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Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs

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. Purpose and Methods.

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Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs

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  1. 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. Purpose and Methods • To evaluate epidemiologic data from the published literature plus 2 currently unpublished studies evaluated by this reviewer • Focus: studies providing estimates of risk of acute myocardial infarction in the setting of use of COX-2 selective NSAIDs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. 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. Overview of Epidemiologic Studies on COX-2 AMI Risk (1) Source Ref Popln Person-Yrs StudyPoplnDesignGroupSizeObservedAge 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. Overview of Epidemiologic Studies on COX-2 AMI Risk (2) Number of Cases Case Rofecoxib Celecoxib StudyDefnCasesAll doses25 mg>25 mgAll 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. Overview of Epidemiologic Studies on COX-2 AMI Risk (3) Special StudyAspirinSmokingFeaturesLimitations 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. 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. Unmeasured CV Risk Factors and NSAID Use Graham CelecoxibRofecoxibNaproxenRemote Aspirin 19% 23% 28% 24% Smoking 9% 7% 11% 11% OTC NSAIDs 15% 14% 12% 13% Solomon CelecoxibRofecoxibNSAIDs 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 Kimmel CelecoxibRofecoxibNSAIDsRemote 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. Risk of AMI with Rofecoxib StudyRefAll 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. Preliminary Results: Medi-Cal Study Dose Response for AMI Risk with Rofecoxib Odds Ratio 2.40 1.54 1.31 1.16 Singh et al.

  11. Risk of AMI for Rofecoxib vs Celecoxib Rofecoxib StudyAll 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. 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 estimate95% 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. 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. 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 1-30 Solomon et al. 1.43 (1.12-1.83) Ingenix 1.51 (0.98-2.34)

  15. Risk of AMI with Celecoxib Relative Risk

  16. Risk of AMI with Celecoxib – the effect of dose Relative Risk

  17. Preliminary DataRisk 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. Overview of Epidemiologic Studies on Naproxen AMI Risk (1) Source Ref Person-Yrs StudyPoplnDesignGroupObservedAge 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. Overview of Epidemiologic Studies on Naproxen AMI Risk (2) Case Naproxen StudyDefnAspirinSmokingCases 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* Yes26* Ingenix +SCD No No 179* Medi-Cal HAMI Yes No 368

  20. 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

  21. Risk of AMI with Naproxen Relative Risk

  22. A Closer Look at 4 “Positive” Naproxen Studies Rahme Current naproxen vsother NSAIDs: 0.79 (0.63-0.99) Reanalyzed, current naproxen vsnonuse: 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 Solomon Any useCurrent useRecent useRemote 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 AgeSexYrDMCVriskComorbSmokeDMARDsSteroids 0.61 (0.39-0.94) + + + + + + 0.57 (0.31-1.06) + + + + + + 0.53 (0.22-1.28) + + + + + +

  23. Preliminary Data: Medi-Cal StudyOther 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. Dose-Response Relationship of AMI risk with NSAIDs Odds Ratio

  25. 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)

  26. 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. 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. Open Questions • Differential NSAID risk • Dose response • Duration effect • Persistency of risk • Actual benefit in the population • CHF • Stroke

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