Use of non-invasive cardiac investigations topredict clinical endpoints after coronary bypassgraft surgery in coronary artery disease patients:results from the prognosis and evaluation of riskin the coronary operated patient (PERISCOP)study

Philippe Selliera*, Gilles Chatellierb, Marie C. D'Agrosa-Boiteuxc,Herve Douardd, Claude Duboise, Pierre C. Goepfertf,Catherine Monpe`reg, Alain Saint Pierreh, on behalf of the investigatorsof the PERISCOP studyaService de readaptation cardiaque, Hopital Broussais, 96 rue Didot-75014, Paris, FrancebDepartement d'informatique hospitalie`re, HEGP, 20-40 Rue Leblanc, Paris, FrancecClinique Medicale cardio-pneumologique, 63830 Durtol, FrancedService de cardiologie, Hopital cardiologique du Haut Leve`que, Avenue de Magellan 33604 Pessac,FranceeService de chirurgie cardiovasculaire, Hopital Foch, 40 Rue Worth, 92151 Suresnes, FrancefDepartement de Reeducation, Hopital Brabois, Avenue du Morvan, 54500 Vandoeuvre le`s Nancy, FrancegCentre Bois-Gibert, BP 37510 Ballan-Mire, FrancehCabinet Medical, 1 Rue des Belges, 69006 Lyon, France

Received 20 November 2002; revised 14 January 2003; accepted 14 January 2003

Aims Little is known about which patients who have undergone coronary bypasssurgery are at risk of future clinical cardiovascular events and may benefit fromfurther medical treatment. We sought to determine if routine non-invasivecardiac investigations performed early after surgery were able to stratify the risk ofcardiovascular events in this population.Methods Two thousand and sixty-five consecutive patients were enrolled in a prospec-tive multicenter study (PERISCOP). Exercise testing, echocardiography, and 24-hambulatory ECG monitoring were performed at day 2010 after coronary bypasssurgery. Follow-up was performed 1 year after coronary bypass surgery. Causes of allhospitalisation and death occurring within 1 year were documented and classified byan End-point Committee. The principal endpoint was the combination of all-causedeaths and cardiovascular events requiring hospitalisation (myocardial infarction,unstable or severe angina, stroke, congestive heart failure).Results The 1-year frequency of first events was 155 (8%). In multivariate analysis,exercise duration

depression >1 mm (RR1.90; 95% CI: 1.183.05), and left ventricular (LV) dysfunction(wall motion index

aneurysm resection, carotid intervention), did nothave an artificial pacemaker, or contraindication orinability to perform an exercise test, and werewilling and able to participate in the follow-up1 year after discharge were included in the study.Written informed consent was obtained from allstudy participants.

Sample size

According to the available literature, cardiovascu-lar mortality in this population was estimated to be1% per year.13 After a 1-year follow-up, 10 deathsfor 1000 included patients were expected. Based onthe results of the 4S study,19 we could expect fourto five events requiring hospitalisation (myocardialinfarction, acute coronary events, myocardialrevascularisation) for one death. As a whole, 4050major events for 1000 patients (a 45% event rateper year) were expected. According to Peduzziet al.,20 the description of a valid multivariatestatistical model requires at least 10 events perpredictive variable. We therefore decided toinclude 2000 patients, giving between 100 and 120major events requiring hospitalisation, and allow-ing us to describe a 10-variable predictive model.

Non-invasive cardiac evaluation

The PERISCOP study comprised three mandatorycardiac explorations, one symptom-limited exer-cise test, one 24-h ambulatory ECG recording, andone echocardiography. These three cardiac testshad to be performed between 10 and 30 days aftercoronary artery bypass surgery.

To validate LV function evaluation by echo-cardiography in comparison to reference radio-nuclide LV angiography, a sub-study was set up. Incentres where appropriate equipment was avail-able, LV function (ejection fraction) was also evalu-ated by radionuclide LV angiography under thesame treatment and at a few days interval.

Exercise testThe exercise test was performed on an ergometricbicycle using the same standardised protocol.Briefly, the test began with a starting level of 30 W,with a 10-W increase per minute. This symptom-limited test was stopped if the patient complainedof angina, dyspnoea, or fatigue. In the absence ofsymptoms, the test was stopped according to theRecommendations of the European Society ofCardiology.21 The test was considered abnormal ifat least one of the following characteristics waspresent: ST segment depression >1 mm compared

to baseline, horizontal or downsloping, measured0.06 s after J point, in leads V4, V5, or V6; frequentor complex premature ventricular contractions orruns of ventricular tachycardia; or drop in systolicblood pressure >10 mmHg or absence of bloodpressure increase during two successive stages.Exercise duration was recorded for each patient.

EchocardiographyLV systolic function was determined using the wallmotion index (WMI), which has been previouslyvalidated22 as a method to estimate risk after myo-cardial infarction. The LV wall kinetics were evalu-ated in nine segments and a score between 1 and+3 was attributed according to the segmentalventricular wall motion and thickening.

Continuous 24-h ambulatory ECG monitoringThe following were considered abnormal:ischaemic episodes with ST segment depression>1 mm in comparison to baseline, horizontal ordownsloping, measured 0.06 s after J point, formore than 60 s, separated from the precedent oneby more than 1 min; ventricular arrhythmias withthe number of premature ventricular contractionsand episodes of ventricular tachycardia.

Data collection

At enrolment, participants were interviewed andunderwent a complete clinical examinationperformed by the cardiologists participating in thestudy. Clinical data and results of the cardiac testswere recorded in a standardised case report form.

One year after coronary artery bypass surgery, aself-administered questionnaire was sent to allpatients by the rehabilitation centres. Patients hadto record detailed information about their clinicalcondition and the occurrence of any medical eventleading to hospitalisation, and to send back thisquestionnaire to the rehabilitation centre. When ahospitalisation had occurred, the coordinatingcentre obtained all necessary information from thepatient's cardiologist, general practitioner, or theadmitting hospital (discharge summary, investiga-tion reports, etc.). When a patient was lost tofollow-up (no answer to the questionnaire), hisfamily and the city hall of the town in which he wasborn were contacted to find out whether he haddied. An End-point Committee comprising threetrained senior physicians then validated and classi-fied all events using a set of pre-defined rules.Finally, data were entered (double entry) in acomputerised database for statistical analyses.

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Study endpoints

The study end-points were all-cause deaths andnon-fatal cardiovascular events (new or recurrentmyocardial infarction, unstable or severe angina,stroke, congestive heart failure) requiring hos-pitalisation during the 1-year follow-up period. Toavoid multiple statistical tests, the primary out-come measure was defined as the combination ofall-cause deaths and the defined cardiovascularevents. In patients with multiple events, only thefirst event was considered. All statistical analyseswere performed using this composite end-point.

Statistical analysis

Statistical associations between occurrence of theoutcome and prognostic variables were tested byPearson's chi-square test for categorical variablesand either t-test (Gaussian variables) or non-parametric tests (non-Gaussian variables) for con-tinuous variables. The risk of all-cause deaths andcardiovascular events was estimated by theKaplanMeier method, and the significance ofthe difference between two survival curves wasassessed by the logrank test. Multivariate analysisof associations between outcome and prognosticfactors were done by Cox's proportional hazardsmodel. We included all variables that were signifi-cant in univariate analysis, plus age and sex sincethese are usually strongly associated with the inci-dence of cardiovascular disease. We checked theproportional hazards assumption by plottingKaplanMeier curves. To comply with the hypoth-esis of proportional hazards, continuous variableswere dichotomised using either standard thresholds(ST depression >1 mm, LV ejection fraction

(1.7%). Eighteen were of cardiac origin, mainly dueto sudden death (n8) or heart failure (n5).Among the 17 non-cardiovascular deaths, 13 weredue to cancer. Of the total of 159 events or deaths,155 (8% of the total included population) were firstevents (Table 3).

Predictors of poor outcomeUnivariate analysisAmong the clinical variables including sex, riskfactors, history of myocardial infarction, andnumber of coronary vessels involved, only gender(p0.041), smoking habits (proportion of events 10vs. 6.7%, p0.041), and occurrence of a cardiovas-cular event before discharge from the rehabilita-tion centre (proportion of events 12.6 vs. 7.2%,p0.013) were predictive of the 1-year incidenceof death or non-fatal cardiovascular events. Theresults of initial non-invasive investigations inpatients experiencing at least one end-point (groupA) and in patients without end-point (group B) arecompared in Table 4.

Exercise testA large majority of the patients (1778: 86%) werereceiving one or several antianginal therapy at thetime of exercise testing (betablockers: 66%; cal-cium channel blockers: 32% nitrates: 16%; amio-darone: 17%). There was no significant relationshipbetween the presence of exercise induced STdepression >1 mm and a history of myocardialinfarction. A positive exercise test was found in 119out of 1312 patients (9%) without a history ofmyocardial infarction and in 56 out of 753 (7.4%)patients with a history of myocardial infarction(p0.53).

The rate of cardiovascular events and deaths at1 year was 12.4% in the group of patients who had apositive exercise test (exercise induced ST depres-sion >1 mm) and 7.2% in those who had a negative

test (p0.016). The prognostic value of exercisetesting is summarised in.Table 4 Heart rate, systolicblood pressure at rest, and systolic blood press-ure at peak exercise did not differ significantlybetween the two groups. The percentage ofpatients with exercise induced ST segment depres-sion >1 mm, abnormal systolic blood pressureresponse, and exercise duration differed signifi-cantly between group A and group B. When combin-ing these exercise test abnormalities, the risk ofcardiovascular events and deaths in patients with 0,1, 2, and 3 abnormalities was 4.7, 8.3, and 17.5%,respectively (p

exercise test (p0.0028) (Fig. 5). Patients witha WMI

of coronary arteries involved, had no independentprognostic value in our study. The absence of pre-dictive value of age may be explained by the factthat the follow-up was limited to 1 year in thisstudy and that most of the events occurred after1 year in other studies.5 In contrast, the presence ofevents during the rehabilitation programme had ahigh predictive value, probably because this com-posite clinical variable reflects the expertise of theclinician which has already been emphasised inother studies.7

Studies of risk stratification in patients who haveundergone coronary bypass surgery are rare. Mosthave been based on preoperative data.4,5,2527 In

these studies, the significant prognostic factorswere age, number of coronary arteries involved,and LV dysfunction. It is important to note thatthe event rate during the follow-up period of thePERISCOP study was similar to that observed inother published studies.5,28 Also, the few studies ofthe prognostic value of the presence of ischaemicepisodes during 24-h ambulatory ECG monitoringafter coronary bypass surgery concluded that thisfactor was unable to identify patients at high risk ofcardiac events during follow-up.14,15 On the otherhand, although exercise thallium-201 scintigraphymay identify patients at high risk of future cardio-vascular events, this investigation is not widelyavailable and was shown to increase the cost fromUS$553 to US$1285 per patient identified to be at

Table 4 Prognostic value of non-invasive investigations (univariate analysis)

Variables Whole population(n=2023)

With events(n=155)

Without events(n=1868)

pvalue

Exercise testMean resting heart rate (b/min) 80.315 80.216 80.415 0.91Mean peak heart rate (b/min) 115.321 112.222 115.621 0.06Mean resting systolic blood pressure (mmHg) 124.217 123.719 124.317 0.66Mean peak systolic blood pressure (mmHg) 164.827 160.929 165.227 0.06Peak ST segment depression >1 mm (%) 8.4 13.5 8.0 0.016Abnormal systolic blood pressure response (%) 5.5 11 5.1 0.002Exercise duration (s) 430169 372167 435168

high risk.17 Furthermore, poor exercise capacitywas considered a much stronger predictor ofdeath and major events than thallium-perfusiondefects.17 Any comparison with the study per-formed by Miller et al.18 is hardly possible: first,this study was retrospective; second, the evalua-tion investigation (thallium-201 imaging) was per-formed later than in PERISCOP study (within 2 yearsafter coronary bypass surgery). Interestingly, theauthor found that exercise variables alone werepredictive of mortality and myocardial infarction.

In patients with recent myocardial infarction,risk stratification by exercise testing has shown theprognostic value of similar variables: short durationof exercise,9 occurrence of ST segment depression>1 mm,7,8 exercise induced premature ventricularcontractions, and abnormal systolic blood pressureresponse.9 The prognostic value of alteration in

LV function has already been assessed inpost-myocardial infarction patients, with aninverse relationship between LVEF and 1-year mor-tality.11 The LVEF threshold determined as a nega-tive factor in the latter study was close to 0.40, afigure which was comparable in our study.

The prognostic value of ambulatory ECG moni-toring after myocardial infarction is more contro-versial. The presence of ischaemic episodes isrelated10 or is not related29 to an increased risk offuture cardiovascular events. The results of thepresent study show only a trend in favour of theprognostic value of the presence of ischaemic epi-sodes after coronary bypass surgery. The presenceof frequent premature ventricular beats has beenshown to be an independent risk factor of total andsudden death in the large GISSI-2 trial involving8676 patients.30 This was not found in the PERISCOPstudy, perhaps because only one-third (753) of thepatients only had a history of myocardial infarction.

Our results are in keeping with those of Myerset al.,31 who showed that exercise testing, andparticularly peak exercise capacity, was a strongerpredictor of an increased risk of death than clinicalvariables or established risk factors in a populationof patients with cardiovascular risk factors orestablished coronary artery disease.

Limitations of the study

Firstly, the inclusion of patients only at thebeginning of a cardiac rehabilitation programme1520 days after the intervention may have induceda bias because this study did not take into account

Fig. 4 KaplanMeier survival curve of the proportion ofpatients remaining free of cardiovascular events according toexercise induced ST segment depression (1 mm inleads V4V6).

Fig. 5 KaplanMeier survival curve of the proportion ofpatients remaining free of cardiovascular events according toexercise systolic blood pressure response abnormalities.

Fig. 6 KaplanMeier survival curve of the proportion ofpatients remaining free of cardiovascular events according toWMI (cut-off value 1.15). LVEF, left ventricular ejectionfraction.

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the events which occurred during the first 2 or3 weeks after coronary bypass surgery. However,the objective of the PERISCOP study was not toassess the short-term post-operative prognosisafter coronary bypass surgery. And the rate ofevents occurring during the early post-operativeperiod is limited, around 3% in the first month aftercoronary bypass surgery.5

Secondly, as the ability to perform an exercisetest was an inclusion criterion, patients with thepoorest prognosis may have been excluded from ourstudy population. Patients unable to perform anexercise test are usually a high-risk group ofpatients.7 However, the percentage of coronarybypass surgery patients excluded for this reasonwas very low in the PERISCOP study (less than 1%)and may not bias the study.

Thirdly, the size of the population prevented acentralised analysis of cardiac investigations forlogistic reasons and this may have induced a lack ofprecision in the results. However, all the cardiacinvestigations were performed in rehabilitationcentres where these techniques are routinelyperformed by trained physicians. Moreover, anyheterogeneity among investigators would only havedecreased the value of the hazard ratio, andthus would not have masked any significantrelationships.

Fourthly, the follow-up period of the study wasvoluntarily limited to 1 year. So our study wasunable to detect prognostic factors related to laterevents.

Furthermore, by using a self-administeredquestionnaire, we may have missed some events.However, the number of patients who did notanswer to the questionnaire is very small (2%). Andif we may have been missed some events, there isno reason to think that there is a relation-ship between missing events and the results ofnon-invasive evaluation.

Finally, the extent to which cardiac rehabilita-tion influenced the prognosis of our coronary arterydisease patients after coronary bypass surgerycould not be assessed because, to our knowledge,there is no evidence available in the literature toanswer this question. However, all our patientsunderwent a similar cardiac rehabilitation pro-gramme at the same time after coronary bypasssurgery. Furthermore, as coronary bypass surgeryis widely accepted as an indication to cardiacrehabilitation, the conclusions of this study arefully applicable to the whole population ofpost-CABG patients.

Clinical implications

This study demonstrates that in post-coronarybypass surgery patients, low-cost, non-invasiveevaluation, especially by exercise testing, canidentify a subgroup of patients at high risk of futureevents. The risk of an event at short or mediumterm after coronary bypass surgery is still present,confirming that myocardial revascularisation doesnot completely protect the patient. Consequently,it is important to ensure that appropriate evidence-based medical therapy is used in all patients, andshould be reinforced in those patients who are athighest risk of future events. The occurrence ofcardiac events in coronary bypass surgery patientswho are often already receiving medical treatmentsuggests that further improvement, especially insecondary prevention, is needed to achieve optimalmanagement of these patients.

AcknowledgementsThis study was undertaken by the Working Group onFunctional Evaluation and Cardiac Rehabilitation ofthe French Society of Cardiology, with grant sup-port from NOVARTIS PHARMA. We thank all theinvestigators who made this study possible. We

Table 5 Cox proportional analysis of the prognostic factors of death or cardiovascular events in 1998 patients

Variable Hazard ratio 95% CI p value

Age (years) 1.01 0.991.03 0.217Gender (male=1) 1.54 1.002.38 0.051Current smoker 1.70 1.192.43 0.004No. of coronary vessels involved

2 vs. 1 2.10 0.894.95 0.0883 vs. 1 1.82 0.794.17 0.159

Presence of post-operative events (yes=1) 1.70 1.062.72 0.027Exercise duration (1 mm 1.90 1.183.05 0.008Abnormal SBP response (yes=1) 1.59 0.922.73 0.094LV dysfunction (WMI

also thank Mrs Pamela Johnson for reviewing themanuscript.

Appendix A

List of investigators: B. Avias (83406 Giens-Hyeres), J.M. Feige (84000 Avignon), J. Garaix(83407 Hyeres), M. Ferriere (34295 Montpellier), C.Rocca (38660 St Hilaire du Touvet), S. Frolichman(69565 Saint Genis Laval), K. Sourdais (23000 SainteFeyre), M.C. D'Agrosa-Boiteux (63830 Durtol), H.Ducrot (42400 Saint Chamond), M. Bousquet (31650Saint Orens de Gameville), J. Breton (82500Beaumont de Lomagne), J.L. Breda (66240 SaintEsteve), M. Fischbach (33150 Cenon), Pic (33950Lege Cap Ferret), Borgat (44474 Carquefou), Pavy(44270 Machecoul), J.P Marty (17138 Puilboreau),J. Le Henaff (86021 Poitiers), Monnet de Lorbeau(41600 Lamotte-Beuvron), Monpere (37510 BallanMire), P. Guillo (35044 Rennes), L. Michel (29684Roscoff), P. Sellier (75014 Paris), Fattell (91000Evry), D.M. Marcadet (75116 Paris), O. Stechepin-sky (50190 Saint Martin d'Aubigny), Belin (14360Trouville sur mer), S. Corone-Alden (91640 Briissous Forges), F. Larrazet (77174 Villeneuve SaintDenis), C. Cabanis (78605 Maisons Laffitte), C.Puechavy (78740 Evecquemont), P. Aeberhard(93200 Saint Denis), Dominique (80800 Corbie), P.Delelis (59160 Lomme), D. Souris (57038 Metz), J.J.Maureira (54201 Dommartin-les-touls), M. Ross(57560 Abreschviller), Kessler (57565 Niderviller),R. Grudet Bald (68460 Lutterbach), Verges (21000Dijon), P. Poncelet (62590 Oignies).

Executive committee: P. Sellier, G. Chatellier,E. Dufour (Novartis Pharma), C. Dubois, A. Costa.

Scientific committee: P. Sellier (Chairman),C. Dubois, G. Chatellier, P.C. Goepfert, M.C.D'Agrosa-Boiteux, C. Monpe`re, H. Douard, A,Saint-Pierre.

End-point committee: A. Costa, C. Dubois,P. Sellier.

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IntroductionMethodsPatientsSample sizeNon-invasive cardiac evaluationExercise testEchocardiographyContinuous 24-h ambulatory ECG monitoring

Data collectionStudy endpointsStatistical analysis

ResultsGeneral characteristics of the cohortIncidence of eventsPredictors of poor outcomeUnivariate analysisExercise testEchocardiographyTwenty-four hour ambulatory ECG monitoring

Survival curvesMultivariate analysis

DiscussionLimitations of the study

Clinical implicationsAcknowledgementsReferences