# Presentation: 877527

## Gastrointestinal Review Highlights of the VIGOR Trial

- Lawrence Goldkind M.D.

## Outline of Presentation 

- Study hypothesis and definitions of endpoints
- Review of results
- High risk populations
- Review of meta-analysis of  phase IIb and III studies presented by the sponsor
- Conclusions

## VIGOR Study Design  

- Organ-specific endpoints
-  PUB’s  (Perforation, Symptomatic Ulcers, Bleeding)
-  *Complicated *PUB’s (excludes only symptomatic ulcers)
- 		Statistical plan : All patients will be followed until:
- Minimum 120 confirmed PUBs
- or 40 confirmed *complicated* PUBs
- and 6 months after last patient randomized
- 95% power (******=** 0.05 two-tailed) to detect a reduction in risk of at least 50% for the the primary GI hypothesis.

## Primary study hypotheses

- “The risk of confirmed PUBs during the treatment period will be reduced in the group of patients with rheumatoid arthritis taking 50 mg Vioxx daily, compared to the group of patients with rheumatoid arthritis taking naproxen 1000 mg daily.
- Vioxx administered at a dose of 50 mg daily will be safe and well tolerated.”

## Endpoint definitions

- PUB (perforation, symptomatic ulcer, bleed)
- Complicated PUB

## Confirmed   Event PUBAny one of the following four clinical presentations

**1. Ulcer**: radiographic, endoscopic, surgical (identified based on clinical presentation including pain as the sole symptom/sign)
**2. Perforation**: radiographic, endoscopic, surgical, autopsy
**3. Obstruction**: postprandial nausea and vomiting and evidence of narrowing of the gastric outlet

## Confirmed   Event PUB (continued)

**4. Upper GI hemorrhage:**** **
-    *Health care provider witnessed*:
- a. frank hematemesis
- b. coffee ground emesis
- c. NG aspiration of blood or coffee ground appearing gastric contents
- d. melena (distinguished from other causes of dark stool)
- e. Active UGI bleeding at endoscopy, surgery or angiography

## Confirmed   Event PUB (continued)

-                                     OR
- Heme-positive stool/ patient reported melena or hematemesis associated with a documented UGI lesion judged by a healthcare provider to be the source of bleeding and associated with significant bleeding* or stigmata of recent bleeding at endoscopy
- *decrease of _>_ 2 g/dl Hgb, orthostasis, hypotension, transfusion

## Confirmed Complicated EventPUB

- Perforation
- Obstruction
- GU or DU associated with  significant bleeding*
-   *decrease of _>_ 2 g/dl Hgb, orthostasis, hypotension, transfusion

## Results

## Confirmed PUB’s in VIGOR

-  		 	      N                 n              rate1                  rate2
-     Rofecoxib  (4047)      56         2.08          1.8%
- Naproxen   (4027)     121         4.49            3.87%
*   *
-     Relative Risk:  0.46  p<0.001*
- * cox proportional hazard model
- 1 Per 100 PYR.
- 2 cumulative rate

## Confirmed Complicated PUBs

*                    *N              n                 rate1                 rate2
- Rofecoxib (4047)    16           0.59            0.52  %
-  Naproxen (4027)    37          1.37              1.22 %
- Relative Risk:  0.43    p=0.005*
- *  cox proportional hazard model
- 1 Per 100 PYR.
- 2 cumulative rate

## Types of Confirmed PUBs

## Subanalysis by Risk factorPrior history of PUB

## Subanalysis by Risk factorAge

## High risk populations

_***If***_** age and history of PUB are independent risk factors for ulcer disease...**Findings of high risk in _***association***_ with a therapy may represent intrinsic risk rather than drug effect (no causality) ?
-                                       OR
- Interaction between underlying and drug related risk may produce an exaggerated/ higher risk _***attributable***_ to therapy (causality) ?

## High risk populations

- Outstanding question
- Should high risk patients be treated with “lower relative GI risk”  NSAIDs....... or does overall **residual** GI risk continue to represent a  relative contraindication for these patients?
- Usage implications

## GI Risk in special populationsOther questions

- GI Risk of co-administration of aspirin and Vioxx:  data needed
- GI Risk of  co-administration of aspirin and Vioxx in the elderly: data needed
- GI risk in elderly with a history of PUB ?

## Generalizability of GI Safety

- Relative Risk:
-  Vioxx **< **naproxen
- Degree of Absolute risk : data needed
- Relative Risk compared to other NSAIDs: data needed

## Data from phase IIb and III studies

- Meta-analysis of PUBs  “Vioxx vs NSAIDs”
- Three doses of Vioxx: 12.5 mg, 25 mg, 50 mg
- Two comparators: ibuprofen, diclofenac
- Duration: 12-52 weeks

## Data from phase IIb and III studies

- Meta-analysis of PUBs  “Vioxx vs NSAIDs”
-                               N          Duration* (weeks)
- Vioxx 12.5 mg:     1209                  52
- Vioxx 25 mg:        1603                  52
- Vioxx 50 mg:        545                    12
- Ibuprofen:             590                    12
- Diclofenac:           847                    52
- * at least 200 subjects present at the **end** of the interval

## Meta-analysis of cumulative PUB IIb and III Studies

## Conclusion of meta-analysis of phase IIb and III studies

- Vioxx dose and duration of exposure affect associated rates
- Ibuprofen and diclofenac did not perform similarly
- NSAID as a composite comparator may not be appropriate
- Meta-analyses combining heterogeneous groups may be problematic

## Overall Conclusions

- Vioxx 50 mg associated with a lower rate of symptomatic and complicated ulcers compared to Naproxen 1000 mg  in patients with RA not requiring low dose aspirin  use
-        ( relative risks 0.46, 0.43)
- Risk reduction extends across high risk groups

## Overall Conclusions

- High risk groups: elderly and those with history of prior PUB continue to have a significant _**absolute**_ risk of PUBs
- Generalizability of  GI risk reduction to patients requiring low dose aspirin ?
- Generalizability to other/all traditional NSAIDs ?