Comparative effects of ventricular resynchronization therapy in heart failure patients with or without coronary artery disease

Annales de Cardiologie et d’Angéiologie 53 (2004) 171–176 www.elsevier.com/locate/ancaan

Original article

Comparative effects of ventricular resynchronization therapy in heart failure patients with or without coronary artery disease Comparaison de l’efficacité de la resynchronisation cardiaque chez les patients avec cardiomyopathie ischémique et non ischémique C. Leclercq a,*, D. Gras b, A. Tang c, C. Alonso a, F. Thomas-Revault d’Allones a, P. Mabo a, InSync Study Group a

Département de cardiologie et maladies vasculaires (Professor J. Claude Daubert), Centre cardio-pneumologique, Hôpital Pontchaillou-CHU, rue Henri le Guilloux, 35033 Rennes cedex 9, France b Clinique Saint-Henri, Nantes, France c University of Ottawa Institute, Ottawa, Canada Received 16 February 2004 Disponible sur internet le 10 mars 2004

Abstract In patients with advanced heart failure, intraventricular conduction delay (IVCD) and left ventricular systolic dysfunction (LVSD), multisite cardiac pacing can be proposed as an additive treatment. The aim of this study was to assess the clinical effectiveness of atrioventricular pacing according to the etiology of LVSD, by comparing the outcome of patients with and without coronary artery disease. Between August 1997 and November 1998, 103 patients were included in the InSync trial and received a biventricular pacemaker and a specifically designed left ventricular pacing lead. Baseline evaluation (12 lead ECG, New York Heart Association Class, quality of life (QOL) and distance walked during the 6 min walk test) was repeated in survival patients at 1, 3, 6 and 12 months after pacemaker implantation. Patients were split in two groups, ischemic (N = 48) and non-ischemic (N = 55), according the result of a recent coronary angiography, the existence of coronary angioplasty or coronary artery bypass or the history of a prior myocardial infarction. Results. – The mortality rate was similar in the two groups with a mean 12 months actuarial survival rate of 78%. Nevertheless, the delay between the death and the pacemaker implantation was significantly higher in the non-ischemic group. A significant reduction in QRS duration and a significant improvement in NYHA class (–1.5). QOL score (–50%) and 6 min walking test (+18%) were observed similarly in the two groups. Conclusion. – This study shows that biventricular pacing improves significantly functional status of patients with LVSD, IVCD and advanced heart failure, regardless the etiology of the cardiomyopathy, ischemic or not, without over-mortality in ischemic patients. © 2004 Elsevier SAS. All rights reserved. Résumé La resynchronisation ventriculaire par entraînement multisite a été proposée comme traitement des insuffisants cardiaques avec un délai de conduction intraventriculaire augmenté et une dysfonction ventriculaire gauche systolique. Le but de ce travail a été de comparer les effets du pacing multisite en fonction de l’étiologie de l’insuffisance cardiaque. Entre août 1997 et novembre 1998, 103 patients ont été inclus dans l’essai In-sync et ont été appareillés avec un pace-maker biventriculaire avec une électrode ventriculaire spécifique. L’évaluation initiale (ECG 12 dérivations, classe NYHA, questionnaire de qualité de vie, distance parcourue lors du test de marche de 6 minutes) a été répétée 1, 3, 6 et 12 mois après la pose du pace-maker. Deux groupes ont été constitués en fonction de la présence (n = 48) ou de l’absence (n = 55) d’une atteinte coronaire documentée par une coronarographie récente. Résultats. – La mortalité a été comparable dans les 2 groupes, avec une survie actuarielle à 12 mois de 78 %. Toutefois, le délai entre la pose du pace-maker et le décès était plus long dans le groupe non ischémique. L’évolution de la durée du QRS, l’amélioration de la classe fonctionnelle (–1,5), du questionnaire de qualité de vie (–50 %) et du test de marche de 6 minutes (+18 %) a été comparable dans les 2 groupes. * Corresponding author. E-mail address: [email protected] (C. Leclercq). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.ancard.2004.02.014

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Conclusion. – Cette étude montre que l’entraînement biventriculaire améliore significativement le statut fonctionnel des patients avec dysfonction systolique ventriculaire gauche, retard de conduction intraventriculaire et insuffisance cardiaque sévère, quelle que soit l’étiologie de la cardiopathie. En particulier, les patients ayant une dysfonction d’origine ischémique n’ont pas de surmortalité à un an. © 2004 Elsevier SAS. All rights reserved. Keywords: Heart failure; Cardiac pacing; Cardiac resynchronization Mots clés : Resynchronisation ; Entraînement électrosystolique ; Insuffisance cardiaque

1. Introduction Among the various non-pharmacological treatments that can be proposed for patients in advanced heart failure secondary to left ventricular systolic dysfunction (LVSD), multisite cardiac pacing has been since 1994 developed very encouragingly. The atrioventricular and intraventricular conduction disorders frequently noted in patients with LVSD have deleterious consequences on both left ventricular systolic and diastolic functions and may induce or enhance mitral valve regurgitation [1–5]. Multisite cardiac pacing, by trying to correct those electromechanical abnormalities, aims at improving the hemodynamics of those patients, hence their well being or even their survival. Encouraging results from acute hemodynamic studies [6–11] soon led to implanting multisite cardiac pacemakers in patients in advanced heart failure with LVSD and major intraventricular conduction delay (IVCD). Results from the first open studies showed that biventricular cardiac pacing brought about significant functional improvements in that population [12,13]. The InSync study is a multicenter, Canadian and European, prospective, non-randomized study designed to assess the feasibility, safety and effectiveness of permanent biventricular cardiac pacing using a specifically designed pacemaker and coronary sinus leads in advanced heart failure patients with IVCD [12]. The aim of this sub-study was to assess the clinical effectiveness of atriobiventricular pacing according to the etiology of LVSD, by comparing the outcome of patients with and without coronary artery disease. 2. Methods The inclusion criteria and the study design were those of the InSync trial [12]. 2.1. Inclusion criteria The inclusion criteria were: Severe heart failure (NYHA class III or IV) persisting for more than 1 month despite medical treatment considered as optimal and including at least angiotensin converting enzyme inhibitor (ACE) at the maximum tolerated dose and diuretics. LVSD defined by left ventricular ejection fraction (LVEF) <35% and LV end-diastolic diameter (LVEDD) >60 mm on echocardiography.

IVCD with a QRS duration >150 ms on surface ECG. Stable sinus rhythm. Age >18 years. Having signed informed consent. 2.2. Implantation procedure The pacemaker used in the study was of a model specially designed for atriobiventricular pacing (InSync Model 8040, Medtronic Inc. Minneapolis, MN). The pulse generator header includes a triple connector system for the separate connection of right atrial, right ventricular and left ventricular leads, permitting simultaneous delivery of pacing pulses to both right and left ventricles. Left ventricular pacing was ensured by a specific lead inserted in a tributary vein of the coronary sinus (Attain, Models 2187 or 2188, Medtronic Inc., Minneapolis, MN). The target location of the left ventricular lead was a lateral or posterolateral vein of the coronary sinus. If catheterization failed or pacing thresholds were too high, the left ventricular lead was inserted in the great cardiac vein or in the mid cardiac vein. Proper performance as the leads and pacemaker were checked at every stage of follow-up. 2.3. Data measured The following parameters were measured before pacemaker implantation: QRS duration, as measured on surface ECG (50 mm/s), NYHA functional class, distance covered during a 6 min walking test (6WD), and quality of life (QOL) rated with the Minnesota Living with Heart Failure questionnaire. Those various parameters were reassessed 1, 3, 6 and 12 months after pacemaker implantation. 2.4. Etiology classification Patients included in the InSync trial were split in two groups, ischemic and non-ischemic. Ischemic etiology was defined by the detection of significant coronary artery stenosis by recent coronary angiography, history of previous myocardial infarction (with Q wave on surface ECG) and/or previous coronary artery bypass surgery (CABG) or angioplasty. 2.5. Statistical analysis All results are presented as mean values ± standard deviation (S.D.). Baseline and 1, 3, 6, 12-month data are included.

C. Leclercq et al. / Annales de Cardiologie et d’Angéiologie 53 (2004) 171–176 Table 1 Patients’ baseline data

80%

P value <0.01 =0.01 =0.043 =0.84 =0.81 =0.87 =0.94 NS

NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; 6-min WD, 6-min walked distance; QOL, quality of life score (Minnesota Living with Heart Failure questionnaire).

A repeated measure analysis of variance was performed on the NYHA class, 6WD, QOL, and QRS duration data. When overall significance was obtained at ␣ = 0.05, Tukey’s studentized range test was used for all possible pairwise comparisons of follow-up visits. 3. Results 3.1. Patient characteristics Between August 1997 and November 1988, 117 patients were recruited. In 14 patients, the left ventricular lead could not be implanted or ventricular pacing thresholds were not acceptable. Finally 103 patients were included, whose heart disease was ischemic in 48 and non-ischemic in 55 of them. The clinical characteristics of patients in both groups are listed in Table 1. There were no significant differences in LVEF, QRS duration, QOL, 6WD or NYHA class (3.5 ± 0.5) between the two groups. Seventy percent of patients in both groups were in NYHA class III at the time of pacemaker implantation, and the rest were in Class IV. The proportion of men was higher in group 1 (ischemic) than in group 2 (nonischemic) (92% vs. 67%, respectively; P < 0.01) and patients were older in the ischemic group (70 ± 8 vs. 65 ± 12 years; P < 0.01). In the ischemic group, 43 patients had a history of myocardial infarction and 25 had received a CABG. Seventy percent of patients had a multi-vessel disease and 30% a two vessels disease. At inclusion, 93% of patients received a diuretic, 86% an ACE inhibitor, 58% had digoxine, 17% a beta-blocker, 17% an other vasodilator and 15% a calcium entry blocker. Treatments were not significantly different between the two groups. 3.2. Follow-up 3.2.1. Mortality (Fig. 1) At the end of a 12-month follow-up, 21 patients were deceased, making the actual survival rate in the overall population 78% (CI 95% of 70–87%). Survival was identical in both groups because 10 and 11 patients died in the ischemic group (survival = 79 ± 12%) and in the non-ischemic group

S u r v iv a l

44 (92%)/4 (8%) 70 ± 8 180 ± 29 22 ± 6 33(69%)/15 (31%) 3.3 ± 0.5 289 ± 93 55 ± 20

Non-ischemic (n = 55) 37 (67%)/18 (33%) 65 ± 12 176 ± 27 22 ± 8 37 (67%)/18 (33%) 3.3 ± 0.5 290 ± 122.5 52.5 ± 19.5

60% 40% 20% 0% 0

60

120

180

240

300

360

Days Post-Implant

Non-Ischemic

Ischemic

Fig. 1. Actuarial survival curves in both ischemic and non-ischemic patients.

(survival = 77 ± 12%), respectively. Causes of death were not significantly different between the two groups (Table 2): sudden cardiac death: 6/10 in group 1 and 4/11 in group 2; progressive pump failure: 2/10 in group 1 vs. 5/11 in group 2 and non-cardiovascular cause: 2/10 in group 1 vs. 2/11 in group 2. In contrast, the mean time interval between inclusion and death was significantly shorter in the ischemic group than in the non-ischemic one (58 ± 39 vs. 173 ± 129 days; P < 0.01). 3.2.2. QRS duration (Fig. 2) QRS duration was significantly reduced by biventricular pacing in both groups after 1 month (151 ± 23 vs. 180 ± 29 ms at baseline in the ischemic group (P < 0.01) and 150 ± 24 vs. 176 ± 24 ms at baseline in the non-ischemic group (P < 0.01). That reduction of QRS duration was sustained in both groups throughout the follow-up, with respective values of 151 ± 19 and 150 ± 26 ms at the end of FU. No Table 2 Causes of death Total death

Ischemic, N = 10 6 (60%) 2 (20%) 2 (20%)

Sudden cardiac death Progressive pump failure Non-cardiac causes

Non-ischemic, N = 11 4 (37%) 5 (45%) 2 (18%)

P value NS NS NS

QRS Width NS 180 milliseconds

Male/female Mean age (years) Mean QRS (ms) LVEF (%) NYHA class III/IV Mean NYHA Class 6-min WD (m) QOL score

Kaplan Meier Survival

100%

Ischemic (n = 48)

173

**

NS **

**

**

NS **

NS **

**

**

120 60 0

n=40 n=43

1 Month

n=33 n=36

3 Months

n=34 n=40

6 Months

n=34 n=28

12 Months

Ischemic Baseline

Ischemic Follow-up

Non-Ischemic Baseline

Non-Ischemic Follow-up

** p < 0.01 NS p > 0.05 Fig. 2. Intrapatient comparison of baseline (intrinsic) and paced QRS duration at 1, 3, 6 and 12-month follow-up in ischemic and non-ischemic patients.

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NYHA Functional Class NS

4

NS

**

3

**

**

Quality of Life

NS **

**

NS

80

**

**

**

60

2

40

1

20

0

n=43 n=44

1 Month

n=35 n=39

3 Months

n=35 n=40

6 Months

n=33 n=34

12 Months

0

NS **

NS **

n=37 n=39

1 Month

**

NS **

n=32 n=39

3 Months

**

NS **

n=33 n=36

6 Months

**

**

n=30 n=32

12 Months

Ischemic Baseline

Ischemic Follow-up

Ischemic Baseline

Ischemic Follow-up

Non-Ischemic Baseline

Non-Ischemic Follow-up

Non-Ischemic Baseline

Non-Ischemic Follow-up

** p < 0.01 NS p > 0.05

** p < 0.01 NS p > 0.05

Fig. 3. Intrapatient comparison of the baseline and pacing-related NYHA functional class at 1, 3, 6 and 12-month follow-up in ischemic and nonischemic patients.

significant difference in QRS duration was noted between the two groups in the course of follow-up. 3.2.3. NYHA class (Fig. 3) One month after pacemaker implantation, NYHA classification was sensitively improved in both groups, to mean values of 2.5 ± 0.7 in ischemic group and 2.2 ± 0.8 in non-ischemic group, to be related to the same baseline value of 3.5 ± 0.5 in both groups. That functional benefit, identical in both groups, was sustained in surviving patients throughout the follow-up, the mean value at 12 months being 2.2 ± 0.7 in both groups. 3.2.4. Six-minute walk distance (Fig. 4) The distance covered during the 6-min walk test was significantly increased in both groups at 1, 3, 6 and 12 months. Between baseline and 12 months, the distance increased by 21% in ischemic group (354 ± 70 vs. 289 ± 93 m at baseline; P < 0.01) and by 27% in non-ischemic group (370 ± 112 vs. 290 ± 122 m at baseline; P < 0.01). Such a functional benefit was identical in both groups. Distance Walked in 6 Minutes NS 400

**

NS **

**

NS **

**

NS **

**

**

m 300 200 100 0

n=31 n=31

1 Month

n=27 n=27

3 Months

n=26 n=30

6 Months

n=24 n=25

12 Months

Ischem ic Baseline

Ischem ic Follow-up

Non-Ischem ic Baseline

Non-Ischem ic Follow-up

** p < 0.01

NS p > 0.05

Fig. 4. Intrapatient comparison of the baseline and pacing-related 6-min walked distance at 1, 3, 6 and 12-month follow-up in ischemic and nonischemic patients.

Fig. 5. Intrapatient comparison of the baseline and pacing-related quality of life at 1, 3, 6 and 12-month follow-up in ischemic and non-ischemic patients.

3.2.5. Quality of life assessment (Fig. 5) QOL baseline score on the Minnesota Living with Heart Failure questionnaire was impaired in the overall population, with a mean score value of 53 ± 20, and no significant inter-group difference. After 1 month under biventricular pacing, the QOL score was significantly improved in both ischemic group (33 ± 18 vs. 55 ± 18.4 at baseline, P < 0.01) and non-ischemic group (31 ± 19 vs. 50 ± 18.5 at baseline; P < 0.01). Such a similar improvement in both groups was confirmed throughout follow-up, with mean scores at 12 months of 31 ± 21 and 30 ± 18 in surviving patients. 4. Discussion The results from this InSync trial sub-study show that biventricular pacing can significantly improve the functional class, exercise tolerance and QOL of patients with advanced heart failure with IVCD and LVSD, regardless of the ischemic or non-ischemic origin of their heart disease. Multisite cardiac pacing was proposed in 1994, as an adjuvant therapy for patients with advanced heart failure and IVCD. Results from early hemodynamic studies revealed that multisite cardiac pacing (either left ventricular or biventricular) significantly improved hemodynamic parameters (cardiac output, pulmonary capillary wedge pressure, +dP/dt, pulse pressure), in particular when QRS duration was greater than 150 ms [7–11]. These hemodynamic studies also showed that the lateral wall was probably the optimal site for left ventricular pacing [9]. Thanks to the development of leads specifically designed to pace the left ventricle via a tributary vein of the coronary sinus [14], permanent atriobiventricular pacing is now a reliable technique, which opens the way for prospective studies. The first results from permanent multisite cardiac pacing revealed significant functional improvement in patients with dilated cardiomyopathy and IVCD. The French pilot study assessed the long-term benefit of multisite cardiac pacing in 50 patients with advanced heart failure and major IVCD. At

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the time of implantation, 68% of patients were in NYHA class IV and 32% were in NYHA class III. During a mean follow-up duration of 15.4 ± 10.2 months, the patients’ functional status significantly improved by one NYHA class on average and near to 40% increase in VO2 peak [13]. The final results from the InSync prospective study confirmed the functional benefit of cardiac pacing in 103 patients in sinus rhythm [15]. Over a 12-month follow-up, NYHA classification improved by one class, the 6-min walk distance increased by 25% and QOL score was 40% higher. Preliminary results from the PATH-CHF study also demonstrate the functional benefit brought about by multisite pacing and a significant improvement of NYHA classification, QOL and VO2 peak [16]. The results of the MUSTIC and the MIRACLE trials, two controlled and randomized studies with different design (cross-over in MUSTIC and parallel in MIRACLE) confirmed the improvement in symptoms and exercise tolerance [17,18]. All these series involved patients with LVSD of ischemic and non-ischemic origin, thus questioning the weight of etiology on clinical course and outcome after pacemaker implantation. Cardiomyopathies of ischemic origin are thought to have a worse prognosis than non-ischemic heart diseases. So, a number of authors believe that the ischemic origin of LVSD is an independent predictive factor of mortality, with a relative risk of death between 1.5 and 2 [19–23]. In the EPICAL study, 1-year survival rate of patients with advanced heart failure was 69.1% in the non-ischemic group and 57.6% in the ischemic group (P < 0.03) [24]. However, that fact has not been confirmed by other authors [25,26]. One-year mortality in this study was identical in both groups of patients. The only significant difference was the interval between inclusion and death, which was shorter in the ischemic group, but for no obvious reason. In contrast, no difference in the causes of mortality was noted between the two groups; in particular, the proportion of sudden deaths was not higher in the ischemic group. One hypothesis to explain that lack of difference in mortality between the two groups could be that biventricular pacing has a preventive effect on ventricular arrhythmia, as suggested by Walker et al. and Higgins et al. [27,28]. The potential mechanisms of that effectiveness could involve: a decrease in plasma norepinephrine levels with biventricular pacing [29], avoidance of pausedependent tachyarrhythmia and finally a decrease in ventricular conduction delay with biventricular pacing contributing to a reduced propensity to initiate macro re-entry. But the latter hypothesis has yet to be validated, for it could be imagined that biventricular pacing may promote re-entry circuits in scar. The LV lead position in relation to fibrotic areas may be crucial in terms of anti- or pro-arrhythmic effects. Studies, using with biventricular ICD, showed that the occurrence of ventricular arrhythmias was not higher with biventricular pacing as compared to no pacing [30,31]. The improvement of ventricular hemodynamics noted in this study and the absence of unstable angina or myocardial infarction in ischemic patients may also be related to a

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potential preventive effect of biventricular pacing on ventricular arrhythmia. The various pharmacological treatment classes used to treat heart failure are thought to have identical effectiveness regardless of etiology, either ischemic or non-ischemic, as was demonstrated for beta-blockers [32–34] and spironolactone [35]. It had been suggested that ACEI [36,37] or amlodipine [38] were more effective in non-ischemic cases but results from a recent analytical review of the SOLVD, prevention and treatment and Praise II [39,40] studies did not confirm that trend. As with drug treatments, biventricular pacing appeared to carry the same benefit regardless of etiology. The echocardiographic study performed in the MIRACLE trial showed that the magnitude in left ventricular reverse remodeling was significantly higher in non-ischemic cardiomyopathy as compared to ischemic cardiomyopathy [41]. 4.1. Limitations of the study This observational study was not randomized, and therefore, did not include any control group. The results, therefore, will have to be confirmed by randomized, prospective studies. Another criticism is the definition of the ischemic origin of LVSD, based on recent coronariography results, on a history of myocardial infarction and/or previous coronary revascularization. The existence of coronary heart disease does not necessarily imply that chronic LVSD is purely ischemic in origin, just as a patient with “silent” ischemia may be mistaken for a non-ischemic case. 5. Conclusions This multicenter, prospective study has produced encouraging results, showing the functional benefit of cardiac resynchronization therapy by atriobiventricular pacing, regardless of the etiology of cardiomyopathy (ischemic or not). That benefit was noted with no over-mortality in ischemic patients. The results from ongoing randomized studies will define the overall clinical impact of that therapy in patients with advanced heart failure, with regard to mortality in particular. Acknowledgements This study was supported by a grant from Medtronic Inc., Minneapolis, MN, USA. References [1]

[2]

Murkorsky R, Dangas G, Diamond J, Mehta D, Schaffer A, Ambrose J. A prolonged QRS duration on surface ECG is a specific indicator of left ventricular dysfunction. J Am Coll Cardiol 1998;32: 476–82. Nishimura RA, Hayes DL, Holmes Jr DR, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization study. J Am Coll Cardiol 1995;25:281–8.

176 [3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

C. Leclercq et al. / Annales de Cardiologie et d’Angéiologie 53 (2004) 171–176 Xiao HB, Brecker SJD, Gibson DG. Effect of abnormal activation on the time course of the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403–7. Panidis I, Ross J, Munley B, Nestico P, Mintz G. Diastolic mitral regurgitation in patients with atrioventricular conduction abnormalities: a common finding by Doppler echocardiography. J Am Coll Cardiol 1986;7:768–74. Appelton C, Basnignht M, Gonzalez M, Carucci M, Henry C, Olajos M. Diastolic mitral regurgitation with atrioventricular conduction abnormalities: relation of mitral flow velocity to transmitral pressure gradients in conscious dogs. J Am Coll Cardiol 1991;18:843–9. Foster AH, Gold MR, McLaughlin JS. Acute hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg 1995;59:294– 300. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, et al. Multisite pacing for end-stage heart failure: early experience. PACE 1996;19(Part II):1748–57. Blanc JJ, Etienne Y, Gilard M, Mansourati J, Munier S, Boschat J, et al. Evaluation of different ventricular pacing sites in patients with severe heart failure. Circulation 1997;96:3273–7. Aurrichio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999;99:2993–3001. Leclercq C, Cazeau S, Le Breton H. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 1998;32:1825–31. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567–73. Gras D, Mabo P, Tang T, Luttikius T, Chatoor R, Pedersen A-K, et al. Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync study. PACE 1998;21:2249–55. Leclercq C, Cazeau S, Ritter P, Alonso C, Gras D, Mabo P, et al. A pilot experience with permanent biventricular pacing to treat advanced heart failure. Am Heart J 2000;140:862–70. Daubert JC, Ritter P, Le Breton H, Gras D, Leclercq C, Lazarus A, et al. Permanent left ventricular pacing with transvenous leads inserted into the coronary veins. PACE 1998;21:239–45. Gras D, Ritter Ph, Lazarus A, Mabo P, Bucknall C, Tang A, et al. Long term outcome of advanced heart failure patients with cardiac resynchronization therapy. PACE 2000;23(4):423A The InSync Trial Investigators. Aurrichio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, et al. The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 1999;83:130D–5D. Cazeau S, Leclercq C, Lavergne T, Walker S, Carma C, Linde C, et al. Clinical effects of multisite biventricular pacing in heart failure patients without classical pacemaker indications. New Engl J Med 2001;334:873–80. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. New Engl J Med 2002;346(24):1845–53. Adams K, Dunlap S, Sueta C, Clarke S, Patterson J, Blauwet M, et al. Relation between etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol 1996;28:1781–8. Likoff M, Chandler S, Kay H. Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol 1987;59:634–8. Felker M, Thompson R, Hare J, Hruban R, Clemetson D, Howard D, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. New Engl J Med 2000; 342:1077–84.

[22] Cowburn P, Cleland J, Coast A, Komajda M. Risk stratification in chronic heart failure. Eur Heart J 1998;19:696–710. [23] Bart B, Shaw L, McCants C, Fortin D, Lee K, Califf R, et al. Clinical determinants of mortality in patients with angiographically diagnosed ischemic or non-ischemic cardiomyopathy. J Am Coll Cardiol 1997; 30:1002–8. [24] Alla F, Briancon S, Juilliere Y, Mertes P, Villemot JP, Zannad F. Differential clinical pronostic classification in dilated and ischemic advanced heart failure: the EPICAL study. Am Heart J 2000;139:895– 904. [25] Follath F, Cleland J, Klein W, Murphy R. Etiology and response to drug treatment in heart failure. J Am Coll Cardiol 1998;32:1167–72. [26] Ho K, Kannel W, Levy D. The epidemiology of heart failure: the Framingham study. J Am Coll Cardiol 1993;22:6A–13A. [27] Walker S, Levy TM, Rex S, Brant S, Allen J, Ilsley CJ, et al. Usefulness of suppression of ventricular arrhythmia by biventricular pacing in severe congestive cardiac failure. Am J Cardiol 2000;86:231–3. [28] Higgins S, Yong P, Scheck D, Mc Daniel M, Bollinger F, Vadecha M, et al. Biventricular pacing diminishes the need for implantable cardioverter defibrillator therapy. J Am Coll Cardiol 2000;36:824–7. [29] Hamdan M, Zagrodzky J, Joglar J, Sheehan C, Ramaswamy K, Erdner J, et al. Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction. Circulation 2000;102:1027–32. [30] Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003;42(8):1454–9. [31] Young JB, Abraham WT, Smith AL, Leon AR. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. J Am Med Assoc 2003;289(20):2685–94. [32] Packer M, Bristow MR, Cohn J, The US, Carvedilol Study Group. Effect of carvedilol on morbidity and mortality in patients with chronic heart failure. New Engl J Med 1996;334:1349–55. [33] CIBIS-II Investigators. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomized trial. Lancet 1999;353:9–13. [34] MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–7. [35] Pitt B, Zannad F, Remme WJ, The Rales Study Group. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Engl J Med 1999;341:709–17. [36] Cohn J, Johnson G, Ziesche S. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. New Engl J Med 1991;325(5):303–10. [37] SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med 1991;325:293. [38] Packer M, O’Connor C, Pressler M, Carson P, The Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of Amlodipine on morbidity and mortality in severe chronic heart failure. New Engl J Med 1996;335:1107–14. [39] Garg R, Yusuf S. Overview of randomized trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure. J Am Med Assoc 1995;273:1450–6. [40] Packer M, The Prospective Randomized Amlodipine Survival Evaluation Study Group. Prospective randomized Amlodipine survival evaluation II, Praise II trial. ACC 2000 Scientific Session, Anaheim, March 2000. [41] St. John Sutton M, Plappert T, Abraham W, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–90.