Cardiovascular diseases;Patients with a history of coronary heart disease (CHD) or acute coronary syndrome (ACS) benefit more from treatment with a statin in combination with ezetimibe than from treatment with a statin alone. However, there is no hint that the combination therapy of a statin plus ezetimibe is also superior to the combination of a statin plus the lipid lowering drug alirocumab. No studies on other lipid-lowering combination options were available.
Cardiovascular diseases are diseases that originate from the vascular system and/or the heart. These include hypertension, CHD, ACS, heart attack and stroke. Cardiovascular diseases were the most common cause of death worldwide in 2016, accounting for 31% of all deaths. Of these causes of death, 85% result from a heart attack or stroke.
One of the largest modifiable risk factors for cardiovascular diseases is a high LDL cholesterol level. The reduction in LDL cholesterol (LDL-C) is therefore an important goal in the prevention of cardiovascular diseases. In patients with a history of CHD or ACS, the administration of cholesterol-lowering drugs is recommended. Statins are currently the most commonly prescribed group of drugs in this regard.
On behalf of the G-BA, the IQWiG researchers investigated the benefit of treatment with ezetimibe in combination with a statin to reduce the risk of cardiovascular events in patients with a history of CHD or ACS with regard to patient-relevant outcomes—versus treatment with a statin alone (research question 1); also versus treatment with a combination of a statin and another drug influencing lipid metabolism (research question 2).
The assessment of research question 1 was ultimately based only on the IMPROVE-IT study. The other studies identified did not contain any relevant additional information. The IMPROVE-IT study include 18,144 patients who had experienced an ACS within 10 days prior to randomization. The study was designed to examine the effect of ezetimibe on clinical outcomes (the primary outcome was a combined outcome of fatal and non-fatal cardiovascular events) rather than on surrogate outcomes (such as a reduction in LDL-C). The median follow-up period was six years.
Existing statin therapy
For research question 2, the IQWiG researchers identify COMBO II as the only relevant study. This randomize control trial include 720 patients with a high to very high cardiovascular risk whose LDL-C levels were insufficiently control with an existing statin therapy. The primary outcome of the study was the change in LDL-C levels after 24 weeks compare with baseline. The “other drug influencing lipid metabolism” was alirocumab.
In patients with a history of CHD or ACS, the IQWiG researchers see an indication of a greater benefit; hence of ezetimibe in combination with a statin versus a statin alone (research question 1). For these patients, the additional administration of ezetimibe reduces; the risk of suffering a major adverse cardiovascular event. In the benefit assessment, serious adverse cardiovascular events; so were evaluate as a combine outcome of the patient-relevant components of cardiovascular death; non-fatal myocardial infarction, and non fatal stroke.
For the combined outcome “major adverse cardiovascular event,” the COMBO II study did not provide data for the relevant subpopulation. Therefore, the IQWiG team assess the individual components separately; hence for “non-fatal myocardial infarction,” “fatal and non-fatal stroke” and “hospitalization due to unstable angina pectoris,” there were no statistically relevant differences between the treatment groups. However, due to the relatively small number of patients, the data are just as inadequate as for the outcome “all-cause mortality.”