RAFT

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Tang AS, et al. "Cardiac-resynchronization therapy for mild-to-moderate heart failure". The New England Journal of Medicine. 2010. 363(25):2385-2395.
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Clinical Question

Among patients with heart failure (NYHA class II or III), widened QRS and left ventricular ejection fraction ≤30%, does the addition of CRT to an ICD reduce the mortality and morbidity, as compared to ICD alone?

Bottom Line

Among patients with heart failure (NYHA class II or III), widened QRS and left ventricular ejection fraction ≤30%, the addition of CRT to an ICD reduces the mortality and morbidity but increased the rate of adverse events, as compared to ICD alone.

Major Points

The benefit of cardiac resynchronization therapy (CRT) for patients with heart failure has been observed in many trials including the CARE-HF, MIRACLE, MADIT-CRT and REVERSE trials.[1][2][3][4] The CARE-HF showed that in patients with NYHA Class III or IV heart failure and cardiac dyssynchrony, CRT significantly reduced mortality and hospitalization for a major CV event as compared to medical treatment only. In the MADIT-CRT trial, CRT combined with ICD (CRT-ICD) reduced the rate of all-cause mortality or non-fatal heart failure in patients with NYHA class II heart failure, LVEF ≤30% and QRS duration ≥130 msec.

Published in 2010, the multicenter, double-blind, Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) randomized 1,798 patients with NYHA class II or III heart failure, intrinsic QRS duration ≥120 msec or a paced QRS duration ≥200 msec and left ventricular ejection fraction (LVEF) ≤30% from ischemic or non-ischemic causes to receive CRT and ICD (ICD-CRT) as compared to ICD only. The primary outcome was mortality and hospitalization for heart failure. The mean follow-up duration was 40 months. The primary outcome occurred in 33.2% of patients in the ICD-CRT group as compared to 40.3% in the ICD group (HR 0.75; 95% CI 0.64-0.87; P<0.001; NNT=14). However, it is important to note that the survival benefit did not become apparent until approximately 2 years after device implant. Additionally, patients in the ICD-CRT group also had a significantly higher adverse event rate as compared to the ICD group (14% vs. 6.5%, P<0.001; NNH=13).

A meta-analysis published in 2011 (25 trials, 9082 patients) showed that in patients with NYHA class I and II heart failure, CRT reduced all-cause mortality (6 trials, 4572 patients; RR 0.83, 95% CI 0.72-0.96) and hospitalization for heart failure (4 trials, 4349 patients; RR, 0.71, 95% CI 0.57-0.87) without any difference in functional outcome or quality of life. In patients with NYHA class III and IV heart failure, CRT reduced all-cause mortality (19 trials, 4510 patients; RR 0.78, 95% CI 0.67-0.91) and hospitalization for heart failure (11 trials, 2663 patients; RR 0.65, 95% CI 0.50-0.86). However, in this subgroup, CRT was shown to improve functional outcome and quality of life. The success rate of the procedure was estimated to be 94.4% and the risk of mechanical complications was 3.2%.[5]

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[6]

  • For patients with LVEF ≤35% on goal-directed medical therapy:
    • CRT is indicated if sinus rhythm, LBBB, QRS ≥150 msec, and NYHA class II (class I, level B) or NYHA class III or ambulatory IV symptoms (class I, level A)
    • CRT can be useful for patients with sinus rhythm, non-LBBB, QRS ≥150 ms, with NYHA class III or ambulatory class IV symptoms (class IIa, level A)
    • CRT can be useful for patients with sinus rhythm, non-LBBB, QRS ≥150 ms, with NYHA class II symptoms (class IIb, level B)
    • CRT is useful if sinus rhythm, LBBB, QRS 120-149 ms, with NYHA class II, III or ambulatory IV (class IIa, level B)
    • CRT can be considered for patients with sinus rhythm, non-LBBB pattern with QRS 120-149 ms, and NYHA class III/ambulatory class IV (Class IIb, level B)
    • CRT is useful if there is atrial fibrillation requiring ventricular pacing or otherwise meeting CRT criteria and that the patient will be able to have near 100% ventricular pacing with CRT either by AV-nodal ablation or rate-controlling medications (class IIa, level B)
    • CRT is useful if undergoing placement/replacement of a device and anticipated need for >40% ventricular pacing (class IIa, level C)
  • For patients with LVEF ≤30% on goal-directed medical therapy, CRT may be considered for patients WITH ischemic etiology of HF, sinus rhythm, LBBB with a QRS duration≥150 ms, and NYHA class I (Class IIb, level C)
  • CRT is not recommended for NYHA class I or II symptoms, no LBBB, and QRS <150 msec (class III, level B)
  • CRT is not indicated if comorbid conditions limit survival to <1 year (class III, level C)

Design

  • Multicenter, double-blind, randomized, controlled trial
  • N=1,798
    • ICD-CRT (n=894)
    • ICD only (n=904)
  • Setting: 34 centers in Canada, Europe, and Australia
  • Enrollment: January 2003 to February 2009
  • Mean follow-up: 40±20 months
  • Analysis: Intention-to-treat
  • Primary outcome: mortality or hospitalization for heart failure, defined as admission to a health care facility lasting >24hours with symptoms of heart failure and subsequent treatment for heart failure

Population

Some details are presented elsewhere.[7]

Inclusion Criteria

  • Heart failure (NHYA class II or III) on optimal medical therapy
  • Left ventricular ejection fraction (LVEF)≤30% from ischemic or non-ischemic causes, as determined by radionuclide scan, angiography, MRI or echo if LV end diastolic dimension ≥60mm
  • Intrinsic QRS duration ≥120 msec or a paced QRS duration ≥200 msec
  • Sinus rhythm or permanent atrial flutter or atrial fibrillation with a controlled ventricular rate (≤60 per minute at rest and ≤90 per minute during a 6-minute walk test) or planned atrioventricular-junction ablation after device implantation)
  • ICD implantation indicated for primary or secondary prevention of sudden cardiac death

Exclusion Criteria

  • Serious illness limiting life expectancy to <1 year
  • Recent cardiovascular event or revascularization (CABG or PCI) >1 month unless LVEF was documented to be ≤30% prior to event
  • IV inotropic agent 4 days prior to recruitment
  • Planned cardiac transplant within 1 year
  • Acute cardiac or noncardiac illness requiring intensive care
  • Primary valvular disease which was uncorrected or not correctable
  • Cardiomyopathy- restrictive, hypertrophic or any reversible form
  • Severe primary pulmonary disease eg cor pulmonale
  • Tricuspid prosthetic valve
  • Existing ICD
  • Enrolled in another study which will affect this study
  • Noncompliance to treatment
  • Not able to or not willing to provide consent

Baseline Characteristics

From the ICD-CRT group

  • Demographics: Age 66 years, male 85%
  • Cardiovascular history:
    • NYHA Class II 79%, LVEF 22.6±5.4%, permanent AF or A flutter 13%
    • Intrinsic QRS 157±23.6 msec, paced QRS 206.5±24.0 msec, LBBB 73%
    • Ischemic heart disease 69%, HTN 45%, DM 33%, previous PCI 25%, CABG 33%, active smoker 14%, PVD 10%, HF hospitalization in prior 6 months 27%
    • 6-minute walking test 351.3±106.7 m
    • eGFR 59.5 mL/min/1.73 m2
  • Medication use:
    • Beta-blocker 90%, ACE-inhibitor or ARB 96%, spironolactone 42%, digoxin 34%, ASA 65%, warfarin 35%, clopidogrel 15%, statin 68%, diuretic 85%, calcium-channel blocker 11%, amiodarone 16%

Interventions

  • At baseline, medical therapy was optimized in all patients. ECG and a 6-minute walk test were also performed
  • Patients were randomized to receive a group:
    • ICD-CRT - ICD with cardiac resynchronization with maximal ventricular pacing
    • ICD - Minimal ventricular pacing
  • The LV lead was preferentially placed in the lateral or posterolateral wall of the LV
  • Arrhythmia detection and therapy was standardized between groups

Outcomes

Comparisons are ICD-CRT vs ICD.

Outcomes are separated into 3 categories: all patients (894 in the ICD-CRT group, 904 in the ICD group, patients with NYHA class II heart failure at baseline (708 in the ICD-CRT group, 730 in the ICD group) and patients with NYHA class III heart failure at baseline (186 in the ICD-CRT group, 174 in the ICD group).

Primary Outcomes

Mortality or hospitalization for heart failure
33.2% vs. 40.3% (HR 0.75; 95% CI 0.64-0.87; P<0.001; NNT=14)
NYHA class II: 27.3% vs. 34.7% (HR 0.73; 95% CI 0.61-0.88; P=0.001; NNT=14)
NYHA class III: 55.9% vs. 63.8% (HR 0.76; 95% CI 0.58-0.99; P=0.04; NNT=13)

Secondary Outcomes

All-cause mortality
20.8% vs. 26.1% (HR 0.75; 95% CI 0.62-0.91; P=0.003; NNT=19)
NYHA class II: 15.5% vs. 21.1% (HR 0.71; 95% CI 0.56-0.91; P=0.006; NNT=18)
NYHA class III: 40.9% vs. 47.1% (HR 0.79; 95% CI 0.58-1.08; P=0.14)
Cardiovascular mortality
14.5% vs. 17.9% (HR 0.76; 95% CI 0.60-0.96; P=0.02; NNT=29)
NYHA class II: 10.5% vs. 13.7% (HR 0.73; 95% CI 0.54-0.99; P=0.04; NNT=31)
NYHA class III: 30.1% vs. 35.6 % (HR 0.77; 95% CI 0.54-1.10; P=0.15)
Hospitalization for heart failure
19.5% vs. 26.1% (HR 0.68; 95% CI 0.56-0.83; P<0.001; NNT=15)
NYHA class II: 16.2% vs. 21.8% (HR 0.70; 95% CI 0.55-0.89; P=0.003; NNT=18)
NYHA class III: 31.7% vs. 44.3% (HR 0.63; 95% CI 0.45-0.88; P=0.006; NNT=8)

Subgroup Analysis

For the primary outcome

QRS duration
Intrinsic QRS ≥150 msec: Favors ICD-CRT (HR 0.59; 95% CI 0.48-0.73)
Intrinsic QRS <150 msec: No difference (HR 0.99; 95% CI 0.77-1.27; P=0.002 for interaction)
Paced QRS ≥200 msec: No difference (HR 1.07 95% CI 0.63-1.84; P=0.03 for interaction)
QRS morphology
LBBB: Favors ICD-CRT
RBBB: No difference
Non-specific intraventricular conduction delay: No difference
Paced: No difference
P-value for interaction=0.046

There were no significant interactions for age, sex, NYHA class at baseline, underlying heart disease, LV ejection fraction, sinus or atrial rhythm, presence of diabetes, hypertension or eGFR level

Adverse Events

Device- or implantation-related complications within 30 days post-implant
14% vs. 6.5% (P<0.001; NNH=13)
Hemothorax or pneumothorax: 1.2% vs. 0.9% (P=0.47)
Device-pocket hematoma requiring intervention: 1.6% vs. 1.2% (P=0.53)
Device-pocket infection requiring intervention: 2.4% vs. 1.8% (P=0.39)
Lead dislodgement requiring intervention: 6.9% vs. 2.2% (P<0.0001; NNH=21)
Device-pocket problems requiring intervention: 0.5% vs. 0.1% (P=0.22)
Coronary sinus dissection: 1.2% vs. 0% (P=0.0004; NNH=83)

Criticisms

  • The NYHA classification has its limitations, and the Seattle Heart Failure Model has been proposed to be a better tool for assessing patients. However, the model was not available at the time of the trial.[8]
  • The impact of ICD-CRT on left ventricular remodeling or quality of life was not reported.[9]

Funding

  • Canadian Institutes of Health Research
  • Medtronic of Canada

Further Reading

  1. Cleland JG et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N. Engl. J. Med. 2005. 352:1539-49.
  2. Abraham WT et al. Cardiac resynchronization in chronic heart failure. N. Engl. J. Med. 2002. 346:1845-53.
  3. Moss AJ et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N. Engl. J. Med. 2009. 361:1329-38.
  4. Linde C et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J. Am. Coll. Cardiol. 2008. 52:1834-43.
  5. Al-Majed NS et al. Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure. Ann. Intern. Med. 2011. 154:401-12.
  6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
  7. Tang AS et al. Resynchronization/defibrillation for ambulatory heart failure trial: rationale and trial design. Curr. Opin. Cardiol. 2009. 24:1-8.
  8. Rosenstein RS & Parra D Cardiac-resynchronization therapy. N. Engl. J. Med. 2011. 364:1277; author reply 1277-8.
  9. Al-Majed NS & Ezekowitz JA Cardiac resynchronisation therapy is efficacious in patients with mild heart failure symptoms. Evid Based Med 2011. 16:138-9.