Europace Advance Access published online on September 30, 2008
Europace, doi:10.1093/europace/eun263
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Long-term effects of cardiac resynchronization therapy in octogenarians: a comparative study with a younger population
1 Department of Cardiology, University of Birmingham, Good Hope Hospital,Sutton Coldfield, West Midlands B75 7RR, UK; 2 Good Hope Hospital, University of Birmingham,Sutton Coldfield, UK; 3 Department of Cardiovascular Medicine, Queen Elizabeth Hospital, University of Birmingham,Birmingham, UK
Manuscript submitted 27 June 2008. Accepted after revision 12 August 2008.
* Corresponding author. Tel:+44 121 378 6604; fax:+44 121 378 6188.E-mail address:cardiologists{at}hotmail.com
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Abstract |
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Aims: Heart failure is a disease of octogenarians. The evidence base for cardiac resynchronization therapy (CRT) has emerged from trials of patients in their 60s. We compared the effectiveness of CRT in octogenerians with younger patients.
Methods and results: Patients aged 
80 years [n = 53, age 83.7 ± 2.6 years (mean ± SD)] and <80 years (n = 277, age 66.9 ± 9.5 years) with ischaemic or non-ischaemic cardiomyopathy (NYHA class III or IV heart failure, left ventricular ejection fraction <35%, QRS 120 ms) underwent CRT. A clinical assessment, including a 6-min walk test, and a quality of life assessment (Minnesota Living with Heart Failure questionnaire) were undertaken at baseline and after CRT. In octogenarians, CRT was associated with similar changes in NYHA class [–1.28 vs. –1.22,P < 0.0001 (P-values refer to changes from baseline)], 6-min walking distance (77.2 vs. 78.6 m,P < 0.0001), and quality of life scores (–20.4 vs. –31.4,P = 0.0084) to <80 year olds. A symptomatic response to CRT (improvement by 1 NYHA classes or 25% 6-min walking distance) was observed in 80% of <80 year olds and in 81% of octogenarians (P = NS). Using a combined clinical score (CCS; survival for 1 year with no heart failure hospitalizations, and; improvement by 1 NYHA classes or 25% 6-min walking distance), a response was observed in 201 out of 277 (73%) patients <80 years and in 36 out of 53 (68%) octogenarians (P = NS). After a maximum follow-up of 7.6 years (median 634 days), no group differences emerged with respect to the composite endpoints of cardiovascular death or hospitalization for major cardiovascular events, the composite endpoint of cardiovascular death or heart failure hospitalization, cardiovascular mortality, or total mortality.
Conclusion: Octogenarians derive similar benefits from CRT to younger patients.
Key Words: Cardiac resynchronization therapy, Heart failure, Age, Octogenarian, Mortality
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Introduction |
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Cardiac resynchronization therapy (CRT) is now a standard therapy in selected patients with moderate to severe heart failure. The Cardiac Resynchronization in Heart Failure (CARE-HF) study showed that, compared with optimum pharmacological therapy alone, CRT was associated with a 36% relative reduction in mortality.1
This and other studies have shown that CRT also leads to an improvement in symptoms and quality of life, and to a reduction in hospitalizations.2,3
In developed countries, heart failure is becoming a disease of octogenarians.4,5 This is due to the fact that the mean age at the first diagnosis of heart failure is 76 years5 and that populations are becoming increasingly elderly. The mean age of patients treated for heart failure by the United Kingdom National Health Service in 2005 was 79 years.6 In the US, the 1990 and 2000 Census records revealed that people aged 75–84 increased from 10.0 million to 12.1 million (21%) whereas people aged 85 years increased from 30.8 million to 41.8 million (36%).7 To add to the burden of heart failure to health care systems, octogenarians are more than 20 times more likely to be hospitalized for heart failure than patients between the ages of 35 and 64.7
The evidence base for CRT has emerged from trials of patients who are 
15 years younger than patients with heart failure in ‘the real world’. The mean ages in the intervention arms of CRT trials were 67 years in Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial8 and CARE-HF,9 64 years in Multistimulation in Cardiomyopathies-Sinus Rhythm (MUSTIC-SR) study,2 and 65 years in the Multisite InSync Randomized Clinical Evaluation (MIRACLE) study.3 In the CARE-HF trial, the only randomized controlled trial of CRT powered for mortality, only 6.1% patients were 80 years. Our observational study compares the symptomatic response as well as mortality and cardiovascular events after CRT in octogenarians to that of younger patients.
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Methods |
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Patients
A total of 330 patients (53 aged
80 years and 277 aged <80 years) who underwent biventricular pacemaker implantation in a single centre (Good Hope Hospital) from September 2000 to April 2008 were included in this study. Inclusion criteria were: heart failure in NYHA class III or IV, impaired LV function [left ventricular ejection fraction (LVEF) 
35%], a QRS complex 120 ms, and optimal tolerated drug treatment. Echocardiographic measures of dyssynchrony were not used in patient selection. Exclusion criteria included: contraindications to cardiac pacing, myocardial infarction or acute coronary syndrome within the previous month, presence of or indications for an implantable cardioverter-defibrillator, severe structural valvular heart disease, and presence of co-morbidities likely to threaten survival for 12 months. In the UK, implantable cardioverter-defibrillator therapy for the primary prevention of sudden cardiac death in CRT recipients was only recommended in 2007. By that time, most of the patients included in this study had received CRT without implantable cardioverter-defibrillator back-up. For the sake of homogeneity, therefore, this study was restricted to CRT without implantable cardioverter-defibrillator back-up.
The diagnosis of heart failure was made if symptoms of heart failure were associated with objective evidence of LV dysfunction on echocardiography, or if pulmonary oedema had been documented on chest radiography in the absence of valvular disease. The diagnosis of ischaemic cardiomyopathy was made if systolic dysfunction was associated with a history of myocardial infarction10 or if there was angiographically documented coronary heart disease (>50% stenosis in 1 coronary arteries). The study conforms to the Declaration of Helsinki and was approved by the local Ethics Committee.
Study design
Pacemaker implantation was undertaken during an elective admission or after stabilization during the course of an unplanned admission for acute decompensated heart failure. Prospective data were acquired with patients undergoing a clinical assessment on the day prior to implantation and at 1, 3, and every 6 months following pacemaker implantation. This included evaluation of NYHA functional class and a 6-min hall-walk test.11 A quality of life assessment was also undertaken using the Minnesota Living with Heart Failure questionnaire,12 the scores for which range from 0 to 105, with the higher scores reflecting a poorer quality of life. Clinical follow-up data relate to the last available follow-up before death or the end of the study period.
Device therapy
Biventricular pacemaker implantation was undertaken using standard techniques. Patients were followed up in a dedicated device therapy clinic. Patients in atrial fibrillation did not undergo atrioventricular node ablation. For patients in sinus rhythm, trans-mitral Doppler-directed optimization of atrioventricular delay13 was undertaken prior to discharge and at every scheduled visit thereafter. Back-up atrial pacing was set at 60 b.p.m., and the pacing mode was set to DDD with an interventricular delay of 0–4 ms, depending on the manufacturer’s default setting. For patients in atrial fibrillation, right ventricular and LV leads were implanted and a biventricular generator was used, plugging the atrial port and programming the generator to a ventricular-triggered mode. Generators used included the Medtronic InSync III models 8040 and 8042, St Jude Frontier I and II, Vitatron CRT 8000, Biotronik Stratos LV, and Guidant Contak Renewal TR2.
Echocardiography
Standard two-dimensional echocardiography was performed at baseline using Systems 5 and 7 with EchoPAC (General Electric Healthcare Worldwide, Slough, UK). Left ventricular end-diastolic volume and left ventricular end-systolic volume were assessed using planimetry of apical four-chamber views and Simpson’s equation. At the time of the study, no echocardiographic measure of dyssynchrony had been proved to be of value in selecting patients for CRT, over and beyond QRS duration criteria adopted in major outcome trials. Echocardiographic measures of dyssynchrony were therefore not used in patient selection.
Response rates and endpoints
Following pacemaker implantation, patients were monitored in a dedicated CRT clinic. Response to CRT was assessed using the symptomatic response (improvement by 1 NYHA classes or 25% 6-min walking distance) and by the combined clinical score (CCS; survival for 1 year with no heart failure hospitalizations, and; improvement by 1 NYHA classes or 25% 6-min walking distance). The clinical endpoints considered included the composite of cardiovascular death or an unplanned hospitalization with worsening HF and the composite endpoint of total mortality or hospitalization for a major cardiovascular event (MCE). Cardiac transplantation, hospitalizations for worsening HF, myocardial infarction, unstable angina, arrhythmia, stroke, pulmonary embolism, or upgrading to CRT with implantable cardioverter-defibrillator back-up were included in this end point. The first event was included in the analysis. The other endpoints considered were cardiovascular mortality and total mortality. Sudden cardiac death was defined as ‘a natural, unexpected death due to cardiac causes, heralded by an abrupt loss of consciousness within one hour of the onset of acute symptoms'.14 Mortality data were collected through medical records and, where appropriate, from interviews with patient’s caregivers. Clinical outcome data were collected by an investigator who was blinded to other clinical and imaging data. Follow up data refer to the last available follow-up.
Statistical analysis
Continuous variables are expressed as mean ± SD. Normality was tested using the Shapiro–Wilk test. Variables which were not normally distributed were log-transformed before statistical analyses. Comparisons between normally distributed continuous variables were made using ANOVA with Scheffe’s F procedure for multiple comparisons. Categorical variables were analysed using 
2 tests and Scheffe’spost hoc test. Changes in variables from baseline to follow-up were analysed using paired Student’st-tests. Differences in survival curves between the groups were assessed using the log-rank (Mantel–Cox) test. The influence of age on the various endpoints was analysed using Cox proportional hazards analyses. Statistical analyses were performed using Statview (Cary, NC, USA) and SPSS 15.0 (Chicago, IL, USA).
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Results |
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The characteristics of the study group are shown inTable 1. The <80 or
80 year age groups were well matched for gender, heart failure aetiology, co-morbidities, medications, atrial rhythm, QRS duration, and LVEF. More patients in the 80 year age group had undergone upgrading from a conventional pacemaker (P = 0.0117).
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As shown inTable 2, baseline 6-min walking distance was lower in octogenarians than in younger patients (P<0.0001). Complete follow-up data on NYHA class were available in all patients. Complete follow-up data on 6-min walk tests were available in 164 patients (aged <80 years) and in 35 octogenarians. Compared with the <80 year age group, CRT in octogenarians was associated with similar changes in NYHA class (–1.28 vs. –1.22), 6-min walking distance (77.2 vs. 78.6 m), and quality of life scores (–20.4 vs. –31.4) (all changes from baselineP<0.0001). A symptomatic response to CRT was observed in 221 of 277 (80%) patients aged <80 years and in 43 of 53 (81%) octogenarians (P=NS). Using the CCS, a clinical response was observed in 201 of 277 (73) patients aged <80 years and in 36 of 53 (68%) octogenarians (P=NS).
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Kaplan–Meier analysis of survival over a maximum follow-up period was 7.6 years (median 634 days, interquartile range 790 days) (Figure 1). Total mortality was higher in octogenarians, but this did not achieve statistical significance (log rankP = 0.1275). In Cox proportional hazards analyses, age, entered as a continuous or as a dichotomous (<80 or
80 years), failed to emerge as a predictor of the various endpoints (data not shown).
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Complications
There were no intra- or peri-procedural deaths in either group. There were 25 of 277 (9%) failed implantations in the <80 year group and 2 of 53 (4%) in the
80 year group (P = NS). The overall success rate, including second percutaneous implantation, was 92.5%. There were 6 of 277 re-admissions for lead repositioning in the <80 year group and 1 of 53 in the 80 year group (P = NS). Implantation time was not routinely recorded, but there was no perceived group difference in implantation time. |
Discussion |
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Despite optimum pharmacological therapy, mortality and morbidity in octogenarians with heart failure remains high. We have shown that, in this age group, CRT is associated with a similar response to 60 year olds, in terms of symptoms, functional capacity, and quality of life. Furthermore, octogenarians exhibit a similar rate of hospitalizations for MCE and heart failure as younger patients. In the background of the clinical effectiveness of CRT proven by randomized, controlled trials of younger patients,8
,15 these data suggest that octogenarians benefit from CRT to the same degree.
Epidemiological16 and trial registry17 data have shown that mortality from heart failure increases with age. A study in Scotland revealed mortality rates of 0.36/1000 population in <65 year olds and of 49.16/1000 population in >85 year olds.18 The findings from the present study that mortality and morbidity after CRT are similar in octogenarians compared with younger patients raises the possibility that the benefit from CRT is proportionally greater in octogenarians. In this regard, the economic modelling analysis undertaken for the United Kingdom National Institute of Clinical Excellence in 2007 revealed that the proportional increase in overall median survival from CRT compared with drug therapy alone is higher in octogenarians than in 60 year olds.19
An important consideration in the delivery of CRT, as for any other therapy, is cost-effectiveness. The economic modelling analysis undertaken by the United Kingdom National Institute of Clinical Excellence (NICE) in 2007 showed that the incremental cost-effectiveness ratio for CRT (compared with drug therapy alone) in octogenarians was GBP17 087 (2008 
21 492), compared with GBP15 829 (2008 19 910) for 60 year olds. Both of these figures were below the willingness-to-pay threshold of GBP 30 000 (2008 37 734) in the UK and of $40 000 (2008 25 892) in the USA. As a comparison, the cost per quality-adjusted life year of monotherapy with the cholesterol-lowering drug ezetimibe in a similar age group ranges from £33 000 to £42 000 (2008 41 507–52 828).20 The finding that CRT is cost-effective at all ages, including octogenarians, also emerged from the CARE-HF economic model analysis.21
Conventional pacemaker implantation is routinely undertaken in elderly patients with bradyarrhythmias. Registry data from the United Kingdom shows that, in the period 2004–2005, the rate of implantation was 100 per million for 50 year olds and 10 000 per million for 90 year olds.22 With respect to CRT in octogenarians, however, there is evidence of a low uptake. In the InSync/InSync ICD Italian Registry,23 for example, only 7% of patients were octogenarians. This apparent gap in the delivery of CRT to octogenarians reflects a reluctance to treat the elderly with CRT, reflecting, perhaps, a perception that it involves a greater risk of complications. There is, however, no evidence to suggest this. Octogenarians are, admittedly, apt to suffer from poor mobility, frailty, and multiple co-morbidities, all of which preclude invasive procedures. It would appear, however, that they have at least as much to gain from CRT as younger patients.
Limitations of the study
This observational study has several limitations. Most importantly, it does not comprise a placebo control group and therefore, uncertainty remains as to whether the observed effects of CRT in octogenarians are over and above placebo. The finding from randomized trials that CRT is beneficial in younger patients15 together with the finding of similar outcomes in this study suggests that octogenarians do benefit from CRT. In this study we have not assessed the effect of CRT upon mitral regurgitation. We are therefore unable to determine whether CRT has differential effect on mitral regurgitation in the two age groups.
Conclusions
From this observational study of consecutive patients with heart failure undergoing CRT, we conclude that octogenarians derive similar benefits from CRT to younger patients. We have observed comparable changes in functional capacity and quality of life, as well as similar rates of death, cardiovascular events, and hospitalizations over a long follow-up period. These findings suggest that CRT is at least as beneficial to octogenarians as to younger patients. On the basis of these findings, reluctance to administer CRT to octogenarians would appear to be unjustified on the basis of age alone.
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Medtronic Inc. and St Jude Medical provided funding for the research fellowships involved in this study.
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Acknowledgements |
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We are grateful to St Jude Medical and Medtronic Inc for their continued scientific support. We are also grateful to Lisa Ball, Janet Brashaw-Smith and Nick Irwin for their input in the follow-up of patients included in this study.
Conflict of interest: P.W.X.F. has received a research fellowship from Medtronic Inc. and support from St Jude Medical. K.K. has received sponsorship from St Jude Medical S.C. has received sponsorship from Medtronic Inc., Guidant, and St Jude Medical and a fellowship from Medtronic Inc. R.E.A.S. has received sponsorship from Medtronic Inc. F.L. has received sponsorship from Medtronic Inc and St. Jude Medical. M.P.F. is a consultant for, and undertakes research sponsored by, Medtronic Inc. and is also on the End Points Committee for a study funded by Biotronik.
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References |
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