Interact CardioVasc Thorac Surg 2008;7:1141-1146. doi:10.1510/icvts.2008.183707
© 2008 European Association of Cardio-Thoracic Surgery
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 and
Kumaresan Nagarajanb
a Cardiothoracic Division, James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK
b 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
Received 15 May 2008;
accepted 19 May 2008
Corresponding author. Tel.: +44 1642 854623; fax: +44 1642 854190.
E-mail address: a.turley{at}btopenworld.com (A.J. Turley).
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Abstract
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A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether bi-ventricular pacing, also referred to as cardiac resynchronisation therapy (CRT), improves survival and quality of life in patients with severe (NYHA III/IV) symptomatic heart failure. Cardiac pacing can be achieved by stimulation of the right ventricle, left ventricle (LV) or by bi-ventricular 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 III/IV) 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 III/IV 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  35%), prolonged QRS duration (QRS  120 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.
Key Words: Cardiac resynchronisation therapy; Bi-ventricular pacing; Left ventricular systolic dysfunction; Heart failure; Survival; Quality of life
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1. Introduction
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A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
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2. Clinical scenario
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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 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.
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3. Three-part question
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Does [cardiac resynchronisation therapy] improve [survival and quality of life] in patients with [advanced heart failure]?
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4. Search strategy
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The English language scientific literature was reviewed primarily by searching MEDLINE from 1966 through October 2007 using the PubMed interface.
[Cardiac resynchronisation therapy.mp/OR atrio-biventricular pacing/OR atrial-synchronized biventricular pacing/OR CRT] AND [survival] AND [Exp heart failure/OR end-stage heart failure/OR congestive cardiac failure/OR left ventricular systolic dysfunction/OR congestive heart failure.mp].
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 [Cumulative Index to Nursing and Allied Health Literature], DARE [Database of Abstracts of Reviews of Effectiveness] and EMBASE containing published articles were searched for relevant information.
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5. Search outcome
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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 [2–10]. Guidelines by the American Heart Association/American College of Cardiology (AHA/ACC), the European Society Cardiology (ESC) and the UK National Institute for health and Clinical Excellence (NICE) are summarised in Table 2 [11, 12].
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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 11, 12
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6. Discussion
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Four studies compared bi-ventricular pacing with optimal pharmacological therapy, COMPANION, MUSTIC, CARE-HF and MIRACLE [2–5]. 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% [16.9 vs. 20.7%; odds ratio (OR), 0.71; 95% confidence interval (CI), 0.57–0.88] and mortality due to progressive heart failure by 38% (6.7 vs. 9.7%; OR, 0.62; 95% CI, 0.45–0.84) [7]. 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) [4, 5]. 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) [10].
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 [2, 4, 5]. 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 (OR=0.60; 95% CI, 0.45–0.80, P=0.001), increased peak oxygen consumption by 1.77 (95% CI, 0.32–3.22, P=0.017) ml/kg/min and improved heart failure symptoms by at least one NYHA class (OR=1.52; 95% CI, 1.30–1.77, P<0.0001) [8].
McAlister et al. recently published a detailed systematic review of efficacy and safety of bi-ventricular pacing in almost 10,000 patients with LVSD [6]. 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 1 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 [13]. 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 [14], 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), 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 is a field of active clinical research and further data will be available in the near future.
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7. Clinical bottom line
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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 35%) who are severely symptomatic (NYHA class III/IV) despite optimal pharmacological management and are 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) [11, 12].
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.
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Acknowledgements
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We are grateful for the help and advice of Dr CJ Plummer, consultant cardiologist, Freeman Hospital, Newcastle upon Tyne in preparing this manuscript.
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Abstract
1. Introduction