Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007. Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia, and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration. Overview of Presentation. - PowerPoint PPT Presentation
Cardiovascular Risk and Cardiovascular Risk and NSAIDs NSAIDs Arthritis Advisory Committee Arthritis Advisory Committee Meeting April 12, 2007 Meeting April 12, 2007 Sharon Hertz, M.D. Sharon Hertz, M.D. Deputy Director Deputy Director Division of Analgesia, Anesthesia, Division of Analgesia, Anesthesia, and Rheumatology Products and Rheumatology Products Center for Drug Evaluation and Center for Drug Evaluation and Research Research Food and Drug Administration Food and Drug Administration
Transcript
Cardiovascular Risk and Cardiovascular Risk and NSAIDsNSAIDs
Arthritis Advisory Committee Arthritis Advisory Committee Meeting April 12, 2007Meeting April 12, 2007
Sharon Hertz, M.D.Sharon Hertz, M.D.Deputy DirectorDeputy Director
Division of Analgesia, Anesthesia, and Division of Analgesia, Anesthesia, and Rheumatology ProductsRheumatology Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchFood and Drug AdministrationFood and Drug Administration
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Overview of Overview of PresentationPresentation
Cardiovascular findings from COX-2 development FDA conclusions about CV Risk and NSAIDs
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February 2005February 2005
Joint advisory committee meeting with arthritis and drug safety committees
Data presented on rofecoxib, celecoxib, lumiracoxib, etoricoxib
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VioxxVioxx
May 20, 1999May 20, 1999 Approval of New Drug Application for Vioxx Approval of New Drug Application for Vioxx
(rofecoxib) for the treatment of acute (rofecoxib) for the treatment of acute pain in adults, dysmenorrhea and pain in adults, dysmenorrhea and osteoarthritis osteoarthritis
~ 5000 subjects~ 5000 subjects - 700+ at least 1 year (12.5 and 25 mg)- 700+ at least 1 year (12.5 and 25 mg) No cardiovascular signal – small number No cardiovascular signal – small number
of events, no dose responseof events, no dose response
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Vioxx - VIGORVioxx - VIGOR Rofecoxib Rofecoxib 50 mg50 mg daily vs. daily vs.
naproxen 500 mg BID naproxen 500 mg BID 8,000 RA patients, no ASA8,000 RA patients, no ASA Median exposure - 9 monthsMedian exposure - 9 months EndpointsEndpoints
– serious GI eventsserious GI events– serious CV/thrombotic events serious CV/thrombotic events
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Vioxx - VIGORVioxx - VIGORCardiovascular risk identified for rofecoxib vs. naproxen All CV events - RR 2.37 MI - RR 5.0 (20 vs. 4) Incidence increased over time Results taken to AC February, 2001
To slow progression or prevent onset To slow progression or prevent onset 3 placebo-controlled, double-blind, 3 placebo-controlled, double-blind,
multicenter studiesmulticenter studies Rofecoxib 25 mg vs. placebo Rofecoxib 25 mg vs. placebo 15-24 months15-24 months N=~2800 patientsN=~2800 patients No consistent cardiovascular signal No consistent cardiovascular signal
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Vioxx - APPROVeVioxx - APPROVe Reduce incidence of adenomatous Reduce incidence of adenomatous
polyps in patients with history of polyps in patients with history of colorectal adenomascolorectal adenomas
Randomized, placebo-controlled, Randomized, placebo-controlled, double-blind, 3 years + 1 year double-blind, 3 years + 1 year
Rofecoxib 25 mg vs. placeboRofecoxib 25 mg vs. placebo 2586 patients 2586 patients
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Vioxx - APPROVeVioxx - APPROVeSeptember 27, 2004 – Merck informs September 27, 2004 – Merck informs FDA of CV signal for rofecoxib vs. FDA of CV signal for rofecoxib vs. placebo in APPROVeplacebo in APPROVe All CV events – RR 1.8 MI – RR 2.5 Ischemic CVA – RR 1.8 September 30, 2004 – Merck September 30, 2004 – Merck withdraws Vioxx from the marketwithdraws Vioxx from the market
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Vioxx – APPROVeVioxx – APPROVe Effect of ASA on APTC Effect of ASA on APTC
Vioxx 25 mg PlaceboAll patients N=1287
3053 pt-yrsN=1300
3322 pt-yrsn
Rate/100 pt-yrs59 1.9
341.0
Non-ASA Users N=1074 N=1096 n
Rate/100 pt-yrs43 1.7
22 22 0.8 0.8
ASA Users N=213 N=204 n
Rate/100 pt-yrs15 3.1
122.3
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CelebrexCelebrex
December 31, 1998 December 31, 1998 Approval of New Drug Application for Approval of New Drug Application for
Celebrex (celecoxib) for the signs Celebrex (celecoxib) for the signs and symptoms of osteoarthritis and symptoms of osteoarthritis (200 mg/day) and rheumatoid (200 mg/day) and rheumatoid arthritis 200-400 mg/day)arthritis 200-400 mg/day)
N= 9600 patients N= 9600 patients No CV signal with initial applicationNo CV signal with initial application
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Celebrex - CLASSCelebrex - CLASS
CLASSCLASS Double-blind, active-controlled, 1 yearDouble-blind, active-controlled, 1 year ~ 8,000 patients with OA or RA, ASA if ~ 8,000 patients with OA or RA, ASA if
indicatedindicated Celecoxib 400 mg twice daily Celecoxib 400 mg twice daily Endpoint – serious GI events Endpoint – serious GI events No cardiovascular signal vs. ibuprofen No cardiovascular signal vs. ibuprofen
800 mg TID or diclofenac 75 mg 800 mg TID or diclofenac 75 mg BIDBID
Celecoxib Diclofenac Ibuprofen All patients N=3987
2340 pt-yrsN=1996
1080 pt-yrsN=1985
1122 pt-yrsn
Rate/100 pt-yrs19 0.8
40.4
90.8
Non-ASA Users N=3105 N=1551 1573 n
Rate/100 pt-yrs6
0.3 2 2
0.2 0.2 2 2
0.2 0.2 ASA Users N=882 N=445 N=412
nRate/100 pt-yrs
13 2.5
20.8
7 2.8
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Celebrex - APCCelebrex - APCAPC (Prevention of Sporadic Colorectal APC (Prevention of Sporadic Colorectal
Adenomas with Celecoxib)Adenomas with Celecoxib) Double-blind, placebo-controlled, 3 Double-blind, placebo-controlled, 3
years, over 1900 patients, ASA use by years, over 1900 patients, ASA use by ~30%~30%– Celebrex 400 mg twice daily (N=671)Celebrex 400 mg twice daily (N=671)– Celebrex 200 mg twice daily (N=685)Celebrex 200 mg twice daily (N=685)– PlaceboPlacebo (N=679) (N=679)
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Celebrex - APCCelebrex - APC
December 16, 2004 – APC study December 16, 2004 – APC study halted due to CV signal for halted due to CV signal for celecoxib vs. placebocelecoxib vs. placebo
Death from CV causes, MI, or stroke– celecoxib 200 mg bid vs. placebo
RR 2.5– celecoxib 400 mg bid vs. placebo
RR 3.4
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Incidence of Hierarchical Incidence of Hierarchical Cardiovascular Composite Endpoints Cardiovascular Composite Endpoints
in the APC Trialin the APC TrialEndpoint Number of patients (%) Rate/100 pt-yrs
Placebo 200 mg BID
400 mg BID
Placebo
200 mg BID
400 mg BID
Death from CV causes 1 (0.1) 3 (0.4) 6 (0.9) 0.05 0.14 0.29Death from CV causes or MI
4 (0.6) 12 (1.8)
15 (2.2)
0.19 0.58 0.74
Death from CV causes, MI, or stroke
6 (0.9) 15 (2.2)
20 (3.0)
0.29 0.73 0.99
Death from CV causes, MI, stroke, or heart failure
7 (1.0) 16 (2.3)
23 (3.4)
0.34 0.78 0.11
Solomon SD, et al: N Engl J Med 352, 2005
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Hazard Ratios for Hierarchical CV Hazard Ratios for Hierarchical CV Composite Endpoints in the APC TrialComposite Endpoints in the APC Trial
50.3)Death from CV causes or MI 3.0 (1.0-9.3) 3.8 (1.3-
11.5)Death from CV causes, MI, or stroke
2.5 (1.0-6.4) 3.4 (1.4-8.5)
Death from CV causes, MI, stroke, or heart failure
2.3 (0.9-5.5) 3.4 (1.4-7.8)
*Relative to placebo
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Celebrex - APCCelebrex - APC
Solomon SD, et al: N Engl J Med 352, 2005*In this analysis, “serious CV events” include death from CV causes, MI, stroke, or heart failure
671
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Celebrex - PreSAPCelebrex - PreSAP
Celecoxib in Adenoma Prevention Celecoxib in Adenoma Prevention Double-blind, placebo-controlled, Double-blind, placebo-controlled,
3 years, over 1900 patients3 years, over 1900 patients– Celebrex 400 mg once dailyCelebrex 400 mg once daily– PlaceboPlacebo
ASA use by ~16%ASA use by ~16%
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Hazard Ratio for Hierarchical CV Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Composite Endpoints in the PreSAP
TrialTrialEndpoint Placebo
n (%)400 mg
n (%)Hazard Ratio with 95% CI*
Death from CV causes 4 (0.6) 2 (0.2) 0.3 (0.1, 1.8)Death from CV causes or MI
7 (1.1) 11 (1.2) 1.1 (0.4, 2.7)
Death from CV causes, MI, or stroke
12 (1.9) 19 (2.0) 1.1 (0.5, 2.2)
Death from CV causes, MI, stroke, or heart failure
12 (1.9) 20 (2.1) 1.1 (0.6, 2.3)
*Relative to placebo
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Hazard Ratio for Hierarchical CV Hazard Ratio for Hierarchical CV Composite Endpoints in the PreSAP Composite Endpoints in the PreSAP
TrialTrialEndpoint Placebo
N = 628 n (%)
400 mg N = 933
n (%)
Hazard Ratio with 95% CI*
Death from CV causes 4 (0.6) 2 (0.2) 0.3 (0.1, 1.8)Death from CV causes or MI
7 (1.1) 11 (1.2) 1.1 (0.4, 2.7)
MI 3 (0.4) 9 (1.0)
*Relative to placebo
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Celebrex - ADAPTCelebrex - ADAPT
Alzheimer’s prevention study December 17, 2004 – ADAPT trial halted December 17, 2004 – ADAPT trial halted Celecoxib 200 mg bid, naproxen 220
mg bid, placebo N=~2500 patients Cardiovascular risk not found for
celecoxib vs. placebo in this data set, while a risk for naproxen compared to placebo was suggested.
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TARGETTARGET Therapeutic COX-189 Arthritis Research Therapeutic COX-189 Arthritis Research
and Gastrointestinal Event Trial and Gastrointestinal Event Trial 52 weeks52 weeks 18,000 patients with osteoarthritis18,000 patients with osteoarthritis Two sub-studies: Two sub-studies:
LUMLUM NaprNapr LUMLUM IbuIbuNN 47414741 47304730 43764376 43974397Pt-yr at riskPt-yr at risk 36393639 35343534 32423242 30903090APTCAPTC 4040 2727 1919 2121CV DeathCV Death 1111 88 88 1010All MIAll MIRate/100 pt-yrRate/100 pt-yr
18 18 (0.49(0.49
))
1010(0.28(0.28
))
5 5 (0.15)(0.15)
7 7 (0.22)(0.22)
All All Ischemic/hem Ischemic/hem strokestroke
1616 1212 88 99
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TARGET TARGET Confirmed /Probable APTC Endpoint KM plot (%)Confirmed /Probable APTC Endpoint KM plot (%)
Study 0117
Study 2332
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Epidemiological StudiesEpidemiological Studies
Consistent risk associated with high dose rofecoxib
Variable findings of risk associated with other selective and nonselective NSAIDs
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FDA ConclusionsFDA Conclusions April 6, 2005 Decisional April 6, 2005 Decisional
Memorandum: “Analysis and Memorandum: “Analysis and recommendations for Agency recommendations for Agency action regarding non-steroidal action regarding non-steroidal anti-inflammatory drugs and anti-inflammatory drugs and cardiovascular risk” cardiovascular risk”
““The three approved COX-2 selective The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with and valdecoxib) are associated with an increased risk of serious adverse an increased risk of serious adverse CV events compared to placebo. CV events compared to placebo. The available data do not permit a The available data do not permit a rank ordering of these drugs with rank ordering of these drugs with regard to CV risk.”regard to CV risk.”
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FDA ConclusionsFDA Conclusions
“Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs.”
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FDA Regulatory FDA Regulatory ActionsActions
April 7, 2005April 7, 2005 Boxed warning all Rx NSAIDs Boxed warning all Rx NSAIDs – Potential increased risk serious CV eventsPotential increased risk serious CV events– May be higher with prior history of CV May be higher with prior history of CV disease/risk disease/risk – Added GI warnings to boxAdded GI warnings to box– Contraindication perioperative CABGContraindication perioperative CABG
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FDA Regulatory FDA Regulatory ActionsActions
Class Medication Guide for all Rx Class Medication Guide for all Rx NSAIDsNSAIDs Revised warnings for OTC NSAIDsRevised warnings for OTC NSAIDs
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Information RequestInformation Request Review of all clinical trial data Review of all clinical trial data
from controlled studiesfrom controlled studies Unable to draw conclusions Unable to draw conclusions
– Small sample size, even with Small sample size, even with poolingpooling
– Very small number of CV eventsVery small number of CV events– Short duration of treatment Short duration of treatment
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Additional slidesAdditional slides
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TARGETTARGET Confirmed & Probable MI Confirmed & Probable MI
by ASA Useby ASA UseLUMLUM NapNap LUMLUM IbuIbu
Overall Population Overall Population NN
47414741 47304730 43764376 43974397
All MI nAll MI nRate/100 pt-yrRate/100 pt-yr
18 18 0.490.49
10 10 0.280.28
550.150.15
770.230.23
Non-ASA Users NNon-ASA Users N 35493549 35373537 34013401 34313431All MI nAll MI nRate/100 pt-yrRate/100 pt-yr
10100.360.36
440.150.15
440.160.16
550.210.21
ASA Users NASA Users N 11921192 11931193 975975 966966All MI nAll MI nRate/100 pt-yrRate/100 pt-yr
880.910.91
660.670.67
110.140.14
220.300.30
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TARGETTARGET New Analysis -2007New Analysis -2007
Farkouh et. al. Annals of Rheumatic Disease, 2007 Apr 5; [Epub ahead of print]• Post hoc analysis stratified by BL CV risk, treatment assignment and low-dose ASA use• Primary composite endpoint – CV mortality, nonfatal MI, stroke at 1 year• Secondary – congestive heart failure
