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European Journal of Echocardiography 2007 8(4):275-283; doi:10.1016/j.euje.2007.02.005
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Copyright © 2007, The European Society of Cardiology

Predictive value of local and core laboratory echocardiographic assessment of cardiac function in patients with chronic stable angina: The ACTION study

Anthony M. Darta,*, Jan Erik Otterstadb, Bridget-Anne Kirwanc, John D. Parkerd, Sophie de Brouwerc, Philip A. Poole-Wilsone and Jacobus Lubsenc,f

aCardiovascular Medicine, Alfred Hospital, Melbourne, Victoria, Australia
bDivision of Cardiology, Vestfold Hospital, Toensberg, Norway
cSOCAR Research, Nyon, Switzerland
dDivision of Cardiology, University Health Network and Mount Sinai Hospitals, Toronto, Ontario, Canada
eCardiac Medicine, Imperial College, London, UK
fDepartment of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands

Received 2 August 2006; received in revised form 5 February 2007; accepted after revision 14 February 2007.

a.dart{at}alfred.org.au

* Corresponding author. The Heart Centre, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia. Tel.: +61 3 9076 3232; fax: +61 3 9076 2495.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Aims To evaluate the relationship between echocardiographic cardiac function and outcome in patients with stable symptomatic angina.

Methods Baseline echo left ventricular ejection fraction and volume data measured in a central laboratory was available for 7016 patients (92% of the total) participating in the ACTION trial (A Coronary disease Trial Investigating Outcome with Nifedipine GITS). Ejection fraction was also measured by investigators. Evaluation of the different echocardiographic variables was based on adjusted hazard ratios comparing the unfavourable limit of the 90% range of the variable concerned to the favourable limit.

Results The centrally measured ejection fraction was the most powerful predictor of all-cause death (adjusted hazard ratio=2.5), myocardial infarction, any stroke or transient ischaemic attack and overt heart failure (adjusted hazard ratio=4.5). The addition of either end systolic volume or end diastolic volume to ejection fraction did not materially affect the power of prediction. Compared to the central ejection fraction measurement, the investigator-measured ejection fraction was a less powerful predictor for all outcomes considered.

Conclusion Routine echocardiography carefully analysed by standardised methods provides useful prognostic information in patients with stable angina, including for total mortality.

Keywords: Coronary artery disease; Angina; Left ventricular function; Echocardiography; Prognosis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Major predictors of outcome after myocardial infarction include age and left ventricular volumes and function.1,2 However, the predictive value of echo variables for adverse cardiovascular events in patients with chronic stable symptomatic coronary artery disease remains unknown.

The ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) trial3–5 was designed to assess the efficacy and safety of long-acting nifedipine GITS (gastro-intestinal therapeutic system) in patients with stable symptomatic coronary artery disease. In total 7665 patients were included, and were followed for a mean of 4.9years. In the mid 1990s there was vigorous debate about the utility of calcium channel antagonists in the treatment of cardiovascular diseases6–8 and concern about their safety in patients with heart failure.9 Because of these concerns, patients with clinical signs of heart failure and those with a left ventricular ejection fraction below 40% were excluded from the ACTION trial. Hence, all participants in ACTION underwent assessment of ejection fraction at baseline and an echocardiogram was recorded whenever technically possible. The availability of echocardiographic data for 92% of the ACTION cohort allowed us to determine whether these predicted adverse cardiovascular events, and whether the effect of nifedipine is modified by such data.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Patients
The design, methods and main results of the ACTION trial have been published previously.3,4 Briefly, after signing informed consent, ambulatory patients aged 35years or older with proven coronary artery disease and stable symptomatic angina pectoris requiring treatment were randomized in equal proportions to either nifedipine GITS or matching placebo in addition to current treatment. Major exclusion criteria included valvular heart disease, current presence of clinical signs of heart failure, and ejection fraction below 40% as assessed locally by echocardiography or another method if echocardiography was technically impossible.

The starting dose of nifedipine GITS or matching placebo was 30mg once daily, increasing to 60mg once daily within six weeks. Patients were seen at the out-patient clinic two weeks, six weeks and six months after study medication was started and from then onwards every six months.

Echocardiography
Two-dimensional (2D) echocardiography was attempted at baseline in all patients. When echocardiography was technically possible, the investigator assessed ejection fraction according to local routine, and decided on eligibility based on the value obtained. Locally obtained echocardiograms were recorded on videotapes and sent to the Core Laboratory for re-analysis. At the Core Laboratory, echocardiograms were analysed by a single ultrasonographer blinded to patient characteristics and treatment assignment. Endocardial boundaries of the left ventricular cavity from paired biplane (apical 4-chamber and apical 2-chamber) echocardiographic images were traced manually and then digitised at a computer work-station using commercially available software. Biplane left ventricular end-diastolic and end-systolic volumes were calculated by a validated10 modified Simpson's disc method according to the recommendations of the American Society of Echocardiography.11 Ejection fraction was estimated as (end diastolic volume – end systolic volume)/end diastolic volumex100%. All measurements were obtained as the median value for three different cardiac cycles.

Investigators were not required to postpone the start of study medication until the echocardiogram had been evaluated at the Core Laboratory.

Outcomes
We considered all cause death, myocardial infarction, new overt heart failure and the ACTION primary endpoints for efficacy and safety as determined by the critical events committee.4 The primary endpoint for efficacy included any death, myocardial infarction, refractory angina, new overt heart failure, debilitating stroke and peripheral revascularisation; the primary endpoint for safety was limited to any death, myocardial infarction and debilitating stroke. In this analysis, we also evaluated the occurrence of any stroke or transient ischemic attack, which included debilitating stroke as determined by the critical events committee; and any coronary procedure, which included coronary angiography, coronary artery bypass grafting and percutaneous coronary intervention.

Statistical methods
We analyzed all patients who participated in the ACTION trial who had baseline echocardiography suitable for central analysis. Baseline characteristics were tabulated by three strata of Core Laboratory ejection fraction measurement at baseline that were similar in size when using Ejection Fraction <45%, Ejection Fraction 45–50% and Ejection Fraction >50% as cut-off points. We used the Cochran-Armitage test for trend for categorical and linear regression tests for continuous variables to compare the strata.

All analyses for outcomes were based on intention to treat. Event-rates by deciles of echocardiographic variables were taken as the number of patients with event, divided by the total patient-years until event or end of follow-up for event (which could be either death or end of study). We used multivariate Cox proportional hazards analysis to assess which separate variables were conditionally independent predictors of outcome, and assessed combinations of ejection fraction with either end systolic volume or end diastolic volume in a similar manner. These analyses were always adjusted for the following baseline variables: age, gender, history of heart failure, history of myocardial infarction, systolic and diastolic blood pressure, and assignment to either nifedipine or placebo. We used interaction terms to evaluate whether the impact of echocardiographic variables on prognosis differed between patients with and without a history of myocardial infarction, and between patients with and without a history of heart failure prior to inclusion into the trial.

To compare the impact on prognosis of the ejection fraction as assessed by the investigator, and the ejection fraction, end systolic volume and end diastolic volume as assessed by the Core Laboratory respectively while allowing for their between-patient variability, we determined for each of these variables the 5th and the 95th percentiles of their distribution, and then calculated by Cox analysis adjusted hazard ratios and their 95% confidence intervals comparing the unfavourable with the favourable limit of the 90% range concerned (i.e. comparing the 5th with the 95th percentile for ejection fraction and the 95th with the 5th percentile for end systolic volume and end diastolic volume respectively).

To assess the additional impact on prognosis when adding either end systolic volume or end diastolic volume to ejection fraction in adjusted Cox models, we first determined for which events both ejection fraction and end diastolic volume, or ejection fraction and end systolic volume, were significant conditionally independent predictors. For each of the three different models for the events concerned (i.e. ejection fraction plus adjusting variables as mentioned earlier, the same model with end systolic volume added, and the same model with end diastolic volume added) we calculated the corresponding risk score for each patient by multiplying the coefficient of each covariate in the model with the value for the patient concerned and then summed the results. For each model we then determined the deciles of the corresponding score distribution, and plotted event rates by decile.

We also used Cox analysis to perform interaction tests between the effect of nifedipine on the outcomes considered and echocardiographic variables.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
Follow-up of the 7665 patients commenced on double-blind medication was 97.3% complete.4 649 of these were excluded from this analysis (116 because ejection fraction was determined by other means, 491 because no satisfactory echo was available for core laboratory analysis, 42 because baseline echo was not performed).

The local ejection fraction of the remaining 7016 patients (3519 nifedipine, 3497 placebo) ranged from 26% to 88%, with a mean of 56% and a standard deviation of 9%. Six patients were included notwithstanding a local ejection fraction below 40%. The Core Laboratory ejection fraction ranged from 16% to 79%, with a mean of 48% and a standard deviation of 6%. 501 patients had a Core Laboratory ejection fraction below 40%. The mean (standard deviation) Core Laboratory end systolic and end diastolic volumes were 86ml (29ml) and 165ml (44ml).

Table 1 shows baseline characteristics stratified by Core Laboratory ejection fraction (<45%, 45–50% and >50%). The percentage of men and the fraction of patients with a complicated cardiovascular disease history or diabetes increased across categories of decreasing ejection fraction. Patients with lower ejection fractions also had larger end systolic volumes and end diastolic volumes, higher pulse rates and higher systolic and diastolic baseline blood pressure measurements. Risk factors were more frequent among patients with lower ejection fractions. Patients with higher ejection fractions were more often treated with beta-blockers and acetylsalicylic acid. Organic nitrates, ACE-inhibitors or angiotensin receptor blockers, diuretics, vitamin K antagonists, and anti-arrhythmics were prescribed more frequently for patients with lower ejection fractions.


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  		Table 1 Baseline characteristics

 
The numbers of patients who sustained the events considered in this analysis and the corresponding even-rates are shown in Table 2. As shown in Fig. 1, the rates of death of any cause and of new overt heart failure were markedly related to ejection fraction, end diastolic volume and end systolic volume as determined at the Core Lab.


Figure 1
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  		Figure 1 Relationship between deciles of ejection fraction (panel A) or left ventricular systolic volume (panel B) and rates of all cause death and congestive heart failure. Hazard rates in number of events per 100 patient-years (pat-yrs) at risk.

 


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  		Table 2 Impact on prognosis of echocardiographic variables

 
Hazard ratios from local and Core Laboratory echocardiographic variables are compared in Table 2. The Core Laboratory ejection fraction was a significant predictor of all outcomes considered, except for refractory angina and percutaneous coronary intervention. Based on comparing unfavourable to favourable values derived from the same percentiles of their respective distributions (c.f. statistical methods), the Core Laboratory ejection fraction was a stronger predictor than the local ejection fraction, and was also a stronger predictor than either end systolic volume or end diastolic volume of all-cause death, myocardial infarction, any stroke, transient ischemic attack and new overt heart failure. The latter was the event most strongly related to echocardiographic variables: patients with a Core Laboratory ejection fraction value equal to its 5th percentile had 4.5 times the adjusted risk of patients with a value equal to its 95th percentile (95% CI 2.83–7.14). Adding relevant interaction terms to the respective Cox models showed that the results shown in Table 2 are the same for patients with and without a history of myocardial infarction, and for patients with and without a history of heart failure.

Ejection fraction and end systolic volume were significant conditionally independent predictors of both all-cause death and new overt heart failure in Cox models that contained both echocardiographic variables and other determinants of prognosis. The same applied to the combination of ejection fraction and end diastolic volume. Models for both events that contained either ejection fraction only, or ejection fraction and left ventricular volumes are compared in Fig. 2. Despite the statistical significance of the coefficients of either end systolic volume or end diastolic volume, overall prediction based on ejection fraction alone was similar to overall prediction based on ejection fraction in addition to either end systolic volume or end diastolic volume. The addition of either end systolic volume or EDF to models already containing ejection fraction did not significantly improve prediction for the any of the other events considered.


Figure 2
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  		Figure 2 Comparison of predictive power of models based on either ejection fraction alone, or ejection fraction plus end systolic volume or ejection fraction plus end diastolic volume. Deciles of the risk score for each model are plotted on the horizontal axis and rates of all cause death (upper panel) or cardiac heart failure (lower panel) are plotted on the vertical axis. Rates as number of events per 100 patient-years of follow-up.

 
The possibility that treatment with nifedipine GITS was associated with a detrimental effect amongst those at increased risk of developing new overt heart failure was then examined. Event rates by treatment group and hazard ratio comparing nifedipine to placebo for pre-specified outcomes by tertiles of baseline risk of cardiac heart failure based on a Cox model that included ejection fraction and adjusting variables are shown in Fig. 3. There was no significant interaction between the effect of nifedipine and baseline ejection fraction for any of the outcomes considered.


Figure 3
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  		Figure 3 Subgroup analyses for various endpoints, stratified for multivariate risk of congestive heart failure (Cox analysis). HR, hazard ratio; CI, confidence interval. Primary endpoint for efficacy: death from any cause, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke and peripheral revascularisation. Primary endpoint for safety: death from any cause, acute myocardial infarction, debilitating stroke. P-values for interaction. *Rates as number of events per 100 patient-years at risk. {ddagger}Tertile of multivariate risk of cardiac heart failure based on ejection fraction adjusted for age, gender, history of heart failure, history of myocardial infarction, systolic blood pressure, diastolic blood pressure, and assignment to either nifedipine or placebo.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
ACTION is thus far the largest randomised trial assessing the effect of treatment on outcome in patients with stable symptomatic angina. Several large cardiovascular trials have performed echocardiography either in subsets12,13 or in all patients14 but none have been in patients with stable angina. The main findings are that there was a clear relation between left ventricular global systolic function and volumes at baseline and a range of outcomes. These relationships were present despite that fact that the presence of clinical signs of heart failure and an ejection fraction of less than 40% as measured by investigators were ACTION exclusion criteria. There was no evidence that the use of nifedipine GITS was deleterious in subjects with an increased risk of developing new overt heart failure.

Echocardiograms in ACTION were analysed in a central core laboratory. Corroborating earlier findings,15 we found that the local measurement of ejection fraction had less impact on prognosis than the Core Laboratory measurement. A systematic difference between the two measurements cannot be the explanation of this but larger random error in local measurements could. The local ejection fraction values had larger between-patient variability (standard deviation=9.2%) when compared to the Core Laboratory values (standard deviation=6.4%). This can be attributed to a larger random error and/or between-centre differences as to how echocardiograms are analysed. Both would explain our findings.

The prognostic significance of severely impaired left ventricular systolic function is well established in patients with heart failure, including those in whom coronary artery disease as the underlying pathology.16,17 Similarly, the prognostic importance of left ventricular function in patients with recent myocardial infarction is also clear.18,19 This study has demonstrated that even in a relatively low risk population of patients with stable coronary disease but without heart failure, left ventricular systolic function at baseline is a strong predictor of outcome, even after adjustment for other major prognostic factors such as age, blood pressure and gender. Not surprisingly, there was a greater incidence of new overt heart failure in those with lower ejection fractions or increased left ventricular volumes at baseline. The precise mechanisms responsible for other demonstrated associations (e.g. myocardial infarction, stroke) cannot be determined from the available information but likely relate to a number of factors. These include an increased propensity to arrhythmias, thrombosis and systemic embolism.

A previous study suggested the prognostic importance of early remodelling within 3months of myocardial infarction.20 In the current study a recent (less than 3months) myocardial infarction was an exclusion criterion so those subjects with a previous myocardial infarction (approx 50%) had already undergone early remodelling.

The relationship between left ventricular ejection fraction and clinical outcome was curvilinear with evidence that an ejection fraction of less than 45–48% was associated with a poorer prognosis. Similar findings have recently been reported in a broad spectrum of heart failure patients.17 Subjects with an ejection fraction of less than 45% were more likely to have had a history of myocardial infarction, significant coronary stenoses and previous coronary revascularisation, in keeping with the likelihood that ischaemic heart disease was the major determinant of left ventricular dysfunction in this group. In addition subjects with an ejection fraction of less than 45% were more likely to have a history of hypertension and had higher blood pressures, suggesting that hypertension per se, may have contributed to left ventricular dysfunction in this group.

Similar prognostic information was provided by baseline left ventricular volumes although the associations were stronger for the Core Laboratory ejection fraction. A study in 605 male infarct survivors showed that end-systolic volume was statistically the most significant predictor of cardiac death.21 When end systolic volume or end diastolic volume were added to models that included the Core Laboratory ejection fraction, both end systolic volume and end diastolic volume were statistically significant conditionally independent predictors of death or new overt heart failure. However the addition of left ventricular volume data to ejection fraction had little effect on the overall prediction of the outcome. The addition of left ventricular volumes to models containing ejection fraction did not make an independent contribution to the prediction of any other end points.

The present results on the predictive value of echocardiography have implications also for its use in clinical trials. Because of their potential negative inotropic effect, the use of particularly first generation calcium channel blockers22,23 in patients with impaired left ventricular systolic function has been controversial and is not recommended by recent guidelines.24 Hence, patients with clinical signs of heart failure were excluded from the ACTION trial. In addition, a subgroup analysis by baseline ejection fraction was pre-specified in the protocol to elucidate whether nifedipine GITS might be contra-indicated in patients with lower ejection fractions. Our results show that, if the effect of nifedipine was indeed adversely affected by a low baseline ejection fraction, a subgroup analysis based on the core lab ejection might have shown this but an analysis based on the local ejection might not. This is so because the core lab ejection fraction was more strongly related to the risk than the local ejection fraction. From the present analysis it is evident that subjects with angina and no clinical signs of heart failure who are at high risk of developing heart failure because of lower ejection fractions and other factors are not adversely affected by nifedipine GITS. This conclusion from the ACTION trial would not necessarily have been warranted had only the local ejection fraction been available, and is supported by recent data from trials with amlodipine and slow release felodipine.25–27


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
This echocardiographic study in 7016 patients with stable symptomatic coronary artery disease showed that even in subjects without clinical signs of heart failure, left ventricular systolic function and left ventricular volumes are powerful predictors of outcome when quantified carefully using standardised methods. The addition of nifedipine GITS to standard treatment is safe in patients at higher risk of developing heart failure based on reduced cardiac function and other prognostic markers.


   Acknowledgement
 
The study was funded by Bayer Healthcare AG. The contribution of investigators, committee members and other study personnel as listed elsewhere is gratefully acknowledged. In particular, the contributions of all participating patients over the course of this prolonged trial are gratefully acknowledged.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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