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Archives of cardiovascular diseases
Volume 110, n° 1
pages 35-41 (janvier 2017)
Doi : 10.1016/j.acvd.2016.04.003
Received : 14 December 2015 ;  accepted : 20 April 2016
Effect of left ventricular systolic dysfunction on secondary medical prevention and clinical outcome in stable coronary artery disease patients
Impact de la dysfonction systolique ventriculaire gauche sur la prévention secondaire et le pronostic en cas de maladie coronaire stable
 

Nicolas Lamblin a, b, c, Thibaud Meurice d, Olivier Tricot e, Gilles Lemesle a, c, Michel Deneve a, Pascal de Groote a, b, Christophe Bauters a, b, c,
a CHRU de Lille, 59037 Lille, France 
b Inserm U1167, Institut Pasteur de Lille, université Lille Nord de France, 59000 Lille, France 
c Faculté de médecine de Lille, 59045 Lille, France 
d Polyclinique du Bois, 59003 Lille, France 
e Centre hospitalier de Dunkerque, 59240 Dunkerque, France 

Corresponding author. Hôpital Cardiologique, CHRU de Lille, boulevard Professeur-Leclercq, 59037 Lille cedex, France.
Summary
Background

Limited recent data are available in the literature on whether the presence of left ventricular systolic dysfunction (LVSD) affects the therapeutic management of patients with stable coronary artery disease (CAD).

Aims

The objectives of this study were to analyse prevalence, effect on therapeutics and prognosis of LVSD in stable CAD.

Methods

We prospectively included 4184 CAD outpatients free from any myocardial infarction or coronary revascularization for>1year. Left ventricular ejection fraction (EF) was available for 4124 (98.6%) patients. Follow-up was performed at 2years. All events were adjudicated blindly.

Results

The mean EF was 57.5±10.8%, and 201 (4.9%) patients had an EF35%. The prescription of renin–angiotensin system inhibitors and beta-blockers was inversely related to EF, and reached>90% in patients with EF35%. Seventy-five (37.3%) of the patients with EF35% received a mineralocorticoid receptor antagonist. Eighty-five (42.3%) of the patients with EF35% had an implantable cardioverter defibrillator. Clinical follow-up data were obtained for 4090 patients (99.2%). Event rates were higher in patients with low EF (adjusted hazard ratio [95% confidence interval] for EF35%, with EF60% as reference: 3.93 [2.60–5.93] and 7.12 [3.85–13.18], for all-cause death and cardiovascular death, respectively).

Conclusions

In patients with stable CAD, LVSD is well taken into account by cardiologists, with extensive use of evidence-based medications and interventions. Despite this, LVSD remains a major prognostic indicator in this population.

The full text of this article is available in PDF format.
Résumé
Contexte

Il n’existe que peu de données concernant l’impact de la dysfonction systolique ventriculaire gauche (DSVG) sur la prise en charge des patients présentant une maladie coronaire stable.

Objectif

Analyser la prévalence, l’impact sur les thérapeutiques, et le pronostic de la DSVG en cas de maladie coronaire stable.

Méthodes

Nous avons inclus 4184 patients coronariens ambulatoires, sans antécédent d’infarctus du myocarde ou de revacularisation coronaire<1an. Une mesure de fraction d’éjection ventriculaire gauche (FEVG) était disponible pour 4124 (98,6 %) patients. Le suivi clinique a été réalisé après 2ans. Tous les événements ont été adjudiqués en insu.

Résultats

La FEVG moyenne était de 57,5±10,8 % et 201 (4,9 %) des patients avaient une FEVG35 %. La prescription d’antagonistes du système rénine–angiotensine et de bêta-bloquants variait en sens inverse de la FEVG et atteignait>90 % en cas de FEVG35 %. Au total, 37,5 % des patients avec FEVG35 % recevaient une anti-aldostérone ; 42,3 % des patients avec FEVG35 % avaient un défibrillateur automatique implantable. Un suivi clinique a été réalisé pour 4090 patients (99,2 %). Les événements étaient plus fréquents en cas de FEVG basse (HR ajustés [IC 95 %] pour une FEVG35 % [FEVG>60 % en référence] : 3,93 [2,60–5,93] et 7,12 [3,85–13,18], pour la mortalité totale et la mortalité cardiovasculaire, respectivement).

Conclusion

En cas de maladie coronaire stable, la DSVG est bien prise en compte par les cardiologues avec une large utilisation des thérapeutiques et interventions recommandées. En dépit de ce niveau de prise en charge, la DSVG demeure un facteur pronostique majeur dans cette population.

The full text of this article is available in PDF format.

Keywords : Coronary artery disease, Ejection fraction, Prognosis

Mots clés : Maladie coronaire, Fraction d’éjection, Pronostic

Abbreviations : ACEI, ARB, CAD, CI, EF, HF, ICD, HR, LVSD, MI


Background

Left ventricular function is a key determinant of outcome in patients with coronary artery disease (CAD), and therefore the subgroup with left ventricular systolic dysfunction (LVSD) deserves specific therapeutic management [1, 2]. According to recent guidelines [3, 4], there are general secondary prevention measures that apply to all CAD patients, and additional recommendations when the ejection fraction (EF) is<35–40%. However, practice patterns for CAD patients vary considerably [5], and limited recent real-life data are available in the literature on whether the presence of LVSD truly affects therapeutic management in patients with stable CAD. We addressed this question in a population of CAD patients at a distance from any coronary event (i.e. at least 1year after any myocardial infarction [MI] or revascularization procedure). We also analysed the prognostic implications of LVSD in the modern era of stable CAD management.

Methods
Study population

CORONOR (suivi d’une cohorte de patients COROnariens stables en région NORd-pas-de-Calais ) is a prospective multicentre registry that included 4184 consecutive outpatients with stable CAD between February 2010 and April 2011 [6, 7]. The patients were included by 50 cardiologists from the Nord-Pas-de-Calais region in France. Patients were considered eligible if they had evidence of CAD, defined as at least one of the following criteria: previous MI (>1year ago); previous coronary revascularization (>1year ago); and/or obstruction of50% of the luminal diameter of at least one native coronary vessel on coronary angiography. The sole exclusion criterion was hospitalization for MI or coronary revascularization within the previous year.

This study was approved by the French medical data protection committee (CCTIRS) and was authorized by the Commission nationale de l’informatique et des libertés (CNIL) for the treatment of personal health data. All patients consented to the study after being informed via a written document of the objectives of the study and the treatment of data, as well as their rights to object, of access and of rectification.

Study design and follow-up

A case record form, which contained information regarding demographic and clinical details of the patients, including the usual cardiovascular risk factors and treatments, was completed prospectively at the initial visit by the investigators (i.e. the cardiologists). During the outpatient visit, the investigators reviewed the current treatment and entered in the case record form the treatment to be prescribed afterwards. EF was not assessed prospectively at inclusion; the investigators reported in the case record form the most recent echocardiographic assessment of EF that was available for the patient. A 2-year follow-up was performed at outpatient visits or by contacting the general practitioner as well as the patient. In case of any hospitalization during the follow-up period, hospital records were reviewed for evidence of cardiovascular events. As previously described [6], all clinical events were adjudicated by two investigators, and by three investigators in case of disagreement, according to prespecified definitions. The cause of death was determined after a detailed review of the circumstances of death, and was classified as cardiovascular or non-cardiovascular. Deaths from unknown causes (n =15) were classified as cardiovascular.

Statistical analysis

Continuous variables are described as means±standard deviations. Categorical variables are presented as absolute numbers and/or percentages. The distribution of EF was divided into four categories (≥60%, 59–46%, 45–36% and ≤35%). Categorical and continuous variables were compared using the χ2 test and analysis of variance (ANOVA), respectively. Cumulative event rates were estimated using the Kaplan–Meier method, and were compared using the log-rank test. Cox proportional hazard analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). For each variable, the proportional hazards assumption was tested visually using Kaplan–Meier curves, and by examining a plot of –ln [–ln (survival time)] against ln (time). In addition, the proportional hazard was assessed and satisfied by including an interaction time-dependent term in the multivariable Cox regression analysis. All statistical analyses were performed with STATA® 9.2 software (STATA Corporation, College Station, TX, USA). Statistical significance was assumed at a P value<0.05.

Results

The baseline characteristics of the 4184 patients included in the CORONOR study have been reported [6]. CAD was confirmed by coronary angiography in nearly all patients (99.2%). A measurement of EF was reported by the cardiologist for 4124 patients (98.6%). The mean EF was 57.5±10.8%. More than half of the patients (55.2%) had an EF60%, 29.4% had an EF between 59% and 46%, 10.5% had an EF between 45% and 36%, while 4.9% (n =201) had an EF35%.

As shown in Table 1, there were significant differences in baseline characteristics according to EF. Patients with low EF more frequently had a history of diabetes mellitus, atrial fibrillation, stroke, MI and multivessel CAD; they also had more frequently a history of hospitalization for heart failure (HF). By contrast, age did not differ among the four groups. Although the rates of history of myocardial revascularization overall were high in all groups, history of coronary stenting was more frequent in patients with high EF, while history of coronary bypass was more frequent in patients with low EF.

Cardiovascular treatments according to EF are shown in Table 2. Nearly all patients received an antithrombotic drug, with more use of anticoagulants and slightly less use of antiplatelet agents in case of low EF. The use of statins was high, and not different among EF groups. Although already high when EF was normal, the prescription rates for angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) and beta-blockers further increased in patients with low EF, and reached>90% when EF was35%. With few exceptions, the use of mineralocorticoid receptor antagonists was restricted to patients with left ventricular systolic dysfunction (one-third of patients with EF35%). Patients with low EF more often received loop diuretics, and less often received calcium antagonists and thiazides. In addition, among the 201 patients with an EF35%, 85 (42.3%) had received an implantable cardioverter defibrillator (ICD).

Clinical follow-up data were obtained for 4090 patients (99.2%) at a median of 735days (Table 3). Overall, there were 267 (6.5%) deaths, 117 (2.9%) of which were cardiovascular. All-cause and cardiovascular mortality rates during follow-up were significantly higher in patients with low EF (Figure 1 and Table 3). In a multivariable model adjusting for age, sex, history of hypertension, diabetes mellitus, atrial fibrillation at inclusion, history of stroke, history of MI, multivessel CAD and estimated glomerular filtration rate<30mL/min/1.73m2, LVSD was independently associated with all-cause mortality (HR [for EF35% vs. EF60%] 3.93, 95% CI 2.60–5.93; P <0.0001) and with cardiovascular mortality (HR 7.12, 95% CI 3.85–13.18; P <0.0001). During the 2-year follow-up period, there were 89 MIs, 48 strokes and 229 coronary revascularization procedures, which were distributed equally among the four groups (Table 3). By contrast, there was an inverse and significant relationship between EF and the risk of hospitalization for heart failure (Table 3).



Figure 1


Figure 1. 

Clinical outcome in stable coronary artery disease patients according to left ventricular ejection fraction. Kaplan–Meier curves during 2-year follow-up for all-cause death and cardiovascular death. Patients are divided into four groups according to left ventricular ejection fraction at inclusion: ≥60%, 59–46%, 45–36% and35%.

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Discussion

While there have been numerous reports on the level of EF at time of hospital discharge after MI [8, 9, 10, 11, 12] or at time of revascularization procedures [13, 14], the prevalence of LVSD in patients with stable and chronic CAD, at a chronological distance from any acute event or revascularization, is less well known. Our results show that in modern practice, the prevalence of LVSD among stable CAD patients is relatively low. Our observation that EF was35% in 4.9% of cases, and 45–36% in 10.5% of cases, is concordant with data from the Euro Heart Survey of Stable Angina, in which left ventricular function was described as “poor” and “moderately impaired” in 3% and 17% of cases, respectively [15]. Our results are also in line with the data from a recent French cohort, in which EF was<35% in 5.1% of cases, and 44–35% in 10.8% of cases [16].

According to recent guidelines, the presence of LVSD in CAD patients identifies a high-risk group that should benefit from intensive preventive therapies [3, 4]. The present study provides information on how LVSD may influence the therapeutic management of stable CAD patients in real-life practice. Our results demonstrate that an EF measurement is available for a great majority (98.6%) of patients with stable CAD, and that its level is well taken into account by physicians when prescribing secondary prevention medications. Although overall cardiovascular treatments were widely used in the CORONOR registry, patients with lower EF were more likely to receive the three major classes of HF/LVSD evidence-based medications: ACEIs/ARBs, beta-blockers and mineralocorticoid receptor antagonists. The incentive to use these treatments was evident for patients with an EF35%, but already detectable for lower levels of LVSD. As previously reported for overall populations of patients with stable CAD [17, 18], the proportions of patients with LVSD receiving anti-thrombotics and statins were very high, demonstrating that the prevention of vascular events remains an important concern, even when cardiac dysfunction is present. In addition to medical prevention, it should be pointed out that>40% of the patients with an EF35% had an ICD; this rate compares favourably with data from a recent Medicare registry of patients with an EF35% after MI, in which only 8.1% received an ICD [19].

Although the deleterious prognostic effect of LVSD in patients with CAD is long established [20], the exact magnitude of the effect in modern clinical practice is not well known. Our data – obtained in the context of high use of evidence-based medications and devices – demonstrate that LVSD remains a major independent predictor of mortality and morbidity in this setting, and suggest a need for further efforts to reduce the risk. One option would be to further improve medical therapy, and it should be noted that, since recruitment in the present study, there have been new studies suggesting possible refinements to HF/LVSD management, such as ivabradine for patients with a heart rate70beats per minute [21], eplerenone for patients with systolic HF and mild symptoms [22] and, very recently, angiotensin receptor–neprilysin inhibition rather than angiotensin-converting enzyme inhibition [23]. Alternatively, selected patients with LVSD could be considered for implantable assist devices and/or cardiac transplantation.

Study limitations

There was no prospective assessment of EF in the present study. We used the EF value that was entered in the case record form at inclusion by the investigators. By protocol, this value had to be the most recent echocardiographic assessment of EF available for the patient, and a request was not made to repeat/perform echocardiography at time of inclusion. This should be considered as a study limitation, but it should also be recognized, on the other hand, that requiring a prospective echocardiographic assessment at inclusion in the registry would certainly have induced a selection bias. In addition, the last EF value known by the physician makes sense when it comes to analysing the therapeutic management of the patients according to EF. Moreover, the recent demonstration in patients with stable multivessel CAD included in the MASS II study that EF remains preserved in the absence of recurrent MI after 10years of follow-up [24], suggests that the “last known EF value” can reasonably be used instead of EF at inclusion time. Lastly, the fact that the distribution of EF in the present study was nearly the same as in the study by Tabet et al. [16], in which a prospective echographic assessment was performed, supports the validity of our data. As this was primarily a study of stable CAD, several variables that could have been of interest for the present analysis, such as the presence/absence of mitral regurgitation and also the rate of patients with cardiac resynchronization therapy, were not available in our database. Finally, it must also be emphasized that our data reflect the practice in a regional area, and therefore cannot be directly extrapolated to other parts of the world.

Conclusion

In patients with stable CAD, LVSD is well taken into account by physicians, with extensive use of evidence-based medications and interventions. Despite this, LVSD remains an important predictor of altered outcome.

Source of funding

This study was supported by the Fédération française de cardiologie, Paris, France.

Disclosure of interest

The authors declare that they have no competing interest.

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