The Safety of COX-2 Inhibitors

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The Safety of COX-2 Inhibitors

• John J. Cush, MD
• Presbyterian Hospital of Dallas

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(No Transcript)
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GI Outcomes Trials Design
CLASS (n7982)
VIGOR (n8076)
Drug
Celecoxib 400 mg BID (2x max chronic dose)
Rofecoxib 50 mg QD (2x max chronic dose)
Comparator
Ibuprofen 800 mg TID Diclofenac 75 mg BID
Naproxen 500 mg BID
Yes (21 )
No
Low dose ASA
Duration
Median 9 months Maximum 13 months 6 months
reported
Median 9 months Maximum 13 months
Silverstein et al. JAMA. 2000 2841247-1255.
Bombardier et al. N Engl J Med.
20003431520-1528
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NSAID Impact/Cost

• 13 million chronic users (70 million Rx/yr)
• Dyspepsia 20 gt 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 gt 2 billion/year

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NSAID Concerns

• 13 million chronic users (U.S.)
• Dyspepsia in 10-20
• Serious GI complications in 1.3
• Fatalities in 5-10 of these
• Direct cost/year gt 2 billion
• 15th most common cause of death (U.S.)

Mortality for 7 Selected Disorders (1997)
Wolfe, et al NEJM 1999
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Mechanism of Action of NSAIDs
COX-1Constitutive
COX-2Inducible
Non-specific NSAIDs
COX-2 NSAIDs
GI Mucosa
Platelet
Prostaglandins
Prostaglandins
Thromboxane
Mediate pain, inflammation, and fever
Hemostasis
GI mucosal Protection
Bakhle et al. Med Inflamm. 19965305-323. Vane
et al. Inflamm Res. 1995441-10.
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GI Outcomes Trials Design
CLASS (n7982)
VIGOR (n8076)
Drug
Celecoxib 400 mg BID (2x max chronic dose)
Rofecoxib 50 mg QD (2x max chronic dose)
Comparator
Ibuprofen 800 mg TID Diclofenac 75 mg BID
Naproxen 500 mg BID
Yes (21 )
No
Low dose ASA
Duration
Median 9 months Maximum 13 months 6 months
reported
Median 9 months Maximum 13 months
Silverstein et al. JAMA. 2000 2841247-1255.
Bombardier et al. N Engl J Med.
20003431520-1528
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CLASS Trial Upper GI Complications Alone and
With Symptomatic Ulcers
celecoxib
p 0.02
NSAIDs (ibuprofen diclofenac)
49 / 1384
p 0.09
All Patients
30 / 1441
20 / 1384
11 / 1441
p 0.02
p 0.04
Patients Not Taking Aspirin
32 / 1101
16 / 1143
14 / 1101
Annualized Incidence
5 / 1143
p 0.49
17 / 283
14/ 298
p 0.92
Patients Taking Aspirin
6 / 283
6 / 298
Symptomatic Ulcers and Ulcer Complications
Ulcer Complications
Silverstein et al. JAMA 2000 2841247-1255
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COX-2 issues

• JAMA 8/22/01 Metanalysis of CVS risk COX-2 Rx
• VIGOR 8076 RA pts GI Tox rofecoxib vs. naproxen
  (NO ASA). 2 fold increase in CVS events with
  rofecoxib
• CLASS 8059 OA pts GI tox of celecoxib vs.
  ibuprofen vs. diclofenac (ASA). No differences
  between groups
• CLASS VIGOR CVS events signif. More than
  historic controls (EMatteson, J Cush. ACR
  Hotline August 200).
• Naproxen? cardiovascular benefit?
• Positive Arthritis Rheum 44S372S230S266, 2001
• Negative Epidemiology 11382-7, 2000
• Ibuprofen before aspirin, inhibits thromboxane
  B2 and platelet aggregation by ASA
• Ibuprofen (COX-1) limit cardioprotective effect
  of ASA.
• Effect not seen with rofecoxib and diclofenac
  (gtCOX2)
• Lawson, N Engl J Med 3451809, 2001

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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)

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FDA COX-2 SafetyFebruary 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
• Does the agent pose a risk for CV events?
• Does the risk versus benefit profile of the drug
  support its marketing in the U.S.?
• If continued marketing is supported, what actions
  are recommended to ensure its safe use?

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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

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Trial N Populace COX-2 dose/d Duration Results (HRRROR)
APPROVE 2586 Polyps Rofecoxib 25 3 years HR 2.8 (CI, 1.4-5.4)
CABG-II 1671 CABG Valdecoxib 40 10 days RR 3.7 (CI, 1-13.5)
CABG-035 462 CABG Valdecoxib 80 10 days No ?MI but ?CVA
APC 2035 Polyps Celcox400,800 gt2.8 yrs 400 RR3.0 8006.1
Alzheimers 425 Alzheim Celecoxib 400 1 year CV deaths 2.4 v 1.4
Pre-SAP 1561 Polyp Celecoxib 400 ND No CV increase
ADAPT 2463 Alzheim Celecoxib 400 2 years No CV increase
Alzheimer 2091 Alzheim Rofecoxib 25 1 year No CV increase
VICTOR 1976 Polyp Rofecoxib 3 year RR 3.14 (1-9.75)
VIGOR 8076 RA Rofecoxib 50 10 mos. RR 2.38 (1.39-4.0)
Etoricoxib 3457 Metanal Etoricoxib RR 1.70 (0.9-3.18)
TARGET 9471 OA Lumiracoxib 400 1 year HR 1.77 (0.82-3.84)
CLASS 5968 OA, RA Celebrex 800 9-15 mo No CV increase
SUCCESS 13194 OA Celebrx 200 400 ND No CV increase
EDGE 7111 OA/GI Etoricoxib 9-16 mo No CV incr but ? HTN
TARGET 8773 OA Lumiracoxib 400 1 year No CV increase
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Table 1A. Placebo-controlled trials Prospective CV Endpoint Table 1A. Placebo-controlled trials Prospective CV Endpoint Table 1A. Placebo-controlled trials Prospective CV Endpoint Table 1A. Placebo-controlled trials Prospective CV Endpoint Table 1A. Placebo-controlled trials Prospective CV Endpoint Table 1A. Placebo-controlled trials Prospective CV Endpoint
Trial N Population COX-2 dose/d (Rx duration) Control Results
APPROVE 2586 Polyp prevention Rofecoxib 25 mg (3 yr) Placebo Cardiac evnt 31 v 12 HR 2.8 (CI, 1.4-5.4)
CABG-II 1671 High risk CABG Valdecoxib 40 mg Parecoxib 40 mg (10 d) Placebo CV/thromboembolic 11 v 3 RR 3.7 (CI, 1-13.5)
CABG-I (035) 462 CABG Parecoxib IV 80mg Valdecoxib 80 mg (10 days) Placebo No increase in MI Increased CVA in parecoxib/ valdecoxib (2.9 v 0.7)
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Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events Table 1B. Placebo-controlled trials Sporadic, Observed CV Adverse Events
Trial N Population COX-2, dose/day (Rx duration) Control Results
APC 2035 Polyp prevention Celecoxib 400 mg Celecoxib 800 mg (gt2.8 yrs) Placebo HR 400mg RR 3.0 (0.3-28.6) 800 mg RR 6.1 (0.7-50.3)
Alzheimers-001 425 Alzheimers prevention Celecoxib 400 mg (1 yr) Placebo MI 2 v 0 CV deaths 2.4 v 1.4
Pre-SAP 1561 Polyp prevention Celecoxib 400 mg Placebo No CV increase
ADAPT 2463 Alzheimers prevention Celecoxib 400 mg (2 yrs) Placebo Naproxen No CV increase
Alzheimer/MCI 2091 Alzheimers prevention Rofecoxib 25 mg (1 yr) Placebo No CV increase
VICTOR 1976 PY Polyp prevention Rofecoxib (3 yr) Placebo RR 3.14 (1-9.75)
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Table 2A. Naproxen active comparator trials Observed Adverse events Table 2A. Naproxen active comparator trials Observed Adverse events Table 2A. Naproxen active comparator trials Observed Adverse events Table 2A. Naproxen active comparator trials Observed Adverse events Table 2A. Naproxen active comparator trials Observed Adverse events 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 _at_ 8mos RR 2.38 (1.39-4.0)
Etoricoxib 3457 Metaanalyses 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 Table 2B. NSAID active comparator trials Observed Adverse events Table 2B. NSAID active comparator trials Observed Adverse events Table 2B. NSAID active comparator trials Observed Adverse events Table 2B. NSAID active comparator trials Observed Adverse events Table 2B. NSAID active comparator trials Observed Adverse events
CLASS 5968 OA, RA Celebrex800 mg (9-5mos) Diclofenac Ibuprofen No CV increase
Success-1 13194 OA Celebrex 200, 400 mg Naproxen Diclofenac No CV increase
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
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ACR Hotline American College of Rheumatology 1800
Century Place, Suite 250 Atlanta, GA 30345
Update Safety Issues Related to NSAIDs COX-2
Inhibitors Cardiovascular Complications
Simply, we built a better NSAID (COX-2) and in
doing so, we lost the anticoagulant effect.
Vioxx and Celebrex dont cause MI/CVA, they just
dont protect against it. Congestive Heart
Failure higher rates in patients on NSAIDs and
also in COX-2 treated patients H. Pylori testing
for patients on NSAIDs? Not routinely
recommended Aseptic Meningitis Case reports
with COX-2 agents Aspirin-sensitive asthma May
be ok to use COX-2 agents in patients w/ hx of
asthma, nasal polyps and ASA/NSAID
hypersensitivity
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Serious CV/T1 Events Different Endpoints (VIGOR)
64
45
35
32

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Investigator CV/ T
Adjudicated 2
APTC 3
1 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.
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Vioxx - APPROVe APTC Events Time to Event Plot

• Rofecoxib 25

Placebo
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Vioxx APPROVe Effect of ASA on APTC
Vioxx 25 Placebo RR, p-value (95 CI)
All patients n/PYR 1287 33/3053 1299 16/3322 2.25 P0.008
Rate/100 PYR 1.08 0.48 2.25 P0.008
Non-ASA user n/PYR 1074 28/2564 1095 12/2817 2.57 (1.31,5.06)
Rate/100 PYR 1.09 0.43 2.57 (1.31,5.06)
ASA user n/PYR 213 5/489 204 4/505 1.29 (0.28,6.50)
Rate/100 PYR 1.02 0.79 1.29 (0.28,6.50)
Based on October 2004, submission (no final
dataset).
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CV Signal in Vioxx Databases
AAC
Labeling changes
1998 2000
2001-2002
NDA
VIGOR 102 RAe SURs/AD
----Epi and re-analyses----- Versus
PlacNSAIDs Napr Napr Napr Placebo

APTC N N Y t t N
CV Death N N N t t t
NF MI N N Y t t N
NF Stroke NF Stroke N N N N N
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 Alzheimers disease studies. Epi
epidemiologic studies. NF non-fatal.
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CLASS - APTC-like Events
Event Celebrex (n3987) Diclofenac (n1996) Ibuprofen (n1985)
CV death 11 5 5
MI 19 4 9
Stroke 4 6 6
TOTAL 34 (0.9) 15 (0.8) 20 (1.0)
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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

?
?
?
?
?
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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

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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

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FDA Action 4/7/05

• Bextra 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

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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.

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NSAIDs Available by Prescription
NSAIDs SALICYLATES COX-2
INHIBITORS
Diclofenac (Voltaren) Aspirina (Zorprin,
Easprin) Celecoxib (Celebrex) Diclofenac/Misopros
tol (Arthrotec)b Diflunisal (Dolobid)
Valdecoxib (Bextra) Fenoprofen (Nalfon)
Salsalate (Disalcid, Salflex) Flurbiprofen
(Ansaid) Choline salicylate (Trilisate) Ibuprofe
n (Motrin)a Magnesium salicylate
(Magan) Indomethacin (Indocin) Ketoprofen
(Orudis)a In Development Meclofenamate
Etoricoxib Mefenamic acid (Ponstel)
Parecoxibc Nabumetone (Relafen)
Lumiracoxib Naproxen (Naprosyn,
Anaprox)a Oxaprozin (Daypro) Previously
Available Piroxicam (Feldene) Rofecoxib
(Vioxx) Sulindac (Clinoril) Tolmetin
(Tolectin)
a Also available as over-the-counter preparations
in the U.S. b Combination tablet of
NSAID/synthetic prostaglandin E1 c Parenterally
administered
2004 Physicians Desk Reference
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In Vitro Selectivity COX-2/COX-1 Ratio
lumiracoxib
etoricoxib
rofecoxib
valdecoxib
gt 50-fold COX-2 selective
etodolac
nimesulide
5- 50-fold COX-2 selective
diclofenac
celecoxib
meloxicam
fenoprofen
lt 5-fold COX-2 selective
ibuprofen
tolmetin
naproxen
aspirin
indomethacin
ketoprofen
flurbiprofen
Warner et al. FASEB J. 200418790-804
ketorolac
-3
-2
-1
0
1
2
3
Increasingly COX-2 Selective
Increasingly COX-1 Selective
Range of COX Selectivity for COX-1 and
COX-2 (log10 IC50 COX-2/COX-1)
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RR OF MYOCARDIAL INFARCTION
Garcia Rodriguez 2004
RR1.04 1.00-1.08
NSAIDs
RR0.88 0.8-0.95
NAPROXEN
IBUPROFEN
RR 1.03 .96-1.1
NAPROXEN HALF AS GOOD AS ASPIRIN?
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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
  age-matched controls. (Sudbo J, et al. 2005 -
  Manuscript submitted)

CV deaths
2.06
42
Any NSAID
1.16
2
Aspirin
2.86
12
Ibuprofen
1.70
Naproxen
7
2.26
Indomethacin
10
1.84
Piroxicam
7
1.90
Ketoprofen
4
0
1
2
3
5
4
6
Hazard Ratio for CV Death in Long-term NSAID
Users Compared to Non-users (with 95 Confidence
Intervals)
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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 were lead to is a
  life not fully lived
• - Ken Burns