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of life in patients with end-stage heart failure? Andrew J. Turley *, Shahzad .... (6 min walk test, peak O consumption) and quality of life. 2. (Minnesota Living With ...
ARTICLE IN PRESS doi:10.1510/icvts.2008.183707

Interactive CardioVascular and Thoracic Surgery 7 (2008) 1141–1147 www.icvts.org

Best evidence topic - Cardiac general

Does cardiac resynchronisation therapy improve survival and quality of life in patients with end-stage heart failure? Andrew J. Turleya,*, Shahzad G. Rajab, Kareem Salhiyyahc, Kumaresan Nagarajanb a Cardiothoracic Division, James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK Department of Cardiothoracic Surgery (Level 9), Western Infirmary Glasgow, Dumbarton Road, Glasgow, G11 6NT, UK c Department of Cardiac Surgery, Royal Hospital for Sick Children, Dalnair Street, Glasgow, G3 8SJ, UK

b

Received 15 May 2008; accepted 19 May 2008

Summary A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether biventricular pacing, also referred to as cardiac resynchronisation therapy (CRT), improves survival and quality of life in patients with severe (NYHA IIIyIV) symptomatic heart failure. Cardiac pacing can be achieved by stimulation of the right ventricle, left ventricle (LV) or by biventricular pacing. This best evidence topic considers only bi-ventricular pacing. This involves placement of pacing leads in the right ventricle, epicardially on the LV with a lead typically placed in a branch of the coronary sinus and, unless the patient is in permanent atrial fibrillation, in the right atrium. Bi-ventricular pacing allows the optimisation of atrio-ventricular timing and resynchronisation of septal and postero-lateral left ventricular contraction. Symptomatic heart failure has a high morbidity and a poor prognosis. Patients with dyspnoea at rest or on minimal exertion (NYHA IIIyIV) are at high risk of death due to progressive heart failure, while those with less severe symptoms are more likely to experience sudden cardiac death. Up to 50% of patients with NYHA class IIIyIV symptoms have a prolonged QRS duration ()120 ms) on 12-lead ECG (usually in a LBBB pattern). This intra-ventricular conduction delay is a surrogate marker of mechanical dyssynchrony (an uncoordinated regional contraction-relaxation pattern) and is associated with reduced cardiac output and increased mortality. Bi-ventricular pacing can reduce the delay in activation of the LV free wall found in many patients with LV systolic dysfunction, thereby improving mechanical synchrony and cardiac output. It may also reduce pre-systolic mitral regurgitation. Three hundred and fifty-six papers were identified using the search method outlined, nine randomised controlled trials and a meta-analysis in addition to published guidelines presented the best evidence to answer the clinical question. Current best available evidence suggests that in patients with left ventricular systolic dysfunction (LVEF F35%), prolonged QRS duration (QRS G120 ms), and NYHA class III or IV symptoms despite optimal pharmacological therapy, bi-ventricular pacing significantly reduces the number of hospitalisations from heart failure, improves functional status (NYHA class, peak oxygen uptake and exercise tolerance) and improves health related quality of life. The CARE-HF study also demonstrated a reduction in mortality from progressive heart failure and all-cause mortality. 䊚 2008 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Cardiac resynchronisation therapy; Bi-ventricular pacing; Left ventricular systolic dysfunction; Heart failure; Survival; Quality of life

1. Introduction A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS w1x. 2. Clinical scenario You are attending the cardiac transplantation multidisciplinary meeting. The case of a 43-year-old with chronic heart failure (NYHA class III) due to a non-ischaemic dilated cardiomyopathy undergoing cardiac transplantation assessment is discussed. The patient’s clinical condition is gradually deteriorating despite optimal pharmacological therapy with an ACE-inhibitor, beta-blocker, aldosterone *Corresponding author. Tel.: q44 1642 854623; fax: q44 1642 854190. E-mail address: [email protected] (A.J. Turley). 䊚 2008 Published by European Association for Cardio-Thoracic Surgery

antagonist and diuretic. His 12-lead ECG shows sinus rhythm with a LBBB pattern, QRS duration 158 ms. A transthoracic echocardiogram confirms severe left ventricular systolic dysfunction, ejection fraction of 27% and left ventricular end diastolic dimension of 64 mm. One of the cardiologists suggests bi-ventricular pacing, also known as cardiac resynchronisation therapy (CRT), for this patient as he believes it may improve the patient’s quality of life and prolong survival. You have never heard of this treatment and investigate further. 3. Three-part question Does wcardiac resynchronisation therapyx improve wsurvival and quality of lifex in patients with wadvanced heart failurex?

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4. Search strategy The English language scientific literature was reviewed primarily by searching MEDLINE from 1966 through October 2007 using the PubMed interface. wCardiac resynchronisation therapy.mpyOR atrio-biventricular pacingyOR atrial-synchronized biventricular pacingy OR CRTx AND wsurvivalx AND wExp heart failureyOR end-stage heart failureyOR congestive cardiac failureyOR left ventricular systolic dysfunctionyOR congestive heart failure.mpx. The ‘related articles’ function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed. The reference lists of articles found through these searches were also reviewed for relevant articles. In addition, Cochrane Central Register of Controlled Trials and links on web sites CINAHL wCumulative Index to Nursing and Allied Health Literaturex, DARE wDatabase of Abstracts of Reviews of Effectivenessx and EMBASE containing published articles were searched for relevant information. 5. Search outcome A total of 356 papers were found using this search strategy. Nine papers, four randomised-controlled trials and five meta-analysis were deemed to represent the best evidence on the topic and are summarised in Table 1 w2–10x. Guidelines by the American Heart AssociationyAmerican College of Cardiology (AHAyACC), the European Society Cardiology (ESC) and the UK National Institute for health and Clinical Excellence (NICE) are summarised in Table 2 w11, 12x. 6. Discussion Four studies compared bi-ventricular pacing with optimal pharmacological therapy, COMPANION, MUSTIC, CARE-HF and MIRACLE w2–5x. The CARE-HF and COMPANION studies hardware randomised people to receive a device or optimal pharmacological therapy, whereas MIRACLE and MUSTIC software randomised people after device implantation to device switched on compared with switched off. All studies were analysed on an intention to treat basis. 6.1. Mortality Only the CARE-HF study demonstrated a significant reduction in all-cause mortality for bi-ventricular pacing compared with optimal pharmacological therapy. Two trials investigated the rate of death from heart failure. CARE-HF reported a statistically significant reduction in the incidence of death from heart failure for bi-ventricular pacing compared with optimal pharmacological therapy, whereas COMPANION, which combined bi-ventricular pacing with an implantable cardioverter defibrillator (ICD), reported a significant reduction in heart failure death or hospitalisation. In a meta-analysis of five randomised trials that included 2371 patients, bi-ventricular pacing compared with optimal pharmacological therapy significantly reduced all-cause mortality by 29% w16.9 vs. 20.7%; odds ratio (OR), 0.71; 95% confidence interval (CI), 0.57–0.88x and mortality due to progressive heart failure by 38% (6.7 vs. 9.7%; OR,

0.62; 95% CI, 0.45–0.84) w7x. There was no observed effect on sudden cardiac death (OR, 0.86; 95% CI, 0.63–1.19). 6.2. Hospitalisation A meta-analysis of CARE-HF, MUSTIC and MIRACLE comparing bi-ventricular pacing with optimal pharmacological therapy alone, showed a significant reduction in the rate of hospitalisation (HR, 0.48; 95% CI, 0.37–0.61). MIRACLE and CARE-HF also demonstrated significant reductions in the risk of worsening heart failure with bi-ventricular pacing compared to optimal pharmacological therapy (HR, 0.67; 95% CI, 0.46–0.84) w4, 5x. Bradley et al. in their meta-analysis of four randomised trials including 1634 patients, showed that bi-ventricular pacing reduced heart failure hospitalisation by 29% (OR, 0.71; 95% CI, 0.53–0.96) w10x. 6.3. Functional status The CARE-HF, COMPANION and MIRACLE trials all reported significant improvements in NYHA class with bi-ventricular pacing compared with optimal pharmacological therapy w2, 4, 5x. They also showed improvements in exercise capacity (6 min walk test, peak O2 consumption) and quality of life (Minnesota Living With Heart Failure Questionnaire). In a meta-analysis of 10 randomised trials that included 1836 patients in the bi-ventricular pacing arms and 1491 patients in the medical arms, bi-ventricular pacing reduced hospitalisation for heart failure (ORs0.60; 95% CI, 0.45– 0.80, Ps0.001), increased peak oxygen consumption by 1.77 (95% CI, 0.32–3.22, Ps0.017) mlykgymin and improved heart failure symptoms by at least one NYHA class (ORs1.52; 95% CI, 1.30–1.77, P-0.0001) w8x. McAlister et al. recently published a detailed systematic review of efficacy and safety of bi-ventricular pacing in almost 10,000 patients with LVSD w6x. Their analysis suggested that bi-ventricular pacing decreased hospitalisations by 37% (95% CI, 7–57%), and all-cause mortality by 22% (95% CI, 9–33%). Bi-ventricular pacing improved LV ejection fraction (weighted mean difference, 3.0%; 95% CI, 0.9– 5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6–10.4), and functional status (improvements of G1 NYHA class were observed in 59% of bi-ventricular pacing device recipients). During a median 11-month follow-up, 6.6% (95% CI, 5.6–7.4%) of bi-ventricular pacing devices exhibited left ventricular lead problems, the most common postoperative complication being lead displacement. A number of unresolved issues regarding bi-ventricular pacing remain w13x. Why do only 60–70% of patients fulfilling standard selection criteria benefit symptomatically from bi-ventricular pacing? Clearly our current pre-implant techniques lack specificity. Although recent data suggest that patients with narrow QRS (-120 ms) do not benefit from CRT w14x, intraventricular ventricular conduction delay (QRS )120 ms) may not result in mechanical dyssynchrony. The most appropriate means of patient selection, in particular which criteria should be used to assess dyssynchrony, electrical (QRS duration) or mechanical (echocardiographic),

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Table 1 Summary of best evidence papers Author, date and country

Patient group

Outcomes

Key results (placebo vs. CRT)

Commentsyweaknesses

COMPANION Bristow et al., 2004 N Engl J Med, North American, w2x

ns1520

Primary end point: composite of death or hospitalisation for any cause

Mortality: CRT reduced the composite of time to death or hospitalisation for any cause, 68% vs. 56% (HR 0.81, 95% CI, 0.69–0.96, P-0.05) and all-cause mortality by 24% (HR 0.76, 95% CI, 0.58–1.01, Ps0.059)

Ischaemic aetiology 57%

OPT NYHA III–IV

Randomised controlled trial (level 1A)

Secondary end points: All-cause mortality

LVEF F35% LVEDD )60 mm Sinus rhythm QRS G120 ms PR G150 ms

Hospitalisation: CRT reduced death from or hospitalisation for heart failure by 34% (HR 0.66, 95% CI, 0.53–0.87, P-0.002)

Hospitalisation for heart failure within last 12 months

Functional status: CRT improved 6-min walk distance (1"93 m vs. 40"96, P-0.001), quality of life score Minnesota Living With Heart Failure Questionnaire improved (–12"23 vs. –25"26 points, P-0.001) and improvement in NYHA symptom class (38% vs. 61%, P-0.001)

No standard indication for the implantation of a pacemaker

MUSTIC Cazeau et al., 2001, N Engl J Med, European, w3x

ns48 (67 initially recruited)

Primary end point: 6 min walk test distance

OPT

Randomised controlled trial (level 1A)

NYHA III for )1 month

Secondary endpoints: Quality of life peak Oxygen consumption Heart failure hospitalisations Mortality rate

LVEF -35% LVEDD )60 mm Sinus rhythm QRS )150 ms

ns813 OPT NYHA III–IV

Randomised controlled trial (level 1A)

LVEF F35% QRS )120 ms QRS 120–149 ms plus echocardiographic evidence of dyssynchrony LVEDD )30 mmym (height) No standard indication for the

Hospitalisation: CRT decreased hospitalisations for heart failure by 66% (3 vs. 9 patients, P-0.05) Functional status: CRT improved 6 min walk distance by 23% (326"134 m vs. 399"100 m, P-0.001), quality of life score Minnesota Living With Heart Failure Questionnaire improved by 32%, (29.6 points "21.3 vs. 43.2"22.8, P-0.001) and peak oxygen consumption (mlyminykg) improved by 8% (15"4.9 vs. 16.2"4.7, P-0.03)

No standard indication for the implantation of a pacemaker

CARE-HF Cleland et al., 2005, N Engl J Med, European, w4x

Mortality: All-cause mortality was 7.5% (5y67 patients, 2 deaths occurred pre-randomisation). Non-significant, study underpowered

Primary outcome: Composite of time to death from any cause or hospitalisation for major cardiovascular event Secondary outcome: All-cause mortality

Mortality: CRT reduced the composite primary endpoint 55% vs. 39% (HR 0.63, 95% CI, 0.51–0.77, P-0.001) and reduced allcause mortality 30% vs. 20% (HR 0.64, 95% CI, 0.48–0.85, P-0.002) Hospitalisation: CRT decreased hospitalisations for heart failure 33% vs. 18% (HR 0.48, 95% CI, 0.36–0.64, P-0.001) Functional status: At 90 days CRT improved NYHA class 2.1"1 vs. 2.7"0.9,

Randomisation pre-device insertion, not blinded 1:2:2 (OPTyBiVyBiV-ICD) Transvenous LV lead placement Device not successfully implanted 10.9% Follow-up 12–16 months. 26% patients in OPT group withdrew Industry sponsored

Ischaemic aetiology 25y67 Randomisation post device insertion. Single blind crossover study Transvenous LV lead placement Device not successfully implanted 8% 3-month follow-up Small numbers. 9 withdrawn from study pre randomisation, 10 failed to complete protocol Beta-blockers prescribed in 28% and spirinolactone in 22% Industry sponsored Ischaemic 38% Follow-up 29 months Randomisation pre-device. Not blinded Exclusions patients in AF patients paced Transvenous LV lead placement Device not successfully implanted 3.5% Industry sponsored

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1144 Table 1 (Continued) Author, date and country

Patient group

Outcomes

ns453

Randomised controlled trial (level 1A)

NYHA III or IV

OPT

LVEF F35% LVEDD G55 mm QRS G130 ms

Primary outcome: NYHA class quality of life 6 min walk test distance

Mortality: All-cause mortality 12 vs. 16 deaths, Ps0.4

Secondary outcome: Peak oxygen consumption LV ejection fraction LVEDD time on treadmill Severity of MR QRS duration

Hospitalisation: CRT decreased hospitalisations for heart failure 34 vs. 18, (HR 0.5, 95% CI, 0.28–0.88, Ps0.02)

6 min walk test F450 m No standard indication for the implantation of a pacemaker

McAlister et al., 2007, J Am Med Assoc, Canada, w6x Systematic review (level 1A)

14 RCTs 4420 patients

Commentsyweaknesses

(HR 0.6, 95% CI, 0.4–0.7, P-0.001) and quality of life score Minnesota Living With Heart Failure Questionnaire 31"22 vs. 40"22 points, (HR –10, 95% CI, –8 to –12, Ps0.001)

implantation of a pacemaker

MIRACLE Abraham et al., 2002, N Engl J Med, w5x

Key results (placebo vs. CRT)

Efficacy Effectiveness Safety of CRT

OPT

Functional status: CRT improved 6 min walk distance (q10 ms vs. q39 m, Ps0.005), functional status, improvements of 1 NYHA class were observed in 32% vs. 52% (P-0.001), quality of life score Minnesota Living With Heart Failure Questionnaire –9 vs. –18 points, Ps0.001 and LV ejection fraction (–0.2% vs. q4.6% P-0.001). CRT increased peak oxygen consumption mlyminykg (q0.2 vs. q1.1, P-0.01) Mortality: CRT decreased all-cause mortality by 22% (RR 0.78, 95% CI, 0.67–0.91) and progressive heart failure deaths (RR 0.64, 95% CI, 0.49–0.84)

Ischaemic aetiology 54% Randomisation post device insertion. Double blind Transvenous LV lead placement Device not successfully implanted 7.5% Follow-up 6 months 37 did not have 6 month follow-up Industry sponsored

Selection bias in trials

NYHA IIIyIV 91% Hospitalisation: CRT decreased hospitalisations for heart failure by 37% (RR 0.63, 95% CI, 0.43–0.93%)

LVEF F30% QRS )155 ms

Functional status: CRT improved LVEF (weighted mean difference, 3.0%; 95% CI, 0.9%–5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6–10.4 points), and functional status (improvements of G1 NYHA class were observed in 59% of CRT recipients in the randomised trials, RR 1.55, 95% CI, 1.25–1.92) Rivero-Ayerza et al., 2006, Eur Heart J, Netherlands, w7x

5 studies, 2371 patients OPT

Meta-analysis (level 1A)

Impact of CRT on overall mortality and mode of death as compared with optimal pharmacological therapy

NYHA IIIyIV LVEF F35% QRS )120 ms

Abdulla et al., 2006, Cardiology, Denmark, w8x

10 Trials 3327 patients

Effect of CRT in patients with left ventricular systolic dysfunction (LVSD)

Mortality: CRT significantly reduced allcause mortality by 29% (16.9 vs. 20.7%, OR 0.71, 95% CI, 0.57–0.88) and mortality due to progressive HF by 38% (6.7 vs. 9.7%, OR 0.62, 95% CI, 0.45–0.84). No effect on sudden cardiac death (SCD) was observed with CRT (6.4 vs. 5.9%; OR 1.04, 95% CI, 0.73–1.22) Mortality: CRT reduced all-cause mortality by 27% (OR 0.73, 95% CI 0.60–0.89, Ps0.002)

Small number of trials Duration of follow-up varied between analysed studies Possible misclassification of sudden deaths

ICD arm of COMPANION study excluded from metaanalysis

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Table 1 (Continued) Author, date and country

Patient group

Meta-analysis (level 1A)

NYHA II–IV

Outcomes

Key results (placebo vs. CRT)

Commentsyweaknesses

Hospitalisations: CRT reduced hospitalisation for heart failure by 40% (OR 0.60, 95% CI, 0.45–0.80, Ps0.001)

LVEF F26% QRS )120 ms

Functional status: CRT increased peak oxygen consumption by 1.77 mlykgymin, (95% CI, 0.32–3.22, Ps0.017), 6 min walk test by 31.7 m (95% CI, –0.21–63.7, Ps0.052) and improved NYHA class by at least one class (OR 1.52, 95% CI, 1.30–1.77, P-0.0001) McAlister et al., 2004, Ann Intern Med, Canada, w9x Systematic review (level 1A)

9 trials efficacy review, 3216 patients

Efficacy and safety of CRT

18 trials safety review, 3701 patients

Mortality: All-cause mortality was reduced by 21% (RR 0.79, CI, 0.66–0.96), reductions in death from progressive heart failure (RR 0.60, CI, 0.36–1.01)

OPT Hospitalisations: Heart failure hospitalisations were reduced by 32% (RR 0.68, CI, 0.41–1.12), and in patients NYHA class IIIyIV RR 0.65 (95% CI, 0.48–0.88)

NYHA class III or IV, 85% LVEF F40% QRS )120 ms

Functional status: CRT improved ejection fraction (weighted mean difference, 0.035 95% CI, 0.015–0.055), quality of life (weighted mean reduction in score on the Minnesota Living with Heart Failure Questionnaire, 7.6 points CI, 3.8–11.5, and improved NYHA class by at least one class (58% vs. 37%) Bradley et al., 2003, J Am Med Assoc, USA, w10x Meta-analysis (level 1A)

4 Trials

Impact of CRT on mortality from progressive heart failure

1634 patients NYHA II–IV Mean LVEF F23% Mean QRS )158 ms

are still under investigation. Too few patients with atrial fibrillation have been included in clinical trials to be certain of the magnitude of their benefit from CRT, but the available evidence suggests that they respond similarly to patients in sinus rhythm providing that a high proportion of biventricular stimulation is achieved. Do patients with asymptomatic left ventricular dysfunction benefit from CRT? Do patients require left and right ventricular stimulation or is LV pacing alone sufficient? Which patients should receive a combined bi-ventricular pacing-defibrillator? This

Mortality: CRT reduced death from progressive heart failure by 51% (OR 0.49, 95% CI, 0.25–0.93) and showed a trend toward reducing all-cause mortality (OR 0.77, 95% CI, 0.51–1.18) Hospitalisations: CRT reduced heart failure hospitalisation by 29% (OR 0.71, 95% CI, 0.53–0.96)

Small number of trials with short follow-up of 3–6 months Beta-blocker use 28–60% patients Only examined effect on mortality. Possible misclassification of sudden deaths

is a field of active clinical research and further data will be available in the near future. 7. Clinical bottom line The current evidence base and guidelines summarised in Table 2 show that bi-ventricular pacing should be considered for patients with left ventricular systolic dysfunction (EF F35%) who are severely symptomatic (NYHA class IIIy IV) despite optimal pharmacological management and are

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Table 2 Current UK, European and North American recommendations for the use of bi-ventricular pacing therapy in symptomatic patients with left ventricular systolic dysfunction w11, 12x NICE

ESC

AHAyACA

Symptoms

NYHA III or IV

NYHA III or IV

NYHA III or IV

Medical management

Optimal pharmacologic management

Optimal pharmacologic management

Optimal pharmacologic management

Left ventricular systolic function

LVEF F35%

LVEF F35%

LVEF F35%

Left ventricular dimension (LV dilatation)

Not required

LVEDD )55 mm LVEDD )30 mmym2 LVEDD )30 mmym (height)

LVEDD )55 mm LVEDD )30 mmym2 LVEDD )30 mmym (height)

Cardiac rhythm

Sinus rhythm

Sinus rhythm

Sinus rhythm

QRS G150 ms

QRS )120 ms

QRS )120 ms

Dysynchrony

QRS 120–149 ms plus echocardiographic evidence of dyssynchrony National Institute for Health and Clinical Excellence (NICE). TA120 Heart failure – cardiac resynchronisation: Guidance. http:yywww.nice.org.ukyguidanceyindex.jsp?actionsdownload&os33962 2007.

in sinus rhythm. Evidence of ventricular dysschrony is required on 12-lead ECG (QRS duration )120 ms) or and echocardiographic evidence of mechanical dysschrony if the QRS duration is 120–149 ms (UK guidance only). The North American and European guidelines also recommend that there is evidence of LV enlargement (LV end diastolic diameter )55 mm) w11, 12x. In these patients, bi-ventricular pacing significantly reduces mortality from progressive heart failure as well as all-cause mortality. It also reduces the number of hospitalisations due to heart failure, improves functional status (NYHA class, VO2 max and exercise tolerance) and improves quality of life. Acknowledgments We are grateful for the help and advice of Dr CJ Plummer, consultant cardiologist, Freeman Hospital, Newcastle upon Tyne in preparing this manuscript. References w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003;2:405–409. w2x 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. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350:2140–2150. w3x Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873–880. w4x Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. w5x 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. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845– 1853.

w6x McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, Page RL, Hlatky MA, Rowe BH. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. J Am Med Assoc 2007;297:2502–2514. w7x Rivero-Ayerza M, Theuns DA, Garcia-Garcia HM, Boersma E, Simoons M, Jordaens LJ. Effects of cardiac resynchronization therapy on overall mortality and mode of death: a meta-analysis of randomized controlled trials. Eur Heart J 2006;27:2682–2688. w8x Abdulla J, Haarbo J, Kober L, Torp-Pedersen C. Impact of implantable defibrillators and resynchronization therapy on outcome in patients with left ventricular dysfunction – a meta-analysis. Cardiology 2006; 106:249–255. w9x McAlister FA, Ezekowitz JA, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, Klassen T, Abraham W. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 2004;141:381–390. w10x Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. J Am Med Assoc 2003;289:730–740. w11x Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M, Linde C, Bello Morgado F, Oto A, Sutton R, Trusz-Gluza M. ESC Guidelines for Cardiac Pacing and Cardiac Resynchronization Therapy. Rev Esp Cardiol 2007;60:1272 e1–1272 e51. w12x Strickberger SA, Conti J, Daoud EG, Havranek E, Mehra MR, Pina IL, Young J, Endorsed by the American College of Cardiology Foundation and the Heart Failure Society of America. 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. Circulation 2005;111:2146– 2150. w13x Jarcho JA. Biventricular pacing. N Engl J Med 2006;355:288–294. w14x Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, Greenberg SM, Pires LA, Tchou PJ. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357:2461–2471.

eComment: Does cardiac resynchronisation therapy improve survival and quality of life in patients with end-stage heart failure? Authors: Ioanna Koniari, Cardiothoracic Surgery Department, University Hospital of Patras, 22500 Rion Patras, Greece; Spyridon Gkizas, Efstratios Apostolakis doi:10.1510/icvts.2008.183707A The beneficial impact of cardiac resynchronisation therapy (CRT) on Heart Failure (HF)-related morbidity and further mortality w1x is attributed to the

ARTICLE IN PRESS A.J. Turley et al. / Interactive CardioVascular and Thoracic Surgery 7 (2008) 1141–1147 improvement of AV, inter- and intra- ventricular conduction delays which occur in advance heart failure and desynchronize the mechanical activity of the ventricles, thus affecting their pump performance. It is notable that three major types of myocardial asynergy can occur in heart failure patients. One is a progressive loss of integrity of the myocardial collagen matrix, typical of the familial cardiomyopathies but common to all dilated cardiomyopathies. Disruption of the collagen network by altering the ordinate cellular architecture impairs both the intra-ventricular conduction of the electrical impulses and the coordinated mechanical response of the ventricles. The consequences are both prolongation of the QRS and loss of mechanical efficiency. Another type of ventricular asynergy is intra-ventricular conduction delay, generated by bundle branch blocks which most frequently impair conduction through the left bundle branch. A further type of ventricular asynergy is that of regional wall motion abnormalities typical of ischaemic heart disease. Uncoordinated ventricular contraction alters regional workload and stress. The region of early activation contracts against minimal load, rapid early systolic shortening does not translate into pressure because the rest of the myocardium is still inactive; late-activated regions have to face considerable systolic pre-stretch and are subjected to disproportionate load and stress. Much of the ventricular myocardial work is wasted in powerless activity and in transferring ejection from one portion of the chamber to another. Therefore, this pathology results in a prolongation of the ventricular pre-ejection time, a shortening of the ejection and relaxation times, a reduction of ejection fraction, and an increase in mitral regurgitation w2x. Consequently, CRT attempts to resynchronize the desynchronized ventricular activity by modifying their activation sequence. Of course this cannot entirely compensate for intraventricular desynchronization but it can, at least in some patients, improve the ventricular mechanical efficiency. Thus, dyssynchrony seems to represent a patho-physiological process that directly depresses ventricular function, causes LV remodelling and CHF, and as a consequence independently predicts a higher risk of morbidity and mortality. Therefore, there is no doubt that cardiac remodelling constitutes an important target in the treatment of CHF.

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A positive relationship between reverse ventricular remodelling and outcome has been demonstrated with drugs such as angiotensin-converting enzyme-inhibitors, angiotensin-receptor blockers, and beta-adrenergic blockers, with a parallel improvement in ventricular geometry and function and reduction in morbidity and mortality w3x. On the other side, several noncontrolled studies have demonstrated that CRT reverses LV remodelling, decreases LV end-systolic and end-diastolic volumes, and increases LVEF. These benefits were attributed to CRT, since discontinuation of pacing resulted in loss of improvement in cardiac function w4x. Especially, in CAREHF study, the mean reduction in LV end-systolic volume increased from 18.2% after 3 months to 26% after 18 months of CRT. Similarly, mean LVEF increased from 3.7% at 3 months to 6.9% at 18 months. These observations provide consistent evidence of a large, progressive, and sustained reverse remodelling effect conferred by CRT w5x. References w1x Turley AJ, Raja SG, Salhiyyah K, Nagarajan K. Does cardiac resynchronisation therapy improve survival and quality of life in patients with end-stage heart failure? Interact CardioVasc Thorac Surg 2008;7:1141– 1147. w2x Tavazzi L. Ventricular pacing: a promising new therapeutic strategy in heart failure. For whom? Eur Heart J 2000 Aug;21(15):1211–1214. w3x Daubert JC, Leclercq C, Donal E, Mabo P. Cardiac resynchronization therapy in heart failure. Heart Fail Rev 2006;11:147–154. w4x Duncan A, Wait D, Gibson D, Daubert JC. Left ventricular remodeling and hemodynamic effects of multisite pacing in patients with left systolic dysfunction and activation disturbances in sinus rhythm: Substudy of the MUSTIC trial. Eur Heart J 2003;24:430–441. w5x Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization therapy on morbidity and mortality in heart failure (CARE-HF TRIAL). N Engl J Med 2005;352:1539–1549.