does regular lipid apheresis therapy for patients with ... · • lp(a): its association with cvd....

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


(112mg/dL) (30mg/dL )

* LLM= lipid-lowering medication

Changes in annual nonfatal MACE rates before and after initiation of lipid apheresis


Annual rates of nonfatal MACE stratified by LDL-c levels achieved with LLM* alone


* 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


Event-Free Survival Before/During Lipoprotein-apheresis


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


*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.


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.


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


* (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).


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).

does regular lipid apheresis therapy for patients with ... · • lp(a): its association with cvd....

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