Transcript The Safety of COX

The Safety of COX-2
Inhibitors
John J. Cush, MD
Presbyterian Hospital of Dallas
GI Outcomes Trials: Design
VIGOR (n=8076)
CLASS (n=7982)
Drug
Rofecoxib 50 mg QD
(2x max chronic dose)
Celecoxib 400 mg BID
(2x max chronic dose)
Patients
RA
OA (72 %), RA (28 %)
Comparator
Naproxen 500 mg BID
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Low dose ASA No
Yes (21 %)
Duration
Median 9 months
Maximum 13 months
6 months reported
Median 9 months
Maximum 13 months
Bombardier et al. N Engl J Med. 2000;343:1520-1528
Silverstein et al. JAMA. 2000; 284:1247-
NSAID Impact/Cost
 13 million chronic users (70 million Rx/yr)
 Dyspepsia 20% > Gastric ulcers 10%
 Serious GI complications
 1.3 % RA pts
 0.73% OA pts
 Hospitalization (UGI bleed) 103,000/year
 5-10% mortality (est 16,500 deaths/year)
 NSAID deaths 15th most common cause in USA
 Cost > $2 billion/year
NSAID Concerns
 13 million chronic
users (U.S.)
 Dyspepsia in 10-20%
 Serious GI
complications in 1.3%
Mortality for 7 Selected
Disorders (1997)
 Fatalities in 5-10% of
these
 Direct cost/year > $2
billion
 ~ 15th most common
cause of death (U.S.)
Wolfe, et al: NEJM 1999
Mechanism of Action of NSAIDs
CO2H
Arachidonic acid
COX-1
“Constitutive”
COX-2
“Inducible”
Non-specific
NSAIDs
COX-2 NSAIDs
GI Mucosa
Platelet
Prostaglandins
Prostaglandins Thromboxane
GI mucosal
Protection
Hemostasis
Bakhle et al. Med Inflamm. 1996;5:305-323.
Vane et al. Inflamm Res. 1995;44:1-10.
Mediate pain,
inflammation, and fever
GI Outcomes Trials: Design
VIGOR (n=8076)
CLASS (n=7982)
Drug
Rofecoxib 50 mg QD
(2x max chronic dose)
Celecoxib 400 mg BID
(2x max chronic dose)
Patients
RA
OA (72 %), RA (28 %)
Comparator
Naproxen 500 mg BID
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Low dose ASA No
Yes (21 %)
Duration
Median 9 months
Maximum 13 months
6 months reported
Median 9 months
Maximum 13 months
Bombardier et al. N Engl J Med. 2000;343:1520-1528
Silverstein et al. JAMA. 2000; 284:1247-
CLASS Trial: Upper GI Complications
Alone and With Symptomatic Ulcers
= celecoxib
= NSAIDs (ibuprofen +
diclofenac)
Patients Not Taking Aspirin
Patients Taking Aspirin
p = 0.02
5
4
2
1
49 / 1384
p = 0.09
3
Annualized Incidence %
All Patients
6
11 / 1441
20 / 1384
30 / 1441
0
6
p = 0.02
5
4
3
2
1
p = 0.04
14 / 1101
5 / 1143
32 / 1101
16 / 1143
0
p = 0.49
17 / 283
6
14/ 298
5
4
p = 0.92
3
2
6 / 298
6 / 283
1
0
Silverstein et al. JAMA 2000; 284:1247-1255
Ulcer ComplicationsSymptomatic Ulcers and
Ulcer Complications
Events Leading up to FDA Mtg
 Results of VIGOR and CLASS
 9/30/04 Merck voluntary w/d of Vioxx (based




on APPOVE trial)
Reanalyses of all COX2 data
12/9/04 FDA warning of CV events in Bextra
CABG trial
12/17/04 NCI stop APC trial (concerns over
celecoxib data)
12/20/04 NIH stops ADAPT trial (concerns
over naproxen)
FDA: COX-2 Safety
February 16-18, 2005




Arthritis Advisory Committee
Drug Safety and Risk Management
Other speakers, SGEs
8 rheums, 19 physicians, 8 statisticians, 1 ethicist,
patient and industry representatives
 ISSUES:
1. Does the agent pose a risk for CV events?;
2. Does the risk versus benefit profile of the drug support its
marketing in the U.S.?
3. If continued marketing is supported, what actions are
recommended to ensure its safe use?
FDA COX-2 Hearing
 Limitations of available data
 Most trials of short duration, using low dose
 Most trials done with efficacy endpoints
 Few designed with CVS safety endpoint
 Most trials were active comparator and NOT
placebo controlled trials
 Observational studies (presented) are for
generating signals and hypotheses
 Safety signals drawn from other indications are
valid, but not conclusive unless repeated or of
sufficiently great magnitude
Table 1A. Placebo-controlled trials: Prospective CV Endpoint*
Trial
N
Populatio
n
COX-2 dose/d
(Rx duration)
APPROV
Polyp
Rofecoxib 25
2586
E**
prevention mg (3 yr)
CABGII**
CABG-I
(035)**
Control
Results
Placebo
Cardiac evnt 31 v 12;
HR 2.8 (CI, 1.4-5.4)
High risk
1671
CABG
Valdecoxib 40
mg
Parecoxib 40
mg (10 d)
CV/thromboembolic
Placebo 11 v 3;
RR 3.7 (CI, 1-13.5)
462
Parecoxib IV
80mg
Valdecoxib 80
mg (10 days)
No increase in MI;
Increased CVA in
Placebo
parecoxib/ valdecoxib
(2.9% v 0.7%)
CABG
Table 1B. Placebo-controlled trials: Sporadic, Observed CV Adverse Events
Trial
APC
N
203
5
Alzheimer
425
s-001
Population
COX-2, dose/day
(Rx duration)
Control
Results
Polyp
prevention
Celecoxib 400
mg
Celecoxib 800
mg
(>2.8 yrs)
Placebo
HR 400mg RR 3.0
(0.3-28.6)
800 mg RR 6.1 (0.750.3)
Alzheimer’s
prevention
Celecoxib 400
mg (1 yr)
Placebo
MI 2 v 0;
CV deaths 2.4 v 1.4%
Pre-SAP
156
1
Polyp
prevention
Celecoxib 400
mg
Placebo
No CV increase
ADAPT+
246
3
Alzheimer’s
prevention
Celecoxib 400
mg (~2 yrs)
Placebo
Naproxen
No CV increase
Alzheimer 209
/MCI
1
Alzheimer’s
prevention
Rofecoxib 25 mg
(1 yr)
Placebo
No CV increase
Rofecoxib (3 yr)
Placebo
RR 3.14 (1-9.75)
VICTOR$
197 Polyp
6 PY prevention
Table 2A. Naproxen active comparator trials: Observed Adverse events
Trial
N
Populati COX-2,dose
Compared
Results
VIGOR
8076
RA
Rofecoxib
50mg/10 mo
Naproxen
MI: 20 v 4 @ 8mos
RR 2.38 (1.39-4.0)
Etoricoxib
3457
Metaan
alyses
Etoricoxib
Naproxen
RR 1.70 (0.9-3.18)
TARGET
(0117)**
9471
OA
Lumiracoxib
400 mg 1 yr)
Naproxen
HR 1.77 (0.82-3.84)
Table 2B. NSAID active comparator trials: Observed Adverse events
CLASS**
5968
Success-1 13194
Celebrex800 Diclofenac
mg (9-5mos) Ibuprofen
No CV increase
OA
Celebrex
200, 400 mg
Naproxen
Diclofenac
No CV increase
OA, RA
EDGE**
7111
OA/GI
tolerab
Etoricoxib
(9-16 mos)
Diclofenac
No CV increase
Small ↑ HTN
TARGET
(2332)**
8773
OA
Lumiracoxib
400 mg/1 yr
Ibuprofen
No CV increase
Serious CV/T1 Events
Different Endpoints (VIGOR)
Vioxx 50 mg
64
Naproxen
45
35
32
19
Investigator CV/ T
1
Adjudicated 2
18
APTC 3
Cardiovascular Thrombotic. 2Confirmed by CV adjudication committee.
3 Antiplatelet Trialist Collaboration composite endpoint: CV & unknown
cause of death, non-fatal myocardial infarction and non-fatal stroke.
Vioxx - APPROVe APTC Events
Time to Event Plot
Rofecoxib
25
Placebo
Vioxx – APPROVe: Effect of ASA on APTC *
Vioxx 25
Placebo
RR, p-value
(95% CI)
1287
1299
33/3053
16/3322
Rate/100 PYR
1.08
0.48
Non-ASA user
1074
1095
28/2564
12/2817
1.09
0.43
213
204
n/PYR
5/489
4/505
1.29
Rate/100 PYR
1.02
0.79
(0.28,6.50)
All patients
n/PYR
n/PYR
Rate/100 PYR
ASA user
* Based on October 2004, submission (no final dataset).
2.25
P=0.008
2.57
(1.31,5.06)
CV Signal in Vioxx Databases
AAC
1998
NDA
Versus
Plac+NSAIDs
2000
VIGOR
Napr
Labeling changes
2001-2002
102 RAe SURs/AD
----Epi and re-analyses----Napr Napr Placebo
N
Y
t
t
N
CV Death
N
N
t
t
t
NF MI
NF Stroke
N
Y
t
t
N
N
N
N
N
N
APTC
N= no signal. Y= Clear signal. t = Trend. AAC: February 8, 2001 FDA Arthritis Advisory Committee
meeting. RAe: Rheumatoid Arthritis efficacy supplement. SURs/AD: Safety Update Reports including
Alzheimer’s disease studies. Epi= epidemiologic studies. NF= non-fatal.
CLASS - APTC-like Events
Event
Celebrex
(n=3987)
Diclofenac
(n=1996)
Ibuprofen
(n=1985)
CV death
11
5
5
MI
19
4
9
Stroke
4
6
6
TOTAL
34 (0.9%)
15 (0.8%)
20 (1.0%)
FDA COX-2 Hearing
 Vote: Retain on the market
 Celecoxib 32-0
 Valdecoxib 17-13 (2 abstentions)
 Rofecoxib 17-15
 Unanimously in favor of:




?
 “Black box” warning for CV risk & COX-2 drugs
 Education measures for pts and physicians
 Restrictions on direct-to-consumer advertising
 “Warning” added to Current NSAIDs
 Compassionate use liquid rofecoxib for kids
Summary
 COX-2 inhibitors equipotent to NSAIDs
 GI Toxicity lower with COX-2, but negated
by low dose ASA 81 mg/d
 Would this be off-set by use of PPI
 CV risk modestly higher w/ COX-2 inhibitor
 Same for NSAIDs?
 Not affected by use of low dose ASA
FDA: COX-2 Safety
 Risk/benefit of COX-2 inhibitors favors continued use in U.S
 Patients should be counseled about cardiovascular risks.
 While all NSAIDs may impose similar cardiovascular risks,
some agents (naproxen 500 mg bid, celecoxib 200 mg qd)
appear to be safer than others (e.g., rofecoxib, valdecoxib,
diclofenac, and ibuprofen).
 Cardiovascular risks of the COX-2 inhibitors may be greater
with higher doses, longer durations of therapy, and when
used in high risk individuals.
 The use of low dose aspirin does not consistently abrogate
the potential CV risk of a COX-2 inhibitor. Patients who
require the cardioprotective effects of aspirin may not be
ideal candidates for COX-2 inhibitor or NSAID therapy.
 The use of COX-2 inhibitors (and other NSAIDs thought to
increase CV risk) should be avoided in high risk individuals
 Bextra




FDA Action: 4/7/05
We have concluded that the overall risk versus benefit profile for this product is
unfavorable and we have requested Pfizer to voluntarily withdraw the product from
the market. They have agreed to suspend sales and marketing in the U.S., pending
further discussions with the Agency. To resume marketing of the drug, the sponsor
would have to demonstrate that Bextra has a clear benefit over existing therapies or
a lower risk compared to other COX-2 selective inhibitors.
Celebrex
We have concluded that Celebrex should remain available as a prescription drug, but
with changes to the labeling, a MedGuide, and commitments from Pfizer for
additional studies to better define the cardiovascular effects of the drug.
Vioxx
A proposal by Merck to reintroduce Vioxx to the market would require a supplemental
new drug application. Such an application would be reviewed with consideration of
the risk to benefit balance of the proposed indications and populations for use,
warnings in the label, and all relevant data. We expect that the proposal would also
be reviewed at a public Advisory Committee meeting.
Prescription Non-Selective NSAIDs- Based upon the available data, we have
concluded that an increased risk of CV events may be a class effect for
NSAIDs. Therefore, at this time, changes to the prescribing information for all of
these drugs are warranted, until the risk profile of the individual agents can be better
assessed.
Non-prescription Non-Selective NSAIDs- The labeling for low dose, non-prescription
products that contain ibuprofen, naproxen and ketoprofen will be revised to include
warnings about potential CV and GI risks, advisories recommending certain patients
seek physician input before use and stronger reminders to follow the instructions of
the label concerning dose and duration of treatment
A New Standard for Drug
Development
 Any new NSAID, must be clinically better
than current alternatives
 Any new NSAID, must be safer
 Usual phase IV trials must be done before
approval, not after.
NSAIDs Available by Prescription
NSAIDs
SALICYLATES
Diclofenac (Voltaren)
Diclofenac/Misoprostol (Arthrotec)b
Fenoprofen (Nalfon)
Flurbiprofen (Ansaid)
Ibuprofen (Motrin)a
Indomethacin (Indocin)
Ketoprofen (Orudis)a
Meclofenamate
Mefenamic acid (Ponstel)
Nabumetone (Relafen)
Naproxen (Naprosyn, Anaprox)a
Oxaprozin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
COX-2 INHIBITORS
Aspirina (Zorprin, Easprin)
Diflunisal (Dolobid)
Salsalate (Disalcid, Salflex)
Choline salicylate (Trilisate)
Magnesium salicylate (Magan)
Celecoxib (Celebrex)
Valdecoxib (Bextra)
In Development
Etoricoxib
Parecoxibc
Lumiracoxib
Previously Available
Rofecoxib (Vioxx)
Tolmetin (Tolectin)
a Also
b
c
available as over-the-counter preparations in the U.S.
Combination tablet of NSAID/synthetic prostaglandin E1
Parenterally administered
2004 Physician’s Desk Reference
In Vitro Selectivity: COX-2/COX-1 Ratio
lumiracoxib
etoricoxib
rofecoxib
valdecoxib
> 50-fold COX-2 selective
etodolac
nimesulide
diclofenac
celecoxib
meloxicam
5- 50-fold COX-2
selective
fenoprofen < 5-fold COX-2
ibuprofenselective
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
flurbiprofen
ketorolac
Warner et al. FASEB J. 2004:18:790-804
-3
-2
-1
Increasingly COX-2
Selective
0
1
2
Increasingly COX-1
Selective
3
Range of COX Selectivity for COX-1 and COX-2
(log10 IC50 COX-2/COX-1)
Figure 1. Pooled and study specific relative risks and 95% confidence intervals for the
risk of myocardial infarction associated with use of NSAIDs as a class, naproxen and
ibuprofen.
RR OF MYOCARDIAL INFARCTION
Garcia-Rodriguez I
Ray I
Garcia Rodriguez 2004
Solomon
Watson
Schlienger
Ray II
Mamdani
Kurth
Kimme
l
Garcia-Rodriguez II
Pooled NSAIDs
NSAIDs
RR=1.04 [1.00-1.08
Garcia-Rodriguez I
Ray I
Solomon
Watson
Schlienger
Ray II
Mamdani
Kimmel
NAPROXEN
RR=0.88 [0.8-0.95]
Garcia-Rodriguez II
Pooled Naproxen
Garcia-Rodriguez I
Ray I
Solomon
Watson
Ray II
Kimmel
IBUPROFEN
Garcia-Rodriguez II
RR = 1.03 [.96-1.1]
Pooled Ibuprofen
0
1
2
? : Study specific, adjusted RRs; ? Pooled RR; — 95% C
NAPROXEN : HALF AS GOOD AS ASPIRIN?
Long-term NSAID Use May Increase Risks of
Cardiovascular Death-Norwegian Study, 2005
 Population-based, nested case-control study of 454
Scandinavian patients diagnosed with oral cancer
between 1975 and 2003, and 454 gender- and agematched controls. (Sudbo J, et al. 2005 - Manuscript submitted)
CV deaths
2.06
Any NSAID
42
1.16
2
Aspirin
2.86
Ibuprofen
1.70
Naproxen
7
2.26
Indomethacin
10
1.84
Piroxicam
7
1.90
Ketoprofen
0
12
1
4
2
3
4
5
6
Hazard Ratio for CV Death in Long-term NSAID Users Compared to Non-users
(with 95% Confidence Intervals)
On Safety…
“The desire for safety stands against every
great and noble enterprise”
- Tacitus
“ I think we too often make choices based on
the safety of cynicism, and what we’re lead
to is a life not fully lived”
- Ken Burns