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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
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 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
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Statistical ConsiderationsStatistical 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
Independent confirmation of all analyses by Frontier Sciences: CM Hawkins, ScD and D DeMets, PhD
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
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No. of Patients (%)
Etoricoxib (n=17,412)
Diclofenac(n=17,289)
Mean age, years (SD) 63.2 (8.5) 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)
Baseline Patient CharacteristicsBaseline Patient Characteristics
*Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.
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Baseline Patient MedicationsBaseline Patient MedicationsNo. of Patients (%)
Etoricoxib (n=17,412)
Diclofenac(n=17,289)
Cardiac medicationsLow-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.
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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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Etoricoxib (320 events)
Diclofenac (323 events)
Primary Endpoint: Cumulative Incidence of Thrombotic CV EventsPrimary Endpoint: Cumulative Incidence of Thrombotic CV Events
MonthsNo. of patients at risk*
EtoricoxibDiclofenac
16,81916,483
13,359 10,733 8277 6427 4024 80581538326213790110,14212,800
7.0
6.0
5.0
4.0
3.0
2.0
1.0
06 12 18 24 30 36 420
Cu
mu
lati
ve in
cid
ence
(%
) w
ith
95%
CI
Etoricoxib vs diclofenacHR = 0.95 95% CI = (0.81-1.11)
*Per protocol population.
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Etoricoxib (216 events)
Diclofenac (216 events)
Etoricoxib (272 events)
Diclofenac (272 events)
Cumulative Incidence of ArterialThrombotic CV and APTC EventsCumulative Incidence of ArterialThrombotic CV and APTC Events
16,819
16,483
13,362
12,801
10,735
10,144
8277
7903
6427
6214
4024
3832
805
815
No. of patients at risk
Etoricoxib
Diclofenac
Months
Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.79-1.16)
06 12 18 24 30 36 420
7.0
6.0
5.0
4.0
3.0
2.0
1.0
Cu
mu
lati
ve in
cid
ence
(%
) w
ith
95%
CI
06 12 18 24 30 36 420
7.0
6.0
5.0
4.0
3.0
2.0
1.0C
um
ula
tive
inci
den
ce (
%)
wit
h 9
5% C
I
Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.81-1.13)
Months
16,819
16,483
13,366
12,814
10,745
10,155
8282
7906
6429
6218
4026
3832
805
816
No. of patients at risk
Etoricoxib
Diclofenac
Arterial Thrombotic CV Events APTC Events (CVD/MI/Stroke)
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Summary of Primary and Secondary Thrombotic CV Endpoints and AnalysesSummary of Primary and Secondary Thrombotic CV Endpoints and Analyses
Hazard Ratio (Etoricoxib vs Diclofenac)
Etoricoxib Lower Diclofenac Lower
1.02 (0.87-1.18)
0.96 (0.79-1.16)
1.03 (0.89-1.18)
0.96 (0.81-1.13)
1.05 (0.93-1.19)
0.95 (0.81-1.11)
*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.
0.96 (0.83-1.11)
0.97 (0.83-1.14)
0.96 (0.80-1.15)
Arterial Thrombotic Events
Thrombotic Events
APTC Events
Per Protocol
ITT (end of study)†
Per Protocol
ITT (end of study)†
Per Protocol
ITT (end of study)†
ITT (14 days)*
ITT* (14 days)*
ITT* (14 days)*
1.30.5 1.0 2.0
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Thrombotic CV Event TypesThrombotic CV Event TypesEtoricoxib(n=16,819)
Diclofenac(n=16,483)
HR (95% CI)Rate* Rate*
Fatal Thrombotic CV Events 0.17 0.17 0.96 (0.63-1.46)
Cardiac Events Non-fatal MI Fatal MI
Sudden cardiac death Unstable angina pectoris Resuscitated cardiac arrest Cardiac thrombus
0.710.410.020.110.160.010.02
0.780.420.070.090.2100.01
0.90 (0.74-1.10)
Cerebrovascular Events Non-fatal ischemic stroke Fatal ischemic stroke Cerebrovascular venous thrombosis Transient ischemic attack
0.340.210.0200.12
0.320.220.0100.09
1.08 (0.80-1.46)
Peripheral Vascular Events Non-fatal pulmonary embolism Fatal pulmonary embolism Non-fatal peripheral artert. thrombosis Fatal peripheral arterial thrombosis Peripheral venous thrombosis
0.200.0700.0200.11
0.220.1000.0200.11
0.92 (0.63-1.35)
*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)*
POBs†
MonthsNo. of patients at risk
EtoricoxibDiclofenac
1741217289
13704 10972 8400 6509 4063 8218203867630680271039613190
3.0
2.5
2.0
1.5
1.0
0.5
06 12 18 24 30 36 420
Cu
mu
lati
ve in
cid
ence
(%
) w
ith
95%
CI
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.”
Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online) www.thelancet.com
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