Unmet LDL-C target in very high risk cardiovascular patients

Hyperlipidaemia is one of the important risk factors in developing cardiovascular disease. LDL-C of <1.8 mMol/L or a reduction of at least 50% is recommended for very high risk patients. Different classes of lipid- modifying drugs are available. In patients with hypercholesterolaemia or combined hyperlipidaemia, statin mono-therapy is first choice therapy. In a large proportion of patients on statin mono-therapy, however, therapeutical target LDL-C levels are not reached, and ezetimibe should be added. If target LDL-C levels are unmet despite statin-ezetimibe combination therapy, a PCSK9 inhibitor (PCSK9-i) may be added.



In real world care, the proportion of patients with atherosclerotic cardiovascular disease (ASCVD) not reaching target LDL-C levels despite consecutive therapy with statin mono-therapy, statin + ezetimibe or statin + ezetimibe + PCSK9-i is unknown.



In the Netherlands and many other European countries, reimbursement of the PCSK9-i is restricted to a subgroup of “very high risk patients” not reaching target LDL-C levels despite statin-ezetimibe combi-therapy.



In the present study, the prevalence of very high risk patients with ASCVD who remain at very high-residual risk for an acute coronary syndrome (ACS), defined as an LDL-C >1.8 mmMol/L (or non-HDL >2.6 mMol/l) will be analysed by a prospective, stepwise implementation of high intensity statin mono-therapy, followed by high intensity statin + ezetimibe combination-therapy if LDL-C still >1.8 mMol/L after 4 weeks of statin mono-therapy. Lipid levels will be measured 4 weeks after initiation of each step. A subset of patients whose LDL-C remains >1.8 mMol/L despite this intervention, will be treated with the PCSK9 inhibitor Alirocumab, 75 or 150 mg, and the efficacy of this therapy will be measured by lipid levels after 4 weeks of therapy.

To assess the prevalence of LDL-C >1.8 mMol/L in a subgroup of very high risk patients with ASCVD, who remain at a very high-residual risk for ACS, despite treatment with high-intensity statins in combination with ezetimibe. This subgroup of very high risk patients is defined as patients with a history of ASCVD and/or diabetes mellitus type II (T2DM), and a new type I ST elevation or non-ST elevation myocardial infarction ([N]STEMI).

A prospective, open label, stepwise cohort study of consecutive patients admitted for type I STEMI or NSTEMI, characterized by a rise and/or fall of troponin with at least one value above the 99th percentile upper reference limit, and a history of ASCVD and/ or T2DM.



Patients with an LDL-C≤1.8 mMol/L at baseline will be registered, but not included in the study. All patients with an LDL-C>1.8 mMol/L, with or without therapy with statins and/or ezetimibe at baseline, will be treated with high-intensity statin therapy (i.e., atorvastatin ≥40 mg or rosuvastatin ≥20 mg or the maximum tolerated dose of a statin) for a period of 4 weeks. Lower statin doses are acceptable for patients with a valid reason for not using high intensity doses (advanced age and high frailty score, low body weight, drug-drug interaction). Patients with known statin-attributed muscle symptoms or who develop statin-attributed muscle symptoms during the study will be treated following the therapeutic flow-chart for management of patients with statin-associated muscle symptoms of the EAS Consensus Panel.



After 4 weeks, lipids are measured. If LDL-C >1.8 mMol/L, ezetimibe 10 mg is added on top of statin therapy. Patients with documented statin intolerance to at least three different statins, as defined by the EAS Consensus Panel, will be treated with 10 mg ezetimibe mono-therapy. Four weeks later lipids are measured, and if LDL-C >1.8 mMol/L, alirocumab will be added on top of current treatment with a statin and ezetimibe, in accordance with the following dosing-schedule:

• if 1.8<LDL-C<2.6 mMol/L, at the investigator’s discretion no alirocumab, or alirocumab 75 mg, or alirocumab 150 mg will be added

• if 2.6≤LDL-C<3.6 mMol/L, at the investigator’s discretion alirocumab 75 mg or alirocumab 150 mg will be added

• if LDL-C≥3.6 mMol/L, alirocumab 150 mg will be added

Two weeks after the second dose of alirocumab, lipids are measured.

Patients are treated according to cholesterol treatment guidelines, with a step-wise approach (HIST, + ezetimibe, HIST+ ezetimibe + PCSK9-i The choice of PCSK9 inhibitor is directed by the protocol. When a PCSK-9 inhibitor needs to be prescibed, alirocumab is the drug of choice

There are no additional risks or burden for study participants.

The burden for the patient is limited to the drawing of blood samples (at 4, 8 and 12 weeks and 12 months), all of which are standard of care. For this study no extra visits or physical examinations are required.