The FRISC II ECG substudy

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1 European Heart Journal (22) 23, doi:1.153/euhj , available online at on ST depression in ECG at entry indicates severe coronary lesions and large benefits of an early invasive treatment strategy in unstable coronary artery disease The FRISC II ECG substudy E. Diderholm 1, B. Andrén 2, G. Frostfeldt 1, M. Genberg 2, T. Jernberg 1, B. Lagerqvist 1, B. Lindahl 1 and L. Wallentin 1 and the Fast Revascularization during InStability in Coronary artery disease (FRISC II) Investigators 1 Department of Cardiology and 2 Clinical Physiology, University Hospital, Uppsala, Sweden Background In unstable coronary artery disease, STsegment depression indicates a poor prognosis. We evaluated whether the effect of early revascularization and the extent of coronary lesions were related to ST-segment and T wave changes on admission. Methods and Results 2457 patients with unstable coronary artery disease were randomized to an early invasive strategy with coronary angiography/revascularization within 7 days or to a non-invasive strategy with coronary procedures only when symptoms or severe ischaemia recurred. ST depression was present in 1114 (45 5%) patients. In the invasive group, 45% of the patients with ST depression had three-vessel disease or left main stenosis compared with 22% if no ST-segment depression was present, P< 1. In patients with ST-segment depression the invasive strategy reduced death/myocardial infarction at 12 months from 18 2 to 12 %, RR 66 (95% CI 5 88) P= 4 while mortality was changed from 5 8 to 3 3%, P= 5. In patients without ST-segment depression the corresponding rates concerning death/myocardial infarction were 1 4 and 8 9, and for mortality 2 and 1 2% (non-significant). Conclusions In unstable coronary artery disease, STsegment depression is associated with a 1% increase in the occurrence of three-vessel/left main disease and to an increased risk of subsequent cardiac events. In these patients an early invasive strategy substantially decreases death/myocardial infarction. (Eur Heart J 22; 23: 41 49, doi:1.153/euhj ) 21 The European Society of Cardiology Key Words: Unstable angina, coronary angiography, coronary angioplasty, coronary bypass, electrocardiography, myocardial infarction. See page 3, doi:1.153/euhj for the Editorial comment on this article Introduction The clinical diagnosis of unstable coronary artery disease is based on the occurrence of unstable angina or a non-st-segment-elevation myocardial infarction. This group of patients is heterogeneous and the prognosis Revision submitted 14 March 21, accepted 21 March 21, and published online 21 August 21. Correspondence: Erik Diderholm, MD, Department of Cardiology, Cardiothoracic Center, University Hospital, S Uppsala, Sweden X/2/141+9 $35./ varies considerably. Patients with ST-segment depression in the electrocardiogram (ECG) on admission have a markedly increased risk for future cardiac events compared with those without ST-segment depression [1 1]. So far no randomized trial has evaluated whether STsegment and T wave changes could identify patients with a specific response to early revascularization. The FRISC II trial compared an early invasive with a non-invasive strategy regarding death and myocardial infarction in unstable coronary artery disease [11]. After 12 months there were reductions in death, myocardial infarction as well as in late revascularization and need 21 The European Society of Cardiology

2 42 E. Diderholm et al. for readmission [12]. The objective of this study was to evaluate whether the effect of the invasive strategy was related to the occurrence and type of ST-segment and T- wave changes in the ECG on admission. In addition, we evaluated the relationship between different ST-segment and T wave changes in the ECG at entry and outcome in the non-invasive group and the extent of coronary lesions in the invasive group. Methods Patients In the Fast Revascularisation in InStability in Coronary disease trial (FRISC II) 2457 patients were randomized to an invasive or a non-invasive regimen [11,12]. Patients with unstable angina or non-st-segment-elevation myocardial infarction were eligible for the trial. Inclusion criteria were symptoms of cardiac ischaemia associated with either ST-segment depression 1 mv, or T-wave inversion 1 mv in at least one lead, or elevation of biochemical markers indicating myocardial damage. The study complied with the Declaration of Helsinki and all local ethics committees approved the protocol. chest pain, a diagnostic ECG or elevation of biochemical markers of myocardial damage [11]. Only new Q waves were used for the diagnosis of myocardial infarction in association with coronary artery bypass grafting (CABG). Coronary angiography All coronary angiograms performed within 6 months were evaluated locally and recorded in a standardized format. The coronary vessels were divided into 16 segments, four from the right coronary artery, five from the left anterior descending artery diagonal branches, 4 6 from the left circumflex artery obtuse marginal branches and one from the left main coronary artery, in accordance with the AHA committee report on coronary artery disease from 1975 [13]. The degree of stenosis (%) in each of these 16 segments was evaluated into one of five degrees (, <5, 5 7, >7 or 1=occlusion). A 5% stenosis in at least one of the segments in the respective vessel area (right coronary artery, left anterior descending diagonal and circumflex obtuse marginal) was considered significant in respect of the traditional one-, two- and three-vessel disease. For the left main artery, a 5% stenosis was considered significant. Randomized treatment The patients gave informed, written consent and were randomized, using a 2 2 factorial design, to an early invasive or early non-invasive strategy and to short-term or long-term treatment with dalteparin. In the early invasive group, coronary angiography and, if appropriate, revascularization was to be performed within 7 days. Revascularization was recommended in all patients with r7% diameter obstruction in any artery supplying a significant proportion of the myocardium. In the non-invasive group, coronary angiography/ revascularization was recommended in cases of severe angina, severe ischaemia at a pre-discharge exercise test or (new) myocardial infarction [11]. All patients received open label dalteparin for at least 5 days and always until a scheduled revascularization procedure. Thereafter the patients continued on longterm treatment with dalteparin or placebo. As long-term dalteparin treatment had no significant effect on the 12-month outcome, the dalteparin and placebo groups have been combined in the present report. Follow-up and end-points Patients were followed by outpatient visits for 6 months [11]. The 12-month follow-up was performed by telephone interview and, if appropriate, by evaluation of the patient s hospital record [12]. Myocardial infarction was based on the presence of two out of the conventional three criteria, i.e. typical ECG substudy The admission ECG was evaluated at a core laboratory, which was unaware of the patients randomization and clinical outcome. ST-segment depression was considered present if it was horizontal or down-sloping and at least 5 mv. Inverted T wave(s) was considered present if the T wave was isoelectric, negative or biphasic in leads V 3 V 6, avl (if R> 5 mv), I and II. At least 1 mv T-wave inversion was required in leads V 2 and avf (positive QRS also required). In V 1, avr and III T waves were not evaluated. Statistics The statistical evaluation was performed on an intention-to-treat basis. The efficacy analyses were point estimates and only included patients with an adjudicated event or with recorded absence of the evaluated event until at least 335 days of follow-up. Differences between categorical variables were analysed for significance by the Pearson chi-squared test with results presented as risk ratios with 95% confidence intervals. As regards continuous variables, the ANOVA model was used to assess significance of differences. Kaplan Meier 1-survival plots were used to illustrate the timing of events without any analysis of significance. The importance of ST-segment depression was further evaluated with multivariate logistic regression. The interaction between the occurrence of ST-segment depression and the invasive strategy was used in the

3 The FRISC II ECG substudy 43 Table 1 Baseline characteristics in relation to ST-segment and T wave changes in admission ECG ST depression Isolated inverted T No STT changes P n Mean age (years) < 1 Males < 1 Non-smokers ns Hypertension < 1 Cholesterol 5 5 mmol.l 1 * ns Diabetes mellitus ns Previous myocardial infarction < 1 Angina >3 months < 1 Troponin T 1 μg.l < 1 LVEF <45% < 1 Values are percentages unless otherwise indicated. *213 mg.dl 1. Pearson chi-squared test comparing all three ECG groups. LVEF=Left ventricular ejection fraction (echocardiography). regression model. The data processing and statistical analyses were performed using the SPSS 1. statistical program. Results ST-segment and T wave changes in admission ECG The admission ECG was available in 2446 (99 6%) patients. Evaluation of ischaemia via an ECG was not possible in 38 (1 6%) patients, who were excluded from the analyses. ST-segment depression occurred in 1114 (45 5%) patients, isolated T-wave inversion was found in 871 (35 6%) and 423 (17 3%) had no ST-segment and T wave changes. Baseline characteristics in relation to ST-segment and T wave changes There were considerable differences in baseline characteristics between the three groups (Table 1). The patients with ST-segment depression were older and more often had angina pectoris and hypertension. The group with no ST-segment and T wave changes was younger and contained fewer female and patients with previous myocardial infarction. Among patients with any ST-segment and T wave change, 14% had reduced left ventricular function compared with 5 6% in those without STsegment and T wave changes. There were no significant differences in baseline characteristics within the three ECG groups between those randomized to early invasive or non-invasive strategies. Coronary lesions and revascularization procedures in relation to ST-segment and T wave changes in the invasive group Coronary angiography was performed within 7 days in 96% and within 6 months in 98% of patients. There were considerable differences between the ECG subgroups regarding the extent of coronary artery disease (Fig. 1). In the group with ST depression there were significantly more patients with three-vessel or left main disease, 45% compared with 22% if no ST-segment depression was present, RR 2 1 (CI ) P< 1. Almost 2% of the patients without ST-segment depression on admission had no significant stenosis compared with fewer than 1% if ST-segment depression was present. The extent of angiographic coronary artery disease was similar in the groups with isolated T-wave inversion and no ST-segment and T wave changes. There were significantly more revascularization procedures in patients with ST-segment depression compared to the other two groups (Table 2). This difference was caused by significantly more CABG interventions, 48% if ST-segment depression was present compared with 28% in those without ST-segment depression. The corresponding numbers for PTCA were 37% and 45%, respectively, which also was a statistically significant difference. Coronary lesions and cardiac event rates in relation to ST-segment and T wave changes, in the non-invasive group In the non-invasive group, patients with ST-segment depression more often needed coronary angiography, 55% within 6 months, compared with those with isolated T-wave inversion (44%) and when no ST-segment and

4 44 E. Diderholm et al % No STT changes n = 218 Isolated T inv n = 427 ST depression n = 529 Figure 1 Extent of coronary artery disease at angiography in relation to ST-segment and T wave (STT) changes on admission, invasive cohort only. =no significant stenosis;,, =one-, two- and three-vessel disease; =left main disease, inv=inversion. Table 2 Number of revascularization procedures (%) within 12 months in relation to ST-segment and T wave changes on admission and randomization ST-segment and T wave change and randomization n Revasc % CABG % PTCA % Non-invasive ST depression * 3* 21 Isolated inverted T waves No STT changes 24 29* 11* 18 Invasive ST depression * 48* 37 Isolated inverted T waves No STT changes * 5* Revasc=revascularization. CABG=coronary artery bypass grafting. PTCA=percutaneous transluminal coronary angioplasty. STT=ST-segment and T wave changes. *P< 5 compared to the group with isolated inverted T waves. If both CABG and PTCA are performed, it is referred to as CABG. T wave change was present (35%). Among those in whom angiography was performed there was also more three-vessel or left main disease in patients with STsegment depression compared with the other groups: 5, 31 and 29%, respectively. Patients with no ST-segment and T wave changes had a risk of death/myocardial infarction after 12 months similar to patients with isolated T-wave inversion: 1 3% and 1 5%, respectively. However, in patients with STsegment depression the event rate was 18 2%, RR 1 75 (CI ), P< 1 compared with patients without ST-segment depression (Fig. 2). Even at 12- month mortality the risk was higher at ST-segment depression (5 8%) compared with those without STsegment depression (2 %), RR 2 86 (CI ), P= 1. The number of revascularization procedures in the non-invasive group was significantly related to the STsegment and T wave changes on admission. Thus, within 12 months 51% of those with ST-segment depression compared with 39% with isolated T-wave inversion and 29% without ST-segment and T wave changes had undergone coronary procedures (Table 2 and Fig. 3). PTCA was performed in about 2% of the patients without any difference between the three ECG groups. Thus, the difference in coronary procedures between the groups was explained by different rates of CABG (Table 2).

5 The FRISC II ECG substudy 45 Probability of death or myocardial infarction ST depression n = 571 P < 1 No STT changes n = 24 Isolated T wave inversion n = Days Figure 2 Probability of death or myocardial infarction in relation to ST-segment and T wave (STT) changes on admission in the non-invasive cohort only, illustrated by Kaplan Meier (1-survival) plots. The P value is evaluated by chi-squared analysis as a point estimate at 12 months and refers to the difference in outcome between patients with and without ST-segment depression Probability of revascularization ST depression n = 571 P < 1 Isolated T inversion n = 439 No STT change n = 24 P < Days Figure 3 Probability of revascularization in relation to ST-segment and T wave (STT) changes on admission in the non-invasive cohort only, illustrated by Kaplan Meier (1-survival) plots. The P values are evaluated by chi-squared analysis as point estimates at 12 months comparing the group with isolated T-wave inversion with the other two. 36 Effect of the invasive vs the non-invasive strategy in relation to ST-segment and T wave changes In patients with ST-segment depression the invasive strategy reduced the 12-month rate of death/myocardial infarction from 18 2% to 12 % (Table 3, Fig. 4). Even the death rate alone, after 12 months, tended to be reduced, from 5 8% to 3 3%, by the invasive strategy in the ST-segment depression cohort (Table 3, Fig. 5). The groups with no ST-segment and T wave changes and isolated T-wave inversion were similar concerning prognosis and angiographic extent of coronary artery

6 46 E. Diderholm et al. Table 3 Death, death or myocardial infarction, and readmission within 12 months and occurrence of angina pectoris at 3 months, in the invasive and non-invasive strategy in relation to occurrence of ST-segment depression in admission ECG Patients Inv/non-inv n/n Invasive n(%) Events Non-invasive n(%) RR (95% CI)* P ST-segment depression Death 542/ (3 3%) 33 (5 8%) 58 ( ) 5 Death or MI 54/ (12 %) 14 (18 2%) 66 ( 5 88) 4 Readmission within 12 months 54/ (38%) 35 (61%) 63 ( 56 71) < 1 Angina 3 months 518/ (18%) 236 (44%) 42 ( 34 51) < 1 No ST-segment depression Death 651/643 8 (1 2%) 13 (2 %) 61 ( ) 26 Death or MI 65/ (8 9%) 67 (1 4%) 86 ( ) 36 Readmission within 12 months 65/ (35%) 342 (53%) 67 ( 59 76) < 1 Angina 3 months 633/ (22%) 272 (43%) 52 ( 44 62) < 1 Inv/non-inv=invasive/non-invasive. MI=myocardial infarction. *Risk ratios (RR) and 95% confidence intervals refer to the comparison between the effect of the invasive and the non-invasive strategies. 2 Probability of death or myocardial infarction Non-invasive (n = 571) P < 1 Invasive (n = 54) Non-invasive (n = 643) Invasive (n = 65) ST dep No ST dep Days Figure 4 Probability of death or myocardial infarction in relation to strategy and occurrence of ST-segment depression on admission, illustrated by Kaplan Meier (1-survival) curves. The P value is evaluated by chi-squared analysis as a point estimate at 12 months and refers to the difference in outcome between invasive and non-invasive strategies. ST dep=st-segment depression. 36 disease. In the analyses of relationship to outcome they were therefore merged into one group. Death/ myocardial infarction at 12 months in patients without ST-segment depression occurred in 8 9% of the invasive group compared with 1 4% in the non-invasive group (P=ns). In patients with as well as without ST-segment depression, the early invasive strategy was associated with a reduction in readmissions and angina pectoris at follow-up (Table 3). Multivariate analysis The importance of ST depression and invasive strategy were evaluated by multivariate logistic regression in terms of risk of death/myocardial infarction after 12 months. The following clinical parameters were adjusted for in the analysis: age, gender, smoking, hypertension, cholesterol 5 5 mmol.l 1, diabetes, previous myocardial infarction, Troponin T value

7 The FRISC II ECG substudy 47 6 Non-invasive (n = 571) 5 P = 5 ST dep Probability of death Invasive (n = 542) Non-invasive (n = 643) No ST dep 1 Invasive (n = 651) Days Figure 5 Probability of death in relation to strategy and occurrence of ST-segment depression on admission, illustrated by Kaplan Meier (1-survival) curves. The P value is evaluated by chi-squared analysis as a point estimate at 12 months and refers to the difference in outcome between invasive and non-invasive strategies. ST dep=st-segment depression μg.l 1 at randomization and the 3 months doubleblind treatment (dalteparin or placebo). In the total data set, ST-segment depression remained an independent risk factor for death/myocardial infarction after 12 months (Table 4). In the non-invasive group, STsegment depression was an independent risk factor for death/myocardial infarction at 12 months, RR 1 58 ( ) P= 14. In contrast, in the invasive group ST-segment depression did not turn out as a significant independent risk factor, RR 1 32 ( 88 2 ) P= 18. In the total data set we also evaluated whether there was any interaction between the occurrence of STsegment depression and the invasive strategy on death or myocardial infarction. However in the multivariate logistic regression analysis, also including ST-segment depression, invasive strategy and the product of these two factors, no significant interaction was found (P= 37). Table 4 Multivariate logistic regression analysis of the predictive value of ST depression on admission and of the effect of an early invasive strategy for death/myocardial infarction at 12 months after adjustment for other clinical factors* n RR (95% CI) P ST-segment depression ( ) 8 Invasive strategy ( 52 88) 4 *Adjusted for age, gender, smoking, hypertension, cholesterol 5 5 mmol.l 1, diabetes, previous myocardial infarction, Troponin T value 1 μg.l 1 at randomization and the 3 months double-blind treatment (dalteparin or placebo). Risk ratios and 95% confidence interval. Discussion In the present study the randomization of early coronary angiography gave a unique opportunity to evaluate the relationship between ECG changes and the extent of coronary lesions in 98% of the patients treated invasively. The occurrence of ST-segment depression was associated with three-vessel disease in 32% and left main stenosis in 13%. In the 55% of the patients with ST-segment depression in the non-invasive group who, because of ischaemia, were investigated by coronary angiography during the first 6 months, the rates of three-vessel or left main disease were similar, 4% and 1%, respectively. Thus, at ST-segment depression almost half of the patients with three-vessel or left main disease had not been identified within the first 6 months with the noninvasive approach. The occurrence of three-vessel disease in the ST-segment depression cohort of our study was in accord with the GUSTO IIB study [3] where 56% of patients with ST-segment depression had an angiogram, out of which 36% had three-vessel disease. In unstable coronary artery disease, a number of studies have shown the increased risk for subsequent events in patients presenting with ST-segment depression in the ECG at rest [1 1]. If isolated T-wave inversion is present the risk is lower [2 4,1]. The high risk in patients with ST-segment depression is to some extent caused by the fact that these patients have other risk factors, e.g. older age, angina, hypertension and previous myocardial infarction compared with those without ST-segment depression. However, in this as in previous studies multivariate analyses demonstrated that ST-segment depression is an independent risk factor for future cardiac events [2 4,7 1].

8 48 E. Diderholm et al. The prognostic importance of isolated T-wave inversion is more difficult to assess and the results from previous studies are conflicting. In some cases, especially if located in precordial leads, the isolated inverted T waves might reflect a severe proximal left anterior descending stenosis [14,15]. However, many patients with isolated inverted T waves have no coronary stenosis. In the GUSTO IIB study 19% of patients with isolated inverted T waves had no significant stenosis [3], which is in good agreement with the 16% in the total data set of the present study. In ours as in other [4,5] studies, patients with isolated inverted T waves had a similar risk of death or myocardial infarction at 1 year as those with no ST-segment and T wave changes. However, it needs to be emphasized that due to inclusion criteria in our study, patients without ST-segment and T wave changes had to have increased cardiac markers. Early revascularization has been suggested for unstable patients at moderate or high risk. However, FRISC II was the first randomized trial to demonstrate that an early invasive strategy significantly reduced deaths or myocardial infarctions, after 12 months, from 14 1 to1 4%, and mortality from 3 9 to2 2% [12].Inthe present analyses it was demonstrated that the early invasive strategy has a remarkable effect in patients with ST-segment depression at entry: death or myocardial infarction after 12 months was reduced from 18 2 to 12 % (P= 4), and in the numeric reduction mortality was from 5 8 to 3 3% (P= 5). The pronounced effect in the ST-segment depression group was also illustrated by the loss of the independent relationship between ST-segment depression and outcome in the invasive cohort. No previous trial has been able to show such a dramatic reduction in events in this group of patients. To our knowledge, this is the first study demonstrating that ECG changes, in addition to being prognostic, can be used to choose treatment to reduce death/myocardial infarction in unstable coronary syndromes. Among the patients with ST-segment depression, a large proportion were revascularized with CABG because of the common occurrence of threevessel or left main disease. Thus, the better outcome, and especially the lower mortality in the invasive arm in the ST-segment depression cohort, might be related to the well-established life saving effect of CABG in threevessel or left main disease [16]. Patients without STsegment depression had the advantage of an early invasive strategy, although the reduction in death or myocardial infarction was not significant, perhaps because of the lower event rates. However, there were comparable 3 5% reductions in readmissions and symptoms of angina pectoris during follow-up as well in patients without as well as with ST-segment depression. In this substudy, we used a cut-off level of 5 mv for ST-segment depression; in previous studies this measure has been associated with increased risk of future cardiac events [2,1]. However, inclusion criteria for the FRISC II study which, except for randomization to the early invasive strategy, also included 3 months twice daily subcutaneous dalteparin/placebo, were more strict, and at least 1 mv ST-segment depression was needed. This means that the results in patients with ST-segment depression in the present study might not necessarily be applicable to patients presenting with less than 1 mv of ST-segment depression, unless T-wave inversion or a rise in biochemical marker levels is also present. The degree of ST-segment depression is correlated to worsening outcome [1]. In this study, however, ST-segment depression was used as a dichotomous variable. Thus, we have not analysed whether the degree of ST-segment depression would provide further information on the effects of the invasive treatment. Another possible limitation of the study is the definition of myocardial infarction in association with CABG in which only new Q waves were referred to as myocardial infarction. This could be one reason for the more beneficial effect in patients with ST-segment depression where CABG was more common. However, this hypothesis is contradicted by the similar change in mortality and myocardial infarction by early invasive strategy in patients with ST-segment depression. Conclusions In unstable coronary artery disease, patients with STsegment depression on admission have a high proportion of three-vessel or left main disease and, although treated with aspirin and at least 5 days of low molecular weight heparin, an almost doubled risk for future cardiac events including a 6% 1-year mortality. In these patients an early invasive strategy, on top of the above antithrombotic treatment, was associated with a relative reduction of 42% in mortality, 34% in death/myocardial infarction at 1 year and, in addition, a 3 5% reduction in symptoms of angina pectoris and readmissions. Despite the fact that at least half of the patients with ST-segment depression will need revascularization during the following year, half of the patients with threevessel or left main disease will remain undetected with a primarily non-invasive strategy. Therefore, in unstable coronary artery disease with ST-segment depression in ECG at rest, an early invasive approach has a very high priority. The study was supported by and organized in collaboration with the Pharmacia & Upjohn Company. The project organization within the research group was also supported by the Swedish Heart-Lung Foundation. 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