MEDAL LBCT

1
Presenter Disclosure Information
Christopher P. Cannon, MD Results of the
Multinational Etoricoxib and Diclofenac Arthritis
Long-term (MEDAL) Study Program Cardiovascular
Outcomes Following Long-term Treatment with
Etoricoxib vs Diclofenac in Patients with
Osteoarthritis and Rheumatoid Arthritis
DISCLOSURE INFORMATION The following
relationships exist related to this presentation
Research grant support from Accumetrics,
AstraZeneca, Merck, Merck/Schering-Plough, and
Schering-Plough and has spoken at symposia
sponsored by and served on scientific advisory
boards for AstraZeneca, Bristol-Myers Squibb,
Glaxo Smith Kline, Merck, Pfizer, Sanofi-Aventis,
Merck/Schering-Plough, Schering-Plough, and
Vertex Trial sponsor Merck
2
Arthritis Background

• gt46 million individuals with arthritis in US
• 1 in 5 adults in US are affected
• Non-steroidal anti-inflammatory drugs (NSAIDs)
  are central to treating the pain and inflammation
  of arthritis
• COX-2 selective NSAIDs
• Have similar amount of COX-2 inhibition, but
  greatly reduced (or no) COX-1 inhibition at
  standard doses
• Less inhibition of prostaglandins that protect
  the gastric mucosa, thereby ? GI ulcers and
  complications
• Patients frequently need to switch NSAID agents
  due to lack of pain control ? Different
  treatment options needed

Arthritis Foundation. At http//www.arthritis.org
. Accessed October 2006. Decision Resources.
Arthritic Pain. 2005.
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CV Issues With COX-2 Selectiveand Traditional
NSAIDs

• In placebo-controlled randomized trials, COX-2
  selective NSAIDs ?ed the risk of thrombotic CV
  events
• Observational studies suggest ? CV risk for some
  traditional NSAIDs
• CV risk of high-dose naproxen may be different
• Meta-analysis of randomized trials CV risk of
  high-dose naproxen appears lower than COX-2
  inhibitors
• 2005-6 FDA and European regulatory agencies added
  a warning of an increased thrombotic CV risk for
  all NSAIDs (both COX-2 selective and traditional)

Kearney et al. BMJ. 20063321302 Solomon et al.
NEJM. 20053521071 Bresalier et al. NEJM
20053521092 FDA. At http//www.fda.gov/bbs/to
pics/news/2005/NEW01171.html. Accessed October
2006 CHMP. At http//www.emea.eu.int/pdfs/human
/opiniongen/nsaids.pdf. Accessed October 2006.
4
Questions arising with COX-2 selective and
traditional NSAID therapies

• These studies raise many questions
• Does greater COX-2 selectivity increase CV risk
  vs. traditional NSAID?
• Is high-dose naproxen, with its sustained
  antiplatelet effect, different?
• Would use of aspirin attenuate the increased risk
  seen with NSAIDs?
• Need large randomized trials comparing CV
  outcomes between different NSAID agents
• MEDAL aimed to address the first of these issues
• (but cannot address all of them)

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Goal

• To test the hypothesis, using non-inferiority
  statistical testing, that
• The relative risk of thrombotic CV events with
  etoricoxib would not be greater than that with
  diclofenac for treatment of patients with
  osteoarthritis (OA) or rheumatoid arthritis (RA)

Cannon et al. Am Heart J. 2006152237.
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Study drugs

• Etoricoxib
• Highly selective COX-2 inhibitor
• Efficacy for OA/RA, available 62 countries (ex.
  U.S.)
• Diclofenac
• Effective treatment for OA/RA
• Most widely prescribed NSAID worldwide
• Does not interfere with antiplatelet effects of
  aspirin
• Ibuprofen and naproxen may interfere with aspirin
• FDA 2006 warning on interaction for ibuprofen
• Diclofenac inhibits both COX-1 and COX-2 at
  therapeutic doses
• But does not have sustained antiplatelet activity

Capone et al. J Am Coll Cardiol 2005451295
Catella-Lawson et al. N Engl J Med
20013451809FDA. At http//www.fda.gov/cder/dr
ug/infopage/ibuprofen/science_paper.htm. Accessed
October 2006Sikes et al. Eur J Gastroenterol
Hepatol 2002141101 Van Hecken et al. J Clin
Pharmacol 2000401109.
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Design MEDAL Program Trials

• 3 Trials 46 countries 1380 sites
• EDGE (OA) N7,111
• EDGE II (RA) N4,086 34,701
  patients
• MEDAL (OA/RA) N23,504

• 50 years of age
• OA of knee, hip, hand,or spine or RA
• Require long-term therapywith traditional NSAID
  orCOX-2 inhibitor
• Broad CV risk
• Allowed aspirin and PPIuse in appropriate
  patients

R A N D O M I Z E
Etoricoxib60 or 90 mg/d (OA)90 mg/d (RA)
n17,412
Mean duration of therapy18 months
Diclofenac150 mg/d (50 mg tid or 75 mg bid)
n17,289
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Statistical Considerations

• Non-inferiority comparison
• Upper bound of 95 CI of the HR for etoricoxib vs
  diclofenac for primary endpoint must fall below
  1.30
• Event driven to a total of 635 events
• Sample size 34,500 provides 91 power
• CV Endpoints
• Thrombotic CV events (primary)
• Arterial thrombotic CV events
• APTC combined endpoint
• Adjudicated by independent
• blinded review committee

• Analytical Approaches
• Per protocol (primary)
• Patients gt75 compliant with study drug and took
  non-study NSAIDs lt10 of time on study
• ITT (within 14 days)
• ITT to end of study

Independent confirmation of all analyses by
Frontier Sciences CM Hawkins, ScD and D DeMets,
PhD
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Baseline Patient Characteristics
Included hypertension, diabetes mellitus,
dyslipidemia, family history of CV disease, or
smoking.
10
Baseline Patient Medications
Not mutually exclusive. DMARD
disease-modifying anti-rheumatic drug.
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Primary Results

• Does the COX-2 selective NSAID etoricoxib have an
  increased risk of thrombotic CV events compared
  with the traditional NSAID diclofenac?

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Primary Endpoint Cumulative Incidence of
Thrombotic CV Events
7.0
6.0
Etoricoxib vs diclofenacHR 0.95 95 CI
(0.81-1.11)
5.0
4.0
Cumulative incidence () with 95 CI
3.0
2.0
1.0
0
6
12
18
24
30
36
42
0
Months
No. of patients at risk
Etoricoxib
16,819
13,359
10,733
8277
6427
4024
805
Diclofenac
16,483
815
3832
6213
7901
10,142
12,800
Per protocol population.
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Cumulative Incidence of ArterialThrombotic CV
and APTC Events
Arterial Thrombotic CV Events
APTC Events (CVD/MI/Stroke)
7.0
7.0
6.0
6.0
Etoricoxib vs diclofenacHR 0.96 95 CI
(0.79-1.16)
Etoricoxib vs diclofenacHR 0.96 95 CI
(0.81-1.13)
5.0
5.0
4.0
4.0
Cumulative incidence () with 95 CI
Cumulative incidence () with 95 CI
3.0
3.0
2.0
2.0
1.0
1.0
0
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
0
Months
Months
No. of patients at risk
No. of patients at risk
16,819
13,362
10,735
8277
6427
4024
805
Etoricoxib
16,819
13,366
10,745
8282
6429
4026
805
Etoricoxib
Diclofenac
Diclofenac
16,483
12,801
10,144
7903
6214
3832
815
16,483
12,814
10,155
7906
6218
3832
816
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Summary of Primary and Secondary Thrombotic CV
Endpoints and Analyses
Etoricoxib Lower
Diclofenac Lower
Thrombotic Events
0.95 (0.81-1.11)
Per Protocol
0.96 (0.83-1.11)
ITT (14 days)
1.05 (0.93-1.19)
ITT (end of study)
Arterial Thrombotic Events
0.96 (0.81-1.13)
Per Protocol
0.97 (0.83-1.14)
ITT (14 days)
1.03 (0.89-1.18)
ITT (end of study)
APTC Events
0.96 (0.79-1.16)
Per Protocol
0.96 (0.80-1.15)
ITT (14 days)
1.02 (0.87-1.18)
ITT (end of study)
Hazard Ratio (Etoricoxib vs Diclofenac)

Events included while on study drug and within
14 days of drug discontinuation. Includes all
events on and off study drug to end of study.
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Thrombotic CV Event Types
Events per 100 patient-years. Per protocol
population
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Primary Endpoint Thrombotic CV Events Across
Prespecified Subgroups
Etoricoxib Lower
Diclofenac Lower
0.96
lt65
0.85
0.88
Age
0.99
65 to lt75
1.63
1.64
0.81
75
2.51
3.10
0.83
Gender
Male
1.94
2.32
1.04
Female
1.00
0.95
1.21
Yes
2.12
1.75
Diabetes
0.91
No
1.14
1.25
0.94
Yes
3.12
3.33
Established ASCVD
0.96
No
1.02
1.06
Established ASCVD or 2 CV Risk Factors
Yes
1.04
2.00
1.93
No
0.85
0.81
0.95
Low-dose aspirin use at baseline
0.89
Yes
1.67
1.87
1.00
No
1.01
1.01
0.95
OA
1.16
1.22
Disease
0.94
RA
1.40
1.49
0.92
60mg
1.00
1.07
Etoricoxib dose
0.97
90mg
1.43
1.49
0.5
1
1.5
2
Hazard Ratio (Etoricoxib vs Diclofenac)

Per protocol population PNS for all
treatments by subgroup interactions.
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Pre-specified Safety Endpoints by Dose Pooled
MEDAL Program
Absolute difference in incidences () 95 CI
Etoricoxib Lower
Diclofenac Lower
CHF
Etoricoxib Dose
60 mg/d
90 mg/d
D/C Hypertension
60 mg/d
90 mg/d
D/C Edema
60 mg/d
90 mg/d
D/C Renal Dys.
60 mg/d
90 mg/d
D/C Clinical GI AEs
60 mg/d
90 mg/d
D/C Hepatic AEs
60 mg/d
90 mg/d
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Cumulative Incidence of Confirmed Upper GI Events
(Perforations, Ulcers, and Bleeds)
3.0
Diclofenac (246 events)
2.5
Etoricoxib vs diclofenacHR 0.69 95 CI
(0.57-0.83)
2.0
1.5
Cumulative incidence () with 95 CI
1.0
0.5
0
6
12
18
24
30
36
42
0
Months
ITT (14 days) population. 50.6 of patients were
on gastroprotective agents.
No significant difference in perforations,
obstructions, or major bleeds.
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Remaining Questions to be addressed (in
randomized trials - not observational studies)

• Naproxen
• Does the lower risk seen in the meta-analysis
  comparing naproxen to COX-2 inhibitors relate to
  its antiplatelet effect?
• Does high-dose naproxen have increased risk vs.
  placebo?
• Ibuprofen
• Does it negate clinical benefit of ASA?
• Risk vs. naproxen?
• Aspirin effect
• Would aspirin modify the risk of COX-2 inhibitors
  vs. naproxen? (or vs. placebo)

• For Medical Societies/Guidelines committees
• Should one type of agent be tried first?
• Should choice of NSAID be individualized using
  patient characteristics (e.g., increased risk of
  GI ulcer)

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Our results show that patients with arthritis
treated with the COX-2 selective NSAID etoricoxib
and those given the traditional NSAID diclofenac
have nearly identical rates of thrombotic
cardiovascular events.
Dr. Loren Laine is presenting preliminary GI
subgroup data at Am. Coll. Rheumatology in Wash
DC today For the lower risk upper GI clinical
events with etoricoxib ? Generally consistent
benefit in ASA and PPI subgroups
Cannon CP, Curtis S, FitzGerald GA, et al.
Lancet. 2006368 (published online)
www.thelancet.com