therapeutic algorithm for patients with severe ... · therapeutic algorithm for patients with...
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Therapeutic algorithm for Patients with severe Hypercholesterolemia or isolated
Lipoprotein(a)-Hyperlipoproteinemia with progressive cardiovascular disease: PCSK9-
Inhibitors, Lipoprotein Apheresis or both?
Nephrologisches Zentrum Göttingen GbRPriv. Doz. Dr. med. V. Schettler
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Disclosures
The speaker declares, that he had held lectures for:
• Amgen GmbH • B.Braun Avitum AG• DIAMED Medizintechnik GmbH• Fresenius Medical Care AG & Co. KGaA• Genzyme GmbH• Kaneka Pharma Europe N.V. German Branch• KWHC Health Consulting GmbH• MSD SHARP & DOHME GMBH• Novartis Pharma GmbH• Pfizer Consumer Healthcare GmbH• Sanofi-Aventis GmbH
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Familial Hyperlipidaemia (FH) with heterozygous expressions (he) (FHhe)
- burden of high LDL-C levels
Nordestgaard et al., Eur Heart J 2013;34:3478-90a.
Neil et al., Eur Heart J 2008;29:2625–33.
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LDL-C-lowering studies and reduction of coronary events
50 70 110 130 150 170 19090 210
Cor
onar
y Ev
ents
(%)
LDL Cholesterol (mg/dl)
25
20
15
10
5
0?
LRC-PL
AFCAPS-Rx
WOSCOPS-RxWOSCOPS-PL
AFCAPS-PLASCOT-PL
ASCOT-RxLRC-Rx
Primary Prevention
CARE-Rx
4S-Rx
LIPID-PL
4S-PL
CARE-PL
LIPID-Rx
POSCH-PL
POSCH-Rx
Secondary Prevention
HPS-Rx
HPS-PL
HPS
Non-Statin Studies
Statin Studies
based on Kastelein, Atherosclerosis 1999;143:S17-S21*Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.
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…but EUROSPIRE IV says….
Reiner et al., Atherosclerosis 2016;246:243-50.
6648 CHD patients' data from centres in 24 European countries
• Too many CHD patients with dyslipidaemia are still inadequately treated• Most of these patients on statin therapy are not achieving the treatment
targets.
(<70 mg/dl)
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based on Gotto & Moon, Nat Rev Cardiol 2013;10:560-70.
LDL-RiPCSK9
Overview – lipid lowering/ modifying strategies
HMG-ReductaseStatins
PCSK9PCSK9i
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Specific PCSK9 mutations induce low LDL-C levels:low incidence for cardiovascular events
- 88% events
PCSK9 mutation: LDL-C levels: 138 mg/dl vs. 100 mg/dl (black American inhabitants)
Cohen et al., N Engl J Med 2006;354:1264-72.
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New drugs on the block…
• PSCK9-Inhibitiors• MTP-Inhibitors• Antisense therapy targeting Lp(a): ISIS 144367• …
Results of new drugs in lowering lipids/ lipoproteins may be convincing, but we have to wait on results from cardiovascular outcome studies!
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Drug therapy
1) Statin: Maximal tolerable dosage (optimal 80 mg atorvastatin or maximal permitted dosages of other statins) per day
in combination with
2a) Ezetimibe (!): 10 mg per day
or/ and
2b) Bile acid sequestrants (BAS): Maximal tolerable dosages, to meals (optimal 24 g cholestyramine, 30 g colestipol oder 3,75 g colesevelam per day)
or/ and in combination with
3) (Mipomersen), PCSK-9 Antibodies (!), CETP-Inhibitors(?), etc.?
When these therapeutic concepts fail, indication of lipoprotein apheresis should be considered by cardiologist, angiologist, endocrinologist, but not nephrologist!
The first major chapter: Before the initiation of lipoprotein apheresis – LDL-Cholesterol lowering concept: Drugs
German Working Group for Therapeutic Apheresis
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Metabolism of Proprotein convertasesubtilisin/kexin type 9 (PCSK9)
Lambert et al., J Lipid Res. 2012;53:2515-24.Weinreich & Frishman, Cardiol Rev 2014;22:140-46.
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Antibodies target: PCSK9
Lambert et al., J Lipid Res. 2012;53:2515-24.Weinreich & Frishman, Cardiol Rev 2014;22:140-46.
Cellmembrane
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81%
<1.8 mmol/L (70 mg/dL) regardless of risk
P<0.0001 79%
Alirocumab
9% 8%
0
10
50
40
30
20
60
70
80
90 P<0.0001
%pa
tient
s
Very high-risk: LDL-C <1.8 mmol/L (70 mg/dL) High-risk: <2.6 mmol/L (100 mg/dL)
Placebo
Intent-to-treat (ITT) analysis; LLT = lipid-lowering therapy
Most of the patients achieved the LDL-C goal: combination of Alirocumab and
“Background Statin ± Other LLT”
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Patient exampleLA + (statin) + PCSK9i
58y patientLDL-R frame shift mutation in exon 18
since 1989 LA - prior:3 vessel CHD2 myocardial infarctionsCABGrotablator atherectomy (RIVA)
Start of PCSK9i Statins paused
time [months]
chol
este
rola
ndLD
L-ch
oles
tero
l(m
g/dl
)
Schettler VJ et al., Cardiovasc 2016 in press
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Success of PCSK9i therapies ?
Navarese et al., Ann Intern Med 2015;163:40-51.
Total mortality Cardiovascular mortality
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Threshold level for lipoprotein apheresis indication
Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis
The second major chapter: Initiation of lipoprotein apheresis
– LDL-Cholesterol lowering concept
German Working Group for Therapeutic Apheresis
• With respect to the given actual ESC guidelines if LDL-cholesterol levels remain increased (>~100 mg/dl (2.6 mmol/l) for risk patients; > ~70 mg/dl (1.8 mmol/l) for high risk patients) although lipid-lowering diet and drug regimens were proved to be ineffective, lipoprotein apheresis should be initiated.
• During LA all known cardiovascular risk factors should be treated with respect to the given guidelines (AHA, ESC…).
• A decrease of more than 60% from of LDL-Cholesterol initial levels should be achieved by lipoprotein apheresis. The optimal mean goal level is <70 mg/dl (1.8 mmol/l).
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Can Lp(a) levels reduced by PCSK9i (e.g. Evolocumab)?
Desai et al., Circulation 2013;128:962-9.
Reduction rates mean up to xy %!No outcome studies!
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A look in details…
Desai et al., Circulation 2013;128:962-9.Raal et al, Lancet 2015;385:341-50.McConnell et al., J Clin Lipidol 2014;8:550-3.Schettler et al., Cardiovasc 2015;15:41-3.
nmol/l in mg/dl – x* 0,4167 – z.B. 41 nmol/l = 17,1 mg/dl
TESLA Part B)
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Meta-analysis of 20 Studies:Lp(a) decrease induced by PCSK9i
Li et al., J Am Heart Assoc. 2015;4: e001937.
Figure 9. Forest plots depicting the effect of proprotein convertase subtilisin/kexin9 monoclonal antibodies on lipoprotein(a).
For high risk Lp(a) patients these reduction rates induced by PCSK9i are unimportant.
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Threshold level for lipoprotein apheresis indication
Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis
The third major chapter: Initiation of lipoprotein apheresis
– Lp(a)-Cholesterol lowering concept
• If the Lp(a) levels are increased (> 60 mg/dl (~ > 120 nmol/l)), lipoprotein apheresis should be initiated.
• All known cardiovascular risk factors should be treated with respect to the given guidelines (AHA, ESC…).
• A decrease of more than 50% from of Lp(a) initial levels should be achieved by lipoprotein apheresis. The optimal goal level is <30 mg/dl (<70 nmol/l).
German Working Group for Therapeutic Apheresis
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Now, can we create a new lipid loweringalgorithm for patients at very high risk?
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Potential treatment algorithm inrelation to the use of PCSK9-AB and LA
Neumann et al., Blood Purif 2016;41:270-276.
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Therapeutic Algorithm PCSK9i and LDL-Apheresis – or both?
Schettler VJ et al., Internist 2016; ;57:511-6.
…for theGerman Societyof Nephrology(DGfN)
and
Foundation ofGerman Centresof Nephrology(VDN)
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Therapeutic Algorithm – PCSK9i, LA
Schettler VJ et al., Internist 2016; ;57:511-6.
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Patients example: intolerance of statins – use of PCSK9i – approved?
58J. patient with2 vessel CHDStatin intolerance
PCSK9i application induce a decrease of 57% LDL-C
Last tryof statins
PCSK9i-application
Cho
lest
erol
and
LDL-
Cho
lest
erol
(mg/
dl)
Time (months)Schettler VJ et al., Cardiovasc 2016 in press
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Summary – describing the current statein LDL-C and Lp(a) lowering stratgies
• Diet (LDL-C), not for Lp(a)
• Statins and further LLT are necessary (LDL-C), not for
Lp(a)
• Only LDL-C increase may justify the use of PCSK9i…
• ...but CV outcome studies are essential for a general use
• Lp(a) can only decreased with lipoprotein apheresis…
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