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
>46 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: Accessed October 2006.
Decision Resources. Arthritic Pain

3. CV Issues With COX-2 Selective and 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
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. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092; FDA. At: Accessed October 2006;
CHMP. At: 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)
The primary analysis will be of data from the MEDAL program, ie a combined analysis of data from the EDGE study in patients with OA, EDGE II in patients with RA, and the MEDAL study in patients with OA and RA.
The MEDAL study was designed as an endpoint-driven CV outcomes study. A secondary analysis of CV event data derived from the MEDAL study alone will address whether etoricoxib will be non-inferior to diclofenac in the rates of confirmed CV events.

5. 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)
The primary analysis will be of data from the MEDAL program, ie a combined analysis of data from the EDGE study in patients with OA, EDGE II in patients with RA, and the MEDAL study in patients with OA and RA.
The MEDAL study was designed as an endpoint-driven CV outcomes study. A secondary analysis of CV event data derived from the MEDAL study alone will address whether etoricoxib will be non-inferior to diclofenac in the rates of confirmed CV events.
Cannon et al. Am Heart J. 2006;152:237.

6. 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 2005;45:1295; Catella-Lawson et al. N Engl J Med 2001;345:1809; FDA. At: Accessed October 2006; Sikes et al. Eur J Gastroenterol Hepatol 2002;14:1101; Van Hecken et al. J Clin Pharmacol 2000;40:1109.

7. Design: MEDAL Program Trials
3 Trials countries sites
EDGE (OA): N=7,111
EDGE II (RA): N=4, ,701 patients
MEDAL (OA/RA): N=23,504
≥ 50 years of age
OA of knee, hip, hand, or spine; or RA
Require long-term therapy with traditional NSAID or COX-2 inhibitor
Broad CV risk
Allowed aspirin and PPI use in appropriate patients
The primary composite thrombotic CV endpoint was the first occurrence of the following fatal and non-fatal events: myocardial infarction (including silent infarction), unstable angina pectoris, intracardiac thrombus, resuscitated cardiac arrest, thrombotic stroke, cerebrovascular thrombosis, transient ischemic attack, peripheral venous thrombosis, pulmonary embolism, peripheral arterial thrombosis, and sudden and/or unexplained death.
A composite thrombotic CV endpoint was chosen in an effort to be as comprehensive as possible when capturing adverse cardiac events. R A N D O M I Z E
n=17,412
Etoricoxib 60 or 90 mg/d (OA) 90 mg/d (RA)
Mean duration of therapy=18 months
n=17,289
Diclofenac 150 mg/d (50 mg tid or 75 mg bid)

8. 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 >75% compliant with study drug and took non-study NSAIDs <10% 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

9. Baseline Patient Characteristics
No. of Patients (%)
Etoricoxib (n=17,412)
Diclofenac (n=17,289)
Mean age, years (SD)
63.2 (8.5)
Female
12,925 (74.2)
12,823 (74.2)
Osteoarthritis
12,533 (72.0)
12,380 (71.6)
Rheumatoid arthritis
4878 (28.0)
4909 (28.4)
Diabetes
1810 (10.4)
1855 (10.7)
Hypertension
8109 (46.6)
8221 (47.6)
Dyslipidemia
5097 (29.3)
5034 (29.1)
Current smoker
2034 (11.7)
2037 (11.8)
Established atherosclerotic CV disease
2014 (11.6)
2010 (11.6)
≥2 CV risk factors* or established atherosclerotic CV disease
6586 (37.8)
6639 (38.4)
*Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

10. Baseline Patient Medications
No. of Patients (%)
Etoricoxib (n=17,412)
Diclofenac (n=17,289)
Cardiac medications
Low-dose aspirin use
6030 (34.6)
5976 (34.6)
β-blocker
2806 (16.1)
2837 (16.4)
ACE inhibitor or ARB
4571 (26.3)
4535 (26.2)
Ca++ channel blocker
2096 (12.0)
2149 (12.4)
Statin
2859 (16.4)
2890 (16.7)
Diuretic
3129 (18.0)
3147 (18.2)
Baseline Anti-arthritic medications*
Traditional NSAID
14,209 (81.6)
14,174 (82.0)
Acetaminophen
10,852 (62.3)
10,765 (62.3)
COX-2 selective NSAID
4873 (28.0)
4939 (28.6)
High-dose aspirin
173 (1.0)
185 (1.1)
Glucocorticoid
2758 (15.8)
2762 (16.0)
DMARD
2246 (12.9)
2208 (12.8)
*Not mutually exclusive DMARD = disease-modifying anti-rheumatic drug.

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

12. Primary Endpoint: Cumulative Incidence of Thrombotic CV Events
7.0
Etoricoxib (320 events)
6.0
Diclofenac (323 events)
5.0
Etoricoxib vs diclofenac HR = % CI = ( )
4.0
Cumulative incidence (%) with 95% CI
3.0
2.0
1.0 6 12 18 24 30 36 42
Months
No. of patients at risk*
Etoricoxib
16,819
13,359
10,733
8277
6427
4024
805
Diclofenac
16,483
12,800
10,142
7901
6213
3832
815
*Per protocol population.

13. Cumulative Incidence of Arterial Thrombotic CV and APTC Events
Arterial Thrombotic CV Events
APTC Events (CVD/MI/Stroke)
7.0
7.0
Etoricoxib (272 events)
Etoricoxib (216 events)
Diclofenac (272 events)
Diclofenac (216 events)
6.0
6.0
Etoricoxib vs diclofenac HR = % CI = ( )
Etoricoxib vs diclofenac HR = % CI = ( )
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 6 12 18 24 30 36 42 6 12 18 24 30 36 42
Months
Months
No. of patients at risk
No. of patients at risk
Etoricoxib
16,819
13,362
10,735
8277
6427
4024
805
Etoricoxib
16,819
13,366
10,745
8282
6429
4026
805
Diclofenac
16,483
12,801
10,144
7903
6214
3832
815
Diclofenac
16,483
12,814
10,155
7906
6218
3832
816

14. Summary of Primary and Secondary Thrombotic CV Endpoints and Analyses
Etoricoxib Lower
Diclofenac Lower
Thrombotic Events
Per Protocol
0.95 ( )
ITT (14 days)*
0.96 ( )
ITT (end of study)†
1.05 ( )
Arterial Thrombotic Events
Per Protocol
0.96 ( )
ITT* (14 days)*
0.97 ( )
ITT (end of study)†
1.03 ( )
APTC Events
Per Protocol
0.96 ( )
ITT* (14 days)*
0.96 ( )
ITT (end of study)†
1.02 ( )
1.3
0.5
1.0
2.0
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.

15. Thrombotic CV Event Types
Etoricoxib (n=16,819)
Diclofenac (n=16,483)
HR (95% CI)
Rate*
Fatal Thrombotic CV Events
0.17
0.96 ( )
Cardiac Events
Non-fatal MI
Fatal MI
Sudden cardiac death
Unstable angina pectoris
Resuscitated cardiac arrest
Cardiac thrombus
0.71
0.41
0.02
0.11
0.16
0.01
0.78
0.42
0.07
0.09
0.21
0.90 ( )
Cerebrovascular Events
Non-fatal ischemic stroke
Fatal ischemic stroke
Cerebrovascular venous thrombosis
Transient ischemic attack
0.34
0.12
0.32
0.22
1.08 ( )
Peripheral Vascular Events
Non-fatal pulmonary embolism
Fatal pulmonary embolism
Non-fatal peripheral artert. thrombosis
Fatal peripheral arterial thrombosis
Peripheral venous thrombosis
0.20
0.10
0.92 ( )
*Events per 100 patient-years. Per protocol population

16. Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups*
Etoricoxib
Event Rates
Diclofenac
Etoricoxib Lower
Diclofenac Lower
<65
0.85
0.88
0.96
Age
≥65 to <75
1.63
1.64
0.99
≥75
2.51
3.10
0.81
Gender
Male
1.94
2.32
0.83
Female
1.00
0.95
1.04
Yes
2.12
1.75
1.21
Diabetes No
1.14
1.25
0.91
Yes
3.12
3.33
0.94
Established ASCVD No
1.02
1.06
0.96
Established ASCVD or
≥2 CV Risk Factors
Yes
2.00
1.93
1.04 No
0.81
0.95
0.85
Low-dose aspirin use
at baseline
Yes
1.67
1.87
0.89 No
1.01
1.01
1.00 OA
1.16
1.22
0.95
Disease RA
1.40
1.49
0.94
60mg
1.00
1.07
0.92
Etoricoxib dose
90mg
1.43
1.49
0.97
0.5 1
1.5 2
Hazard Ratio (Etoricoxib vs Diclofenac)
*Per protocol population; †P=NS for all treatments by subgroup interactions.

17. Pre-specified Safety Endpoints by Dose: Pooled MEDAL Program
Absolute difference in incidences (%) [95% CI] 2 4 6 8 10
Percent of patients
Etori 60 mg/d
Etori 90 mg/d
Diclo150 mg/d
0.3
0.4
2.2
2.4
4.7
6.6
0.8
1.2
1.0
0.2
1.6
7.1
9.0
1.8
3.2
0.7
0.6
0.9
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 -6 6 -4 -2 2 4

18. Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)*
3.0
Etoricoxib (176 events)
Diclofenac (246 events)
2.5
Etoricoxib vs diclofenac HR = % CI = ( )
2.0
Cumulative incidence (%) with 95% CI
1.5
1.0
POBs†
0.5 6 12 18 24 30 36 42
No. of patients at risk
Etoricoxib
Diclofenac
17412
17289
13704
10972
8400
6509
4063
821
820
3867
6306
8027
10396
13190
Months
†No significant difference in perforations, obstructions, or major bleeds.
*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.

19. 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)

20. For the lower risk upper GI clinical events with etoricoxib:
“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. 2006:368 (published online)