Docstoc

Statins and Cancer

Document Sample
Statins and Cancer Powered By Docstoc
					Cancer Risk–
Does ezetimibe or ezetimibe/simvastatin
increase it?

    Adam Polis, Merck
    NISS Observational Studies Workshop
    June 17, 2011
                                          Focus




          WARNING: These trials were not observational studies.
          All were randomized, double-blind, controlled trials.
                                                                  2
Peto R et al. N Engl J Med. 2008;359(13):1357-66
                       Outline
• Background
• Simvastatin + Ezetimibe in Aortic Stenosis (SEAS)
  Findings
• What followed…
• Peto paper
• Reactions to Peto paper
• Statistical Issues
• Concluding Remarks

                                                      3
Background
               Background-- Statins
• What is a Statin?
   – Class of drug that improves cholesterol levels
   – First marketed statin was lovastatin
       • Developed by Merck
       • Initially sold in the US as MEVACOR® in 1987
   – Other statins
       •   Atorvastatin (LIPITOR®)
       •   Fluvastatin (LESCOL®)
       •   Pitavastatin (LIVALO®)
       •   Pravastatin (PRAVACHOL®)
       •   Rosuvastatin (CRESTOR®)
       •   Simvastatin (ZOCOR®)
   – Multiple trials with different statins showing positive effects on
     CVD risk and mortality

                                                                          5
            Background-- Simvastatin
• Simvastatin is one of a number of –statins, and
  is primarily indicated for:
     – Reducing the risk of total mortality in patients at high
       risk for coronary events
     – Improving lipids (TC, LDL-C, Apo B, TG, HDL-C) in
       patients with primary hyperlipidemia and mixed
       dyslipidemia
•   Marketed in the US as ZOCOR®
•   Dosage strengths: 5, 10, 20, 40, and 80 mg*
•   Developed by Merck
•   Initial US approval 1991
*US label for ZOCOR® changed as of June 2011– no new patients on 80 mg.   6
        Background-- Ezetimibe
• Also indicated for improving lipids
• Discovered and initially developed by Schering-
  Plough
• Later co-developed and marketed as joint
  venture between Merck and Schering-Plough
• Approved in US in 2002 and marketed as
  ZETIA®
• Dosage strength: 10 mg

                                                    7
              Background-- Ezetimibe
• Ezetimibe can be taken alone or with a statin
• Commonly used alone for patients who can not
  tolerate a statin
• Used in combination with a statin as an
  alternative to increasing the statin dose
• VYTORIN® is the name of the US marketed
  combination of ezetimibe and simvastatin
     – Dosage strengths: 10/10, 10/20, 10/40, 10/80 mg*

*US label for VYTORIN® changed as of June 2011– no new patients on 10/80 mg   8
           Background-- Ezetimibe
• Initially approved and indicated for lipid efficacy,
  but no outcome data
• SEAS, SHARP, and IMPROVE-IT

                       SEAS         SHARP     IMPROVE-IT
  Enroll Start     March 2001    June 2003   October 2005
  Enroll Stop      March 2004        2007    2013 est.
  Follow-up Stop   Summer 2008       2010    5250 events




                                                            9
                    Background-- SEAS
• Simvastatin + Ezetimibe in Aortic Stenosis
• Primary Objective
     – In patients with asymptomatic aortic stenosis, to evaluate whether
       treatment with ezetimibe 10 mg/day and simvastatin 40 mg/day
       compared to placebo will reduce the risk of major cardiovascular events
       (MCE):
          •   Cardiovascular death
          •   Aortic valve replacement surgery (AVR)
          •   CHF as a result of progression of AS
          •   Non-fatal myocardial infarction
          •   CABG
          •   PCI
          •   Hospitalized unstable angina
          •   Non-hemorrhagic stroke


Rossebø AB et al.N Engl J Med. 2008;359(13):1343-56                         10
                    Background-- SEAS
• Rationale
     – Aortic-valve stenosis (AS) is a relatively common
       condition in the elderly
          • Associated with significant morbidity and mortality

     – Process of development of AS has similarities to
       development of atherosclerosis
     – Could cholesterol lowering impact on development of
       AS
          • Similar to known effect on atherosclerosis?



Rossebø AB et al.N Engl J Med. 2008;359(13):1343-56               11
                                  Background-- SEAS
•   Randomized, double blind, placebo controlled, multicenter
•   173 centers: Norway, Sweden, Denmark, Finland, Germany, UK, Ireland
•   4-Week placebo/diet run-in
•   1873 patients (Minimum follow-up: 4 years)
      Randomization




                          Ezetimibe/simvastatin 10/40 mg



                          Placebo


                      0     8     24   1.0   1.5   2.0    2.5   3.0   3.5   4.0


                           Week                          Year


Rossebø AB et al.N Engl J Med. 2008;359(13):1343-56                               12
                    Background-- SEAS
• SEAS Committees
     – SEAS Study Group Steering Committee
          • Norway: Terje R. Pedersen (Chairman), Anne B. Rossebø (Coordinator), Eva Gerdts,
            Terje Skjærpe, Ingar Holme (Statistician); Sweden: Ronnie Willenheimer, Kurt Boman;
            Denmark: Kristian Wachtell, Kenneth Egstrup; Finland: Y. Antero Kesäniemi; Germany:
            Christa Gohlke-Bärwolf, Christoph Nienaber; United Kingdom/Ireland: John Chambers,
            Simon Ray
          • Nonvoting members (Merck): Philippe Brudi (MSP), William Malbecq (CBARDS).
     – Independent Data Safety and Monitoring Board
          • United Kingdom: Desmond Julian (Chairman), Stuart J Pocock; Norway: John Kjekshus
     – Independent End Point Classification Committee
          • Denmark: Christian Hassager; Norway: Torstein Gundersen
     – Independent Echo Core Laboratory
          • Norway: Eva Gerdts
     – Monitoring offices, Merck Sharp & Dohme
          • Norway: Gro Karlsen; United States: Gail McPeters
     – National Project Leaders, Merck Sharp & Dohme
          • Denmark: Gert S Andersen; Finland: Pekka Koskinen, I. Puhakainen; Germany:
            Andreas Ketter; H. Ansari Esfahani, M. Meergans; Ireland: Noeleen Farrelly, C. Parish;
            Norway: Vessa Larsen; Sweden: H. Boström, Lena Bergvall; United Kingdom: Kerin
            Wincott

Rossebø AB et al.N Engl J Med. 2008;359(13):1343-56                                             13
                      Background-- SHARP
     • Study of Heart And Renal Protection
     • Key outcome
           – Major atherosclerotic events (coronary death, MI, non-
             haemorrhagic stroke, or any revascularization)

     • Subsidiary outcomes
           – Major vascular events (cardiac death, MI, any stroke, or any
             revascularization)
           – Components of major atherosclerotic events

     • Main renal outcome
           – End stage renal disease (dialysis or transplant)

Baigent et. al. American Society for Nephrology, Nov. 2010.                 14
                         Background-- SHARP
       • Rationale
             – Risk of vascular events is high among patients with
               chronic kidney disease
             – Lack of clear association between cholesterol level
               and vascular disease risk
             – Pattern of vascular disease is atypical, with a large
               proportion being non-atherosclerotic
             – Previous trials of LDL-lowering therapy in chronic
               kidney disease are inconclusive


Baigent et. al. American Society for Nephrology, Nov. 2010.            15
                         Background-- SHARP
     • History of chronic kidney disease
           – not on dialysis: elevated creatinine on 2 occasions
                 • Men: ≥1.7 mg/dL (150 µmol/L)
                 • Women: ≥1.5 mg/dL (130 µmol/L)
           – on dialysis: haemodialysis or peritoneal dialysis
     • Age ≥40 years
     • No history of myocardial infarction or coronary
       revascularization
     • Uncertainty: LDL-lowering treatment not
       definitely indicated or contraindicated
Baigent et. al. American Society for Nephrology, Nov. 2010.        16
                         Background-- SHARP




Baigent et. al. American Society for Nephrology, Nov. 2010.   17
                Background-- IMPROVE-IT
     • IMProved Reduction of Outcomes:
       Vytorin Efficacy International Trial




Cannon CP, et al. Am Heart J 2008;156:826-32.   18
             Background-- IMPROVE-IT
                             High Risk Patients With Acute Coronary Syndromes


                                                                              NSTE / Unstable Angina
          NSTE / Unstable Angina                High-Risk STEMI              According to IMPROVE-IT
                                                                                   Entry Criteria


                                    Enrollment of new STEMI subjects was
                                   closed once they comprised ~30% of the
                                                  population



                    Randomized Treatment Assignment ≤10 Days of Hospital Presentation


                                   EZ/Simva Combo
                                      10/40 mg                 Simva 40 mg


                                                  n= ~18,000

                                        2.5 Year Minimum Follow-up

                       Primary Endpoint: CV Death, Nonfatal MI, Hospital Admission for
                        Unstable Angina, Revascularization >30 Days, Nonfatal Stroke
                                                                                                       19
Cannon CP, et al. Am Heart J 2008;156:826-32.
 Simvastatin + Ezetimibe
in Aortic Stenosis (SEAS)
          Findings
                                                      SEAS Findings--
                                        Primary Endpoint: Major CV Events
                                        50            Intention-to-Treat Population

                                                                                       Placebo
          Percentage of Patients With

                                        40
                                                 Hazard ratio: 0.96, p=0.591
                  First Event



                                        30

                                                                                      EZ/Simva 10/40 mg
                                        20


                                        10


                                        0
                                             0         1         2          3           4        5
  # of Patients at Risk                                               Years in Study
  EZ/Simva 10/40 mg                                    906      817        713          618      53
  Placebo                                              884      791        696          586      56
                                                                                                          21
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
                                                      SEAS Findings–
      Key Secondary Endpoint: Ischemic CV Events
        Percentage of Patients With   30                  Intention to Treat Population




                                              Hazard ratio: 0.78, p=0.024         Placebo
                                      20
                First Event




                                                                                   EZ/Simva 10/40 mg
                                      10




                                      0
                                          0          1         2            3             4   5
                                                                     Years in Study
     # of patients at risk
     EZ/Simva 10/40 mg 917                                     867          823       769     76
     Placebo               898                                 838          788       729     76       22
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
                                  SEAS Findings--
                           Clinical Adverse Events (AE)
                             All Patients as Treated Population
                                                 Placebo          EZ/ Simva

                                                  N=929            N=943

                                                   n (%)            n (%)      p=
  Any AE                                        852 (91.7)        854 (90.6)
  Any serious AE (SAE)                          463 (49.8)        468 (49.6)
  Total Cancer                                   70 (7.5)         105 (11.1)   0.01
     Recurrent, same site                         5 (0.5)          3 (0.3)
     New cancer                                  65 (7.0)         102 (10.8)   0.01
  Drug related AE                               110 (11.8)        134 (14.2)
  Drug related SAE                                3 (0.3)          5 (0.5)
  D/c due to AE                                 122 (13.1)        144 (15.3)
  D/c due to drug related AE                     29 (3.1)          46 (4.9)
  D/c due to SAE                                 79 (8.5)          77 (8.2)
  D/c due to drug related SAE                     1 (0.1)          2 (0.2)            23
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
                                                                   SEAS Findings--
                                                                     Any Cancer
                                          50




                                          40                        EZ/Simva 10/40 mg
Percentage of patients with first event




                                                                    Placebo



                                          30

                                                   Hazard ratio: 1.50, p=0.008


                                          20




                                          10




                                          0
                                               0              1                   2               3      4    5
                                                                                       Years in Study
Number of patients at risk
EZ/Simva 10/40 mg                                            906                 867            822     791   86
Placebo                                                      902                 865            833     800   86


                                                                                                                   24
                                                         SEAS Findings--
                                                           Cancer Mortality
                                                         Intention-to-Treat Population

                                      10
        Percentage of Patients With


                                               Hazard ratio: 1.67
                                               P=0.05 Unadjusted
                                               P=0.06 with Yates continuity
                First Event




                                               correction                                      EZ/Simva
                                                                                               10/40 mg
                                      5                                                        n=39 (4.1 %)
                                                                                               Placebo
                                                                                               n=23 (2.5 %)


                                      0
                                           0         1           2          3       4     5
   # of patients at risk                                             Years in Study
   EZ/Simva 10/40 mg 930                                        912       884       855   89
   Placebo               916                                    890       865       835   94
                                                                                                         25
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
What followed…
             Reaction to SEAS Results

• SEAS Steering Committee (SC) surprised by
  both efficacy and safety findings
• Primary concern: what to tell patients on
  VYTORIN and how to advise physicians
   – 1.4 M prescriptions written for VYTORIN in April of
     2008
• Realization that cancer finding could be false-positive
  and external information/data was needed:
   – Cholesterol Treatment Trialist (CTT) cumulative meta-analysis
   – Ongoing trials: SHARP + IMPROVE-IT

                                                                     27
            Reaction to SEAS Results

• Terje Pedersen (SEAS SC Chair) contacted the SCs for
  SHARP and IMPROVE-IT to discuss +/- of looking at
  cancer data in SHARP + IMPROVE-IT
• Agreement by SCs and Data Safety Monitoring
  Committees to perform analysis of cancer data in
  SHARP and IMPROVE-IT
• Analysis performed by independent, academic
  organization (Clinical Trial Study Unit, Oxford University)
   – They were sent the data for all 3 trials
   – They decided independently on analysis approach
     and data conventions
                                                            28
                        CTT Meta-Analysis




                                                  29
Baigent C et al. Lancet. 2005;366(9493):1267-78
          CTT:Cancer Incidence per mmol/L LDL-C
                    Reduction by Site




                                                  30
Baigent C et al. Lancet. 2005;366(9493):1267-78
          CTT: Cancer Incidence per mmol/L LDL-C
                   Reduction per Year




                                                   31
Baigent C et al. Lancet. 2005;366(9493):1267-78
Peto Paper
                                   Peto Paper




                                                   33
Peto R et al. N Engl J Med. 2008;359(13):1357-66
                                      Peto Paper

 • Will highlight some analyses in paper
 • Statistical Methods
       – Log-rank, stratifying by year, and using continuity correction for chi-square
         statistic
       – Cox regression was used in SEAS paper
       – Site specific cancer p-values were adjusted for multiplicity
       – Subgroup analyses were adjusted for multiplicity by using 99% CIs
 • Paper makes the important points:
       – Unplanned and unexpected finding from SEAS was hypothesis-generating
       – Analysis of SHARP + IMPROVE-IT done to support or refute hypothesis
       – Primary approach not to combine all 3 studies, but also done to show robustness
         of findings
 • SHARP + IMPROVE-IT: 20, 617 patients and 36,501 patient-years
   vs. SEAS with 1873 patients and 7636 patient-years

                                                                                         34
Peto R et al. N Engl J Med. 2008;359(13):1357-66
                 Cancer Onset–
                 Statin Alone vs. Control from CTT
                                                   Statin (N=45,054)           Control (N=45,002)
                                       700
                                                         616                               613
                                                                                                 590
      Number of Patients with Cancer



                                                               588   582 588
                                       600
                                                   535
                                                                                 511 503
                                             488
                                       500
             Onset in Trials




                                       400

                                       300

                                       200

                                       100

                                         0
                                               0-1        >1-2        >2-3        >3-4       >4
                                                                 Year of Onset

                                                                                                       35
Peto R et al. N Engl J Med. 2008;359(13):1357-66
             Relative Risk of Cancer Per Year–
                Ezetimibe and Simvastatin




                                                   36
Peto R et al. N Engl J Med. 2008;359(13):1357-66
           Relative Risk of Cancer by Outcome




           = 99% CI
           = 99% CI
Difference between hypothesis-generating total and the
hypothesis-testing total: 2 = 7.5 (P = 0.006)



                                                         37
Peto R et al. N Engl J Med. 2008;359(13):1357-66
          Relative Risk of Fatal Cancer by Year




           = 99% CI
           = 99% CI
     Trend test: 2 = 1.35 (P = 0.25)
                                                   38
Peto R et al. N Engl J Med. 2008;359(13):1357-66
                      Peto Paper-- Conclusions

 • Data do not support hypothesis generated in SEAS
 • While excess risk of death due to cancer, not hypothesis
   generated in SEAS and not plausible based upon other
   evidence
       – Did not see excess of cancers, which would be expected if
         causing excess deaths due to cancer
 • DSMBs for SHARP and IMPROVE-IT agreed each trial
   could continue
 • Need to perform unblinded analysis of SHARP and
   IMPROVE-IT result of increased public scrutiny of
   products’ efficacy and safety
       – Such a need could be diminished by conducting larger, more
         definitive outcome trials earlier in product lifecycle

                                                                      39
Peto R et al. N Engl J Med. 2008;359(13):1357-66
Reactions to Peto Paper
    Reactions to Peto Paper– Drazen et. al.

•       Drazen et. al. N Engl J Med. 2008 Sep 25;359(13):1398-9
        (Editorial)
    –         Randomized trial most reliable tool, but sometimes find unexpected
              results
          •      Can be due to chance
          •      Require further study to figure out
    –         SHARP + IMPROVE-IT data did not confirm cancer risk observed in
              SEAS, but 3 trials combined show increase risk of mortality due to
              cancer
          1.     Need to be cautious of interpretation of unplanned, data-driven finding
          2.     But should not ignore:
                 •   Agree SHARP and IMPROVE-IT should continue, but patients should
                     be carefully followed
                 •   Other additional data sets on ezetimibe should be evaluated for
                     cancer risk

                                                                                      41
          Reactions to Peto Paper-- Fleming

•       Fleming TR. N Engl J Med 2008; 359:1400-1402 (Editorial)
    –      Recommends the use of 3 criteria to assess the credibility of
           exploratory safety findings:
          1.   Statistical—Is it statistically unlikely that such events can be explained by
               chance, i.e. p-value?
          2.   Is the safety risk biologically plausible?
          3.   Can one identify independent, prospectively obtained data to confirm the
               finding?
    –      Statistical
          –    SEAS data correctly not included with SHARP and IMPROVE-IT to
               evaluate hypothesis; inclusion causes regression to mean effect
          –    Cancer events: HR 0.96; 95% CI: 0.82 to 1.12 rules out increased risk
               greater than 12%
          –    Cancer-related deaths: HR 1.34; 95% CI: 0.98 to 1.84, relative increase
               could be as large as 84%

                                                                                           42
                Reactions to Peto Paper-- Fleming

     •        Concerned by:
          1.     Risks of misinterpreting the interim findings from SHARP and
                 IMPROVE-IT
          2.     Disrupting ongoing trials
          3.     Interim data from ongoing trials should be limited to Data Monitoring
                 Committees
     •        Concludes
          –      Additional data needed to adequately address question regarding
                 increased risk of cancer-related death due to ezetimibe/simvastatin
          –      Data should come from prospective randomized clinical trial designed
                 to assess safety




                                                                                         43
Fleming TR. N Engl J Med 2008; 359:1400-1402
                  Reactions to Peto Paper-- Nissen

     •         Nissen Letter to Editor
           –      Premature unblinding of clinical trial data is unreliable way to evaluate
                  drug safety
           –      Critical of duration of follow-up (median 12 months) in IMPROVE-IT
           –      Disagrees with conclusion that there is no credible evidence of
                  cancer risk with ezetimibe
     •         Collins and Peto’s Response
           –      Not in the interest of public health to label potentially useful drugs
                  unsafe without credible evidence
           –      Four times as many cancers in SHARP and IMPROVE-IT compared
                  to SEAS, but no treatment difference found




                                                                                         44
Nissen SE. N Engl J Med. 2009 Jan 1;360(1):86-7; author reply 87.
              Reactions to Peto Paper– Califf et. al.

     •        Take opportunity to comment that improvements could be made
              to drug development and conduct of outcome trials
          –         Ezetimibe and Ezetimibe/Simvastatin approved with:
                •      Mostly short-term trials
                •      Exposure limited for patients with more severe disease
                •      Limited adverse event database
                •      No outcome data
     •        Reasons a public statement made prior to scientific presentation
          –         Transparency in industry-funded trials
          –         Alerting patients and providers would allow a more informed
                    decisions
          –         Findings are material information to Merck and SP shareholders
     •        Sponsors needed to inform global regulators about SEAS results
              and SHARP + IMPROVE-IT analysis
                                                                                     45
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
                   Reactions to Peto Paper-- Califf

     •        SHARP and IMPROVE-IT leaders need to ask DSMBs
          –     OK to continue studies?
               •    Yes, with increased surveillance of cancer-related events in
                    IMPROVE-IT
          –     OK to release further info. to investigators and subjects?
               •    More difficult decision to make
               •    SEAS results could influence:
                    1.   Performance of SHARP and IMPROVE-IT
                    2.   Impact how patients are treated outside of these trials
               •    Decision–
                    1.   Pool cancer data from SHARP and IMPROVE-IT and analyze by
                         independent statisticians with experience with CV and cancer data
                    2.   Results from this analysis along with SEAS results were presented at
                         the press conference

                                                                                           46
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
                 Reactions to Peto Paper-- Califf

     •     Recommendations for improving conduct of outcome
           trials
          1.    Improve requirements for Data Safety Monitoring Committees
          2.    House the data in not-for-profit institutions
          3.    Chair of steering committee should be recognized as leader in
                field of study with clinical trial experience
          4.    Reform Securities and Exchange Commission regulations
                around reporting of results from major clinical trials




                                                                            47
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
                Reactions to Peto Paper

• Congressional Inquiry
   – Interesting and worth checking out on the Clinical Trial Service Unit’s (at
     Oxford University) web site:
       http://www.ctsu.ox.ac.uk/news/ctsu-response


• FDA review of the data
   – August 2008 sent out a preliminary communication of an association
     between VYTORIN and increased cancer risk based on SEAS data
   – December 2009
       • Unlikely that ZETIA or VYTORIN increase the risk of cancer
       • Not advising patients to stop using these meds, but weigh risk/benefit
       http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatient
          sandproviders/drugsafetyinformationforheathcareprofessionals/ucm194964.
          htm

                                                                                  48
                                               SHARP: Cancer incidence

                                      25
     Proportion suffering event (%)




                                      20
                                                     Risk ratio 0.99 (0.87 – 1.13)
                                                           Logrank p=0.89
                                      15
                                                                                     Eze/simv
                                      10
                                                                                     Placebo


                                      5


                                      0
                                           0     1         2           3        4    5
                                                                                          49
                                                          Years of follow-up
Baigent et. al. American Society for Nephrology, Nov. 2010.
Statistical Issues
                        Statistical Issues

• Ezetimibe studies were not Observational Studies
    – Similar issues can arise in prospective, randomized, controlled trials
      when see unexpected result or perform post hoc analyses
• Regression to the mean
    – Avoided by not combining all 3 trials together
    – SEAS considered as hypothesis-generating; SHARP + IMPROVE-IT to
      test the hypothesis
    – Barnett, et. al. International Journal of Epidemiology 2005;34:215–220
• Multiplicity
    – Initial finding of increased cancer rate in SEAS was not pre-specified,
      many AEs from the trial evaluated
    – Comparisons of cancer rates by site of cancer were adjusted by
      multiplying unadjusted p-value by number of comparisons (Hochberg,
      Tamhane. Multiple comparison procedures. New York: Wiley, 1987)

                                                                                51
                      Statistical Issues

• Unplanned Interim Analysis and Risk of Misinterpreting
  Findings
   –   Fleming, et. al., Clinical Trials 2008; 5: 157–167.
   –   Treatment effect fluctuates over time
   –   Multiple unplanned or unadjusted looks increase type I error
   –   When duration of exposure is important, early look could be
       misleading




                                                                      52
Concluding Remarks
                    Concluding Remarks

• Good example of unexpected challenges one can face
• In medical setting, putting the patient first is critically important
  perspective to have
• World renown experts (SEAS, SHARP, and IMPROVE-IT SCs and
  DSMBs) deciding best course of action and world renown experts
  conducting the analysis
• Conduct outcome study earlier in product life cycle
• Performing the unblinded interim analysis is/was controversial
    – Without doing so, patients and physicians likely would have been left to
      think ezetimibe increases the risk of cancer
    – The way in which the interim was performed does not appear to have
      effected the conduct of the trials
    – Without other randomized controlled trials, a potential link between
      ezetimibe and cancer may have had to rely on an observational study,
      subject to all the biases inherent in such studies
                                                                             54
                                References
1.   Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A,
     Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT)
     Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective
     meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
     Lancet. 2005;366(9493):1267-78.
2.   Barnett AG,van der Pols JC, and Dobson AJ. Regression to the mean: what it is
     and how to deal with it. International Journal of Epidemiology 2005;34:215–220.
3.   Califf RM, Harrington RA, Blazing MA. Premature release of data from clinical
     trials of ezetimibe. N Engl J Med. 2009 Aug 13;361(7):712-7.
4.   Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-
     IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial):
     comparison of ezetimibe/simvastatin versus simvastatin monotherapy on
     cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J
     2008;156:826-32.
5.   Drazen JM, D'Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and
     cancer--an uncertain association. N Engl J Med. 2008 Sep 25;359(13):1398-9.
     Epub 2008 Sep 2.
6.   Fleming TR. Identifying and Addressing Safety Signals in Clinical Trials. N Engl J
     Med 2008; 359:1400-1402.


                                                                                          55
                                  References
7.    Fleming TR, Sharples K, McCall J, Moore A, Rodgers A, and Stewart R.
      Maintaining confidentiality of interim data to enhance trial integrity and credibility.
      Clinical Trials 2008; 5: 157–167.
8.    Nissen SE. Comment on: Analyses of cancer data from three ezetimibe trials. N
      Engl J Med. 2009 Jan 1;360(1):86-7; author reply 87.
9.    Peto R, Emberson J, Landray M, Baigent C, Collins R, Clare R, Califf R. Analyses
      of cancer data from three ezetimibe trials. N Engl J Med. 2008 Sep
      25;359(13):1357-66. Epub 2008 Sep 2.
10.   Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts
      E,Gohlke-Bärwolf C, Holme I, Kesäniemi YA, Malbecq W, Nienaber CA, Ray S,
      Skjaerpe T, Wachtell K, Willenheimer R; SEAS Investigators. Intensive lipid
      lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med.
      2008;359(13):1343-56.
11.   Sharp Collaborative Group. Study of Heart and Renal Protection (SHARP):
      randomized trial to assess the effects of lowering low-density lipoprotein
      cholesterol among 9,438 patients with chronic kidney disease. Am Heart J. 2010
      Nov;160(5):785-794.e10. Epub 2010 Sep 18.




                                                                                                56
Backups
         SEAS– Secondary Objectives
 • In patients with asymptomatic AS, to evaluate whether treatment
   with ezetimibe 10 mg/day and simvastatin 40 mg/day compared to
   placebo will reduce the risk of:
            • The composite endpoint of aortic valve events (AVEs):
                  – AVR surgery,
                  – CHF as a result of progression of AS,
                  – Cardiovascular death
            • The composite endpoint of ischemic cardiovascular events (ICEs):
                  –   Cardiovascular death
                  –   Nonfatal MI
                  –   CABG
                  –   PCI
                  –   Hospitalized unstable angina
                  –   Nonhemorrhagic stroke



                                                                                 58
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
         SEAS– Secondary Objectives
 • In patients with asymptomatic AS
            • To evaluate whether treatment with ezetimibe 10 mg/day and
               simvastatin 40 mg/day will retard the progression of AS based on
               echocardiographic measurements compared to placebo

            • Assess the safety of ezetimibe 10 mg/day and simvastatin 40
               mg/day




                                                                                  59
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:6
posted:2/5/2012
language:English
pages:59