An epidemiologic perspective on etoricoxib

David J. Graham, MD, MPHOffice of Surveillance and Epidemiology

April 12, 2007

Introduction

What is known about NSAID-related UGI hospitalization and mortality?

What is known about NSAID-related cardiovascular risk?

Is diclofenac a reasonable comparator for a drug that will be marketed to millions in the US, many with underlying CV disease?

What is known about the performance of COX-2 selective coxibs compared to other therapies with respect to

– GI risk– CV risk

Based on current state of knowledge, should etoricoxib be approved?

Deaths due to NSAID gastropathy (1)

Singh, Rheumatology 1999; Suppl 56

Estimated total GI deaths while taking NSAIDs, not deaths due to NSAIDs.Case fatality rate estimated @ 17%.

Deaths due to NSAID gastropathy (2)

Gutthann et al., Epidemiology 1997

First time hospitalization for UGI events among patients ever treated with NSAIDs, Saskatchewan, Canada, 1982-1986

Deaths due to NSAID gastropathy (3) US hospitalization and mortality data, 1999-2003

Acute + chronic UGI ulcers, perforations, bleeds

Mean population Hospital discharges1 Mortality2

284,887,691 332,000 4,714 (1.4%)

(includes gastric ulcer, duodenal ulcer, peptic ulcer site unspecified, gastrojejunal ulcer, gastritis and duodenitis ± hemorrhage, perforation, or obstruction: 1 ICD 9 codes 531-535; 2 ICD 10 codes K25-K29)

1 National Hospital Discharge Survey, 1999-2003, available at: http://www.cdc.gov/nchs/about/major/hdasd/listpubs.htm2 Compressed Mortality File (CMF) compiled from CMF 1999-2003, Series 20, No. 2I 2006 on CDC WONDER On-line Database

Meta-analysis of clinical trials of AMI risk with coxib NSAIDs compared to placebo

Kearney, et al., BMJ 2006

Coxib Placebo

Meta-analysis of clinical trials of AMI risk with coxibs compared to traditional NSAIDs

Kearney, et al., BMJ 2006

RR=0.45 (0.30-0.68)naproxen v. coxib

Coxib tNSAID

Risk estimates for AMI with various NSAIDs compared to non-use from meta-analysis of observational studies

Rel

ativ

e ris

k

Diclo(9)

Ibuprof(16)

Indo(6)

Naprox(15)

Pirox(4)

Other(19)

Celecox(11)

Rofecox(11)

.7

.9

1

1.2

1.4

1.7

McGettigan & Henry, JAMA 2006

Observational studies of AMI risk with NSAIDs published since JAMA meta-analysis

Diclofenac Ibuprofen Naproxen Celecoxib Etoricoxib Rofecoxib

.6

.8

1

1.2

1.5

2

3

4

Rel

ativ

e ris

k

Andersohn, Circulation 2006Helin-Salmivera, Eur Heart J 2006Brophy, Heart 2007

Risk of AMI with selected NSAIDs from meta-analyses of observational (▬) and randomized (▬) studies

Diclofenac Ibuprofen Naproxen

.6

.8

1

1.4

2

2.5

Rel

ativ

e ris

k

(9)

(26)

(16)

(24)

(15)(42)

COX-2 selectivity of various NSAIDs

Patrono, et al. J Clin Invest 2001

COX-1 and COX-2 selectivity of various pain relievers

FitzGerald and Patrono, N Engl J Med 2001

Prescription NSAID use in the US, 2000-2006

0.05.0

10.015.020.025.030.035.040.0

Coxibs Ibuprofen Naproxen Diclofenac All others

Pe

rce

nt

NS

AID

Ma

rke

t

Source: Verispan, Vector One™: National,Extracted March 2007

Prescription non-coxib NSAID use in the US, 2000-2006

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

Ibuprofen Naproxen Diclofenac All others

Perc

en

t N

SA

ID M

ark

et

Source: Verispan, Vector One™: National, Extracted March 2007

Diclofenac as a reference group (1)

Rofecoxib vs. Diclofenac

Hospitalized AMI: RR = 0.99 (0.82-1.19)

Pharmacoepidemiology Drug Saf 2006; (epub November)

Etoricoxib vs. Diclofenac

APTC events: RR = 0.96 (0.79-1.16)

Lancet 2006; (epub November)

Diclofenac as a reference group (2)What if an appropriate reference had been used?

Drug n Risk (per 100 pyrs) Relative risk (95% CI)

Etoricoxib 1960 1.09 (0.72-1.58) 2.72 (1.18-6.27)

Naproxen 1497 0.41 (0.16-0.83)

Dr. Robert Shibuya,FDA presentation

Cumulative probability of recurrent ulcer bleeding in patients treated with celecoxib or diclofenac+omeprazole

Chan et al, New Engl J Med 2002

p=0.60 (logrank test)

Cumulative probability of recurrent ulcer bleeding in patients treated with celecoxib or diclofenac+omeprazole (2)

Chan et al., New Engl J Med 2002

Cumulative probability of recurrent ulcer bleeding in patients treated with celecoxib or naproxen+lansoprazole (1)

Lai, et al., Amer J Med 2005

Cumulative probability of recurrent ulcer bleeding in patients treated with celecoxib or naproxen+lansoprazole (2)

Cum prob (95% CI)

Celecoxib 3.7% (0%-7.3%)

Naproxen+PPI 6.3% (1.6%-11.1%)

Difference -2.6% (-9.1%-3.7%)

Lai, et al., Amer J Med 2005

Summary of published observational studies of NSAID+PPI use

Study Outcome # CasesNSAID+PPIvs. Nonuse

NSAID+PPIvs. NSAID

Epidemiology1999

RecurrentUGIB 76 0 (0-1.0)

Epidemiology2001 PUBs 2105 0.5 (0.2-1.1)

Aging Clin Exp Res2003 UGIB 225 1.05 (0.2-5.7)

BMJ2005 PUBs 9407 0.83 (not avail) 0.3 (0.2-0.5)

Gut, 2006Am J Gastro 2007 UGIB 2777 0.9 (0.7-1.3) 0.13 (0.09-0.19)

Pharmacoepi Drug2007 PUBs 979 1.3 (0.7-2.5) 0.4 (0.2-0.7)

FD&C Act Sec 505(d)

Requirement for approval of a new drug:

"...adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof"

Public health considerations (1)

Cardiovascular disease leading cause of mortality in US

– Background risk of AMI in males 65-74: 2% (1 in 50 per year)

This demographic is a large segment of target population for etoricoxib

Potential impact based on RR=2.72 (etoricoxib v. naproxen)

– Among males 65-74, risk of 5.4% (1 in 18 per year)

– NNHEtoricoxib = 147 person-years

– 6,800 extra APTC events per 1,000,000 person-years etoricoxib use

If etoricoxib use becomes extensive, multiplier effect on number of premature and excess CV events, compounded year after year

– Estimated 88,000-140,000 excess AMI events with rofecoxib

Public health considerations (2)

Not all NSAIDs are the same with respect to CV risk– Diclofenac

Low use in USIncreases AMI riskInappropriate and deceptive comparator for CV safety

– NaproxenMore widely usedNeutral with respect to AMI riskDoes not interfere with beneficial CV effects of aspirin

tNSAID + PPI equivalent to coxibs for UGI outcomes– RCT data – Epidemiologic data

No apparent or demonstrable added benefit to etoricoxib use

Conclusions (1)

Diclofenac is an inappropriate comparator for assessment of population cardiovascular risk

– Applicant’s program is based on this inappropriate comparator

Etoricoxib probably confers substantial increase in CV risk– Enormous public health and population consequence

Etoricoxib is no more effective for pain relief than tNSAIDs

Naproxen + PPI equivalent to coxibs for gastroprotection– Substantial cardiovascular safety advantage– Substantially less expensive

Conclusions (2)

Approval should be based on “...adequate tests by all methods reasonably applicable…”

– Demonstration of efficacy:Current “tests” probably adequate

Etoricoxib comparable to tNSAIDs for pain relief; no advantage to 60 mg dose over 30 mg

– Demonstration of safety:No cardiovascular safety data for 30 mg strength

Current “tests” not adequate or reasonableCoxib superiority over naproxen + PPI for UGI

outcomesCoxib superiority over naproxen + PPI for CV

outcomes