1 Presenter Disclosure Information 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 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
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Presenter Disclosure Information
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 VertexTrial sponsor: Merck
Christopher P. Cannon, MDResults 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
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Arthritis: BackgroundArthritis: 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
CV Issues With COX-2 Selectiveand Traditional NSAIDsCV 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. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092; FDA. At: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed October 2006; CHMP. At: http://www.emea.eu.int/pdfs/human/opiniongen/nsaids.pdf. Accessed October 2006.
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Questions arising with COX-2 selective and traditional NSAID therapiesQuestions arising with COX-2 selective and traditional NSAID therapies
These studies raise many questions:
1. Does greater COX-2 selectivity increase CV risk vs. traditional NSAID?
2. Is high-dose naproxen, with its sustained antiplatelet effect, different?
3. 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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GoalGoal
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. 2006;152:237.
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Study drugsStudy 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: http://www.fda.gov/cder/drug/infopage/ibuprofen/science_paper.htm. Accessed October 2006;Sikes et al. Eur J Gastroenterol Hepatol 2002;14:1101; Van Hecken et al. J Clin Pharmacol 2000;40:1109.
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Design: MEDAL Program TrialsDesign: MEDAL Program Trials
n=17,412RANDOMIZE
Etoricoxib60 or 90 mg/d (OA)
90 mg/d (RA)
Diclofenac150 mg/d
(50 mg tid or 75 mg bid)
n=17,289
≥ 50 years of age OA of knee, hip, hand,
or spine; or RA Require long-term therapy
with traditional NSAID orCOX-2 inhibitor
Broad CV risk Allowed aspirin and PPI
use in appropriate patients
Mean duration of therapy=18 months
3 Trials 46 countries 1380 sites EDGE (OA): N=7,111
EDGE II (RA): N=4,086 34,701 patients MEDAL (OA/RA): N=23,504
*Events per 100 patient-years. Per protocol population
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0.94 0.96
1.040.85
0.891.00
0.960.99
0.831.04
0.81
0.950.94
0.920.97
1.210.91
0.5 1 1.5 2
Age
Gender
Low-dose aspirin use at baseline
Hazard Ratio (Etoricoxib vs Diclofenac)
Established ASCVD or ≥2 CV Risk Factors
Diabetes
Established ASCVD
Etoricoxib Lower Diclofenac Lower
YesNo
YesNo
YesNo
Disease
<65≥65 to <75
MaleFemale
≥75
Etoricoxib dose
OARA
60mg90mg
YesNo
*Per protocol population; †P=NS for all treatments by subgroup interactions.
Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups*Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups*
3.12 1.02
2.000.81
1.671.01
0.851.63
1.941.00
2.51
1.161.40
1.001.43
2.121.14 3.33
1.06
1.930.95
1.871.01
0.881.64
2.320.95
3.10
1.221.49
1.071.49
1.751.25
HR†EtoricoxibEvent Rates
Diclofenac
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Pre-specified Safety Endpoints by Dose: Pooled MEDAL ProgramPre-specified Safety Endpoints by Dose: Pooled MEDAL Program
CHF60 mg/d90 mg/d
Absolute difference in incidences (%) [95% CI]
Etoricoxib Lower Diclofenac Lower
D/C: Edema60 mg/d90 mg/d
D/C: Renal Dys. 60 mg/d90 mg/d
D/C: Clinical GI AEs60 mg/d90 mg/d
D/C: Hepatic AEs60 mg/d90 mg/d
D/C: Hypertension60 mg/d90 mg/d
-6 6-4 -2 0 2 4 0 2 4 6 8 10
Percent of patients
Etori 60 mg/dEtori 90 mg/dDiclo150 mg/d
0.3
0.4
2.2
2.4
4.7
6.6
0.3
0.3
0.8
1.2
0.8
1.0
0.2
0.2
1.6
1.2
7.1
9.0
1.8
3.2
0.7
0.6
0.8
0.9
EtoricoxibDose
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Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)*Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)*
Etoricoxib vs diclofenacHR = 0.69 95% CI = (0.57-0.83)
*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.
Etoricoxib (176 events)
Diclofenac (246 events)
†No significant difference in perforations, obstructions, or major bleeds.
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Remaining Questions to be addressed (in randomized trials - not observational studies)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 todayFor the lower risk upper GI clinical events with etoricoxib: Generally consistent benefit in ASA and PPI subgroups