EHRA Key References on Pacing for heart failure

2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task
force on cardiac pacing and resynchronization therapy of the European Society of
Cardiology (ESC). Developed in collaboration with the European Heart Rhythm
Association (EHRA). European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA),
Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G,
Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW,
Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE
Europace. 2013 Aug;15(8):1070-118.

The latest guideline on cardiac pacing and resynchronization therapy.

Cardiac electronic implantable devices in the treatment of heart failure.
Tan TC, Sindone AP, Denniss AR. Heart Lung Circ. 2012 Jun;21(6-7):338-51.

The article examines current evidence for the use of ICD-s in the reduction of sudden cardiac death in patients with advanced systolic dysfunction and the use of cardiac resynchronisation therapy in improving ventricular performance as well as mortality and morbidity rates.

Implantable cardioverter defibrillators and cardiac resynchronisation therapy.
Holzmeister J, Leclercq C. Lancet. 2011 Aug 20;378(9792):722-30.

This article summarizes and critically assesses the landmark randomized trials REVERSE, MADIT-CRT, and RAFT, and discusses the rationale and available evidence for other emerging indications of CRT, including its use in patients with a mildly reduced left ventricular ejection fraction, in those with a narrow QRS complex, and in those with concomitant bradyarrhythmic pacemaker indications.

Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review.
Ganesan AN, Brooks AG, Roberts-Thomson KC, Lau DH, Kalman JM, Sanders P.  J Am Coll Cardiol.2012 Feb 21;59(8):719-26.

AV nodal ablation was associated with a substantial reduction in all-cause mortality and cardiovascular mortality and with improvements in New York Heart Association functional class compared with medical therapy in CRT-AF patients.

Cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration: the RESPOND study.
Foley PW, Patel K, Irwin N, Sanderson JE, Frenneaux MP, Smith RE, Stegemann B, Leyva F. Heart. 2011 Jul;97(13):1041-7. 

The article’s aim was to evaluate the clinical response to cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration. They found that CRT leads to an improvement in symptoms, exercise capacity and quality of life in patients with heart failure and a normal QRS duration.

Cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 milliseconds: theEvaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial.
Thibault B, Harel F, Ducharme A, White M, Ellenbogen KA, Frasure-Smith N, Roy D, Philippon F, Dorian P, Talajic M, Dubuc M, Guerra PG, Macle L, Rivard L,Andrade J, Khairy P; LESSER-EARTH Investigators. Circulation. 2013 Feb 26;127(8):873-81.

In patients with a left ventricular ejection fraction ≤35%, symptoms of heart failure, and a QRS duration <120 milliseconds, cardiac resynchronization therapy did not improve clinical outcomes or left ventricular remodeling and was associated with potential harm.

Comparison of CRT and CRT-D in heart failure: systematic review of controlled trials.
Jiang M, He B, Zhang Q. Int J Cardiol. 2012 Jun 28;158(1):39-45.

The authors performed a systematic analysis to assess the therapeutic effects of CRT and CRT-D in patients with LV impairment and heart failure. They found that evidence from current randomised and non-randomised trials demonstrates some superiorities of CRT-D over CRT, such as all-cause death rate after one-year follow-up and cardiac death, in patients with LV impairment.

Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the european cohort of the reverse (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial.
Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G, Szili-Török T, Linde C; REVERSE Study Group.
J Am Coll Cardiol. 2009 Nov 10;54(20):1837-46. Epub 2009 Oct

This study shows that cardiac resynchronization therapy prevents the progression of disease in patients with asymptomatic or mildly symptomatic left ventricular dysfunction.

Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure.
St John Sutton M, Ghio S, Plappert T, Tavazzi L, Scelsi L, Daubert C, Abraham WT, Gold MR, Hassager C, Herre JM, Linde C; REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) Study Group.
Circulation. 2009 Nov 10;120(19):1858-65. Epub 2009 Oct 2

A prospective randomized study showing that cardiac resynchronization therapy results in major structural and functional reverse remodeling in patients with NYHA class I or II.

Cardiac-resynchronization therapy for the prevention of heart-failure events.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators.
N Engl J Med. 2009 Oct 1;361(14):1329-38. Epub 2009 Sep 1

This interesting study showed that CRT combined with ICD decreased the risk of heart failure events in patients with NYHA class I or II.

Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.
Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A.
J. Am. Med. Assoc. 2002;288:3115-3123.

The ‘DAVID’ trial, randomizing 506 patients with a LVEF ≤40% implanted with a DDD-ICD to VVI pacing at 40/min or DDD rate-responsive pacing at 70/min, showed a significantly higher rate of hospitalization for congestive heart failure (and a trend to higher mortality) with DDD pacing, thus indicating that unnecessary ventricular pacing may be detrimental.

Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, Lamas GA.
Circulation 2003;107:2932-2937.

Analysis of the ‘MOST’ study dataset, showing that in patients with a baseline QRS duration of <120 ms, the cumulative percent ventricular pacing was greater in DDDR versus VVIR and that it was a strong predictor of HF hospitalization and atrial fibrillation. Thus, ventricular desynchronization imposed by ventricular pacing (even with preserved AV synchrony) has adverse effects.

Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.
Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC.
N Engl J Med 2001;344:873-880.

First controlled trial (albeit single-blind, ‘MUSTIC’) showing clinical benefit of cardiac resynchronisation therapy by biventricular pacing in patients with chronic heart failure and intraventricular conduction delay.

Cardiac resynchronization in chronic heart failure.
Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P,

Messenger J.
N Engl J Med 2002;346:1845-1853.

First double blind trial (‘MIRACLE’) on CRT, randomizing 453 patients with moderate-to-severe symptoms of heart failure, a LVEF ≤35%  and a QRS interval of ≥130 msec to CRT or conventional therapy for heart failure CRT resulted in significant clinical improvement, but the study was underpowered to detect differences in mortality.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM.
N Engl J Med 2004;350:2140-2150.

Large ‘COMPANION’ trial comparing optimal pharmacologic therapy  alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. Both device groups showed a significant reduction of the combined end point of death from or hospitalization for heart failure, but the defibrillator group only significantly reduced mortality.

The effect of cardiac resynchronization on morbidity and mortality in heart failure.
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L.
N Engl J Med 2005;352:1539-1549.

The ‘CARE-HF’ study compared medical therapy alone or with cardiac resynchronization in 813 patients followed for a mean of 29.4 months. CRT reduced the end-systolic LV volume index, mitral regurgitation and significantly reduced the risk of death (HR 0.64; 95 percent confidence interval, 0.48 to 0.85; P<0.002).

Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial.
Calvert MJ, Freemantle N, Yao G, Cleland JG, Billingham L, Daubert JC, Bryan S.
Eur Heart J 2005;26:2681-2688.

This prospective analysis based on intention to treat data from all patients enrolled in the CARE-HF trial calculated an incremental cost-effectiveness ratio of CRT of 19319 Euro per QALY gained and 43596 Euro per life-year gained, thus showing that CRT appears cost-effective in the selected group of patients.

Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure.
Hoppe UC, Casares JM, Eiskjaer H, Hagemann A, Cleland JG, Freemantle N, Erdmann E.
Circulation 2006;114:18-25.

This substudy of CARE-HF analysed the effect of cardiac resynchronization therapy (CRT) on the incidence of atrial fibrillation (AF) and the outcome of patients with new-onset AF.

The hazard ratio for AF was 1.05 in the CRT-group (95% confidence interval, 0.73 to 1.50; P=0.79). Mortality was higher in patients who developed AF, but AF was not a predictor in the multivariable model. CRT improved the outcome regardless of whether AF developed.

Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal
Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJ, Sogaard P, St John Sutton M, Nihoyannopoulos P.
J Am Coll Cardiol 2004;44:1-9.

Review on the use of echocardiography (and, in particular, tissue Doppler imaging) on the identification of potential responders to CRT. Proper identification may reduce the current non-responder rate of 20 to 30% in patients receiving CRT therapy based on electrocardiographic criteria.

Patient selection for cardiac resynchronization therapy: from the Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in collaboration with the Heart Rhythm Society
Strickberger SA, Conti J, Daoud EG, Havranek E, Mehra MR, Pina IL, Young J. Circulation 2005;111:2146-2150.

This advisory identifies appropriate candidates for CRT on the basis of the inclusion criteria and results from the published clinical trials until 2004 (i.e. without CARE-HF)

Results of the Predictors of Response to CRT (PROSPECT) trial
Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J, 3rd, St John Sutton M, De Sutter J, Murillo J.
Circulation 2008;117:2608-2616.

This prospective, multicenter study (n = 498) tested which echocardiographic parameters of mechanical dyssynchrony, based on both conventional and tissue Doppler-based methods, might improve patient selection for cardiac resynchronization therapy (CRT). The patients had standard CRT indications (NYHA III or IV heart failure, LVEF ≤35%, QRS ≥130 ms, stable medical regimen). The ability of the 12 echocardiographic parameters to predict clinical improvement and LV end-systolic volume decrease with ≥15% varied widely, with sensitivity ranging from 6% to 77% and specificity ranging from 31% to 93%. Moreover, there was large variability in the analysis of the dyssynchrony parameters. In conclusion, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond the inclusion criteria.

Cardiac-Resynchronization Therapy in Heart Failure with Narrow QRS Complexes
Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, Greenberg SM, Pires LA, Tchou PJ; the RethinQ Study Investigators.
N Engl J Med. 2007;357:2461-2471

The RethinQ study showed that CRT did not improve peak oxygen consumption, as compared with a control group, in patients with NYHA class III heart failure with an ejection fraction of 35% or less, a QRS interval of less than 130 msec, and mechanical dyssynchrony (which was defined as an opposing- wall delay of 65 msec or more on tissue Doppler imaging or a mechanical dyssynchrony in the septal-to-posterior wall of 130 msec or more on M-mode echocardiography). Although patients in the CRT group had a significant improvement in NYHA class (a secondary end point that was determined by subjective assessment), there was no significant improvement in other end points, including the quality-of-life score, the results on a 6-minute walking test, and left ventricular reverse remodeling. These findings were consistent with the lack of benefit observed in peak oxygen consumption, the primary end point .

Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms
Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C. J Am Coll Cardiol 2008;52:1834-1843.

Although many trials have shown improvee left ventricular (LV) structure and function and clinical outcomes in NYHA functional class III and IV HF with prolonged QRS, its value in functionally better patients is unknown. To test early CRT therapy can improve prognosis was tested in the REVERSE study, randomising 610 patients with NYHA functional class I or II heart failure with a QRS > or =120 ms and a LV ejection fraction < or =40% to active CRT (CRT-ON; n = 419) or control (CRT-OFF; n = 191) for 12 months. The HF clinical composite response primary end point, showed that 16% worsened in CRT-ON compared with 21% in CRT-OFF (p = 0.10). However, patients assigned to CRT-ON experienced a greater improvement in LV end-systolic volume index (-18.4 +/- 29.5 ml/m2 vs. -1.3 +/- 23.4 ml/m2, p < 0.0001) and other measures of LV remodeling. Time-to-first HF hospitalization was significantly delayed in CRT-ON (hazard ratio: 0.47, p = 0.03).