Does Regular Lipid Apheresis Therapy for Patients With Isolated Elevated
Lipoprotein(a) Levels Reduce the Incidence of Cardiovascular Events?
Patrick M. MoriartyProfessor of Medicine
Director of Clinical Pharmacology andThe Atherosclerosis and Lipid-apheresis Center
(University of Kansas)
Conflict of Interest
COMMERCIAL INTEREST RELATIONSHIP CATEGORY ROLE
Amgen, Inc. Research, grants Principle InvestigatorKowa Pharmaceuticals America Inc., Lilly USA, LLC Research, grants
Investigator initiated trialDSMB
Novartis Pharmaceuticals, Corp Research, grants Principle Investigator
Sanofi (Regeneron, Genzyme)Research, Grants,
Consult Fees, HonorariaPrinciple Investigator
speaker
Amarin Pharma Inc. Research, grants Principle Investigator
Pfizer, Inc. Research, grants Principle Investigator
Catabasis Research, grants Principle Investigator
Espirion Research, grants Principle Investigator
B. Braun, Kaneka Inc. Research, grants Investigator initiated trial
Overview
• Lp(a): Its association with CVD.
• Background of Lipid-apheresis.
• Clinical trials.
• Potential mechanism.
Risk of myocardial infarction by levels of Lp(a) in the general population.
Nordestgaard B G et al. Eur Heart J 2010;31:2844-2853
Typical distributions of lipoprotein(a) levels in the general population. These graphs are based on non-fasting fresh serum samples from 3000 men and 3000 women from the Copenhagen General Population Study collected from 2003 through 2004. Green color indicates levels below the 80th
percentile, whereas red color indicates levels above the 80th percentile.
0 50 100 150 200 0 50 100 150 200Lp(a) mg/dLLp(a) mg/dL
Frac
tion
of p
opul
atio
n
Men Women
20% 20%
Nordesgaard BG et al. Eur Heart J. 2010 (23):2844-53
Distribution of Lp (a) Levels in the General Population
Association of the LPA Genotype Score with Lp(a) Levels and the Risk of CHD
in the PROCARDIS Cohort
Clarke R et al. N Engl J Med 2009;361:2518-2528
In all subjects at intermediate or high risk of CVD/CHD with:
•Premature CVD.•Familial hypercholesterolemia. •A family history of premature CVD and/or elevated Lp(a). •Recurrent CVD despite statin treatment. •≥3% 10-year risk of fatal CVD (European guidelines).•≥10% 10-year risk of fatal/non-fatal CHD (American guidelines).•Repeat measurement if treatment for Lp(a) levels is initiated.
When to Measure Plasma Level of Lp(a)
Nordesgaard BG et al. Eur Heart J. 2010 Dec;31(23):2844-53
Therapeutic Agents For Decreasing Lp(a)Agent MechanismEstrogen Acts on LPA promoterAnabolic Steroids May act on gene expressionTocilizumab IL-6 receptor antagonistFXR Acts on hepatic LPA gene expressionAspirin Reduces LPA expressionApheresis Removes LDL/Lp(a) Niacin Inhibits DGAT2 with apoB degradationStatins Increase LDLR and LDL degredationAnacetrapib CETEP inhibitor and lowers LDLEprotirone Thyroid mimetic. Increase LDLR and LDL clearencePCSK9 inhibitors Increase LDLR and decrease Lp(a)PUFA Long term consumptionCarnitine Increase mitochondrial B-oxidationMipomersen Antisense nucleotide, decreases LDL synthesisApoB Peptides Inhibit Lp(a) assembly
Hoover-Plow J,et al. Metabolism Volume 62, Issue 4, 2013; 479 - 491
The odds of MACE for those subjects* with the highest levels of Lp(a)
O'Donoghue M., et al. JACC, Vol.63, 2014, 520-27.
* Meta-Analysis of Published Studies in Secondary Prevention.
The odds of MACE for those subjects* with the highest levels of Lp(a) stratified
by LDL-c concentration
O'Donoghue M., et al. JACC, Vol.63, 2014, 520-27.
* Meta-Analysis of Published Studies in Secondary Prevention.
A Randomized Trial of Rosuvastatin in the Preventionof Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels of C-Reactive Protein (hsCRP):
The JUPITER Trial*
Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*,
James Shepherd*, James Willerson, and Robert Glynn* on behalf of the JUPITER Trial Study Group
Ridker PM, et al. N Engl J Med 2008;359:2195-207.
*Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69P < 0.00001
- 44 %
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cum
ulat
ive
Inci
denc
e
Follow-up (years)
Ridker PM, et al. N Engl J Med 2008;359:2195-207.
mg/dL Baseline Follow-up
LDL-C 108 (94-119) 55 (44-70)
JUPITER Trial
Lipoprotein(a) Concentrations, Rosuvastatin Therapy, and Residual Vascular Risk
by Amit V. Khera, Brendan M. Everett, Michael P. Caulfield, Feras M. Hantash, Jay Wohlgemuth, Paul M Ridker, and Samia Mora
CirculationVolume 129(6):635-642
February 11, 2014
JUPITER Trial
Association Between Baseline Lipoprotein(a) and Incident CVD Among White Participants in JUPITER
•Model One: Adjusted for age, sex, and treatment group.•Model Two: Adjusted for age, sex, treatment group ,Tob, FH, BMI, SBP, FG, HDL-c, LDL-c, Trigs, and hsCRP
Khera A V et al. Circulation. 2014;129:635-642
Efficacy of rosuvastatin* according to Baseline Lp(a)
Khera A V et al. Circulation. 2014;129:635-642
*On-statin Lp(a) concentrations were associated with residual risk of CVD (adjusted hazard ratio, 1.27; 95% CI, 1.01-1.59; P=0.04), which was independent of LDL-c and other factors.
“In patients with evidence of progressive coronary disease and markedly elevated plasma Lp(a), serious consideration should be given to instituting Lipid-apheresis.”
-2010 European Atherosclerosis Society Consensus Panel on Lp(a)
Nordesgaard BG et al. Eur Heart J. 2010 (23):2844-53
Plasmapheresis
Preparative Plasmapheresis Therapeutic Plasmapheresis
Conserved Plasma Plasma Fractions Blood cells
Coagulation Factors
Fresh-frozen-Plasma
Human Albumin
Plasma Protein
ConcentratesLeukocyte Erythrocyte
Thrombocyte Concentrates
non-selective semi-selective selective
Ion Exchange Adsorption
Cascade Filtration
Enzyme Adsorption (Bioreaction)
Therapeutic Plasma
Exchange
Cryofiltration Immuno-adsorption
Activated Charcoal
Adsorption
Protein A
LDL-Apheresis
Heparin Precipitation
Dextransulfate Adsorption
Immunoadsorption
Hemopheresis
Phenylalanin
Tryptophan
Collection of blood components
Removal of
blood components
Immuno-adsorption
Lipid-Apheresis Procedures
Plasma Exchange Plasma substitution Single use and non-selective
Cascade Filtration Plasma filtrationSingle use and semi-selective
Dextran sulfate Adsorption Liposorber, Plasma adsorption Single use and selective
Immuno Adsorption Therasorb and Lipopak, Plasma adsorptionReuse and selective
Heparin Precipitation H.E.L.P., Plasma modulationSingle use and selective
Polyacrylamide Adsorption Whole blood adsorption Single use and selective
Mean Percentage Reduction of Plasma Proteinswith Different Methods of Lipid-Apheresis
mg/dL MDF Lipid Filtration HELP DALI DSA IA*
LDL-C 56-62% 61% 55-61% 53-76% 49-75% 62-69%HDL-C 25-42% 6% 5-17% 5-29% 4-17% 9-27%Lp(a) 53-59% 61% 55-68% 28-74% 19-70% 51-71%Triglycerides 37-49% 56% 20-53% 29-40% 26-60% 34-49%Fibrinogen 52-59% 42% 51-58% 13-16% 17-40% 15-21%
High variation of values are partially due to differences in treated plasma and blood volumes.MDF, membrane differential filtration; HELP, heparin-induced extracorporeal LDL precipitation; DALI, direct adsorption of lipoproteins; DSA, dextran sulfate adsorption; IA*, immunoadsorption.
Moriarty PM. Clinical Lipidology, Ballantyne: A Companion to Braunwald’s Heart Disease; 363-74. 2009
Mean Percentage Reduction of Plasma Proteinswith Different Methods of Lipid-Apheresis
mg/dL MDF Lipid Filtration HELP DALI DSA IA*
Lp(a) 53-59% 61% 55-68% 28-74% 19-70% 51-71%
High variation of values are partially due to differences in treated plasma and blood volumes.MDF, membrane differential filtration; HELP, heparin-induced extracorporeal LDL precipitation; DALI, direct adsorption of lipoproteins; DSA, dextran sulfate adsorption; IA*, immunoadsorption.
Moriarty PM. Clinical Lipidology, Ballantyne: A Companion to Braunwald’s Heart Disease; 363-74. 2009
*A type of immunoadsorption system uses antibodies to Lp(a) to remove only Lp(a).Lipopak (POCARD Ltd., Russia) = 80-85% reduction of Lp(a)
LDL-C > 200 mg/dL (with CHD)
LDL-C > 300 mg/dL (without CHD)
International Guidelines forInitiating Lipid-Apheresis
North America
Japan TC > 250 mg/dL (with CHD)
Germany LDL-C > 130 mg/dL (with CHD)
Lp(a) > 60mg/dL (with progressive CHD)*
*German federal Committee of Physicians and Health Insurance Funds. June 2008.
Longitudinal Cohort Study on the effectiveness of Lipid Apheresis to
reduce high lipoprotein (a) levels and prevent major adverse coronary events
Beate R Jaeger, Yvonne Richter, Dorothea Nagel, Franz Heigl, Anja Vogt, Eberhard Roeseler, Klaus Parhofer, Wolfgang Ramlow, Michael Koch, Gerd
Utermann, Carlos A Labarrere, Dietrich Seidal
Nature Clinical Practice Cardiovascular Medicine. 2009
Laboratory values before and during LDL-apheresis treatment
Jaeger BR et al. (2009). Nat Clin Pract Cardiovasc Med.
(30 mg/dL) 117 33 75200 219 102 159
100 126 45 8540 54 46 52
180 181 86 130340 370 226 327
Absolute numbers of MACE during LLM* alone and during combined LLM* and lipid apheresis
Jaeger BR et al. (2009). Nat Clin Pract Cardiovasc Med.
(112mg/dL) (30mg/dL )
* LLM= lipid-lowering medication
Changes in annual nonfatal MACE rates before and after initiation of lipid apheresis
Jaeger BR et al. (2009). Nat Clin Pract Cardiovasc Med.
Annual rates of nonfatal MACE stratified by LDL-c levels achieved with LLM* alone
Jaeger BR et al. (2009). Nat Clin Pract Cardiovasc Med.
* LLM= lipid-lowering medication
Does regular Apheresis in Patients With Isolated Elevated Lp(a) levels Reduce the
Incidence of Cardiovascular Events?
Adrian Rosada, Ursula Kassner, Anja Vogt, Michael Willhauck, Klaus Parhofer, and Elisabeth Steinhagen-Thiessen
Artificial Organs, Vol. 38, No. 2, 2013; 135-41.
mg/dL Before apheresis After apheresis (%reduction)
Time-average concentration (% reduction)
Total cholesterol 155 85 (−45%) 137 (−11%)
LDL-c 84 33 (−60%) 71 (−15%)
HDL-c 48 40 (−16%) 46 (−4%)
Lp(a) 112 36 (−68%) 83 (−26%)
Triglycerides 126 67 (−47%) Not calculated
Mean Laboratory Findings before and After Lipid-apheresis Therapy
Rosada A, et al.Artificial Organs. Vol.38, No.2;2013:135-41
Cardiovascular eventsPre-apheresis
5.2 years (194 patient treatment years)
Post-apheresis 6.8 years
(253 patient treatment years)
Total 78 24MI 29 1PCI 27 16
CABG 11 3
PAD with intervention 8 3CVD with intervention 3 1
Event-Free Survival Before/During Lipoprotein-apheresis
Rosada A, et al.Artificial Organs. Vol.38, No.2;2013:135-41
Event-Free Survival Before/During Lipoprotein-apheresis
Rosada A, et al.Artificial Organs. Vol.38, No.2;2013:135-41
Eve
nt-F
ree
Surv
ival
Time (years)
75% (61-89%)
38% (22-54%)
61% (50-72%)
13% (2-24%)
Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering
Therapy, Lp(a)-Hyperlipoproteinemia, and Progressive CVD
Prospective Observational Multicenter Study
Circulation 2013;128:2567-2576
Josef Leebmann, MD; Eberhard Roeseler, MD; Ulric Julius, MD; Franz Heigl, MD; Ralf Sptthoever, MD; Dennis Heutling, MD; Paul Breitenberger, MD; Winfried Maerz, MD;
Walter Lehmacher, PhD; Andreas Heibges, PhD; Reinhard Klingel, MD; for the pro(a)Life Study Group*
*Prospective documentation of isolated Lp(a) elevation with progressive CVDand lipoprotein-apheresis for effective treatment of hyperlipidemia
Trial flow diagram with numbers of patients.
Leebmann J et al. Circulation 2013;128:2567-2576
Incidence of events by type and total number in 2 years before and 2 years after commencing chronic LA
Leebmann J et al. Circulation 2013;128:2567-2576
*P<0.0001; †P=0.001; ‡number of MI’s included 1 cardiovascular death at the beginning of year +2 in a patient with critical limb ischemia, ESRD, and subsequent multi-organ failure.
Absolute numbers of MACE and ACVE 2 years before and after commencing chronic LA.
Leebmann J et al. Circulation 2013;128:2567-2576
Depicted P values are derived from the analysis of corresponding mean annual rates.
Absolute numbers of MACE and ACVEeach year before and after commencing chronic LA.
Leebmann J et al. Circulation 2013;128:2567-2576
Depicted P values are derived from the analysis of corresponding mean annual rates.
y-2 + y-1) (y+1 + y+2) Δ, %* P Value MACE 0.41±0.45 0.09±0.22 −78.0 <0.0001ACVE 0.58±0.53 0.14±0.31 −75.9 <0.0001
MI 0.14±0.24 0.02±0.10 −85.7 <0.0001PCI 0.22±0.35 0.07±0.19 −68.2 <0.0001
CABG 0.05±0.15 0.01±0.05 −80.0 0.001
ACVE indicates adverse cardiac or vascular events; CABG, coronary artery bypass graft; LA, lipoprotein apheresis; MACE, major adverse coronary events; MI, myocardial infarction; and PCI, percutaneous coronary intervention.
Mean Annual Rates for MACE, ACVE, MI, PCI, and CABG for 2 Years Before and After Commencing Chronic LA
Leebmann J et al. Circulation 2013;128:2567-2576
* (Δ,%)= Percentage changes between periods before and during LA
rs10455872hom het wt total
rs3798220
hom 0 0 0 0het 0 6* 30* 36wt 3* 45* 53 101
total 3 51 83 137
Values indicate absolute numbers (percentages) or mean±SD. SD indicates standard deviation.* Individuals exhibited at least 1 risk allele (n=84).
Leebmann J et al. Circulation 2013;128:2567-2576
Distribution of Genetic Variantsrs10455872 and rs3798220
Homozygous (hom), Heterozygous (het), and Wild Type (wt)
Rosada Leebmann
Apheresis Pre- Post- Pre- Post- Pre- Post-
Patients 120 120 37 37 170 166
Duration (years) 5.5 5.0 5.2 6.8 2 2
LDL-C mg/dL 125 45 (-65%) 84 34 (-60%) 100 33 (-60%)
Lp(a) mg/dL 118 33 (-72%) 112 36 (-68%) 87 26 (-70%)
MACE* (total) 297 57 (-81%) 67 20 (-70%) 142 31 (-78%)
MACE* (per year) 1.05 0.14 (-86%) 2.80 0.08 (-97%) 0.41 0.09 (-78%)
Jaeger BR et al. (2009). Nat Clin Pract Cardiovasc MedRosada A, et al.Art. Organs. Vol.38, No.2;2013:135-41Leebmann J et al. Circ. 2013;128:2567-2576
*MACE= Major Coronary Event percentages are mean percent change
Lipid-apheresis Therapy for Elevated Lp(a)Jaeger
Specific Lp(a) Apheresis for Coronary Atherosclerosis Regression
Aim: To determine if Lp(a)-apheresis for patients with CHD and elevated Lp(a) can alter coronary plaque volume and composition.
Methods: 32 patients (54+/-8 years, 20 males) with CHD and Lp(a)= 50 mg/dL. Medical therapy included atorvastatin with LDL-C< 77mg/dL. Active group (15) treated with Lp(a) Lipopak (POCARD Ltd., Russia). Total atheroma volume (TAV), minimal lumen area (MLA), volume of necrotic core (NC) and dense calcium (DC) were measured by intravascular ultrasound at baseline and 18 months later to compare active and control (atorvastatin) groups.
Results: Mean Lp(a) (92+/-33mg/dL) decreased by 73%.
*p<0.05
Conclusion: Lp(a)-apheresis in CHD patients with elevated Lp(a) levels can stabilize plaque phenotype and regress atherosclerotic lesions in coronary arteries.
TAV NC size NC/DC MLA
Lp(a)-apheresis -22%* -45%* -64%* NC
Control NC NC NC -11%*
Safarova M, et al. EAS meeting Milano 5-2012
Lipid-apheresis Improves Cardiac Function in Patients with Elevated Lp(a) (117 mg/dL)* and CAD:
Detection by Stress/Rest Perfusion MRI
Bohl S. et al. Therapeutic Apheresis and Dialysis; 2009.
EER-S/R = the ratio of subendo- and subepicardial perfusion at stress and resting conditions*LDL-C 77 mg/dL
Control Group Treatment Group
* = P<0.03
Oxidation-Specific Biomarkers, Lp(a), and Risk of Fatal and Nonfatal Coronary Events
Odds Ratios for Fatal and Nonfatal Coronary artery disease (CAD) Based on Tertiles of oxidized phospholipids on apolipoprotein B-100 (OxPL/apoB) and Lp(a). The tertile cutoffs for OxPL/apoB are <1,150, 1,151 to 2,249, and >2,249 RLUs and <7.25, 7.25 to 11.69, and >11.69 mg/dl for Lp(a).
Figure Legend:
Tsimikas, S. et al. J Am Coll Cardiol 2010;56:946-955
Sequestration of oxidized phospholipids (oxPL) on Lp(a) and degradation by Lp(a)-associated Lp-PLA 2 (Lp(a)-Lp-PLA 2 ). (A) oxPL are formed during LDL oxidation or on cells submitted to oxidative stress or underwent apoptosis. (B) oxPL are then preferentially transferred to Lp(a). (C) Once oxPLs are bound on Lp(a), they become accessible to Lp-PLA2 and degraded to lysophosphatidylcholine (Lyso-PC) and oxidized free fatty acids (oxFFA).
Τhe role of Lp-PLA2 in atherosclerosis may depend on its lipoprotein carrier in plasma
Constantinos C. BBA, Molecular and Cell Biology of Lipids, Vol. 1791, 2009, 327-38.
Lipid-apheresis (LA) and the Acute Reduction* of Lp-PLA2
mg/dL Pre-LA Post-LA (% change) p value
Lp-PLA2 229 178 (29%) <0.003LDL 262 99 (60%) <0.043
Moriarty P. M., Gibson C. A. Am J Cardiol 2005;1246-47
* Chronic LA (3 months) reduced mean baseline Lp-PLA2 by 29%.
Presence of Lp-PLA2 on apoB, apo(a), or apoA-I captured on microtiter wells with specific murine monoclonal antibodies pre- and postapheresis in different Lp(a) groups.
Arai K et al. J. Lipid Res. 2012;53:1670-1678
Conclusion• Lp(a) is an independent risk factor for CVD
• Testing plasma levels should be considered in high risk populations.
• Lipid-apheresis can lower levels of Lp(a) by 70% and has demonstrated clinical benefit for patients with elevated Lp(a) and CVD.
• Lipid-apheresis should be considered for patients with progressive CVD and elevated Lp(a).