# Presentation: 757637

## Cardiovascular Risk and NSAIDsArthritis Advisory Committee Meeting April 12, 2007

- Sharon Hertz, M.D.
- Deputy Director
- Division of Analgesia, Anesthesia, and Rheumatology Products
- Center for Drug Evaluation and Research
- Food and Drug Administration

## Overview of Presentation

-  Cardiovascular findings from COX-2 development
-  FDA conclusions about CV Risk and NSAIDs

## February 2005

- Joint advisory committee meeting with arthritis and drug safety committees
- Data presented on rofecoxib, celecoxib, lumiracoxib, etoricoxib

## Vioxx

- May 20, 1999** **
- Approval of New Drug Application for Vioxx (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and osteoarthritis
- ~ 5000 subjects
- - 700+ at least 1 year (12.5 and 25 mg)
- No cardiovascular signal – small number of events, no dose response

## Vioxx - VIGOR

- Rofecoxib _50 mg_ daily vs. naproxen 500 mg BID
- 8,000 RA patients, no ASA
- Median exposure - 9 months
- Endpoints
- serious GI events
- serious CV/thrombotic events

**Notes:**
Submitted June 29, 2000
Advisory committee February 8, 2001
April 6, 200 1approvable action on vigor supplement
July 12, 2001 complete response to AE letter

## Vioxx - VIGOR

- Cardiovascular risk identified for rofecoxib vs. naproxen
-  All CV events - RR 2.37
-  MI - RR 5.0 (20 vs. 4)
-  Incidence increased over time
-  Results taken to AC February, 2001

## Vioxx - Alzheimer’s Disease

- To slow progression or prevent onset
- 3 placebo-controlled, double-blind, multicenter studies
- Rofecoxib 25 mg vs. placebo
- 15-24 months
- N=~2800 patients
- No consistent cardiovascular signal

## Vioxx - APPROVe

- Reduce incidence of adenomatous polyps in patients with history of colorectal adenomas
- Randomized, placebo-controlled, double-blind, 3 years + 1 year
- Rofecoxib 25 mg vs. placebo
- 2586 patients

**Notes:**
September 2005

## Vioxx - APPROVe

- September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. placebo in APPROVe
-  All CV events – RR 1.8
-  MI – RR 2.5
-  Ischemic CVA – RR 1.8
- September 30, 2004 – Merck withdraws Vioxx from the market

## Vioxx – APPROVe  Effect of ASA on APTC

|  | Vioxx 25 mg  | Placebo |
| --- | --- | --- |
| All patients | N=1287
3053 pt-yrs | N=1300
3322 pt-yrs |
| n
Rate/100 pt-yrs | 59 
1.9 | 34
1.0 |
| Non-ASA Users  | N=1074 | N=1096  |
| n
Rate/100 pt-yrs | 43 
1.7 | 22 
0.8  |
| ASA Users  | N=213  | N=204  |
| n
Rate/100 pt-yrs | 15 
3.1  | 12
2.3 |

## Celebrex

- December 31, 1998
- Approval of New Drug Application for Celebrex (celecoxib) for the signs and symptoms of osteoarthritis (200 mg/day) and rheumatoid arthritis 200-400 mg/day)
- N= 9600 patients
- No CV signal with initial application

## Celebrex - CLASS

- CLASS
- Double-blind, active-controlled, 1 year
- ~ 8,000 patients with OA or RA, ASA if indicated
- Celecoxib 400 mg twice daily
- Endpoint – serious GI events
- No cardiovascular signal vs. ibuprofen     800 mg TID or diclofenac 75 mg BID

## CLASSMyocardial Infarction

|  | Celecoxib  | Diclofenac  | Ibuprofen  |
| --- | --- | --- | --- |
| All patients | N=3987
2340 pt-yrs | N=1996
1080 pt-yrs | N=1985
1122 pt-yrs |
| n
Rate/100 pt-yrs | 19 
0.8 | 4
0.4 | 9
0.8 |
| Non-ASA Users  | N=3105 | N=1551  | 1573  |
| n
Rate/100 pt-yrs | 6 
0.3  | 2 
0.2  | 2 
0.2  |
| ASA Users  | N=882  | N=445  | N=412  |
| n
Rate/100 pt-yrs | 13 
2.5  | 2
0.8  | 7 
2.8  |

## Celebrex - APC

- APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib)
- Double-blind, placebo-controlled, 3 years, over 1900 patients, ASA use by ~30%
- Celebrex 400 mg twice daily (N=671)
- Celebrex 200 mg twice daily (N=685)
- Placebo (N=679)

## Celebrex - APC

- December 16, 2004 – APC study halted due to CV signal for celecoxib vs. placebo
- Death from CV causes, MI, or stroke
- celecoxib 200 mg bid vs. placebo
- 	RR 2.5
- celecoxib 400 mg bid vs. placebo
- 	RR 3.4

## Incidence of Hierarchical Cardiovascular Composite Endpoints in the APC Trial

| Endpoint | Number of patients (%) |  |  | Rate/100 pt-yrs |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Placebo | 200 mg BID | 400 mg BID | Placebo | 200 mg BID | 400 mg BID |
| Death from CV causes | 1 (0.1) | 3 (0.4) | 6 (0.9) | 0.05 | 0.14 | 0.29 |
| Death from CV causes or MI | 4 (0.6) | 12 (1.8) | 15 (2.2) | 0.19 | 0.58 | 0.74 |
| Death from CV causes, MI, or stroke | 6 (0.9) | 15 (2.2) | 20 (3.0) | 0.29 | 0.73 | 0.99 |
| Death from CV causes, MI, stroke, or heart failure | 7 (1.0) | 16 (2.3) | 23 (3.4) | 0.34 | 0.78 | 0.11 |

*Solomon SD, et al: N Engl J Med 352, 2005*

## Hazard Ratios for Hierarchical CV Composite Endpoints in the APC Trial

*Solomon SD, et al: N Engl J Med 352, 2005*

| Endpoint | Hazard Ratio  with 95% CI* |  |
| --- | --- | --- |
|  | 200 mg BID | 400 mg BID |
| Death from CV causes | 3.0 (0.3-28.6) | 6.1 (0.7-50.3) |
| Death from CV causes or MI | 3.0 (1.0-9.3) | 3.8 (1.3-11.5) |
| Death from CV causes, MI, or stroke | 2.5 (1.0-6.4) | 3.4 (1.4-8.5) |
| Death from CV causes, MI, stroke, or heart failure | 2.3 (0.9-5.5) | 3.4 (1.4-7.8) |

- *Relative to placebo

## Celebrex - APC

*Solomon SD, et al: N Engl J Med 352, 2005*

- *In this analysis, “serious CV events” include
- death from CV causes, MI, stroke, or heart failure

- 671

## Celebrex - PreSAP

- Celecoxib in Adenoma Prevention
- Double-blind, placebo-controlled, 3 years, over 1900 patients
- Celebrex 400 mg once daily
- Placebo
- ASA use by ~16%

## Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial

| Endpoint | Placebo 
n (%) | 400 mg 
n (%) | Hazard Ratio  with 95% CI* |
| --- | --- | --- | --- |
| Death from CV causes | 4 (0.6) | 2 (0.2) | 0.3 (0.1, 1.8) |
| Death from CV causes or MI | 7 (1.1) | 11 (1.2) | 1.1 (0.4, 2.7) |
| Death from CV causes, MI, or stroke | 12 (1.9) | 19 (2.0) | 1.1 (0.5, 2.2) |
| Death from CV causes, MI, stroke, or heart failure | 12 (1.9) | 20 (2.1) | 1.1 (0.6, 2.3) |

- *Relative to placebo

**Notes:**
I would simplify – delete %’s in the first three columns – simplify endpoint description. See suggestions

## Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Trial

| Endpoint | Placebo
N = 628 
n (%) | 400 mg 
N = 933
n (%) | Hazard Ratio  with 95% CI* |
| --- | --- | --- | --- |
| Death from CV causes | 4 (0.6) | 2 (0.2) | 0.3 (0.1, 1.8) |
| Death from CV causes or MI | 7 (1.1) | 11 (1.2) | 1.1 (0.4, 2.7) |
| MI | 3 (0.4) | 9 (1.0) |  |

- *Relative to placebo

**Notes:**
I would simplify – delete %’s in the first three columns – simplify endpoint description. See suggestions

## Celebrex - ADAPT

- Alzheimer’s prevention study
- December 17, 2004 – ADAPT trial halted
- Celecoxib 200 mg bid, naproxen 220 mg bid, placebo
- N=~2500 patients
- Cardiovascular risk not found for celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo was suggested.

## TARGET

- Therapeutic COX-189 Arthritis Research and Gastrointestinal Event Trial
- 52 weeks
- 18,000 patients with osteoarthritis
- Two sub-studies:
- 0117: lumiracoxib 400 mg, naproxen 500 mg bid
- 2332: lumiracoxib 400 mg, ibuprofen 800 mg tid
- 25% of patients on low dose aspirin (ASA)

## TARGET Confirmed & Probable APTC Events

|  | LUM | Napr | LUM | Ibu |
| --- | --- | --- | --- | --- |
| N | 4741 | 4730 | 4376 | 4397 |
| Pt-yr at risk | 3639 | 3534 | 3242 | 3090 |
| APTC | 40 |  27 | 19 | 21 |
| CV Death | 11 | 8 | 8 | 10 |
| All MI
Rate/100 pt-yr | 18 (0.49) | 10
(0.28) | 5 (0.15) | 7 (0.22) |
| All Ischemic/hem stroke | 16 | 12 | 8 | 9 |

##  TARGET Confirmed /Probable APTC Endpoint KM plot (%)

- Study 0117

- Study 2332

## Epidemiological Studies

- Consistent risk associated with high dose rofecoxib
- Variable findings of risk associated with other selective and nonselective NSAIDs

## FDA Conclusions

- April 6, 2005 Decisional Memorandum: “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk”
- _[http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf](http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf)_

## FDA Conclusions

-   “The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with an increased risk of serious adverse CV events compared to placebo.  The available data do not permit a rank ordering of these drugs with regard to CV risk.”

## FDA Conclusions

- “Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs.”

## FDA Regulatory Actions

- April 7, 2005
-  Boxed warning all Rx NSAIDs
-  Potential increased risk serious CV events
-  May be higher with prior history of CV disease/risk
-   Added GI warnings to box
-  Contraindication perioperative CABG

## FDA Regulatory Actions

-  Class Medication Guide for all Rx NSAIDs
-  Revised warnings for OTC NSAIDs

## Information Request

- Review of all clinical trial data from controlled studies
- Unable to draw conclusions
- Small sample size, even with pooling
- Very small number of CV events
- Short duration of treatment

## Additional slides

## TARGET Confirmed & Probable MI by ASA Use

|  | LUM | Nap | LUM | Ibu |
| --- | --- | --- | --- | --- |
| Overall Population  N | 4741 | 4730 | 4376 | 4397 |
|  All MI  n
Rate/100 pt-yr | 18 
0.49 | 10 
0.28 | 5
0.15 | 7
0.23 |
| Non-ASA Users   N | 3549 | 3537 | 3401 | 3431 |
| All  MI  n
Rate/100 pt-yr | 10
0.36 | 4
0.15 | 4
0.16 | 5
0.21 |
| ASA Users   N | 1192 | 1193 | 975 | 966 |
| All MI  n
Rate/100 pt-yr | 8
0.91 | 6
0.67 | 1
0.14 | 2
0.30 |

## TARGET New Analysis -2007

- Farkouh et. al.  Annals of Rheumatic Disease, 2007 Apr 5; [Epub ahead of print]
-  Post hoc analysis stratified by BL CV risk, treatment assignment and low-dose ASA use
-  Primary composite endpoint – CV mortality, nonfatal MI, stroke at 1 year
-  Secondary – congestive heart failure

## TARGET New Analysis -2007

| Composite endpoint – CV mortality, nonfatal MI, stroke |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | LUM | Nap | LUM | Ibu |
| High Risk/ASA Users | n=541 | n=505 | n=394 | n=373 |
| % | 1.48 | 1.58 | 0.25 | 2.14 |
| High Risk/No ASA | n=318 | n=335 | n=326 | n=250 |
| % | 1.57 | 0 | 0.92 | 0.80 |
| Low Risk/ASA Users | n=651 | n=688 | n=581 | n=593 |
| % | 1.54 | 0.73 | 0.86 | 0.34 |
| Low Risk/No ASA | n=3231 | n=3202 | n=3075 | n=3181 |
| % | 0.53 | 0.44 | 0.33 | 0.35 |