Clinical trial NCT00202878: IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103)
Official title: A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial - IMPROVE IT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Myocardial Infarction
Keywords: hypercholesterolemia
myocardial infarction
cholesterol
randomized controlled trials
acute coronary syndrome
angina
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
First posted: 2005-09-20
Enrollment: 18144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome (ACS). The primary objective is to evaluate the clinical benefit of Ezetimibe/Simvastatin Combination 10/40 (single tablet, under the brand VYTORIN in the United States) compared with Simvastatin 40 mg. As per the original protocol, if low-density lipoprotein cholesterol (LDL-C) response was inadequate, the dose of simvastatin in the VYTORIN arm or simvastatin arm, could be increased to 80 mg (Note: per June 2011 protocol amendment, criteria for continued use of 80 mg simvastatin were modified and new increases of simvastatin dose to 80 mg were stopped). Clinical benefit will be defined as the reduction in the risk of the occurrence of the composite endpoint of cardiovascular (CV) death, major coronary events, and stroke.


Eligibility criteria: Inclusion Criteria:

* Clinically stable participants may be eligible to enroll within 10 days following hospital admission with high-risk acute coronary syndrome (either ST-elevation myocardial infarction \[STEMI\] or Non-STEMI or unstable angina)
* Participants not taking a statin must have an LDL-C of 125 mg/dl or less. Participants taking a statin must have an LDL-C of 100 mg/dl or less.

Exclusion Criteria:

* Pregnant or lactating woman, or intending to become pregnant
* Participant with active liver disease or persistent unexplained serum transaminase elevation
* History of alcohol or drug abuse
* History of sensitivity to statin or ezetimibe
* A participant for whom discontinuation of existing lipid lowering regimen poses an unacceptable risk.

Primary outcomes:
measure: Time to First Occurrence of Cardiovascular Death, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
timeFrame: Up to approximately 9 years
Secondary outcomes:
measure: Time to First Occurrence of Death From Any Cause, Major Coronary Event, or Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
timeFrame: Up to approximately 9 years
measure: Time to First Occurrence of Coronary Heart Disease (CHD) Death, Non-fatal MI, or Urgent Coronary Revascularization With PCI or CABG ≥ 30 Days After Randomization (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
timeFrame: Up to approximately 9 years
measure: Time to First Occurrence of CV Death, Nonfatal MI, UA With Hospitalization, All Revascularization Occurring ≥30 Days After Randomization, and Non-fatal Stroke (Kaplan-Meier Estimate of Percentage of Participants Experiencing a Qualifying Event)
timeFrame: Up to approximately 9 years
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Blazing MA, Giugliano RP, Cannon CP, Musliner TA, Tershakovec AM, White JA, Reist C, McCagg A, Braunwald E, Califf RM. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. Am Heart J. 2014 Aug;168(2):205-12.e1. doi: 10.1016/j.ahj.2014.05.004. Epub 2014 May 15.
citation: Califf RM, Lokhnygina Y, Cannon CP, Stepanavage ME, McCabe CH, Musliner TA, Pasternak RC, Blazing MA, Giugliano RP, Harrington RA, Braunwald E. An update on the IMProved reduction of outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design. Am Heart J. 2010 May;159(5):705-9. doi: 10.1016/j.ahj.2010.03.004. Epub 2010 Mar 15. No abstract available.
citation: Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3.
citation: Bohula EA, Giugliano RP, Cannon CP, Zhou J, Murphy SA, White JA, Tershakovec AM, Blazing MA, Braunwald E. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015 Sep 29;132(13):1224-33. doi: 10.1161/CIRCULATIONAHA.115.018381. Epub 2015 Sep 1.
citation: Patel SM, Qamar A, Giugliano RP, Jarolim P, Marston NA, Park JG, Blazing MA, Cannon CP, Braunwald E, Morrow DA. Association of Serial High-Sensitivity Cardiac Troponin T With Subsequent Cardiovascular Events in Patients Stabilized After Acute Coronary Syndrome: A Secondary Analysis From IMPROVE-IT. JAMA Cardiol. 2022 Dec 1;7(12):1199-1206. doi: 10.1001/jamacardio.2022.3627.
citation: Fordyce CB, Giugliano RP, Cannon CP, Roe MT, Sharma A, Page C, White JA, Lokhnygina Y, Braunwald E, Blazing MA. Cardiovascular Events and Long-Term Risk of Sudden Death Among Stabilized Patients After Acute Coronary Syndrome: Insights From IMPROVE-IT. J Am Heart Assoc. 2022 Feb 15;11(4):e022733. doi: 10.1161/JAHA.121.022733. Epub 2022 Feb 3.
citation: Oyama K, Giugliano RP, Blazing MA, Park JG, Tershakovec AM, Sabatine MS, Cannon CP, Braunwald E. Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT. J Am Coll Cardiol. 2021 Oct 12;78(15):1499-1507. doi: 10.1016/j.jacc.2021.08.011.
citation: Giugliano RP, Gencer B, Wiviott SD, Park JG, Fuchs CS, Goessling W, Musliner TA, Tershakovec AM, Blazing MA, Califf R, Cannon CP, Braunwald E. Prospective Evaluation of Malignancy in 17,708 Patients Randomized to Ezetimibe Versus Placebo: Analysis From IMPROVE-IT. JACC CardioOncol. 2020 Sep 15;2(3):385-396. doi: 10.1016/j.jaccao.2020.07.008. eCollection 2020 Sep.
citation: Nanna MG, Navar AM, Giugliano RP, White JA, Lokhnygina Y, Mitchel YB, Musliner TA, Cannon CP, Blazing MA. Muscle Complaints or Events in Patients Randomized to Simvastatin or Ezetimibe/Simvastatin. J Am Coll Cardiol. 2020 Feb 25;75(7):835-837. doi: 10.1016/j.jacc.2019.12.022. No abstract available.
citation: Bach RG, Cannon CP, Giugliano RP, White JA, Lokhnygina Y, Bohula EA, Califf RM, Braunwald E, Blazing MA. Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2019 Sep 1;4(9):846-854. doi: 10.1001/jamacardio.2019.2306.
citation: Sharma A, Sun JL, Lokhnygina Y, Roe MT, Ahmad T, Desai NR, Blazing MA. Patient Phenotypes, Cardiovascular Risk, and Ezetimibe Treatment in Patients After Acute Coronary Syndromes (from IMPROVE-IT). Am J Cardiol. 2019 Apr 15;123(8):1193-1201. doi: 10.1016/j.amjcard.2019.01.034. Epub 2019 Jan 25.
citation: Navar AM, Roe MT, White JA, Cannon CP, Lokhnygina Y, Newby LK, Giugliano RP, Tershakovec AM, Braunwald E, Califf RM, Blazing MA. Medication Discontinuation in the IMPROVE-IT Trial. Circ Cardiovasc Qual Outcomes. 2019 Jan;12(1):e005041. doi: 10.1161/CIRCOUTCOMES.118.005041.
citation: Bonaca MP, Gutierrez JA, Cannon C, Giugliano R, Blazing M, Park JG, White J, Tershakovec A, Braunwald E. Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. Lancet Diabetes Endocrinol. 2018 Dec;6(12):934-943. doi: 10.1016/S2213-8587(18)30290-0. Epub 2018 Nov 2.
citation: Simon TG, Corey KE, Cannon CP, Blazing M, Park JG, O'Donoghue ML, Chung RT, Giugliano RP. The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int J Cardiol. 2018 Nov 1;270:245-252. doi: 10.1016/j.ijcard.2018.05.087. Epub 2018 May 26.
citation: Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalan R, Spinar J, Park JG, White JA, Bohula EA, Braunwald E; IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018 Apr 10;137(15):1571-1582. doi: 10.1161/CIRCULATIONAHA.117.030950. Epub 2017 Dec 20.
citation: Kato ET, Cannon CP, Blazing MA, Bohula E, Guneri S, White JA, Murphy SA, Park JG, Braunwald E, Giugliano RP. Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc. 2017 Nov 18;6(11):e006901. doi: 10.1161/JAHA.117.006901.
citation: Bohula EA, Wiviott SD, Giugliano RP, Blazing MA, Park JG, Murphy SA, White JA, Mach F, Van de Werf F, Dalby AJ, White HD, Tershakovec AM, Cannon CP, Braunwald E. Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2017 Dec 19;136(25):2440-2450. doi: 10.1161/CIRCULATIONAHA.117.029095. Epub 2017 Sep 30.
citation: Pokharel Y, Chinnakondepalli K, Vilain K, Wang K, Mark DB, Davies G, Blazing MA, Giugliano RP, Braunwald E, Cannon CP, Cohen DJ, Magnuson EA. Impact of Ezetimibe on the Rate of Cardiovascular-Related Hospitalizations and Associated Costs Among Patients With a Recent Acute Coronary Syndrome: Results From the IMPROVE-IT Trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circ Cardiovasc Qual Outcomes. 2017 May;10(5):e003201. doi: 10.1161/CIRCOUTCOMES.116.003201.
citation: Giugliano RP, Wiviott SD, Blazing MA, De Ferrari GM, Park JG, Murphy SA, White JA, Tershakovec AM, Cannon CP, Braunwald E. Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017 May 1;2(5):547-555. doi: 10.1001/jamacardio.2017.0083.
citation: Bohula EA, Morrow DA, Giugliano RP, Blazing MA, He P, Park JG, Murphy SA, White JA, Kesaniemi YA, Pedersen TR, Brady AJ, Mitchel Y, Cannon CP, Braunwald E. Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention. J Am Coll Cardiol. 2017 Feb 28;69(8):911-921. doi: 10.1016/j.jacc.2016.11.070.
citation: Murphy SA, Cannon CP, Blazing MA, Giugliano RP, White JA, Lokhnygina Y, Reist C, Im K, Bohula EA, Isaza D, Lopez-Sendon J, Dellborg M, Kher U, Tershakovec AM, Braunwald E. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016 Feb 2;67(4):353-361. doi: 10.1016/j.jacc.2015.10.077.
citation: Azar RR, Badaoui G, Sarkis A, Azar M, Aydanian H, Harb S, Achkouty G, Kassab R. Effect of ezetimibe/atorvastatin combination on oxidized low density lipoprotein cholesterol in patients with coronary artery disease or coronary artery disease equivalent. Am J Cardiol. 2010 Jul 15;106(2):193-7. doi: 10.1016/j.amjcard.2010.03.016.
citation: Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM, Strony J, Musliner TA, McCabe CH, Veltri E, Braunwald E, Califf RM; IMPROVE-IT Investigators. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008 Nov;156(5):826-32. doi: 10.1016/j.ahj.2008.07.023. Epub 2008 Sep 2.
citation: 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. doi: 10.1056/NEJMsa0806603. Epub 2008 Sep 2.
citation: Drazen JM, Jarcho JA, Morrissey S, Curfman GD. Cholesterol lowering and ezetimibe. N Engl J Med. 2008 Apr 3;358(14):1507-8. doi: 10.1056/NEJMe0801842. Epub 2008 Mar 30. No abstract available.