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![Page 1: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/1.jpg)
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Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials
Arthritis Advisory Committee
March 4, 2003
Ellis F. Unger, M.D.
Office of Therapeutics Research and Review (OTRR)
Center for Biologics Evaluation and Research (CBER)
U.S. Food and Drug Administration (US FDA)
![Page 2: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/2.jpg)
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Why the Interest in Anti-TNF- Strategies in CHF?
• Clinical observations:
• elevated TNF- levels in patients with CHF, especially cardiac cachexia
• Preclinical data showing:
• TNF--induced LV dysfunction
• deleterious effects on LV remodeling
![Page 3: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/3.jpg)
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Anti-TNF- Hypotheses in CHF:
• TNF- contributes to the morbidity of CHF
• Anti-TNF- therapies would have salutary effects in patients with CHF
![Page 4: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/4.jpg)
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Randomized Controlled Trials of TNF- Blockers in CHF:
• Etanercept
2 Randomized Controlled Studies:
• “RENAISSANCE”
• “RECOVER”
• Infliximab
1 Randomized Controlled Study:
• “ATTACH”
![Page 5: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/5.jpg)
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Studies of Etanercept in CHF:
“RENAISSANCE”
“RECOVER”
![Page 6: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/6.jpg)
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Etanercept in CHF:
“RENAISSANCE” - conducted by Immunex in North America; ~900 subjects
“RECOVER” - conducted by Wyeth in Europe, Israel, Australia, New Zealand; ~1100 subjects
Both:
• phase 2/3
• randomized
• double-blind
• placebo-controlled
• multicenter
![Page 7: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/7.jpg)
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Inclusion Criteria:
• CHF on ischemic or non-ischemic basis
• ejection fraction < 30%
• symptoms of CHF X 3 months
• NYHA Functional Class 2, 3, or 4
• receiving diuretic and ACE inhibitor
![Page 8: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/8.jpg)
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Randomization - Dosing Regimens:
Randomization 1:1:1 - blocked by study site, NYHA FC, and -blocker use
RENAISSANCE RECOVER
Enbrel 1X per week
25 mg SC 2X per week * 2X per week *
3X per week
Placebo 2X or 3X per week
Treatment duration > 24 weeks
* regimen licensed for RA
![Page 9: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/9.jpg)
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RENAISSANCE & RECOVER: Endpoints
Primary endpoints:
• “Clinical Composite Score” at 24 weeks
(Score improved, worse, unchanged)
• Combined endpoint across both studies:
Mortality or CHF hospitalization
(BIW + TIW) vs. placebo
![Page 10: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/10.jpg)
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Clinical Composite Score “Worse” if:
· subject died
· was hospitalized for CHF
· worsened NYHA FC
· “Global Assessment” (judged by subject) moderately or markedly worse
![Page 11: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/11.jpg)
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Clinical Composite Score “Improved” if:
· the Clinical Composite Score was not worse
AND
· NYHA FC is improved OR
· “Global Assessment” moderately or markedly improved
![Page 12: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/12.jpg)
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Clinical Composite Score “Unchanged” if:
Clinical Composite Score neither better nor worse.
![Page 13: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/13.jpg)
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Results
![Page 14: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/14.jpg)
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March 2001: Studies Stopped for Futility
At a planned interim review, the DSMB recommended that both RENAISSANCE and RECOVER be halted because the pre-specified results indicating futility had been observed.
Median follow-up:
RENAISSANCE - 12.7 months
RECOVER - 5.7 months
![Page 15: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/15.jpg)
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Patient Demographic & Baseline Disease Characteristics: RENAISSANCE
Age: 62.3 years (mean)
Gender: 78% male
Race: 84% Caucasian;
11% African Ancestry
CHF duration: 5.6 years (mean)
Ejection Fraction: 22.3% (mean)
NYHA FC: FC II – 24%
FC IIIa – 47%
FC IIIb – 25%
FC IV – 5%
![Page 16: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/16.jpg)
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Imbalances in Patient Demographics & Disease Characteristics: RENAISSANCE
Treatment groups well balanced with respect to demographic and baseline characteristics
4 notable exceptions. For the placebo group, on average, baseline:
• BP was higher
• 6-minute walk was longer
• antiarrhythmic use was less frequent
• atrial fib/flutter was less frequent
These imbalances were small, but all would be associated with a more favorable prognosis in the placebo group.
![Page 17: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/17.jpg)
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Demographic & Baseline Characteristics: RECOVER
Age: 64.6 years
Gender: 78% male
Caucasian: 99%
CHF duration: 4.6 years
Ejection Fraction: 24.2%
NYHA FC: FC II – 27%
FC IIIa – 45%
FC IIIb – 25%
FC IV – 3%
* Good balance across treatment groups
![Page 18: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/18.jpg)
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Clinical Composite Score at Week 24: RENAISSANCE
placebo Enbrel BIW Enbrel TIW0
20
40
60
80
100
% o
f P
atie
nts
improved same worse
44% 39% 42%
36%32% 31%
20% 29% 27%
![Page 19: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/19.jpg)
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Clinical Composite Score at Week 24: RECOVER
placebo Enbrel QW Enbrel BIW0
20
40
60
80
100
% o
f P
atie
nts
improved same worse
32% 33% 38%
50% 47% 43%
19% 21% 19%
![Page 20: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/20.jpg)
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1° Endpoint: All-Cause Mortality and CHF Hospitalizations Across Both Studies (Enbrel BIW + TIW vs. placebo)
0 8 16 24 32 40 48 56 64 72 80 88 96
time (weeks)
0.5
0.6
0.7
0.8
0.9
1.0
cum
ula
tive
eve
nt-
free
su
rviv
al
placebo (n=682)
TNFR biw + tiw (n=991)
log-rank p-value = 0.15
Placebo (n=682)
Enbrel BIW +TIW (n=991)
![Page 21: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/21.jpg)
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0 8 16 24 32 40 48 56 64 72 80 88 96
time (weeks)
0.6
0.7
0.8
0.9
1.0cu
mu
lati
ve s
urv
ival
placebo (n=309)
TNFR biw (n=308)
TNFR tiw (n=308)
All-Cause Mortality: RENAISSANCE
14.2%
17.9%
19.8%
Placebo (n=309)
Enbrel BIW (n=308)
Enbrel TIW (n=308)
1/4 remain at risk
![Page 22: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/22.jpg)
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All-Cause Mortality: RECOVER
0 8 16 24 32 40 48 56 64 72 80 88 96
time (weeks)
0.6
0.7
0.8
0.9
1.0cu
mu
lati
ve s
urv
ival
placebo (n=373)
TNFR qw (n=375)
TNFR biw (n=375)
Placebo (n=373)
Enbrel QW (n=375)
Enbrel BIW (n=375)
5.9%
7.2%
8.8%
1/4 remain at risk
![Page 23: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/23.jpg)
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Comparison of Subject Populations:
RENAISSANCE vs. RECOVER
RENAISSANCE RECOVER
age (years) 62.3 64.6Caucasian (%) 83.6 99.4weight (kg) 84.5 79.0BPs (mm Hg) 108 120BPd (mm Hg) 66 75VT / VF (%) 23 11HTN (%) 55 45hyperlipidemia (%) 61 44use of K+ sparing diuretic (%) 33 91use of digitalis compounds (%) 82 54use of lipid lowering agents (%) 55 37use of nitrates (%) 44 52
exploratory analyses performed
![Page 24: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/24.jpg)
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RENAISSANCE: Mortality by Treatment and NYHA Functional Class
0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)
0.4
0.5
0.6
0.7
0.8
0.9
1.0
cum
ula
tive
su
rviv
al
placebo (n=77)
TNFR biw (n=75)
TNFR tiw (n=75)
0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)
0.4
0.5
0.6
0.8
0.9
1.0
cum
ula
tive s
urv
ival
placebo (n=142)
TNFR biw (n=141)
TNFR tiw (n=141)
0 8 16 24 32 40 48 56 64 72 80 88 96time (weeks)
0.4
0.5
0.6
0.8
0.9
1.0
placebo (n=76)
TNFR biw (n=76)
TNFR tiw (n=77)
FC II FC IIIa FC IIIb
Placebo (n=77)
Enbrel BIW (n=75)
Enbrel TIW (n=75)
Placebo (n=142)
Enbrel BIW (n=141)
Enbrel TIW (n=141)
Placebo (n=76)
Enbrel BIW (n=76)
Enbrel TIW (n=77)
![Page 25: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/25.jpg)
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RENAISSANCE: Cardiovascular SAEs
Placebo Etanercept
BIW TIW
n = 307 n = 305 n = 307
increased CHF 67 (22%) 81 (27%) 77 (25%)
cardiac arrest 6 (2%) 12 (4%) 10 (3%)
ventricular tachycardia 10 (3%) 7 (2%) 12 (4%)
angina pectoris 13 (4%) 12 (4%) 6 (2%)
syncope 9 (3%) 10 (3%) 7 (2%)
atrial fibrillation 5 (2%) 6 (2%) 7 (2%)
acute MI 7 (2%) 0 4 (1%)
coronary artery disease 5 (2%) 0 1 (<1%)
![Page 26: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/26.jpg)
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RENAISSANCE: Selected AEs
Placebo Etanercept
BIW TIW
n = 307 n = 305 n = 307
dizziness 52 (17%) 62 (20%) 71 (23%)
pain chest 37 (12%) 42 (14%) 56 (18%)
angina pectoris 20 (7%) 17 (6%) 10 (3%)
hypotension 33 (11%) 32 (10%) 24 (8%)
syncope 18 (6%) 21 (7%) 21 (7%)
atrial fibrillation 14 (5%) 19 (6%) 16 (5%)
ventricular tachycardia 18 (6%) 16 (5%) 18 (6%)
palpitations 16 (5%) 5 (2%) 12 (4%)
![Page 27: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/27.jpg)
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RECOVER: Cardiovascular SAEs
Placebo Etanercept
BIW TIW
n = 373 n = 375 n = 375
increased CHF 9% 13% 12%
angina pectoris 2% 2% 2%
cardiac arrest 2% 2% 2%
V-tach 1% 1% 0%
V-fib <1% <1% 1%
syncope 1% <1% 1%
atrial fibrillation 1% 1% <1%
AMI 1% 1% 1%
![Page 28: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/28.jpg)
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Summary: Etanercept in CHF (1)
• No evidence that Etanercept is beneficial in CHF
• The data suggest harm, though the results are not conclusive.
• The key finding of concern was a trend towards higher mortality in Etanercept-treated subjects in RENAISSANCE; this was heightened by the apparent dose-response relation.
• The results of RECOVER do not substantiate the findings of Renaissance with respect to Etanercept-induced mortality in CHF.
• The greatest concern is for an Enbrel dose higher than that currently licensed for RA in the US.
![Page 29: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/29.jpg)
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Summary: Etanercept in CHF (2)
• The data do not suggest a specific mechanism of action leading to Etanercept-related adverse outcomes in the CHF patient population.
• Exploratory analyses failed to identify specific factors associated with increased risk of adverse events. In particular, patients in Renaissance with milder CHF (NYHA FC II) did not appear to be at a lower risk of adverse outcomes.
In labeling, there is no basis to provide:
• a measure of reassurance for patients with mild forms of CHF;
• a listing of factors that appear to predispose to worsening CHF
![Page 30: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/30.jpg)
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Study of Infliximab in CHF:
“ATTACH”
![Page 31: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/31.jpg)
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ATTACH:
• phase 2 pilot trial
• randomized
• double-blind
• placebo-controlled
• multicenter (32 centers in USA)
![Page 32: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/32.jpg)
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Randomization - Dosing Regimens:
150 subjects randomized 1:1:1 to:
infliximab 5 mg/kg at 0, 2 and 6 weeks
infliximab 10 mg/kg at 0, 2 and 6 weeks
placebo at 0, 2 and 6 weeks
![Page 33: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/33.jpg)
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ATTACH: Inclusion Criteria
• symptoms of CHF X 3 months
• NYHA functional class 3, or 4
• LV ejection fraction 35%
• receiving diuretic and ACE inhibitor
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ATTACH: Primary Endpoint
“Clinical Status” at 14 weeks:
improved, worse, or unchanged
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ATTACH: Clinical Status at Week 14
placebo 5 mg/kg 10 mg/kg0
20
40
60
80
100
% o
f P
atie
nts
improved same worse
8% 10%22%
59% 52%39%
33% 38% 39%
![Page 36: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/36.jpg)
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ATTACH: Clinical Status at Week 28
placebo 5 mg/kg 10 mg/kg0
20
40
60
80
100
% o
f P
atie
nts
improved same worse
14% 16%31%
49%43%
31%
37%35%43%
![Page 37: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/37.jpg)
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ATTACH: All-Cause Mortality Through One Year
InfliximabPlacebo 5 mg/kg 10 mg/kg(n = 48) (n = 50) (n = 51)
Deaths 4 (8.2%) 4 (8.0%) 8 (15.7%)
worsening heart failure 2 2 3
arrhythmia 0 1 0
acute MI 0 1 1
other cardiac 2 0 2
non-cardiovascular 0 0 2
![Page 38: Anti-TNF- Strategies in CHF: Data from Randomized, Controlled Clinical Trials Arthritis Advisory Committee March 4, 2003 Ellis F. Unger, M.D. Office.](https://reader036.fdocuments.net/reader036/viewer/2022070412/56649d885503460f94a6deaa/html5/thumbnails/38.jpg)
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Infliximab:
Dear Healthcare Professional letter issued October 18, 2001
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ATTACH: Selected AEs
InfliximabPlacebo 5 mg/kg 10 mg/kg(n = 48) (n = 51) (n = 50)
Dizziness 2 (4.2%) 16 (31.4%) 10 (20.0%)
Dyspnea 6 (12.5%) 10 (19.6%) 12 (24.0%)
Cardiac failure 12 (25.0%) 6 (11.8%) 11 (22.0%)
Chest pain 4 (8.3%) 4 (7.8%) 5 (10.0%)
Angina pectoris 1 (2.1%) 3 (5.9%) 4 (8.0%)
Hypotension 0 (0.0%) 3 (5.9%) 4 (8.0%)
Pulmonary edema 3 (6.3%) 1 (2.0%) 4 (8.0%)
Ventricular tachycardia 4 (8.3%) 2 (3.9%) 3 (6.0%)
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Summary: Infliximab in CHF
• No evidence that Infliximab is beneficial in patients with CHF.
• Although the numbers of subjects treated are small, there is a strong trend suggesting increased mortality in CHF patients treated with Infliximab.
• The data do not show an increase in mortality with the 5 mg/kg dose; however, adverse event data suggest that the 5 mg/kg dose is deleterious.
• The mechanism underlying this apparent effect is unclear.
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Post-Marketing Reports of CHF:
51 cases reported as of February, 2002:
30 received Etanercept; 21 received Infliximab
• 42 reports of new onset CHF - - half with no identifiable risk factors
• 9 reports of CHF exacerbation
Median age = 64 yrs (range 19 to 87 years)
Median time to onset 3.5 months (range: 24 hours to 24 months)
20% were < 50 years old
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• 10 cases:– 6 received infliximab & 4 received
etanercept – Median ejection fraction = 20%
(range 10 to 45%, n=9)– 3 with underlying risk factors for CHF– After discontinuation of TNF antagonists
and HF treatment:• 3 reported complete resolution of CHF• 6 reported improvement• 1 reported death
CHF Cases in Patients Under 50 Years Old
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• Significant overlap between CHF and RA in the general population, to a lesser extent CHF & Crohn’s Disease
• Data from RCT’s in the CHF population raise concerns about the safety of Infliximab and Etanercept.
• Post-marketing data raise concern regarding new-onset CHF.
• CBER plans comprehensive analyses of the RCT databases of all 3 TNF-blockers.
• Specific language for labeling is under discussion.
Summary: TNF Blockers and CHF: