# Presentation: 249210

- Lourdes Villalba, M.D.
- DAAODP, ODE V
- February 16, 2005

- Vioxx
- Cardiovascular Safety

## Overview of Presentation

- Goals
- Brief background/chronology
- Overview of Vioxx data sources
- Classification of CV events
- CV safety in different Vioxx databases
- Summary of Vioxx CV safety
- Challenges in interpreting Vioxx CV safety

## Vioxx Milestones

**97**

**98**

**99**

**00**

**01**

**02**

**03**

**04**

**05**

**96**

**94**

- NDA submit: Acute Pain/DYSM/OA

-  IND for Alzheimer’s
-  3/98 COX-II Safety AC

- First IND

-   2/01 AAC Meeting
-   Review of additional information
-   Internal Briefings COX-II Safety

- Arthritis/DSaRM COX-II Safety Meeting

-  GIDAC Meeting (APPROVe)

-  4/02    Label Update
-  10/02  PCPS Prostate Ca. prevention
-  10/02  Merck Pooled CV analysis
-  12/02  Advice letter to Merck

-  3/04 Updated Alzh CV Data
-  3/04 Migraine approval
-  8/04 JRA approval
-  8/04 Kaiser Study Abstract

-   9/04 APPROVe results
-   Ongoing Studies Stopped
-   Product Withdrawn

-  6/00 VIGOR results

-  IND for APPROVe

-   4/99 AAC meeting
-  5/99 NDA approved

## Overview of VioxxData Sources Before APPROVe

|  | 1998 | 2000 | 2001-2004 |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | NDA | VIGOR | 102 | RAe1 | SUR2 | AER3 | Epi & |
| Indication | OA | RA | OA | RA | Various |  | Re-analysis |
| Vioxx 12.5  | + |  |  |  | + | + | + |
|          25 | + |  |  |  | + | + | + |
|           50 | + | + |  | + | + | + | + |
| Ibuprofen | + |  |  |  | + |  | + |
| Diclofenac | + |  |  |  | + |  | + |
| Nabumetone | + |  |  |  | + |  | + |
| Placebo | +4 |  |  | +5 | +6 |  | + |
| Naproxen |  | + | + | + | + |  | + |

- 1RAe: RA efficacy supplement. 2 SURs: Safety Update Reports, include Alzheimer’s studies.  3FDA Adverse Event Reporting. 4up to 18 weeks.   5up to 12 weeks.   6Alzheimer’s studies up to 3 years.    Epi: epidemiologic studies.

## Cardiovascular Endpoints

- All events reported under CV system
- CV Deaths
- Discontinuations due to CV adverse events
- Serious CV adverse events
- CV/Thrombotic (pre-specified definition) referred for blinded CV adjudication
- Confirmed CV/Thrombotic
- APTC (Anti-platelet Trialist Collaboration)
- CV and unknown cause of death
- Non-fatal MI
- Non-fatal stroke  (ischemic & hemorrhagic)
-      (does not include unstable angina, transient ischemic attack &  peripheral events)

- 1

-  2

- 1. Routine FDA review   2. VIGOR and all subsequent Vioxx studies

## Serious CV/T1 Events Different Endpoints (VIGOR)

- 64

- 45

- 35

- 32

- 19

- 18

- Investigator CV/ T

- Adjudicated **2**

- APTC **3**** **

**1** Cardiovascular Thrombotic. **2**Confirmed by CV adjudication committee.  **3** Antiplatelet Trialist Collaboration composite endpoint: CV & unknown cause of death, non-fatal myocardial infarction and non-fatal stroke.

## Vioxx NDA Database (Nov. 1998)

- Large NDA, approx. 5,400 patients on rofecoxib
- Approx. 3,300 patients in multiple dose OA trials  (6-week, 6-month and one-year studies, some with extension up to 21 months).
- 371 patients exposed for ≥ 1 year at 12.5 mg
- 381 patients exposed for ≥ 1 year at 25 mg doses
- 270 patients exposed to 50 mg for ≥ 6 months
- (Greater exposure than International Conference on Harmonisation Guidances)

## Vioxx NDA – All CV EventsPotentially Thrombotic, Serious and            Non-serious1 (Nov 1998)

| 6-week Studies |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Vioxx 12.5 | Vioxx   25 | Vioxx  50 | Ibuprofen  | Nabum  |  | Placebo |
| N= 725 | N= 735 | N= 97 | N= 470 | N= 115 | ______ | N= 412 |
| 5 (0.7%) | 5 (0.7%)  | 1 (1.1%) | 2 (0.4%) | 0 |  | 1 (0.2%) |
| 24-week Studies |  |  |  |  |  |  |
| Vioxx 12.5 | Vioxx   25 | Vioxx  50 | Ibuprofen  |   | Diclofenac | Placebo* |
|  N= 490 | N= 879 | N= 379 | N= 377 | _____ | N= 498 | N= 371  |
| 7 (1.4%) | 10 (1.1%) | 4 (1.1 %) | 2 (0.5 %) |  | 10 (2.0 %) | 3 (0.8 %) |

- CV safety: Vioxx appears between ibuprofen and diclofenac.                                 1 Includes terms such as coronary artery disease, angina pectoris, myocardial infarction, cerebrovascular accident (These are not confirmed events) * Placebo only 18 weeks exposure

## Vioxx NDA Approved May, 1999

- Adequate evidence of efficacy for
- Acute pain (50 mg) for five days
- Dysmenorrhea (50 mg)
- Osteoarthritis (12.5 and 25 mg dose)
- Adequate evidence of safety for the intended uses as indicated in the label
- Safety profile similar to comparators NSAIDs
- CV safety profile in between ibuprofen & diclofenac
- HTN:  Dose response, 50 mg> 12.5 and 25 mg
- Endoscopic data suggest Vioxx better than ibuprofen
- Liver: Vioxx better than diclofenac

## Vioxx - Patients with Confirmed               APTC Events VIGOR (June 2000)*

|  | Vioxx 50 mg      |  | Naproxen   |  | 
 |
| --- | --- | --- | --- | --- | --- |
|  | N= 4047 |  | N= 4029 |  |  |
|  | n | Rate2 | n | Rate2  |  RR3 |
| APTC1 | 35 | 1.30 | 18 | 0.67 | 1.94 |
|   CV Deaths | 6 | 0.22  | 6 | 0.22  |  1.00 |
|   NF4 MI   | 18 | 0.67 | 4 | 0.15  | 4.514 |
|   NF Isch. Stroke | 9 | 0.33 | 8 | 0.30 | 1.10 |
|   NF Hem. Stroke | 2 | 0.07  | 1 | 0.04  | 2.00 |

**1**Patients may have more than one event. n= number of events   **2** Rate: Rate per 100 patient years based on PYR: Vioxx= 2697, naproxen= 2698.  **3** Overall relative Risk Vioxx vs naproxen.  **4** NF= Non fatal.  *Date of submission to FDA.

## VIGOR Confirmed CV/ Thrombotic Events  Time to Event Plot 

**Hazard Ratio Vioxx vs. Naproxen **
**                  ****Overall = 2.4 **
**                   ****> 8 months= 4.0**

## Vioxx- VIGOR CV/Thrombotic Events Over Time* 

- * Included in April, 2002 Vioxx label

## CV Death, Non-fatal MI, & Stroke Vioxx Studies 090 & 0851 (June 2000)*

|  | Vioxx 12.5 mg | Nabum | Placebo |
| --- | --- | --- | --- |
| 090 | N=390 | N=392 | N=196 |
|    CV Death | 0 | 0 | 0 |
|    Non fatal MI | 3 | 1 | 0 |
|    Non fatal stroke  | 1 | 0 | 0 |
| 085 | N=424 | N=410 | N=208 |
|    CV Death | 0 | 0 | 0 |
|    Non-fatal MI | 1 | 0 | 0 |
|    Non-fatal stroke | 0 | 0 | 0 |

-   **1 **6-week OA studies.  12% Low dose ASA. *Date of submission to FDA, along with VIGOR.

## February 8, 2001                        Arthritis Advisory Committee Conclusions

- Vioxx GI safety profile superior to naproxen
- CV signal of concern
- Given study design, unclear how it applies to
- 12.5 and 25 mg doses (approved for chronic use)
- populations other than RA
- NSAIDs other than naproxen
- population at CV risk using low dose aspirin
- Labeling changes should reflect both, benefits                    and potential harms
- Additional data needed to clarify these issues

## Vioxx - APTC Events  RA Efficacy Database  (February, 2001)*  

- Complex database. Vioxx 25, 50 and naproxen** **
- 		 - Studies 068, 096 & 097, 098 & 103
- 		12-week base studies (Part I) with blinded extensions up                          	to 3 years. Re-randomization of low doses and placebo to                      	Vioxx 25, 50 or naproxen after initial 12 weeks.
-                            Vioxx 25     50            Placebo **       **Naproxen
-       Part I(N)           823        729         989              516
-       Extensions

** **

- *Date of submission to FDA

## APTC events - VioxxRA Efficacy Database    

- Treatment          Events         Pt-years              Risk per
-                                                at risk             100 pt-years
- Placebo	         1              160                0.6
- Vioxx 12.5              2              29                 6.9
- Vioxx 25                 5             501                1.0
- VIoxx 50                6             430                 1.4
- Naproxen               1             406                 0.3

- Studies 096, 097, 098 & 103 (068 not included). 12 week base studies with extensions up to 3 years.   ASA not allowed.

- Increased CV risk for Vioxx 25 and 50 mg as _compared to naproxen_.

##  Vioxx -  APTC Events   ADVANTAGE (March and April, 2001)*

|  | Vioxx 25 mg
N=2785
       n         Rate2 |  | Naproxen  
N=2771
       n          Rate2 |  | 

  RR3 |
| --- | --- | --- | --- | --- | --- |
| APTC1 | 10 | 1.56  | 7 | 1.11 | 1.41  |
|   CV Deaths | 4 | 0.63  | 0 | -  | - |
|   NF MI   | 5 | 0.78  | 1 | 0.16  | - |
|   NF Isch. Stroke | 1 | 0.16  | 6 | -  | - |

**1** Patients may have more than one event. 12 week, OA, 12% low dose ASA.      n= events. %= crude rate.  Include 3 sudden deaths (one re-adjudicated by FDA reviewer) and one ruptured aortic aneurism on Vioxx.  2 Rate per 100 patient years at risk. PYR: Vioxx = 640 and naproxen = 629. * Date of submission to FDA. Also known as Study 102.

## Vioxx - Safety Update Reports (July 2001) *

- Studies in the original NDA (follow up)
- New studies
-  Short term (4 - 6 week)
-  Long-term (>1 year)
- Study 083 (bone density) Vioxx 25 vs. ibuprofen
- Alzheimer’s: Vioxx 25 vs. placebo
- Updated meta-analysis of CV events
- No differences in confirmed CV/thrombotic or  APTC events

- * Date of submission to FDA Does not include Sponsor’s responses to FDA information requests.

## Vioxx in Alzheimer’s Disease (AD)1 Long-term Vioxx 25 mg vs. Placebo (July 2001)*     

- Established AD
- 091	- 15 months, 350 patients per arm, age ≥ 65 y
- 		  Completed: showed no efficacy
- 	 	  Median exposure: 13 months
- 026  - Similar design to 091; terminated early
-              Median exposure 6 months
- Prevention of AD in Mild Cognitive Impairment age ≥ 50 y
- 078  - 2 years or until 220 AD events, extended to
-              4 years; 730 patients per arm, ongoing at the time
-              of the SURs; median exposure: 18 months

**1** 60% male; mean age 75 years; amended to allow low dose aspirin (7%)

## APTC events in Alzheimer’s Studies 091+ 078   (July 2001 – February 2002)

- * Date of submission to FDA.** ****1** One patient may have more than one event.   n = events.    **2** Rate per 100 patient years. PYR exposure: Vioxx= 1267, placebo= 1464.  **3**Overall relative risk of Vioxx vs. placebo. Median duration 14 months.

|  |    Vioxx 25 mg
   N= 1069
    n           Rate2 |  |  Placebo
 N= 1069
      n          Rate |  | 

  RR3 |
| --- | --- | --- | --- | --- | --- |
| APTC1 | 17 | 1.34  | 27 | 1.84 | 0.37  |
|   CV Deaths |  8 | 0.63 | 5 | 0.34 | 1.84 |
|   NF MI   | 6 | 0.47 | 11 | 0.75 | 0.63 |
|   NF Isch Stroke | 2 | 0.16 | 12 | 0.82 | 0.19 |
|   NF Hem Stroke | 1 | 0.08 | 1 | 0.07 | 1.15 |

## Vioxx - Safety Update Reports (July 2001) *

|  | Vioxx all doses | Placebo | RR (95% CI) |
| --- | --- | --- | --- |
|  | Case/PYR1
 Rate2 |  Case/PYR1
 Rate2 |  |
| Totals Vioxx vs Placebo |  38/2518 (1.51) |  34/2099 (1.62) | 0.93 (0.57,1.53) |
| Totals Vioxx vs non-naproxen NSAIDs |  29/2648 (1.10)  | 17/1303 (1.30)  | 0.84 (0.45,1.63)  |

- PYR= patient years at risk.   Rate= rate per 100 patient years.

- Meta-analysis of APTC endpoints Vioxx vs. Placebo and                     vs. non-naproxen NSAIDs

## CV Signal in Vioxx Databases

-                               NDA         VIGOR     102    RAe    SURs/AD
- Versus          Plac+NSAIDs     Napr       Napr  Napr    Placebo

|    APTC |   NA |  | Y |  t        t |      N |      |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|      CV Death   |   N |  | N |  t        t |       t  |      |   |
|      NF MI   |   N |  | Y |  t        t |      N |     |   |
|      NF Stroke |  |   N | N |  N      N |      N |      |   |

- N= no signal. **Y**= Clear signal.   **t **=** **Trend.  AAC: February 8, 2001 FDA Arthritis Advisory    Committee meeting. RAe: Rheumatoid Arthritis efficacy supplement. SURs/AD: Safety Update Reports including Alzheimer’s disease studies.   NF= non-fatal

- AAC

## CV Signal in Vioxx Databases

-                               NDA         VIGOR     102   RAe    SURs/AD
- 				            ----Epi and re-analyses-----
- Versus          Plac+NSAIDs     Napr       Napr  Napr    Placebo

|    APTC |   N |  | Y |  t        t |      N |      |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|      CV Death   |   N |  | N |  t        t |       t  |      |   |
|      NF MI   |   N |  | Y |  t        t |      N |     |   |
|      NF Stroke |  |   N | N |  N      N |      N |      |   |

- N= no signal. Y= Clear signal.   **t **=** **Trend.  AAC: February 8, 2001 FDA Arthritis Advisory Committee meeting. RAe: Rheumatoid Arthritis efficacy supplement. SURs/AD: Safety Update Reports including Alzheimer’s disease studies.   Epi= epidemiologic studies. NF= non-fatal.

- AAC

- Labeling changes

## Vioxx – CV Labeling Changes April 2002 

- Clinical Studies, Special studies, VIGOR
- Cardiovascular findings
- Description of results
- Two tables - Table 3: CV/T events over time
-                      - Table 4: CV/T events by category
- Precautions
- Indications
- Adverse reactions
- HTN in patients with RA with 25 mg dose
-  Dosage and administration

## Precautions - Cardiovascular Effects
The information below should be taken into consideration and caution should be exercised when VIOXX is used in patients with a medical history of ischemic heart disease. 
[Description CV results in VIGOR]
Reference to a placebo-controlled database derived from 2 studies with a total of 2142 elderly patients (Alzheimer’s data) including CV mortality (8 and 3 cases). 
The significance of the cardiovascular findings from these 3 studies (VIGOR and 2 placebo-controlled studies) is unknown. 
Prospective studies specifically designed to compare the incidence of serious CV events in patients taking VIOXX versus NSAID comparators or placebo have not been performed. 
Prospective, long-term studies on concomitant administration of VIOXX and aspirin evaluating cardiovascular outcomes have not been conducted. 

- The information below should be taken into consideration and _caution_ should be exercised when VIOXX is used _in patients with a medical history of ischemic heart disease. _
- [Description CV results in VIGOR]
- Reference to a placebo-controlled database derived from 2 studies with a total of 2142 elderly patients (Alzheimer’s data) including CV mortality (8 and 3 cases).
- The significance of the cardiovascular findings from these 3 studies (VIGOR and 2 placebo-controlled studies) is unknown.
- Prospective studies specifically designed to compare the incidence of serious CV events in patients taking VIOXX versus NSAID comparators or placebo have not been performed.
- Prospective, long-term studies on concomitant administration of VIOXX and aspirin evaluating cardiovascular outcomes have not been conducted.

- Vioxx CV Labeling Changes April 2002 (cont’d)

## Indications: Rheumatoid Arthritis  
Adverse Reactions
    Rheumatoid Arthritis. In studies of at least three months, the incidence of hypertension in RA patients receiving the 25 mg dose once daily was 10% and the incidence of hypertension in patients receiving naproxen 500 mg twice daily was 4.7%.

Dosage and Administration
Rheumatoid Arthritis:  
The recommended dose is 25 mg once daily. The maximum recommended daily dose is 25 mg. 
Acute Pain and Primary Dysmenorrhea
     Chronic use of Vioxx 50 mg daily is not recommended.  

- Adverse Reactions
*    **Rheumatoid Arthritis.* In studies of at least three months, the incidence of hypertension in RA patients receiving the 25 mg dose once daily was 10% and the incidence of hypertension in patients receiving naproxen 500 mg twice daily was 4.7%.
- Dosage and Administration
*Rheumatoid Arthritis: *
- The recommended dose is 25 mg once daily. The maximum recommended daily dose is 25 mg.
*Acute Pain and Primary Dysmenorrhea*
-      Chronic use of Vioxx 50 mg daily is not recommended.

- Vioxx CV Labeling ChangesApril 2002 (cont’d)

## Study 203 (October 2002)*

- Prospective analysis of Cardiovascular Thrombotic events in three long-term placebo-controlled studies:
- APPROVe (colon polyp prevention)
- VICTOR (Oxford study)
- PCPS (prostate cancer prevention)

- *Data of submission of proposed analysis to FDA

## APTC Events in Alzheimer’s Studies 091 + 078 (Updated March 04)*

- * Date of submission to FDA.** ****1** One patient may have more than one event.  n = events.    **2** Rate per 100 patient years at risk (PYR). PYR: Vioxx= 1699, placebo= 1930.  3Overall relative risk of Vioxx vs. placebo, based on PYR.

|  |     Vioxx 25mg
   N=  1069
     n          Rate2 |  |  Placebo
 N=  1074
     n          Rate2 |  | 

  RR3 |
| --- | --- | --- | --- | --- | --- |
| APTC1 | 32  | 1.88 | 40  | 2.07 |  0.91 |
|   CV Deaths | 11  | 0.65  | 10   | 0.52   | 1.25   |
|   NF MI   | 14  | 0.82  | 14 | 0.73          | 1.14  |
|   NF Isch Stroke | 6 | 0.35 | 17 | 0.88  | 0.40  |
|   NF Hem. Stroke | 1 | 0.06 | 1 | 0.05 | 1.13 |

## CV/T events, Risk Over Time Alzheimer’s 091 + 078 (Updated March 2004)

## APTC Events KM Estimates (95% CI) Vioxx Alzheimer’s Disease (091 + 078) (Updated March 2004) 

- _Overall _= RR Vioxx 25 mg vs naproxen = 1.0

## Vioxx - All Cause Mortality (On-Drug)*                                 Alzheimer’s Disease Studies 091 & 078.

- * All cause mortality: 36/19 (V 25 /Placebo)

## Vioxx & NaproxenEpidemiologic Studies (2001-2004)

- Suggest increased CV/T risk for Vioxx 50 mg dose
- No clear evidence of
- 		- CV/T risk with Vioxx 12.5 mg and 25 mg doses
- 		- Cardioprotective effect of naproxen
- FDA awaiting results of long-term placebo controlled studies  (ongoing Pooled Analysis of CV/T events)

## Vioxx - APTC events in APPROVe1 (as per January, 2005)* 

**1**3 year on-treatment, 1 year F.U.; history of colonic polyps; mean age: 59 years; 62% male;  19% low dose aspirin.  **2** Patients with events (patients with multiple events may be counted more than once).  3 Rate per 100 patient-years at risk.    PYR= patient years at risk:             Vioxx= 3070  and placebo= 3334. 4** **RR= Overall relative risk Vioxx to placebo.  5 Stat significant.

|  | Vioxx 25 mg
N=1287 
  n            Rate3 |  | Placebo
N=1299 
      n            Rate             |  | 
   RR4 |
| --- | --- | --- | --- | --- | --- |
| APTC2 | 34 | 1.11   | 18 | 0.54  | 2.055  |
|   CV Deaths | 6 | 0.20   | 5   | 0.15   | 1.30  |
|   MI (all)  | 21  | 0.68 | 9 | 0.27 | 2.535 |
|   NF Isch Stroke  | 10 | 0.33 | 6 | 0.18 | 1.81  |
|   NF Hem. Stroke | 1 | 0.03 | 1 | 0.03 | 1.09 |

## Vioxx - APPROVe APTC Events Time to Event Plot

- Rofecoxib 25

- Placebo

## Vioxx – APPROVe:  Effect of ASA on APTC *

|  | Vioxx 25 | Placebo | RR, p-value (95% CI) |
| --- | --- | --- | --- |
| All patients   n/PYR | 1287
33/3053 | 1299
16/3322 | 2.25
P=0.008 |
| Rate/100 PYR | 1.08 | 0.48 |  |
| Non-ASA user 
n/PYR | 1074
28/2564 | 1095
12/2817 | 2.57
(1.31,5.06) |
| Rate/100 PYR | 1.09 | 0.43 |  |
| ASA user
n/PYR | 213
5/489 | 204
4/505 | 1.29
(0.28,6.50) |
| Rate/100 PYR | 1.02 | 0.79 |  |

- * Based on October 2004, submission (no final dataset).

## Vioxx – APPROVeEffect of BP on CV/T Events

| On treatment HTN* | Rofecoxib 25 mg  n/PYR
Rate x 100 pt years | Placebo
n/PYR
Rate x 100 pt years |
| --- | --- | --- |
| Patients with no HTN | 35/2058 (1.7) | 32/2510 (1.3) |
| Patients with HTN once | 20/449 (4.5) | 4/413  (1.0) |
|  Patients with HTN (twice or more) | 18/520 (3.5) | 8/381 (2.1) |

- Patients with investigator reported thromboembolic or APTC events (excluding non CV deaths) by on-treatment Hypertension

- n=events. * Hypertension defined as patients with DBP ≥ 100 or   SBP ≥ 160 mm Hg.

## Summary - Cardiovascular Signal                             in Vioxx Databases

-        NDA         VIGOR    102/RA  Alzheimer  Epi     APPROVe
- 					    Studies
-  Plac+NSAIDs   Napr       Napr     Placebo                  Placebo

|    APTC          | NA  | Y | t |    N |  | Y |
| --- | --- | --- | --- | --- | --- | --- |
|    CV Death2 | N | N | t |    Y |  | N |
|    NF MI  | N | Y | t |    N |  | Y |
|   NF Stroke | N | N | N |    N |  | Y |

-   ** **

- N= no signal. Y= Clear signal.   t** **=** **Trend. Epi: epidemiologic studies and meta-analyses.

## Summary: Selected CV Endpoints   Large Vioxx Databases  

| 

PTY risk 1 |       VIGOR
Vioxx 50   Naprox
 N=2697   N=2698          |  |  Alzheimer’s
Vioxx 25  Placebo
N=1699    N=1930 |  | APPROVe
Vioxx 25  Placebo
N=3070     N=3334   |  |
| --- | --- | --- | --- | --- | --- | --- |
| APTC events |  |  |  |  |  |  |
| n
PY-rate 2 | 35
1.30 | 18
0.77 | 32
1.88 | 40
2.07 | 34 
1.11 | 18
 0.54 |
| Myocardial Infarction (fatal and non-fatal) |  |  |  |  |  |  |
| n
PY-rate 2 | 20
0.74 | 4
0.14 | 15
0.88 | 15
0.77 |  21
 0.68 |  9
0.27  |
|  All cause mortality (on drug) |  |  |  |  |  |  |
| n
PY-rate 2 | 22
0.82 | 15
0.56 | 36
2.12 | 19
0.98 | 10
0.36 | 10
0.30 |

- n= events. **1** PYR patient years at risk, assuming constant overall risk.  **2** PY-rate: Overall rate per 100 patient years.

## Challenges in Interpreting Vioxx CV Safety  

- Vioxx CV signal was clear when compared to naproxen
- CV findings inconsistent when compared to placebo  (APPROVe different from Alzheimer’s)
- No adequate comparative CV safety data for Vioxx &   non-naproxen NSAIDs
- Until recently, no long-term placebo-controlled data for any of the traditional NSAIDs
- Extent of role of BP on CV/T events with Vioxx is unclear
- Role of low dose ASA in protecting for CV/T events with Vioxx unknown

## Issues to Consider in Trial Design for COX-2 inhibitors

- Different ways of looking at CV endpoints
- All CV events                    APTC (which is best?)
- In addition to overall risk, need to consider _risk over time_ (long time)?
- Different rates of CV/T events in different populations. Which one is the best to address CV safety?
- Need to control for BP effects
- Need to include more than one traditional NSAID comparator