An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Aortic Stenosis
Interventions:	Drug: ezetimibe (+) simvastatin Drug: Comparator: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Phase III. Study Initiation Date (FPI) was 06-Jan-2003 and Study Completion Date (LPO) was 17-Apr-2008. Primary therapy period 02-Mar-2001 to 31-Mar-2008 includes start date of therapy from the Simvastatin in Aortic Stenosis (SAS) study. 173 study centers worldwide (Denmark, Finland, Germany, Great Britain, Ireland, Norway, and Sweden)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Included patients with asymptomatic aortic stenosis as assessed on echocardiography, not requiring lipid-lowering therapy, and without known coronary heart disease or diabetes mellitus. 4 week placebo/diet run-in period was followed by treatment period lasting until 4 years after the last patient was randomized.

Reporting Groups

	Description
EZ/Simva 10/40 mg	Ezetimibe 10 mg + Simvastatin 40 mg
Placebo	No text entered.

Participant Flow: Overall Study

	EZ/Simva 10/40 mg	Placebo
STARTED	944	929
COMPLETED	939 ^[1]	918 ^[2]
NOT COMPLETED	5	11
Lost to Follow-up	0	2
Adminstrative	5	9

[1]	EZ/Simva: 694 (on drug), 140 (after drug discon), 105 (at death)
[2]	Placebo: 698 (on drug), 120 (after drug discon), 100 (at death)

Baseline Characteristics

Hide Baseline Characteristics

Reporting Groups

	Description
EZ/Simva 10/40 mg	Ezetimibe 10 mg + Simvastatin 40 mg
Placebo	No text entered.

Baseline Measures

	EZ/Simva 10/40 mg	Placebo	Total
Number of Participants [units: participants]	944	929	1873
Age [units: years] Mean ( Full Range )	67.7 ( 41 to 86 )	67.4 ( 28 to 85 )	67.5 ( 28 to 86 )
Gender [units: participants]
Female	363	360	723
Male	581	569	1150
Race/Ethnicity, Customized [units: participants]
White	940	928	1868
Asian	3	1	4
Other	1	0	1
High-density Lipoprotein Cholesterol (HDL-C) [units: mmol/L] Mean ± Standard Deviation	1.49 ± 0.43	1.49 ± 0.43	1.49 ± 0.43
Low-density Lipoprotein Cholesterol (LDL-C) [units: mmol/L] Mean ± Standard Deviation	3.62 ± 0.93	3.59 ± 0.91	3.60 ± 0.92
Peak Transaortic Jet Velocity [units: m/sec] Mean ± Standard Deviation	3.09 ± 0.55	3.10 ± 0.54	3.09 ± 0.54
Total Cholesterol [units: mmol/L] Mean ± Standard Deviation	5.76 ± 1.04	5.73 ± 0.99	5.74 ± 1.02
Triglycerides (TG) [units: mmol/L] Mean ± Standard Deviation	1.42 ± 0.71	1.42 ± 0.68	1.42 ± 0.69

Outcome Measures

Show All Outcome Measures

1. Primary:

Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of MCE (Major Cardiovascular Events) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 1

2. Secondary:

Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of AVE (Aortic Valve Events) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 2

3. Secondary:

Number of Participants That Experienced One or More Components of the Composite Clinical Endpoint of ICE (Ischemic Cardiovascular Events) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 3

4. Secondary:

Change From Baseline in Peak Transaortic Jet Velocity [ Time Frame: Baseline to End of follow-up (median = 4.35 years) or pre-aortic valve replacement ]

Show Outcome Measure 4

5. Other Pre-specified:

Cardiovascular Death [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 5

6. Other Pre-specified:

Aortic Valve Replacement (AVR) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 6

7. Other Pre-specified:

Congestive Heart Failure (CHF) Due to Progression of Aortic Stenosis (AS) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 7

8. Other Pre-specified:

Nonfatal Myocardial Infarction (MI) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 8

9. Other Pre-specified:

Coronary Artery Bypass Grafting (CABG) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 9

10. Other Pre-specified:

Percutaneous Coronary Intervention (PCI) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 10

11. Other Pre-specified:

Hospitalization for Unstable Angina [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 11

12. Other Pre-specified:

Nonhemorrhagic Stroke [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 12

13. Other Pre-specified:

Death (Any Cause) [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 13

14. Post-Hoc:

Death Due to Cancer [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 14

15. Post-Hoc:

Incident Cancer [ Time Frame: Entire follow-up (median = 4.35 years) ]

Show Outcome Measure 15

16. Other Pre-specified:

Percent Change in Time Weighted Average Total Cholesterol From Baseline to End of Follow-up [ Time Frame: Baseline to End of follow-up (median = 4.35 years) ]

Show Outcome Measure 16

17. Other Pre-specified:

Percent Change in Time Weighted Average Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to End of Follow-up [ Time Frame: Baseline to End of follow-up (median = 4.35 years) ]

Show Outcome Measure 17

18. Other Pre-specified:

Percent Change in Time Weighted Average High-density Lipoprotein Cholesterol (HDL-C) From Baseline to End of Follow-up [ Time Frame: Baseline to End of follow-up (median = 4.35 years) ]

Show Outcome Measure 18

19. Other Pre-specified:

Percent Change in Time Weighted Average Triglycerides From Baseline to End of Follow-up [ Time Frame: Baseline to End of follow-up (median = 4.35 years) ]

Show Outcome Measure 19

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

Hide More Information

Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
It is important to note that several of the ischemic outcomes making up the composite ischemic endpoint can occur as a causal consequence of aortic stenosis progression itself, or in association with its standard treatment (aortic valve replacement).

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

Publications:

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 Sep 25;359(13):1343-56. Epub 2008 Sep 2.

Steine K, Rossebø AB, Stugaard M, Pedersen TR. Left ventricular systolic and diastolic function in asymptomatic patients with moderate aortic stenosis. Am J Cardiol. 2008 Oct 1;102(7):897-901. Epub 2008 Aug 26.

Publications automatically indexed to this study:

Cramariuc D, Cioffi G, Rieck AE, Devereux RB, Staal EM, Ray S, Wachtell K, Gerdts E. Low-flow aortic stenosis in asymptomatic patients: valvular-arterial impedance and systolic function from the SEAS Substudy. JACC Cardiovasc Imaging. 2009 Apr;2(4):390-9.

Responsible Party:	Executive Vice President, Clinical and Quantitative Sciences, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00092677 History of Changes
Other Study ID Numbers:	2004_050, MK0653A-043
Study First Received:	September 23, 2004
Results First Received:	March 31, 2009
Last Updated:	June 4, 2010
Health Authority:	Norway: Norwegian Medicines Agency