Analysis of Cardiovascular Thromboembolic Events With Etoricoxib

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Analysis of Cardiovascular Thromboembolic Events
With Etoricoxib

• Joel Schiffenbauer, M.D.
• DAAODP, ODE V
• February 17, 2005

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Etoricoxib

• NDA indications include OA, CLBP, RA, AS, acute
  gout, acute pain, dysmenorrhea
• Proposed doses 60 and 90 mg chronically and 120
  mg acutely
• EDGE study Etoricoxib vs. Diclofenac Sodium
  Gastrointestinal Tolerability and Effectiveness

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Etoricoxib

• Exposure
• Mortality data
• CV/TE data
• NDA
• EDGE

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Etoricoxib

• Exposure

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Chronic Exposure to Etoricoxib Across the NDA
Dose of etoricoxib Total number of patients Mean number of days on drug
lt60 mg 535 145
60 1193 390
90 1736 361
120 1052 314
gt120 35 5.4
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EDGE Study
Etoricoxib 90 mg (N3593) Etoricoxib 90 mg (N3593) Diclofenac 150 mg (N3518) Diclofenac 150 mg (N3518) Total (N7111)
Duration of study therapy (months) Duration of study therapy (months) Duration of study therapy (months) Duration of study therapy (months) Duration of study therapy (months) Duration of study therapy (months)
Mean Mean 9.3 8.9 9.1 9.1
SD SD 4.4 4.5 4.5 4.5
Median Median 11.5 11.3 11.4 11.4
Range Range 0.5 to 16.5 0.5 to 16.6 0.5 to 16.6 0.5 to 16.6
Total patient years Total patient years 2789 2604 5393 5393
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Etoricoxib

• Mortality Data

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NDA/Deaths(rates are per 100 PYR)
Placebo PYR360 Etoricoxib PYR4129 Non-naproxen PYR527 Naproxen PYR1728
Total deaths 1 (rate 0.28) 20 (0.48) 2 (0.38) 5 (0.29)
CV Deaths 0 (0) 10 (0.24) 2 (0.38) 3 (0.17)
Thrombotic CV Deaths 0 (0) 9 (0.22) 2 (0.38) 2 (0.12)
Non-CV Deaths 1 (0.28) 10 (0.24) 0 (0) 2 (0.12)
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EDGE/Deaths
ETORICOXIB (2792 pt-yrs) DICLOFENAC (2608 pt yrs)
TOTAL 8 6
CV THROMBOTIC 3 1
CVA (hemorrhagic) 1 2
NEOPLASM 2 3
Other 2 (endocarditis, hemorrhagic shock) 0
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Etoricoxib

• CV/TE Events in NDA

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Serious Adverse Events Included in Thrombotic CV
SAEs

• Cardiac
• Acute MI
• Fatal MI
• Unstable angina
• Sudden death
• Peripheral
• Pulmonary embolism
• Fatal PE
• Peripheral arterial or venous thrombosis
• Cerebrovascular
• Ischemic cerebrovascular stroke
• Fatal stroke
• TIA

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NDA/Absolute Rate Relative Risk
Comparisons N Cases/PYR Rate Relative risk (95 CI)
Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events
Etoricoxib Placebo 2818 1767 7/560 4/335 1.25 1.19 1.11 (0.32, 3.81)
Etoricoxib Non-naproxen NSAIDs 1266 718 12/1522 4/501 0.79 0.80 0.83 (0.26, 2.64)
Etoricoxib Naproxen 1960 1497 34/2480 14/1727 1.37 0.81 1.70 (0.91, 3.18)
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NDA/Absolute Rate Relative Risk
Comparisons Comparisons N Cases/PYR Rate Relative risk (95 CI)
Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events
Etoricoxib Placebo 2818 1767 2818 1767 7/560 4/335 1.25 1.19 1.11 (0.32, 3.81)
Etoricoxib Non-naproxen NSAIDs 1266 718 1266 718 12/1522 4/501 0.79 0.80 0.83 (0.26, 2.64)
Etoricoxib Naproxen 1960 1497 1960 1497 34/2480 14/1727 1.37 0.81 1.70 (0.91, 3.18)
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NDA/Placebo
Endpoint terms Etoricoxib Etoricoxib Placebo Placebo
Endpoint terms PYR560 PYR560 PYR335 PYR335
Endpoint terms N Rate (per 100 PYR) N Rate
Patients with one or more thrombotic CV SAEs 7 1.25 4 1.19
Cardiac (MI, fatal MI, unstable angina, sudden death) 4 0.71 0 0
Peripheral 1 0.18 2 0.60
Cerebrovascular (ischemic stroke) 3 0.54 2 0.60
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NDA (KM Estimates for CV Events)
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NDA/Absolute Rate Relative Risk
Comparisons N Cases/PYR Rate Relative risk (95 CI)
Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events
Etoricoxib Placebo 2818 1767 7/560 4/335 1.25 1.19 1.11 (0.32, 3.81)
Etoricoxib Non-naproxen NSAIDs 1266 718 12/1522 4/501 0.79 0.80 0.83 (0.26, 2.64)
Etoricoxib Naproxen 1960 1497 34/2480 14/1727 1.37 0.81 1.70 (0.91, 3.18)
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NDA/Non-naproxen NSAIDs
Endpoint etoricoxib etoricoxib combined combined diclofenac diclofenac ibuprofen ibuprofen
Endpoint PYR1522 PYR1522 PYR501 PYR501 PYR447 PYR447 PYR54 PYR54
Endpoint N Rate N Rate N Rate N Rate
Patients with one or more thrombotic CV SAE 12 0.79 4 0.80 4 0.89 0 0
Cardiac 11 0.72 2 0.40 2 0.45 0 0
MI 3 0.20 0 0 0 0
Fatal MI 2 0.13 1 0.14 1 1
Sudden Death 2 0.13 1 0.14 1 1
Unstable Angina 4 0.26 0 0 0 0
Cerebrovascular Ischemic stroke TIA 2 0.13 2 0.40 2 0.45 0 0
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NDA/KM
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NDA/Absolute Rate Relative Risk
Comparisons N Cases/PYR Rate Relative risk (95 CI)
Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events Confirmed thrombotic CV serious adverse events
Etoricoxib Placebo 2818 1767 7/560 4/335 1.25 1.19 1.11 (0.32, 3.81)
Etoricoxib Non-naproxen NSAIDs 1266 718 12/1522 4/501 0.79 0.80 0.83 (0.26, 2.64)
Etoricoxib Naproxen 1960 1497 34/2480 14/1727 1.37 0.81 1.70 (0.91, 3.18)
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NDA/Naproxen
Endpoint Etoricoxib Etoricoxib Naproxen Naproxen
Endpoint PYR2480 PYR2480 PYR1727 PYR1727
Endpoint N Rate N Rate
Patients with one or more thrombotic CV SAE 34 1.37 14 0.81
Cardiac 21 0.85 9 0.52
MI 10 0.40 5 0.29
Fatal MI 2 0.08 1 0.07
Sudden Death 3 0.12 0 0
Unstable Angina 6 0.24 3 0.17
Peripheral 2 0.08 5 0.29
Cerebrovascular 12 0.48 2 0.12
Ischemic Stroke 10 0.40 0 0
Fatal Ischemic Stroke 0 0 1 0.06
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NDA/KM
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Etoricoxib

• CV Events in EDGE Study

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EDGE

• 7000 patient GI tolerability study collect CV
  data non-inferiority to diclofenac (upper limit
  of 95 CI for hazard ratio is 1.3)
• Issues
• Non-inferiority trial (no placebo)
• diclofenac only comparator
• only OA, no RA
• ASA use (30)
• previous Cox-2 use allowed (15 rofecoxib
• 13 celecoxib 5 valdecoxib)
• 2600 with gt2 CV risk factors

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EDGE/KM Estimates
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EDGE/Confirmed Thrombotic CV SAEs
Endpoint Etoricoxib Etoricoxib Diclofenac Diclofenac
Endpoint PYR2789 PYR2789 PYR2607 PYR2607
Endpoint N Rate N Rate
Patients with one or more thrombotic CV SAE 35 1.25 30 1.15
Cardiac 27 0.93 19 0.73
MI 19 0.65 11 0.42
Sudden Death 2 0.07 1 0.04
Unstable Angina 6 0.22 7 0.27
Peripheral 3 0.11 4 0.15
Cerebrovascular 7 0.25 7 0.27
Ischemic Stroke 3 0.11 6 0.23
Fatal Ischemic Stroke 1 0.04 0 0
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EDGE/ASA Users Combined
Etoricoxib Diclofenac
Number of Events Number of Events
Cardiac MI MI plus unstable angina CNS PVS Cardiac plus CNS 12 7 11 4 1 16 9 5 9 3 1 12
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EDGE/Non-ASA Users Combined
Etoricoxib Diclofenac
Number of events Number of events
Cardiac MI MI plus unstable angina CNS PVS Cardiac plus CNS 15 12 14 3 2 18 10 6 9 4 3 14
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EDGE/Hypertension
Etoricoxib 90 mg N3593 Etoricoxib 90 mg N3593 Diclofenac 150 mg N3518 Diclofenac 150 mg N3518
n n
Hypertension Hypertension Hypertension Hypertension Hypertension
Number () of patients With serious hypertension related AE With a hypertension related AE associated with systolicgt180 mm Hg or diastolic gt110 mm Hg 5 69 (0.14) (1.9) 2 30 (0.05) (0.9)
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EDGE/Hypertension
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EDGE/CHF
Adverse Experience Etoricoxib Diclofenac
Adverse Experience N () N ()
Incidence of CHF, pulmonary edema-related, or cardiac failure Cardiac failure Cardiac failure congestive 14 (0.4) 1 (0) 12 (0.3) 6 (0.2) 0 (0) 6 (0.2)
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Summary

• In NDA, etoricoxib trends worse in terms of CV/TE
  particularly cardiac/MI
• Comparisons of etoricoxib to naproxen for CV/TE
  events are similar to rofecoxib/naproxen
  comparisons
• Trial design concerns in EDGE (2 ongoing trials
  of similar design)
• Trends in EDGE for cardiac events worse for
  etoricoxib, mainly in non-ASA users