Impact of CRT on Mortality: What Are the Preliminary Results from the CARE-HF Trial?
M. LUNATI, G. MAGENTA
CARE-HF Study Design and Study Results
The Cardiac Resynchronization-Heart Failure (CARE-HF) trial [1] was a multicentre, international randomised trial whose aims were:
1. To assess the effect on morbidity and mortality of adding CRT to opti- mised pharmacological therapy in patients with moderate and severe heart failure (HF) due to left ventricular systolic dysfunction (LVSD) complicated by cardiac dyssynchrony (CD)
2. To investigate the mechanisms underlying the observed effect and to identify markers predicting success or failure of CRT.
The main inclusion criteria were: chronic HF, NYHA class III/IV, with a high standard of pharmacological therapy, LVSD and dilation (EF ≤ 35% ; LVEDD ≥ 30 mm/heights in meters), cardiac dyssynchrony (QRS ≥ 150 ms or QRS ≥ 120 ms and two of the following echo criteria: aortic preejection delay ≥ 140 ms, interventricular mechanical delay ≥ 40 ms, delayed activation of the posterolateral LV wall).
Between January 2001 and March 2003, 813 patients were enrolled at 82 European centres. Patient randomised to CRT (404) received a Medtronic Insync or Insync III device that provided atrial-biventricular stimulation (without backup ICD); the implant success rate was 96%.
The primary endpoint was a composite of death from any cause or an unplanned hospitalisation for a major cardiovascular event. The principal secondary outcome was death from any cause, classified according to mode.
At completion of the study (September 30, 2004) the rate of cross-over before primary endpoint was < 5%, survival status was ascertained on all patients,
SC Elettrofisiologia, Dipartimento Cardiologico ‘A. De Gasperis’, Azienda Ospedaliera Niguarda Cà Granda, Milan, Italy
mean follow-up from randomisation was 29.4 months.
Baseline characteristics were similar in the two groups (males 73%, mean age 66 years, mean ejection fraction 25%, mean QRS duration 160 ms, mean use of a beta-blocker 74%).
By the end of the study, the primary endpoint had been reached in 159 patients in the CRT group vs 224 patients in the control group (39% vs 55%;
HR 0.63, 95% confidence interval 0.51–0.77, P < 0.001).
In the CRT group, 82 patients died as compared with 120 patients assigned to medical therapy alone (20% vs 30%; HR 0.64, 95% confidence interval 0.48–0.85, P < 0.002). The mode of death was sudden in 35% of the patients in the CRT group and in 32 % of the patients assigned to medical therapy; the cause of death was attributed to worsening HF in 40% of the patients in the CRT group and in 47% of the patients assigned to medical therapy.
Compared with medical therapy alone, CRT reduced interventricular mechanical delay, end-systolic volume index, area of mitral regurgitation jet.
CRT increased EF and improved symptoms and quality of life (P < 0.01).
The benefits were similar among patients with ischaemic heart disease and in those without, and were in addition to those afforded by pharmacological therapy.
In summary, the study demonstrated that in patients with advanced HF and cardiac dyssynchrony CRT improves symptoms and quality of life and reduces complications and risk of death (37% risk reduction of death or unplanned hospitalisation, 36% risk reduction of death from any cause) and should be routinely considered in such patients.
Impact of CRT on Mortality and Update on Guidelines
Approximately 20–25% of patients with advanced HF have electrocardio- graphic or echocardiographic evidence of inter or intraventricular dyssyn- chrony. CRT with the simultaneous stimulation of both ventricles improves coordination of ventricular contraction and, in a series of trials lasting up to 6 months, decreased symptoms and improved exercise capacity and ventric- ular function [2, 3].
In the COMPANION trial [4], the primary endpoint, composite outcome of mortality and hospitalisation for any reason, was reduced by 20% in the CRT arm and in the CRT+ICD arm during a mean follow-up of 16 months.
Mortality, the secondary endpoint, was reduced by 24% relative (4%
absolute), P < 0.06, by CRT and 36% relative (7% absolute), P < 0.003, by CRT + ICD. There was no difference in mortality when CRT and CRT+ICD were compared.
528 M. Lunati, G. Magenta
Meta-analyses have left some uncertainty about the effects of CRT on mortality [5, 6].
The CARE-HF trial [1] demonstrated a 37% relative (16% absolute), P <
0.001, reduction in the composite of death or hospitalisation for major events and a 36% relative (10% absolute), P < 0.001, reduction in all-cause death.
Thus, there is now clear-cut evidence that CRT, without ICD, significantly reduces the risk of death in patients with advanced HF and ventricular dys- synchrony. An ICD might further reduce the risk of sudden death, but if all cause mortality curves of COMPANION and CARE-HF are compared, it seems that HF patients died for arrhythmic events in the first 5–6 months after CRT, and after that period they died of HF progression; in other words, it seems that reverse remodelling influences electrical remodelling.
Retarding the progression of cardiac dysfunction to prevent malignant arrhy thmias and sudden death may be a better strategy than treating arrhythmias with an ICD once they occur, but obviously this issue needs fur- ther evaluation.
Owing to the striking evidence of the CARE-HF trial, in the recently pub- lished new guidelines (update 2005) for the diagnosis and treatment of chronic HF of the European Society of Cardiology [7], CRT can be consid- ered in the treatment of patients with reduced EF and ventricular dyssyn- chrony (QRS duration [NYHA III–IV] despite optimal medical therapy:
• To improve symptoms (class of recommendation I, level of evidence A)
• To reduce hospitalisations (class of recommendation I, level of evidence A)
• To decrease mortality (class of recommendation I, level of evidence B).
CRT in combination with an ICD can be considered in patients with severe HF (NYHA III–IV), reduced EF, and ventricular dyssynchrony (QRS duration ≥ 120 ms):
• To improve morbidity and mortality (class of recommendation IIa, level of evidence B)
References
1. Cleland JG, Daubert JC, Erdmann E et al (2005) The effect of cardiac resynchroni- zation on morbidity and mortality in heart failure. N Engl J Med 352:1539–1549 2. Cazeau S, Leclerq C, Lavergne T et al (2001) Effects of multisite biventricular
pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344:873–880
3. Abraham WT, Fisher WG, Smith AL et al (2002) Cardiac resynchronization in chro- nic heart failure. N Engl J Med 346:1845–1853
4. Bristow MR, Saxon LA, Boehmer J et al (2004) Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:2140–2150
5. Mc Alister FA, Ezekowitz JA, Wiebe N et al (2004) Systematic review: cardiac resyn- 529 Impact of CRT on Mortality: What Are the Preliminary Results from the CARE-HF Trial?
chronization in patients with symptomatic heart failure. Ann Intern Med 141:381–390
6. Calvert M, Freemantle N, Cleland JG et al (2005) Cardiac resynchronization the- rapy in heart failure. Ann Intern Med 142:305–307
7. Anonymous (2005) Guidelines for the diagnosis and treatment of chronic heart failure: full text (update 2005). The Task Force for the diagnosis and treatment of CHF in the European Society of Cardiology. Eur Heart J 26:1115–1140
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