cancer risk– does ezetimibe or ezetimibe/simvastatin increase it? adam polis, merck niss...

Cancer Risk– Does ezetimibe or ezetimibe/simvastatin increase it?

Adam Polis, Merck

NISS Observational Studies Workshop June 17, 2011

2

Focus

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

WARNING: These trials were not observational studies. All were randomized, double-blind, controlled trials.

3

Outline

• Background

• Simvastatin + Ezetimibe in Aortic Stenosis (SEAS) Findings

• What followed…

• Peto paper

• Reactions to Peto paper

• Statistical Issues

• Concluding Remarks

Background

5

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

6

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.

7

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

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• 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

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• 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

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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

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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?


12

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)


Ra

nd

om

izat

ion

0 2.0 2.51.58 24 1.0 3.53.0 4.0

Week Year

Ezetimibe/simvastatin 10/40 mg

Placebo

Ra

nd

om

izat

ion

0 2.0 2.51.58 24 1.0 3.53.0 4.0

Week Year

Ezetimibe/simvastatin 10/40 mg

Placebo

13

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


14

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.

15

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


16

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


17

Background-- SHARP


18

Background-- IMPROVE-IT

• IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

Cannon CP, et al. Am Heart J 2008;156:826-32.

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Background-- IMPROVE-IT

NSTE / Unstable Angina

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

population

Randomized Treatment Assignment ≤10 Days of Hospital Presentation

EZ/Simva Combo10/40 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

High Risk Patients With Acute Coronary Syndromes

High-Risk STEMINSTE / Unstable Angina

According to IMPROVE-ITEntry Criteria

Cannon CP, et al. Am Heart J 2008;156:826-32.

Simvastatin + Ezetimibe in Aortic Stenosis (SEAS)

Findings

21

SEAS Findings--Primary Endpoint: Major CV Events

Intention-to-Treat Population

0 1 2 3 4 5Years in Study

0

10

20

30

40

50P

erce

ntag

e of

Pat

ient

s W

ith

Firs

t E

vent

EZ/Simva 10/40 mg

Placebo

PlaceboEZ/Simva 10/40 mg

# of Patients at Risk

Hazard ratio: 0.96, p=0.591

906 817 713 618 53 884 791 696 586 56

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

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SEAS Findings– Key Secondary Endpoint: Ischemic CV Events

PlaceboEZ/Simva 10/40 mg# of patients at risk

917 898

867 838

823 788

769 729

76 76

Per

cent

age

of P

atie

nts

With

F

irst

Eve

ntIntention to Treat Population

Years in Study


EZ/Simva 10/40 mg

Placebo

0 1 2 3 4 50

10

20

30


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SEAS Findings--Clinical Adverse Events (AE)

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)

All Patients as Treated Population


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SEAS Findings--Any Cancer

0 1 2 3 4 5Years in Study

0

10

20

30

40

50P

erce

ntag

e of

pat

ient

s w

ith fi

rst e

vent EZ/Simva 10/40 mg

Placebo

Placebo

EZ/Simva 10/40 mg

Number of patients at risk


906

902

867

865

822

833

791

800

86

86

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SEAS Findings--Cancer Mortality

P=0.05 UnadjustedP=0.06 with Yates continuity correction

Years in Study

PlaceboEZ/Simva 10/40 mg# of patients at risk

Hazard ratio: 1.67

930 916

912 890

884 865

855 835

89 94

Per

cent

age

of P

atie

nts

With

F

irst

Eve

nt EZ/Simva 10/40 mg n=39 (4.1 %)

Placebo n=23 (2.5 %)

0 1 2 3 4 50

5

10

Intention-to-Treat Population


What followed…

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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

28

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

29

CTT Meta-Analysis

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

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CTT:Cancer Incidence per mmol/L LDL-C Reduction by Site


31

CTT: Cancer Incidence per mmol/L LDL-C Reduction per Year


Peto Paper

33

Peto Paper


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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


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Cancer Onset– Statin Alone vs. Control from CTT

Nu

mb

er o

f P

atie

nts

wit

h C

ance

r O

nse

t in

Tri

als

582

511

613588 588

503

590616

488535

0

100

200

300

400

500

600

700Statin (N=45,054) Control (N=45,002)

Year of Onset

0-1 >1-2 >2-3 >3-4 >4


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Relative Risk of Cancer Per Year– Ezetimibe and Simvastatin


37

Relative Risk of Cancer by Outcome

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

= 99% CI = 99% CI


38

Relative Risk of Fatal Cancer by Year

Trend test: 2 = 1.35 (P = 0.25)

= 99% CI = 99% CI


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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


Reactions to Peto Paper

41

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

42

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%

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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

Fleming TR. N Engl J Med 2008; 359:1400-1402

44

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.

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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

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

46

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


47

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


48

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/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformationforheathcareprofessionals/ucm194964.htm

http://www.ctsu.ox.ac.uk/news/ctsu-response



49

SHARP: Cancer incidence

0 1 2 3 4 5 0

5

10

15

20

25

Prop

ortio

n su

fferin

g ev

ent (

%)

Placebo Eze/simv

Risk ratio 0.99 (0.87 – 1.13) Logrank p=0.89

Years of follow-up Baigent et. al. American Society for Nephrology, Nov. 2010.

Statistical Issues

51

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)

52

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

Concluding Remarks

54

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

55

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.

56

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.

Backups

58

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


59

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


cancer risk– does ezetimibe or ezetimibe/simvastatin increase it? adam polis, merck niss...

Documents

background slide

ezetimibe ezetimibe

simvastatin simvastatin

mortality slide

seas simvastatin ezetimibe

marketed statin

us label

simvastatin dosage strengths