# Presentation: 760416

## An epidemiologic perspective on etoricoxib

**David J. Graham, MD, MPH**
**Office 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 discharges**__**1**_**       **_**Mortality**__**2**_
**         ****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.htm**
**2**** 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**

## 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 **

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

- Relative risk

- 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

- Relative risk

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

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

- Relative risk

- (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

**Source: Verispan, Vector OneTM: National,**
**Extracted March 2007**

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

**Source: Verispan, Vector OneTM: 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 | 
# Cases | NSAID+PPI
vs. Nonuse | NSAID+PPI
vs. NSAID |
| --- | --- | --- | --- | --- |
| Epidemiology
1999 | Recurrent
UGIB | 
76 |  | 
0 (0-1.0) |
| Epidemiology
2001 | 
PUBs | 
2105 |  | 
0.5 (0.2-1.1) |
| Aging Clin Exp Res
2003 | 
UGIB | 
225 | 
1.05 (0.2-5.7) |  |
| BMJ
2005 | 
PUBs | 
9407 | 
0.83 (not avail) | 
0.3 (0.2-0.5) |
| Gut, 2006
Am J Gastro 2007 | 
UGIB | 
2777 | 
0.9 (0.7-1.3) | 
0.13 (0.09-0.19) |
| Pharmacoepi Drug
2007 | 
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)
- NNH**Etoricoxib** = 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 US
- Increases AMI risk
- Inappropriate and deceptive comparator for CV safety
- Naproxen
- More widely used
- Neutral with respect to AMI risk
- Does 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 reasonable
- 		Coxib superiority over naproxen + PPI for UGI outcomes
- 		Coxib superiority over naproxen + PPI for CV outcomes