-3 echocardiographic data base provide epidemiologically sound evidence that reversibly dysfunctional myocardium may be a relatively common phenomenon after infarction, especially in the presence of extensive wall motion abnormalities.^{15 27} Recent clinical data indicate that spontaneous recovery of regional contraction and perfusion may occur even after the subacute phase.²⁸ Thus, in light of these data and previous information, it appears that in a sizable subgroup of patients, left ventricular dysfunction may result from the presence of large areas of reversibly damaged myocardium. These patients might benefit from coronary revascularization whenever coronary anatomy appears suitable for angioplasty or bypass surgery.

In-hospital recurrent ischemia has generally been thought to represent a serious complication associated with an unfavorable prognosis.²⁹ This view, which was based on data collected in the prethrombolytic era, has led many institutions to adopt a uniform policy of coronary angiography followed by revascularization procedures (whenever possible) for patients exhibiting recurrent ischemic episodes. In the past few years, the findings of postthrombolytic studies have to some extent confirmed the short-term negative prognostic implications of these recurrences in terms of survival, reinfarction, and heart failure.^{30 31} High-risk patients appear to be those exhibiting concurrent hemodynamic deterioration³² and those with evidence of prolonged (>20 minutes) ischemia at the time of their first recurrence.³³ Contrary to expectations, patients treated with thrombolytic agents do not have an increased incidence of early ischemia.^{1 2} Of note, according to the findings of two GISSI substudies,^{31 33} early recurrent ischemia occurred in the majority of cases in the same ECG location as the index infarction. This suggests the presence of an unstable infarct-related lesion as the most frequent source of early ischemic recurrences. Regarding postdischarge prognosis, the notion that early postinfarction recurrent ischemia portends a poor outcome has not been substantiated in survivors of infarcts associated with ST-segment elevation who had thrombolytic therapy within 6 hours of symptom onset. Indeed, among GISSI-2 hospital survivors, early postinfarction angina with concomitant ECG changes did not prove to be an independent predictor of 6-month mortality; even very early ischemia was not a risk predictor.^{11 31} Moreover, it is worth noting that 45% of hospital survivors with early postinfarction angina during hospitalization could perform maximal symptom-limited exercise testing nearly 1 month after the index infarction.³⁴ Of these patients, only one third showed an exercise-related ischemia. This fact suggests that for a sizable proportion of hospital survivors whose infarct was complicated by recurrent angina, the presence of critical coronary stenoses is unlikely, and once stabilized, they share the risk of events of patients without angina. However, despite the favorable postdischarge outcome of patients with early postinfarction angina noted in the GISSI-2 study, it is fair to recall that data from a GISSI-3 substudy³³ suggest a cumulative (in-hospital plus postdischarge) excess of both fatal and nonfatal events during the first 6 months after the index infarction for patients with early recurrent ischemia. Admittedly, there remains a need for additional data to establish the optimal management of these patients.

The role of stress testing for prognostic assessment has long been debated.³⁵ More recently, its usefulness in patients who had undergone thrombolysis has been challenged in view of the declining postdischarge event rates, which according to bayesian principles would imply a quite low positive predictive accuracy. Aggregate data have indicated that by itself postinfarction exercise testing has a low positive but a high negative predictive accuracy in both thrombolysed and nonthrombolysed patients.³⁶ The recently reported data from the GISSI-2 data base add a further perspective to the growing body of knowledge regarding the prognostic implications of exercise testing in the thrombolytic era.³⁴ As shown in studies conducted before the advent of lytic therapy, exclusion from exercise testing is the strongest negative prognostic indicator. Conversely, the ability to undergo exercise testing after myocardial infarction identifies a low-risk population, regardless of the test results. In this category of patients involving >6000 patients, a test positive for residual ischemia was observed in approximately one fourth of the population, a figure that is consistent with the percentages reported in the prethrombolytic era.³⁵ Exercise-induced ischemia retains a significant but weak positive predictive value. Although both exercise-induced symptomatic ischemia and low-work capacity are still independent risk predictors for 6-month mortality, it is worth underscoring that the absolute risk of death appears low even in these subsets of patients (regardless of whether the degree of ST-segment depression was >2 or <2 mm or whether it manifested at a workload of >75 or <75 W) who exhibited a 6-month mortality rate of 1.6% (0.9% was the rate of those who had a maximal negative exercise test). In patients with symptomatic ischemia who exhibited the highest observed value for mortality, the rate was 2.6%. Accordingly, these patients should undergo further diagnostic evaluation, including stress imaging techniques, nonexercise stress testing procedures, and possibly coronary angiography, to single out those who may have left main stem or proximal triple-vessel disease.

The fact that complex ventricular arrhythmias detected with ambulatory ECG monitoring had consistently predicted mortality in major prethrombolytic studies prompted the reassessment of their prognostic relevance in survivors of AMI who were treated with thrombolytics. In 8676 patients enrolled in the GISSI-2 trial who underwent an ambulatory 24-hour ECG recording before hospital discharge and were followed for 6 months, frequent premature ventricular beats (PVBs) were confirmed as predictors of total and sudden death.³⁷ Approximately 36% of patients recovering from AMI presented with <1 PVB per hour, whereas almost 20% of patients showed frequent (>10 PVBs per hour) ventricular arrhythmias. Mortality rate was 2.0% by 6 months in the former subgroup and 5.5% in the latter. Even after adjustment for other known risk factors, the presence of frequent ventricular arrhythmias still predicted mortality. The relation between the frequency of ventricular arrhythmias and left ventricular ejection fraction was more specifically addressed in a subgroup of patients. The number of PVBs was shown to be dependent in a linear, inverse fashion on residual left ventricular function, and this relation was independent of the occurrence of reperfusion in the acute phase of infarction.³⁸ Surprisingly, in the GISSI-2 study population, nonsustained ventricular tachycardia, which was observed in 7% of the patients, did not turn out to be an independent risk predictor. This discrepancy with the results of other studies³⁹ could be explained by the effects of lytic therapy on electrical substrate or alternatively might reflect the extreme variability of nonsustained ventricular tachycardia in 24-hour ECG recordings. At the very least, these data challenge the importance generally attributed to nonsustained ventricular tachycardia as a risk stratifier. Overall, in light of the conflicting conclusions of available studies, the prognostic value of nonsustained ventricular tachycardia appears to still be controversial.

One approach to further risk stratification relies on the noninvasive assessment of autonomic function. The critical role of the autonomic nervous system in influencing vulnerability to lethal ventricular arrhythmias during AMI was first established in experimental animal studies. More recently, markers of autonomic nervous dysfunction such as low heart rate variability (HRV) and impaired baroreflex sensitivity have been shown to be powerful risk indicators in patients recovering from AMI. Kleiger et al⁴⁰ showed that diminished HRV demonstrated early after myocardial infarction was the strongest predictor of mortality. Similarly, Farrel et al⁴¹ observed that HRV was a strong independent predictor of arrhythmic events. More recently, Bigger et al⁴² demonstrated that a low HRV 1 year after myocardial infarction predicted subsequent mortality. In line with the findings of the prethrombolytic investigations, data from a GISSI-2 substudy highlight the independent prognostic value of time-domain indexes of HRV in thrombolysed patients.⁴³ In a subgroup of almost 600 patients with adequate 24-hour ECG recordings, a low HRV was associated in the adjusted analysis with an approximately threefold increased risk of dying. According to the preliminary findings of a multicenter investigation designed to evaluate the long-term prognostic significance of autonomic dysfunction, both a low HRV and impaired baroreflex sensitivity add independent prognostic information to the prediction of outcome based on conventional risk variables.⁴⁴

	Unpredictability of Ischemic Recurrences

Top Introduction The Changing Early and... Outcome Predictors Revised Unpredictability of Ischemic... References

 
It is widely acknowledged that recurrent myocardial infarction is a strong independent risk factor for subsequent mortality. The suggestion that clinical variables are of value in predicting reinfarction⁴⁵ has not been borne out by the findings of either the GISSI-2 or TIMI-IIB data bases.^{18 19} Overall evidence indicates that the prediction of recurrent infarction is even less accurate than the prediction of fatal outcome (Table 2). Variables consistently identified as being predictive of reinfarction (ie, a history of previous angina, prior infarction, and diabetes) do not allow great discrimination in distinguishing which patients are likely to develop a new acute coronary event.^{17 18 19 20} Efforts directed at detecting higher risk patterns by means of stress echocardiography have not been much more fruitful. According to a recent study,⁴⁶ dipyridamole echocardiography has a limited, positive predictive accuracy for recurrent myocardial infarction in patients evaluated early after uncomplicated infarction. This disappointing realization is reinforced by the negative or at best contradictory findings of studies examining the predictive value of angiographic variables and underlines the limitations of the present knowledge of factors that govern the evolution of coronary artery disease and precipitate acute coronary events. Taken together, these data are by no means surprising because it is being increasingly realized that acute coronary syndromes are most commonly produced by abrupt evolution of minor plaques whose presence cannot be exposed by stress testing and whose angiographic appearance can be misleading.⁴⁷ This suggests that the conceptual framework of current postinfarct risk assessment is fragile because it is essentially focused on the detection of flow-limiting coronary narrowings, whereas other factors, which are still unknown, play a major role in the evolution of coronary artery disease. Thus, the systematic use of behavioral preventive measures and prophylactic pharmacological interventions still appears to be the most rewarding approach to prevention of recurrent coronary episodes.

View this table: [in this window] [in a new window]   Table 2. Ranked Independent Predictors of Nonfatal Reinfarction Among 6580 Hospital Survivors With Echocardiographic and Holter Monitoring Data Available (Cox Model)

Ischemic heart disease remains a major public health problem both because of its prevalence in the population and mortality rate and because of its demand on resources. Intervention trials such as GISSI and others, which were designed to test the efficacy and safety of new therapeutic strategies, have great potential as tools with which to gather epidemiological and clinical physiopathological information, and they can make important contributions to a rational approach to the clinical management of ischemic heart disease.

	References

Top Introduction The Changing Early and... Outcome Predictors Revised Unpredictability of Ischemic... References

 

1. Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-401.[Medline] [Order article via Infotrieve]
   
2. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico. GISSI-2: a factorial randomized trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet. 1990;336:65-71.[Medline] [Order article via Infotrieve]
   
3. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico. GISSI-3: effect of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115-1122.[Medline] [Order article via Infotrieve]
   
4. Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambrew CT, Rubison RM, Tiefenbrunn AJ, Weaver WD, for the Participants in the National Registry of Myocardial Infarction. Treatment of myocardial infarction in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation. 1994;90:2103-2114.[Abstract/Free Full Text]
   
5. Rouleau JL, Moye LA, Pfeffer MA, Malcolm J, Arnold O, Bernstein V, Cuddy TE, Dagenais GR, Geltman EM, Goldman S, Gordon D, Hamm P, Klein M, Lamas GA, McCans J, McEwan P, Menapace FJ, Parker JO, Sestier F, Sussex B, Braunwald E, for the SAVE Investigators. A comparison of management patterns after acute myocardial infarction in Canada and the United States. N Engl J Med. 1993;328:779-784.[Abstract/Free Full Text]
   
6. Hennekens CH, Jonas MA, Buring JE. The benefits of aspirin in acute myocardial infarction: still a well-kept secret in the United States. Arch Intern Med. 1994;154:37-39.[Abstract]
   
7. Brand DA, Newcomer LN, Freiburger A, Tian H. Cardiologists' practices compared with practice guidelines: use of beta-blockade after acute myocardial infarction. J Am Coll Cardiol. 1995;26:1432-1436.[Abstract]
   
8. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-685.[Medline] [Order article via Infotrieve]
   
9. Gomez-Marin O, Folsom AR, Kottke TE, Wu SCH, Jacobs DR Jr, Gillum RF, Edlavitch SA, Blackburn H. Improvement in long-term survival among patients hospitalized with acute myocardial infarction, 1970 to 1980: the Minnesota Heart Survey. N Engl J Med. 1987;316:1353-1359.[Abstract]
   
10. Aberg A, Bergstrand R, Johansson S, Ulvenstam G, Vedin A, Wedel H, Wilhelmsson C, Wilhelmsen L. Declining trend in mortality after myocardial infarction. Br Heart J. 1984;51:346-351.[Abstract/Free Full Text]
    
11. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G, the Ad Hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI)-2 database. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis: results of the GISSI-2 data-base. Circulation. 1993;88:416-429.[Abstract/Free Full Text]
    
12. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the Anglo-Scandinavian Study of Early Thrombolysis. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Lancet. 1990;335:1175-1178.[Medline] [Order article via Infotrieve]
    
13. Yusuf S, Sleight P, Held P, McMahon S. Routine medical management of acute myocardial infarction: lessons from overviews of recent randomized controlled trials. Circulation. 1990;82(suppl II):II-117-II-134.
    
14. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
    
15. Nicolosi GL, Latini R, Marino P, Maggioni AP, Barlera S, Franzosi MF, Geraci E, Santoro L, Tavazzi L, Tognoni G, Vecchio C, Volpi A. The prognostic value of predischarge quantitative two-dimensional echocardiographic measurements and the effects of early lisinopril treatment on left ventricular structure and function after acute myocardial infarction in the GISSI-3 trial. Eur Heart J. 1996;17:1646-1656.[Abstract/Free Full Text]
    
16. Marino P, Zanolla L, Zardini P, on behalf of the Gruppo Italiano per lo Studio della Streptochinasi nell' infarto Miocardico (GISSI). Effect of streptokinase on left ventricular modelling and function after myocardial infarction: the GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto Miocardico) trial. J Am Coll Cardiol. 1989;14:1149-1158.[Abstract]
    
17. Volpi A, Cavalli A, Tavazzi L. Risk stratification after myocardial infarction. J Myocard Ischemia. 1993;5:35-57.
    
18. Ad Hoc Working Group of GISSI-2 data-base: Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G. 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. J Am Coll Cardiol. 1994;24:608-615.[Abstract]
    
19. Mueller HS, Forman SA, Menegus MA, Cohen LS, Knatterud GL, Braunwald E, for the TIMI Investigators. Prognostic significance of nonfatal reinfarction during 3-year follow-up: results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial. J Am Coll Cardiol. 1995;26:900-907.[Abstract]
    
20. Gilpin E, Ricou F, Dittrich H, Nicod P, Henning H, Ross J. Factors associated with recurrent myocardial infarction within one year after acute myocardial infarction. Am Heart J. 1991;121:457-465.[Medline] [Order article via Infotrieve]
    
21. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico. Six-month effects of early treatment with lisinopril and transdermal glyceril trinitrate singly and together withdrawn six-weeks after acute myocardial infarction: the GISSI-3 trial. J Am Coll Cardiol. 1996;27:337-344.[Abstract]
    
22. Maggioni AP, Maseri A, Fresco C, Franzosi MG, Mauri F, Santoro E, Tognoni G, on behalf of the Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico GISSI-2. Age-related increase in mortality among patients with first myocardial infarction treated with thrombolysis. N Engl J Med. 1993;329:1442-1448.[Abstract/Free Full Text]
    
23. Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coll Cardiol. 1989;14:1382-1388.[Medline] [Order article via Infotrieve]
    
24. Volpi A, Cavalli A. High- and low-risk groups: early and late prognostic stratification. J Cardiovasc Risk. 1994;1:295-300.[Medline] [Order article via Infotrieve]
    
25. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med. 1992;327:685-691.[Abstract]
    
26. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G, for the Meeting Participants. ACE inhibitor use in patients with myocardial infarction: summary of evidence from clinical trials. Circulation. 1995;92:3132-3137.[Free Full Text]
    
27. Nicolosi GL, Badano L, Bosimini E, Gentile F, Giannuzzi P, Heyman J, Lucci D, on behalf of the GISSI 3 Echo Investigators. Temporal improvement of regional wall motion abnormalities after myocardial infarction: preliminary data from the GISSI-3 echo substudy. Circulation. 1995;92(suppl I):I-461. Abstract.
    
28. Galli M, Marcassa C, Bolli R, Giannuzzi P, Temporelli PL, Imparato A, Silva Orrego PL, Giubbini R, Giordano A, Tavazzi L. Spontaneous delayed recovery of perfusion and contraction after the first 5 weeks after anterior infarction: evidence for the presence of hibernating myocardium in the infarcted area. Circulation. 1994;90:1386-1397.[Abstract/Free Full Text]
    
29. Ross J, Gilpin EA, Madsen EB, Henning H, Nicod P, Dittrich H, Engler R, Rittelmeyer J, Smith SC, Viquerat C. A decision scheme for coronary angiography after acute myocardial infarction. Circulation. 1989;79:292-303.[Abstract/Free Full Text]
    
30. Barbagelata A, Granger CB, Topol EJ, Workley SJ, Kereiakes DJ, George BS, Ohman EM, Leimberger JD, Mark DB, Califf RM, for the TIMI Study Group. Frequency, significance, and cost of recurrent ischemia after thrombolytic therapy for acute myocardial infarction. Am J Cardiol. 1995;76:1007-1013.[Medline] [Order article via Infotrieve]
    
31. Silva P, Galli M, Campoli L, for the IRES (Ishemia Residual) Study Group. Prognostic significance of early ischemia after acute myocardial infarction in low-risk patients. Am J Cardiol. 1993;71:1142-1147.[Medline] [Order article via Infotrieve]
    
32. Betriu A, Califf R, Granger C, for the GUSTO Investigators. Importance of clinical findings during postinfarction angina in determining prognosis: results from the GUSTO trial. J Am Coll Cardiol. 1994;23:27A. Abstract.
    
33. The GISSI-3 APPI Study Group. Early and six-month outcome in patients with angina pectoris early after myocardial infarction (the GISSI-3 APPI-Angina Precoce Post-Infarto Study). Am J Cardiol. 1996;78:1191-1197.[Medline] [Order article via Infotrieve]
    
34. Villella A, Maggioni AP, Villella M, Giordano A, Turazza FM, Santoro E, Franzosi MG, on behalf of the GISSI 2 Investigators. Prognostic significance of maximal exercise testing after myocardial infarction treated with thrombolytic agents: the GISSI 2 data-base. Lancet. 1995;346:523-529.[Medline] [Order article via Infotrieve]
    
35. Froelicher VF, Perdue S, Atwood JE, De Pois P, Sivarajan ES. Exercise testing of patients recovering from acute myocardial infarction. Curr Probl Cardiol. 1986;11:369-444.[Medline] [Order article via Infotrieve]
    
36. Peterson ED, Shaw LJ, Kesler K, Califf RM. Is exercise treadmill testing useful for postinfarction risk stratification in the thrombolytic era? A meta-analysis of the literature. Circulation. 1995;92(suppl I):I-272. Abstract.
    
37. Maggioni AP, Zuanetti G, Franzosi MG, Rovelli F, Santoro E, Staszewsky L, Tavazzi L, Tognoni G, on behalf of GISSI 2 Investigators. Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era: GISSI-2 results. Circulation. 1993;87:312-322.[Abstract/Free Full Text]
    
38. Marino P, Nidasio G, Golia G, Franzosi MG, Maggioni AP, Santoro E, Santoro L, Zardini P, on behalf of the GISSI-2 Investigators. 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. J Am Coll Cardiol. 1994;23:290-295.[Abstract]
    
39. Hodges M, Denes P, Morris M, Hallstrom AP, for the Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Ventricular arrhythmias and mortality after myocardial infarction: a follow-up study of 14,534 patients in the CAST Holter registry. J Am Coll Cardiol. 1994;23:296A. Abstract.
    
40. Kleiger ER, Miller JP, Bigger JT Jr, Moss AJ, and the Multicenter Postinfarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256-262.[Medline] [Order article via Infotrieve]
    
41. Farrel TG, Bashir Y, Cripps T, Malik M, Poloniecki J, Bennet ED, Ward DE, Camm AJ. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables, and the signal-averaged electrocardiogram. J Am Coll Cardiol. 1991;18:687-697.[Abstract]
    
42. Bigger JT Jr, Fleiss JL, Rolnitzky LM, Steinman RC. Frequency domain measures of heart period variability to assess risk late after myocardial infarction. J Am Coll Cardiol. 1993;21:729-736.[Abstract]
    
43. Zuanetti G, Neilson JMM, Latini R, Santoro E, Maggioni AP, Ewing DJ, on behalf of GISSI 2 Investigators. Prognostic significance of heart rate variability in post-myocardial infarction patients in the fibrinolytic era: the GISSI 2 results. Circulation. 1996;94:432-436.[Abstract/Free Full Text]
    
44. La Rovere MT, Bigger T, Marcus FI, Mortara A, Camm AJ, Hohnloser SH, Nohara R, Schwartz PJ, on behalf of the ATRAMI Investigators. Prognostic value of depressed baroreflex sensitivity: the ATRAMI study. Circulation. 1995;92(suppl I):I-676. Abstract.
    
45. Kornowski R, Goldbourt U, Zion M, Mandelzweig L, Kaplinsky E, Levo Y, Behar S, and the SPRINT Study Group. Predictors and long-term prognostic significance of recurrent infarction in the year after a first myocardial infarction. Am J Cardiol. 1993;72:883-888.[Medline] [Order article via Infotrieve]
    
46. Picano E, Pingitore A, Sicari R, Minardi G, Gandolfo N, Seveso G, Chiarella F, Bolognese L, Chiaranda G, Sclavo MG, Previtali M, Margaria F, Magaia O, Bianchi F, Pirelli S, Severi S, Raciti M, Landi P, Vassalle C, Bento de Sousa JM, De Moura Duarte LF, on behalf of the Echo Persantine International Cooperative (EPIC) Study Group. Stress echocardiographic results predict risk of reinfarction early after uncomplicated acute myocardial infarction: large-scale multicenter study. J Am Coll Cardiol. 1995;26:908-913.[Abstract]
    
47. Fuster V. Lewis A. Conner Memorial Lecture: mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation. 1994;90:2126-2146.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				J. J. Goldberger, M. E. Cain, S. H. Hohnloser, A. H. Kadish, B. P. Knight, M. S. Lauer, B. J. Maron, R. L. Page, R. S. Passman, D. Siscovick, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on Noninvasive Risk Stratification Techniques for Identifying Patients at Risk for Sudden Cardiac Death: A Scientific Statement From the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention Circulation, September 30, 2008; 118(14): 1497 - 1518. [Full Text] [PDF]

				P. J. Zimetbaum A 59-Year-Old Man Considering Implantation of a Cardiac Defibrillator JAMA, May 2, 2007; 297(17): 1909 - 1916. [Abstract] [Full Text] [PDF]

				E. G. Manios, E. M. Kallergis, E. M. Kanoupakis, H. E. Mavrakis, D. C. Kambouraki, D. A. Arfanakis, and P. E. Vardas Amino-Terminal Pro-Brain Natriuretic Peptide Predicts Ventricular Arrhythmogenesis in Patients With Ischemic Cardiomyopathy and Implantable Cardioverter-Defibrillators Chest, October 1, 2005; 128(4): 2604 - 2610. [Abstract] [Full Text] [PDF]

				F. Grigioni, D. Detaint, J.-F. Avierinos, C. Scott, J. Tajik, and M. Enriquez-Sarano Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction J. Am. Coll. Cardiol., January 18, 2005; 45(2): 260 - 267. [Abstract] [Full Text] [PDF]

				P. Pascale, L. Kappenberger, M. Fromer, D. J. Wilber, A. C. Lin, M. Burke, W. Zareba, M. W. Brown, M. L. Andrews, A. J. Moss, et al. Mortality Risk and Defibrillator Benefit After Myocardial Infarction * Response Circulation, September 14, 2004; 110(11): e304 - e304. [Full Text] [PDF]

				D. J. Wilber, W. Zareba, W. J. Hall, M. W. Brown, A. C. Lin, M. L. Andrews, M. Burke, and A. J. Moss Time Dependence of Mortality Risk and Defibrillator Benefit After Myocardial Infarction Circulation, March 9, 2004; 109(9): 1082 - 1084. [Abstract] [Full Text] [PDF]

				A. E. Buxton The Clinical Use of Implantable Cardioverter Defibrillators: Where Are We Now? Where Should We Go? Ann Intern Med, March 18, 2003; 138(6): 512 - 514. [Full Text] [PDF]

				S. H. Hohnloser and B. J. Gersh Changing Late Prognosis of Acute Myocardial Infarction: Impact on Management of Ventricular Arrhythmias in the Era of Reperfusion and the Implantable Cardioverter-Defibrillator Circulation, February 25, 2003; 107(7): 941 - 946. [Full Text] [PDF]

				J. A. Gomes, M. E. Cain, A. E. Buxton, M. E. Josephson, K. L. Lee, and G. E. Hafley Prediction of Long-Term Outcomes by Signal-Averaged Electrocardiography in Patients With Unsustained Ventricular Tachycardia, Coronary Artery Disease, and Left Ventricular Dysfunction Circulation, July 24, 2001; 104(4): 436 - 441. [Abstract] [Full Text] [PDF]

				P. Bogaty, S. Dumont, G. E. O'Hara, L. Boyer, L. Auclair, J. Jobin, and J.-R. Boudreault Randomized trial of a noninvasive strategy to reduce hospital stay for patients with low-risk myocardial infarction J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1289 - 1296. [Abstract] [Full Text] [PDF]

				A. E. Buxton, K. L. Lee, L. DiCarlo, M. R. Gold, G. S. Greer, E. N. Prystowsky, M. F. O'Toole, A. Tang, J. D. Fisher, J. Coromilas, et al. Electrophysiologic Testing to Identify Patients with Coronary Artery Disease Who Are at Risk for Sudden Death N. Engl. J. Med., June 29, 2000; 342(26): 1937 - 1945. [Abstract] [Full Text] [PDF]

				A. E. Buxton, K. L. Lee, J. D. Fisher, M. E. Josephson, E. N. Prystowsky, G. Hafley, and The Multicenter Unsustained Tachycardia Trial Inve A Randomized Study of the Prevention of Sudden Death in Patients with Coronary Artery Disease N. Engl. J. Med., December 16, 1999; 341(25): 1882 - 1890. [Abstract] [Full Text] [PDF]

				A. E. Buxton, G. E. Hafley, M. H. Lehmann, M. Gold, M. O'Toole, A. Tang, J. Coromilas, B. Hook, N. J. Stamato, and K. L. Lee Prediction of Sustained Ventricular Tachycardia Inducible by Programmed Stimulation in Patients With Coronary Artery Disease : Utility of Clinical Variables Circulation, April 13, 1999; 99(14): 1843 - 1850. [Abstract] [Full Text] [PDF]

This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tavazzi, L. Articles by Volpi, A. Search for Related Content PubMed PubMed Citation Articles by Tavazzi, L. Articles by Volpi, A.