Importance of congestive heart failure and interaction of congestive heart failure and left ventricular systolic function on prognosis in patients with acute myocardial infarction

Importance of Congestive Heart Failure and Interaction of Congestive Heart Failure and Left Ventrwular Systolic Function on Prognosis in Patients With Acute Myocardial Infarction Lars Kaber, MD, Christian Torp-Pedersen, MD, Ole D. Pedersen, MD, Serren H&berg, and A. John Camm, MD, on behalf of the TRACE Study Group

MD,

left ventricular (LV) systolic function and congestive heart failure (CHF) are important predictors of long-term mortality after acute myocardial infarction. The importance of transient CHF and the interaction of CHF and LV function on prognosis has not been studied in detail previously. In the TRAndolapril Cardiac Evaluation Study, 6,676 consecutive patients with acute myocardial infarction 1 to 6 days earlier had LV systolic function quantified as wall motion index (echocardiography), which is closely correlated to LV ejection fraction. To study the interaction of CHF and wall motion index on long-term mortality, separate analyses were performed in patients with different levels of LV function. Risk ratio (95% confidence intervals [Cl]) were determined from proportional hazard models subgrouped by wall motion index or CHF adiusted for age and gender. Heart failure was separated into transient or persistent. Wall motion index

and CHF are correlated. Furthermore, there is an interaction between wall motion index and CHF. The prognostic importance of wall motion index depends on whether patients have CHF or not: the risk ratio associated with decreasing 1 wall motion index unit is 3.0 (2.6 to 3.4) in patients with CHF, and 2.2 (1.7 to 2.9) in patients without CHF when adiusted for age and gender. Similarly, the prognostic importance of CHF depends on the level of wall motion index: the risk ratio associated with CHF is 3.9 (1.8 to 8.3) when the wall motion index is <0.8 and 1.9 (1.5 to 2.3) when the wall motion index is > 1.6. Transient CHF is an independent risk factor (risk mtio 1 S, confidence interval (Cl1 1.3 to 1.8) although milder than persistent CHF (risk ratio 2.8, Cl 2.5 to 3.2). 0 J996 by Excerpta Medica, Inc. (Am J Cardiol 1996;78: 1124- 1128)

n patients with an acute myocardial infarction, mortality increases as left ventricular (LV) ejection fraction decreases.le3Pulmonary congestion after infarction is correlated to LV ejection fraction and also has prognostic importance.4.5 Patients with pulmonary edema but normal LV systolic function after an infarction have a worse prognosis than patients without congestive heart failure (CHF) and normal LV function6 In some patients CHF is transient and only requires diuretic treatment for a few days. The prognostic importance of transient versus persistent CHF has not been previously evaluated in a large, well-defined population of patients with acute myocardial infarction. The present study assessesthe interrelation and interaction of CHF with LV systolic function in a large cohort of patients shortly after a myocardial infarction. The analyses were retrospective using data collected in a prospective, Danish

multicenter trial, the TRAndolapril Cardiac Evaluation (TRACE) study.

I

From the Department of Cardiology P, Gentofte University Hospital of Copenhagen, Denmark, Department of Internal Medicine, Ribe County Hospital, Esbierg, Denmark, Department of Cardiology, Bisebierg Hospital of Copenhagen, Denmark, Department of CardioPogrcal Sciences, St. George’s Hospital Medical School, London, England. This study was sponsored by Roussel Uclaf and Knoll A/G. Manuscript received February 6, 1996; revised manuscript received and accepted May 28, 1996 Address for reprints: tars Kaber, MD, Department of Cardiology P,aGkentofte Umversity Hospital, 2900 Hellerup, Copenhagen, Den-

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D 1996 by Excerpta Medico, All rights reserved.

inc.

METHODS Patients: The characteristics of the patients screened for the TRACE study have previously been reported.’ In brief, 7,001 consecutive cases of myocardial infarction were screened in 27 Danish coronary care units. Myocardial infarction was defined as typical symptoms and/or electrocardiographic changes accompanied by elevated cardiac enzymes. The screening.procedure took place between 1 and 6 days after the initial symptoms. In case of reinfarction, patients were screened again unless already included in the TRACE trial. The total of 7,001 myocardial infarctions occurred in 6,676 patients hospitalized between May 1990 and June 1992. The cohort in the present study comprised the 6,676 patients at their first screening. In the comparisons of CHF and LV systolic function, only patients who were alive at day 6 after the myocardial infarction (n = 6,282) and had LV function determined were included (n = 5,987). Day 6 was chosen because it was the last day echocardiography could be performed and because the diagnosis of CHF may have been missed in patients dying during the initial days of hospital admission. Patients dying early or with a missing wall motion index differed significantly from the remaining study population: they were 0002.9 149/96/s 15.00 PII SOOO2-9149(96)00576-

older (74 vs 67 years; p 1 during hospitalization or a history of CHF treated medically. For the diagnosis of transient CHF, patients had to have been treated with diuretics for CHF at any time during the hospital stay, and therapy discontinued before discharge. To ensure that withdrawal of diuretic treatment properly reflected transience of CHF, only patients discharged alive were included (n = 5,683) in the analyses of the interrelation of transient versus persistent CHF and wall motion index. Persistent CHF could either be known (history), develop during the first 2 days after infarction, or develop later during the hospital stay. Analysis of the relation between wall motion index and the time of developing CHF included only these patients alive at day 6 in whom wall motion index was assessable. left ventricular function: The echocardiographic method used in the TRACE study has been described in detail.’ Briefly, 2-dimensional echocardiograms were recorded on videotape in the parasternal longaxis view, in multiple short-axis views, and in the apical 2- and 4-chamber views. All recorded videotapes were sent within 24 hours to a central office and were evaluated by 1 of 2 of the authors (L.K., C. T-P8). LV systolic function was expressed as wall motion index using a 9-segment model as described by Heger et a1.9Wall motion score was graded as described by Beming et al.” The score 3 was used for hyperkinesia, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia and -1 for dyskinesia. Wall motion index was calculated by dividing the sum of the scores in each segment by 9. Wall motion index has been shown to be closely correlated with LV ejection fraction determined by radionuclide cardiography or invasive ventriculography.“-” The use of a scale with descending scores corresponding to descending ventricular function ensured easy correspondence between wall motion index and LV ejection fraction. A linear relation between wall motion index and LV ejection fraction has been demonstrated: Wall motion index multiplied TV 0.3 is approximate with LV ejection fraction. However, wall motion index is different from LV ejection fraction, being a regional measure of LV dysfunction. Patients were prospectively divided into 4 patient groups according to wall motion index <0.8, 10.8, 5 1.2, < 1.2, 5 1.6, and > 1.6, approximately correCONGESTIVE

HEART

FAILURE/CONGESTIVE

sponding to LV ejection fraction <0.25, ~0.25, ~0.35, ~0.35, ~0.50, and >0.50, respectively. Mortality: Patient survival information was obtained on July 15, 1994, by interrogating the Danish central personal register. Twenty-eight non-Danish residents were censored from the mortality analysis at the time of hospital discharge, because further information regarding survival could not be guaranteed. There was no survival status on 3 persons owing to misrecorded admission or birth dates. Statistical methods: Continuous variables are shown as medians with 5 and 95 percentiles. Comparisons were done using the Wilcoxon test. A 2sided p value <0.05 was considered significant. Categorical parameters are given in percentages. Comparisons were done using the chi-square or Fisher’s exact test whenever appropriate. Univariate comparisons of mortality were done with the log rank test. Multivariate analyses were done for all types of CHF, together with age and gender, in order to establish the hazard ratio for CHF. Regression models were constructed with wall motion index and the types of CHF as interaction parameters, and all were tested by comparison of log likelihood ratios from models without interaction parameters. Also, multivariate analyses were done including other baseline variables in order to find which types of CHF had independent prognostic importance. All analyses were performed with the SAS system (SAS, Cary, North Carolina). The hazard ratio calculated by the SAS program is denoted as the risk ratio.

RESULTS Congestive heart failure: Characteristics of the 5,987 patients are listed in Table I where patients have been divided in 2 groups according to the presence of CHF. Patients with CHF had a higher mortality than patients without CHF (p 2 TABLE

I

Baseline

Patients

With

to the

Presence

Characteristics

Myocardial

and

Infarction

of Congestive

Mortality Within

Heart

of 5,987 Six

Days

in Relation

Heart

Failure

Failure Congestive Absent

Present

Characteristics

(n = 2,943)

(n = 3,044)

Agelyrsl

63

71

Men

(%)

Diabetes

mellitus

Systemic

hypertension

History

Non-Q-wave

infarction

infarction infarction

Thrombolytic

(“A)

(%I

therapy.(%]

Ventricular

fibrillation

Ventricular

tachycardia

3-year

13.5*

20.8

24.1’

0

30.5

16.4

30.4*

22.7

18.4*

21.9 47.5

30.3* 37.2*

/%I (%)

motion index (median) mortality (%I mortolily

64.7*

7.1

(%)

myocordial

Anterior

Wall l-year

(%)

1.6

(52-85)*

72.9 (%)

of CHF

Previous

(44-80)

3.5

8.7*

9.5

14.8*

(1 .O-2.0)

(%)

1.2

(0.7-2.0)*

7.2

28.4*

15.4

46.3*

*p tO.OO1; ‘p <0.002. CHF = congestive heart foilure.

HEART

FAILURE

AFTER

MYOCARDIAL

INFARCTION

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TABLE II Baseline

Characteristics in Relation to Time to Development After Myocardial Infarction

By History (n = 928)

Characteristics Age (~4 Men (%) Diabetes mellitus (%) Systemic hypertension (%) Previous myocardial infarction (%) Anterior infarction (%) Non-Q-wave infarction (“‘) Thrombolytic therapy (%) Ventricular fibrillation (%) Ventricular tachycardia (%) Wall motion index 1-year mortality (%) 3.year mortality (%)

TABLE

Ill

Surviving

and Mortality of 3,044 Patients With of Congestive Heart Failure

70 (50-84) 67.0 9.9 24.0 19.5

69 (50-83) 65.9

20.5 20.9 20.8 7.0 14.0 1.1 (0.6-2.0) 39.1 64.1

33.8 16.8 44.8 8.8 14.8 1.2 (0.7-l 23.4 38.6

37.7 19.4 43.0 12.7 17.1 1.2 (0.7-2.0)

,9)

Transient (n = 683)

63 (44-80) 72.9 7.0 20.8 16.3

68 (47-82) 68.8 8.1 20.6 20.1

21.9 22.7 47.7 3.2 9.5 1.6 (1.0-2.0) 6.5 14.8

30.6 19.0 52.5 8.1 13.8 1.5 (0.9-2.0) 1 1.4

24.0

same mortality as those with onset of CHF on days 1 to 2 after infarction (p = NS). Patients with a history of CHF had a higher mortality than patients who developed CHF during hospital admission. Transient CHF was present in 25% of patients (683 of 2,775) with CHF. Characteristics of these patients are listed in Table III. The mortality was lower in patients with transient CHF than in patients with persistent CHF, but higher than in patients without CHF (p 1.6 was 54.9% (76.4%), 32.6% (52.7%), 21.4% (3&l%), and 17.3% (30.7%), respectively (p
Failure

p Value
0.002

10.4


24.3 19.8

NS 10.00 1

24.8 37.6

of 5,683 Patients With Myocardial to Type of Heart Failure

Absent (n = 2,908)

Age (yrsl Men (%) Diabetes mellitus (“‘X) Systemic hypertension (%) Previous myocordiol infarction (“A) Anterior infarction (%) Non-Q-wave infarction (%) Thrombolytic therapy (%) Ventricular fibrillation (%) Ventricular tachycardio (%) Wall motion index 1 -year mortality (%) 3.year mortality (%)

After Day 2 (n = 416)

74 (58-87) 60.1 21.4 24.1 55.1

Baseline Characteristics to Discharge in Relation

Characteristics

On Days 1 to2 (n = 1,700)

Heart


Infarction

Persistent (n = 2,092) 72 (55-85) 64.0 15.3

24.8 33.3 35.6 18.7

34.3 6.4

14.4 1.2 (0.7-2.0) 25.2 46.9

p Value
NS 0.001
Relation of congestive and wall motion index:

heart failure

The relation The p value given is between transient and persistent heart failure. between wall motion index and the time of developing CHF for 5,987 patients alive at day 6 and having a wall motion index determined is TABLE IV Relation of Wall Motion Index and Onset of Congestive Heart Failure in shown in Table IV. In general, the 5,987 Patients Alive at Day Six After infarction lower the wall motion index the Wall Motion Index more patients had CHF, but 28 paCongestive Heart 0.8-l .2 1.3-l .6 >1.6 ~0.8 tients had a wall motion index <0.8 (n = 283) (n = 2,022) (n = 1,538) (n = 2,144) Failure and no clinical signs of CHF. Most patients (61.5%) had a wall motion Absent 28 (9.9) 635 (3 1.4) 838 (54.5) 1,442 (67.3) (n = 2,943) index > 1.2 (corresponding to LV History of 148 (52.3) 418 (20.7) 167 (10.9) 195 (9.1) ejection fraction >35%), but even (n = 928) in that group, 38% (1,402 of 3,682) Developed day 1 or 2 86 (30.4) 778 (38.5) 430 (28.0) 406 (18.9) at some stage had clinical CHF. (n = 1,700) Developed after day 2 21 (7.4) 191 (9.5) 103 (6.7) 101 (4.7) Thus, there is a considerable over(n = 416) lap in the wall motion index values for patients with and without CHF. Number of patients with percentages of patients with same wall motion index in parentheses. The relation between wall motion index and CHF (separated into days, after myocardial infarction. Characteristics of transient and persistent) is shown in Table V. In papatients divided in groups according to the time of tients with transient CHF l-year (3-year) mortality developing CHF are listed in Table II. Wall motion was 9.3% (20.4%) when wall motion index was index did not differ between patients who developed > 1.2, and 15.8% (3 1.2%) when wall motion index CHF within the first 2 days and those who developed was 5 1.2. The corresponding mortality of patients CHF later. Patients with late onset of CHF had the with persistent CHF was 13.6% (36.7%) and 29.9% 1126

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index after a myocardial infarction in a large population into “Transient” -. of consecutive patients in a small geographic area, Wall Motion Index Denmark. The principal finding is Congestive that both CHF and reduced wall mo<0.8 0.8-l .2 1.3-l .6 >1.6 Heart Failure (n = 236) (n = 1,862) (n = 1,483) (n = 2,102) tion index predict mortality independently of each other. Only apAbsent 27 (1 1 .4) 624 (33.5) 827 (55.8) 1,430 (68.0) (n = 2,908) proximately 40% of the patients had Transient 17 (7.2) 212 (11.4) 187 (12.6) 267 (12.7) both a wall motion index > 1.2 (LV (n = 683) ejection fraction >0.35) and‘ no Persistent 192 (81.4) 1,026 (55.1) 469 (3 1.6) 405 (19.3) signs of CHF, which is lower than (n = 2,092) that reported in an earlier study Number of patients with percentages of patients with sane wall motion index in parentheses. which, however, did not include consecutive patients.5 In general, the lower the wall motion index the greater the proTABLE VI Risk Ratios of Congestive Heart Failure in 5,987 portion with CHF, but a large variability of wall moPatients With Myocordial Infarction and Alive at Day Six* tion index distribution is seen in patients both with Wall Motion Number of and without CHF. This adds to the general knowlIndex Patients % Heart Failure Risk Ratio’ edge of CHF as not just depending on systolic LV function. There was no estimation of mitral insuffi<0.8 283 90.1 3.9 (1.8-8.3) 0.8-l .2 2,022 68.6 2.6 (2.1-3.1) ciency or diastolic dysfunction. 1.3-l .6 1,538 45.5 2.1 (1.7-2.6) Interaction: If wall motion index and CHF did not >1.6 2,144 32.7 1.9 (1.5-2.3) interact, the risk ratios of CHF would be similar at Total 5,987 50.7 2.8 (2.5-3.1) different levels of LV function. Also, the risk ratio ‘Subgrouped according to leh ventricular systolic function. of wall motion index would have been the same ir‘Risk rotlo is adjusted for age and gender. respective of the presence of CHF. There was a significant interaction showing that reduced LV func(54.2%), whereas the mortality for patients without tion and CHF augment the risk associated with each CHF was 5.6% (13.4%) and 9.8% (19.5%), respec- other. For prognostic reasons it is important to contively. In a multivariate analysis with age and gender, sider both, as well as the combination, in evaluatng the risk ratio of CHF was 2.8 (2.5 to 3.1). Repeating the patient with myocardial infarction. Transient heart failure: Some patients (approxithe multivariate analyses with different types of CHF patients with a history of CHF before their new in- mately 10%) have CHF after infarction, which later farction had a risk ratio of 4.0 (3.5 to 4.6). The risk resolves and these patients are usually discharged ratio of CHF developed on day 1 to 2 was 2.3 (2.0 without diuretic treatment. These patients have better to 2.6), and after day 2, it was 2.4 (2.0 to 2.8). The preserved LV function than patients with persistent risk ratio of persistent CHF was 2.8 (2.5 to 3.2) and CHF (median wall motion index 1.6 vs 1.2). How1.5 (1.3 to 1.S) for transient CHF, which did not ever, this study has shown that these patients have show any interacton with wall motion index (p = an intermediate prognosis between patients without NS). The risk ratio of transient CHF was 1.5 (1.1 to CHF and patients with persistent CHF. More ag2.0) when wall motion index was I 1.2, and 1.4 (1.1 gressive treatment of these patients may be needed. Patients with transient CHF were included in the to 1.S) when wall motion index was > 1.2. The risk ratio of decreasing 1 wall motion index Acute Infarction Remipril Efficacy study,14 and in unit was 3.0 (2.6 to 3.4) in patients with CHF, and this important subgroup it appeared that angiotensin2.2 (1.7 to 2.9) in patients without CHF when ad- converting enzyme inhibition probably did not imjusted for age and gender. The risk ratio of CHF prove the prognosis. However, this may not be the for different levels of wall motion index is shown case if follow-up for this group of patients was to be in Table VI. An interaction of CHF and wall mo- extended for several years. Development of heart failure: This study showed tion index is found with a p value
of Wall Motion Index and Congestive Heart and “Persistent” in 5,683 Patients Discharaed

CONGESTIVE

HEART

Failure Separated Alive After Infarction

FAILURE/CONGESTIVE

HEART

FAILURE AFTER MYOCARDIAL

INFARCTION

1127

stay differed considerably, which may have influenced the diagnosis of CHF. Thus, CHF could be detected at a late stage during hospital stay, whereas the reliability of wall motion index as a prognostic factor depends on 1 single measurement in this study. 1. Beming .I, Steensgaard-Hansen F. Early estimation of risk by echocardiographic determination of wall motion index in an unselected population with acute myocardial infarction. Am .I Cardiol 1990,65:567-576. 2. Ong L, Green S, Reiser P, Morrison .I. Early prediction of mortality in patients with acute myocardial infarction: a prospective study of clinical and radionuelide risk factors. Am J Cardiol 1986;57:33-38. 3. Kelly MJ, Thompson PL, Quinlan MF. Prognostic significance of left ventricular ejection fraction after acute myocardial infarction. A bedside radionuelide study. Br Heart J 1985;53:16-24. 4. Dwyer EM, Greenberg HM, Steinberg G, and The Multicenter Postinfarction Research Group. Clinical characteristics and natural history of survivors of pulmonary congestion during acute myocardial infarction. Am J Cardiol 1989;63:1423-1428. 5. Gottlieb S, Moss AI, McDermott M, Eberly S. Interrelation of left ventricular ejection fraction, pulmonary congestion and outcome in acute myocardial infarction. Am J Cardiol 1992;69:977-984. 6. Wamowicz MA, Parker H, Cheitlin MD. Prognosis of patients with acute pulmonary edema and normal ejection fraction after acute myocardial infarction. Am J Cardiol 1983;67:330-334.

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