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 EventPUB

• 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

ConfirmedPUBs

Vioxx

56 (1.38%)

Naproxen

121 (3.00%)

Perforations

Gastric ulcersDuodenal ulcers

Upper GIBleeds

Obstruction

3

28 27

14

1

4

81 39

35

0

Subanalysis by Risk factorPrior history of PUB

No prior PUB Prior PUB

Vioxx Naproxen Vioxx NaproxenN#events

per/100PYR

Cruderate

373343

1.72

1.15%

371392

3.67

2.5%

31413

6.72

4.1%

31629

15.33

9.2%

Subanalysis by Risk factorAge

<65 yr >65yr

Vioxx Naproxen Vioxx NaproxenN#events

per 100PYR

Cruderate

305034

1.64

1.1%

295964

3.15

2.2%

99722

3.54

2.2%

107057

8.63

5.3%

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 populationsOther 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

0

0.5

1

1.5

2

2.5

6-week 12-week 24-week 52-week

%

Vioxx 12.5mgVioxx 25mgVioxx 50 mgibuprofen diclofenac

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 ?