# Presentation: 167805

##     VIOXXTM Gastrointestinal Outcome Research(VIGOR)Arthritis Advisory Committee Meeting   February 8, 2001

- Lourdes Villalba, M.D.
- DAAODP, CDER, FDA

## Rofecoxib Overall Safety  

- VIGOR - General safety
- CV safety in other databases
- Risk/benefit assessment - Co-use of ASA
- Post-marketing safety
- Conclusions

## VIGOR General Safety

- Evaluation of routine safety parameters
-  Deaths
-  Serious Clinical AE’s
-  Dropouts due to Clinical AE’s
-  Laboratory AE’s
-  Number of Hospitalizations
- Pre-specified NSAID-related AE’s

## VIGOR General Safety Deaths  

-  **Rofecoxib (N=4047)**
** ****22 (0.5%)**
-  9 cardiovascular
-  5 pneumonia
-  4 worsening ILD
-  2 GI bleeding
-  1 gastric malignancy
-  1 unknown (CHF?)

-  **Naproxen (N=4029)**
**	****	****15 (0.4 %)**
-   7 cardiovascular
-   3 pneumonia
-   1 worsening ILD
-   1 GI bleeding
-   1 hepatic necrosis
-   2 malignant neoplasm

## Definition of Serious AE’s  

- Death
- Life threatening
- Results in persistent or significant disability/incapacity
- Results in or prolongs patient hospitalization
- Is a congenital anomaly/birth defect
- Cancer
- The result of an overdose
- Or event may jeopardize the patient and require medical or surgical intervention to prevent one of the outcomes listed above

## VIGOR General Safety   Serious AE’s (>1%)

**                 ****	****	****	****	****	****	****	**
**  ****	****	****	**** ****	****  **Rofecoxib     	   Naproxen
- 			 	 N=4047 (%)     	   N=4029 (%)
**Any**** * ****	****           378 (9.3) ****	****    315 (7.8) **
- 	CV*****		   101 (2.5)     	      46 (1.1)
- 	Digestive*****             48 (1.2)                 97 (2.4 )
- 	MS1      	 	     83 (2.1)	         	      70 (1.7)
-    Resp    	              52 (1.3)	         	      39 (1.0)
***** p < 0.05   1MS: musculo-skeletal

## VIGOR General Safety  Dropouts due to AE’s (>1%)

**        ****	****	****    ****	****	****	****	****	****	**
- 			       Rofecoxib       	Naproxen
- 			      N=4047 (%)            N=4029 (%)
**Any****	****	****       643 (15.9) ****	****	****635 (15.8)**
- 	CV*    	        109 (2.7) 	  	    33 (0.8)
-    Digestive         292 (7.2) 		  392 (9.7)
-    Nervous*           44 (1.1)	 	    24 (0.6)
- 	Body1    	        100 (2.5)	            107 (2.7)
- * p < 0.05    1Body: body as a whole

## VIGOR General Safety   Lab AE’s

**          ****	****     **Rofecoxib  	      Naproxen 		               N=4047 (%)	       N=4029 (%)
**Any****	**	     418 (10.4)           368 (9.2)
- 	Dropouts        22 (0.6) 	         12 (0.3)
- 	Serious            3 (<0.1)                0
*	** *

## VIGOR General Safety   Hospitalizations

**            ****	****	**Rofecoxib  	Naproxen 			         	  N=4047  		  N=4029
- Any	    		    338   	 	       265
- 	CV   	               65   	                  24
-    GI			      29         		49
-    Hematologic	       7  		           6
-    Hepatobiliary         12  		     	  8
-    Renal		       6    	 	           6
-    Other

## VIGOR General Safety      Pre-specified NSAID-related AE’s

**          ****	****      **Rofecoxib 	    Naproxen   p-value				N=4047 	     N=4029
**Dropouts**
** **
- GI + abdom. pain   307                 416          <0.001
- Edema-related        25   	 	13            0.057
- HTN-related    	    28  	  	 6           <0.001
- Liver-related 	    10  	  	 3             0.067
- Renal-related            8               	 7             0.796
**CHF-related**         19         	  	 9             0.065

## VIGOR General Safety   Summary

- GI safety favored rofecoxib
- Overall, general safety parameters trended in favor of naproxen, particularly due to the excess in serious cardiovascular events in the rofecoxib group.

## Rofecoxib Overall Safety  

- VIGOR - General Safety
- CV safety in other databases
- Risk/benefit assessment - Co-use of ASA
- Post-marketing safety
- Conclusions

## Time to event plot. Adjudicated serious CV thrombotic events in VIGOR

**RR = 2.37 **
**(R vs. N)****  **

## Serious CV/thrombotic EventsDefinitions

- 1) Investigator reported
- 2) Adjudicated: confirmed by the CV Case Review Committees (_Pre-specified analysis in SOP_)(excludes hemorrhagic stroke)
- 3) APTC:  Anti-platelet Trialists’ Collaboration composite endpoint:  cardiac death, non-fatal MI and stroke (includes hemorrhagic stroke and excludes peripheral events)

## VIGORAdjudicated Serious CV thrombotic Events Included for Analyses

- Cardiac Event
- Acute myocardial infarction
- Unstable angina
- Sudden cardiac death** **
- Cerebrovascular Event
- Ischemic CVA stroke with documentation** **
- Transient ischemic attack (TIA)
- Peripheral Vascular Event
- Peripheral arterial thrombosis
- Peripheral venous thrombosis

## VIGORSerious CV thrombotic eventsThree Different Endpoints

- 64

- 45

- 35

- 32

- 19

- 18

- 0

- 20

- 40

- 60

- 80

- Investigator

- Adjudicated** **

- APTC** 1**

- # patients with events

- rofecoxib

- naproxen

- APTC** 1: ****Anti-platelet Trialists’ Collaboration composite**

## VIGOR CV SafetyHypotheses

- Pro-thrombotic effect with rofecoxib? (biological plausibility)
- Cardio-protective effect of naproxen? (biological plausibility)
- Unknown factors?

## VIGOR CV SafetyHypotheses (2)

- Cardio-protective effect of naproxen?
-  Adjudication criteria: RR = 0.42  N vs. R
-  APTC combined endpoint:  RR = 0.51  N vs. R
- 	(8,000 patients, median f.u. 9 months, population  of patients with no recent CV/thrombotic event)
- No controlled studies of naproxen vs. placebo for CV prophylaxis.

## Rofecoxib CV SafetyImportant Limitations to Sponsor’s Meta-analysis

- Studies of different length (4 - 86 weeks)
- Most patients exposed < 6 months
- Different doses (rofecoxib 12.5, 25 and 50 mg)
- Most patients exposed  25 mg
- Multiple comparators which may be associated with different risk of CV events.
- Different diseases that may be associated with different risk of CV events.

## Rofecoxib Exposure Data from Meta Analysis Data Sets

- Total number included in sponsor’s meta-analysis:
- 				  28,349 patients
- Exposure to rofecoxib 50 mg/day for at least 6 months in studies other than VIGOR:
- 				     638 patients

## Rofecoxib CV Safety   Summary

- Cardiovascular Safety in VIGOR favored naproxen (CV/thrombotic, HTN and CHF)
- HTN/fluid retention/edema for rofecoxib: dose dependent (signal present in original NDA)
- CV/thrombotic events:
- Original NDA small database
- Sponsor’s meta-analysis has serious methodological limitations to answer the question

## Rofecoxib Overall Safety  

- VIGOR - General Safety
- CV safety in other studies
- Risk/benefit assessment - Co-use of ASA
- Post-marketing safety
- Conclusions

## Rofecoxib Risk/benefit Assessment

- Patients at increased risk of certain CV thrombotic events should be on concomitant low dose ASA
- The effect of concomitant use of rofecoxib with low dose ASA on GI and CV risk is unknown.
- 	Studies that allowed ASA from the start were small and short in duration, except for study 102 (“Advantage” study)

## Study 1021    Preliminary safety data

- 				    **Rofecoxib* ****	****Naproxen***
**	****	****	****	****	**25 mg             1000 mg
** ****	**		                    N=2785  	  N=2771
**Serious CV****2****      ****	****          10                     7**
- 	Cardiac			  7                     1
- 	   MI                                         5                         1
- 	   Sudden death                       2                         0
**    **Ischemic CVA            0                      6
- 	 Other events**3 **           3                      0
**Confirmed UGI**	           **6                     12**
**1**** **12- week**  ****2**** **APTC terms**   3 **Arterial rupture, hemorrhagic CVA, unknown cause of death  * 12 % low dose ASA

## Rofecoxib Risk/benefit AssessmentCo-use with low dose ASASummary

- Insufficient data on concomitant ASA use.

## Rofecoxib Overall Safety  

- VIGOR - General Safety
- CV safety in other studies
- Risk/benefit assessment - Co-use of ASA
- Post-marketing safety
- Conclusions

## Rofecoxib Overall SafetyPost-marketing Surveillance

- Post-marketing reports include:
- GI
- Renal
- Liver
- Anaphylactoid reactions
- Prothrombin time prolongation with coumadin co-use

## Rofecoxib Overall Safety  

- VIGOR - General Safety
- CV Safety in other studies
- Risk/benefit assessment - Co-use of ASA
- Post-marketing safety
- Conclusions

## Rofecoxib Overall Safety   Conclusions (1)

- VIGOR: GI Safety favored rofecoxib vs. naproxen (in a population of patients not taking ASA)
- VIGOR: Overall, no safety superiority of rofecoxib over naproxen due to an excess of serious CV events in the rofecoxib group compared to the naproxen group
- Rofecoxib 50 mg is twice the upper dose labeled for chronic use in OA. The chronic use of the 50 mg dose is not recommended.

## Rofecoxib Overall Safety   Conclusions (2)

- Post-marketing safety: risk of serious GI events still a concern in high risk population
- Questions raised in VIGOR:
- Is there a pro-thrombotic effect of rofecoxib?
- What would be the impact of chronic co-use of low dose ASA in GI and CV events?

## Slide 31