Effect of Lipoprotein(a) Elimination by Lipoprotein Apheresis on Cardiovascular Outcomes

Study Overview
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Brief Summary
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This multicenter multinational prospective two-arm matched-pair observational study aims to establish a prospective comparison of active lipoprotein apheresis treatment approved and conducted according to German guidelines for the indication of elevated Lp(a) versus a maximum tolerated lipid-lowering therapy as standard care. Due to the prospective character and the inclusion of a control arm, this will be the first clinical study that can confirm the relevance of the established approach to use lipoprotein apheresis in those subjects and its effects to reduce the individual cardiovascular risk. The optimized management of subjects in the control group (not receiving lipoprotein apheresis) will also help to clarify the controversial issue, to which extent intensive medical care per se can influence the occurence of subsequent cardiovascular events. Primary objective of the trial is to evaluate the clinical benefit of Lp(a) reduction using lipoprotein apheresis on myocardial infarction, PCI, CABG, fatal and non- fatal stroke, transient ischemic attack, interventional or surgical revascularization of peripheral arteries and death from cardiovascular disease. The primary objective of this study evaluates the clinical benefit of weekly lipoprotein apheresis in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee as indication for subjects with elevated Lp(a). Comparator will be matched subjects under maximum tolerated lipid lowering therapy without access to lipoprotein apheresis treatment. The clinical benefit will be defined as the reduction of the composite endpoint of major adverse cardiovascular events (MACE), defined as either myocardial infarction, PCI, CABG, fatal and non-fatal stroke, transient ischemic attack or death from cardiovascular disease over a period of at least 2 years after completion of visit 1b and until at least 60 events of the primary end-point occurred in group B. If the number of at least 60 documented primary endpoint events within 2 years of the completion of enrolment did not occur, the study will continue until this number of primary endpoint events has accumulated.

Official Title
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A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by Lipoprotein Apheresis on Cardiovascular Outcomes

Conditions
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Lipoprotein Types--Lp System Lp(A) Hyperlipoproteinemia

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 70 Male or female Written informed consent Lipoprotein(a) > 60 mg/dL, or > 120 nmol/L using an alternative laboratory method Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment. Established cardiovascular disease with disease progression indicated by one major cardiovascular event, which might be either myocardial infarction PCI CABG Stroke or revascularization of peripheral arteries using PTA, stenting or bypass surgery (with or without subsequent cardiovascular events/interventions) despite adequately controlled cardiovascular risk factors* occuring within the last 2 years prior to enrolment (*Hypertension, Diabetes, tobacco consumption, LDL Cholesterol) Platelet aggregation inhibitors or systemic anticoagulation according to cardiologic indication Positive recommendation by central Trial Expert Committee Exclusion Criteria: Previous lipoprotein apheresis therapy Triglyceride concentrations ≥ 250 mg/dL (2.8 mmol/L) Known homozygous or compound heterozygous familial hypercholesterolemia Known type III hyperlipoproteinemia Pregnancy, breast feeding Active smoking, defined as any inhaled tobacco consumption with in the last 3 months Uncontrolled hypertension (>160/90 mmHg) Active malignant disease Planned major surgical procedures Current participation in an interventional trial Contraindication for apheresis therapy (e. g. necessity of ACE inhibitor therapy) CKD stages IV and V Diabetes mellitus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group A: Lipoprotein apheresis subjects<br>Established cardiovascular disease with disease progression indicated by one major cardiovascular event. With or without subsequent cardiovascular events/interventions, despite adequately controlled cardiovascular risk factors occuring within the last 2 years prior to enrolment. Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment. Additional lipoprotein apheresis is established following enrolment using the following established systems: Dextran-sulfate adsorption (DSA) from plasma and whole blood, Heparin-induced LDL precipitation apheresis (HELP®), Polyacrylate adsorption from whole blood and simple DFPP (DALI® and Monet®), ApoB100-immunoadsorption (TheraSorbLDL®, Temperature-optimized double filtration plasmapheresis (DFPP). | |
| Group B: Control group<br>Established cardiovascular disease with disease progression indicated by one major cardiovascular event. With or without subsequent cardiovascular events/interventions, despite adequately controlled cardiovascular risk factors occuring within the last 2 years prior to enrolment. Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment. The control group will not undergo a sham apheresis procedure. It is an open trial. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary end-point is an at least 10 % reduction of the proportion of events | The primary end-point is an at least 10 % reduction of the proportion of events regarding the composite end-point consisting either of myocardial infarction, PCI, CABG, fatal and non-fatal stroke, transient ischemic attack, interventional or surgical revascularization of peripheral arteries or death from cardiovascular disease (or any combination of these) at the final visit. | 2 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| An at least 10 % reduction of the proportion of events | An at least 10 % reduction of the proportion of events regarding the composite endpoint of cardiovascular death, major coronary event, cerebrovascular accidents and stroke. | 2 years of follow-up | 
| An at least 10 % reduction of the proportion of events | An at least 10 % reduction of the proportion of events regarding the composite endpoint of cardiovascular death, major coronary events and all cerebrovascular events. | 2 years of follow-up | 
| An at least 10 % reduction of the proportion of events regarding the composite Secondary endpoints of the Trial | An at least 10 % reduction of the proportion of events regarding the composite endpoint of CV death, non-fatal MI, documented unstable angina that requires admission into a hospital, all revascularization (including both coronary and non-coronary) occurring at least 30 days after the MACE event, the rate of in-stent restenosis and non-fatal stroke. | 2 years of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lipoprotein(a), lipoprotein/lipid apheresis, CV disease