# Presentation: 891772

## Testimony of Sidney M. Wolfe M.D.Director, Health Research Group  of Public Citizen FDA Arthritis Advisory Committee Meeting on Etoricoxib (Arcoxia) for Treatment of Osteoarthritis

- April 12, 2007

**Notes:**
Thank you for the opportunity of appearing before this advisory committee. I have no financial conflicts of interest.

## Introduction

- The consideration of approval of etoricoxib involves three outcome variables:
- Relative efficacy for osteoarthritis
- Relative cardiovascular risk
- Relative gastrointestinal toxicity (serious complications such as perforation, bleed and obstruction)

**Notes:**
The consideration of approval of etoricoxib involves three outcome variables: Relative efficacy for osteoarthritis, relative cardiovascular risk and 
relative gastrointestinal toxicity (serious complications such as perforation, bleed and obstruction).

##  “Once daily treatment with etoricoxib 60 mg 

- shows comparable efficacy to naproxen 1000 mg
- (500 mg 2 times daily) and to diclofenac 150 mg
- (50 mg 3 times daily) in patients with OA.”
- “Once daily treatment with etoricoxib 30 mg shows comparable efficacy to ibuprofen 2400 mg (800 mg 3 times daily) and to celecoxib 200 mg once daily in patients with OA.

- Merck Conclusions of Etoricoxib Efficacy
- (Page 66 of Merck Advisory Committee Briefing package)

**Notes:**
The first consideration is easiest to discuss because Merck admits, in its conclusions, that “Once daily treatment with etoricoxib 60 mg 
shows comparable efficacy to naproxen 1000 mg (500 mg 2 times daily) and to diclofenac 150 mg (50 mg 3 times daily) in patients with OA.” 
The consideration of approval of etoricoxib involves three outcome variables: Relative efficacy for osteoarthritis, relative cardiovascular risk and 
relative gastrointestinal toxicity (serious complications such as perforation, bleed and obstruction).

## Sponsors need

***incentives to***
***evaluate drugs***
***in a manner***
***that highlights***
***potential***
***clinical value,***
***not marketing***
***potential.***

- NSAID Trials and the Choice of Comparators--Questions of Public Health Importance.  Psaty and Weiss. NEJM, January, 2007

**Notes:**
For the second variable, relative cardiovascular risk, the paper in the New England Journal of Medicine in January of this year by Bruce Psaty and Noel Weiss concerning the choice of comparator drugs is extremely important. They are concerned, as shown in this slide, that “Sponsors need
incentives to evaluate drugs in a manner that highlights potential clinical value, not marketing potential.” In reviewing studies in which naproxen or diclofenac were compared to other drugs, they concluded that “These data suggest that as compared with naproxen, diclofenac may increase the risk of vascular events by about 70%.”

## RCTs: COX-2 vs Placebo

- Kearney, et al 2006, BMJ. Do selective cyclo-oxygenase-2 inhibitors and  traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis?  Meta-analysis of randomised trials

- Favors  Placebo

-             MIs with COX-2/
-                     Placebo

**Notes:**
The overall statistically significantly increased rate of vascular events for the 121 trials in which various COX-2 drugs were compared with a placebo was 1.86 times higher with the COX-2 drugs.

## RCTs: COX-2 Drugs vs Older NSAIDs

- Kearney, et al 2006, BMJ

- Ratio favoring older NSAIDs:
- COX-2 MI/Older NSIAD MI

**Notes:**
The next slide shows comparisons between COX-2 drugs and older NSAIDs. As can be seen, when COX-2 drugs are compared with naproxen, the earlier “problem”  with Vioxx, the aggregate statistically significant increased risk with the COX-2 drugs for myocardial infarctions is 2.04 times that of naproxen. When the comparison is with diclofenac or other non-naproxen NSAIDs, the increased risk decreases to 1.2 and is no longer statistically significant.

## AHA Recommendations: Antman, et al Circulation.  March 2007

- AHA Recommendations: Antman, et al *Circulation.*  March 2007

**Notes:**
Yet another way of illustrating the importance of the comparator drug that is chosen is reviewed in last months American Heart Association recommendations concerning the use drugs to relieve pain. As shown in the slide, they found that, compared to a placebo, the cardiovascular risk of naproxen was 0.92, not significantly different from 1. But for diclofenac, the increased cardiovascular risk was a significant 1.63 times placebo. These recommendations included naproxen as the drug of choice for anyone with cardiovascular risk factors or cardiovascular disease and recommended, for such people, COX-2 drugs as a last choice.

## Non-Selective NSAIDs and Cardiovascular Risk (cont’d)

- AHA Recommendations: Antman, et al *Circulation.*  March 2007

**Notes:**
The following slide, also from the AHA paper, compares the odds of vascular events in randomized controlled trials of COX-2 drugs in which naproxen is the comparator with those in which another non-naproxen NSAID, primarily diclofenac is the comparator to the COX-2 inhibitor.
Whereas the relative risk of naproxen, compared to the COX-2 drug, was 0.64, the relative risk of the non-naproxen NSAIDs was 1.14, not siginificantly different from the COX-2 drugs.

## NDA/Deaths(rates are per 100 PYR)

|  | Placebo
PYR=360 | Etoricoxib
PYR=4129 | Non-naproxen
PYR=527 | Naproxen
PYR=1728 |
| --- | --- | --- | --- | --- |
| Total deaths | 1
(rate 0.28) | 20
(0.48) | 2
(0.38) | 5
(0.29) |
| CV Deaths | 0
(0) | 10
(0.24) | 2
(0.38) | 3
(0.17) |
| Thrombotic CV Deaths | 0
(0) | 9
(0.22) | 2
(0.38) | 2
(0.12) |
| Non-CV Deaths | 1
(0.28) | 10
(0.24) | 0
(0) | 2
(0.12) |

- FDA Presentation at 2/05 Meeting

**Notes:**
The first slide shows that for all of the studies submitted as part of the NDA several years ago, etoricoxib had a much more unfavorable comparison with naproxen than with non-naproxen NSAIDs. Thrombotic cardiovascular deaths occurred at a rate of  0.12 with naproxen but
0.22 with etoricoxib.  

## NDA/Absolute Rate & Relative Risk

| Comparisons | N | Cases/PYR | Rate  | Relative risk (95% CI) |
| --- | --- | --- | --- | --- |
| Confirmed thrombotic CV serious adverse events |  |  |  |  |
| Etoricoxib
Placebo | 2818
1767 | 7/560
4/335 | 1.25
1.19 | 1.11 
(0.32, 3.81) |
| Etoricoxib
Non-naproxen NSAIDs | 1266
718 | 12/1522
4/501 | 0.79
0.80 | 0.83 
(0.26, 2.64) |
| Etoricoxib
Naproxen | 1960
1497 | 34/2480
14/1727 | 1.37
0.81 | 1.70 
(0.91, 3.18) |

- FDA Presentation at 2/05 Meeting

**Notes:**
This is further illustrated on the next slide in which the relative risk of confirmed thrombotic CV serious adverse events with etoricoxib is 1.70 times higher than with naproxen but only 0.83 times as high compared with non-naproxen NSAIDs.

## NDA/Naproxen

| Endpoint | Etoricoxib |  | Naproxen |  |
| --- | --- | --- | --- | --- |
|  | PYR=2480 |  | PYR=1727 |  |
|  | N | Rate | N | Rate |
| Patients with one or more thrombotic CV SAE | 34 | 1.37 | 14 | 0.81 |
| Cardiac | 21 | 0.85 | 9 | 0.52 |
| MI | 10 | 0.40 | 5 | 0.29 |
| Fatal MI | 2 | 0.08 | 1 | 0.07 |
| Sudden Death | 3 | 0.12 | 0 | 0 |
| Unstable Angina | 6 | 0.24 | 3 | 0.17 |
| Peripheral | 2 | 0.08 | 5 | 0.29 |
| Cerebrovascular | 12 | 0.48 | 2 | 0.12 |
| Ischemic Stroke | 10 | 0.40 | 0 | 0 |
| Fatal Ischemic Stroke | 0 | 0 | 1 | 0.06 |

- FDA Presentation at 2/05 AAC Meeting

## NDA/Naproxen

| Endpoint | Etoricoxib |  | Naproxen |  |
| --- | --- | --- | --- | --- |
|  | PYR=2480 |  | PYR=1727 |  |
|  | N | Rate | N | Rate |
| Patients with one or more thrombotic CV SAE | 34 | 1.37 | 14 | 0.81 |
| Cardiac | 21 | 0.85 | 9 | 0.52 |
| MI | 10 | 0.40 | 5 | 0.29 |
| Fatal MI | 2 | 0.08 | 1 | 0.07 |
| Sudden Death | 3 | 0.12 | 0 | 0 |
| Unstable Angina | 6 | 0.24 | 3 | 0.17 |
| Peripheral | 2 | 0.08 | 5 | 0.29 |
| Cerebrovascular | 12 | 0.48 | 2 | 0.12 |
| Ischemic Stroke | 10 | 0.40 | 0 | 0 |
| Fatal Ischemic Stroke | 0 | 0 | 1 | 0.06 |

- FDA Presentation at 2/05 AAC Meeting

**Notes:**
The next slide shows that categories within the thrombotic cardiac events included MI, fatal, MI, sudden death, and unstable angina as well as strokes. It can be seen that the greatest numbers of events were MI’s and strokes.

## EDGE/Hypertension

|  | Etoricoxib 90 mg
N=3593 |  | Diclofenac 150 mg
N=3518 |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| Hypertension |  |  |  |  |
| Number (%) of patients :
With serious                       hypertension related AE

With a hypertension related AE associated with systolic>180 mm Hg or diastolic  >110 mm Hg | 
5

69 | 
(0.14)

(1.9) | 
2

30 | 
(0.05)

(0.9) |

- FDA Presentation at 2/05 AAC Meeting

**Notes:**
The earlier EDGE study used a comparison with diclofenac and, as seen in the next slide, found a marked increase in significant hypertension in patients using etoricoxib.

## EDGE/CHF

| Adverse Experience | Etoricoxib | Diclofenac |
| --- | --- | --- |
|  | N (%) | N (%) |
| Incidence of CHF, pulmonary edema-related, or cardiac failure

Cardiac failure

Cardiac failure congestive | 14 (0.4)

1 (0)

12 (0.3) | 6 (0.2)

0 (0)

6 (0.2) |

- FDA Presentation at 2/05 AAC Meeting

**Notes:**
The same increased cardiac risk, even in comparison to diclofenac, can be seen in the next slide in which there is more than a two-fold increase in patients getting etoricoxib.

## Summary

- In NDA, etoricoxib trends worse in terms of CV/TE particularly cardiac/MI
- Comparisons of etoricoxib to naproxen for CV/TE events are similar to  rofecoxib/naproxen comparisons
- Trial design concerns in EDGE (2 ongoing trials of similar design)
- Trends in EDGE for cardiac events worse for etoricoxib, mainly in non-ASA users

- FDA Presentation at 2/05 AAC Meeting

##             Summary statistics for CV outcomes, pooled MEDAL Program

**            ****Summary statistics for CV outcomes, pooled MEDAL Program**
**    ****Confirmed APTC (Antiplatelet Trialists’ Collaboration) Combined Endpoint**
**       ****(from Summary of FDA Medical Officer Review for this meeting  4/12/07**)

**Notes:**
Confirming the “wisdom” of Merck’s choice of diclofenac as the comparator for the MEDAL study, are the results as shown in the FDA presentation for this meeting as shown in the slide below. As predicted from comparisons between diclofenac, itself having an increased cardiac risk, and other COX-2 inhibitors, there is no significant difference in the confirmed APTC endpoint between etoricoxib and diclofenac.

## from Summary of FDA Medical Officer Review for this meeting 4/12/07

**Notes:**
Even though the increase in thrombotic events did not show up because diclofenac was chosen as the comparator, there was clearly an increase in patients discontinuing etoricoxib because of hypertension-related adverse events as shown in the following slide. At either the 60 or 90 milligram dose of etoricoxib, significantly more patients had to discontinue the drug.

## from Summary of FDA Medical Officer Review for this meeting 4/12/07

**Notes:**
Finally, in the case of serious gastrointestinal toxicity, there was no benefit to etoricoxib compared with diclofenac as shown in the next slide.the Rate of serious confirmed G-I events with etoricoxib was 0.30 per 100 patient years vs 0.32 with diclofenac, not significantly different.

## In Vitro Selectivity: COX-2/COX-1 Ratio

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**ketorolac**

**In Vitro Selectivity: COX-2/COX-1 Ratio**

- Warner *et al. FASEB J*. 2004:18:790-804

**flurbiprofen**

**ibuprofen**

**tolmetin**

**naproxen**

**aspirin**

**indomethacin**

**ketoprofen**

**fenoprofen**

**etoricoxib**

**rofecoxib**

**valdecoxib**

**celecoxib**

**nimesulide**

**diclofenac**

**etodolac**

**meloxicam**

**> 50-fold COX-2 selective**

**5- 50-fold COX-2 selective**

**< 5-fold COX-2 selective**

** ****Range of COX Selectivity for COX-1 and COX-2**
**(log****10 ****IC****50**** COX-2/COX-1)**

**Increasingly COX-2 Selective**

**Increasingly COX-1 Selective**

**lumiracoxib**

**Notes:**
The next slide, presented at the AAC meeting in February, 2005, shows the range of COX selectivity for various NSAIDs. It is clear that both rofecoxib and etoricoxib are at the far end of the spectrum of increased COX-2 selectivity with diclofenac showing much more COX-2 selectivity than naproxen. Thus, similarity in the cardio-toxic properties of rofecoxib and etoricoxib are not surprising. Nor is the fact that diclofenac is much more cardio-toxic than naproxen.

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**Notes:**
As can be seen in the next slide, the sulfone moiety S02CH3 is common to both rofecoxib and etoricoxib and might be related to the increased cardiac toxicity of both drugs.