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Cardiac Cardiac Resynchronisation Resynchronisation
TherapyTherapy
September 2008September 2008
The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure (CARE-HF)
John G.F. Cleland, M.D., Jean-Claude Daubert, M.D., Erland Erdmann, M.D., Nick Freemantle, Ph.D., Daniel Gras, M.D., Lukas Kappenberger, M.D. and Luigi Tavazzi,
M.D.
N Engl J MedVolume 352;15:1539-1549
April 14, 2005
BackgroundBackground
Despite pharmacological advances in treatment of HF, mortality & morbidity remain high
Cardiac dyssynchrony (regions of delayed myocardial activation & contraction) is common
Small studies (up to 6/12) cardiac resynchronisation therapy (CRT) improved quality of life, exercise capacity & ventricular function
Trials with CRT +/- ICD (COMPANION) showed that with CRT alone the decrease in risk of death was insignificant
Meta-analysis are inconclusive This trial was designed to assess the effect of CRT on mortality in patients
with severe HF
MethodsMethods
Multicenter, randomised, non blinded, international trial comparing
“the risk of complications & death of standard pharmacological therapy alone with that of combination of standard therapy and CRT
(without ICD) in patients with LV systolic dysfunction, cardiac dyssynchrony and symptomatic heart failure”
82 European centers between Jan 2001 & March 2003
Inclusion Criteria: 18yrs+ HF for at least 6 weeks NYHA III/IV LVEF < 35% QRS of at least 120ms
Exclusion Criteria: Conventional indications for PPM/ICD Major CV event in last 6/52 HF requiring IV therapy Atrial arrhythymias
MethodsMethods
End Points
Primary: Composite of death from any cause or an unplanned hospitalisation for major CV event (worsening HF, MI, USA, Stroke, Arrhythmia)
Secondary: Death from any cause, Quality of life assessment
Statistical Analysis
Intention to treat Principle
Statistical power of 80% to identify a 14% relative reduction given an α value of 0.025 & predicted number of events as 300
Baseline Characteristics of the Patients
Cleland, J. et al. N Engl J Med 2005;352:1539-1549
Kaplan-Meier Estimates of the Time to the Primary End Point (Panel A) and the Principal Secondary Outcome (Panel B)
Cleland, J. et al. N Engl J Med 2005;352:1539-1549
Study Outcomes in Analyses Stratified According to NYHA Class
Cleland, J. et al. N Engl J Med 2005;352:1539-1549
Hemodynamic, Echocardiographic, and Biochemical Assessments
Cleland, J. et al. N Engl J Med 2005;352:1539-1549
DiscussionDiscussion
CRT substantially reduced risk of complications & death among patients with moderate/severe heart failure
Consistent with a reduction in cardiac dyssynchrony leading to improved physiological parameters and clinical outcome:
Quality of Life Ventricular function Blood pressure Mortality
For every 9 devices implanted 1 death and 3 hospitalisations are prevented
Cardiac Resynchronisation Cardiac Resynchronisation TherapyTherapy
BackgroundBackground11
Approx 25% of patients with CHF have intraventricular conduction delay; commonly LBBB
Electrical activation of lateral aspect of LV can be delayed in relation to that of RV and/or interventricular septum
This results in Dyssynchronous electrical activation & contraction Unequal distribution of myocardial workload Altered myocardial blood flow & metabolism
Patients with conducting disease have worse prognosis from CHF Patients with a paced RV end up having an artificially induced
interventricular conducting delay and overall systolic function is poorer
ProcedureProcedure22
Simultaneous pacing of RV & LV = Biventricular pacing
RA, RV & LV
LV paced via coronary sinus
Physiological EffectsPhysiological Effects
Doesn’t restore normal physiological conducting pattern RA pacing with short AV delay ensures all beats are paced RV & LV pacing reduces the delay in electrical activation of LV free wall QRS duration tends to decrease
Haemodynamic response:
Increase in rate of rise of LV pressure Increases pulse pressure, LV stroke volume Improves myocardial function without increasing myocardial energy
consumption
EvidenceEvidence
Early Trials: <500 patients, up to 1 year showed increases in functional capacity & improvements in quality of life
COMPANION3 (ICD): mortality from all causes was reduced with CRT & ICD (p=0.003) but not from CRT alone (p=0.059)
CARE-HF4: mortality from all causes was reduced (p<0.002)
Guidance for CRTGuidance for CRT55
NICE May 2007; must fulfil ALL the below
NYHA III or IV SR with QRS >150ms SR with QRS 120-149ms & echo evidence of dyssynchrony LVEF < 35% Optimal pharmacological therapy
Cost: £3809
Number: 500/year
Guidance for CRT-DGuidance for CRT-D66
NICE May 2007 & January 2006
Criteria as before plus: Primary Prevention
MI (>4/52) & either (LVEF <35% and NSVT on holter and inducible VT on EP studies) OR (LVEF <30% and QRS >120ms)
Familial Tendency (longQT, Brugada, HOCM, ARVD) Secondary Prevention (in absence of treatable cause)
Post VT/VF arrest Spontaneous sustained VT causing compromise Sustained VT without compromise but LVEF >35%
Cost: £16000
Number: 500/year
Adverse EffectsAdverse Effects
Unable to implant LV lead due to unfavourable anatomy (3-10%) Diaphragmatic stimulation due to proximity of phrenic nerve Coronary sinus dissection (0.3-4.0%) Coronary sinus perforation & tamponade (0.8-2.0%) Periprocedural death (0.4%) Dislodgement of LV lead (10%)
Pneumothorax Complete Heart Block Asystole Pacemaker pocket infection External electromagnetic field
Further StudyFurther Study
? Benefit in NYHA I/II patients REVERSE7: no significance at end point MADIT-CRT: late 2009
Approx. 20-30% of patients with CRT are non-responders Is the QRS duration a good predictor of CRT response? Could echo evidence of ventricular dyssynchrony be more predictive?8
“Dyssynhcrony study”9
Application in patients with AF?
ReferencesReferences
1. Jarcho JA. Biventricular Pacing. N Engl J Med 2006;355:288-294 http://content.nejm.org/cgi/content/full/355/3/288
2. Jarcho JA. Resynchronising Ventricular Contraction in Heart Failure. N Engl J Med 2005;352:1594-1597 http://content.nejm.org/cgi/content/full/352/15/1594
3. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. (COMPANION) N Engl J Med 2004;350:2140-2150 http://content.nejm.org/cgi/content/full/352/15/1539
4. Cleland JGF, Daubert J-C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure (CARE-HF) N Engl J Med 2005;352:1539-1549 http://content.nejm.org/cgi/content/full/350/21/2140
5. NICE: Heart Failure – Cardiac Resynchronisation; May 2007 http://www.nice.org.uk/TA1206. NICE: Arrhythmias – Implantable Cardioverter defibrillators: January 2006 http://www.nice.org.uk/TA957. Linde C, Abraham WT, Gold MR, Daubert J-C. Results of the REVERSE trial. Program and abstracts from
the American College of Cardiology 2008 Scientific Sessions, March 29-April 1, 2008, Chicago, Illinois http://www.medscape.com/viewarticle/573311
8. Yu CM, Bax JJ, Monaghan M, Nihoyannopoulos. Echocardiographic evaluation of cardiac dyssynchrony for predicting a favourable response to cardiac resynchronisation therapy. Heart 2004;90:vi17-vi22 http://heart.bmj.com/cgi/content/full/90/suppl_6/vi17
9. Bax JJ, Ansalone G, Breithardt et al. Echocardiographic evaluation of CRT: ready for routine clinical use? J Am Coll Cardiol 2004;44:1-9 http://content.onlinejacc.org/cgi/content/full/44/1/1