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 COX Membrane phospholipids Arachidonate PGG 2 PGH 2 PGE 2 PGF 2 PGD 2 PGI 2 TXA 2

Prostanoids Cell Signaling Molecules

Phospholipase A2 Phospholipids, Arachidonic Acid PGG2 PGH2 NSAIDs Peroxidase Isomerase Prostaglandins Thromboxanes Angiogenesis Platelet function Apoptosis Invasiveness Inflammation Vascular Reactivity

Cyclooxygenase 2 Isoforms Cox-1 consitutive house-keeping Cox-2 inducible inflammation, cancer 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)

Thrombotic CV Events: Phase II OA Overall RR 1.09 (0.69,1.73)

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)

APPROVe Study

(Adenomatous Polyp Prevention with VIOXX) Standard Adenoma Prevention Study Subjects with recent adenoma 3-year adenoma endpoint 1-year research colonoscopy Rofecoxib 25 mg vs. placebo 107(!) sites, 39 in U.S.

APPROVe Study

Study overseen by External Steering Committee External Safety Monitoring Board (ESMB) Adjudication of Serious CV Events Prespecified Protocol for CV effects

APPROVe Study Design

Randomization Rofecoxib 25 mg (N~1214) Placebo (N~1214) Colo Study Visit Colo* Colo Month -4.5

-1.5

0 12 24

*non-study, within 3 months prior to screening

36

APPROVe Eligibility

Inclusion Criteria ≥ 40 years old histologically confirmed large bowel adenoma Prior MI, PTCA, CABG OK if > 1year prior T 0 Exclusion Criteria Uncontrolled hypertension (>165/95 mm Hg), angina at rest or minimal activity, CHF at rest

APPROVe Baseline Characteristics Rofecoxib N=1287 Male (%) Mean age Aspirin use (%) Hypertension (%)  CV risk* (%) Current Smoker (%) 62 59 years 19 36 29 22 Placebo N=1299 62 59 years 18 34 26 22 * CV hx, or ≥2 of: hx of DM,  cholesterol, HTN, smoker

APPROVe CV Events, as of 8/16/2004 118 Investigator-reported events 70 Confirmed Thrombotic Events MI, Unstable Angina, Sudden Death Stroke, TIA DVT, PE, Arterial Thrombosis 49 Confirmed APTC events* Death: CV or unknown cause MI Stroke

*APTC = Antiplatelet Trialists’ Collaboration BMJ. 1994

APPROVe CV Events Rate per 100 (N/ P-Yrs) Placebo N=1299 Rofecoxib N=1287 Thrombotic (70 Events) 0.75

(25/3315) 1.48 (45/3041 ) Relative Risk (95%CI) 1.96 (1.20, 3.19) APTC (49 Events) 0.48 (16/3322) 1.08 (33/3053) 2.25 (1.24, 4.08) RR for CHF/PE/Cardiac Failure: 4.29 (1.43, 12.82)

APPROVe Confirmed Thrombotic Events Placebo (N=1299) Rofecoxib (N=1287)

Cardiac Events 11 30 Cerebrovascular Events 7 15 Peripheral Vascular Events 7 3

APPROVe Confirmed Thrombotic Endpoints Overall RR: 1.96 (1.20, 3.19)

Thrombotic CV Events Alzheimer’s Disease Studies Overall RR 1.01 (0.67,1.53)

APPROVe Thrombotic Events Subgroup analyses Age Hypertension Diabetes Hypercholesterolemia • Aspirin use • Cigarette smoking •  CV risk* No treatment by Subgroup Interactions *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

APPROVe CV Events

Summary  risk of thrombotic CV events after 18 months of Tx 1 st 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 uncertain Analyses ongoing Patients will be followed for one year per protocol Adenoma data will be analyzed Study 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

Cumulative Metaanalysis MI (

not

Total CVD)

Combined RR = 2.24 (1.24-4.02 # Patients # Events Year 1997 1998

Juni et al, 2004

1999 2000 5193 13,269 16 40

VIGOR Study

2002 21,432 64

Naproxen & MI Risk Observational Data Juni et al, 2004

Jick (2000) Rahme (2002) Ray (2002) Ray (2002) Schlienger (2002) Solomon (2002) Watson (2002) Mamdani (2003) Kimmel (2004) Graham (2004) Garcia Rdoriguez (2004) Combined RR (0.86 0.75-0.99)

COX-2 Inhibitors & CVD What are the Possible Mechanisms?

COX-1 Aspirin COX-2 Inhibition Prostacyclin Thromboxane COX-2 Thromboxane Prostacyclin Decreased CV events Increased CV events

Atherosclerosis An Inflammatory Process • Cox-2 over expressed in atheroma • Cox-2 inhibitors might be beneficial??

NSAIDs and Blood Pressure Frishman, Am J Cardiol, 2002

Baseline mean = 136 mm Hg Baseline mean = 136 mm Hg

Frishman, 2002

Baseline mean = 81 mm Hg

NSAIDs & GFR Harris, 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  • COX-2  vascular prostacyclin 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 Published commentary uninformed