Heart Failure: Improving the quality of life and survival of heart failure patients through Cardiac Resynchronisation Therapy
Submitting InstitutionUniversity of Birmingham
Unit of AssessmentPublic Health, Health Services and Primary Care
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
Heart failure affects more than 22 million people worldwide, including 6
million in Europe and 5 million in the United States, with approximately
500,000 new patients diagnosed each year.
The cardiac resynchronisation in heart failure trial (CARE-HF)
demonstrated that, in patients with heart failure and cardiac
dyssynchrony, use of an implantable pacemaker to improve heart contraction
led to a 37% reduction in the risk of death and hospitalisations and
significant improvements in patient quality of life. The benefits are in
addition to those of standard pharmacologic therapy. As a result of the
CARE-HF trial, international and NICE guidelines have recommended the use
of cardiac resynchronization therapy in patients with heart failure and
dyssynchrony resulting in an increased use of cardiac resynchronisation
throughout the world and significant improvements in quality of life and
survival for heart failure patients.
Heart failure affects more than 22 million people worldwide, including 6
million in Europe and 5 million in the United States, with approximately
500,000 new patients diagnosed each year (http://www.medtronic.com/physician/care_hf/faqs.html).
Despite improvements in pharmacological treatment, many patients with
heart failure have severe and persistent symptoms and their prognosis
remains poor. Early studies of an implantable pacemaker — cardiac
resynchronization therapy (CRT) suggested that it was a promising new
intervention for patients with heart failure, left ventricular systolic
dysfunction and ventricular dyssynchrony with evidence that CRT decreased
symptoms, improved exercise capacity, quality of life, and ventricular
function. The COMPANION trial (2004) showed that CRT alone or combined
with an implantable defibrillator reduced the composite end point of death
from any cause or hospitalization during a mean follow-up of 16 months;
however, the decrease in the risk of death was not significant with CRT
alone (P=0.06). Meta-analyses left lingering uncertainty about the effects
of cardiac resynchronization on the risk of complications and death.
From 2001 to 2005, a team from the University of Birmingham (Professor
Nick Freemantle, Professor of Clinical Epidemiology and
Biostatistics, UoB up to April 2011; Dr Melanie Calvert, Reader in
Epidemiology, UoB) led the design and analysis of the landmark Cardiac
Resychronisation in Heart Failure Trial (CARE-HF) and its extension study.
The CARE-HF trial (PI Cleland, University of Hull; funded by Medtronic
Ltd; design & analysis Freemantle, Calvert) was a
multi-centre, international, randomised controlled trial to evaluate
long-term effects of CRT on the mortality and morbidity of patients with
heart failure due to left ventricular systolic dysfunction and cardiac
dyssynchrony who were receiving standard pharmacologic therapy. A total of
813 patients were recruited between January 2001 and March 2003 at 82
centres across 12 European countries. Patients were randomly assigned to
receive medical therapy alone or with CRT and followed for a mean of 29.4
The primary end point was the time to death from any cause or unplanned
hospitalisation for a major cardiovascular event. The principal secondary
end point was death from any cause. The primary end point was reached by
159 patients in the cardiac-resynchronization group, as compared with 224
patients in the medical-therapy group (39 percent vs. 55 percent; hazard
ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001).
There were 82 deaths in the CRT group, as compared with 120 in the
medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95
percent confidence interval, 0.48 to 0.85; P<0.002). As compared with
medical therapy, CRT reduced the interventricular mechanical delay, the
end-systolic volume index, and the area of the mitral regurgitant jet;
increased the left ventricular ejection fraction; and improved symptoms
and the quality of life (P<0.01 for all comparisons). This landmark
trial thus demonstrated significant improvements in survival and quality
of life in patients randomised to CRT. These benefits are in addition to
those afforded by standard pharmacologic therapy and it was recommended
that the implantation of a cardiac-resynchronization device should
routinely be considered in such patients. The results were published in
the New England journal of Medicine  and have been cited 2715 times accessed
via Scopus online 30th July 2013. The
observed benefits in survival and quality of life were sustained over time
Whilst the CARE-HF trial demonstrated reduced morbidity and mortality,
CRT is relatively costly thus it was essential to establish the
incremental cost-effectiveness of using the device compared to standard
care. Within trial and life-time simulation model based cost-effectiveness
analyses were led from the University of Birmingham (Freemantle;
Calvert; Professor Stirling Bryan, Professor of
Health Economics, UoB, up to August 2008; Dr Lily Yao,
Senior Lecturer in Health Economics, UoB, up to February 2013; Professor
Lucinda Billingham, Professor of Biostatistics, UoB) in
conjunction with CARE-HF investigators from elsewhere (Cleland, Daubert).
The aim of the within trial cost-effectiveness analysis was to evaluate
the incremental cost per QALY gained and incremental cost per life year
gained of CRT plus medical therapy compared to medical therapy alone. It.
CRT was associated with increased costs (€4316, 95% CI: 1327 to 7485),
survival (0.10 years, 95% CI: — 0.01 to 0.21), and QALYs (0.22, 95% CI:
0.13 to 0.32). The incremental cost-effectiveness ratio was €19 319 per
QALY gained (95% CI: 5482 to 45 402) and €43 596 per life-year gained (95%
CI: — 146 236 to 223 849) . A further long term cost-effectiveness
analysis used a lifetime simulation model developed based upon individual
patient data from the CARE-HF trial to examine the additional effect of
CRT with an implantable cardioverter-defibrilator (ICD) function, which
further reduces risk of death. Both CRT + medical therapy and CRT-ICD +
medical therapy were cost-effective at a notional willingness to pay
threshold of €29 400 (£20,000) but the latter to a lesser extent .
There were also contributions to cost-effectiveness analyses for the
Nordic region and Greece (Freemantle, Calvert).
The CARE-HF trial has resulted in a further 24 publications (including
Birmingham authors Freemantle; Calvert; Dr Puvanendran Tharmanathan,
doctoral student, UoB up to December 2008; Matthew Richardson,
research fellow, UoB up to April 2012; Aparna Shankar,
research associate, UoB up to August 2008) on topics including quality of
life , neurohormonal effects, procedure success rate and predictors of
References to the research
1. Cleland J, Daubert J-C, Erdmann E, Freemantle N, Gras
D, Kappenberger L et al . CARE-HF Study Investigators (inc. Calvert M).
The effect of cardiac resynchronization on morbidity and mortality in
heart failure N Engl J Med 2005; 352(15) :1539-1549.
2. Cleland JG, Calvert MJ, Verboven Y, Freemantle N.
Effects of cardiac resynchronization therapy on long-term quality of life:
an analysis from the CArdiac Resynchronisation-Heart Failure (CARE-HF)
study. Am Heart J. 2009 ;157(3):457-66. Epub 2009 Jan 20.
3. Calvert MJ, Freemantle N, Yao G, Cleland JG, Billingham
L, Daubert JC et al. CARE-HF investigators. FASTTRACK.
Cost-effectiveness of cardiac resynchronization therapy: results from the
CARE-HF trial. Eur Heart J. 2005;26(24) : 2681-8. Epub 2005 Nov
4. Yao G, Freemantle N, Calvert MJ, Bryan S,
Daubert JC, Cleland JG. The long-term cost-effectiveness of cardiac
resynchronization therapy with or without an implantable
cardioverter-defibrillator. Eur Heart J. 2007;28(1): 42-51. Epub
2006 Nov 16.
5. Calvert MJ, Freemantle N, Cleland JGF. The impact of
chronic heart failure on health-related quality of life data acquired in
the baseline phase of the CARE-HF study. Eur J Heart Fail. 2005;
7(2) : 243-51. http://www.ncbi.nlm.nih.gov/pubmed/15701474
Details of the impact
Impact on Public Policy
CARE-HF has been used as key evidence supporting the use of cardiac
resynchronization therapy in a series of international guidelines at both
regional (Europe ) and national level, in countries as diverse as
Australia , Brazil , Canada , Czech Republic , New Zealand
[2,6], and USA [7,8,9]. Examples include:
1) European Society of Cardiology Guidelines for the Diagnosis and
Treatment of Heart Failure, were initially published in 2005 and later
revised during the 2008-13 impact period, in both 2008 and 2012 . These
guidelines all cite CARE-HF as a source of key evidence for recommending
the use of cardiac resynchronization therapy in patients with moderate to
severely symptomatic heart failure (Section 9.2.1, reference 157 in 2012
2) American College of Cardiology Foundation/American Heart Association
Guidelines for the Diagnosis and Management of Heart Failure in Adults
2005 and 2009 . CARE-HF is cited as one of the trials providing strong
evidence supporting the use of CRT in selected patients (Section
188.8.131.52.4., reference 101).
3) Guidelines for the prevention, detection and management of chronic
heart failure in Australia published in 2011  (Section 8.1; pg 36,
reference 204). These guidelines cite CARE-HF (reference 204) as
supporting use of biventricular pacing for patients with: NYHA symptoms
Class III/IV despite optimal medical therapy; dilated heart failure with
an ejection fraction less than or equal to 35%; QRS duration greater than
or equal to 120 ms; sinus rhythm.
The 2012 expert consensus statement on cardiac resynchronization therapy
in heart failure from EHRA/HRS cites evidence from the CARE-HF trial as
influencing a number of recommendations including around use of biomarkers
in assessing heart failure (Section 1.2.2, reference 8), around
considerations for patients with CRT and concomitant atrial fibrillation
(Section 6.2, reference 264), and concerning the cost-effectiveness of CRT
(Section 6.8, references 348, 350) . This consensus statement is
endorsed by the governing bodies of European Association of
Cardiovascular Imaging, American Heart Association, American Society of
Echocardiography, Heart Failure Society of America, Heart Failure
Association of the European Society of Cardiology, European Heart Rhythm
Association, and Heart Rhythm Society.
Impact on Clinical Practice and Patient Health
There has been impact on UK patients throughout the 2008-2013 impact
period, resulting from both the UK guidelines included above and also the
incorporation of the research into NICE guidance just prior to the impact
period. In the UK, CARE-HF provided evidence that underpins the NICE
Technology Appraisal Guidance: Cardiac resynchronisation therapy for the
treatment of heart failure, 2007  and which recommended the use of CRT
in selected patients with left ventricular dysfunction. CARE-HF was one of
4 RCTs considered by the NICE Appraisal Committee on CRT-P versus optimal
pharmacological therapy alone (see p7-15). In addition the strict clinical
inclusion criteria was adopted by the committee as a requirement in
clinical practice (see pages 14/15):
"The Committee noted that in one of the large studies (CARE-HF)
additional evidence of mechanical dyssynchrony from echocardiography was
required in patients with a QRS duration of between 120 ms and 150 ms,
and was therefore persuaded that such a requirement would be appropriate
to use in clinical practice." (p14)
"The Committee also understood from the clinical specialists that
confirmation of the presence of mechanical dyssynchrony by
echocardiography was considered appropriate in patients with electrical
dyssynchrony as indicated by a QRS duration of between 120 ms and 149
ms. The Committee noted that this approach was the same as the inclusion
criteria for the CARE-HF trial." (p15)
The publication of the CARE-HF Trial was a substantial contribution
within the overall portfolio of evidence which has seen the use of CRT
substantially increased throughout Europe. Eucomed data, based on reports
from major device manufacturers, suggest an increase in CRT (+/-ICD) use
across Europe rising from 86 units per million inhabitants in 2008 to 141
units per million inhabitants in 2012 . In the UK new CRT implants
have increased significantly following the publication of the CARE-HF
trial in 2005  and are now over 100/million population .
Sources to corroborate the impact
- European Society of Cardiology. ESC guidelines for the diagnosis and
treatment of acute and chronic heart failure. ESC Task Force for the
Diagnosis and Treatment of Acute and Chronic Heart Failure. European
Heart Journal 2012; 33: 1787-1847
- National Heart Foundation of Australia and the Cardiac Society of
Australia and New Zealand. Guidelines for the prevention, detection
and management of chronic heart failure in Australia.
Revised July 2011. http://www.csanz.edu.au/LinkClick.aspx?fileticket=TGB_bO-
- Bocchi EA, Braga FG, Ferreira SM, Rohde LE, Oliveira WA, Almeida DR,
et al. [III Brazilian Guidelines on Chronic Heart Failure]. Arq Bras
Cardiol 2009;93(1 Suppl 1):3-70.
- Howlett JG et al . Canadian Cardiovascular Society Consensus
Conference Guidelines on heart failure, update 2009: Diagnosis and
management of right-sided heart failure, myocarditis, device therapy and
recent important clinical trials. Can J Cardiol
- Spinar J, Vitovec J, Hradec J, Malek I, Meluzin J, Spinarova L, et al.
Czech Society of Cardiology guidelines for the diagnosis and treatment
of chronic heart failure 2011. Cor et vasa 54, e113-e134.
- Smith W. New Zealand primary implantable cardioverter defibrillator
implantation and biventricular pacing guidelines. New Zealand Med J
2010 Feb 19;123(1309):86-96.
- Heart Failure Society of America. Comprehensive Heart Failure Practice
Guideline. Journal of Cardiac Failure: 2010; 475-506:16(6).
- Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA, III, Freedman RA,
Gettes LS, et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy
of cardiac rhythm abnormalities. Heart Rhythm 2008
- Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, et
al. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and
Management of Heart Failure in Adults. Circulation 2009 Apr
- 2012 EHRA/HRS expert consensus statement on cardiac resynchronization
therapy in heart failure: implant and follow-up recommendations and
management. Heart Rhythm. 2012;9(9),1524-1576. http://dx.doi.org/10.1016/j.hrthm.2012.07.025
- National Institute for Health and Clinical Excellence . Heart
failure — cardiac resynchronisation: guidance. NICE TA120 .
London: National Institute for Health and Clinical Excellence; 2007
(proposed for review July 2010). http://guidance.nice.org.uk/TA120/Guidance/pdf/English.
National Institute for Health and Clinical Excellence. Chronic heart
failure: Management of chronic heart failure in adults in primary and
secondary care. NICE Clinical Guideline CG108; August 2010. http://guidance.nice.org.uk/CG108/NICEGuidance/pdf/English
- Eucomed, 2013.
- Cunningham D, Charles R, Cunningham M, Whittaker T. Cardiac Rhythm
Management. NICOR, 2013.