How to select the patients? Wolfgang Koenig, MD, FRCP, FACC, FAHA, - - PowerPoint PPT Presentation

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How to select the patients? Wolfgang Koenig, MD, FRCP, FACC, FAHA, - - PowerPoint PPT Presentation

Apr 27, 2023 179 likes •430 views

OPTICS in Cardiology Zrich, April 20./21., 2018 New LDL lowering drugs - How to select the patients? Wolfgang Koenig, MD, FRCP, FACC, FAHA, FESC Professor of Medicine/Cardiology Klinik fr Herz - & Kreislauferkrankungen Deutsches

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OPTICS in Cardiology Zürich, April 20./21., 2018

New LDL lowering drugs - How to select the patients?

Wolfgang Koenig, MD, FRCP, FACC, FAHA, FESC Professor of Medicine/Cardiology Klinik für Herz- & Kreislauferkrankungen Deutsches Herzzentrum München Technische Universität München

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Conflict of Interest (COI) - Disclosure

  • Honorarium for Lectures: AstraZeneca, Novartis, MSD, Amgen,

Sanofi, Actavis, Berlin-Chemie

  • Consulting: Novartis, Pfizer, The Medicines Company, Amgen,

AstraZeneca, MSD, Kowa

  • Participation in Clinical Trials: LEADER (Novo Nordisk), CANTOS

(Novartis), FOURIER, GLAGOV (Amgen), OPTIONS I und II (Sanofi/Regeneron), SPIRE (Pfizer), CAIN III (MHICC), PROMINENT (Kowa), DalGene (DalCor), COLCOT (MHICC)

  • Research Contracts: Abbott, Roche Diagnostics, Beckmann,

Singulex

  • Stockholder of a Healthcare Company: none
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Preferred Pharmacotherapy Formulary

Gidding et al. Circulation 2015;132 Initial drug monotherapy Two-drug Combination Three-drug Combination Complex-therapy Combination High-intensity Statin Therapy (>50% LDL-C reduction) Rosuvastatin or atorvastatin If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to two-drug combination

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Preferred Pharmacotherapy Formulary

Gidding et al. Circulation 2015;132 Initial drug monotherapy Two-drug Combination Three-drug Combination Complex-therapy Combination High-intensity Statin Therapy (>50% LDL-C reduction) Rosuvastatin or atorvastatin If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to two-drug combination If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to three-drug combination Rosuvastatin or Atorvastatin Ezetimibe +

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Preferred Pharmacotherapy Formulary

Gidding et al. Circulation 2015;132 Initial drug monotherapy Two-drug Combination Three-drug Combination Complex-therapy Combination High-intensity Statin Therapy (>50% LDL-C reduction) Rosuvastatin or atorvastatin If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to two-drug combination If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to three-drug combination Rosuvastatin or Atorvastatin Ezetimibe +

Rosuvastatin or Atorvastatin Rosuvastatin or Atorvastatin Rosuvastatin or Atorvastatin + + + Ezetimibe Ezetimibe Ezetimibe + + +

If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to complex-therapy combination

PCSK9 inhibitors Colesevelam or other bile acid sequestrant Niacin

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Preferred Pharmacotherapy Formulary

Gidding et al. Circulation 2015;132 Initial drug monotherapy Two-drug Combination Three-drug Combination Complex-therapy Combination High-intensity Statin Therapy (>50% LDL-C reduction) Rosuvastatin or atorvastatin If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to two-drug combination If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to three-drug combination Rosuvastatin or Atorvastatin Ezetimibe +

Rosuvastatin or Atorvastatin Rosuvastatin or Atorvastatin Rosuvastatin or Atorvastatin + + + Ezetimibe Ezetimibe Ezetimibe + + +

If LDL-C above goal after 3 months of therapy and patient is adherent, proceed to complex-therapy combination

PCSK9 inhibitors Colesevelam or other bile acid sequestrant Niacin

Consider four-drug combination and LDL Apheresis

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High Risk Patients Achievining a LDL-C <70 mg/dL, stratified by Baseline LDL-C ≥160 mg/dL

Based on those studies providing direct comparisons for patients with baseline LDL-C ≥160 mg/dL, rosuvastatin 10–40 mg doses were significantly superior to equal and double doses of atorvastatin and simvastatin (p<0.01)

Rosuvastatin Atorvastatin Simvastatin Dose (mg)

Note: p values for rosuvastatin vs simvastatin are data on file, AstraZeneca

Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Lundman P et al. Atheroscler Suppl 2011; 12: 164 (abstract)

Adapted by permission from Elsevier Inc.

Unmet Medical Need:

  • Familial Hypercholesterolemie (he/ho)
  • Patients with statin intolerance
  • High risk patients with progressive

atherosclerosis manifestations who do not achieve a LDL-C goal <70 mg/dL

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Hepatic LDL-Rs Play a Key Role in the Regulation

  • f Plasma LDL-C Concentrations

LDL

  • 1. Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76:3330-3337.
  • 2. Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106:9546-9547.
  • 3. Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
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PCSK9 Regulates the Expression

  • f Hepatic LDL-Rs on the Cell Surface
  • 1. Qian YW, Schmidt RJ, Zhang Y, et al. J Lipid Res. 2007;48:1488-1498.
  • 2. Horton JD, Cohen JC, Hobbs HH. J Lipid Res. 2009;50(suppl):S172-S177
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Anti-PCSK9 Monoclonal Antibodies Block the PCSK9/LDL-R Interaction and Lower LDL-C

  • 1. Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.
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Proprotein Convertase Subtilisin/kexin 9: PCSK9 Inhibitors

  • Lower LDL-C by 50-60% independent of the patient`s

background risk and the lipid lowering regime

  • Long-term efficacy with 2 or 4-weekly injections

(DESCARTES, FOURIER, ODYSSEY)

  • LDL-C goal (<70 mg/dL) achieved in 70-90% of patients
  • Lowering of Lp(a) by appr. 30%
  • So far excellent tolerability and safety
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FOURIER Study Design

Sabatine MS et al. Am Heart J 2016;173:94-101

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Summary of Effects

  • f the PSK9 Inhibitor Evolocumab
  •  LDL-C by 59% down to a median of 30 mg/dl
  •  First CV endpoint trial in patients on statin therapy
  • Safe and well-tolerated (42% of patients had a LDL-C < 25 mg/dl)

Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) Placebo 59% reduction P<0.00001 Absolute  56 mg/dl HR 0.85 (0.79-0.92) P<0.0001 HR 0.80 (0.73-0.88) P<0.0001

CVD, MI, stroke UA, cor revasc CVD, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

  • No reduction of cardiovascular death
  • Clinical benefit driven by a reduction of MI, stroke

and coronary revascularisation

  • Efficacy increases with extended FU (Landmark

Analysis)

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Primary and Secondary Endpoint in Patients With and Without PAD

Bonaca et al. Circulation 2018;137:338-350

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MACE or MALE in Patients With and Without PAD

MACE: MI, stroke, CV death – MALE : acute ischemia, revasc. amputations Bonaca et al. Circulation 2018;137:338-350

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Benefit of Evolocumab Based

  • n Time From Qualifying MI

Sabatine et al Circulation 2018 (epub ahead of print)

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Benefit of Evolocumab Based

  • n Number of Prior MIs

Sabatine et al Circulation 2018 (epub ahead of print)

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Benefit of Evolocumab Based

  • n Multivessel Disease

Sabatine et al Circulation 2018 (epub ahead of print)

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Randomized 18,924 patients *Ascertainment was complete for 99.1% and 99.8% of potential patient-years of follow-up for the primary endpoint and all-cause death, respectively 1955 patients experienced a primary endpoint 726 patients died Follow-up*: median 2.8 (Q1–Q3 2.3–3.4) years 8242 (44%) patients with potential follow-up ≥3 years Alirocumab (N=9462) Placebo (N=9462) 1343 (14.2%) 1496 (15.8%)

  • Premature treatment

discontinuation

  • Blinded switch to placebo (2

consecutive LDL-C values <15 mg/dL)

  • Patients lost to follow-up (vital

status) 730 (7.7%)

Not applicable

14 9

ODYSSEY: Study Design

Steg et al ACC 2018

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ODYSSEY: Primary Endpoint

ARR* 1.6% *Based on cumulative incidence

MACE: CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization HR 0.85 (95% CI 0.78, 0.93) P=0.0003

Steg et al ACC 2018

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Incidence (%) Subgroup Patients Alirocumab Placebo HR (95% CI) p-value*

*P-values for interaction Years Since Randomization MACE (%) 1 2 3 4 4 8 12 16 20

Number at Risk Placebo Alirocumab 3583 3347 3122 1290 256 3581 3365 3183 1327 233

Placebo Alirocumab Years Since Randomization MACE (%) 1 2 3 4 4 8 12 16 20

Number at Risk Placebo Alirocumab 3062 2889 2708 1195 195 3066 2880 2732 1194 213

Years Since Randomization MACE (%) 1 2 3 4 4 8 12 16 20

Number at Risk Placebo Alirocumab 2815 2568 2371 986 178 2814 2602 2431 1053 207

<80 mg/dL 80 to <100 mg/dL 100 mg/dL

ODYSSEY: Prespecified Subgroups

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Algorithm for the Use of PCSK9 I in Patients With ASCVD and Substantially Elevetaed LDL-C

Landmesser et al. EHJ 2017;0:1-13 Patients with clinical ASCVD (CAD, symptomatic PAD, ischaemic stroke) On maximally tolerated statin therapy ± Ezetimibe* LDL-C >3.6 mmol/L (>140 mg/dl)

LDL-C >2.6 mmol/L (>100 mg/dL) and with additional indices of risk severity§

§Including

  • Familial hypercholesterolaemia
  • Diabetes mellitus with target organ damage (e.g. proteinuria),
  • r with a major risk factor such as marked hypertension
  • Severe and/or extensive ASCV (e.g. severe polyvascular

disease, extensive coronary disease – refer to Box 3)

  • Rapid progression of ASCVD, i.e. repeated ACS, unplanned

coronary revascularization, or ischaemic strokes within 5 years

  • f the index event

Consider a PCSK9 inhibitor

*According to clinical judgement and local guidance

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Summary and Conclusions

  • ESC/EAS Consensus: Present LDL-C goal for high risk patients < 70mg/dL
  • Evidence from meta-analyses of statin trials as well as PCSK9i trials

FOURIER, SPIRE und GLAGOV: „The lower the better“

  • Results of FOURIER and ODYSSEY compatible with CTT meta-analyses
  • With PCSK9 Inhibitors LDL-C levels around 30 mg/dL (and lower) can be

achieved with excellent tolerability and safety

  • Pharmakoeconomic aspects crucial (GBA indications: FH, statin intolerance,

progression of atherosclerosis despite maximally tolearble statin therapy)

  • Lipid apheresis justified in select cases (e.g. in hoFH; based on trial

eveidence 2/3 of patients with FH can be treated with PCSK9 inhibitors to achiev the LDL-C goal).

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Thank You for Your Attention!

  • Prof. Wolfgang Koenig

koenig@dhm.mhn.de