WHEN DISTORTED EVIDENCE-BASED MEDICINE LEADS TO OVERTREATMENTThe IMPROVE-IT trial caseErviti J, Saiz LC, Aranguren I, Azparren A, García I, Garjón J.Navarre Regional Health Service, Pamplona, Spain

Ezetimibe was an evidence-lacking drug

SEAS trial showed no differences vs placebo in patients with aortic valve stenosis. SHARP trial only compared combination ezetimibe/simvastatin vs placebo in patients with chronic kidney disease. There was scarcity of morbi-mortality data.

IMPROVE-IT trial to fix this situation?

Patients aged ≥ 50 years with LDL-C 50-125 mg/dL (50-100 mg/dL with previous lipid-lowering therapy), hospitalized within the previous ten days for acute coronary syndrome with associated CV risk factors such as diabetes mellitus, previous coronary angiography or percutaneous coronary intervention during the index hospitalization.

ezetimibe 10 mg/simvastatin 40 mg vs placebo/simvastatin 40 mg

IMPROVE-IT results are not directly applicable to

●all ACS patients ●primary prevention of cardiovascular disease in high-risk patients

●secondary prevention after atherothrombotic events other than ACS

• Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372:2387-2397• FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC). December 14, 2015• Erviti J. The IMPROVE-IT trial (ezetimibe added to simvastatin for acute coronary syndrome). A critical appraisal. Drug and Therapeutics Bulletin of Navarre (Spain) 2015; 23 (5):1-8

A critical appraisal

No data on blinding and randomization concealment methods

Enlargement in the search of statistical significance

Planned:10,000 patients2.5 years

Amended to12,500 patients

Amended to18,000 patients

7 years

p<0.05

Statistical significance was inappropriately attained after imputing data to the 11% patients for whom ACS-episode data were lacking

Pre-specified minimum relevant

difference

Clinically non-relevant differences

Favours ezetimibe Favours placebo

Absolute risk differences clinically irrelevant

In spite of this

Navarre: population 640,000

4,158 patients received ezetimibe

63.5% ezetimibe without statin

44.8% for primary CV prevention

2.6% for familial hypercholesterolemia

Cost 1.7 million € Data as of 2015

The IMPROVE-IT trial does not provide sufficient evidence supporting the use of ezetimibe in combination with a statin for ACSThe FDA advisory committee recommended prohibiting the pharmaceutical company from promoting the addition of ezetimibe to simvastatin to reduce the incidence of cardiovascular eventsOvertreatment risk with ezetimibe should be seriously considered and actively managed

www.dtb.navarra.es