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:	Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment
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

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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

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1. Primary:

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

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2. Secondary:

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

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3. Secondary:

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

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4. Secondary:

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

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5. Other Pre-specified:

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

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6. Other Pre-specified:

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

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7. Other Pre-specified:

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

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8. Other Pre-specified:

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

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9. Other Pre-specified:

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

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10. Other Pre-specified:

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

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11. Other Pre-specified:

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

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12. Other Pre-specified:

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

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13. Other Pre-specified:

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

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14. Post-Hoc:

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

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15. Post-Hoc:

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

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16. Other Pre-specified:

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

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17. Other Pre-specified:

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

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18. Other Pre-specified:

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

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19. Other Pre-specified:

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

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

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 & Co., Inc.
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:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2004_050, MK0653A-043
Study First Received:	September 23, 2004
Results First Received:	March 31, 2009
Last Updated:	November 6, 2009
ClinicalTrials.gov Identifier:	NCT00092677 History of Changes
Health Authority:	Norway: Norwegian Medicines Agency