Cardiovascular Risk and Cardiovascular Risk and NSAIDsNSAIDs

Arthritis Advisory Committee Arthritis Advisory Committee Meeting April 12, 2007Meeting April 12, 2007

Sharon Hertz, M.D.Sharon Hertz, M.D.Deputy DirectorDeputy Director

Division of Analgesia, Anesthesia, and Division of Analgesia, Anesthesia, and Rheumatology ProductsRheumatology Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchFood and Drug AdministrationFood and Drug Administration

22

Overview of Overview of PresentationPresentation

Cardiovascular findings from COX-2 development FDA conclusions about CV Risk and NSAIDs

33

February 2005February 2005

Joint advisory committee meeting with arthritis and drug safety committees

Data presented on rofecoxib, celecoxib, lumiracoxib, etoricoxib

44

VioxxVioxx

May 20, 1999May 20, 1999

Approval of New Drug Application for Approval of New Drug Application for Vioxx (rofecoxib) for the treatment of Vioxx (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and acute pain in adults, dysmenorrhea and osteoarthritis osteoarthritis

~ 5000 subjects~ 5000 subjects - 700+ at least 1 year (12.5 and 25 mg)- 700+ at least 1 year (12.5 and 25 mg) No cardiovascular signal – small number No cardiovascular signal – small number

of events, no dose responseof events, no dose response

55

Vioxx - VIGORVioxx - VIGOR

Rofecoxib Rofecoxib 50 mg50 mg daily vs. daily vs. naproxen 500 mg BID naproxen 500 mg BID

8,000 RA patients, no ASA8,000 RA patients, no ASA Median exposure - 9 monthsMedian exposure - 9 months EndpointsEndpoints

– serious GI eventsserious GI events– serious CV/thrombotic events serious CV/thrombotic events

66

Vioxx - VIGORVioxx - VIGOR

Cardiovascular risk identified for rofecoxib vs. naproxen

All CV events - RR 2.37

MI - RR 5.0 (20 vs. 4)

Incidence increased over time

Results taken to AC February, 2001

77

Vioxx - Alzheimer’s Vioxx - Alzheimer’s DiseaseDisease

To slow progression or prevent To slow progression or prevent onset onset

3 placebo-controlled, double-blind, 3 placebo-controlled, double-blind, multicenter studiesmulticenter studies

Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 15-24 months15-24 months N=~2800 patientsN=~2800 patients No consistent cardiovascular signal No consistent cardiovascular signal

88

Vioxx - APPROVeVioxx - APPROVe

Reduce incidence of adenomatous Reduce incidence of adenomatous polyps in patients with history of polyps in patients with history of colorectal adenomascolorectal adenomas

Randomized, placebo-controlled, Randomized, placebo-controlled, double-blind, 3 years + 1 year double-blind, 3 years + 1 year

Rofecoxib 25 mg vs. placeboRofecoxib 25 mg vs. placebo 2586 patients 2586 patients

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Vioxx - APPROVeVioxx - APPROVe

September 27, 2004 – Merck informs September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. FDA of CV signal for rofecoxib vs. placebo in APPROVeplacebo in APPROVe

All CV events – RR 1.8

MI – RR 2.5

Ischemic CVA – RR 1.8

September 30, 2004 – Merck September 30, 2004 – Merck withdraws Vioxx from the marketwithdraws Vioxx from the market

1010

Vioxx – APPROVeVioxx – APPROVe Effect of ASA on APTC Effect of ASA on APTC

Vioxx 25 mg Placebo

All patients N=12873053 pt-yrs

N=13003322 pt-yrs

nRate/100 pt-yrs

59 1.9

341.0

Non-ASA Users N=1074 N=1096

nRate/100 pt-yrs

43 1.7

22 22 0.8 0.8

ASA Users N=213 N=204

nRate/100 pt-yrs

15 3.1

122.3

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CelebrexCelebrex

December 31, 1998 December 31, 1998 Approval of New Drug Application for Approval of New Drug Application for

Celebrex (celecoxib) for the signs Celebrex (celecoxib) for the signs and symptoms of osteoarthritis (200 and symptoms of osteoarthritis (200 mg/day) and rheumatoid arthritis mg/day) and rheumatoid arthritis 200-400 mg/day)200-400 mg/day)

N= 9600 patients N= 9600 patients No CV signal with initial applicationNo CV signal with initial application

1212

Celebrex - CLASSCelebrex - CLASS

CLASSCLASS Double-blind, active-controlled, 1 yearDouble-blind, active-controlled, 1 year ~ 8,000 patients with OA or RA, ASA if ~ 8,000 patients with OA or RA, ASA if

indicatedindicated Celecoxib 400 mg twice daily Celecoxib 400 mg twice daily Endpoint – serious GI events Endpoint – serious GI events No cardiovascular signal vs. ibuprofen No cardiovascular signal vs. ibuprofen

800 mg TID or diclofenac 75 mg BID 800 mg TID or diclofenac 75 mg BID

1313

CLASSCLASSMyocardial InfarctionMyocardial Infarction

Celecoxib Diclofenac Ibuprofen

All patients N=39872340 pt-yrs

N=19961080 pt-yrs

N=19851122 pt-yrs

nRate/100 pt-yrs

19 0.8

40.4

90.8

Non-ASA Users N=3105 N=1551 1573

nRate/100 pt-yrs

6 0.3

2 2 0.2 0.2

2 2 0.2 0.2

ASA Users N=882 N=445 N=412

nRate/100 pt-yrs

13 2.5

20.8

7 2.8

1414

Celebrex - APCCelebrex - APC

APC (Prevention of Sporadic Colorectal APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib)Adenomas with Celecoxib)

Double-blind, placebo-controlled, 3 Double-blind, placebo-controlled, 3 years, over 1900 patients, ASA use by years, over 1900 patients, ASA use by ~30%~30%– Celebrex 400 mg twice daily (N=671)Celebrex 400 mg twice daily (N=671)– Celebrex 200 mg twice daily (N=685)Celebrex 200 mg twice daily (N=685)– PlaceboPlacebo (N=679) (N=679)

1515

Celebrex - APCCelebrex - APC

December 16, 2004 – APC study December 16, 2004 – APC study halted due to CV signal for celecoxib halted due to CV signal for celecoxib vs. placebovs. placebo

Death from CV causes, MI, or stroke– celecoxib 200 mg bid vs. placebo

RR 2.5– celecoxib 400 mg bid vs. placebo

RR 3.4

1616

Incidence of Hierarchical Incidence of Hierarchical Cardiovascular Composite Endpoints Cardiovascular Composite Endpoints

in the APC Trialin the APC TrialEndpoint Number of patients (%) Rate/100 pt-yrs

Placebo 200 mg BID

400 mg BID

Placebo

200 mg BID

400 mg BID

Death from CV causes 1 (0.1) 3 (0.4) 6 (0.9) 0.05 0.14 0.29

Death from CV causes or MI

4 (0.6) 12 (1.8)

15 (2.2)

0.19 0.58 0.74

Death from CV causes, MI, or stroke

6 (0.9) 15 (2.2)

20 (3.0)

0.29 0.73 0.99

Death from CV causes, MI, stroke, or heart failure

7 (1.0) 16 (2.3)

23 (3.4)

0.34 0.78 0.11

Solomon SD, et al: N Engl J Med 352, 2005

1717

Hazard Ratios for Hierarchical CV Hazard Ratios for Hierarchical CV Composite Endpoints in the APC TrialComposite Endpoints in the APC Trial

Solomon SD, et al: N Engl J Med 352, 2005

Endpoint Hazard Ratio with 95% CI*

200 mg BID 400 mg BID

Death from CV causes 3.0 (0.3-28.6)

6.1 (0.7-50.3)

Death from CV causes or MI 3.0 (1.0-9.3) 3.8 (1.3-11.5)

Death from CV causes, MI, or stroke

2.5 (1.0-6.4) 3.4 (1.4-8.5)

Death from CV causes, MI, stroke, or heart failure

2.3 (0.9-5.5) 3.4 (1.4-7.8)

*Relative to placebo

1818

Celebrex - APCCelebrex - APC

Solomon SD, et al: N Engl J Med 352, 2005*In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure

671

1919

Celebrex - PreSAPCelebrex - PreSAP

Celecoxib in Adenoma Prevention Celecoxib in Adenoma Prevention Double-blind, placebo-controlled, Double-blind, placebo-controlled,

3 years, over 1900 patients3 years, over 1900 patients– Celebrex 400 mg once dailyCelebrex 400 mg once daily– PlaceboPlacebo

ASA use by ~16%ASA use by ~16%

2020

Hazard Ratio for Hierarchical CV Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Composite Endpoints in the PreSAP

TrialTrialEndpoint Placebo

n (%)400 mg

n (%)Hazard Ratio with 95% CI*

Death from CV causes 4 (0.6) 2 (0.2) 0.3 (0.1, 1.8)

Death from CV causes or MI

7 (1.1) 11 (1.2) 1.1 (0.4, 2.7)

Death from CV causes, MI, or stroke

12 (1.9) 19 (2.0) 1.1 (0.5, 2.2)

Death from CV causes, MI, stroke, or heart failure

12 (1.9) 20 (2.1) 1.1 (0.6, 2.3)

*Relative to placebo

2121

Hazard Ratio for Hierarchical CV Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Composite Endpoints in the PreSAP

TrialTrial

Endpoint PlaceboN = 628

n (%)

400 mg N = 933

n (%)

Hazard Ratio with 95% CI*

Death from CV causes 4 (0.6) 2 (0.2) 0.3 (0.1, 1.8)

Death from CV causes or MI

7 (1.1) 11 (1.2) 1.1 (0.4, 2.7)

MI 3 (0.4) 9 (1.0)

*Relative to placebo

2222

Celebrex - ADAPTCelebrex - ADAPT

Alzheimer’s prevention study December 17, 2004 – ADAPT trial December 17, 2004 – ADAPT trial

halted halted Celecoxib 200 mg bid, naproxen 220

mg bid, placebo N=~2500 patients Cardiovascular risk not found for

celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo was suggested.

2323

TARGETTARGET

Therapeutic COX-189 Arthritis Research Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial and Gastrointestinal Event Trial

52 weeks52 weeks 18,000 patients with osteoarthritis18,000 patients with osteoarthritis Two sub-studies: Two sub-studies:

– 0117: lumiracoxib 400 mg, naproxen 500 mg 0117: lumiracoxib 400 mg, naproxen 500 mg bid bid

– 2332: lumiracoxib 400 mg, ibuprofen 800 mg 2332: lumiracoxib 400 mg, ibuprofen 800 mg tidtid

25% of patients on low dose aspirin (ASA)25% of patients on low dose aspirin (ASA)

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TARGET TARGET Confirmed & Probable APTC EventsConfirmed & Probable APTC Events

LUMLUM NaprNapr LUMLUM IbuIbu

NN 47414741 47304730 43764376 43974397Pt-yr at riskPt-yr at risk 36393639 35343534 32423242 30903090

APTCAPTC 4040 2727 1919 2121

CV DeathCV Death 1111 88 88 1010

All MIAll MI

Rate/100 pt-yrRate/100 pt-yr18 18

(0.49(0.49))

1010(0.28(0.28

))

5 5 (0.15)(0.15)

7 7 (0.22)(0.22)

All All Ischemic/hem Ischemic/hem strokestroke

1616 1212 88 99

2525

TARGET TARGET Confirmed /Probable APTC Endpoint KM plot (%)Confirmed /Probable APTC Endpoint KM plot (%)

Study 0117

Study 2332

2626

Epidemiological StudiesEpidemiological Studies

Consistent risk associated with high dose rofecoxib

Variable findings of risk associated with other selective and nonselective NSAIDs

2727

FDA ConclusionsFDA Conclusions

April 6, 2005 Decisional April 6, 2005 Decisional Memorandum: “Analysis and Memorandum: “Analysis and recommendations for Agency recommendations for Agency action regarding non-steroidal action regarding non-steroidal anti-inflammatory drugs and anti-inflammatory drugs and cardiovascular risk” cardiovascular risk”

http://www.fda.gov/cder/drug/infohttp://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.ppage/COX2/NSAIDdecisionMemo.pdfdf

2828

FDA ConclusionsFDA Conclusions

““The three approved COX-2 The three approved COX-2 selective NSAIDs (i.e., celecoxib, selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are rofecoxib, and valdecoxib) are associated with an increased risk of associated with an increased risk of serious adverse CV events serious adverse CV events compared to placebo. The available compared to placebo. The available data do not permit a rank ordering data do not permit a rank ordering of these drugs with regard to CV of these drugs with regard to CV risk.”risk.”

2929

FDA ConclusionsFDA Conclusions

“Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs.”

3030

FDA Regulatory FDA Regulatory ActionsActions

April 7, 2005April 7, 2005 Boxed warning all Rx NSAIDs Boxed warning all Rx NSAIDs – Potential increased risk serious CV eventsPotential increased risk serious CV events– May be higher with prior history of CV May be higher with prior history of CV disease/risk disease/risk – Added GI warnings to boxAdded GI warnings to box– Contraindication perioperative CABGContraindication perioperative CABG

3131

FDA Regulatory FDA Regulatory ActionsActions

Class Medication Guide for all Rx Class Medication Guide for all Rx NSAIDsNSAIDs Revised warnings for OTC NSAIDsRevised warnings for OTC NSAIDs

3232

Information RequestInformation Request

Review of all clinical trial data Review of all clinical trial data from controlled studiesfrom controlled studies

Unable to draw conclusions Unable to draw conclusions – Small sample size, even with Small sample size, even with

poolingpooling– Very small number of CV eventsVery small number of CV events– Short duration of treatment Short duration of treatment

3333

3434

Additional slidesAdditional slides

3535

TARGETTARGET Confirmed & Probable MI Confirmed & Probable MI

by ASA Useby ASA UseLUMLUM NapNap LUMLUM IbuIbu

Overall Population Overall Population NN

47414741 47304730 43764376 43974397

All MI nAll MI n

Rate/100 pt-yrRate/100 pt-yr18 18

0.490.4910 10

0.280.2855

0.150.1577

0.230.23

Non-ASA Users NNon-ASA Users N 35493549 35373537 34013401 34313431

All MI nAll MI n

Rate/100 pt-yrRate/100 pt-yr1010

0.360.3644

0.150.1544

0.160.1655

0.210.21

ASA Users NASA Users N 11921192 11931193 975975 966966

All MI nAll MI n

Rate/100 pt-yrRate/100 pt-yr88

0.910.9166

0.670.6711

0.140.1422

0.300.30

3636

TARGETTARGET New Analysis -2007New Analysis -2007

Farkouh et. al. Annals of Rheumatic Disease, 2007 Apr 5; [Epub ahead of print]

• Post hoc analysis stratified by BL CV risk, treatment assignment and low-dose ASA use

• Primary composite endpoint – CV mortality, nonfatal MI, stroke at 1 year

• Secondary – congestive heart failure

3737

TARGETTARGET New Analysis -2007New Analysis -2007

Composite endpoint – CV mortality, nonfatal MI, stroke

LUMLUM NapNap LUMLUM IbuIbu

High Risk/ASA Users

n=541n=541 n=505n=505 n=394n=394 n=373n=373

% 1.481.48 1.581.58 0.250.25 2.142.14

High Risk/No High Risk/No ASAASA

n=318n=318 n=335n=335 n=326n=326 n=250n=250

%% 1.571.57 00 0.920.92 0.800.80

Low Risk/ASA Low Risk/ASA UsersUsers

n=651n=651 n=688n=688 n=n=581581 n=n=593593

%% 1.541.54 0.730.73 0.860.86 0.340.34

Low Risk/No Low Risk/No ASAASA

n=323n=32311

n=320n=32022

n=n=30753075 n=n=31831811

%% 0.530.53 0.440.44 0.330.33 0.350.35