# Presentation: 872701

## FDA Advisory Committee Meeting

- 16 February 2005

- Cardiovascular Safety of Celecoxib
- &
- Risk-Benefit Assessment

## Delegation

- Dr Jeffrey Borer		Cardiology
- Dr Andrew Dannenberg 	Gastroenterology
- Dr Gerry Faich		Epidemiology/Drug Safety
- Dr Norman Gitlin		Gastroenterology
- Dr Gary Koch 		Statistician
- Dr Bernard Levin		Oncology
- Dr Scott Lippman		Oncology
- Dr Nancy Nussmeier	Anesthesiology
- Dr Lee Simon		Rheumatology
- Dr Vibeke Strand 		Rheumatology
- Dr Andrew Whelton		Nephrology
- Dr William White		Hypertension

## Overall Conclusions

**There are few therapeutic alternatives for patients with chronic arthritis-related pain**
**Patients who discontinue celecoxib will likely turn to NSAIDs**
**Celecoxib provides improved GI safety compared to NSAIDs**
**All lines of evidence show the CV safety of celecoxib is similar to NSAIDs for up to 1 yr; **
**beyond 1 yr little is known for any of these agents**
**evidence for COXIB vs NSAID class effect on CV safety ****is not established**
**rofecoxib is distinct from celecoxib and NSAIDs  **
**Only further study of NSAIDs/COXIBs will define the longer-term CV risks against the known risks of GI ulcer complications**

## Arthritis is a Leading Cause of Disability

**% All Disabilities**

**Stroke**

**Blindness or Vision**

**Diabetes**

**Mental or Emotional**

**Limb/Extremity Stiffness**

**Deafness or Hearing**

**Lung or Respiratory**

**Heart Trouble, Hardening of the Arteries**

**Back or Spine**

**Arthritis **

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**2.8%**

**3.3%**

**3.4%**

**3.7%**

**4.2%**

**4.4%**

**4.7%**

**7.8%**

**16.5%**

**17.5%**

**Arthritis is a Leading Cause of Disability**

**About 39 million physician visits/ yr****1****More than 500,000 hospitalizations/ yr****1**

**1 ****CDC, Arthritis Foundation. National Arthritis Action Plan: A Public Health Strategy. 1999. **

## Efficacy in OA  

**NSAIDs are an important treatment option**

**Pincus et al. Arthritis Rheum  2001;44:1587-1598**

*** p<0.05 vs acetaminophen **

**0**

**25**

**30**

**35**

**40**

**45**

**50**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**acetaminophen**

**diclofenac + ****misoprostol**

**acetaminophen**

**diclofenac + ****misoprostol**

**WOMAC Target Joint Score (mm)**

**0**

**6**

**0**

**6**

**washout ****&**
**crossover**

**washout **

**Acetaminophen 1000 mg qid**
**Diclofenac 75 mg/misoprostol 200 ********g bid **
**N=227**

*****

*****

**Greater**
**improvement**

**Weeks**

## Incidence of Hospitalization for GI Bleeding or Perforations

**0**

**5**

**10**

**15**

**20**

**25**

**Non-users Men**** **

**Non-users Women**** **

**Current users Men **

**Current users Women**

**Saskatchewan, Canada **

**Per 1000 Pt-yrs**

** ****Perez-Guttha****n****n et al. Epidemiology 1997;8:18-24**

**Incidence of Hospitalization for GI Bleeding or Perforations**

## COX-2 Inhibitor Hypothesis: 1992

**Arachidonic Acid**

***COX-1***
**(Constitutive)**

***COX-2***
**(Inducible)**

**Stomach**
**Intestine**
**Kidney**
**Platelet**

**Disease Targets:****	**
** ****Arthritis, Pain**

**x**

**COX-2 Inhibitor Hypothesis: ****1992**

***NSAIDs***

***COX-2 inhibitor***

## Clinical Effects of Celecoxib in RA

*****p***** <0.001 vs other treatments**

******

**Patients with Ulcer (%)**

**Celecoxib ****(mg bid)**

**Naproxen ****(mg bid)**

**25**

**0**

**5**

**10**

**15**

**20**

**Placebo**

**200**

**400**

**500**

** ****100**

**ACR 20 Responders **** ****(%)**

**0**

**10**

**20**

**30**

**40**

**50**

**100**

**200**

**400**

**500**

**Celecoxib**
**(mg bid)**

**Naproxen**
**(mg bid)**

*****

*****

*****

*****

**Placebo**

**Simon et al. JAMA 282 20:1921-1928, 1999**

****p***** <0.001 vs placebo**

**Celecoxib**

**Naproxen **

**Placebo **

**N =1149**

**Efficacy**** **

**Upper GI Safety**** **

## GI Safety Profile of Celecoxib                          Meta Analysis of Arthritis RCTs

**GI Safety Profile of Celecoxib                          ****Meta Analysis of Arthritis RCTs**

**0.35 (0.22, 0.56)**

_**Reductions in Hgb > 2g/dL **_

_**Symptomatic ulcers/GI bleeding **_

_**Withdrawal due to GI intolerance **_

**Celecoxib (200/400 mg) vs NSAIDs **

**Celecoxib (any dose) vs NSAIDs **

**Celecoxib (200/400 mg) vs NSAIDs **

**Celecoxib (any dose) vs NSAIDs **

**Celecoxib (200/400 mg) vs NSAIDs **

**Celecoxib (any dose) vs NSAIDs **

**0.61 (0.46, 0.81)**

**0.71 (0.55, 0.91)**

**0.72 (0.56, 0.92)**

**0.70 (0.60, 0.80)**

**0.75 (0.70, 0.80)**

**Favors NSAIDs**

**0.50**

**0.25**

**1.0**

**0.75**

**1.25**

**Favors celecoxib**

**0.0**

**Moore et al. Arthritis Research & Therapy 2005: (Feb) **

**39,605  OA/RA patients; mean exposure ~7 mo**

## Risk of Hospitalization for Upper GI Bleeding with COXIBs

**3.0**

**4.0**

**1.9**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Adjusted Rate Ratio**

**0**

**Non-use**

**celecoxib**

**rofecoxib**

**diclo+miso**

**NSAIDs**

** ****Mamdani et al. BMJ 2002;325(7365):624-7**

**1.0**

**1.0**

**Risk of Hospitalization for Upper GI Bleeding with COXIBs**

**>55% women****Mean age >75 yrs**
**>1% with Hx of GI bleed ****>16% Use of gastroprotective agent**
**>12% Use of aspirin**

**100,000 (2.2)***

**18,908 (3.6)***

**14,583 (7.3)***

**5,087 (9.6)***

**5,391 (12.6)***

***n (no. upper GI bleeds per 1000 person-yrs)**

## Risk of Hospitalization of Upper GI Bleeding in High Risk Patients

**3.3**

**1.3**

**2.1**

**1.0**

**0**

**1**

**2**

**3**

**4**

**5**

**Non-use**

**celecoxib**

**rofecoxib**

**NSAIDs**

**Adjusted Odds Ratio**

**Risk of Hospitalization of Upper GI Bleeding in High Risk Patients**

** ****N****ø****g****å****rd et al. Aliment Pharmacol Ther 2004;19:817-25**

**Patients with prior gastrointestinal diseases**

**46% female ****Mean age >68 yrs**
**>22% with Hx of non-bleeding GI ulcer ****>70% Use of gastroprotective agent**
**>21% Use of aspirin**

## GI Safety Benefit - Conclusions

- Medical need for improved GI safety is fulfilled with celecoxib
- Randomized Controlled Trials
- Celecoxib has a favorable GI safety profile vs NSAIDs
- Epidemiology Studies
- Celecoxib is associated with a lower risk of hospitalization due to GI bleeding than NSAIDs

## Thromboembolic CV Adverse Events:VIGOR and CLASS Studies

**Thromboembolic CV Adverse Events:****VIGOR and CLASS Studies**

**Days**

**0**

**40**

**80**

**120**

**160**

**200**

**240**

**280**

**320**

**360**

**VIGOR**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**R**

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

- R

**Rofecoxib 50 mg qd (n=4047)**

**Naproxen 500 mg bid (n=4029)**

- Q

**p < 0.05**

**White et al. Am J Cardiol;2002:89:425-430**** **

**www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_cardio.doc**

**% of Patients**

**J**

**Celecoxib 400 mg bid (n=3987)**

**P**

**NSAIDs (n=3981)**

**CLASS**** **

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

**J**

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**J**

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**P**

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**P**

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**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**p***** *****= 0.973**

**Days**

**0**

**40**

**80**

**120**

**160**

**200**

**240**

**280**

**320**

**360**

**P**

**P**

**% of Patients**

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk factors
- Epidemiology studies
- Considerations of mechanism
- Conclusions: Risk-benefit

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk factors
- Epidemiology studies
- Considerations of mechanism
- Conclusions: Risk-benefit

## CV Event Definitions

**CV Event Definitions**

- APTC* composite endpoint
- non-fatal myocardial infarctions,
- non-fatal strokes, or
- vascular deaths (all deaths attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular, or unknown causes)
- Meta-analysis – similar construct to APTC; based upon investigator reports of serious adverse events
- Epidemiologic studies - hospitalization for acute MI alone or plus coronary death (1 study with APTC endpoint)

***Antiplatelet Trialists Collaboration. *****BMJ*****. 1994;308:81-106**

## Sporadic Adenoma Prevention Trials (SAP)

- Colorectal adenomas: precursors of colon cancer
- Over-expression of COX-2 (pre-cancer, cancer, metastatic disease)
- Two celecoxib SAP trials (still ongoing)
- APC (005) & PreSAP (018)
- 3 year placebo controlled RCTs
- Hypothesis: celecoxib will reduce polyp recurrence by >35% in a high risk cohort (prior adenoma).

- Setting allowed for first longer-term placebo comparison; Celecoxib - agent of choice based on GI safety

## Sources Available to Evaluate CV Safety of Celecoxib

|  | APC | Pre-SAP  |
| --- | --- | --- |
| Study Description |  |  |
|   Number of patients | 2035 | 1561 |
|   Pt-years | 4778 | 3939 |
|   Mean exposure (yrs) | 2.3 | 2.5 |
|   Number of CV events | 41 | 31 |
|  |  |  |
|   Mean age (yrs) | 60 | 61 |
|   Hx of hypertension | 41% | 35% |
|   Hx of CHD | 39% | 48% |
|   Concomitant aspirin | 30% | 16% |

**Sources Available to Evaluate CV Safety ****of Celecoxib**

**Patient Population**

## Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT)

- RCT evaluating celecoxib 200 mg bid or naproxen 220 mg bid vs placebo
- Elderly population (>70 yrs) at risk for AD (first degree relative with the disease)
- Except for uncontrolled hypertension, no other restrictions for CV disease
- Hypothesis: celecoxib will reduce the incidence of AD by >30% in a high risk cohort.

- First longer-term placebo-controlled trial with an NSAID

## Sources Available to Evaluate CV Safety of Celecoxib

|  | APC | Pre-SAP  | ADAPT |
| --- | --- | --- | --- |
| Study Description |  |  |  |
|   Number of patients | 2035 | 1561 | 2463 |
|   Pt-years | 4778 | 3939 | 3888 |
|   Mean exposure (yrs) | 2.3 | 2.5 | 1.6 |
|   Number of CV events | 41 | 31 | ~70 |
|  |  |  |  |
|   Mean age (yrs) | 60 | 61 | >70 |
|   Hx of hypertension | 41% | 35% | n/a |
|   Hx of CHD | 39% | 48% | n/a |
|   Concomitant aspirin | 30% | 16% | n/a |

**Sources Available to Evaluate CV Safety ****of Celecoxib**

**Patient Population**

## CV Safety of Chronic Celecoxib vs Placebo – Conclusions: Longer-term Studies

- Three longer-term placebo-controlled trials with celecoxib
- APC - showed a CV risk with celecoxib vs placebo after ~1 yr of continuous treatment
- Pre-SAP - no differences observed with continuous treatment of celecoxib up to 3 yrs
- ADAPT - Naproxen showed a CV risk (over 1.5 yrs) vs placebo, in contrast to celecoxib
- Celecoxib requires further study to estimate longer-term CV risks; an NSAID comparator in such a trial is critical

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk factors
- Epidemiology studies
- Considerations of mechanism
- Conclusions: Risk-benefit

## Cardiovascular Safety of Celecoxib: Meta-analysis of RCTs

- 41 completed randomized controlled trials and a total of 44,307 treated patients (>91% OA/RA)
- 24,932 celecoxib-treated patients
- 4,057 placebo-treated patients
- 15,318 patients treated with active comparators
- Celecoxib doses; 50 – 800 mg daily
- Primary NSAIDs – naproxen, ibuprofen, diclofenac
- Study duration – 2 wks to 1 yr

- _Celecoxib exposure_
- _>_ 3 months – 11206 (55%) of patients
- _>_ 9 months – 2472 (12%) of patients
- _>_ 1 yr – 803 (4%) of patients

## Meta-analysis: CV Endpoints

- Composite endpoint of any CV death, non-fatal MI or non-fatal stroke
- Any CV death
- Non-fatal MI
- Non-fatal stroke

## Sources Available to Evaluate CV Safety of Celecoxib

|  | APC | Pre-SAP  | ADAPT | Meta-analysis of RCTs
2 wks – 1 yr |  |
| --- | --- | --- | --- | --- | --- |
| Study Description |  |  |  | vs. Placebo | vs. 
NSAIDs  |
|   Number of patients | 2035 | 1561 | 2463 | 11519 | 33763 |
|   Pt-years | 4778 | 3939 | 3888 | 1853 | 10037 |
|   Mean exposure (yrs) | 2.3 | 2.5 | 1.6 | 0.16 | 0.30 |
|   Number of CV events | 41 | 31 | ~70 | 31 | 111 |
|  |  |  |  |  |  |
|   Mean age (yrs) | 60 | 61 | >70 | 59 | 60 |
|   Hx of hypertension | 41% | 35% | n/a | 45% | 25% |
|   Hx of CHD | 39% | 48% | n/a | 22% | 10% |
|   Concomitant aspirin | 30% | 16% | n/a | 13% | 11% |

**Sources Available to Evaluate CV Safety ****of Celecoxib**

**Patient Population**

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs  

|  | Celecoxib 200 mgN=19773 | NSAIDs
N=13990 |
| --- | --- | --- |
| Patient-years | 5651 | 4386 |
| Mean exposure/patient (mos.) | 3.4 | 3.8 |
| CV death, MI, stroke | 57 (1.0) | 54 (1.2) |
|    CV death | 15 (0.3) | 19 (0.4) |
|    MI | 35 (0.6) | 19 (0.4) |
|    Stroke | 7 (0.1) | 16 (0.4) |

**n (events per 100 patient-years)**

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs  

**0.72 (0.37, 1.39)**

**1.49 (0.82, 2.70)**

**Celecoxib daily dose **_**>**_** 200 mg**

**0.33 (0.14, 0.78)**

**CV death, MI, or stroke**

**CV death**

**MI**

**Stroke**

**Favors celecoxib**

**Favors NSAIDs**

**Relative Risk (95%CI)**

**CV Death, MI and Stroke:****Celecoxib vs. NSAIDs **** **

## CV Death, MI and Stroke:Celecoxib vs. Pbo, NSAIDs Combined & Individually  

**1.26 (0.57, 2.80)**

**0.86 (0.59, 1.26)**

**0.81 (0.49, 1.35)**

**0.88 (0.43, 1.82)**

**Celecoxib daily dose **_**>**_** 200 mg**

**1.11 (0.41, 3.01)**

**vs. Placebo**

**vs. NSAID**

**vs. Naproxen**

**vs. Diclofenac**

**vs. Ibuprofen**

**0.1**

**1.0**

**10.0**

**Favors celecoxib**

**Favors comparator**

**0.3**

**3.0**

**Relative Risk (95%CI)**

**CV Death, MI and Stroke:****Celecoxib vs. Pbo, NSAIDs Combined & Individually **** **

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs: By Dose  

**0.93 (0.52, 1.68)**

**0.75 (0.34, 1.67)**

**0.91 (0.53, 1.58)**

****** ****200 mg**

**200 mg**

**400 mg**

**800 mg**

**Favors celecoxib**

**Favors NSAIDs**

**CV Death, MI and Stroke:****Celecoxib vs. NSAIDs: By Dose **** **

**Relative Risk (95%CI)**

## CV Death, MI and Stroke:CLASS and CAESAR Studies

**CV Death, MI and Stroke:****CLASS and CAESAR Studies**

**P**

**P**

**P**

**P**

**J**

**P**

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**3.0**

**2.0**

**1.0**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**270**

**300**

**330**

**360**

**390**

**Celecoxib 200 – 800 mg daily, n=4445**
**NSAIDs (diclofenac, ibuprofen), n=4439**

**% of Patients**

**Days**

**P**

**J**

**p = 0.601, by log rank test**

**J**

**0**

**J**

## CV Safety in RCTs - Conclusions

- No association for increased CV risk detected with use of celecoxib up to 1 yr compared to:
- NSAIDs combined
- naproxen, diclofenac or ibuprofen individually
- A dose-related increase in CV risk with celecoxib is not observed

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk factors
- Epidemiology studies
- Considerations of mechanism
- Conclusions: Risk-benefit

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By CV Risk Factors* 

**0.0**

**1.0**

**2.0**

**3.0**

**CV death, MI, stroke**

**CV death**

**MI**

**Stroke**

**Events per 100 pt yrs**

**0.0**

**1.0**

**2.0**

**3.0**

**CV death, MI, stroke**

**CV death**

**MI**

**Stroke**

**No Risk Factors (n = 21,974)**

**Celecoxib ******** 200 mg**

**NSAIDs**

**CV Death, MI and Stroke:****Celecoxib vs. NSAIDs – By CV Risk Factors***** **

***Hypertension, diabetes, hyperlipidemia, CHD **

**1 Risk Factor (n = 6,710)**

****** ****2 Risk Factors (n = 5,079)**

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By CV Risk Factors* 

**CV Death, MI and Stroke:****Celecoxib vs. NSAIDs – By CV Risk Factors***** **

***Hypertension, diabetes, hyperlipidemia, CHD **

## CV Death, MI and Stroke:Celecoxib vs. NSAIDs – By Aspirin Use

**Celecoxib daily dose **_**>**_** 200 mg**

## CV Death, MI and Stroke:CLASS Study

**P**

**CV Death, MI and Stroke:****CLASS Study**

**P**

**P**

**P0**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**P**

**J**

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**P**

**J**

**J**

**J**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**270**

**300**

**330**

**360**

**390**

**30**

**0**

**1.0**

**2.0**

**3.0**

**P**

**J**

**No Aspirin**

**4.0**

***p *****= 0.333****Log-rank test**

**% of Patients**

**Celecoxib 400 mg BID (n=3105)**

**NSAIDs (n=3124)**

**J**

**P**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**270**

**300**

**330**

**360**

**390**

**30**

**0**

**1.0**

**2.0**

**3.0**

**Aspirin**

**P**

**J**

**P**

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**P**

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**4.0**

***p *****= 0.666****Log-rank test**

**Celecoxib 400 mg BID (n=882)**

**NSAIDs (n=857)**

**J**

**P**

**P**

**Days**

## Risk Factors - Conclusion

- The CV safety profile of celecoxib remains comparable to NSAIDs regardless of CV risk factors
- as determined by medical history or use of low dose aspirin

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk factors
- Epidemiology studies
- Considerations of mechanism
- Conclusions: Risk-benefit

## Risk of MI with COXIBs

- Ray WA et al. 	Lancet  2002
- Mamdani M et al. 	Arch Intern Med 2003
- Solomon DH et al. 	Circulation 2004
- Kimmel SE et al. 	Ann Intern Med 2005
- Graham DJ et al. 	Lancet 2005
- Lévesque LE et al.	Ann Intern Med 2005
- Shaya FT et al.	Arch Intern Med 2005

## Risk of MI and Use of COXIBs

|  | Epidemiological Studies |  |  |
| --- | --- | --- | --- |
| Number of events* |  |  |  |
| Total | 30,367 |  |  |
| Celecoxib | 1,005 |  |  |
| Number of patients | Cohort | Case-control |  |
| Total | 2,135,867 | 12,613 / 50,380 |  |
| Celecoxib | 94,169 | 443 / 1,802 |  |
| Person-years |  |  |  |
| Total | 2,795,452 | NA |  |
| Celecoxib | 12,647† |  |  |
| Source data | Cohort/nested - Mamdani M, Ray WA, Graham DJ, Shaya FT, Lévesque LECase-control   - Solomon DH, Kimmel SE |  |  |

- * Ray WA and Graham DJ include MI and CHD death. Kimmel SE non-fatal MI only
**†** Person-time of exposure to celecoxib not provided in studies of Graham DJ, Shaya FT, and Lévesque LE.
- Number of cases exposed to celecoxib not provided in Shaya FT.

## Relative Risk of MI/Coronary Death: Use of COXIBs or NSAIDs vs. Non-use

**1.70**

**1**

**0.93**

**0.91**

**1.03**

**0.96**

**0.94**

**0**

**1**

**2**

**3**

**Non-use**

**naproxen**

**celecoxib**

_**>**_**300mg**

**rofecoxib**

**>25mg**

**Adjusted Rate Ratio**

**Ray et al. Lancet 2002; 360:1071-73**

**ibuprofen**

**celecoxib**

**<300mg**

**rofecoxib**

_**<**_**25mg**

**Relative Risk of ****MI/Coronary Death****: ****Use of COXIBs or NSAIDs vs. Non-use**

**mean age >60 yrs**
**66% women****37% with Hx of major CV disease **

**Celecoxib **
**   ****22,337 users**
**    ****3  months mean exposure**

## Relative Risk of MI: Use of COXIBs or NSAIDs vs. Non-use

**Relative Risk of ****MI****: ****Use of COXIBs or NSAIDs vs. Non-use**

**mean age >75 yrs**
**>56% women****>5% with Hx of MI, ****>9% with Hx of CHD**

**Celecoxib **
**   ****15,271 users**
**    ****5.5 months mean follow-up**

**1.20**

**1.00**

**0.90**

**1.00**

**1**

**0**

**1**

**2**

**3**

**Non-use**

**celecoxib**

**rofecoxib**

**naproxen**

**other**

**NSAIDs**

**Adjusted Rate Ratio**

## Relative Risk of MI: Use of COXIBs vs. Non-use

**celecoxib**

**celecoxib**

_**<**_** 200 mg**

**celecoxib**

**> 200 mg**

**rofecoxib**

**rofecoxib**

_**<**_** 25 mg**

**rofecoxib**

**> 25 mg**

**Solomon et al. Circulation 2004;109:2068-73 &****Arthritis Rheum 2003;48 (Suppl 9) S697 (Presentation ****ACR Oct 2003)**

**Relative Risk of ****MI****: ****Use of COXIBs vs. Non-use**

**Adjusted Odds Ratio**

**mean age >80 yrs**
**77% women**
**57% with Hx of Htn**
**14% with Hx of angina**
**9% with Hx of MI **

## Relative Risk of MI: Use of COXIBs or NSAIDs vs. Non-use

**Relative Risk of ****MI****: ****Use of COXIBs or NSAIDs vs. Non-use**

**Adjusted Odds Ratio**

**mean age >52 yrs**
**59% women****31% with Hx of Htn**
**4% with Hx of angina/CHD **

## Relative Risk of MI/Coronary Death: Use of COXIBs or NSAIDs vs. Remote-use

**1.30**

**1.60**

**1**

**1.23**

**0.84**

**1.14**

**3.00**

**1.06**

**0**

**1**

**2**

**3**

**4**

**Remote use**

**celecoxib**

**rofecoxib **_**<**_** 25 mg**

**rofecoxib >25 mg**

**ibuprofen**

**naproxen**

**indomethacin**

**diclofenac**

**Adjusted Odds Ratio**

**Relative Risk of ****MI/Coronary Death****: ****Use of COXIBs or NSAIDs vs. Remote-use**

**Graham et al. Lancet 2005;365:475-481**

**mean age >66 yrs**
**38% women****1% with Hx of MI/ revascularization**

## Relative Risk of CV Death, MI or StrokeUse of COXIBs vs. Non-naproxen NSAIDs

**0.99**

**1.09**

**1.19**

**1**

**0**

**1**

**2**

**3**

**Non-naproxen**

**NSAIDs**

**COXIBs**

**celecoxib**

**rofecoxib**

**Adjusted Odds Ratio**

**Relative Risk of CV Death, MI or Stroke****Use of COXIBs vs. Non-****naproxen**** NSAIDs**

**Shaya et al.  Arch Intern Med 2005;165:181-6**

**11% >60 yrs**
**70% women****43% with Hx of Htn**
**12% with Hx of CV event **

## Relative Risk of MI:

**1.06**

**1.00**

**1**

**1.00**

**0.98**

**1.17**

**1.21**

**1.73**

**0**

**1**

**2**

**3**

**Non-use**

**celecoxib **_**<**_** 200 mg**

**celecoxib > 200 mg**

**rofecoxib **_**<**_** 25 mg**

**rofecoxib > 25 mg**

**naproxen**

**meloxicam**

**other NSAIDs**

**Relative Risk of ****MI****:**
**Use of COXIBs or NSAIDs vs. ****Non****-use**

**Adjusted Rate Ratio**

**Lévesque**** et al. Ann Intern Med 2005;142(7), www.annals.org**

**mean age >78 yrs**
**67% women****50% with Hx of Htn**
**17% with Hx of CHD **

## Risk of MI by ASA Use Relative Risk of COXIBs vs. Non-use 

**Celecoxib **_**<**_** 200 mg**

**Celecoxib > 200 mg**

**Rofecoxib **_**<**_** 25 mg**

**Rofecoxib > 25 mg**

**Non-use**

**Celecoxib **_**<**_** 200 mg**

**Celecoxib > 200 mg**

**Rofecoxib **_**<**_** 25 mg**

**Rofecoxib > 25 mg**

**1.04**

**1.16**

**1.38**

**1.23**

**1.00**

**0.91**

**0.80**

**2.36**

**1**

**1**

**0**

**1**

**2**

**3**

**4**

**No ASA use**

**ASA use**

**Risk of MI by ****ASA Use**** ****Relative Risk of COXIBs vs. Non-use **

**Adjusted Rate Ratio**

**Lévesque**** et al. Ann Intern Med 2005;142(7), www.annals.org**

## Summary of MI Risk by Dose:Relative Risk vs. Non-use/Remote Use 

**1.23**

**3.00**

**0.94**

**1**

**0.92**

**0.96**

**1.03**

**0.98**

**1.11**

**1.21**

**0.94**

**1.00**

**1.70**

**1.58**

**1.73**

**0**

**1**

**2**

**3**

**4**

**Non-use**

**Ray WA**

**Solomon DH**

**Lévesque LE**

**Ray WA**

**Solomon DH**

**Lévesque LE**

**Graham DJ**

**Ray WA**

**Solomon DH**

**Lévesque LE**

**Ray WA**

**Solomon DH**

**Lévesque LE**

**Graham DJ**

**Low dose**

**High dose*******

**celecoxib**

**rofecoxib**

**celecoxib**

**rofecoxib**

**Summary of MI Risk by Dose:****Relative Risk vs. Non-use/Remote Use**** **

***High-dose: ****  rofecoxib >25 mgr/day****  celecoxib >200 mg/day in Solomon DH and Lévesque LE****  celecoxib **_**>**_** 300 mg/day in Ray WA**

**Relative Risk**

## CV Epidemiology Studies - Conclusions

- The risk of MI with celecoxib as used in the real world population (dose & duration)
- is consistently similar to nonselective NSAIDs, and non- or remote use of NSAIDs
- These findings are in contrast to increased risk with rofecoxib
- The available data suggest that the risk of MI is similar for low and high celecoxib doses

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk Factors
- Epidemiology Studies
- Considerations of Mechanism
- Conclusions: Risk-benefit

## Potential Mechanism(s) of CV Risk 

- Hypothesis that attributes CV risk to COXIBs only;
- Could explain
- VIGOR, APPROVe and APC results
- Could not explain consistent comparability between celecoxib and NSAIDs
- meta-analysis
- vs non-use in epidemiology studies
- Could not explain Pre-SAP and ADAPT results

## Potential Mechanisms

- NSAIDs may not provide ‘effective’ blockade of platelets – even though TxA2 production is reduced
- Does not account for other PGs produced from COX-2 (e.g. PGE2, TxA2)

- Can PGI2/TxA2 imbalance lead to prothrombotic potential?

## Pharmacologic Responses to Celecoxib and Ibuprofen 

**P**

***Significant difference from baseline; p<0.05 **

**H**

**Celecoxib 400 mg (n=9)**

**B**

**Placebo (n=7)**

**J**

**Celecoxib 100 mg (n=7)**

**F**

**Celecoxib 800 mg (n=7)**

**Ibuprofen 800 mg (n=7)**

**Hours**

*****

**B**

**B**

**H**

**F**

**F**

**F**

**P**

**P**

**-100**

**-80**

**-60**

**-40**

**-20**

**0**

**20**

**Pre-****Dose**

**2**

**4**

**6**

**0**

**24**

**8**

** ****% (Mean Change ******** SE)**

**B**

**J**

**Platelet Aggregation**

**Pharmacologic Responses to Celecoxib ****and Ibuprofen **

**J**

**H**

**F**

**P**

**J**

**H**

**J**

**B**

**P**

**H**

**McAdam et al. PNAS 1999;96:272-277**

****Significantly different from placebo; p<0.05**

**0**

**25**

**50**

**75**

**100**

**125**

**150**

**175**

**200**

**4-6 hrs**

**6-12 hrs**

**Urinary PGI-M **

**pg/ mg creatinine**

**NR**

**NR**

- **

- **

- **

- **

- **

- **

**NR = not reported**

## COX-2 Prostaglandins Linked to CV Disease

****** ****TxA****2**

****** ****PGE****2**

****** ****MMPs**

****** ****Plaque stability**

** ****Endothelial function**
****** ****Platelet aggregation**

**Endothelial function**
****** ****Platelet aggregation**

**COX-2 Prostaglandins Linked to CV Disease**

****** ****COX-2 expression**

## Putative Novel Rofecoxib Pathways Leading to Increased HTN and CV Risk 

**Chikani G et al. Am J Physiol Endocrinol Metab 287 (2004): E386-E389**

**Rofecoxib and/or Reactive Metabolites**

- ↑Ox-LDL

- ↑F2-Isoprostanes

- ↑Blood Pressure /↑Atherothrombosis

- ↓Nitric Oxide Bioavailability

**Putative Novel Rofecoxib Pathways ****Leading to Increased HTN and CV Risk **

## 24-Hour Mean SBP Change at 6 &12 Wks in OA Hypertensive Patients

**Sowers et al. Arch Int Med; 2005;165:161-168**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Celecoxib**
**200 mg qd**
**n=136**

**Rofecoxib**
**25 mg qd**
**n=138**

**Naproxen**
**500 mg bid**
**n=130**

**Mean SBP Change (mm Hg)**

**6 Wks**

**12 Wks**

**6 Wks**

**12 Wks**

**6 Wks**

**12 Wks**

- *

- *

*** p < 0.05 vs other treatments**

**SBP from ABPM data**

## Mechanism Summary

- It is not established that PGI2/TxA2 imbalance contributes to effects observed for COXIBs or NSAIDs
- Furthermore, the underlying pharmacology is more complex involving other PGs and pathways and raises the potential for benefit with a COX-2 blockade
- Evidence for molecule-specific mechanisms is emerging

## Overview 

- Celecoxib - CV safety vs placebo
- Longer-term studies
- Celecoxib – CV safety vs NSAIDs
- Meta analysis of RCTs
- Risk Factors
- Epidemiology Studies
- Considerations of Mechanism
- Conclusions: Risk-benefit

## Summary of GI and CV Safety 

- Celecoxib vs NSAIDs
- GI safety
- RCTs: lower incidence of clinically significant GI outcomes
- Epidemiology studies: similar risk of         hospitalization for GI bleeding vs non-users
- CV safety
- RCTs: comparable CV safety profile
- Epidemiology studies: similar CV risk vs non-users

## Risk-Benefit of Celecoxib in Arthritis -  Conclusions

- In the currently approved arthritis indications, the risk-benefit of celecoxib remains positive relative to NSAIDs
- Comparable efficacy
- GI safety benefit
- Comparable CV risk
- Shared uncertainty of the CV safety beyond   1 year of continuous treatment

- Further studies are planned to evaluate the longer-term GI and CV safety of celecoxib vs NSAIDs in arthritis patients