cox 2 cv safety valdecoxib parecoxib
Download
Skip this Video
Download Presentation
COX-2 CV Safety valdecoxib-parecoxib

Loading in 2 Seconds...

play fullscreen
1 / 33

COX-2 CV Safety valdecoxib-parecoxib - PowerPoint PPT Presentation


  • 96 Views
  • Uploaded on

COX-2 CV Safety valdecoxib-parecoxib. James Witter MD, PhD DAAODP/ODE V February 16, 2005. Bextra (valdecoxib). Original NDA (January 15, 2001) 60 studies Phase 1-2: 31 studies Arthritis (OA/RA): 10 studies Included open-label exposure Post-surgical analgesia: 19 studies CABG 035

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' COX-2 CV Safety valdecoxib-parecoxib' - evania


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
cox 2 cv safety valdecoxib parecoxib

COX-2 CV Safetyvaldecoxib-parecoxib

James Witter MD, PhD

DAAODP/ODE V

February 16, 2005

bextra valdecoxib
Bextra (valdecoxib)
  • Original NDA (January 15, 2001)
    • 60 studies
      • Phase 1-2: 31 studies
      • Arthritis (OA/RA): 10 studies
        • Included open-label exposure
      • Post-surgical analgesia: 19 studies
        • CABG 035
  • Original approval did not contain sulfonamide warning
    • Addressed by subsequent label changes and DHCP letters
valdecoxib oa and ra exposure pt yrs
Valdecoxib - OA and RA Exposure (pt-yrs)

From Medical Officer review: November 7, 2001

valdecoxib deaths
Valdecoxib - Deaths
  • Total of 22 deaths in NDA
    • 17 occurred during double-blind studies
      • 4 in CABG trials (discussed in parecoxib data)
        • 2 were CV related
      • 8 in patients receiving valdecoxib
        • 4 were CV related
      • 3 in patients receiving NSAIDs
        • 2 were CV related
      • 2 non-CV deaths occurred in cancer pain trial
    • 5 during open-label studies
      • 3 were CV related
valdecoxib cv safety special analysis
Valdecoxib - CV SafetySpecial Analysis

Rates of Serious Thromboembolic CV Adverse Events Calculated for High- and At-risk Patients:

  • High-risk patients:

- angina, myocardial infarction, coronary artery disease and cerebrovascular accident

  • At-risk patients:

- hypertension, hyperlipidemia or smoking

  • FDA-defined endpoints:

- MI, myocardial ischemia, unstable angina, cardiac arrest, sudden cardiac death, CVA/TIA, PE, venous thrombosis, embolism, peripheral gangrene and peripheral ischemia

valdecoxib cv safety high risk patients
Valdecoxib - CV safetyHigh Risk Patients

From Medical Officer review (Nov. 7, 2001)

All valdecoxib groups: incidence = 1.3%; events/100 pt-yrs = 4.6%

valdecoxib cv safety at risk patients
Valdecoxib - CV safetyAt Risk Patients

From Medical Officer review (Nov. 7, 2001)

All valdecoxib groups: incidence = 0.4%; events/100 pt-yrs = 1.2%

cv adverse events study 047 6 month oa ra
CV Adverse Events - Study 0476-month (OA/RA)
  • Table 2.3b.2 and 7.0.1: 6/25/01 consult. Labeled doses for OA/RA = 10 mg QD.
  • P < 0.05
parecoxib
Parecoxib
  • Parenteral precursor to valdecoxib
    • T1/2 = 15-30 minutes
  • Allows exposure to different patient population with different risk factors
  • Intended to address the issues
    • multi-modal analgesia
      • COX-2 role in pain
    • pre-emptive analgesia
    • opioid sparing
  • Certain studies conducted with valdecoxib
    • CABG studies
parecoxib1
Parecoxib
  • Original NDA (September 11, 2000)
    • 36 studies
      • Phase 1-2: 14 studies
      • GI-renal-platelet: 7 studies
      • Post-surgical analgesia: 8 studies
      • Pre-operative analgesia: 4 studies
      • Opioid-sparing analgesia: 2 studies
        • CABG-035
      • Long-term safety (with valdecoxib): 1 study
parecoxib cabg i 035
Parecoxib - CABG I (035)
  • First time via median sternotomy
  • 2:1 randomization
      • 311 parecoxib
      • 151 placebo (standard-of-care; PCA/opioids)
  • Study with 2 phases
      • parecoxib IV/IM 40 mg q12 hrs for 72 hours
      • valdecoxib 40 mg orally q 12 hrs to day 14
  • ASA (≤ 325 mg) during study
safety assessment cabg i
Safety Assessment-CABG I

Complex (patients, procedures, co-meds)

Blinded committees established to:

verify AE meet criteria established

addressed date and attribution to include:

CRAEs (clinically relevant adverse events)

No active controls in CABG trials

Are NSAIDs appropriate?

slide16

CABG (035) - Exposure

Data from Medical Officer review (December 1, 2000)

craes cabg 035
CRAEs - CABG (035)
  • Death
    • All cause death following randomization within 30 days of last dose of study drug
  • Cardiovascular Events
    • myocardial infarction.
    • severe myocardial ischemia
    • cerebrovascular accident (CVA, TIA, or hemorrhage)
    • peripheral arterial occlusion
    • deep vein thrombosis
    • pulmonary embolism
  • Pericarditis
  • Congestive Heart Failure (new onset or exacerbation)
  • Renal Failure/Dysfunction
  • Gastrointestinal Event
  • Major non-GI bleed (requiring transfusion)
  • Infection (requiring institution of antibiotics)
  • Pulmonary complications (non-infectious)
myocardial infarction crae 035 diagnosed by 2 of following criteria
Myocardial Infarction - CRAE (035)diagnosed by 2 of following criteria
  • Prolonged (>20 min) typical chest pain not relieved by rest and/or nitrates
  • Enzyme level elevation, either by:
        • CK-MB >5% of total CPK
        • CK greater than 2x normal
        • LDH subtype 1>LDH subtype 2
        • troponin >0.2 micrograms/ml
  • New wall motion abnormalities
  • Serial ECG (at least two) showing changes from baseline or serially in ST-T and/or Q waves that are 0.03 seconds in width and/or > or + one third of the total QRS complex in two or more contiguous leads
craes 035
CRAEs - 035

* P = 0.012 (Fischer’s)

mi cabg 035
MI - CABG (035)
  • Of 13 possible MI, 11 sent to committee:
      • 9 events (parecoxib)
      • 2 events (placebo)
  • Of these, 2 MIs believed met CRAE definition
      • 1 parecoxib
      • 1 placebo
  • One rejected event in parecoxib group resulted in death (probable MI) of patient
      • Difficulty of adjudication
        • Timing of drug vs. event
parecoxib deaths
Parecoxib - Deaths
  • 58 y/o male- 4 doses (IV):
    • died on day 15 of duodenal ulcer
  • 69 y/o female-20 doses (IV/PO):
    • died on day 19 of probable MI
  • 67 y/o male-12 doses (IV/PO):
    • died day 12 septicemia, pneumonia
  • 62 y/o male-7 doses (IV):
    • died day 5 of infarct-left cerebellum
slide22

CABG II(Study 071)

          • 50% dose reduction
          • dosing on day 1
          • timing of events (IV vs. PO)
craes 071 entire study
CRAEs - 071 (entire study)

* p < 0.05; information included in valdecoxib label

dea ths 071
Deaths - 071
  • Placebo
    • Intestinal perforation
  • Placebo/valdecoxib
    • Cardiac arrest
    • Pneumonia
    • Cardiac failure
  • Parecoxib/valdecoxib
    • Cardiac arrest
    • PE
    • MI
    • VF
slide25

General Surgery (study 069)

-40 mg LD, then 20 mg BID

-General Surgery Patients including orthopedic, GI, GYN, thoracic, other

craes 069 entire study
CRAEs - 069 (Entire Study)

Data included in valdecoxib label

deaths 069
Deaths - 069
  • Placebo
    • Cardiac failure
    • Carcinoma
    • Mesenteric vein thrombosis
    • Cardiac arrest
  • Parecoxib/valdecoxib
    • GI hemorrhage
    • MI
    • PE
slide29

Safety: Selectivity or Drug ?

Celecoxib NSAID

Diclofenac COX-2

endoscopic ulceration ra 6 month
Endoscopic UlcerationRA (6 month)

* p < 0.001 (CMH); included in original label.

class gi outcomes
CLASS - GI outcomes
  • Compared to diclofenac, celecoxib did not demonstrate statistical superiority for any prospectively defined, adjudicated endpoint including:
    • Primary endpoint (complicated ulcers)
      • Including non-ASA users
    • Expanded endpoint of complicated and symptomatic ulcers
      • Including non-ASA users
safety data nsaids vs cox 2
Safety Data - NSAIDs vs COX-2
  • Think about the data we have
  • Worry about the data we don’t have
    • Absence of evidence, is not evidence of absence
ad