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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. Christopher P. Cannon, MD Senior Investigator, TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Associate Professor of Medicine Harvard Medical School Boston, MA. Cardiovascular Risk with COX-IIs-

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slide1
Welcome

Ask The Experts

March 24-27, 2007

New Orleans, LA

slide2
Christopher P. Cannon, MDSenior Investigator, TIMI Study GroupCardiovascular DivisionBrigham and Women's HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA

Cardiovascular Risk with COX-IIs-

MEDAL Program:

Multinational Etoricoxib and

Diclofenac Arthritis Long-term

slide3
Cardiovascular Outcomes with COX-2 Inhibitors: The MEDAL Program

Christopher P Cannon, MD

Senior Investigator, TIMI Study Group

Associate Professor of Medicine

Harvard Medical School

Cardiovascular Division

Brigham and Women’s Hospital

Boston, Massachusetts

slide4
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

the cox 2 hypothesis
The COX-2 Hypothesis

CO2H

Arachidonic Acid

COX-1

Constitutive

PGs

COX-2

Inducible

PGs

  • GI cytoprotection
  • Platelet aggregation
  • Renal function (blood flow)
  • Inflammation
    • Fever
    • Pain
    • Headache
  • Carcinogenesis
arthritis background
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 and PPI each shown to ↓ 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.

rates of mi in original randomized trials of vioxx and celecoxib
Rates of MI in Original Randomized Trials of Vioxx and Celecoxib

VIGOR

CLASS

1.0

1.0

0.8

0.8

0.6

0.6

Rates per 100 patient-years

0.4

0.4

0.2

0.2

0.0

0.0

Rofecoxib

50 mg qd

(n=4047)

Naproxen

500 mg bid

(n=4029)

Celecoxib

400 mg bid

(n=3995)

Diclofenac

75 mg tid

(n=1999)

Ibuprofen

800 mg bid

(n=1998)

Bombardier C NEJM. 2000;343:1520-8 Silverstein FE,JAMA. 2000;284:1247-55.

Mukherjee D, Nissen SE, Topol EJ JAMA 2001;286(8):954-959.

cardiovascular results from chemo prevention trials of rofecoxib and celecoxib
Celecoxib 400 mg/d

Celecoxib 200 mg/d

Placebo

P=0.01

Cardiovascular Results From Chemo-prevention Trials of Rofecoxib and Celecoxib

Confirmed Serious Thrombotic Events

Composite CV Endpoint*

6

0.05

Placebo

Rofecoxib 25 mg/d

5

0.04

P=0.008

4

0.03

% of patients

3

Probability of composite endpoint

0.02

2

0.01

1

0

0

0

6

12

18

24

30

36

0

6

12

18

24

30

36

Months

Months

*Includes death from cardiovascular causes, myocardial infarction, stroke, or heart failure.

Bresalier et al. N Engl J Med. 2005;352:1092.

Solomon et al. N Engl J Med. 2005;352:1071.

meta analysis of randomized trials of cox 2 selective nsaids vs placebo
Meta-analysis of Randomized Trials ofCOX-2 Selective NSAIDs vs Placebo

Kearney et al. BMJ. 2006;332:1302.

adapt trial
ADAPT Trial

3-Year Risk of Cardiovascular or Cerebrovascular Death, MI, Stroke, CHF, or TIA

3.5

Placebo (referent) 5.68% (37/1070)

Naproxen 220 BID 8.25% (40/713)

Celecoxib 200 QD 5.54% (28/717)

3.0

2.5

2.0

Hazard Ratio vs. Placebo

1.5

1.0

0.5

0

Overall

PLOS online 2006

cv events indirect comparisons imputed from coxib meta analysis traditional nsaids vs placebo
CV Events: Indirect Comparisons Imputed from Coxib Meta-analysis: Traditional NSAIDs vs Placebo

Kearney, et al. BMJ. 2006;332;1302.

meta analysis of randomized trials of cox 2 selective vs traditional nsaids
Meta-analysis of Randomized Trials of COX-2 Selective vs Traditional NSAIDS

Kearney et al. BMJ. 2006;332:1302.

fda class warning
FDA Class Warning
  • 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)

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS and CLINICAL TRIALS).

http://www.fda.gov/cder/drug/infopage/cox2/default.htm

slide14
Effect of NSAIDs on Platelet AggregationSteady State % Inhibition from Baseline During Dosing Interval

100

90

80

Placebo

Rofecoxib (25 mg)

Diclofenac

Ibuprofen 800 tid

Naproxen 500 bid

70

60

50

40

30

20

10

0

-10

-20

Day 60 hours

Day 62 hours

Day 64 hours

Day 68 hours

Day (Hours)

cyclooxygenase inhibitors and the antiplatelet effects of aspirin
Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin

Could NSAIDS block the effect of ASA?

  • Aspirin led to platelet inhibition
  • Treatment with ibuprofen prior to ASA blocked this effect -> no platelet inhibition after ASA
  • Rofecoxib and diclofenac had no reduction in the platelet inhibition of ASA.
slide16
B

A

With aspirin

Acetyl

serine

Platelet cyclooxygenase-1

Serine residue at position 529

Y

Catalytic site

C

With ibuprofen + ASA

Ibuprofen

Arachidonic acid

Channel of access

Platelet

Aspirin

questions arising with cox 2 selective and traditional nsaid therapies
Questions arising with COX-2 selective and traditional NSAID therapies

These studies raise many questions:

  • Does greater COX-2 selectivity increase CVrisk vs traditional NSAIDs?
  • 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)
design medal program trials
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
  • ≥ 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)

n=17,412

Mean duration of therapy=18 months

Diclofenac150 mg/d (50 mg tid or 75 mg bid)

n=17,289

Design: MEDAL Program Trials
baseline patient characteristics
Baseline Patient Characteristics

*Included hypertension, diabetes mellitus, dyslipidemia, family history of CV disease, or smoking.

primary endpoint cumulative incidence of thrombotic cv events
Diclofenac (323 events)

Etoricoxib (320 events)

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

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.

cumulative incidence of arterial thrombotic cv and aptc events
Diclofenac (272 events)

Diclofenac (216 events)

Etoricoxib (272 events)

Etoricoxib (216 events)

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 = (0.81-1.13)

Etoricoxib vs diclofenacHR = 0.96 95% CI = (0.79-1.16)

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

0

6

12

18

24

30

36

42

0

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

Diclofenac

16,483

12,801

10,144

7903

6214

3832

815

16,483

12,814

10,155

7906

6218

3832

816

thrombotic cv event types
Thrombotic CV Event Types

*Events per 100 patient-years. Per protocol population

slide23
Event Rates

Etoricoxib

Diclofenac

HR†

Primary Endpoint: Thrombotic CV Events Across Prespecified Subgroups*

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.

pre specified safety endpoints by dose pooled medal program
Percent of patients

Etori 60 mg/d

Etori 90 mg/d

0.3

Diclo 150 mg/d

0.2

2.2

1.6

0.8

0.7

0.8

0.8

4.7

7.1

0.3

1.8

-6

-4

-2

0

2

4

6

0

2

4

6

8

10

0.4

0.2

2.4

1.2

1.2

0.6

1.0

0.9

6.6

9.0

0.3

3.2

Pre-specified Safety Endpoints by Dose: Pooled MEDAL Program

Absolute difference in incidences (%) [95% CI]

Etoricoxib 60 mg/d

Etoricoxib Lower

Diclofenac Lower

CHF

D/C: Hypertension

D/C: Edema

D/C: Renal Dys.

D/C: Clinical GI AEs

D/C: Hepatic AEs

Etoricoxib 90 mg/d

CHF

D/C: Hypertension

D/C: Edema

D/C: Renal Dys.

D/C: Clinical GI AEs

D/C: Hepatic AEs

renovascular effects of nsaids cox 2 inhibitors
Renovascular Effects of NSAIDs & COX-2 Inhibitors

Arachidonic Acid

NSAIDs

COXIBs

COX-2

PGE2 /PGI2

  • Sodium Retention
  • Peripheral edema
  • Hypertension
  • CHF
  • Acute Renal Failure
  • Prerenal azotemia
  • ATN
  • Hyperkalemia
  • Type 4 Renal Tubular Acidosis
  • Hyponatremia

Perazella, M. Expert Opin Drug Saf. 2002;1:53-64.

effect of naproxen and coxibs on blood pressure in the elderly
Effect of Naproxen and Coxibs on Blood Pressure in the Elderly

Changes in BP on Day 14 of Treatment

7

Placebo (n=16)

Naproxen 500 mg bid (n=17)

6

Celecoxib 200 mg bid (n=17)

Rofecoxib 25 mg qd (n=17)

LS mean change from baseline ± SE

Systolic BP

Diastolic BP

-3

Schwartz JL, et al. EULAR, 2001. Abstract SAT0055.

cumulative incidence of confirmed upper gi events perforations ulcers and bleeds
Etoricoxib (176 events)

POBs†

No. of patients at risk

Etoricoxib

17412

13704

10972

8400

6509

4063

821

Diclofenac

17289

13190

10396

8027

6306

3867

820

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

0

6

12

18

24

30

36

42

Months

*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.

†No significant difference in perforations, obstructions, or major bleeds.

conclusion
Conclusion
  • Comparable CV thrombotic event rates
  • Significantly lower upper GI clinical events (no difference in complicated upper GI events)

Long-term treatment with COX-2 selective NSAID etoricoxib vs traditional NSAID diclofenac in largest arthritis trial to date

These results with a new agent provide data to help physicians and guideline committees determine the optimal treatment for patients with arthritis

Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368:1771-81.

acr treatment guidelines for osteoarthritis
ACR Treatment Guidelines for Osteoarthritis
  • Acetaminophen <4 g/d is first-line pharmacologic intervention
  • Alternative pharmacologic agents for patients who fail to obtain adequate symptomatic relief with acetaminophen
    • Treatment choice following evaluation of risk factors for GI, renal, and CV toxicity
    • Options include COX-2 selective NSAIDs, traditional NSAIDs, or pure analgesics
    • Intraarticular therapy with hyaluronic acid or glucocorticoids is an alternative to oral therapy

ACR. Arthritis Rheum. 2000;43:1905.

cox selectivity of cox 2 selective and traditional nsaids
COX Selectivity of COX-2 Selective and Traditional NSAIDs

Ketorolac

Flurbiprofen

3

Suprofen

COX-1selectivity

Indomethacin

Ketoprofen

2

Naproxen

Ampyrone

Ibuprofen

Aspirin

Tolmetin

1

0

Relative inhibition(log[IC80 ratio, COX-2/COX-1])

-1

Niflumic

Zomepirac

Diflunisal

Fenoprofen

Piroxicam

Tomoxiprol

Diclofenac

-2

COX-2selectivity

Celecoxib

Eclofenamate

Nimesulide

Sodium salicylate

Meloxicam

Etodolac

-3

Valdecoxib

-4

Etoricoxib

Rofecoxib

Lumiracoxib

Antman et al. Circulation. 2005;112:759.

urinary prostanoid metabolites following treatment with nsaids
Urinary TxB2

Urinary PGI-M

Naproxen500 mg bid1

Diclofenac50 mg tid2

Ibuprofen800 mg/d3

Urinary Prostanoid Metabolites* Following Treatment With NSAIDs

40

20

0

-20

LS Mean Percent Change (SE)

-40

-60

-80

-100

Placebo1

Etoricoxib90 mg/d1

Celecoxib200 mg bid1

*Assays performed in different laboratories.

1.Data on file, Merck; 2.Van Hecken et al. J Clin Pharmacol, 2000;40:1109; 3.McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

inhibition of cox 1 and cox 2 by nsaids
Serum TxB2 (COX-1)

WBA PGE2 (COX-2)

Inhibition of COX-1 and COX-2 by NSAIDs*

40

20

0

-20

Weighted Average ChangeFrom Baseline

-40

-60

-80

-100

Etoricoxib90 mg/d

Celecoxib200 mg bid

Diclofenac75 mg bid

Ibuprofen800 mg tid

Naproxen500 mg bid

Placebo

Placebo

Study 091 (Preliminary Data).Data on file, Merck.

Van Hecken et al.

WBA = whole blood assay.

*Assays performed in different laboratories.

Data on file, Merck.; Van Hecken et al. J Clin Pharmacol, 2000;40:1109.

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 with COX-2 selective NSAIDs relate to its antiplatelet effect?
    • What is the CV risk of high-dose naproxen vs placebo?
  • Ibuprofen
    • Does it negate clinical benefit of aspirin?
    • Risk vs naproxen?
  • Aspirin effect
    • Would aspirin modify the risk the risk of COX-2 inhibitors (and some traditional NSAIDs) 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 (eg, increased risk of GI ulcer)
slide36
Question

&

Answer

slide37
Thank You!

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