EMTORIALS

Relation of Thrombolysis During Acute Myocardial Infarction

to Left Ventricular Function and Mortality Harvey D. White, MB

efore the thrombolytic era, it was well proven that B left ventricular (LV) function was the most im- portant prognostic factor after recovery from

acute myocardial infarction and that there was a curvi- linear relation between ejection fraction and mortali- ty.Q After thrombolytic therapy, achievement of paten- cy of the infarct-related artery may confer additional benefits to those achieved by reduced infarct size and preservation of LV function.3,4 The significance of LV function as a criterion for the efficacy of thrombolytic therapy, and its relation to mortality, is now the subject of debate.

Reservation of LV function is closely related to pa- tency of the infarct-related artery. After successful thrombolysis with reperfusion of the infarct-related ar- tery, the ejection fraction improves. If reperfusion does not take place, no change or often deterioration in LV function results.

Effect of thrombolysis on left ventricular function: Several studies have compared streptokinase to placebo and tissue plasminogen activator to placebo.5m9 Two of these studies have evaluated patients with fust infarc- tions only.5,6 In our laboratory, the mean ejection frac- tion after a first infarction is 53 f 13.5%; in normal subjects without coronary disease it is 71 f 7%. After thrombolytic therapy, the mean ejection fraction is ap- proximately 59%. Thrombolysis has therefore achieved about one third of what is possible in terms of returning resting ejection fraction toward normal.rO

End-systelic volume and long-term survival: Al- though the resting global ejection fraction is a very pow- erful prognostic factor, end-systolic volume has been shown to be even more important.’ Like ejection frac- tion, end-systolic volume is dependent on both afterload and contractility but is independent of preload.

In comparison with ejection fraction, which de- creases by 25%, and end-diastolic volume, which in- creases by 10 to 20% after infarction, end-systolic vol- ume increases by 50% and is the best variable to charac- terize the amount of LV damage.lO The additional predictive power of end-systolic volume is seen when the ejection fraction is <50%.’

From Green Lane Hospital, Auckland, New Zealand. Manuscript re- ceived October 27, 1989; revised manuscript received and accepted February 27,199O.

Address for reprints: Harvey D. White, MB, Green Lane Hospital, Auckland 3, New Zealand.

Effect of thrombolysir on left ventricular volumes: After thrombolytic therapy with streptokinase, we showed that patients’ LV end-systolic volumes were 18 ml lower 3 weeks after infarction.5 Thrombolytic thera- py not only decreases infarct size but also decreases in- farct expansion and dilatation of the ventricle. In a head-to-head comparison of the effects of tissue plas- minogen activator and streptokinase on LV function, we found that the 2 agents had remarkably similar effects on ejection fraction. l l However, the end-systolic volume was 8 ml lower in patients with anterior infarctions treated with streptokinase, which has a more marked afterload-reducing effect (difference not significant). It remains to be seen whether adjunctive therapy with agents such as angiotensin-converting enzyme inhibitors will add to the very substantial benefit achieved by thrombolytic therapy.

Numbers of patients required for clinical trials: The effects of thrombolysis on mortality should not be con- cluded from small trials that have insufficient statistical power. In sizing calculations for randomized trials, large numbers of patients are required for mortality trials.lO For a mortality trial in which the baseline mortality rate is about 10% (as it was before thrombolysis), several thousand patients are required. This is because mortali- ty is measured as an endpoint in only 10% of the pa- tients and is not a continuous variable. Now that the mortality rate is about 5%, the numbers of patients re- quired are even larger (15,000 to 20,000).

For a trial of LV function, ejection fraction can be measured in most patients and is a continuous variable. A trial of 200 to 300 patients can have the same statisti- cal power (beta error 80%, alpha error 0.05) as a mor- tality trial of thousands of patients. It is therefore poten- tially confusing to emphasize mortality differences in small LV function trials. For example, in our LV func- tion trial of intravenous streptokinase, we found the largest reduction in mortality reported for thrombolytic therapy (81% relatively from 12.9% to 2.5%, p = 0.012).5 Because this was an LV function trial, the sur- vival benefit could have occurred by chance. In another trial of thrombolysis with tissue plasminogen activator, 30-day mortality was, in fact, higher (7 deaths in the tissue plasminogen activator group [9.6%] vs 2 in the placebo [2.8%], p = 0.09) in the thrombolytic-treated patients.6

Relation between left ventricular function, threm- bolysis and long-term survival: It has been asserted that no thrombolytic trial has shown a statistically sig-

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nificant beneficial effect for both LV function and sur- vival.12 However, in the Interuniversity Study of 533 patients both survival and LV function improved in pa- tients whose invasive strategy consisted of intracoronary streptokinase or intravenous streptokinase or angio- plasty or some combination of these.13gt4 This trial was designed to address whether opening up a coronary ar- tery by whatever means possible would improve surviv- al. In our trial of intravenous streptokinase versus place- bo in 172 patients, LV function was also improved by 6% (absolute) (p <O.OOS), and 30-day survival im- proved5 In this study, the primary endpoint was LV function of patients with first infarctions. We also ran- domized patients with second infarctions but, as would be expected with such a heterogenous group, there was only a trend for improvement of LV ejection fraction (3.3%, p = 0.09). In addition to the heterogeneity of second infarctions, recurrent infarcts in the same terri- tory are usually smaller. Thus, benefit for preservation of LV function with thrombolysis would not be expected to be as great as for first infarctions.r5 For studies of LV function, it is important to evaluate patients with first infarctions.5,6J ’ Clearly, including patients with baseline ejection fractions of 20 to 30% would make it very likely that 2 randomized groups of patients would have a baseline inequality of the primary endpoint. In addition, a recurrent inferior infarction after an inferior infarct is different (probably much smaller with less LV dysfunc- tion) from an anterior infarct plus a previousinferior in- farct. This is particularly important when angiograms are done at only 1 point late in the trial.

The European Cooperative Study Group random- ized 721 patients to receive either tissue plasminogen activator or placebo.9 There was a 2.2% improvement in ejection fraction for patients treated with tissue plas- minogen activator. For patients with first infarctions, there was no difference in global ejection fractions. There was a trend (not conventionally significant) for mortality to be reduced. It is possible that the reason for the small ejection fraction difference is due to the fact that patients with poor LV function were saved from dying by thrombolytic therapy. However, if this were the case, one would not expect thrombolytic trials to show a lower incidence of heart failure in patients treat- ed with thrombolytic therapy.’ Our data show that not only is the mean ejection fraction improved, but the number of patients with ejection fractions <40% is de- creased.5 Before the thrombolytic era, about 20% of pa- tients left the hospital after a first infarction with an ejection fraction <40%. Now the number of patients in this category is about 10%. Clearly, each of these LV function trials is too small for lirm conclusions to be drawn about mortality benefit.

Beneficial effects of late thrombolysis: In the Sec- ond International Study of Infarct Survival, survival was improved when streptokinase was given beyond the traditionally accepted window of 4 to 6 hours for sal- vage of myocardium.i6 The odds reduction for mortality at 35 days was 35% for treatment within 4 hours, 16% for treatment between 5 and 12 hours and 21% for

treatment between 13 and 24 hours. The mechanism for this late benefit is uncertain. It has been hypothesized that late reperfusion could reduce LV dilatation and therefore improve prognosis by reducing end-systolic volume.’ After infarction, there is expansion of both the infarct and noninfarct zones and dilatation of the ventri- cle. Late reperfusion may increase the tensile strength of the infarct zone and ventricular dilatation may be decreased.17,18 There are in addition other mechanisms that could decrease LV dilatation; late reperfusion can accelerate infarct zone healing, blood in a patent in- farct-related artery could splint the infarct zone by act- ing as a skeleton and salvage of islets of epicardium could also act as a splint.

Importance of patency of the infarct-related artery and relation to left ventricular function and survival: Achievement of patency of the infarct-related artery may well confer benefits in terms of reduced mortali- ty, 19,20 reduced arrhythmias*’ or reduced LV dilata- tion.3s5 There are, however, no data to show by multi- variate analysis that patency of the infarct-related artery is superior to LV function as a long-term prog- nostic factor. Indeed, in the Interuniversity Study, which now has a 5-year follow-up, the only factor of prognostic importance was LV function, and patency of the infarct-related artery was not a prognostic factor.22 In the Western Washington trial of intracoronary strep- tokinase,‘9~23 early mortality was improved and long- term survival was significantly improved in patients with sustained reperfusion compared to patients in whom the infarct artery either did not reperfuse or re- occluded. Overall there was no improvement in LV function as intervention was late, up to 12 hours after onset of infarction. However, on multivariate analysis, LV ejection fraction measured at day 3 was more pre- dictive of survival than patency.23 Indeed, only the ejec- tion fraction measured on day 3 (p <O.OOl) and age (p = 0.005) were significant predictors. In the Thromboly- sis and Angioplasty in Myocardial Infarction Trial, ejection fraction has been shown to be the most impor- tant predictor of hospital survival (chi-square = 6.6) on multivariate analysis, along with complete filling of the infarct-related artery at angiography (chi-square = 4.2).24 Long-term follow-up (at 18 months) in this study in patients in whom intensive medical management was given has shown that out-of-hospital mortality is low at 3.8% and that ejection fraction is higher in survivors (52%) than in nonsurvivors (46%).25 Because of the low event rate, analysis of the prognostic role of the patent artery is not possible.

Although LV function is closely related to mortality, they are not synonymous. The early survival benefit of thrombolytic therapy clearly cannot be predicted by lat- er measurement of LV function. It is of interest, how- ever, that in both the Italian Streptokinase Mortality Tria126 and the Second International Study of Infarct Survival,r6 there was no mortality reduction on day 1 and the mortality curves did not begin to diverge for several days. This is partly due to an increase in early cardiac rupture with thrombolytic therapy. In the

THE AMERICAN JOURNAL OF CARDIOLOGY JULY 1, 1990 93

APSAC Intervention Mortality Study at 1 year, the mortality curves are diverging (5.8% absolute difference at 30 days and 8.6% at 1 year), implying that there is a continuing beneficial effect of thrombolytic therapy.27 Perhaps improved LV function or continuing patency of the infarct-related artery could be adding to the mortal- ity benefit. The survival curves in the Interuniversity Study are also diverging. For patients with anterior in- farctions, the difference at 1 year was 11% (absolute) between patients treated with streptokinase and the con- trol group, and at 5 years the difference was 16%.22 As noted, LV function was the only prognostic factor found to be significant in this study.

The benefit of patency cannot be extrapolated di- rectly to mortality or patient benefit. This has clearly been shown by the trials of early angioplasty after thrombolytic therapy. When patency of the artery was achieved, it did not result in improved LV function or mortality. In fact, mortality was higher in each of 3 trials of early angioplasty.28-30 The Anglo-Scandina- vian Study of Early Thrombosis also concluded, after reviewing the large thrombolytic mortality trials, that there was no direct relation between reperfusion effica- cy and improved surviva13i

LV function appears to override other prognostic factors. If the ejection fraction is X0%, then prognosis is generally good, regardless of whether there is 3-vessel coronary artery disease or ventricular arrhythmias. When the ejection fraction is <40%, prognosis is usually poor. Within the group of patients with low ejection fractions, there are patients with differing prognoses. For example, patients with an ejection fraction of <40% and an end-systolic volume <130 ml have a 27% better 5-year survival than patients with the same ejection fraction and end-systolic volumes > 130 ml. l It may be better to have an ejection fraction of 50% with a blocked infarct-related artery than to have an ejection fraction of 40% with an open infarct-related artery.

Thrombolysis clearly improves survival after the on- set of an acute coronary occlusion. Early reperfusion with salvage of myocardium will save some patients with cardiogenic shock and some lives will be saved by reduced frequency of ventricular fibrillation. However, some patients could be harmed by bleeding or increased frequency of cardiac rupture. It appears that a major mechanism of the survival benefit of thrombolytic ther- apy is through preservation of LV function. If the ejec- tion fraction is improved or, more importantly, end-sys- tolic volumes are made smaller, then long-term survival will be improved.

Cot~I~sions: Mortality as a trial endpoint assesses only 1 possible aspect of patient benefit from a thera- peutic intervention. To assess the overall balance of ben- efit and adverse effect, large mortality trials of approxi- mately 20,000 patients are required. These trials are expensive and although the Italian Streptokinase Mor- tality Trial Group and the International Studies of In- farct Survival organizations have shown that they can be done, they can really only assess early mortality be- cause of the difficulties of following large numbers of

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patients on a long-term basis. These trials do not assess quality of life, symptomatic status, exercise capacity or mechanisms of benefit.

Smaller trials with endpoints such as LV function, particularly end-systolic volume, will also be necessary to evaluate the effects of the many new therapies avail- able for the treatment of acute myocardial infarction.

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