Accreditation/Credit Designation

Physicians' Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physicians’ Education Resource®, LLC, is approved by the California Board of Registered Nursing, Provider #16669, for 1.5 Contact Hours.

Acknowledgment of Commercial Support

This activity is supported by an independent educational grant from Amgen.

Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know


Release Date: May 31, 2019
Expiration Date: May 31, 2020
Media: Internet - based

Activity Overview

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab have been available since 2015, with growing evidence to support their role in patients with familial hypercholesterolemia and in those with or at high risk of cardiovascular disease (CVD). Although statins have been the mainstream of hypercholesterolemia treatment for over 30 years, PCSK9 inhibitors provide a more aggressive mechanism of action for lipid lowering when patients are not meeting lipid-lowering goals despite being on a maximally tolerated statin therapy with or without ezetimibe or when patients present with statin intolerance. The 2018 American College of Cardiology/American Heart Association multisociety guideline for cholesterol management in part recommends PCSK9 inhibitors as primary prevention for patients with very high-risk atherosclerotic cardiovascular disease (ASCVD) who are already on a high-intensity or maximal statin.

In this Community Practice Connections™ activity, 2 leading clinical lipidologists will provide insight into the latest evidence for PCSK9 inhibitors in the reduction of not only low-density lipoprotein cholesterol (LDL-C) but also non–high-density lipoprotein cholesterol and lipoprotein while maintaining a favorable safety and tolerability profile. Key points for incorporating PCSK9 inhibitors into clinical practice and tips to facilitate patient access will be included to readily broaden clinicians’ armamentarium of lipid-lowering treatments.

Benefits of Participation

  • Translate recent guidelines for cholesterol management into practice
  • Gain insight from expert lipidologists into adding nonstatin therapies when LDL-C goals are not met
  • Understand the implications of PCSK9 inhibitors for helping patients achieve absolute ASCVD risk reduction

CME Activity Table of Contents

  • Pretest
  • Module 1: Statin Therapy Is the Cornerstone of Cholesterol Management and CVD Risk Reduction
  • Module 2: 2018 Guidelines and Impact of PCSK9 Inhibitors on Reduction of ASCVD Risks
  • Module 3: Future Directions and Key Points for Practitioners
  • Posttest, Evaluation, and Request For Credit

Acknowledgement of Commercial Support

This activity is supported by an independent educational grant from Amgen.

Instructions for This Activity and Receiving Credit

  • You will need to log in to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review audio files/content until you finish the presentation.
  • At the end of the activity, educational content/audio files will be available for your reference.
  • In order to receive a CME/CE certificate, you must complete the activity.
  • Complete the Posttest and pass with a score of 70% or higher, complete the Evaluation, and then click on “Request for Credit.” You may immediately download a CME/CE certificate upon completion of these steps.


Target Audience

This CME activity is primarily intended for internists, family physicians, nurse practitioners and physician assistants who treat patients with cardiovascular risk factors including hypercholesterolemia.

Educational Objectives

Upon successful completion of this educational program, you should be better prepared to:

  • Summarize key recommendations of the current blood cholesterol management guidelines for ASCVD risk assessment and cholesterol management in patients with very high-risk ASCVD
  • Identify patient criteria for considering non-statin therapy(ies) for treatment of hyperlipidemia
  • Describe additional benefits observed in patients on PCSK9 inhibitors beyond reduction of LDL-C

Faculty, Staff, and Planners’ Disclosures

James A. Underberg
James A. Underberg, MD, MS, FACPM, FACP, FNYAM, FASPC, FNLA
Clinical Assistant Professor of Medicine
New York University Medical School and New York University Center for the Prevention of Cardiovascular Disease
Director, Bellevue Hospital Lipid Clinic
New York, NY

Disclosures: Consultant: Akcea Therapeutics, Amgen; Speakers Bureau: Alexion, Amgen, Amarin Corporation, Sanofi, Regeneron; Grant/Research Support: Aegerion.

Daniel Soffer
Daniel Soffer, MD, FNLA, FACP
University of Pennsylvania Health System Internal Medicine/Clinical Lipidology
Preventive Cardiology
Perelman School of Medicine, University of Pennsylvania
Philadelphia, PA

Disclosures: Consultant: Akcea Therapeutics, Amgen, Medicure, Regeneron; Speakers Bureau: Akcea Therapeutics (FCS disease state), Sanofi (FH disease state).

The staff of Physicians' Education Resource®, LLC (PER®), have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest (COI).

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical education purposes only, and is not meant to substitute for the independent clinical judgment of a physician and nurse relative to diagnostic, treatment, or management options for a specific patient’s medical condition.

The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER® or any of the companies that provided commercial support for this program.

PER Pulse Recaps

1 of 3

PER Pulse™ Recap: Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know

The online continuing medical education activity Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know features videos and text that highlight key clinical concepts presented at a satellite symposium during the American College of Physicians’ 2019 annual meeting. Faculty for this Community Practice Connections™ are James A. Underberg, MD, MS, FACPM, FACP, FNYAM, FASPC, FNLA, and Daniel Soffer, MD, FNLA, FACP.

This first of 3 PER Pulse™ Recaps will focus on key recommendations of the current blood cholesterol management guidelines for atherosclerotic cardiovascular disease (ASCVD) risk assessment and cholesterol management in patients with very-high-risk ASCVD, as explored in Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know.

The 2018 American College of Cardiology/American Heart Association Multisociety Guidelines emphasize a heart-healthy lifestyle for all individuals throughout their life course as a primary intervention for metabolic syndrome. The guidelines recommend using an ASCVD risk calculator to conduct a detailed risk assessment of patients and then engaging them in a discussion on risks and treatment options. Risk-enhancing factors are defined for patients who may require further low-density lipoprotein cholesterol (LDL-C) lowering with statins as a first-line pharmacological therapy and provided as shared decision-making checklists for 4 statin benefit groups:

  • Secondary prevention in patients with clinical ASCVD
  • Severe hypercholesterolemia (LDL-C ≥190 mg/dL)
  • Diabetes
  • Primary prevention over the life span

In patients with clinical ASCVD in a very-high-risk category or with familial hypercholesterolemia and at or above a defined threshold, a nonstatin therapy is recommended. Nonstatin therapies include ezetimibe, PCSK9 inhibitors, and in some cases, bile acid sequestrants.

The updated guidelines also focus on special populations, including women, children, ethnic/racial groupings, elderly patients, and individuals with concomitant disorders such as diabetes, chronic kidney disease, or HIV.

Key points:

  • Updated cholesterol management guidelines target a threshold rather than a specific goal
  • Risk-enhancing factors have been added to the guidelines in conjunction with traditional cardiovascular disease (CVD) risk factors for certain individuals aged 40 to 75 years
  • Evidence-based considerations for special populations in the United States have also been added to the updated guidelines

Reference

  • Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [erratum in Circulation. 2019;139(25):e1182-e1186]. Circulation. 2019;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625.

2 of 3

PER Pulse™ Recap: Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know

As a follow-up to the online continuing medical education activity Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know, this second of 3 PER Pulse™ Recaps for the activity will focus on adding on or switching to nonstatin therapy.

Statin therapy is the cornerstone of cholesterol therapy, heavily supported by clinical trials. Although statins are generally well tolerated, about 20% of patients may report muscle-related complications, most commonly myalgias.1,2 This must be distinguished from myositis or myopathy, which have elevated creatine kinase levels, unlike myalgia. The overall benefits of statin therapy outweigh the risks3 and clinicians should work with their patients to continue treatment as follows:

  • Try at least 3 statins
  • Switch to a high-potency statin at a lower dose
  • Allow the patient a 1-month drug holiday before starting on a different statin

Nonstatin low-density lipoprotein cholesterol (LDL-C)–lowering treatments include the cholesterol absorption inhibitor ezetimibe, bile acid sequestrants, and most recently, PCSK9 inhibitors, all with cardiovascular outcomes data and varying LDL-C–lowering potency. Guidelines recommend first adding ezetimibe in patients with very-high-risk atherosclerotic cardiovascular disease (CVD) who are on a maximal statin with an LDL-C ≥70 mg/dL and reserving PCSK9 inhibitors when LDL-C remains ≥70 mg/dL or non–HDL-C is ≥100 mg/dL on maximal LDL-C–lowering therapy.4

In patients with severe hypercholesterolemia with LDL-C ≥100 mg/dL despite treatment with a high-intensity statin, ezetimibe should be added, followed by a bile acid sequestrant if LDL-C remains ≥100 mg/dL and triglycerides <300 mg/dL. In patients aged 30 to 75 years, a PCSK9 inhibitor may be considered when LDL-C is still ≥100 mg/dL.4

PCSK9 inhibitors have been compared with ezetimibe in patients with statin intolerance, demonstrating significant reductions of LDL-C with good tolerability.5-8

Key points:

  • Guideline provisions incorporate add-on therapy with nonstatin therapies
  • In patients reporting statin intolerance, stepped-up options should be tried before discontinuing treatment
  • PCSK9 inhibitors are an option in patients with true statin intolerance

References

  1. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534. doi: 10.7326/0003-4819-158-7-201304020-00004.
  2. Mancini GJ, Baker S, Bergeron J, et al. Diagnosis, prevention and management of statin adverse effects and intolerance: Canadian Consensus Working Group update (2016). Can J Cardiol. 2016;32(suppl 7):S35-S65. doi: 10.1016/j.cjca.2016.01.003.
  3. Newman CB, Preiss D, Tobert JA, et al; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association [erratum in Arterioscler Thromb Vasc Biol. 2019;39(5):e158. doi: 10.1161/ATV.0000000000000081]. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81. doi: 10.1161/ATV.0000000000000073.
  4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [erratum in Circulation. 2019;139(25):e1182-e1186]. Circulation. 2019;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625.Moriarty PM, Thompson PD, Cannon CP, et al; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769. doi: 10.1016/j.jacl.2015.08.006.
  5. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308(23):2497-2506. doi: 10.1001/jama.2012.25790.
  6. Stroes E, Colquhoun D, Sullivan D, et al; GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548. doi: 10.1016/j.jacc.2014.03.019.
  7. Nissen SE, Dent-acosta RE, Rosenson RS, et al; GAUSS-3 Investigators. Comparison of PCSK9 inhibitor evolocumab vs ezetimibe in statin-intolerant patients: design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) trial. Clin Cardiol. 2016;39(3):137-144. doi: 10.1002/clc.22518.

3 of 3

PER Pulse™ Recap: Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know

As a follow-up to the online continuing medical education activity Community Practice Connections™: Cutting CVD Risk by Adding PCSK9 Inhibitors: What the Internist Needs to Know, this third of 3 PER Pulse™ Recaps for the activity will focus on lowering -density lipoprotein cholesterol (LDL-C) with PCSK9 inhibitors.

PCSK9 inhibitors have changed the treatment landscape for patients at high risk for cardiovascular disease (CVD) or with inherited cholesterol disorders, primarily familial hypercholesterolemia. In clinical trials, PCSK9 inhibitors alirocumab and evolocumab lowered LDL-C levels by 40% to 60%.1,2 They can be used in combination with statins or other lipid-lowering agents or as monotherapy in patients who are statin intolerant. PCSK9 inhibitors are generally well tolerated; adverse effects include injection-site reactions, mild flu-like symptoms, or nasopharyngitis.3,4

In addition to LDL-C lowering, PCSK9 inhibitors have also demonstrated reduced risk of certain cardiovascular events. In the ODYSSEY OUTCOMES, among patients with a previous acute coronary syndrome on a high-intensity statin or maximum-tolerated dose, those who received alirocumab demonstrated a lower risk of myocardial infarction (MI), stroke, and unstable angina requiring hospitalization, with a median LDL-C of 53.3 mg/dL versus those who took placebo.5 The FOURIER trial enrolled patients with clinically evident atherosclerotic cardiovascular disease (ASCVD; history of MI, nonhemorrhagic stroke, or symptomatic peripheral artery disease) on a high-intensity statin with or without ezetimibe. Patients receiving evolocumab versus placebo in the FOURIER trial attained a median LDL-C of 30 mg/dL, with a reduced risk of MI and stroke.6

Remarkably, in both trials, an accrued benefit after the first year occurred such that the longer patients were treated with either alirocumab or evolocumab, the greater the benefit.

Key points:

  • PCSK9 inhibitors can reduce LDL-C levels up to 60%
  • Besides LDL-C lowering, PCSK9 inhibitors also reduce the risk of MI, stroke, and unstable angina requiring hospitalization (alirocumab)
  • Accrued duration of LDL-C lowering with PCSK9 inhibitors increases the ASCVD risk-lowering benefit

References

  1. Koren MJ, Giugliano RP, Raal FJ, et al; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014;129(2):234-243. doi: 10.1161/CIRCULATIONAHA.113.007012.
  2. Henry RR, Müller-Wieland D, Taub PR,et al. Diabetes. Obes Metab. 2018;20(7):1632-1641. doi: 10.1111/dom.13273.
  3. Praluent [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2018/125559s018lbl.pdf. Accessed August 2, 2019.
  4. Repatha [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2017. www.accessdata.fda.gov/drugsatfda_docs/label/2019/125522s022lbl.pdf. Accessed August 2, 2019.
  5. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. doi: 10.1056/NEJMoa1801174.
  6. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664.

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