Department of Health and Human Services
Center for Drug Evaluation and Research
Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs
David J. Graham, MD, MPH
Office of Drug SafetyCenter for Drug Evaluation and Research
February 17, 2005
Department of Health and Human Services
Center for Drug Evaluation and Research
Purpose and Methods
• To evaluate epidemiologic data from the published literature plus 2 currently unpublished studies evaluated by this reviewer
• Focus: studies providing estimates of risk of acute myocardial infarction in the setting of use of COX-2 selective NSAIDs or naproxen– PubMed search by specific NSAID, with cross-checking of
cited references
Department of Health and Human Services
Center for Drug Evaluation and Research
Comments on Estimation of Excess Cases of AMI
• Tomorrow, FDA will present its estimation of the number harmed by rofecoxib, modeling RCT survival curves
• Assumes “grace period” based on VIGOR & APPROVe– Unreliable due to extremely low statistical power– Based on total of small # MI events over duration of trial– Epi studies based on 3- to 50-fold more events: more power
– Based on epi data, rofecoxib risk begins early in therapy
– No “grace period”
• Patients enrolled in RCTs are generally healthier than “real-world”– Therefore, RCTs will underestimate true risk and population
impact because their background rate is lower
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on COX-2 AMI Risk (1)
Source Ref Popln Person-Yrs Study Popln Design Group Size Observed Age
Ray Medicaid Cohort Nonuse 454 K 428 K 50-84
Graham HMO NCC Remote 1.4 M 2.3 M 18-84 Celecoxib Solomon Medicare CC Multiple 54 K - 65
Mamdani Ontario Cohort Nonuse 167 K 76 K 66
Kimmel Community CC Remote - - 40-75
Ingenix MCO Cohort Ibu/Diclo 424 K 177 K 40-64
Medi-Cal Medicaid NCC Remote 651 K 2.4 M 18-84
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on COX-2 AMI Risk (2)
Number of Cases Case Rofecoxib CelecoxibStudy Defn Cases All doses 25 mg >25 mg All doses
Ray +SCD 5,316 68 55 13 74
Graham +SCD 8,143 68 58 10 126
Solomon HAMI 10,895 225 202 23 425
Mamdani HAMI 701 58 - - 75
Kimmel HAMI* 1,718 27 25 2 18
Ingenix +SCD 628* 124* 83* 9* 139*
Medi-Cal HAMI 15,343 1,117 960 157 1,862
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on COX-2 AMI Risk (3)
SpecialStudy Aspirin Smoking Features Limitations
Ray No No New-user analysis Low rofecoxib use; no med recs possible dose misclassification
Graham No* No* Inception cohort Low rofecoxib use; *Survey of controls
Solomon No No Duration analysis No SCD; multiple comparisons; Beneficiary survey no med recs; possible dose misclassification
Mamdani No No - Low rofecoxib use; prevalence cohort; excluded < 30 d users; no SCD; no dose/duration analysis; no med recs
Kimmel Yes Yes Direct interview Low rofecoxib use, very low high dose use; 55% case/50% control participation; no fatal AMI or SCD; self-report-?recall bias
Ingenix No No NDI search Identified 1798 cases; included only 628; New-user analysis no non-user reference; low high-dose use; Med record review possible dose misclassification
Medi-Cal Yes No Inception cohort New database for research purposes; no med recs; possible dose misclassification
Department of Health and Human Services
Center for Drug Evaluation and Research
California Medicaid
• Strengths
– Large sample size – over 7 million persons per year
– OTC aspirin data
– No censoring at age 65 (dual coverage with Medicare)
– Matching with multiple cause-of-death data
– Long durations of follow-up with low drop-out rates
– Sicker population than private-payors, so easier to detect drug safety
signals
• Limitations
– No access to medical records (HIPAA)
– Very complicated data – difficult to understand and analyze. Therefore, not
used often for drug safety research.
Department of Health and Human Services
Center for Drug Evaluation and Research
Unmeasured CV Risk Factors and NSAID Use
Graham Celecoxib Rofecoxib Naproxen Remote Aspirin 19% 23% 28% 24%
Smoking 9% 7% 11% 11%OTC NSAIDs 15% 14% 12% 13%
Solomon Celecoxib Rofecoxib NSAIDsBMI 27.5 27.2 27.7Aspirin 8.2% 11.5% 10.2%Smoking 8.7% 7.0% 9.8%College+ 29.6% 31.8% 26.5%Income Same Same Lower
Kimmel Celecoxib Rofecoxib NSAIDs RemoteBMI 29.7 28.0 27.7 27.2Aspirin 27.6% 32.1% 21.7% 28.8%Smoking Current 17.2% 6.5% 19.9% 21.2% Past 43.7% 42.9% 31.8% 32.0%Physical activity 7.0 7.2 7.4 7.4
Department of Health and Human Services
Center for Drug Evaluation and Research
Risk of AMI with Rofecoxib
Study Ref All doses 25 mg >25 mg
Ray Non - 1.02 (0.76-1.37) 1.93 (1.09-3.43)
Graham Rem 1.34 (0.98-1.82) 1.23 (0.89-1.71) 3.00 (1.09-8.31)
Solomon Rem 1.14 (1.00-1.31) - -
Mamdani Non 1.00 (0.80-1.40) - -
Kimmel Rem 1.16 (0.70-1.93) - -
Ingenix Active 1.41 (1.07-1.84) 1.54 (1.15-2.04) 0.81 (0.41-1.60)*
Medi-Cal Rem 1.32 (1.22-1.42) 1.29 (1.19-1.40) 1.56 (1.28-1.90)
Department of Health and Human Services
Center for Drug Evaluation and Research
Preliminary Results: Medi-Cal Study Dose Response for AMI Risk with Rofecoxib
0
1
2
3
4
5
6
7
8
Rofecoxib <= 12.5mg
Rofecoxib 12.5 -25 mg
Rofecoxib 25 - 50mg
Rofecoxib > 50 mg
Od
ds
Rat
io
1.161.31
1.54
2.40
Singh et al.
Department of Health and Human Services
Center for Drug Evaluation and Research
Risk of AMI for Rofecoxib vs Celecoxib
RofecoxibStudy All doses 25 mg >25 mg
Ray - - 2.20 (1.17-4.10)
Graham 1.59 (1.10-2.32) 1.47 (0.99-2.17) 3.58 (1.27-10.11)
Solomon 1.24 (1.05-1.46) 1.21 (1.01-1.44) 1.70 (1.07-2.71)
Kimmel 2.72 (1.24-5.95) - -
Medi-Cal 1.22 (1.11-1.33) - -
Department of Health and Human Services
Center for Drug Evaluation and Research
Individual Excess Risk of AMI or SCD per Year from Rofecoxib Use for an Average 65-74 Year Old US Man, based on
Epidemiolgic Data
Based on Based onpoint estimate 95% upper bound
25 mg
Ray 1/2500 1/135Graham 1/217 1/70Ingenix 1/93 1/48Medi-Cal 1/172 1/125
>25 mg
Ray 1/54 1/21Graham 1/25 1/7Medi-Cal 1/89 1/56
Department of Health and Human Services
Center for Drug Evaluation and Research
Excess Population Risk of AMI or SCD in 1 Million US Men 65-74 Years Old Treated with Rofecoxib per Year, Based on
Epidemiolgic Data
Based on Based onpoint estimate upper 95% bound
25 mg
Ray 400 7,400Graham 4,600 14,200Ingenix 10,800 20,800Medi-Cal 5,800 8,000
>25 mg
Ray 18,600 48,000Graham 40,000 146,200Medi-Cal 11,200 18,000
Department of Health and Human Services
Center for Drug Evaluation and Research
AMI Risk with Rofecoxib and Duration of Use
Graham et al. 50% 75% 95% 25 mg <2 m 5 m 13 m >25 mg <3 m 6 m 9 m
Solomon et al. Days 1-90 25 mg 1.37 (1.15-1.63) >25 mg 1.38 (0.80-2.37)
Kimmel et al. 25/27 cases 25 mg 102/105 patients 12 m
Days 1-30Solomon et al. 1.43 (1.12-1.83) Ingenix 1.51 (0.98-2.34)
Department of Health and Human Services
Center for Drug Evaluation and Research
Risk of AMI with Celecoxib
0.2
0.4
0.6
0.8
1
1.2
1.4
Ray Graham Solomon Mamdani Kimmel
Rel
ati
ve
Ris
k
Department of Health and Human Services
Center for Drug Evaluation and Research
Risk of AMI with Celecoxib – the effect of dose
0.6
0.8
1
1.2
1.4
1.6
1.8
Ingenix All Ingenix 200 mg Ingenix 400 mg MediCal All MediCal <=200mg
MediCal >200mg
Rel
ati
ve
Ris
k
Department of Health and Human Services
Center for Drug Evaluation and Research
Preliminary DataRisk of AMI with Valdecoxib
# cases OR (95% CI)
Medi-Cal 54 0.99 (0.72-1.37)
Mostly 10 and 20 mg. Medi-Cal only reimburses 10 mg tabs
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on Naproxen AMI Risk (1)
Source Ref Person-Yrs Study Popln Design Group Observed Age
Ray Medicaid Cohort Nonuse 428 K 50-84
Graham HMO NCC Remote 2.3 M 18-84
G Rodriguez GPRD NCC Nonuse - 50-84
Rahme Quebec NCC Other NSAIDs - 65
Mamdani Ontario Cohort Nonuse 76 K 66
Schlienger GPRD NCC Nonuse - 18-75
Kimmel Community CC Remote - 40-75
Solomon Medicaid/Medicare CC Remote - -
Watson GPRD NCC Nonuse - 40-79
Ingenix MCO Cohort Ibu/Diclo 177 K 40-64
Medi-Cal Medicaid NCC Remote 52 K 18-84
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on Naproxen AMI Risk (2)
Case NaproxenStudy Defn Aspirin Smoking Cases
Ray +SCD No No 201
Graham +SCD No* No* 367
G Rodriguez +SCD No Yes 49
Rahme HAMI Yes* No 397
Mamdani HAMI No No 15
Schlienger HAMI No Yes 19
Kimmel HAMI* Yes Yes ?
Solomon HAMI No No ?
Watson Composite No* Yes 26*
Ingenix +SCD No No 179*
Medi-Cal HAMI Yes No 368
Department of Health and Human Services
Center for Drug Evaluation and Research
Overview of Epidemiologic Studies on Naproxen AMI Risk (3)
Study Limitations
Ray Poisson assumption of constant hazard
G Rodriguez Definition of current exposure included potentially unexposed time (Rx ended within 30d of index date)
Rahme Excluded past AMI; relied on current exposure to another NSAID as reference; no external reference
Schlienger Small # events; excluded patients with underlying CV disease
Kimmel 2o or 3o analysis; small # events
Solomon Misclassified exposure (any exposure in past 6 mos); excluded patients with CV risk; adjustment based on diagnoses rather than Rxs
Watson Small # events; excluded prior CV disease & Rxs; composite outcome (AMI, CVA, SAH, SDH); failed to adjust, or poorly adjusted for CV risk
Department of Health and Human Services
Center for Drug Evaluation and Research
Risk of AMI with Naproxen
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Ray Graham Rodriguez Mamdani Schlienger Ingenix MediCal
Rel
ati
ve
Ris
k
Department of Health and Human Services
Center for Drug Evaluation and Research
A Closer Look at 4 “Positive” Naproxen Studies
Solomon
Any use Current use Recent use Remote use
0.84 (0.72-0.98) 0.86 (0.64-1.16) 0.84 (0.63-1.12) 0.76 (0.56-1.03)
Watson Age Sex Yr DM CVrisk Comorb Smoke DMARDs Steroids 0.61 (0.39-0.94) + + + + + + 0.57 (0.31-1.06) + + + + + + 0.53 (0.22-1.28) + + + + + +
Rahme
Current naproxen vs other NSAIDs: 0.79 (0.63-0.99)
Reanalyzed, current naproxen vs nonuse: 1.28 (1.10-1.49), p=.001
Kimmel
0.48 (0.32-0.73) Small #s; 50% participation rate; mixing of Rx & OTC use; “reverse” recall bias
Department of Health and Human Services
Center for Drug Evaluation and Research
Preliminary Data: Medi-Cal StudyOther NSAIDs
# cases OR (95% CI)
Ibuprofen 719 1.11 (1.01-1.22)
Indomethacin 109 1.71 (1.35-2.17)
Meloxicam 81 1.37 (1.05-1.78)
Nabumetone 51 0.83 (0.60-1.14)
Sulindac 56 1.41 (1.01-1.96)
Non-coxib NSAIDs 2,006 1.12 (1.06-1.19)
Department of Health and Human Services
Center for Drug Evaluation and Research
Dose-Response Relationship of AMI risk with NSAIDs
0.5
1
1.5
2
2.5
Cel
eco
xib
<=
200
mg
Cel
eco
xib
> 2
00m
g
Dic
lofe
nac
<=
150
mg
Dic
lofe
nac
> 1
50m
g
Nap
roxe
n <
=10
00 m
g
Nap
roxe
n >
100
0m
g
Ro
feco
xib
<=
25
mg
Ro
feco
xib
> 2
5m
g
Od
ds
Rat
io
Department of Health and Human Services
Center for Drug Evaluation and Research
Preliminary Data: Medi-Cal StudyRisk of AMI Compared to Non-Coxib NSAIDs
OR (95% CI)
Celecoxib 0.97 (0.90-1.05)
Rofecoxib 1.18 (1.07-1.29)
Valdecoxib 0.88 (0.64-1.22)
Department of Health and Human Services
Center for Drug Evaluation and Research
Conclusions Regarding Risk of Acute MI:COX-2 Selective NSAIDs
• Celecoxib 200 mg: no apparent effect• > 200 mg: probable increased risk
• Rofecoxib 25 mg: probable increased risk• >25 mg: definite increased risk• Risk begins early in therapy, and is
apparent during days 1-30 of use
• Valdecoxib 20 mg: no apparent effect
Department of Health and Human Services
Center for Drug Evaluation and Research
Conclusions Regarding Risk of Acute MI:“Non-selective” NSAIDs
• As a class, non-coxib NSAIDs may increase risk
• Differences exist between non-coxib NSAIDs with respect to risk
• Naproxen is not cardio-protective
Department of Health and Human Services
Center for Drug Evaluation and Research
Open Questions
• Differential NSAID risk
• Dose response
• Duration effect
• Persistency of risk
• Actual benefit in the population
• CHF
• Stroke