CARE-HF: Long-term Effects of Cardiac Resynchronization on Mortality and Echocardiography and Cost-effectiveness Analyses

Luis Gruberg, MD, FACC

Disclosures

October 24, 2005

Editorial Collaboration

Medscape &

The Cardiac Resynchronization in Heart Failure (CARE-HF)[1] trial was an open-label, randomized, controlled study that evaluated the effects of cardiac resynchronization therapy (CRT) on morbidity and mortality in patients with reduced left ventricular (LV) function and ventricular dyssynchrony on optimal medical therapy for heart failure. The trial enrolled patients with New York Heart Association class III or IV heart failure, wide QRS duration ≥ 120 ms, and LV ejection fraction (EF) ≤ 35%. A total of 813 patients were randomized to receive CRT (n = 409) or to control (n = 404).

Baseline characteristics of patients were well balanced; average age was 66 years, 35% to 40% of patients had ischemic heart disease, mean EF was 25%, and mean QRS duration was 160 ms. All patients were treated with optimal medical therapy, including 95% of patients in each group on angiotensin converting enzyme inhibitors or angiotensin receptor blockers and 72% on beta-blockers; 44% of patients were on diuretic therapy (Table 1).

Table 1. Baseline Characteristics
  Control
(n = 404)
CRT
(n = 409)
Age (yrs) 66 67
Female (%) 27 26
Ischemic heart disease (%) 36 40
Ejection fraction (%) 25 (22-29) 25 (21-29)
Concomitant Medical Treatment
ACE/ARB (%) 95 95
Beta-blockers (%) 73 71
Furosemide > 80 mg/day (%) 44 43
Spironolactone (%) 59 54
ACE/ARB = angiotensin converting enzyme/angiotensin receptor blocker; CRT = cardiac resynchronization therapy

The CARE-HF trial was one of the first trials that documented a mortality benefit from CRT. At 2 years, the use of CRT was associated with a 37% reduction in the trial's primary endpoint (the composite of all-cause mortality or unplanned hospitalization for a cardiovascular event) compared with control. In addition, CRT was associated with a 36% reduction in the risk of mortality and a 46% reduction in the combined endpoint of death or heart failure hospitalizations (Table 2). The results of the study remained consistent across various subgroups, including patients with and without ischemic heart disease.

Table 2. CARE-HF: Primary and Main Secondary Endpoints
  Control
(n = 404)
CRT
(n = 409)
HR 95% CI P
Primary endpoint:
All-cause mortality or unplanned hospitalization for a CV event (%) 224
(55%)
159
(39%)
0.63 0.51-0.77 < .001
Secondary endpoints:
All-cause mortality 120
(30%)
82
(20%)
0.64 0.48-0.85 < .002
All-cause mortality or unplanned hospitalization for worsening HF (%) 191
(47%)
118
(29%)
0.54 0.43-0.68 < .001
CI = confidence interval; CRT = cardiac resynchronization therapy; CV = cardiovascular; HF = heart failure; HR = hazard ratio
Extension Phase of CARE-HF Presenter: John G. F. Cleland, MD (Castle Hill Hospital, Kingston-upon-Hull, United Kingdom)

Before knowing the overall results, the trial's Steering Committee added an extension phase of the study until May 2005, in which the primary endpoint was all-cause mortality. During this extension phase, there were no further tests and crossover was strongly discouraged until the main results were known.

At a mean follow-up of 36.4 months, compared with control, the use of CRT was associated with a 40% reduction in the risk of all-cause mortality, a 45% reduction in the risk of heart failure mortality, and a 46% reduction in sudden death (Figure 1).

Figure 1. Results of extension phase of CARE-HF trial.

According to Prof. Cleland, speaking on behalf of the trial investigators, the CARE-HF program provides overwhelming evidence that CRT reduces all-cause mortality and that CRT reduces sudden death and death due to worsening heart failure.

CARE-HF Echocardiographic Substudy Presenter: Luigi Tavazzi, MD (San Mateo Hospital, Pavia, Italy)

In the main CARE-HF study, echocardiograms were performed in all patients at baseline, 3, 9, 18 months, and at the end of the study. Variables such as severity of cardiac dyssynchrony, ventricular function, and mitral regurgitation (MR) were measured. Baseline echo studies were available in 803 patients and were of analyzable quality in 735 patients (91%). Baseline measurements of these 735 studies are shown in Table 3:

Table 3. Baseline Echocardiography Measurements (N = 735)
Measurement Results
LVEDV (cm2) 320 (244-381)
LVESV (cm2) 243 (177-291)
LVEF (%) 25.5 (21.3-28.9)
Detectable MR (%) 72
MR index of LA area 24 (11-34)
Detectable TR (%) 48
IVMD (ms) 47.9 (29.3-66.4)
IVMD = interventricular mechanical delay; LA = left atrium; LVEDV = left ventricular end diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end systolic volume; MR = mitral regurgitation; TR = tricuspid regurgitation

Compared with the medical therapy group, at all follow-up periods, CRT was associated with significant reductions in LV end-systolic (Figure 2) and end-diastolic volume indices (Figure 3), area of MR (Figure 4), and interventricular mechanical delay (IVMD) (Figure 5).

Figure 2. LV end-systolic volume index.
Figure 3. LV end-diastolic volume index.
Figure 4. Mitral regurgitation index.
Figure 5. Interventricular mechanical delay.

In addition, CRT was associated with a significant increase in EF compared with control, a finding that remained consistent across all follow-up periods (Figure 6). Furthermore, changes in EF were more pronounced in CRT patients with nonischemic vs ischemic disease (Figure 7); similar findings were also noted in the CRT group with respect to changes in LV end-systolic volume.

Figure 6. Ejection fraction.
Figure 7. Change in LVEF from baseline: ischemic vs nonischemic etiology.

These findings, according to Prof. Tavazzi, demonstrate that reverse remodeling associated with CRT is sustained over the long term, both in patients with ischemic and nonischemic etiology.

Cost-effective Analysis Presenter: Nick Freemantle, PhD (University of Birmingham, United Kingdom)

The objective of the cost-effective analysis of CARE-HF was to evaluate the within-trial incremental cost per quality-adjusted life year (QALY) of CRT therapy vs medical therapy alone. Costs were collected at baseline, 1, 3, 6, 9, 12, and 18 months, and at the end of the study. At each period, data on CRT device and lead costs (€5,825; mean European list price), cardiac surgical procedures, consultations, hospital stay, and cardiovascular medications were collected. The resources used in the overall study are shown in Table 4.

Table 4. Resource Use
  Control (n = 404) CRT (n = 409)
Mean hospital days 22 21
Mean ICU days 0.8 0.4
Mean CCU days 2.5 2.9
Total PCI/CABG 8 6
Heart transplants 9 10
Total CRT procedures 48 467
Total CRT-ICD procedures 27 9
CABG = coronary artery bypass graft; CCU = cardiac care unit; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator; ICU = intensive care unit; PCI = percutaneous coronary intervention

In the overall CARE-HF study, investigators found that at 90-day follow-up, patients in the CRT group reported significant improvements in quality of life compared with patients in the medical therapy group (P < .001). Despite a higher mean cost associated with CRT, the therapy was associated with a QALY improvement of 0.22 units compared with medical therapy alone (Table 5). The overall cost per QALY was £13,142 (€19,367). Prof. Freemantle noted that the rate associated with CRT was lower than the cost per QALY of bare-metal stents for revascularization and was comparable to cost per QALY of using carvedilol in heart failure. Treatments under €44,100 per QALY gained are considered to be cost-effective.

Table 5. Cost-effectiveness Analysis
  Control
(n = 404)
CRT
(n = 409)
Mean Difference
(95% CI)
Mean cost (£) 10,745 13,680 2,936
(903-5092)
Mean QALY 1.19 1.42 0.22
(0.13-0.32)
CI = confidence interval; CRT = cardiac resynchronization therapy; QALY = quality-adjusted life years
Discussant: K. Swedberg (Gotheburg, Sweden)

Discussing the results of the extension study and subanalyses of the CARE-HF trial, Prof. Swedberg noted that the data provide further evidence of the benefits of CRT, as is already reflected in the European Society of Cardiology guidelines on the diagnosis and treatment of congestive heart failure, where CRT is a class I, level of evidence A indication. He also stated that the results provide additional information that support and extend the trial's initial report and also demonstrate that the therapy is cost-effective. However, there are further questions that were not answered with this study, including whether CRT is sufficient in these patients or whether there is a concomitant need for ICD implantation. Such issues warrant further study.

Reference
  1. Cleland JGF, Daubert J-C, Erdmann E, et al; the Cardiac Resynchronization -- Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549.

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