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.
Peto R et al. N Engl J Med. 2008;359(13):1357-66
2
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 ScheringPlough
• 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
Week
24
1.0
1.5
2.0
2.5
3.0
3.5
4.0
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, nonhaemorrhagic 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
High-Risk STEMI
NSTE / Unstable Angina
NSTE / Unstable Angina
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
Percentage of Patients With
First Event
50
Intention-to-Treat Population
Placebo
40
Hazard ratio: 0.96, p=0.591
30
EZ/Simva 10/40 mg
20
10
0
0
# of Patients at Risk
EZ/Simva 10/40 mg
Placebo
1
2
3
4
5
618
586
53
56
Years in Study
906
884
817
791
713
696
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
First Event
30
20
Intention to Treat Population
Hazard ratio: 0.78, p=0.024
Placebo
EZ/Simva 10/40 mg
10
0
0
1
# of patients at risk
EZ/Simva 10/40 mg 917
Placebo
898
2
3
Years in Study
867
838
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
823
788
4
5
769
729
76
76
22
SEAS Findings-Clinical Adverse Events (AE)
All Patients as Treated Population
Placebo
EZ/ Simva
N=929
N=943
n (%)
n (%)
Any AE
852 (91.7)
854 (90.6)
Any serious AE (SAE)
463 (49.8)
468 (49.6)
70 (7.5)
105 (11.1)
Recurrent, same site
5 (0.5)
3 (0.3)
New cancer
65 (7.0)
102 (10.8)
Drug related AE
110 (11.8)
134 (14.2)
3 (0.3)
5 (0.5)
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)
Total Cancer
Drug related SAE
D/c due to AE
Rossebø AB et al. N Engl J Med. 2008;359(13):1343-56
p=
0.01
0.01
23
SEAS Findings-Any Cancer
Percentage of patients with first event
50
40
EZ/Simva 10/40 mg
Placebo
30
Hazard ratio: 1.50, p=0.008
20
10
0
0
1
2
EZ/Simva 10/40 mg
906
867
Placebo
902
865
3
Years in Study
4
5
822
791
86
833
800
86
Number of patients at risk
24
SEAS Findings-Cancer Mortality
Percentage of Patients With
First Event
Intention-to-Treat Population
10
Hazard ratio: 1.67
P=0.05 Unadjusted
P=0.06 with Yates continuity
correction
EZ/Simva
10/40 mg
n=39 (4.1 %)
5
Placebo
n=23 (2.5 %)
0
0
1
# of patients at risk
EZ/Simva 10/40 mg 930
Placebo
916
2
3
4
Years in Study
912
890
884
865
855
835
5
89
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)
Number of Patients with Cancer
Onset in Trials
700
616
588
600
535
500
613
582 588
590
511 503
488
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.
2.
Need to be cautious of interpretation of unplanned, data-driven finding
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.
2.
3.
–
Statistical—Is it statistically unlikely that such events can be explained by
chance, i.e. p-value?
Is the safety risk biologically plausible?
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.
2.
3.
•
Risks of misinterpreting the interim findings from SHARP and
IMPROVE-IT
Disrupting ongoing trials
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
Fleming TR. N Engl J Med 2008; 359:1400-1402
43
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
Nissen SE. N Engl J Med. 2009 Jan 1;360(1):86-7; author reply 87.
44
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:
•
•
•
•
•
Reasons a public statement made prior to scientific presentation
–
–
–
•
Mostly short-term trials
Exposure limited for patients with more severe disease
Limited adverse event database
No outcome data
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
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
45
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.
2.
•
Performance of SHARP and IMPROVE-IT
Impact how patients are treated outside of these trials
Decision–
1.
2.
Pool cancer data from SHARP and IMPROVE-IT and analyze by
independent statisticians with experience with CV and cancer data
Results from this analysis along with SEAS results were presented at
the press conference
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
46
Reactions to Peto Paper-- Califf
•
Recommendations for improving conduct of outcome
trials
1.
2.
3.
4.
Improve requirements for Data Safety Monitoring Committees
House the data in not-for-profit institutions
Chair of steering committee should be recognized as leader in
field of study with clinical trial experience
Reform Securities and Exchange Commission regulations
around reporting of results from major clinical trials
Califf RM, et. al. N Engl J Med. 2009 Aug 13;361(7):712-7.
47
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
Proportion suffering event (%)
25
20
Risk ratio 0.99 (0.87 – 1.13)
Logrank p=0.89
15
Eze/simv
Placebo
10
5
0
0
1
2
3
Years of follow-up
Baigent et. al. American Society for Nephrology, Nov. 2010.
4
5
49
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