# Presentation: 709611

## Analysis of Cardiovascular Thromboembolic Events With Etoricoxib 

- Joel Schiffenbauer, M.D.
- DAAODP, ODE V
- February 17, 2005

## Etoricoxib

- NDA indications include: OA, CLBP, RA, AS, acute gout, acute pain, dysmenorrhea
- Proposed doses: 60 and 90 mg chronically and 120 mg acutely
- EDGE study: Etoricoxib vs. Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness

## Etoricoxib

- Exposure
- Mortality data
- CV/TE data
- NDA
- EDGE

## Etoricoxib

- Exposure

## Chronic Exposure to Etoricoxib Across the NDA

| Dose of etoricoxib | Total number
 of patients | Mean number 
of days on drug |
| --- | --- | --- |
| <60 mg | 535 | 145 |
| 60 | 1193 | 390 |
| 90 | 1736 | 361 |
| 120 | 1052 | 314 |
| >120 | 35 | 5.4 |

## EDGE Study

|  | Etoricoxib 90 mg (N=3593) |  | Diclofenac 150 mg (N=3518) |  | Total
(N=7111) |
| --- | --- | --- | --- | --- | --- |
| Duration of study therapy (months) |  |  |  |  |  |
| Mean |  | 9.3 | 8.9 | 9.1 |  |
| SD |  | 4.4 | 4.5 | 4.5 |  |
| Median |  | 11.5 | 11.3 | 11.4 |  |
| Range |  | 0.5 to 16.5 | 0.5 to 16.6 | 0.5 to 16.6 |  |
| Total patient years |  | 2789 | 2604 | 5393 |  |

## Etoricoxib

- Mortality Data

## 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) |

## EDGE/Deaths

|  | ETORICOXIB 
(2792 pt-yrs) | DICLOFENAC
(2608 pt yrs) |
| --- | --- | --- |
| TOTAL | 8 | 6 |
| CV THROMBOTIC | 3 | 1 |
| CVA (hemorrhagic) | 1 | 2 |
| NEOPLASM | 2 | 3 |
| Other | 2
(endocarditis,
hemorrhagic shock) | 0 |

## Etoricoxib

- CV/TE Events in NDA

## Serious Adverse Events Included in Thrombotic CV SAEs

- Cardiac
- Acute MI
- Fatal MI
- Unstable angina
- Sudden death
- Peripheral
- Pulmonary embolism
- Fatal PE
- Peripheral arterial or venous thrombosis
- Cerebrovascular
- Ischemic cerebrovascular stroke
- Fatal stroke
- TIA

## 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) |

## 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) |

## NDA/Placebo

| Endpoint terms | Etoricoxib |  | Placebo |  |
| --- | --- | --- | --- | --- |
|  | PYR=560 |  | PYR=335 |  |
|  | N | Rate 
(per 100 PYR) | N | Rate |
| Patients with one or more thrombotic CV SAEs | 7 | 1.25 | 4 | 1.19 |
| Cardiac (MI, fatal MI, unstable angina, sudden death) | 4 | 0.71 | 0 | 0 |
| Peripheral | 1 | 0.18 | 2 | 0.60 |
| Cerebrovascular
(ischemic stroke) | 3 | 0.54 | 2 | 0.60 |

## NDA (KM Estimates for CV Events)

## 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) |

## NDA/Non-naproxen NSAIDs

| Endpoint | etoricoxib |  | combined |  | diclofenac |  | ibuprofen |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | PYR=1522 |  | PYR=501 |  | PYR=447 |  | PYR=54 |  |
|  | N | Rate | N | Rate | N | Rate | N | Rate |
| Patients with one or more thrombotic CV SAE | 12 | 0.79 | 4 | 0.80 | 4 | 0.89 | 0 | 0 |
| Cardiac | 11 | 0.72 | 2 | 0.40 | 2 | 0.45 | 0 | 0 |
| MI | 3 | 0.20 | 0 | 0 | 0 | 0 |  |  |
| Fatal MI | 2 | 0.13 | 1 | 0.14 | 1 | 1 |  |  |
| Sudden Death | 2 | 0.13 | 1 | 0.14 | 1 | 1 |  |  |
| Unstable Angina | 4 | 0.26 | 0 | 0 | 0 | 0 |  |  |
| Cerebrovascular
Ischemic stroke; TIA | 2 | 0.13 | 2 | 0.40 | 2 | 0.45 | 0 | 0 |

## NDA/KM

## 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) |

## 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 |

## NDA/KM

## Etoricoxib

- CV Events in EDGE Study

## EDGE

- 7000 patient GI tolerability study; collect CV data; non-inferiority to diclofenac (upper limit of 95% CI for hazard ratio is 1.3)
- Issues:
- Non-inferiority trial (no placebo)
- diclofenac only comparator
- only OA, no RA
- ASA use (30%)
- previous Cox-2 use allowed (15% rofecoxib;
- 	13% celecoxib; 5% valdecoxib)
- 2600 with >2 CV risk factors

## EDGE/KM Estimates

## EDGE/Confirmed Thrombotic CV SAEs

| Endpoint | Etoricoxib |  | Diclofenac |  |
| --- | --- | --- | --- | --- |
|  | PYR=2789 |  | PYR=2607 |  |
|  | N | Rate | N | Rate |
| Patients with one or more thrombotic CV SAE | 35 | 1.25 | 30 | 1.15 |
| Cardiac | 27 | 0.93 | 19 | 0.73 |
| MI | 19 | 0.65 | 11 | 0.42 |
| Sudden Death | 2 | 0.07 | 1 | 0.04 |
| Unstable Angina | 6 | 0.22 | 7 | 0.27 |
| Peripheral | 3 | 0.11 | 4 | 0.15 |
| Cerebrovascular | 7 | 0.25 | 7 | 0.27 |
| Ischemic Stroke | 3 | 0.11 | 6 | 0.23 |
| Fatal Ischemic Stroke | 1 | 0.04 | 0 | 0 |

## EDGE/ASA Users Combined

|  | Etoricoxib | Diclofenac |
| --- | --- | --- |
|  | Number of Events | Number of Events |
| Cardiac
MI 
MI plus unstable angina
CNS
PVS
Cardiac plus CNS | 12
7
11

4
1
16 | 9
5
9

3
1
12 |

## EDGE/Non-ASA Users Combined

|  | Etoricoxib | Diclofenac |
| --- | --- | --- |
|  | Number of events | Number of events |
| Cardiac
MI 
MI plus unstable angina
CNS
PVS
Cardiac plus CNS | 15
12
14

3
2
18 | 10
6
9

4
3
14 |

## 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) |

## EDGE/Hypertension

## 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) |

## 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