Remarks About Postinfarction Prognosis in Light of the Experience With the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI) Trials
1997; Lippincott Williams & Wilkins; Volume: 95; Issue: 5 Linguagem: Italiano
10.1161/01.cir.95.5.1341
ISSN1524-4539
Autores Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculationVol. 95, No. 5Remarks About Postinfarction Prognosis in Light of the Experience With the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI) Trials Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBRemarks About Postinfarction Prognosis in Light of the Experience With the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI) Trials Luigi Tavazzi, Alberto Volpi and Luigi TavazziLuigi Tavazzi 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. , Alberto VolpiAlberto Volpi 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. and 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. and for the GISSI Investigators Originally published4 Mar 1997https://doi.org/10.1161/01.CIR.95.5.1341Circulation. 1997;95:1341–1345The 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.123 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 AMIThe establishment of a new therapeutic standard for AMI that is centered on thrombolytics and aspirin in addition to intravenous β-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,4567 it is worth noting that a >70% use of thrombolytic drugs has been reported in the multinational ISIS-4 and Italian GISSI-3 trials.38 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.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.910 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%).1112 Similarly, low mortality rates ( 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 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 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.12 Of note, according to the findings of two GISSI substudies,3133 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.1131 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 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 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.44Unpredictability of Ischemic RecurrencesIt 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.1819 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.17181920 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.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.Download figureDownload PowerPoint 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. Table 1. Ranked Independent Predictors of 6-Month Mortality Among 10 219 Hospital Survivors Based on the Cox ModelVariableRelative Risk95% Confidence IntervalIneligibility for exercise test Cardiac reasons3.302.36–4.62 Noncardiac reasons3.282.23–4.72Early LV failure2.411.87–3.09Recovery-phase LV dysfunction2.301.78–2.98Age >70 y1.811.43–2.30Electrical instability1.701.32–2.19Late LV failure1.541.17–2.03Previous myocardial infarction1.471.14–1.89History of treated hypertension1.321.05–1.65LV indicates left ventricular. Table 2. Ranked Independent Predictors of Nonfatal Reinfarction Among 6580 Hospital Survivors With Echocardiographic and Holter Monitoring Data Available (Cox Model)VariableRelative Risk95% Confidence IntervalIneligibility (cardiac) for exercise test2.321.41–3.82Previous myocardial infarction1.781.20–2.64History of angina1.581.10–2.25Angina at follow-up1.471.01–2.15FootnotesCorrespondence to Prof Luigi Tavazzi, Fondazione Salvatore Maugeri, Via P Azzario 19, 27100 Pavia, Italy. 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