1. Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-controlled Trials: The Cross Trial Safety Analysis
Scott D. Solomon, MD, Janet Wittes, PhD,
Ernest Hawk, MD, MPH for the Celecoxib
Cross Trials Safety Analysis Investigators
On behalf of the individual trial investigators, I’m pleased to present the results of the Celecoxib Cross Trials Safety analysis.
A manuscript based on these results will be available immediately following this presentation in Circulation.
Manuscript available simultaneously online in Circulation

2. This research was funded entirely by the National Cancer Institute
DISCLOSURES
No Disclosures
This research was funded entirely by the National Cancer Institute
I have no conflicts of interest to disclose.
This analysis was funded entirely by the National Cancer Institute.

3. Background
Observational studies and randomized controlled trials have reported increased cardiovascular risk associated with cyclooxygenase-2 (cox-2) inhibitors (coxibs) 1,2,3,4
Strong biologic basis for this risk supported by abundant basic research5,6,7
Most clinical studies compared coxibs with active comparators in short-term arthritis trials
Observational studies and randomized controlled trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors, also known as coxibs.
Moreover, numerous experimental studies have supported a strong biologic basis for this risk.
While most clinical studies with these agents have compared coxibs with active comparators in relatively short-term arthritis trials, initial evidence of increased cardiovascular risk associated with rofecoxib, valdecoxib and celecoxib emerged from longer duration, placebo-controlled trials designed to study the role of coxibs in other therapeutic areas.
1McGettigan JAMA 2006; 2Graham et al. Lancet 2005; 3Bresalier et al. NEJM 2005; 4Solomon et al. NEJM 2005
5McAddam et al. PNAS 1999; 6Fitzgerald NEJM 2001; 7Fitgerald et al. NEJM 2004

4. Background
In December 2004, Interim results from the Adenoma Prevention with Celecoxib (APC) trial results led to stopping drug in that trial and in 5 other long-term trials comparing celecoxib to placebo:
The Prevention of Sporadic Adenomatous Polyps (PreSAP) trial1
The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT)2
The MA-27 Breast Cancer Trial,
The Celecoxib Diabetic Macular Edema (CDME) trial
The Celecoxib/Selenium Trial.
FDA hearing resulted in Black Box Warning.
Celecoxib is the only available cox-2 inhibitor in US.
In December 2004, two months after the withdrawal of rofecoxib because of increased cardiovascular risk observed in a polyp-prevention trial,
similar findings in the NCI- and Pfizer-sponsored Adenoma Prevention with Celecoxib (APC) trial
led to stopping drug administration in that and five other long-term trials comparing celecoxib to placebo:
These trials, which are listed here, were the the Prevention of Sporadic Adenomatous Polyps (PreSAP) trial, the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT), the MA-27 breast cancer recurrence trial, the Celecoxib Diabetic Macular Edema (CDME) trial, and The Celecoxib/Selenium Trial.
Subsequent to the FDA hearing in february 2005, a black box warning was placed on celecoxib,
which remains the only cox-2 inhibitor available currently in the US.
1 Arber et al. NEJM 2006; ADAPT Invest. PLOS 2006

5. Low event rates Lead to Challenges in Risk Assessment with Coxibs
Low Precision of the estimates
Inability to test observational and RCT data suggesting
coxib-associated CV risk may be dose related
dose and interval may be important in CV risk.1
Inability to assess whether CV risk associated with celecoxib varies by baseline CV risk
The relatively low cardiovascular event rate in all coxib cardiovascular risk analyses to date has reduced the certaintly of the estimates of risk and has thwarted our ability to answer some important yet vexing questions:
While Observational data and our previous analyses of the APC and PreSAP studies have suggested that coxib-associated cardiovascular risk may be dose related, and that both dose and dosing interval may be important factors in cardiovascular risk, these relationships have been obscured by the low event rate.
Moreover, Prior trials have had too few cardiovascular events to assess whether the cardiovascular risk associated with celecoxib use risk varies according to a patient’s baseline cardiovascular risk.
1Solomon et al Circulation 2006

6. Objective
To understand more fully the cardiovascular risk profile associated with long-term use of celecoxib
NCI commissioned and funded analysis of long-term placebo controlled trials with a planned follow-up  3 years
To understand more fully the cardiovascular risk profile associated with long-term use of celecoxib,
the National Cancer Institute asked investigators in four long-term, placebo-controlled trials with a planned follow-up of 3 years or greater
to submit their data for central adjudication and combined analysis by the same process used to analyze the APC and PreSAP studies.

7. Selection of Studies
Randomized, double-blind, placebo-controlled trials
Planned follow-up of at least 3 years
Source documentation available for adjudication
4 trials + APC and PreSAP fulfilled these criteria:
ADAPT
MA-27
CDME
Celecoxib/Selenium Trial
Prior to collecting data we specified that trials included in the analysis would have the following characterisitics:
(1) they would be randomized, double blind, and placebo-controlled
2) the planned follow-up for each participant would be at least three years, and
3) source documentation would be available for central adjudication.
All trials fulfilling these two criteria studied the therapeutic potential of celecoxib for a condition other than arthritis. In addition to the APC and PreSAP trials that we had previously adjudicated and analyzed we identified 4 trials that fulfilled these criteria.

8. Methodology Each study submitted patient-level data:
Baseline data
Outcomes
Adverse events
A blinded adjudication team identified all potential cardiovascular events from broad list of SAEs and AEs
Requested source documentation for all relevant events
All potential cardiovascular events were adjudicated by two reviewers masked to treatment allocation
Categorized all deaths
Adjudicated all non-fatal events
Each study submitted patient-level data, including baseline data, outcomes data and adverse events.
A blinded adjudication team identified all potential cardiovascular events from a broad list of SAEs and AEs, and requested source documentation for all relevant events
All potential cardiovascular events were adjudicated by two reviewers masked to treatment allocation; we categorized all deaths and adjudicated all non-fatal events
Endpoint Definitions: Solomon et al. NEJM 2005

9. Endpoints The following endpoints were adjudicated: Primary endpoint:
Death (cardiovascular or non-cardiovascular)
Myocardial Infarction
Stroke
Hospitalization for heart Failure
Thromboembolic event
Other cardiovascular
Primary endpoint:
CV death, MI, stroke, heart failure or thromboembolic event
We adjudicated the following endpoints: Death, which was classified as cardiovascular or noncardiovascular, myocardial infarction, stroke, hosp for heart failure, thromboembolic event, and other cardiovascular.
For the purposes of this analysis the primary endpoint was a composite of cardiovascular death, MI, stroke, Heart failure, or thromboembolic event.

10. Statistical Analysis Intention-to-treat
Time-to-event analyses for each study
Calculated incidence of each outcome, rate (per 1000 pt-yrs) by Rx group
Cox models and KM curves
Pooled (meta) analysis:
Estimated hazard ratios calculated from the average of the log-hazard ratio for each individual trial weighted by the inverse of its variance
Sensitivity of method assessed by standard Mantel-Haenszel pooled odds ratios and Cox models stratified by study.
Analyses adjusted for baseline cardiovascular risk
Pooled analyses assessed overall risk and dosing regimen-related risk
We performed an intention to treat, time to event analysis for each study,
and calculated the incidence of each outcome,
and generate Cox models and Kaplan Meier curves.
For the pooled analysis, we estimated hazard ratios calculated from the average of the log-hazard ratio for each individual trial weighted by the inverse of its variance,
and the sensitivity of this method was assessed by both standard mantel-haenzel pooled odds ratios and Cox models stratified by study.
We adjusted our analyses for baseline cardiovascular risk, and assessed both overall and dose-regimen related risk.

11. Dose and Baseline Risk Studies were grouped according to dose regimen:
400mg once daily (2 studies)
200mg twice daily (2 studies, 3 groups)
400mg twice daily (2 studies)
We tested for interaction between dose regimen and celecoxib risk
We created a 3-category risk score using a modified Framingham Risk model conforming to the availability of data from these studies:
Low: No known risk factor
Moderate: One of following , age > 75, hypertension, hyperlipidemia, current smoker, low-dose ASA
High: Diabetes, prior CV disease, or ≥ 2 risk factors in “moderate” category
Studies were grouped according to dose regimen
We tested for interaction between dose regimen and celecoxib risk
We created a 3-category risk score using a modified Framingham Risk model conforming to the availability of data from these studies, according to the following scheme:
Patients were consider Low risk if they had No known risk factor
Moderate risk if they had One of following , age > 75, hypertension, hyperlipidemia, current smoker, low-dose ASA
High risk if they had Diabetes, prior history of CV disease, or two or more of the risk factors in the “moderate” category

12. Placebo-Controlled Trials
Study N
Sponsor
Disease being Studied
Celecoxib Dose
Planned follow-up time
APC
2035
NCI and Pfizer
Colorectal polyps
Celecoxib 200mg BID,
celecoxib 400mg BID,
or placebo
3+ Years
PreSAP
1561
Pfizer
Colorectal Polyps
Celecoxib 400mg QD or placebo
MA27
1635
NCI, NCI Canada, & Pfizer
Breast Cancer Recurrence
celecoxib 400 mg BID or placebo
ADAPT
1809
NIA
Alzheimer’s disease and cognitive decline
Celecoxib 200mg BID or Naproxen sodium 220 mg BID, or placebo
Up to 7 years
CDME 86
NEI
Diabetic Retinopathy
Celecoxib 200mg BID or placebo
Cel/Sel
824
NCI
Celecoxib 400 mg QD or placebo
3-5 Years
The six trials studied are listed here and with the exception of the PreSAP trial were all sponsored or jointly sponsored by the National Institutes of Health.
The number of patients enrolled in each trial ranged from 86 in the CDME trial to 2035 in the APC trial.
Each of the trials were designed to study the role of celecoxib for a condition other than arthritis, and these included prevention of colorectal adenoma recurrence, breast cancer recurrence, alzheimer’s disease, and diabetic retinopathy.
The doses of celecoxib tested ranged from 400mg once daily in two studies, 200mg Twice Daily in 2 studies and 400 mg twice daily in two studies. Combined there were patient-years of follow-up.

13. Baseline Characteristics (%)
ADAPT
APC
CDME
MA27
PreSAP
Cel/Sel
Total
# enrolled
Pt-Years
1809
3530
2035
6234 86
101
1635
695
1561
4141
824
1369
7950
16070
Age, mean (SD)
75 ± 4
59 ± 10
59 ± 9
64 ± 9
60 ± 10
63 ± 9
64 ± 10
Male 54 68 62 66 50
White race 97 92 67 94 89 96 93
Diabetes
7.4
9.5
100
6.1 10
7.5
9.2
HTN or med 40 41 34 37 36 38
Hyperlipidemia or med 33 55 17 28
Current smoker 3 ? 24 16 14
Low-dose ASA use 31 45
Prior CV event 13
1.2 7 12
Low CV risk 32 19
Moderate CV risk 26 29 23 27
High CV risk 59 47 51
Baseline characteristics are shown here. Overall the mean age was 64, and ranged from 59 in the APC and CDME trials to 75 in the ADAPT study. Approximately half of the overall patients were male, the majority were caucasian. 9% of patients were diabetic; of note all of the patients in the retinopathy study were diabetic. 38% were hypertensive or on hypertensive medications; 28% were hyperlipidemic or on lipid lowering drugs;14% were current smokers. 31% were low-dose aspirin users. Based on our modified risk score, we categorized 28% of patients as low-risk, 27% as moderate risk, and 45% as high risk for CV events. There was some heterogeneity between the trials – most importantly, the ADAPT patients were older, by design, and the retinopathy study patients were all diabetic, also by design.

14. Event Numbers, Rates and Hazard Ratios
Events (Event Rate per 1000/pt-yrs)
Hazard Ratio
400mg QD
placebo
celecoxib
PreSAP
12/628 (7.2)
23/933 (9.4)
1.3 (0.6, 2.5)
Cel/Sel
8/410 (11.8)
7/414 (10.3)
0.9 (0.3, 2.4)
400mg QD Pooled
20/1038 (8.6)
30/1347 (9.6)
1.1 (0.6, 2.0)
200mg BID
ADAPT
18/1083 (8.6)
18/725 (12.8)
1.5 (0.8, 2.9)
APC
8/679 (3.9)
20/685 (9.7)
2.5 (1.1, 5.7)
200mg BID Pooled
29/1809 (6.9)
38/1450 (10.8)
1.8 (1.1, 3.1)
400mg BID
27/671 (13.4)
3.6 (1.6, 8.0)
MA-27
3/817 (8.7)
6/818 (17.2)
1.8 (0.4, 7.3)
400mg BID pooled
11/1496 (4.6)
33/1489 (13.9)
3.1 (1.5, 6.1)
Shown here are the event rates and hazard ratios for the individual trials, grouped by dose regimen. Of note, the CDME trial had a total of 3 events and very short follow-up time, so we performed all analyses with and without the CDME data included; the overall results were no different whether these data were included or not.
The two trials of the 400mg once daily dose, PreSAP and CEL/SEL had very similar hazard ratios, with a combined hazard ratio of 1.1, and 95% confidence interval ranging from 0.6 to 2.0;
The combined hazard ratio for the 200mg twice daily doses, ADAPT and APC, was 1.8, with a 95% confidence interval of 1.1 to 3.1
And the trials of the 400mg twice daily dose, APC and MA-27 had a combined hazard ratio of 3.1, with a 95% CI ranging from 1.5 to 6.1
*CDME Not included in this table because of extremely low event rates
Solomon et al. Circulation 2008

15. CV Death, MI, Stroke, HF or thrombo-embolic event
Hazard Associated with Celecoxib at Various Doses Stratified by Study and low-dose ASA use and Adjusted for Baseline CV Risk
400 mg bid
3.1 (1.5, 6.1)
Dose-regimen effect
P =
Regimen
1.8 (1.1, 3.1)
200 mg bid
Celecoxib
1.1 (0.6, 2.0)
400 mg qd
We tested for a dose-regimen response in a linear trend model which showed a significant trend for increased risk progressing from 400mg qd to 400 mg bid, with a p-value of
The overall risk associated with pooling all doses of celecoxib was 1.6, with 95% CI ranging from 1.1 to 2.3
1.6 (1.1, 2.3)
Overall
0.5
0.5
0.7
0.7
0.9
0.9 1 1 2 2 3 3 4 4 5 5 6 6
Hazard Ratio
CV Death, MI, Stroke, HF or thrombo-embolic event
Solomon et al. Circulation 2008

16. Composite Outcomes (Hazard ratio and 95% CI)
400mg QD
200mg BID
400mg BID
CV Death
0.5 (0.2, 1.7)
1.8 (0.5, 6.2)
6.5 (0.8, 54)
+ MI
1.0 (0.5, 2.1)
2.1 (1.0, 4.1)
3.4 (1.2, 9.6)
+Stroke
1.0 (0.5, 1.9)
1.6 (0.9, 3.0)
2.9 (1.3, 6.6)
+ HF
1.1 (0.6, 2.1)
1.7 (1.0, 3.1)
2.7 (1.3, 5.6)
+ Embolic event
1.1 (0.6, 2.0)
1.8 (1.1, 3.1)
3.1 (1.5, 6.1)
Any CV Event
1.3 (0.9, 1.9)
1.4 (1.0, 1.8)
1.6 (1.1, 2.3)
We tested for the robustness of our findings by examining other composite endpoints. We obtained qualitatively similar results whether we used a traditional ATPC endpoint of CV death, MI and stroke or by adding failure or thromboembolic events to the primary composite.
Stratified by study and baseline aspirin use and adjusted for baseline risk
Solomon et al. Circulation 2008

17. Celecoxib Regimen and Baseline Cardiovascular Risk
Baseline Risk – Dose Regimen Interaction p = 0.034
High Risk
High Risk
400 bid
400 bid
200 bid
200 bid
400
400 qd qd
Moderate Risk
400 bid
Celecoxib Regimen and pre-treatment Cardiovascular Risk
200 bid
400
400 qd qd
The overall event rate increased across the three baseline risk categories regardless of the use of celecoxib,
with a doubling of risk between the low and moderate risk groups and a further doubling of risk between the moderate and high risk groups.
We observed an interaction between baseline risk and dose with respect to outcomes. Patients in the low risk category showed the least effect of dose, and patients in the high risk category showed the greatest effect of dose, with an interaction p-value of
Low Risk
400 bid
200 bid
400qd
0.3
0.3
0.4
0.4
0.5
0.5
0.6
0.6
0.8
0.8 1 1 2 2 3 3 4 4 5 5 6 6 7 7
Hazard Ratio
CV Death, MI, Stroke, HF or Thromboembolic Event
Solomon et al. Circulation 2008

18. Prespecified Subgroups
P-Interaction
p = 0.37
p = 0.64
p = 0.54
p = 0.89
p = 0.17
p = 0.09
p = 0.40
p = 0.57
Non-Smoker
Current Smoker
No Diabetes
Diabetes
No Hyperlipidemia
Hyperlipidemia
No Hypertension
Hypertension
No CV Event
CV Event History
No Low Dose ASA
Low Dose ASA
Non-White
White
We observed no differential effect based on any of the prespecified subgroup comparisons, including smoking, diabetes, hypertension, hyperlipidemia, CV event history, race or gender. In particular, we did not observe an interaction with respect to low-dose aspirin use, although higher hazard ratios in the low-dose aspirin patients suggest that this characteristic is simply behaving as a surrogate of baseline risk.
Female
Male
0.3
0.4
0.6
0.8 1 2 3 4 5 6
Hazard Ratio
Solomon et al. Circulation 2008

19. Limitations and Caveats
None of the trials included in this analysis was designed or powered with the intent of assessing cardiovascular risk.
Doses tested higher than those typically used in osteoarthritis patients.
recommended doses in rheumatoid arthritis, acute pain and dysmenorrhea, FAP.
These data provide the strongest evidence of a dose-related risk
Data do not address the cardiovascular risk of doses lower than those tested.
Some limitations and caveats of this analysis should be noted.
None of the trials included in this analysis was designed or powered with the intent of assessing cardiovascular risk.
As a result, we used data collected for other purposes to assess the effect of celecoxib on cardiovascular outcomes.
The increased risk observed in this analysis needs to be considered in light of the high doses of celecoxib tested.
All the tested doses are higher than the doses of celecoxib typically used in osteoarthritis patients (recommended daily dose 200mg);
however, our data are directly relevant to doses recommended in the current celecoxib prescribing guidelines for patients with rheumatoid arthritis, acute pain and dysmennorhea, familial adenomatous polyposis, as well as doses currently being tested for non-arthritic conditions. Moreover, these data provide strong evidence of a dose and dose-regimen related risk.
Our data do not, however, address whether doses lower than those tested in any of these trials would lead to lower cardiovascular risk, or whether non-selective non-steroidal anti-inflammatory agents would be associated with similar risk. We must therefore be cautious in extrapolating these results to doses not tested.

20. Conclusions (1)
A pooled analysis of six randomized trials comparing celecoxib to placebo, with over 16,000 patient-years of follow-up, shows an overall increase in cardiovascular risk, with evidence for differences in risk based on the dose and dose-regimen of celecoxib.
The data showed evidence of an interaction between baseline cardiovascular risk and the effect of celecoxib, suggesting that patients at highest baseline risk had an increased relative risk for celecoxib-related adverse cardiovascular events.
In conclusion, A pooled analysis of six randomized trials comparing celecoxib to placebo, with over 16,000 patient-years of follow-up, shows an overall increase in cardiovascular risk, with evidence for differences in risk based on the dose and dose-regimen of celecoxib.
The data showed evidence of an interaction between baseline cardiovascular risk and the effect of celecoxib, suggesting that patients at highest baseline risk had an increased relative – and not just absolute - risk for celecoxib-related adverse cardiovascular events.

21. Conclusions (2)
That both the relative and absolute risks of cardiovascular events increases with baseline cardiovascular risk may provide more comfort in prescribing the drug in patients with very low baseline risk, and would argue for more caution in prescribing the drug in patients with higher baseline risk.
Since celecoxib, which currently carries an FDA-mandated black-box warning, remains the only coxib available in the United States, and is the most commonly used coxib worldwide, these data should help guide rational clinical decisions regarding celecoxib use.
That both the relative and absolute risks of cardiovascular events increases with baseline cardiovascular risk have important clinical implications; these data may provide a measure of comfort in prescribing celecoxib in patients with very low baseline risk, but would argue for caution in prescribing celecoxib in patients with higher baseline risk.
Since celecoxib, which currently carries an FDA-mandated black-box warning, remains the only coxib available in the United States, and is the most commonly used coxib worldwide, these data should help guide rational clinical decisions regarding celecoxib use.

23. Composite KM Curves Combined studies (excluding CDME)
0.050
Combined studies (excluding CDME)
0.045
Log-rank p-value (3 df) = 0.026
0.040
0.035
0.030
Probability of event
0.025
0.020
0.015
0.010
0.005
0.000 6 12 18 24 30 36
Sample size
Months of follow-up
C 400 bid
1489
990
714
654
648
645
641
C 200 bid
1411
1342
1258
1157
1033
894
768
C 400 QD
1347
1231
1134
1042
939
841
514
Placebo
3617
2943
2453
2168
1894
1598
1196