The Vioxx Withdrawal

What Happened?

John A. Baron Dartmouth Medical School

for the APPROVe Investigators

Vioxx

A Recent Quote

The licensing of Vioxx and its continued use …. have been public-health catastrophes.

(Lancet, Nov 5)

COX-2 Inhibitors

What are They? Should we Care?

Cyclooxygenase & Prostaglandins

Membrane phospholipids

Arachidonate

PGH2

PGE2 PGF2 PGD2 PGI2 TXA2

PGG2COX

ProstanoidsCell Signaling Molecules

Peroxidase

Isomerase

Phospholipase A2

PGG2

PGH2

Prostaglandins Thromboxanes

Angiogenesis

Apoptosis

Vascular ReactivityInvasiveness

Inflammation

Platelet function

NSAIDs

CO

X

Phospholipids, Arachidonic Acid

Cyclooxygenase

2 Isoforms

Cox-1 Cox-2 consitutive induciblehouse-keeping inflammation, cancer

Cox-2 w/o Cox-1 inhibition may offer:

Anti-inflammatory effects Cancer prevention

AND Protection of stomach No bleeding

Cox-2 w/o Cox-1 inhibition may offer:

Anti-inflammatory effects Cancer prevention

AND Protection of stomach No bleeding

Vioxx

Early History

• Vioxx (Rofecoxib) released in 1999• An “early” COX-2 inhibitor

more selective than celecoxib• Premise of COX-2 inhibitors:

greater safety than traditional NSAIDs at least equal efficacy

Thrombotic CV Events: the VIGOR Study

Overall RR: 2.38 (1.39, 4.00)

Overall RR 1.09 (0.69,1.73)Overall RR 1.09 (0.69,1.73)

Thrombotic CV Events: Phase II OA

Cardiovascular Background

Summary

In randomized trials prior to APPROVe cardiovascular risk for rofecoxib was:

• Higher than for naproxen• Similar to non-naproxen NSAIDs• Similar to Placebo

(limited data beyond 2 years)

Summary

In randomized trials prior to APPROVe cardiovascular risk for rofecoxib was:

• Higher than for naproxen• Similar to non-naproxen NSAIDs• Similar to Placebo

(limited data beyond 2 years)

APPROVe Study

(Adenomatous Polyp Prevention with VIOXX)

Standard Adenoma Prevention Study

Subjects with recent adenoma3-year adenoma endpoint1-year research colonoscopyRofecoxib 25 mg vs. placebo107(!) sites, 39 in U.S.

(Adenomatous Polyp Prevention with VIOXX)

Standard Adenoma Prevention Study

Subjects with recent adenoma3-year adenoma endpoint1-year research colonoscopyRofecoxib 25 mg vs. placebo107(!) sites, 39 in U.S.

APPROVe Study

Study overseen by

External Steering CommitteeExternal Safety Monitoring Board (ESMB)

Adjudication of Serious CV Events

Prespecified Protocol for CV effects

Study overseen by

External Steering CommitteeExternal Safety Monitoring Board (ESMB)

Adjudication of Serious CV Events

Prespecified Protocol for CV effects

APPROVe Study Design

Study Visit Study Visit

RandomizationRandomizationPlaceboPlacebo (N~1214) (N~1214)

Rofecoxib 25 mgRofecoxib 25 mg (N~1214) (N~1214)

*non-study, within 3 months prior to screening*non-study, within 3 months prior to screening

36361212Month -4.5Month -4.5 00-1.5-1.5

Colo*Colo* ColoColo ColoColo

2424

APPROVe Eligibility

Inclusion Criteria ≥ 40 years oldhistologically confirmed large bowel adenomaPrior MI, PTCA, CABG OK if > 1year prior T0

Exclusion Criteria Uncontrolled hypertension (>165/95 mm Hg),

angina at rest or minimal activity, CHF at rest

Inclusion Criteria ≥ 40 years oldhistologically confirmed large bowel adenomaPrior MI, PTCA, CABG OK if > 1year prior T0

Exclusion Criteria Uncontrolled hypertension (>165/95 mm Hg),

angina at rest or minimal activity, CHF at rest

Male (%)

Mean age

Aspirin use (%)

Hypertension (%)

CV risk* (%)

Current Smoker (%)

Male (%)

Mean age

Aspirin use (%)

Hypertension (%)

CV risk* (%)

Current Smoker (%)

62

59 years

19

36

29

22

62

59 years

19

36

29

22

62

59 years

18

34

26

22

62

59 years

18

34

26

22

* CV hx, or ≥2 of: hx of DM, cholesterol, HTN, smoker* CV hx, or ≥2 of: hx of DM, cholesterol, HTN, smoker

RofecoxibN=1287

RofecoxibN=1287

PlaceboN=1299PlaceboN=1299

APPROVeBaseline Characteristics

APPROVe CV Events, as of 8/16/2004

118 Investigator-reported events

70 Confirmed Thrombotic EventsMI, Unstable Angina, Sudden DeathStroke, TIADVT, PE, Arterial Thrombosis

49 Confirmed APTC events*

Death: CV or unknown cause MIStroke

118 Investigator-reported events

70 Confirmed Thrombotic EventsMI, Unstable Angina, Sudden DeathStroke, TIADVT, PE, Arterial Thrombosis

49 Confirmed APTC events*

Death: CV or unknown cause MIStroke

*APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994*APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994

APPROVe CV Events

PlaceboN=1299PlaceboN=1299

RofecoxibN=1287

RofecoxibN=1287

Relative Risk (95%CI)

Relative Risk (95%CI)

0.75(25/3315)

0.48 (16/3322)

0.75(25/3315)

0.48 (16/3322)

1.48 (45/3041)

1.08 (33/3053)

1.48 (45/3041)

1.08 (33/3053)

Thrombotic(70 Events)

APTC(49 Events)

Thrombotic(70 Events)

APTC(49 Events)

1.96 (1.20, 3.19)

2.25 (1.24, 4.08)

1.96 (1.20, 3.19)

2.25 (1.24, 4.08)

Rate per 100 (N/ P-Yrs)

RR for CHF/PE/Cardiac Failure: 4.29 (1.43, 12.82)RR for CHF/PE/Cardiac Failure: 4.29 (1.43, 12.82)

APPROVe Confirmed Thrombotic Events

Cardiac Events

Cerebrovascular Events

Peripheral Vascular Events

Placebo (N=1299) Rofecoxib (N=1287)

11

7

7

30

15

3

APPROVe Confirmed Thrombotic Endpoints

Overall RR: 1.96 (1.20, 3.19)

Thrombotic CV Events

Overall RR 1.01 (0.67,1.53)

Alzheimer’s Disease Studies

APPROVe Thrombotic Events

Subgroup analyses

Age • Aspirin useHypertension • Cigarette

smokingDiabetes • CV risk*Hypercholesterolemia

No treatment by Subgroup Interactions

Subgroup analyses

Age • Aspirin useHypertension • Cigarette

smokingDiabetes • CV risk*Hypercholesterolemia

No treatment by Subgroup Interactions

*CV hx, or ≥2 of: hx of DM, cholesterol, HTN, smoker*CV hx, or ≥2 of: hx of DM, cholesterol, HTN, smoker

APPROVe: Blood Pressure

Preliminary analyses not suggestive of a relationship between blood pressure rise and risk

Preliminary analyses not suggestive of a relationship between blood pressure rise and risk

APPROVe CV Events

Summary risk of thrombotic CV events

after 18 months of Tx

1st 18 months consistent with prior placebo-controlled and nonnaproxen controlled data

On the basis of these data, VIOXX was withdrawn

Summary risk of thrombotic CV events

after 18 months of Tx

1st 18 months consistent with prior placebo-controlled and nonnaproxen controlled data

On the basis of these data, VIOXX was withdrawn

APPROVe: The Future

Mechanism of CV toxicity uncertainAnalyses ongoingPatients will be followed for one year per

protocol

Adenoma data will be analyzedStudy within 3 months of completion anyway

~75% of subjects had completed treatment

Mechanism of CV toxicity uncertainAnalyses ongoingPatients will be followed for one year per

protocol

Adenoma data will be analyzedStudy within 3 months of completion anyway

~75% of subjects had completed treatment

APPROVe Research Team

John Baron†, Robert S Bresalier††, Robert Sandler‡, Robert Riddell§, Angel Lanas║, Dion Morton¶, Alise Reicin#, Bettina Oxenius#, Kevin Horgan#, Hui Quan#

†Dartmouth Medical School ††University of Texas MD Anderson Cancer Center; ‡University of North Carolina at Chapel Hill; §Mount Sinai Hospital, Toronto; ║University Clinic Hospital, Zaragoza, Spain; ¶University of Birmingham, UK; #Merck Research Laboratories

John Baron†, Robert S Bresalier††, Robert Sandler‡, Robert Riddell§, Angel Lanas║, Dion Morton¶, Alise Reicin#, Bettina Oxenius#, Kevin Horgan#, Hui Quan#

†Dartmouth Medical School ††University of Texas MD Anderson Cancer Center; ‡University of North Carolina at Chapel Hill; §Mount Sinai Hospital, Toronto; ║University Clinic Hospital, Zaragoza, Spain; ¶University of Birmingham, UK; #Merck Research Laboratories

MI (not Total CVD)

Year19971998

1999

2000

2002

# Events

1640

64

# Patients

519313,269

21,432

Combined RR = 2.24 (1.24-4.02

Cumulative Metaanalysis

Juni et al,2004Juni et al,2004

VIGOR Study

Naproxen & MI RiskObservational Data

Combined RR (0.86 0.75-0.99)

Jick (2000)

Rahme (2002)

Ray (2002)

Ray (2002)

Schlienger (2002)

Solomon (2002)

Watson (2002)

Mamdani (2003)

Kimmel (2004)

Graham (2004)

Garcia Rdoriguez (2004)Juni et al, 2004Juni et al, 2004

COX-2 Inhibitors & CVD

What are the Possible Mechanisms?

Aspirin

COX-1

Thromboxane

Prostacyclin Thromboxane

COX-2 Inhibition

Decreased CV eventsDecreased CV events

Prostacyclin

Increased CV events

COX-2

Atherosclerosis

An Inflammatory Process

• Cox-2 over expressed in atheroma• Cox-2 inhibitors might be beneficial??

NSAIDs and Blood Pressure

Frishman, Am J Cardiol, 2002Frishman, Am J Cardiol, 2002

Baseline mean = 136 mm Hg

Cha

nge

from

bas

elin

e (m

m H

g)

Baseline mean = 136 mm Hg

Baseline mean = 81 mm HgFrishman, 2002Frishman, 2002

NSAIDs & GFR

Harris, Am J Cardiol, 2002Harris, Am J Cardiol, 2002

NSAIDs and CHF

“An Underrecognized Public Health Problem”

• NSAIDs can CHF • Stronger effect with Hx of CVD (Especially drugs w/ long half life)

Heerdink et al, Arch Intern Med, 1998 Page & Henry, Arch Intern Med, 2000 Feenstra et al, Arch Intern Med, 2002

COX-2 & Cardiovascular Disease

Background

• COX-2 vascular prostacyclin• COX-2 inflammation

Net effect on atherosclerotic disease?

• COX-2 involved in renal tubular function• COX-2 inhibition may lead to: fluid retention

HTN

Vioxx

Summary

• Increases in CVD• Probably delayed• Probably rare

Summary

• Increases in CVD• Probably delayed• Probably rare

Published commentary uninformedPublished commentary uninformed