HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Higgins, S. L. Articles by Yong, P. G. Search for Related Content PubMed PubMed Citation Articles by Higgins, S. L. Articles by Yong, P. G.

CLINICAL RESEARCH: HEART FAILURE

Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias

Steven L. Higgins, MD, FACC^*,*, John D. Hummel, MD, FACC, Imran K. Niazi, MD, FACC, Michael C. Giudici, MD, FACC, Seth J. Worley, MD, FACC^||, Leslie A. Saxon, MD, FACC^¶, John P. Boehmer, MD, FACC^#, Michael B. Higginbotham, MD^**, Teresa De Marco, MD, FACC^¶, Elyse Foster, MD, FACC^¶ and Patrick G. Yong, MSEE

^* Scripps Memorial Hospital, La Jolla, California, USA
Riverside Methodist Hospital, Columbus, Ohio, USA
St. Luke's Presbyterian Hospital, Milwaukee, Wisconsin, USA
Genesis Medical Center, Davenport, Iowa, USA
^|| Lancaster General Hospital, Lancaster, Pennsylvania, USA
^¶ University of California San Francisco Medical Center, San Francisco, California, USA
^# The Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA
^** Duke University School of Medicine, Durham, North Carolina, USA
Guidant Corporation, St. Paul, Minnesota, USA

^* Reprint requests and correspondence: Dr. Steven L. Higgins, Scripps Regional Cardiac Arrhythmia Center, 9888 Genesee Ave., La Jolla, California 92038-0028, USA.
EPDocHiggins{at}msn.com

	Abstract

Top Abstract Methods Results Discussion APPENDIX References

 
OBJECTIVES: This study was conducted to assess the safety and effectiveness of cardiac resynchronization therapy (CRT) when combined with an implantable cardioverter defibrillator (ICD).

BACKGROUND: Long-term outcome of CRT was measured in patients with symptomatic heart failure (HF), intraventricular conduction delay, and malignant ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]) requiring therapy from an ICD.

METHODS: Patients (n = 490) were implanted with a device capable of providing both CRT and ICD therapy and randomized to CRT (n = 245) or control (no CRT, n = 245) for up to six months. The primary end point was progression of HF, defined as all-cause mortality, hospitalization for HF, and VT/VF requiring device intervention. Secondary end points included peak oxygen consumption (VO₂), 6-min walk (6 MW), New York Heart Association (NYHA) class, quality of life (QOL), and echocardiographic analysis.

RESULTS: A 15% reduction in HF progression was observed, but this was statistically insignificant (p = 0.35). The CRT, however, significantly improved peak VO₂ (0.8 ml/kg/min vs. 0.0 ml/kg/min, p = 0.030) and 6 MW (35 m vs. 15 m, p = 0.043). Changes in NYHA class (p = 0.10) and QOL (p = 0.40) were not statistically significant. The CRT demonstrated significant reductions in ventricular dimensions (left ventricular internal diameter in diastole = –3.4 mm vs. –0.3 mm, p < 0.001 and left ventricular internal diameter in systole = –4.0 mm vs. –0.7 mm, p < 0.001) and improvement in left ventricular ejection fraction (5.1% vs. 2.8%, p = 0.020). A subgroup of patients with advanced HF (NYHA class III/IV) consistently demonstrated improvement across all functional status end points.

CONCLUSIONS: The CRT improved functional status in patients indicated for an ICD who also have symptomatic HF and intraventricular conduction delay.

Abbreviations and Acronyms   CRT = cardiac resynchronization therapy   HF = heart failure   HFEC = Heart Failure Events Committee   ICD = implantable cardioverter defibrillator   LV = left ventricle/left ventricular   LVEF = left ventricular ejection fraction   LVIDd = left ventricular internal diameter in diastole   LVIDs = left ventricular internal diameter in systole   NYHA = New York Heart Association classification   QOL = quality of life   VO2 = oxygen consumption   VT/VF = ventricular tachycardia/ventricular fibrillation   6 MW = 6-min walk

Published studies suggest that short-term improvements in hemodynamics (5,6) and long-term improvements in functional status are possible with CRT (7–9). Previously published studies have been restricted to patients with symptomatic HF but without conventional indications for an implantable cardioverter defibrillator (ICD) or had relatively small sample sizes and lacked a concurrent control group. This study is the first to describe the results of CRT in a double-blind, randomized controlled study in patients with both symptomatic HF and ventricular tachyarrhythmias.

	Methods

Top Abstract Methods Results Discussion APPENDIX References

 
Study design.   Major entry criteria for participation in the study include New York Heart Association (NYHA) class II to IV, left ventricular ejection fraction (LVEF) 35%, QRS interval 120 ms, and conventional indications for implant of an ICD. Patients could not be enrolled if they had atrial tachyarrhythmias or conventional indications for a permanent pacemaker. The full eligibility criteria have been previously described (10). Because of the immediate need for ICD therapy, investigators implanted the system first and then programmed the randomized therapy after a minimum 30-day period with no CRT. During this period, investigators were permitted to optimize pharmacologic therapy before initiating the randomized therapy. This step was added to reduce bias so that the observed changes could be attributed to CRT rather than changes in background medical therapy. The original study design (Phase I) was a crossover design with two three-month observation periods; its design and end point metrics of peak oxygen consumption (VO₂), 6-min walk (6 MW) distance, and quality of life (QOL) using the Minnesota Living with Heart Failure Questionnaire have been previously described (10).

The study design was later modified (Phase II) due to regulatory concerns over morbidity and mortality associated with CRT and the length of follow-up in the randomized mode. However, no changes were made to the study's eligibility criteria. Both designs are shown in Figure 1. The sponsor elected to change the primary end point from peak VO₂ to a composite end point driven by events associated with worsening HF, and the study was changed from a crossover to a parallel design. A Heart Failure Events Committee (HFEC) adjudicated all deaths and hospitalizations.

View larger version (22K): [in this window] [in a new window]   Figure 1 Study design for each phase. Phase I (top) was a crossover design (n = 248); Phase II (bottom) was a parallel design (n = 333). CRT = cardiac resynchronization therapy; Rand = randomization time.

Statistical methods.   The primary end point was progression of HF, defined as a composite of all-cause mortality, hospitalization for worsening HF, and ventricular tachyarrhythmias requiring device therapy. It was postulated that the therapy would reduce the overall incidence of these events by 25%. The primary end point was analyzed such that patients in Phase I contributed data from a three-month treatment phase and patients in Phase II contributed data from a six-month treatment phase. Cox proportional hazard models were fit for the combination of events with the treatment effect adjusted for covariates chosen by the HFEC before primary end point analysis. These covariates included NYHA class, QRS interval, ischemic etiology, LVEF, and bundle-branch morphology. The Wei method was used to calculate a composite effect of the treatment and covariates (11).

The longitudinal (repeated measures) analysis method was performed on continuous variables to compare the difference in the sample means. This method accounted for the patterns of missing data, took full advantage of the correlation structure, and used all the data to estimate the model parameters (12). Model parameters were estimated using maximum likelihood (SAS/STAT Version 8.1, SAS Institute, Inc., Cary, North Carolina). Values of p < 0.05 were considered to be significant for all tests.

	Results

Top Abstract Methods Results Discussion APPENDIX References

 
Patient disposition.   A total of 581 patients were enrolled at 47 investigational centers in the U.S. from February 1998 through December 2000. All patients enrolled provided written informed consent approved by each participating center's Institutional Review Board, and procedures were conducted in accordance with each participating investigator's institutional guidelines. All patients were indicated for implantation of an ICD in accordance with American College of Cardiology/American Heart Association guidelines (13).

Of the 581 patients enrolled in the study, 14 patients either withdrew informed consent or were determined not to meet eligibility criteria and were withdrawn by the investigator before an implant procedure. Another 66 patients did not receive an investigational system because of the inability to place the coronary venous lead; they received a conventional ICD system instead. Thus, 501 patients were implanted with the investigational system, with 448 (89%) receiving a transvenous system and 53 (11%) receiving a transthoracic system.

Of the transvenous leads, 242 (54%) were in a lateral vein, 142 (32%) were in an anterior vein, and 59 (13%) were posterior. Lead location was not recorded for the remaining five patients (1%). Of the leads placed transthoracically, 24 (45%) were placed apically, 14 (26%) were placed lateral, 11 (21%) were placed anterior, and 4 (8%) were implanted in a posterior position. Of the patients implanted, 222 were enrolled in Phase I (51 patients receiving transthoracic leads) and 279 were enrolled in Phase II (two patients receiving transthoracic leads).

Ten patients died and one withdrew within the 30-day post-implant recovery period before the randomized therapy could be programmed, leaving 490 patients available for analysis. Two of the 10 deaths were perioperative, with one death attributed to pulseless electrical activity resulting from defibrillation threshold testing and the other due to incessant ventricular tachycardia (VT) during the implant procedure. Of the remaining eight deaths, five were due to pump failure, two were attributed to cardiac causes unrelated to pump failure, and one was due to unknown cause as adjudicated by the HFEC. None of the latter eight deaths were attributed to the implant procedure. Patient demographics at the time of implant are reported in Table 1. The two randomized groups were balanced with no statistically significant differences with respect to baseline characteristics.

Baseline predictors of improvement.   Significant interactions of the five covariates chosen by the HFEC were found with the secondary end points (Table 2) as part of a post hoc analysis, but no interactions were found with the primary end point. The NYHA class, measured at the time of the randomization visit, was found to be the most consistent predictor of improvement with CRT across the functional status end points. Demographics for the NYHA class III/IV patient population are presented in Table 3. Results for all patients are presented in Table 4 and are stratified by NYHA class I/II and NYHA class III/IV at the conclusion of the post-implant recovery period.

View larger version (15K): [in this window] [in a new window]   Figure 2 Kaplan-Meier curves for all-cause mortality (left) and all-cause mortality and heart failure (HF) hospitalization (right). CRT = cardiac resynchronization therapy.

Patients with NYHA class III/IV demonstrated improvement in peak VO₂ (p = 0.003), 6 MW distance (p = 0.029), NYHA class (p = 0.006), and QOL (p = 0.017). Patients with NYHA class I/II showed no significant improvement in any of these parameters.

Echocardiographic data.   Cardiac resynchronization therapy was associated with significant decreases in LV dimensions in the all-patients group. The LVID_d was significantly improved (p < 0.001) as was left ventricular internal diameter in systole (LVID_s) (p < 0.001). The LVEF also significantly increased with CRT (p = 0.020). Decreases in LV dimensions were also noted in NYHA class III/IV patients with CRT in left ventricular internal diameter in diastole (LVID_d) (p = 0.001), LVID_s (p = 0.002), and LVEF (p = 0.029). Patients in NYHA class I/II demonstrated significant reductions in LVID_d (p = 0.024) and in LVID_s (p = 0.014) with CRT.

All-cause mortality.   A total of 109 deaths were reported throughout the study (27 deaths during the study treatment phase and 70 deaths during the long-term follow-up phase) and were adjudicated by an independent events committee. Of the 109 deaths, 47 (43%) were due to pump failure, 21 (19%) were non-cardiac, 9 (8%) were arrhythmic, 2 (2%) were ischemic, and 2 (2%) were cardiac in nature but of unknown etiology. The remaining 28 (26%) deaths had insufficient documentation for the committee to adjudicate cause of death. Operative mortality, defined as death from any cause within 30 days of the implant procedure, accounted for 12/567 (2%) of patients who underwent the implant procedure. Total survival at one, two, and three years was 85%, 74%, and 70%, respectively.

Spontaneous ventricular tachyarrhythmias.   There was no statistically significant difference in the incidence or frequency of ventricular tachyarrhythmias when comparing CRT with no CRT. Of the 245 patients programmed to CRT, 36 (15%) received appropriate treatment of ventricular tachyarrhythmias with 25 (10%) having VT alone, 7 (3%) having VF alone, and 4 (2%) having both VT and VF. Of the 245 patients programmed to no CRT, 39 (16%) received appropriate device therapy. Ventricular tachycardia alone was reported in 27 (11%) patients, VF alone in 6 (2%) patients, and both VT and VF in 6 (2%) patients.

When excluding patients who had no VT/VF episodes, those patients randomized to CRT had a median of 2.5 episodes while those randomized to no CRT had a median of 2 episodes during the therapy evaluation phase. The device delivered antitachycardia pacing in a biventricular fashion. Spontaneous monomorphic VT was successfully treated with biventricular antitachycardia pacing in 927 of 1,053 (88%) episodes.

	Discussion

Top Abstract Methods Results Discussion APPENDIX References

 
Progression of HF.   The present study is the first report of CRT with an ICD in a double-blind, randomized, clinical study in a patient population with an ICD indication and symptomatic HF and intraventricular conduction delay. Although relative improvements in HF progression were observed that were favorable towards CRT, the magnitude of improvement was not statistically significant.

The primary end point analysis was based on an expected rate of HF events. The study was not adequately powered to detect a statistically significant difference because the actual event rate observed was approximately half that expected in the original study design. In addition to the relatively brief follow-up period of three months for Phase I patients, the widespread adoption of HF medications, such as beta-blockers and spironolactone, after the publication of positive clinical trial results and an evolution in HF management that focused on increased outpatient surveillance may have contributed to the reduction in expected events. Many patients responded positively once medical management was optimized before randomization. This improvement in status made it more difficult to show benefit in healthier patients while reducing the statistical power to show improvement in those who remained in NYHA class III/IV despite optimizing HF medications.

Secondary end points.   Although this study was negative in terms of its primary end point, several important findings were observed about functional capacity, QOL, and reverse remodeling. Peak VO₂, which was the primary end point of the original study design, and 6 MW distance both demonstrated statistically significant improvements. Although angiotensin-converting enzyme inhibitors and beta-blockers have been proven to reduce mortality and hospitalization, these agents generally do not improve exercise tolerance (14–16). Thus, CRT appears to complement existing pharmacologic therapy by improving functional status without evidence for increased morbidity or mortality.

Echocardiographic analysis also revealed a statistically significant improvement in LV dimensions and LVEF. These findings are important because they provide evidence for reversal of the remodeling effects of HF. Interestingly, significant reductions in LV dimensions were noted in NYHA class I/II patients. Future studies may demonstrate benefit in patients with dyssynchrony but without overt symptoms by preventing remodeling.

Comparison with other studies.   The results of two other studies, Multisite Insync Randomized Clinical Evaluation (MIRACLE) and InSync ICD (also referred to as "MIRACLE ICD"), have recently been publicized (17,18). These two studies enrolled patients with intraventricular conduction delay, LV dysfunction, and symptomatic HF while on stable HF medications. Patients without an ICD indication were enrolled in MIRACLE; those with an ICD indication were enrolled in InSync ICD.

The studies were similar in that CRT consisted of biventricular stimulation with LV stimulation from a lead placed in the coronary venous vasculature. All three designs called for patients to be randomized to CRT or no CRT for a six-month period, and all used similar methods for quantifying changes in functional status (peak VO₂, 6 MW, QOL, NYHA class, and echocardiography).

Dissimilarities in the studies were related to the patient populations (NYHA class II to IV in Contak CD and InSync ICD vs. NYHA class III to IV in MIRACLE) and how baseline testing was performed. Patients in the advanced HF subgroup of the Contak CD study most closely correspond to the patient population in MIRACLE and the NYHA class III/IV subgroup of patients in InSync ICD for whom results were reported. In Contak CD, baseline testing was performed post-implant after a minimum 30-day waiting period, whereas the other two studies had most baseline tests performed pre-implant. Finally, the major difference in the studies was the use of mortality, hospitalization, and VT/VF events as the primary end point in the Contak CD study, whereas the MIRACLE and InSync ICD studies selected 6 MW, NYHA class, and QOL as co-primary end points.

All three studies showed directional improvement in mortality with CRT, but none achieved statistical significance or were powered to detect a difference. Similarly, all three studies demonstrated that CRT was safe. Improvements in functional capacity were highly consistent among the functional status end points when comparing the advanced HF subgroup with the results from the other two studies. Thus, the results of the published studies are highly concordant in demonstrating the safety and effectiveness of CRT across trials with similar patient populations.

Study limitations.   Patients were studied in a randomized mode for only six months, with some patients followed for only three months. Ongoing studies with longer follow-up intervals, such as the Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) and CArdiac REsynchronization in Heart Failure (CARE-HF) studies, are expected to determine long-term benefit (19,20). Applicability to patients with arrhythmias besides VT/VF is not well known, and it is unknown if the results can be generalized to patients with chronic atrial fibrillation, chronotropic incompetence, and sinus bradycardia. Furthermore, CRT was delivered in an atrial synchronous manner (i.e., VDD mode). The effects of atrial pacing as well as adaptive-rate pacing delivered with the DDD(R) modes were not studied (Appendix).

	APPENDIX

Top Abstract Methods Results Discussion APPENDIX References

 
Primary Investigators: A. Almquist, S. Bailin, U. Birgersdotter-Green, M. Burke, H. Calkins, D. Callans, M. Chisner, J. Coman, C. Costeas, A. Curtis, T. Edel, K Ellenbogen, M. Faddis, C. Fellows, J. Franklin, R. Freedman, F. R. Gilliam, M. Gold, W. K. Haisty, J. Herre, R. Kinn, B. P. Knight, H. Kopelman, A. Leon, B. Lerman, P. Ludmer, S. Mester, C. Movsowitz, A. Pacifico, V. Payne, E. Prystowsky, L. Rosenthal, S. Saba, C. Schuger, P. Wang, B. Williamson, S. Winston, M. Wish.

Heart Failure Events Committee: J. Boehmer, M. Carlson, T. De Marco, B. Jaski.

Core Laboratories: E. Foster, M. Higginbotham, L. Saxon.

	Acknowledgments

 
The authors acknowledge the assistance of the clinical engineers and clinical heart failure team that helped make this study possible.

	Footnotes

 
The study received financial support from Guidant Corporation, St. Paul, Minnesota.

	References

Top Abstract Methods Results Discussion APPENDIX References

 

1. Adams KF. Heart Failure Society of America guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction—pharmacologic approaches. J Card Fail 1999;5:357–82
2. Packer M, Cohn JN, editors. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83:1A–38A
3. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block: the effect of interventricular asynchrony. Circulation. 1989;79:845–853[Abstract/Free Full Text]
4. Bakker PF, Meijburg H, de Vries JW, et al. Biventricular pacing in end-stage heart failure improves functional capacity and left ventricular function. J Interv Card Electrophysiol. 2000;4:395–404[CrossRef][Medline]
5. Foster AH, Gold MR, McLaughlin JS. Hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg. 1995;59:294–300[Abstract/Free Full Text]
6. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol. 1996;19:1748–1757[CrossRef][Medline]
7. Gras D, Mabo P, Tang T, et al. Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol. 1998;21:2249–2255[CrossRef][Medline]
8. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:873–880[Abstract/Free Full Text]
9. Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol. 2000;85:1154–1156[CrossRef][Medline]
10. Saxon LA, Boehmer JP, Hummel J, et al. Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. Am J Cardiol. 1999;835:120D–123D
11. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Am Stat Assoc. 1989;84:1065–1073[CrossRef]
12. Jennrich RI, Schlucter MD. Unbalanced repeated measures models with structured covariance matrices. Biometrics. 1986;42:805–820[CrossRef][Medline]
13. Gregatoros G, Cheitlin MD, Conill A, et al. ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). J Am Coll Cardiol. 1998;31:1175–1209[Free Full Text]
14. collaborative group on ACE inhibitor trialsGarg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitor on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450–1456[Abstract/Free Full Text]
15. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation. 1996;94:2793–2799[Abstract/Free Full Text]
16. The RESOLVD Study Investigators. Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy: the randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation. 2000;101:378–384[Medline]
17. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845–1853[Abstract/Free Full Text]
18. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. JAMA 2003;289:2685–94
19. Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION). J Card Fail. 2000;6:276–285[CrossRef][Medline]
20. Cleland JG, Daubert JC, Erdmann E, et al. The CARE-HF study (CArdiac REsynchronization in Heart Failure study): rationale, design and end-points. Eur J Heart Fail. 2001;3:481–489[CrossRef][Medline]

This article has been cited by other articles:

				T. Stanton, N. M. Hawkins, K. J. Hogg, N. E.R. Goodfield, M. C. Petrie, and J. J.V. McMurray How should we optimize cardiac resynchronization therapy? Eur. Heart J., August 28, 2008; (2008) ehn380v1. [Abstract] [Full Text] [PDF]

				S. Buck, A. H. Maass, W. Nieuwland, R. L. Anthonio, D. J. Van Veldhuisen, and I. C. Van Gelder Impact of interventricular lead distance and the decrease in septal-to-lateral delay on response to cardiac resynchronization therapy Europace, August 11, 2008; (2008) eun208v1. [Abstract] [Full Text] [PDF]

				M Marciniak, B Bijnens, A Baltabaeva, A Marciniak, C Parsai, P Claus, and G R Sutherland Interventricular interaction as a possible mechanism for the presence of a biphasic systolic velocity profile in normal left ventricular free walls Heart, August 1, 2008; 94(8): 1058 - 1064. [Abstract] [Full Text] [PDF]

				M. O. Sweeney and F. W. Prinzen Ventricular Pump Function and Pacing: Physiological and Clinical Integration Circ Arrhythmia Electrophysiol, June 1, 2008; 1(2): 127 - 139. [Full Text] [PDF]

				L. J. Anderson, C. Miyazaki, G. R. Sutherland, and J. K. Oh Patient Selection and Echocardiographic Assessment of Dyssynchrony in Cardiac Resynchronization Therapy Circulation, April 15, 2008; 117(15): 2009 - 2023. [Full Text] [PDF]

				M. M. Borggrefe, T. Lawo, C. Butter, H. Schmidinger, M. Lunati, B. Pieske, A. R. Misier, A. Curnis, D. Bocker, A. Remppis, et al. Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure Eur. Heart J., April 2, 2008; 29(8): 1019 - 1028. [Abstract] [Full Text] [PDF]

				J G F Cleland, N Freemantle, J-C Daubert, W D Toff, F Leisch, and L Tavazzi Long-term effect of cardiac resynchronisation in patients reporting mild symptoms of heart failure: a report from the CARE-HF study Heart, March 1, 2008; 94(3): 278 - 283. [Abstract] [Full Text] [PDF]

				G Lin, R F Rea, S C Hammill, D L Hayes, and P A Brady Effect of cardiac resynchronisation therapy on occurrence of ventricular arrhythmia in patients with implantable cardioverter defibrillators undergoing upgrade to cardiac resynchronisation therapy devices Heart, February 1, 2008; 94(2): 186 - 190. [Abstract] [Full Text] [PDF]

				J. F. Beshai, R. A. Grimm, S. F. Nagueh, J. H. Baker II, S. L. Beau, S. M. Greenberg, L. A. Pires, P. J. Tchou, and the RethinQ Study Investigators Cardiac-Resynchronization Therapy in Heart Failure with Narrow QRS Complexes N. Engl. J. Med., December 13, 2007; 357(24): 2461 - 2471. [Abstract] [Full Text] [PDF]

				C. Leclercq, G. B. Bleeker, C. Linde, E. Donal, J. J. Bax, M. J. Schalij, and C. Daubert Cardiac resynchronization therapy: clinical results and evolution of candidate selection Eur. Heart J. Suppl., December 1, 2007; 9(suppl_I): I94 - I106. [Abstract] [Full Text] [PDF]

				F. Tabrizi, A. Englund, M. Rosenqvist, L. Wallentin, and U. Stenestrand Influence of left bundle branch block on long-term mortality in a population with heart failure Eur. Heart J., October 2, 2007; 28(20): 2449 - 2455. [Abstract] [Full Text] [PDF]

				Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Europace, October 1, 2007; 9(10): 959 - 998. [Full Text] [PDF]

				Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Eur. Heart J., September 2, 2007; 28(18): 2256 - 2295. [Full Text] [PDF]

				C Leclercq New guidelines for cardiac resynchronisation therapy: simplicity or complexity for the doctor? Heart, September 1, 2007; 93(9): 1017 - 1019. [Abstract] [Full Text] [PDF]

				S. H. Hohnloser and E. N. Prystowsky CRT-D use in heart failure: too little or too much? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G9 - G16. [Abstract] [Full Text] [PDF]

				F. A. McAlister, J. Ezekowitz, N. Hooton, B. Vandermeer, C. Spooner, D. M. Dryden, R. L. Page, M. A. Hlatky, and B. H. Rowe Cardiac Resynchronization Therapy for Patients With Left Ventricular Systolic Dysfunction: A Systematic Review JAMA, June 13, 2007; 297(22): 2502 - 2514. [Abstract] [Full Text] [PDF]

				J. D. Burkhardt and B. L. Wilkoff Interventional Electrophysiology and Cardiac Resynchronization Therapy: Delivering Electrical Therapies for Heart Failure Circulation, April 24, 2007; 115(16): 2208 - 2220. [Abstract] [Full Text] [PDF]

				J. Lindenfeld, A. M. Feldman, L. Saxon, J. Boehmer, P. Carson, J. K. Ghali, I. Anand, S. Singh, J. S. Steinberg, B. Jaski, et al. Effects of Cardiac Resynchronization Therapy With or Without a Defibrillator on Survival and Hospitalizations in Patients With New York Heart Association Class IV Heart Failure Circulation, January 16, 2007; 115(2): 204 - 212. [Abstract] [Full Text] [PDF]

				L. P. Badano, O. Gaddi, C. Peraldo, G. Lupi, M. Sitges, F. Parthenakis, S. Molteni, M. R. Pagliuca, B. Sassone, P. Di Stefano, et al. Left ventricular electromechanical delay in patients with heart failure and normal QRS duration and in patients with right and left bundle branch block Europace, January 1, 2007; 9(1): 41 - 47. [Abstract] [Full Text] [PDF]

				L. A. Saxon, M. R. Bristow, J. Boehmer, S. Krueger, D. A. Kass, T. De Marco, P. Carson, L. DiCarlo, A. M. Feldman, E. Galle, et al. Predictors of Sudden Cardiac Death and Appropriate Shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial Circulation, December 19, 2006; 114(25): 2766 - 2772. [Abstract] [Full Text] [PDF]

				W. T. Abraham Response to Abraham Circulation, December 12, 2006; 114(24): 2692 - 2698. [Full Text] [PDF]

				J. A. White, R. Yee, X. Yuan, A. Krahn, A. Skanes, M. Parker, G. Klein, and M. Drangova Delayed Enhancement Magnetic Resonance Imaging Predicts Response to Cardiac Resynchronization Therapy in Patients With Intraventricular Dyssynchrony J. Am. Coll. Cardiol., November 21, 2006; 48(10): 1953 - 1960. [Abstract] [Full Text] [PDF]

				M. Rivero-Ayerza, D. A.M.J. Theuns, H. M. Garcia-Garcia, E. Boersma, M. Simoons, and L. J. Jordaens Effects of cardiac resynchronization therapy on overall mortality and mode of death: a meta-analysis of randomized controlled trials Eur. Heart J., November 2, 2006; 27(22): 2682 - 2688. [Abstract] [Full Text] [PDF]

				J. G.F. Cleland, J.-C. Daubert, E. Erdmann, N. Freemantle, D. Gras, L. Kappenberger, L. Tavazzi, and on behalf of The CARE-HF Study Investigators Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase] Eur. Heart J., August 2, 2006; 27(16): 1928 - 1932. [Abstract] [Full Text] [PDF]

				J. A. Jarcho Biventricular pacing. N. Engl. J. Med., July 20, 2006; 355(3): 288 - 294. [Full Text] [PDF]

				C. Ermis and D. G. Benditt Cardiac resynchronization pacing without defibrillator capability: is this a viable option? Europace, July 1, 2006; 8(7): 499 - 501. [Abstract] [Full Text] [PDF]

				N. M. Hawkins, M. C. Petrie, M. R. MacDonald, K. J. Hogg, and J. J.V. McMurray Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur. Heart J., June 1, 2006; 27(11): 1270 - 1281. [Abstract] [Full Text] [PDF]

				E. Donal, C. Leclercq, C. Linde, and J.-C. Daubert Effects of cardiac resynchronization therapy on disease progression in chronic heart failure Eur. Heart J., May 1, 2006; 27(9): 1018 - 1025. [Abstract] [Full Text] [PDF]

				Z. Goldberger and R. Lampert Implantable Cardioverter-Defibrillators: Expanding Indications and Technologies JAMA, February 15, 2006; 295(7): 809 - 818. [Abstract] [Full Text] [PDF]

				F. A. McAlister, J. V. Tu, A. Newman, D. S. Lee, S. Kimber, B. Cujec, and P. W. Armstrong How many patients with heart failure are eligible for cardiac resynchronization? Insights from two prospective cohorts Eur. Heart J., February 1, 2006; 27(3): 323 - 329. [Abstract] [Full Text] [PDF]