Heart Failure

Heart Failure
Effects of Cardiac Resynchronization Therapy With or Without a
Defibrillator on Survival and Hospitalizations in Patients With
New York Heart Association Class IV Heart Failure
JoAnn Lindenfeld, MD; Arthur M. Feldman, MD, PhD; Leslie Saxon, MD; John Boehmer, MD;
Peter Carson, MD; Jalal K. Ghali, MD; Inder Anand, MD; Steve Singh, MD;
Jonathan S. Steinberg, MD; Brian Jaski, MD; Teresa DeMarco, MD; David Mann, MD;
Patrick Yong, MSEE; Elizabeth Galle, MS; Fred Ecklund, MA; Michael Bristow, MD, PhD
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Background—Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has
been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and
mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device
procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV
patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)
trial to assess the potential benefits of CRT and CRT-D.
Methods and Results—The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical
therapy, CRT, or CRT-D. In the class IV patients (n⫽217), the primary end point of time to death or hospitalization for any
cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94; P⫽0.02) and CRT-D (HR,
0.62; 95% CI, 0.42 to 0.90; P⫽0.01). Time to all-cause death and HF hospitalization was also significantly improved in both
CRT (HR, 0.57; 95% CI, 0.37 to 0.87; P⫽0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75; P⫽0.001) Time to all-cause
death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10; P⫽0.11) and CRT-D (HR, 0.63; 95% CI,
0.39 to 1.03; P⫽0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI,
0.08 to 0.90; P⫽0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to
1.37; P⫽0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52; P⫽0.48).
Conclusions—CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV
patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF
patients similar to those enrolled in COMPANION. (Circulation. 2007;115:204-212.)
Key Words: defibrillation 䡲 heart failure 䡲 pacemakers 䡲 survival
C
ardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has
been shown to improve exercise capacity and quality of life
and to reduce heart failure (HF) hospitalizations and mortality
in patients with New York Heart Association (NYHA) class
III and IV HF.1–7 Only small numbers of patients enrolled in
these trials have been classified as NYHA class IV, however.
Class IV patients typically have limited myocardial reserve
and a poor survival. It has been suggested that class IV
patients may not benefit from CRT or indeed even CRT-D, as
Editorial p 161
Clinical Perspective p 212
the implant procedure may destabilize the HF and worsen shortterm outcomes before the benefits of device therapy can be realized.
Therefore, we sought to examine the outcomes of NYHA class IV
HF patients enrolled in the Comparison of Medical Therapy,
Pacing, and Defibrillation in Heart Failure (COMPANION) trial, a
trial that randomized patients to 1 of 3 treatment groups: optimal
medical therapy (OPT), OPT ⫹ CRT, and OPT ⫹ CRT-D.
Received April 7, 2006; accepted October 11, 2006.
From the Department of Medicine, University of Colorado Health Sciences Center (J.L., M.R.B.), and Women’s Health Research Center (J.L.), Denver,
Colo; Thomas Jefferson Medical College (A.M.F.), Philadelphia, Pa; University of Southern California (Keck School of Medicine) (L.A.S.), Los Angeles;
Milton Hershey Medical Center, Penn State School of Medicine (J.B.), Hershey, Pa; Washington DC Veterans Administration (S.S., P.C.), Washington,
DC; Wayne State School of Medicine (J.K.G.), Detroit, Mich; Minneapolis Veterans Administration (I.A.), Minneapolis, Minn; San Diego Cardiac Center
(B.J.), San Diego, Calif; University of California (T.M.), San Francisco; Cardiovascular Associates and St Mary and Elizabeth Hospital (D.M.),
Louisville, Ky; and Boston Scientific (P.Y., E.G., F.E.), St. Paul, Minn.
Clinical trial registration information—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00180258.
Correspondence to Dr JoAnn Lindenfeld, Division of Cardiology, University of Colorado Health Sciences Center, 4200 E. Ninth Ave, B-130, Denver,
CO 80262. E-mail [email protected]
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.629261
204
Lindenfeld et al
Methods
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The COMPANION trial was performed in 128 US centers. The
complete protocol as well as the results for the entire cohort are
reported elsewhere.3,8 Criteria for enrollment included NYHA class
III or IV HF caused by either ischemic or nonischemic cardiomyopathy, an electrocardiographic QRS interval of at least 120 milliseconds with a PR interval of ⬍150 milliseconds, sinus rhythm, no
clinical indication for pacemaker or implantable defibrillator, a left
ventricular ejection fraction (LVEF) of ⱕ0.35, and a hospitalization
for the treatment of HF or the equivalent in the 12 months preceding
enrollment.8 Exclusion criteria included expectation of a heart
transplantation in the subsequent 6 months, medically refractory
atrial arrhythmias, unexplained syncope, myocardial infarction
within 60 days, surgically uncorrected primary valvular heart disease, coronary artery intervention (catheter or surgical) within 60
days, progressive or unstable angina, and life expectancy ⬍6 months
for non-HF conditions.8 In addition, no patient could have a
scheduled or unscheduled admission for HF or intravenous inotropic
or vasoactive therapy in excess of 4 hours in the previous month.8
The steering committee, clinical endpoints committee, and sponsor
were blinded to treatment assignments. Physicians, patients, independent statisticians, and members of the data-management group
and the data and safety monitoring board were not blinded to
treatment assignments.
Enrolled patients were randomly assigned in a 1:2:2 ratio to
treatment with OPT, CRT, or CRT-D. Randomization was stratified by clinical site and ␤-blocker use, but not by NYHA class.
All patients were taking diuretics (unless not needed), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers
(unless not tolerated), ␤-blockers (unless not tolerated), and
spironolactone (unless not tolerated). Successful implantation of
CRT or CRT-D was defined as successful implantation of all
leads.
Once randomized, patients received CRT with implantation of
a biventricular pacemaker (Contak TR model 1241, Guidant,
Indianapolis, Ind) or a CRT-defibrillator (Contak CD model 1823,
Guidant) with the use of commercially available leads for right
atrial pacing and right ventricular pacing or for pacing with
defibrillation (Endotak models 0125, 0154, and 0155, Guidant).
Implantation techniques were described elsewhere.3
The primary end point of the present study, as well as the main
trial, was a composite of death from any cause and hospitalization
from any cause analyzed from the time of randomization to the
time of first event. Unscheduled administration of intravenous
vasoactive or inotropic agents for ⬎4 hours in the emergency
department was counted as a hospitalization. The implant hospitalization was not included in the primary end point. All-cause
mortality was a secondary end point. An additional end point of
interest was death from any cause or hospitalization for heart
failure. Components of the primary end point were adjudicated by
a blinded 7-member endpoints committee. Sudden death was
defined as observed or unobserved sudden death in the absence of
progressive HF. This category included patients who experienced
sudden cardiac death and survived in a postresuscitative course
but never regained consciousness and did not leave the hospital.
HF death was defined as progressively worsening HF manifested
by increased symptoms that required increases in medications,
which included intravenous medications. HF hospitalization was
defined as a hospitalization for the treatment of HF that required
increases in medications, which included intravenous
medications.
Statistical Analyses
All analyses were performed according to intention to treat. Comparisons between baseline characteristics were conducted by
ANOVA for continuous variables and a ␹2 test for categorical
variables. Hazard ratios (HRs) and associated probability values
were calculated based on time to first event with a Cox proportional
hazard model. All hazard ratios are unadjusted except where indicated. Hazard ratios were adjusted with stepwise selection (entry
Effects of CRT on Class IV Heart Failure Patients
205
0.30, stay 0.05) and included the following baseline variables:
treatment, systolic blood pressure, diastolic blood pressure, heart
rate, LVEF, QRS, NYHA class, ischemic status, diabetes status, left
bundle-branch block, right bundle-branch block, atrial fibrillation,
renal disease, hypertension, peripheral vascular disease, body mass
index, age, gender, and medication (␤-blocker, angiotensin
converting-enzyme or angiotensin receptor blocker, digoxin, diuretic). A log(-log) plot was used for each survival analysis to validate
the proportionality assumption. To analyze the end points of mortality and hospitalization, data on patients who withdrew before
reaching an end point, who were not known to have died and for
whom complete postwithdrawal information on hospitalization could
not be obtained, were censored at the time of elective hospitalization
for device implantation or on the date of the last contact. For the
NYHA class IV patients, some were censored before the end of the
present study. That is, for the primary end point of all-cause death or
hospitalization, 6 (11%), 0 (0%), and 0 (0%) of the OPT, CRT, and
CRT-D patients, respectively, were censored; for the mortality end
points, 2 (4%), 0 (0%), and 5 (6%) of the OPT, CRT, and CRT-D
patients were censored. Survival curves were plotted based on the
Kaplan-Meier method. Two-year rates for mode of death adjusted for
follow-up time were calculated based on life table survival estimates
from SAS software’s LIFETEST procedure. Continuous functional
capacity variables were tested with a Wilcoxon 2-sample test.
NYHA class change was evaluated with the Mantel-Haenszel ␹2 for
NYHA class change and implant success by the Fisher exact test. For
the functional capacity end points (6-minute walk, quality of life,
NYHA class), CRT and CRT-D were combined in the original
protocol design because there was no expectation that CRT-D would
influence exercise capacity in a manner dissimilar to CRT. The
duration of implant hospitalization days was based on the sum of all
implants (ie, some patients had ⬎1 attempt or successful implant)
and tested with a Wilcoxon 2-sample test. All probability values are
2-sided.
The authors had full access to the data and take full responsibility
for the integrity of the data. All authors have read and agreed to the
manuscript as written.
Results
Baseline Characteristics
Fourteen percent (n⫽217) of the 1520 COMPANION patients were NYHA class IV, whereas the remaining 86% were
NYHA class III. Table 1 compares baseline demographics of
participants with NYHA class III and class IV HF. NYHA
class IV patients had lower LVEF, a larger left ventricular
end-diastolic diameter, higher resting heart rate, and lower
systolic and diastolic blood pressure than NYHA class III
subjects. Ischemic heart disease was more often the cause of
HF in patients with NYHA class IV compared with class III
patients, and diabetes was more common in NYHA class IV.
Six-minute walk distance was significantly lower in the
NYHA class IV subjects. Conduction disorders and QRS
width were not significantly different. Patients with NYHA
class IV HF were less likely to be taking angiotensin
converting-enzyme inhibitors or angiotensin receptor blockers and ␤-blockers. The use of diuretics was slightly and
significantly more common in class IV (100%) participants
than in class III participants (95%). Spironolactone and
digoxin use was similar in both groups.
Table 2 presents the baseline characteristics of the NYHA
class IV patients by treatment group. There were no signifi-
206
Circulation
January 16, 2007
TABLE 1.
Baseline Demographics for NYHA Class III and NYHA Class IV Patients
NYHA Class III
(N⫽1303)
NYHA Class IV
(N⫽217)
65.6⫾11.5
66.7⫾10.4
0.19
Male
890 (68)
137 (63)
0.13
Female
413 (32)
80 (37)
Characteristic
Age, y, mean⫾SD
P
Gender, n (%)
4.5⫾4.1
5.4⫾4.9
䡠䡠䡠
⬍0.01
LVEF, %, mean⫾SD
22.6⫾6.9
20.8⫾6.6
⬍0.01
LVEDD, mean⫾SD
68.8⫾8.1
70.9⫾10.0
⬍0.01
Resting heart rate, bpm, mean⫾SD
72.5⫾12.6
76.6⫾13.1
⬍0.01
Systolic blood pressure, mm Hg, mean⫾SD
114.9⫾16.8
110.5⫾18.0
⬍0.01
Diastolic blood pressure, mm Hg, mean⫾SD
67.2⫾9.9
65.6⫾10.2
6-Minute walk distance, m, mean⫾SD
265.3⫾106.5
167.0⫾104.9
QRS width, ms, mean⫾SD
158.1⫾24.0
161.0⫾26.6
0.10
Yes
704 (54)
134 (62)
0.03
No
599 (46)
83 (38)
No
785 (60)
112 (52)
0.02
Yes
517 (40)
105 (48)
䡠䡠䡠
926 (71)
148 (68)
0.54
Duration of HF, y, mean⫾SD
0.02
⬍0.01
Ischemic, n (%)
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䡠䡠䡠
History of diabetes, n (%)
Conduction disorder, n (%)
Left bundle-branch block
Nonspecific intraventricular
235 (18)
46 (21)
䡠䡠䡠
Right bundle-branch block
142 (11)
23 (11)
䡠䡠䡠
Yes
1176 (90)
177 (82)
⬍0.01
No
127 (10)
40 (18)
䡠䡠䡠
Yes
914 (70)
112 (52)
⬍0.01
No
389 (30)
105 (48)
䡠䡠䡠
ACE inhibitor or angiotensin II, n (%)
␤-Blocker, n (%)
ACE inhibitor/angiotensin II ⫹ ␤-blocker, n (%)
Yes
824 (63)
96 (44)
⬍0.01
No
479 (37)
121 (56)
䡠䡠䡠
Yes
1240 (95)
216 (100)
⬍0.01
No
63 (5)
1 (0)
䡠䡠䡠
Yes
944 (72)
156 (72)
No
359 (28)
61 (28)
Yes
704 (54)
122 (56)
No
599 (46)
95 (44)
Loop diuretics, n (%)
Digoxin, n (%)
0.86
䡠䡠䡠
Spironolactone, n (%)
0.55
䡠䡠䡠
LVEDD indicates left ventricular end-diastolic diameter; ACE, angiotensin-converting enzyme.
cant differences by treatment group in any of the baseline
demographics.
Efficacy of Device Therapy
For NYHA class IV patients, the median duration of
follow-up for the primary end point was 7.2 months for
OPT, 14.2 months for CRT, and 14.1 month for CRT-D.
Figure 1 demonstrates the primary, secondary and addi-
tional end point of the study in NYHA class IV subjects.
The primary end point of time to death or hospitalization
for any cause was significantly prolonged by both CRT
(HR, 0.64; P⫽0.02) and by CRT-D (HR, 0.62; P⫽0.01)
compared with optimal medical therapy (OPT). Despite
favorable trends, time to death from any cause was not
significantly different when CRT (HR, 0.67; P⫽0.11) or
CRT-D (HR, 0.63; P⫽0.06) was compared with OPT.
Lindenfeld et al
TABLE 2.
Effects of CRT on Class IV Heart Failure Patients
207
Baseline Characteristics of NYHA Class IV Patients by Treatment Group
Characteristic
CRT-D (N⫽83)
CRT (N⫽79)
OPT (N⫽55)
P
64.8⫾11.4
66.9⫾10.4
69.0⫾8.4
0.07
Male
50 (60)
56 (71)
31 (56)
0.18
Female
33 (40)
23 (29)
24 (44)
5.1⫾4.7
5.6⫾5.3
5.4⫾4.4
䡠䡠䡠
0.79
LVEF, %, mean⫾SD
21.5⫾6.8
20.2⫾5.8
20.7⫾7.3
0.42
LVEDD, mean⫾SD
70.1⫾9.5
71.2⫾8.9
71.7⫾12.4
0.68
Resting heart rate, bpm, mean⫾SD
77.7⫾13.4
75.9⫾13.1
76.0⫾12.9
0.62
Systolic blood pressure, mm Hg, mean⫾SD
109.1⫾15.9
112.2⫾18.8
110.0⫾19.9
0.54
Diastolic blood pressure, mm Hg, mean⫾SD
66.8⫾10.4
65.5⫾10.3
63.8⫾9.5
0.23
6-Minute walk distance, m, mean⫾SD
177.9⫾112.6
161.2⫾98.2
158.5⫾102.6
0.50
QRS width, ms, mean⫾SD
161.4⫾27.2
160.1⫾26.2
161.9⫾26.9
0.93
Yes
47 (57)
51 (65)
36 (65)
0.47
No
36 (43)
28 (35)
19 (35)
䡠䡠䡠
No
45 (54)
43 (54)
24 (44)
0.39
Yes
38 (46)
36 (46)
31 (56)
䡠䡠䡠
Left bundle-branch block
59 (71)
49 (62)
40 (73)
0.46
Nonspecific intraventricular
18 (22)
18 (23)
10 (18)
䡠䡠䡠
Right bundle-branch block
6 (7)
12 (15)
5 (9)
䡠䡠䡠
Yes
69 (83)
63 (80)
45 (82)
0.86
No
14 (17)
16 (20)
10 (18)
䡠䡠䡠
Yes
47 (57)
40 (51)
25 (45)
0.43
No
36 (43)
39 (49)
30 (55)
䡠䡠䡠
Yes
44 (53)
43 (54)
34 (62)
0.57
No
39 (47)
36 (46)
21 (38)
䡠䡠䡠
83 (100)
78 (99)
55 (100)
0.42
䡠䡠䡠
1 (1)
䡠䡠䡠
䡠䡠䡠
Yes
56 (67)
61 (77)
39 (71)
0.38
No
27 (33)
18 (23)
16 (29)
䡠䡠䡠
Yes
52 (63)
39 (49)
31 (56)
0.23
No
31 (37)
40 (51)
24 (44)
䡠䡠䡠
Age, y, mean⫾SD
Gender, n (%)
Duration of HF, y, mean⫾SD
Ischemic, n (%)
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History of diabetes, n (%)
Conduction disorder, n (%)
ACE inhibitor or angiotensin II, n (%)
␤-Blocker, n (%)
ACE inhibitor/angiotensin II ⫹ ␤-blocker, n (%)
Loop diuretics, n (%)
Yes
No
Digoxin, n (%)
Spironolactone, n (%)
LVEDD indicates left ventricular end-diastolic diameter; ACE, angiotensin-converting enzyme.
Time to mortality or HF hospitalization was significantly
improved by both CRT (HR, 0.57; P⫽0.01) and CRT-D
(HR, 0.49; P⫽0.001) compared with OPT. Analysis of
time to HF death or HF hospitalization demonstrated a
significant benefit of CRT-D (CRT-D versus OPT: HR,
0.58; P⫽0.03). There was a strong trend for a benefit of
CRT versus OPT in time to HF death or HF hospitalization
(CRT versus OPT: HR, 0.64; P⫽0.07). CRT did not differ
from CRT-D for any of these endpoints.
Figure 2 depicts the time to sudden death and time to HF death
in each of the 3 treatment groups of NYHA class IV patients. The
time to sudden death was significantly prolonged by CRT-D
compared with OPT (HR, 0.27; P⫽0.03). The time to sudden death
was not affected by CRT compared with OPT (HR, 0.81; P⫽0.64).
The time to HF death was not significantly altered by either CRT
(HR, 0.68; P⫽0.28) or CRT-D (HR, 0.79; P⫽0.48) compared with
OPT. CRT was not significantly different from CRT-D for either
time to sudden death or HF death.
208
Circulation
January 16, 2007
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Figure 2. Time to mode of death by treatment arm for NYHA
class IV. A, Time to sudden death. B, Time to HF death. FU
indicates follow-up.
Figure 1. NYHA class IV endpoints by treatment arm. A, Primary time to all-cause death or hospitalization. B, Secondary
time to all-cause death. C, Time to all-cause death or HF hospitalization. FU indicates follow-up.
Although baseline covariates were not significantly
different among the 3 treatment groups, an analysis adjusted for covariates was performed for all the end points.
The adjusted analysis differed from the unadjusted analysis in only 1 comparison, which became significant in the
adjusted analysis: time to all-cause death in CRT versus
OPT (HR, 0.58; 95% CI, 0.35 to 0.96; P⫽0.04). The
proportionality assumption appeared to be met in all
analyses except the sudden death and the HF death
analyses.
At 1 year in the NYHA class IV patients, 44% of OPT
patients died, compared with 36% of CRT and 30% of
CRT-D patients. Table 3 shows mode of death over 2
years, adjusted for follow-up time: 62% of OPT subjects
died compared with 45% of CRT and 55% of CRT-D
subjects. Total mortality, HF mortality, and sudden cardiac
death, as expected, were higher in NYHA class IV subjects
than in class III subjects: 29%, 26%, and 41% of NYHA
Lindenfeld et al
TABLE 3.
Effects of CRT on Class IV Heart Failure Patients
Mode of Death at 2 Years
OPT
(n/N⫽55/253)
Mode of Death
TABLE 5.
CRT
(n/N⫽79/538)
Device Implantation Attempts and Success
CRT-D
(n/N⫽83/512)
Treatment
All death
209
Successful on
First Attempt
Successful
After ⬎1
Attempt
Unsuccessful
After ⬎1
Attempt
No
Attempt
NYHA class IV
29 (62)
34 (45)
34 (55)
Class IV (N⫽162)
NYHA class III
46 (26)
92 (23)
68 (20)
CRT-D (N⫽83)
64 (77)
6 (7)
10 (12)
3 (4)
CRT (N⫽79)
63 (80)
2 (3)
14 (18)
0 (0)
Class III (N⫽1050)
CRT-D (N⫽512)
440 (86)
31 (6)
37 (7)
4 (1)
CRT (N⫽538)
447 (83)
27 (5)
57 (11)
7 (1)
HF
NYHA class IV
14 (29)
17 (26)
21 (41)
NYHA class III
18 (10)
34 (10)
29 (8)
Sudden cardiac death
NYHA class IV
8 (25)
NYHA class III
10 (5)
11 (16)
4 (9)
36 (9)
13 (5)
Values expressed as n (%).
Other
NYHA class IV
7 (28)
NYHA class III
18 (14)
6 (12)
9 (18)
22 (6)
26 (8)
Values are expressed as n (%).
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class IV OPT, CRT, and CRT-D patients died of HF over
2 years, but time to HF death was not significantly
different (Figure 2B). In the OPT, CRT, and CRT-D
groups, 25%, 16%, and 9% of NYHA class IV patients
died of sudden cardiac death. Time to sudden death was
prolonged by CRT-D compared with OPT, but CRT and
CRT-D were not significantly different (Figure 2A). In
OPT patients, HF was the cause of death in 48% and 39%
of all deaths in the NYHA class IV and III subjects
respectively. Also in OPT patients, sudden death accounted for 28% and 22% of all deaths in the NYHA class
IV and III groups, respectively.
By the time of the 1-month visit, 67% of NYHA class IV
CRT-D and CRT patients improved at least 1 NYHA class,
compared with only 31% of OPT patients. Of those patients
who improved, there was a significant treatment benefit with
regard to mortality (CRT-D versus OPT: HR, 0.43; Pⱕ0.01;
CRT versus OPT: HR, 0.41; P⫽0.02). No mortality benefit
was seen in those who did not improve in NYHA class status
by 1 month.
Table 4 shows the baseline to 6-month changes in
6-minute walk, quality of life, and NYHA class for
combined CRT-D/CRT versus OPT patients. The 6-minute
TABLE 4. Functional Capacity in NYHA Class IV Patients:
Change From Baseline to 6 Months
Indicator
Number
Median (Q1, Q3)
% Improved
P
6-Minute walk
CRT/CRT-D
69
45.6 (⫺15.2, 106.4)
䡠䡠䡠
0.55
OPT
12
45.6 (⫺22.3, 60.9)
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
⬍0.01
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
78
⬍0.01
䡠䡠䡠
52
䡠䡠䡠
Quality of life
CRT/CRT-D
OPT
109
29
⫺25.0 (⫺44.0, ⫺8.0)
⫺4.0 (⫺20, 9.0)
NYHA
CRT/CRT-D
OPT
119
27
Q indicates quartile.
walk test did not improve significantly when CRT/CRT-D
was compared with OPT, but there were only 12 patients in
the OPT group. However, quality-of-life score and percent
of patients who improved at least 1 NYHA class improved
significantly in the CRT/CRT-D patients compared with
OPT.
No NYHA class IV patients died during the implantation
hospitalization. The duration of implantation hospitalization did not differ between NYHA class IV and III
patients, both of whom averaged ⬇4 days. Implantation
success rates by NYHA class and treatment group are
shown in Table 5. Success rates were slightly higher in
NYHA class III subjects compared with class IV subjects
in the CRT patients (88% versus 83%, respectively), and
significantly higher in the CRT-D patients (92% versus
84%, P⫽0.04, respectively).
Adverse Events
Overall, 40% (n⫽87) of NYHA class IV patients had a severe
adverse event within 1 year of randomization compared with
21% (n⫽275) of NYHA class III patients (P⬍0.0001). For
NYHA class III patients, the percent of patients with a severe
adverse event was consistent across all 3 treatment arms;
however, for NYHA class IV patients, the percent varied
across OPT, CRT, and CRT-D arms (47%, 43%, and 33%,
respectively; all P⬍0.015).
Crossovers
There were 19 patients (35%) in the OPT class IV group that
“crossed over” to device therapy during the course of the
study. Seven (9%) of the CRT and 4 (5%) of CRT-D class IV
patients crossed over. In class III, the crossovers were 37%,
11%, and 3% for OPT, CRT, and CRT-D, respectively. There
were no significant differences in crossovers between NYHA
class III and IV.
Discussion
Our present analysis of the COMPANION trial demonstrates
that both CRT and CRT-D improve the time to all-cause
mortality or first hospitalization in patients with NYHA class
IV HF. Both CRT and CRT-D also improved time to
all-cause mortality or HF hospitalization. There was a nonsignificant trend toward improved time to all-cause mortality
in both groups, and, in an analysis adjusted for covariates,
CRT did demonstrate a significant benefit for time to all-
210
Circulation
TABLE 6.
January 16, 2007
Demographics and Mortality in Studies of Patients With Advanced HF
REMATCH17
RALES17
BEST (IV)16
COPERNICUS17
COMPANION
(OPT)
FIRST18
PROMISE17
NYHA class
III/IV
III/IV
IV
IV
IV
IV
IV
IV
No.
ORAL
IV
471
527
841
15
46
217
65
64
65
䡠䡠䡠
63
1133
Age, y
64
68
68
67
LVEF, %
18
21
25
21
20
17
17
21
105
115
122
113
125
107
100
110
Systolic blood pressure, mm Hg
ACE inhibitor or ARB, %
84
䡠䡠䡠
95
88
97
66
53
82
␤-Blocker, %
䡠䡠䡠
䡠䡠䡠
11
䡠䡠䡠
randomized 1:1 to ␤-blocker
34
13
48
All
62
51
76
44
䡠䡠䡠
䡠䡠䡠
18
22
Treatment
䡠䡠䡠
37
Mortality, y, %
䡠䡠䡠
11.5
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
30
26
18.5
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
FIRST indicates the Flolan International Randomized Survival Trial; PROMISE, Prospective Randomized Milrinone Survival Evaluation
trial; RALES, Randomized Aldactone Evaluation Study; BEST, Beta-Blocker Evaluation of Survival Trial; COPERNICUS, Carvedilol
Prospective Randomized Cumulative Survival Study; REMATCH, Randomized Evaluation of Mechanical Assistance in Treatment if
Chronic Heart Failure; ACE, angiotensin-converting enzyme; and ARB, angiotensin receptor blocker.
Placebo
Downloaded from http://circ.ahajournals.org/ by guest on March 3, 2017
cause mortality. CRT-D was associated with a significant
improvement in time to HF deaths and HF hospitalization
with a strong trend for improvement in the same end point
with CRT. A significant survival benefit was demonstrated
for both the CRT and CRT-D patients who had symptomatic
improvement by at least 1 NYHA class at 1 month. Improvement in the primary end point was demonstrated for both
CRT and CRT-D despite an 18% and 12% rate of failed
implantation for CRT and CRT-D, respectively. Although
only CRT-D prolonged the time to sudden death, our data do
not demonstrate a significant difference between CRT and
CRT-D in any of the end points examined. These data
represent the first demonstration that NYHA class IV patients
benefit from either CRT or CRT-D. These results are particularly impressive given the high rate of crossovers in the OPT
group.
Only a few trials of CRT have included patients with
NYHA class IV HF.1,5,7 The number of NYHA class IV
patients was ⬍200 in all these trials and only 1 other trial
randomized patients before device implantation was attempted.5 None of the trials have reported NYHA class IV
patients separately, although 1 trial of CRT alone reported
no significant difference in outcomes between class III and
IV patients.5 There were only 50 NYHA class IV subjects,
however, and wide confidence intervals.
Progressive HF was the cause of death in 39% of class
III OPT patients and 48% of class IV OPT patients in the
present study at 2 years. This compares to 26% and 56% of
deaths caused by progressive HF in NYHA class III and IV
in Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).9 It is likely that
progressive HF was a more common cause of death in
NYHA class III patients in COMPANION than in
MERIT-HF because of the requirement for a HF hospitalization in the preceding 12 months in COMPANION,
which led to a more advanced degree of HF in COMPANION class III patients versus those in MERIT-HF.
None of the large trials of prophylactic implantable
cardiac defibrillators alone have included patients with
NYHA class IV HF.10 –14 Our data demonstrate that CRT-D
decreases sudden death (P⫽0.03) in class IV patients.
Similar to the entire cohort data, CRT-D improved sudden
death, although there was no significant difference between CRT and CRT-D.3 Salutary effects of CRT-D on
all-cause or HF hospitalizations as measured in the combined end points, which include mortality, was similar to
results with CRT alone.
Although COMPANION NYHA class IV subjects were
ambulatory at the time of randomization, they clearly had
severe HF. Our NYHA class IV OPT subjects were very
comparable to subjects in other studies with ambulatory
but advanced HF (Table 6). LVEF was 21% in the present
study, which was equivalent to the LVEF of the NYHA
class IV subjects in the Beta-Blocker Evaluation of Survival Trial (BEST) and Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), a trial of
carvedilol in subjects with advanced HF.15,16 COMPANION class IV subjects had a systolic blood pressure of
110 mm Hg, lower than the 123 mm Hg in COPERNICUS
and 117 mm Hg in the NYHA class IV subjects in
BEST.15,16 Indeed, the 1-year mortality of 44% in the
NYHA class IV OPT group was exceeded only by the
1-year mortality of 62% for patients in the Flolan International Randomized Survival Trial (FIRST) and the 1-year
mortality of 51% and 76% of noninotrope- and inotropedependent patients in the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure
(REMATCH).17,18 Thus, COMPANION NYHA class IV
patients were more ill than patients in previous studies of
NYHA class IV ambulatory patients, but slightly less ill
and perhaps more stable than patients in FIRST, more than
half of whom required intravenous inotropes, or those in
the noninotrope group of REMATCH–NYHA class IV
patients who were felt to need cardiac transplantation but
Lindenfeld et al
Downloaded from http://circ.ahajournals.org/ by guest on March 3, 2017
had an absolute contraindication. It is important to recognize that the class IV patients in COMPANION were
ambulatory outpatients who had had at least 1 HF hospitalization or equivalent in the 12 months prior to randomization. They could not be enrolled, however, if they had
had a hospitalization for HF or intravenous inotropic or
vasoactive therapy in excess of 4 hours in the 30 days
before randomization. They also did not have a recent
coronary intervention, refractory atrial arrhythmias, or a
recent myocardial infarction.
To date, it has been uncertain whether patients with
NYHA class IV CHF benefit from either CRT or CRT-D.
Arguments have been made that a procedure in these very
ill patients may destabilize the HF and thus cause prolonged hospitalization and increased mortality. Furthermore, it has been argued that implantable cardioverterdefibrillator therapy may not be warranted as these patients
primarily die of progressive HF. However, the absolute
number of lives saved and hospitalizations prevented were
much greater than in a less-ill population. Our data argue
strongly that CRT devices can be employed with an
excellent risk-benefit ratio in class IV HF patients who did
not require a hospitalization for HF in the preceding
month. Furthermore, our data demonstrate that an implantable cardioverter-defibrillator added to CRT may benefit
class IV patients in that it may produce the same incremental reduction in sudden death noted in the entire
COMPANION cohort.19 Thus, CRT and CRT-D are both
beneficial in altering mortality and morbidity in this very
ill population of NYHA class IV patients.
Effects of CRT on Class IV Heart Failure Patients
2.
3.
4.
5.
6.
7.
8.
9.
Limitations
The present study was not stratified by NYHA class, but the
treatment groups were similar in all baseline demographics. A
proportionality assumption was violated in the time to sudden
death and time to HF death analyses. The present study is
limited by the retrospective nature of the evaluation. The
present study, however, is the only evaluation of CRT or
CRT-D in NYHA class IV patients alone and is the largest
group yet studied.
10.
Disclosures
12.
Dr Lindenfeld has received speaking honoraria and consulting fees
from Boston Scientific and Medtronic, as well as consulting fees
from St. Jude. Dr Feldman is a consultant to Boston Scientific. Dr
Saxon has received consultant fees and research support from Boston
Scientific and Medtronic. Dr Boehmer has received consulting fees
from Boston Scientific and research funding from Boston Scientific
and Medtronic. Dr Ghali has received research funding from
Guidant. Dr Anand has received consulting fees and research funds
from Boston Scientific. Dr Steinberg has received speaking honoraria, consulting fees, and research support from Boston Scientific;
speaking honoraria and research support from Medtronic; and
research support from St. Jude. Dr Jaski has received speaking
honoraria and consulting fees from Boston Scientific. Dr DeMarco is
a consultant for Boston Scientific. P. Yong, E. Galle, and F. Ecklund
are employees of Boston Scientific. Dr Bristow has received consulting fees from Boston Scientific. Drs Carson and Singh report no
conflicts.
References
1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E,
Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ,
11.
13.
14.
15.
211
Underwood J, Pickering F, Truex C, McAtee P, Messenger J; MIRACLE
Study Group. Multicenter InSync randomized clinical evaluation. Cardiac
resynchronization in chronic heart failure. N Engl J Med. 2002;346:
1845–1853.
Auricchio A, Kloss M, Trautmann SI, Rodner S, Klein H. Exercise
performance following cardiac resynchronization therapy in patients with
heart failure and ventricular conduction delay. Am J Cardiol. 2002;89:
198 –203.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, DeMarco T,
Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM;
Comparison of Medical Therapy, Pacing, and Debibrillation in Heart
Failure (COMPANION) Investigators. Cardiac-resynchronization therapy
with or without an implantable defibrillator in advanced chronic heart
failure. N Engl J Med. 2004;350:2140 –2150.
Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C,
Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C,
Daubert JC; Multisite Stimulation in Cardiomopathies (MUSTIC) Study
Investigators. Effects of multisite biventricular pacing in patients with
heart failure and intraventricular conduction delay. N Engl J Med. 2001;
344:873– 880.
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; 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.
Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA,
Boehmer JP, Higginbotham MB, DeMarco T, Foster E, Yong PG.
Cardiac resynchronization therapy for the treatment of heart failure in
patients with intraventricular conduction delay and malignant ventricular
tachyarrhythmias. J Am Coll Cardiol. 2003;42:1454 –1459.
Young JB. Cardiac transplantation 2003. Curr Opin Cardiol. 2003;18:
127–128.
Bristow MR, Feldman AM, Saxon LA. Heart failure management using
implantable devices for ventricular resynchronization: Comparison of
Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure
(COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J Card Fail. 2000;6:276 –285.
Merit-HF Study Investigators. Effect of metoprolol CR/XL in chronic
heart failure: Metoprolol CR/XL Randomised Intervention Trial
in-Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007.
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine
JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved
survival with an implanted defibrillator in patients with coronary disease
at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:
1933–1940.
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert
JP, Higgins SL, Brown MW, Andrews ML; Multicenter Automatic
Debibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced
ejection fraction. N Engl J Med 2002;346:877– 883.
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R,
Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, ClappChanning N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip
JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237.
Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP,
Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A,
Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy Treatment
Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med
2004;350:2151–2158.
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley
G. A randomized study of the prevention of sudden death in patients with
coronary artery disease. Multicenter Unsustained Tachycardia Trial
Investigators. N Engl J Med. 1999;341:1882–1890.
Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H,
Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL,
Amann-Zalan I, DeMets DL; Carvedilol Prospective Randomized Cumulative urvival (COPERNICUS Study Group. Effect of carvedilol on the
morbidity of patients with severe chronic heart failure: results of the
carvedilol prospective randomized cumulative survival (COPERNICUS)
study. Circulation. 2002;106:2194 –2199.
212
Circulation
January 16, 2007
16. Anderson JL, Krause-Steinrauf H, Goldman S, Clemson BS, Domanski
MJ, Hager WD, Murray DR, Mann DL, Massie BM, McNamara DM,
Oren R, Rogers WJ; Beta-Blocker Evaluation of Survival Trial (BEST)
Investigators. Failure of benefit and early hazard of bucindolol for class
IV heart failure. J Card Fail. 2003;9:266 –277.
17. Stevenson LW, Miller LW, Desvigne-Nickens P, Ascheim DD, Parides
MK, Renlund DB, Oren RM, Krueger SK, Costanzo MR, Wann LS,
Levitan RG, Mancini D; REMATCH Investigators. Left ventricular assist
device as destination for patients undergoing intravenous inotropic
therapy: a subset analysis from REMATCH (Randomized Evaluation of
Mechanical Assistance in Treatment of Chronic Heart Failure). Circulation. 2004;110:975–981.
18. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF,
McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E,
Harrell FE Jr., Wheeler W, Soler-Soler J, Swedberg K. A randomized
controlled trial of epoprostenol therapy for severe congestive heart
failure: The Flolan International Randomized Survival Trial (FIRST). Am
Heart J. 1997;134:44 –54.
19. Carson P, Anand I, O’Conner C, Jaski B, Steinberg J, Lwin A, Lindenfeld
J, Ghali J, Barnet JH, Feldman AM, Bristow MR. Mode of death in
advanced heart failure: the Comparison of Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) Trial. J Am Coll
Cardiol. 2005;46:2329 –2334.
CLINICAL PERSPECTIVE
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Cardiac resynchronization therapy (CRT) alone or in combination with an implantable defibrillator (CRT-D) improves
quality of life, exercise capacity, and survival in patients with New York Heart Association (NYHA) class III to IV heart
failure (HF) and systolic dysfunction. However, very few patients with NYHA class IV HF have been studied, and there
are concerns that the implantation procedure might destabilize the HF and that either CRT or CRT-D may not significantly
prolong life in these very ill patients who most often die of progressive HF. In the COMPANION trial, patients with
systolic dysfunction and NYHA class III and IV HF were randomized to receive optimal medical therapy, optimal medical
therapy ⫹ CRT, or optimal medical therapy ⫹ CRT-D. There were 217 NYHA class IV patients randomized. The patients
were relatively clinically stable in that they could not be randomized if they had had a hospital admission in the previous
30 days. In these NYHA class IV patients, both CRT and CRT-D prolonged the time to all-cause death and hospitalization.
There was also a strong trend for an improvement in all-cause death by both CRT and CRT-D. Both CRT and CRT-D
improved the time to all-cause death and HF hospitalizations. The duration of the implantation hospitalization was not
significantly different between NYHA class III and class IV subjects. Thus, in ambulatory, clinically stable NYHA class
IV patients with systolic dysfunction, both CRT and CRT-D may provide a clinical benefit.
Effects of Cardiac Resynchronization Therapy With or Without a Defibrillator on
Survival and Hospitalizations in Patients With New York Heart Association Class IV
Heart Failure
JoAnn Lindenfeld, Arthur M. Feldman, Leslie Saxon, John Boehmer, Peter Carson, Jalal K.
Ghali, Inder Anand, Steve Singh, Jonathan S. Steinberg, Brian Jaski, Teresa DeMarco, David
Mann, Patrick Yong, Elizabeth Galle, Fred Ecklund and Michael Bristow
Downloaded from http://circ.ahajournals.org/ by guest on March 3, 2017
Circulation. 2007;115:204-212; originally published online December 26, 2006;
doi: 10.1161/CIRCULATIONAHA.106.629261
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2006 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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