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European Journal of Heart Failure 2004 6(1):71-77; doi:10.1016/j.ejheart.2003.09.008
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© 2004 European Society of Cardiology

Importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction

Erik Kjøllera,*, Lars Køberb, Kasper Iversenc, Christian Torp-Pedersend Trace Study Group

a Department of Cardiology S 105, Herlev University Hospital, DK-2730 Herlev, Denmark
b Department of Cardiology Rigshospitalet, DK-2100 Copenhagen Ø, Denmark
c Cardiology Clinic, Medical Center Amager Hospital, DK-2300 Copenhagen S, Denmark
d Department of Cardiology Bispebjerg University Hospital, DK-2400 Copenhagen NV, Denmark

* Corresponding author. Tel.: +45-44-88-42-17; fax: +45-44-53-27-02. E-mail address: erikj{at}herlevhosp.kbhamt.dk, lk{at}heart.dk, ctp{at}heart.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: To evaluate the importance of chronic obstructive pulmonary disease for prognosis and diagnosis of congestive heart failure in patients with acute myocardial infarction.

Methods and results: Prospective registration of 6669 consecutive patients admitted with infarction and screened for a randomised controlled trial. A history of COPD was present in 765 (11.5%) patients. Thirty-day and 5-year survival in patients with chronic obstructive pulmonary disease was 86.3 and 42.9%. In patients without pulmonary disease the figures were 87.7 and 57.5%, respectively, giving a relative risk of 1.49 (1.35–1.65). In multivariate analysis the relative risk was 1.15 (1.04–1.28). The prevalence of congestive heart failure was 65.9% in patients with chronic obstructive pulmonary disease and 52.0% in patients without. This difference was most distinct in patients with normal or only slightly decreased left ventricular systolic function. In patients without congestive heart failure, chronic obstructive pulmonary disease was of prognostic importance [RR=1.44 (1.17–1.78)], but not in patients with congestive heart failure [RR=1.09 (0.96–1.23)].

Conclusion: Chronic obstructive pulmonary disease is a predictor of long-term mortality in patients with acute myocardial infarction without congestive heart failure, but is also a confounding factor for the diagnosis of congestive heart failure.

Key Words: Acute myocardial infarction • Chronic obstructive pulmonary disease • Heart failure • Prognosis • Diagnosis

Received November 12, 2002; Revised May 14, 2003; Accepted September 15, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The prognosis after acute myocardial infarction (AMI) is most frequently described in relation to well-known risk factors and complications observed during hospitalisation—but rarely is the importance of other common diseases included in the analyses. One very important and overlooked entity is chronic obstructive pulmonary disease (COPD)—a condition which in itself is a well-known risk factor for premature death [1] and which also is a condition where the symptoms may mimic signs of congestive heart failure (CHF)—known to be of major prognostic importance in AMI. The aim of the present investigation was to study the importance of a history of COPD for the prognosis after a myocardial infarction—and to unravel whether COPD causes an apparent overdiagnosing of CHF in this patient group.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Patients in this study were screened (and subsequently one-quarter randomised) for the TRAndolapril Cardiac Evaluation (TRACE) study, which was designed to evaluate the effect of trandolapril on mortality in patients with moderate to severe reduced left ventricular systolic dysfunction after AMI [2]. A detailed description of the TRACE study and demographic information from the screened population has been reported previously [3]. Information was collected prospectively for all patients with AMI in 27 hospitals in Denmark. Consecutive male and female patients over 18 years old with AMI were screened and registered between day 1 and day 6 after onset of symptoms. The diagnosis was confirmed by the combination of chest pain and electrocardiographic changes suggestive of infarction or ischemia accompanied by an increase in cardiac enzymes to twice the upper normal value of the local hospital laboratory.

Between May 1, 1990 and July 7, 1992 a total of 7001 consecutive episodes of AMI were evaluated in 6676 patients. In seven patients information on COPD had not been obtained and for the present study excluded. The study population thus consisted of 6669 patients.

Baseline data as well as in hospital complications were collected for all patients, enabling a detailed description of the entire screened population, irrespective of whether they were eligible and subsequently entered into the TRACE study. History of COPD was obtained from hospital records or from questioning the patient. If information relied solely on the patient, treatment by specific inhalation or oral medication for COPD was required. Pulmonary function was not available for all patients but used if known. However, results of pulmonary function were not registered. Congestive heart failure was defined as either a history of heart failure treated medically (history of CHF) or development of a Killip class of I or higher at any time during the hospitalisation for the index infarction (new CHF). Medical treatment for CHF had to consist of at least one diuretic drug given specifically for the diagnosis of CHF. Investigators were asked to complete case record forms describing worst Killip class every second day for the initial 6 days of the hospital stay. This ensured a high focus on registration of whether CHF developed. All Danish residents have a unique Central Personnel Register number and all deaths taking place within the country are recorded using this number. Interrogating the Central Personnel Register where all deaths in the country are registered within 2 weeks checked mortality status of all screened patients after at least 5 years of follow up.

2.2. Echocardiography
At the time of screening an echocardiographic examination was recorded on videotape by the investigator and sent to a core laboratory, where the Wall Motion Index (WMI) was calculated by two people using the nine-segment model described by Heger et al. [4]. The evaluation was performed blinded to other information. Segmental scores and WMI were calculated as described by Berning and Steensgaard-Hansen [5]. The validation of this method has previously been published [6]. In this model –1 represents dyskinesia, 0 akinesia, 1 hypokinesia, 2 normokinesia and 3 hyperkinesia. With this reverse scoring system a normal left ventricle has a WMI of 2.0. A WMI of 1.2 corresponds to an ejection fraction of 35% [7].

2.3. Ethics
The TRACE study was registered with the Danish National Board of Health and the Danish Data Protection Agency, and was approved by all local ethics committees in Denmark. Patients were informed about the study both orally and in writing before written consent was obtained.

2.4. Statistical analyses
The baseline characteristics of patients with and without COPD were compared using the chi-square test for discrete variables and the Kruskal–Wallis test for continuous variables. For continuous variables the median and the 5 to 95 percentiles are quoted. Survival curves were generated with the use of Kaplan–Meier estimates using log-rank test for significance. Multivariate analyses and relative risk were calculated as a hazard ratio (and denoted relative risk throughout the paper) derived from the Cox proportional-hazards regressions using a backward selection procedure initially including relevant baseline variables (referred to in Table 1). For continuous variables the hazard ratio is given per unit. For the analyses of subgroups, estimates of hazard ratio (relative risk) and the associated 95% confidence intervals were generated with a Cox proportional-hazard model. The assumption of Cox-models—proportional hazard assumption, interaction, linearity of continuous variables—were tested and found valid. Calculations were performed with the SAS software (SAS Institute, Cary, North Carolina). All tests of statistical significance were two-tailed, and P-values of <0.05 were considered significant.


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  		Table 1 Characteristics of 6669 patients with and without anamnestic chronic obstructive pulmonary disease (COPD)

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
A history of COPD was present in 765 (11.5%) patients. The difference between the baseline characteristics in patients with and without COPD is shown in Table 1. Patients with COPD were older than patients without COPD, but no gender difference was present between the two groups. Patients with COPD were smokers or ex-smokers more often than patients without COPD. In patients with COPD only 14.4% had never smoked opposed to 28.8% in patients without COPD. Previous CHF was recorded more often in patients with COPD, whereas hypertension was found more frequently in patients without COPD. Left ventricular systolic function measured as WMI was significantly lower in patients with COPD as was the prevalence of atrial fibrillation. Thrombolysis was not given as frequently to patients with COPD than to patients without. Newly developed CHF was recorded as frequently in patients with COPD as in patients without.

Based on the diagnostic problem of separating symptoms of COPD and CHF and the high prevalence of recording CHF in patients with COPD, further tests for CHF were performed. WMI was used as an objective quantitative sign of and supportive for diagnosing congestive heart failure. The correlation between WMI and CHF is not strong but it would be assumed that the relation between CHF and WMI was not dependent on the presence of COPD. This analysis is shown in Table 2. Altogether 53.6% of the population had previous or new CHF with increasing prevalence with decreasing WMI and yet 33.4% of patients with normal left ventricular function (WMI>1.6) were reported to have CHF. The prevalence of CHF was significantly higher in patients with COPD than in patients without, especially in patients with normal or only slightly decreased left ventricular systolic function. These differences are mainly due to a higher prevalence of a history of CHF as opposed to newly developing CHF in patients with COPD (also in patients with normal left ventricular systolic function).


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  		Table 2 Prevalence of previous and/or new congestive heart failure (CHF) in relation to left ventricular Wall Motion Index (WMI) in patients with and without chronic obstructive pulmonary disease (COPD)

 
Overall survival curves according to the presence or absence of COPD are shown in Fig. 1. Patients with anamnestic COPD had a 30-day survival of 86.3% and a 1-, 3- and 5-year survival of 72.2, 54.8 and 42.9%. In patients without COPD the corresponding figures were 87.7, 77.5, 66.1 and 57.5%, respectively. In univariate analyses the relative risk (RR) of COPD was 1.49 (95% confidence interval 1.35–1.65; P=0.0001).


Figure 1
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  		Fig. 1 Survival curves for 6669 patients with acute myocardial infarction in relation to concomitant chronic obstructive pulmonary disease (COPD).

 
The results of multivariate backward selection analyses after including all variables that either at univariate analyses were of prognostic importance and/or occurred with significant difference in the groups with or without COPD, are shown in Table 3. COPD still had long-term prognostic value after including other important variables, RR=1.15 (1.04–1.28).


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  		Table 3 Relative risk of death following acute myocardial infarction

 
In multivariate analyses COPD was without prognostic value in smokers [RR=1.11 (0.96–1.28)] and in ex-smokers [RR=1.14 (0.93–1.38)], whereas COPD was of prognostic importance in never-smokers [RR=1.35 (1.05–1.73); P-value for interaction=0.03].

Due to the correlation between COPD and congestive heart failure (Table 2), further multivariate analyses were performed. In patients without CHF, COPD was of prognostic importance (RR=1.44, 1.17–1.78), but not in patients with CHF [RR=1.09 (0.96–1.23)]. Overall survival is shown in Fig. 2. The relative risk of COPD in patients without previous CHF was 1.19 (1.05–1.36) but no increased risk was found in patients with previous CHF (RR=1.09, 0.92–1.30). In patients with new CHF, COPD was without prognostic importance [RR=1.02 (0.86–1.21)]. The relative risk of COPD in patients without new CHF was 1.38 (1.21–1.57). The figures were unchanged if patients with previous CHF are excluded. The increased relative risk of COPD in patients without CHF was present if WMI was greater than 0.8.


Figure 2
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  		Fig. 2 Survival curves in relation to congestive heart failure (CHF) and concomitant chronic obstructive pulmonary disease (COPD).

 
As the analysis reflected a time period of up to 7 years it was important to see if the prognostic importance of COPD was present during the acute phase of AMI and if it disappeared rapidly. This was evaluated by performing tests only looking at death occurring up to 30 days after the infarction. In univariate analysis COPD was associated with a relative risk of 1.12 (0.90–1.36). In multivariate analysis COPD was without prognostic importance [RR=0.89 (0.68-1.11)] for the initial 30 days.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The principal finding of this study is that concomitant COPD is a predictor of long-term mortality in patients with AMI but only in patients without CHF. Only two studies have taken concomitant pulmonary disease into consideration when describing the prognoses following AMI. In the study by Behar et al. [8] COPD was not important for hospital prognosis or 5-year survival. Multivariate analysis was performed but the study did not include objective signs of heart failure such as an objective measure of left ventricular systolic function. In a clinical database study [9] with 201 752 patients, followed 24 months after discharge with the purpose of evaluating the prognostic importance of beta-blocker treatment, COPD was of prognostic importance in univariate analyses. The absolute or relative risk was not stated. Left ventricular ejection fraction was included, but multivariate analyses were not performed.

The results per se may not be surprising since the 5-year survival following admission for COPD is only 45% [1]. In epidemiological studies, other symptoms of pulmonary disease such as shortness of breath [10], chronic bronchitis, i.e. expectoration in more than 3 months within the last year, is accompanied by an increased risk of coronary death [11] just as chronic mucus hypersecretion is accompanied by an increased risk of death [12]. In epidemiological studies, objective signs of decreased lung function is followed by an increased risk [13]. In a 29-year follow-up study the adjusted hazard ratios, for all-cause mortality in the lowest quintile of Forced Expiratory Volume in 1st second (FEV1) in percent of predicted compared with the highest quintile, were 2.24 for men and 1.96 for women [14].

The prognostic importance of COPD has been seen in relation to a history of COPD being recorded in 11.5% of patients, a large number of patients. In the only study dealing with a similar question [8] the prevalence of COPD was 7%. In a prospective clinical database study with 139.057 Medicare AMI patients, prevalence of COPD was 22.7% in men and 18.1% in women [15,16]. In patients with stable ischaemic heart disease without signs of heart failure a decreased pulmonary function was observed in 60% [17]. In the reported study, no correlation was found between pulmonary function and left ventricular systolic function. In patients with heart failure the prevalence was 18–20% [18] and twice as high as in patients without heart failure [19].

Accurate information on the prevalence of ischaemic heart disease in patients with stable COPD is unknown, but following acute exacerbation of COPD the prevalence is 21% [20]. The prevalence of airway obstruction (FEV1/FVC<60%) [forced vital capacity (FVC)] in the age group 40–70 years is 7% for men and 4% for women [21,22]. Left ventricular dysfunction is rarely seen in patients with COPD, except in patients with known ischaemic heart disease [23,24].

Corresponding to this, prior myocardial infarction did not add prognostic information in patients discharged following acute exacerbation of COPD, but an electrocardiographic diagnosis of ischaemic heart disease, increased the hazard ratio to 1.42 (1.02–1.96) [20]. The importance of heart failure in this context is unknown.

In patients with AMI, clinical symptoms and signs of CHF are prognostically the most important information. The inaccuracy of these in relation to diagnosing heart failure are reviewed in the recent guidelines on heart failure [25]. In patients with suspicion of heart failure all signs and symptoms have low positive and negative predictive values [26–29]. The uncertainty of diagnosing heart failure is accentuated by a considerable inter-individual variation at observing these symptoms and signs in patients with AMI [30]. This lack of agreement on observations and in the clinical diagnosis of heart failure is supported by the present study, where a history of CHF is found more often in patients with COPD. This is in agreement with a recently published study in patients referred for CHF from general practitioners to a tertiary centre. Decreased pulmonary function (FEV1 and FVC) and increased body weight was found more often in patients with clinical heart failure than in patients without [31] and independent of left ventricular ejection fraction. In a similar study with 106 patients referred due to suspected heart failure and where a clinical diagnosis of heart failure was made—in spite of good left ventricular function—other explanations than diastolic dysfunction were found in 94% of the patients [32]. The explanatory symptoms were overweight in 37%, decreased FEV1 (<70%) in 50% and decreased peak-flow (<70%) in 92%. These problems in diagnosing heart failure are probably the reason that self-reported CHF could only be confirmed by investigation in 73% of men and 77% of women [33]. Similar diagnostic problems are present with an acute episode of dyspnoea where the clinician has to evaluate if the dyspnoea is caused by left ventricular failure and/or decreased pulmonary function. In patients admitted to the emergency department due to moderate or severe dyspnoea, peak expiratory flow measurement did not help to differentiate between CHF or chronic pulmonary disease [34]—also when mixed presentations of CHF and COPD were excluded along with other diagnoses producing respiratory distress. All of this may lead to CHF being over-diagnosed. The present study stresses the uncertainty of (anamnestic) CHF in relation to anamnestic COPD and is a limitation of this type of study. Still COPD is prognostically important, in addition to other clinical information.

The only previous study to have focused on the prognostic importance of concomitant COPD in patients with AMI [8], found a higher Killip classification, more frequent radiological signs of congestion and more clinical CHF in patients with chronic bronchitis or airway obstruction than in the group without. In a subpopulation of AMI Medicare patients under the age of 65 years, prior CHF [and decreased ejection fraction (<35%)] is more frequent in patients with COPD than in patients without [15]. The number of patients with decreased ejection fraction was, however, limited: 7.8–9.3%.

In conclusion, COPD is a long-term prognostic factor following AMI, but is also a confounding factor for the diagnosis of CHF. The consequence of these diagnostic problems, the prognostic importance of concomitant COPD and the frequency of pulmonary disease in patients with AMI suggests that more advanced evaluation of right and left ventricular function, including estimation of volume, diastolic (dys)function and valve dysfunction may be necessary. Another possibility could be measurement of brain natriuretic peptide, which to some extent is able to distinguish between cardiac and pulmonary dyspnoea [35] and/or routinely performing objective measurements of pulmonary function in patients with AMI.


   Acknowledgements
 
The TRACE study was supported by a grant from Knoll AG, Ludwigshafen, Germany and Roussel Uclaf, Paris, France.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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