IMPROVE-IT ( IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial ), was an international, multi-center, randomised, double-blind active comparator trial of 18,144 high-risk patients presenting with acute coronary syndromes ( ACS ), including unstable angina ( UA ), non-ST-segment elevation acute myocardial infarction ( NSTEMI ), and ST-segment elevation acute myocardial infarction ( STEMI ).
The study assessed the incidence of major cardiovascular events, as measured by a composite of cardiovascular death, non-fatal MI, non-fatal stroke, re-hospitalisation for ACS, or coronary revascularisation ( occurring 30 days or more after the initial event ), in patients treated with Simvastatin plus Ezetimibe compared with patients treated with Simvastatin alone.
All patients in the trial were started at doses of Ezetimibe / Simvastatin 10/40 mg or Simvastatin 40 mg. Prior to a 2011 protocol amendment, the dose could be titrated to Ezetimibe / Simvastatin 10/80 mg or Simvastatin 80 mg if successive LDL-C values exceeded 79 mg/dL ( 2 mmol/L ).
The study enrolled patients within 10 days of ACS hospitalisation who had sufficient risk as defined in the protocol and who had an initial LDL-C of less than or equal to 125 mg/dL ( 3.2mmol/L ) if lipid-lowering drug naïve or less than 100 mg/dL ( 2.6mmol/L ) if on a prior prescription lipid-lowering therapy identified as no more potent than Simvastatin 40 mg/day.
IMPROVE-IT compared very low LDL-C levels ( a range at or below 70 mg/dL [ 1.81mmol/L ] ).
The LDL-C entry limitations were designed to enroll patients reasonably anticipated to achieve LDL-C levels of 70 mg/dL ( 1.81mmol/L ) or less in the Simvastatin only cohort, which was the optional recommended target set in the 2004 update to the Adult Treatment Panel ( ATP ) III guidelines.
This is also in line with the The European Society of Cardiology guidelines that recommend less than 1.8 mmol/L for those at very high risk or a 50% LDL cholesterol reduction when the target level cannot be reached.
At one year, the mean LDL-C level was 1.37mmol/L ( 53 mg/dL ) in the Ezetimibe / Simvastatin and 1.81 mmol/L ( 70 mg/dL ) in the Simvastatin group, with a between-group difference of 0.44mmol/L ( 17 mg/dL ).
Prior cardiovascular outcomes studies of statins have not compared treatments at such low LDL-C levels.
At the start of the study, the average baseline LDL-C was approximately 95 mg/dL ( 2.46 mmoL/L ).
Among treatment-naïve patients ( about two-thirds of those in the study ), the mean baseline LDL-C was 101 mg/dL ( 2.62mmol/L ).
Among patients on prior lipid lowering therapy at enrollment, the mean baseline LDL-C was 80 mg/dL ( 2.07mmol/L ).
Patients were followed for up to nine years, with a median clinical follow-up of approximately six years.
In this event-driven study, 5,314 primary endpoint events were reported. In addition to the significant result on the primary composite efficacy endpoint, patients taking Ezetimibe / Simvastatin experienced significant reductions compared to patients taking Simvastatin alone on the three secondary composite efficacy endpoints, as follows:
Ezetimibe / Simvastatin reduced the incidence of the composite endpoint of death due to all causes, major coronary events, and non-fatal stroke; this endpoint occurred in 38.7% of patients taking Ezetimibe / Simvastatin and 40.3% of patients taking Simvastatin only ( hazard ratio of 0.948, p=0.034 );
Ezetimibe / Simvastatin reduced the incidence of the composite endpoint of death due to coronary heart disease ( CHD ), non-fatal myocardial infarction ( MI ), and urgent coronary revascularisation with either percutaneous coronary intervention ( PCI ) or coronary artery bypass graft ( CABG ) occurring at least 30 days after randomisation; this endpoint occurred in 17.5% of patients taking Ezetimibe / Simvastatin and 18.9% of patients taking Simvastatin only ( hazard ratio of 0.912, p=0.016 );
Ezetimibe / Simvastatin reduced the incidence of the composite endpoint of cardiovascular death, non-fatal myocardial infarction, documented unstable angina that requires admission into a hospital, all revascularisation ( including both coronary and non-coronary ) occurring at least 30 days after randomisation, and non-fatal stroke; this endpoint occurred in 34.5% of patients taking Ezetimibe / Simvastatin and 36.2% of patients taking Simvastatin only ( hazard ratio of 0.945, p=0.035 ).
Ezetimibe is a cholesterol absorption inhibitor, licensed for the following indications: a) Ezetimibe, co-administered with a statin, is indicated as adjunctive therapy to diet in patients with primary ( heterozygous familial and non-familial ) hypercholesterolaemia who are not appropriately controlled with a statin alone; b) Ezetimibe monotherapy is indicated as adjunctive therapy to diet in patients with primary ( heterozygous familial and non-familial ) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated; c) Ezetimibe, co-administered with a statin, is indicated as adjunctive therapy to diet in patients with homozygous familial hypercholesterolaemia. Patients may also receive adjunctive treatments; d) Ezetimibe is indicated as adjunctive therapy to diet in patients with homozygous familial sitosterolaemia.
With Simvastatin as a combination product, Ezetimibe is licensed for the following indications: a) as adjunctive therapy to diet for use in patients with primary ( heterozygous familial and non-familial ) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate; b) as adjunctive therapy for diet for use in patients with homozygous familial hypercholesterolaemia. Patients may also receive adjunctive treatments ( e.g. low-density lipoprotein apheresis ).
In clinical studies, the overall incidence of side effects was similar between Ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between Ezetimibe and placebo.
The most common side effects ( greater than or equal to 1/100 to less than 1/10 ) include abdominal pain; diarrhoea; flatulence and feeling tired.
Less frequent side effects ( up to 1% ) include increases in liver transaminases, elevation of muscle ( CK ) function, cough, indigestion, heartburn, nausea, joint pain, muscle spasms, decreased appetite, pain, hot flushes, chest pain, or high blood pressure.
Adding Ezetimibe to statin therapy has been found to have a similar side effect profile to using statin therapy alone. ( Xagena )
Source: MSD UK, 2014