1. 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 Safety Center for Drug Evaluation and Research February 17, 2005

2. 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and Research Purpose and Methods To evaluate epidemiologic data from the published literature plus 2 currently unpublished studies evaluated by this reviewer Focus: studies providing estimates of risk of acute myocardial infarction in the setting of use of COX-2 selective NSAIDs or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

3. 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

4. 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

5. 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 Celecoxib Study 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

6. Department of Health and Human Services Center for Drug Evaluation and Research Overview of Epidemiologic Studies on COX-2 AMI Risk (3) Special Study 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

7. 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.

8. Department of Health and Human Services Center for Drug Evaluation and Research Unmeasured CV Risk Factors and NSAID Use GrahamCelecoxib Rofecoxib Naproxen Remote Aspirin 19% 23% 28% 24% Smoking 9% 7% 11% 11% OTC NSAIDs 15% 14% 12% 13% SolomonCelecoxib Rofecoxib NSAIDs BMI 27.5 27.2 27.7 Aspirin 8.2% 11.5% 10.2% Smoking 8.7% 7.0% 9.8% College+ 29.6% 31.8% 26.5% Income Same Same Lower KimmelCelecoxib Rofecoxib NSAIDs Remote BMI 29.7 28.0 27.7 27.2 Aspirin 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

9. 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)

10. Department of Health and Human Services Center for Drug Evaluation and Research Preliminary Results: Medi-Cal Study Dose Response for AMI Risk with Rofecoxib Odds Ratio 1.16 1.31 1.54 2.40 Singh et al.

11. Department of Health and Human Services Center for Drug Evaluation and Research Risk of AMI for Rofecoxib vs Celecoxib Rofecoxib Study 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) - -

12. 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 on point estimate 95% upper bound  25 mg Ray 1/2500 1/135 Graham 1/217 1/70 Ingenix 1/93 1/48 Medi-Cal 1/172 1/125 >25 mg Ray 1/54 1/21 Graham 1/25 1/7 Medi-Cal 1/89 1/56

13. 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 on point estimateupper 95% bound  25 mg Ray 400 7,400 Graham 4,600 14,200 Ingenix 10,800 20,800 Medi-Cal 5,800 8,000 >25 mg Ray 18,600 48,000 Graham 40,000 146,200 Medi-Cal 11,200 18,000

14. 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 mg1.37 (1.15-1.63) >25 mg1.38 (0.80-2.37) Kimmel et al. 25/27 cases  25 mg 102/105 patients  12 m Days 1-30 Solomon et al. 1.43 (1.12-1.83) Ingenix 1.51 (0.98-2.34)

15. Department of Health and Human Services Center for Drug Evaluation and Research Risk of AMI with Celecoxib Relative Risk

16. Department of Health and Human Services Center for Drug Evaluation and Research Risk of AMI with Celecoxib – the effect of dose Relative Risk

17. Department of Health and Human Services Center for Drug Evaluation and Research Preliminary Data Risk of AMI with Valdecoxib # casesOR (95% CI) Medi-Cal 54 0.99 (0.72-1.37) Mostly 10 and 20 mg. Medi-Cal only reimburses 10 mg tabs

18. 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

19. Department of Health and Human Services Center for Drug Evaluation and Research Overview of Epidemiologic Studies on Naproxen AMI Risk (2) Case Naproxen Study 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

20. 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 2 o or 3 o 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

21. Department of Health and Human Services Center for Drug Evaluation and Research Risk of AMI with Naproxen Relative Risk

22. 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

23. Department of Health and Human Services Center for Drug Evaluation and Research Preliminary Data: Medi-Cal Study Other NSAIDs # casesOR (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)

24. Department of Health and Human Services Center for Drug Evaluation and Research Dose-Response Relationship of AMI risk with NSAIDs Odds Ratio

25. Department of Health and Human Services Center for Drug Evaluation and Research Preliminary Data: Medi-Cal Study Risk of AMI Compared to Non-Coxib NSAIDs OR (95% CI) Celecoxib0.97 (0.90-1.05) Rofecoxib1.18 (1.07-1.29) Valdecoxib0.88 (0.64-1.22)

26. 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

27. 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

28. 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