Emerging Diagnosis and Management Funded by the Kaneka Corporation. Lp(a) and Peripheral Artery Disease
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3 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management 4 ����������������� Contributing Authors 6 ����������������� Defining PAD 8 ����������������� Defining Lp(a) and Why It Matters 10 ����������������� Why Is Lp(a) Important to Know Beyond LDL? 11 ����������������� Raising Awareness of Lp(a) 12 ����������������� Intersection of Lp(a) With PAD 13 ����������������� High Lp(a) Is Associated With Increased Adverse PAD Events 14 ����������������� Current Therapies for Lp(a) 15 ����������������� Emerging Therapies for Lp(a) 16 ����������������� What Can Health Care Professionals (HCPs) Do Now? 18 ����������������� Proposed Action Plan for Practicing Clinicians 19 ����������������� Top Takeaways 20 ����������������� Glossary 21 ����������������� References Contents
Danielle Vlazny, PA-C, MS, CWS, FSVM, is a physician assistant, assistant professor with the Gonda Vascular Center at Mayo Clinic Rochester, Minnesota. She has provided care to vascular patients over the past eight years in outpatient general vascular medicine, thrombophilia, vein clinic, wound care, and inpatient consulting service. In addition, she works on numerous evidence-based medicine and quality improvement projects within the center and teaches at the Mayo Clinic Physician Assistant Program. Disclosures: Professional Services and Activities – Employment: Mayo Clinic Professional Services and Activities – Other Professional Activities: Mayo Foundation for Medical Education and Research Nkechinyere (Nkechi) Ijioma, MBBS, FAHA, FACC, is an interventional cardiologist, and assistant professor of medicine at The Ohio State University. Her research interests include endovascular interventions, acute coronary syndrome, and cardiovascular health equity. Dr. Ijioma currently serves as the program director of Peripheral Vascular Interventions in the Division of Cardiovascular Medicine at The Ohio State University Wexner Medical Center. Disclosures: Professional Services and Activities – Employment: The Ohio State University Wexner Medical Center Contributing Authors Danielle Vlazny, PA-C, MS, CWS, FSVM Nkechinyere (Nkechi) Ijioma, MBBS, FAHA, FACC John Giacona, PA-C, PhD Geoffrey Barnes, MD, MSc, FAHA Heather Harker Ryan, RN, PhD, CPN, FPCNA
5 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management John Giacona, PA-C, PhD, is a physician assistant at the University of Texas Southwestern Medical Center. Dr. Giacona practices in the Hypertension Section within the Division of Cardiology – Department of Internal Medicine. His research interests include highdensity lipoprotein metabolism, skeletal muscle mitochondrial function, and the autonomic control of blood pressure. Dr. Giacona currently serves as chair of Preventive Cardiology for the Academy of Physician Associates in Cardiology. Reported no disclosures Geoffrey Barnes, MD, MSc, FAHA, is a cardiologist and vascular medicine specialist at the University of Michigan Frankel Cardiovascular Center. Dr. Barnes is an NIH-funded health services researcher who is active in advancing the care of patients with thrombotic conditions, including peripheral artery disease. He is a leader with several national societies and currently serves as the fellowship director for the University of Michigan Vascular Medicine Fellowship program. Disclosures: Professional Services and Activities – Employment: University of Michigan Professional Services and Activities – Other Professional Activities: Acelis Connected Health, Bayer, Janssen Biotech, Inc., AstraZeneca, Pfizer, Anthos, Bristol-Myers Squibb, Sanofi, Abbott Vascular Financial Support – Grant/ Contract: Boston Scientific Corporation Heather Harker Ryan, RN, PhD, CPN, FPCNA, is the clinical nurse educator and nurse scientist for the ambulatory division of the Cambridge Health Alliance in Cambridge, Massachusetts. Her program of research focuses on the identification and treatment of children and families affected by familial hypercholesterolemia. She currently holds leadership positions in a number of national organizations related to nursing leadership and cardiovascular care. Disclosures: Professional Services and Activities – Employment: Cambridge Health Alliance, Massachusetts General Hospital, University of Massachusetts Boston, Boston Children’s Hospital
Peripheral artery disease refers to peripheral (noncoronary – blood vessels outside the heart) artery obstruction secondary to atherosclerotic disease. Aorta Femoral Iliac Popliteal Posterior Tibial Anterior Tibial Peroneal PVD Arteries Most Commonly Affected by PAD “PAD” is the preferred term for Peripherial Artery Disease, not PVD 6 PAD most commonly affects the lower extremities, but can also affect the upper extremities. PAD Defining
7 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Risk Factors for PAD Older age Male sex Smoking Diabetes Hyperlipidemia Family history of atherosclerosis PAD is overrepresented in the Black community. Prevalence of PAD Lifetime risk of PAD (80-year horizon) was estimated at: 3, 4 22%Hispanic people Source: pooled data from six U.S. community-based cohorts 19%White people 30%Black people of PAD are called major adverse limb events (MALE) and include recurrent limb ischemia and/or amputation. Complications In the U.S., approximately 6.5M age 40+ have PAD.1, 2 people
8 • Fibrinolysis • Inflammation • Endothelial function • Oxidative stress High Lp(a) can affect: Leading to: Lipoprotein(a) - Lp(a) - is a type of low-density lipoprotein (LDL) in which a large glycoprotein, apolipoprotein(a) - apo(a) - is covalently bonded. Lp(a) Defining and Why It Matters LDL Lp(a) apo(a) 90% Genetically predetermined 5, 6, 7 Synthesized in the liver with proinflammatory and proatherogenic properties 8 Epigenetic studies show an association between elevated Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD). 9, 10 Lp(a) is: • Atherosclerosis • Thrombosis • Calcification
9 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management An estimated 20-25% of the world’s population has elevated levels of Lp(a).12 Disease/condition Atherosclerosis Thrombosis Aortic Valve Calcification Lp(a) structure & property Molecular mass: 300-800 kDa High carbohydrate content: 28% Apo(a) KIV3-10 KIV1 KIV2 (multiple copies) KV Lipid-rich domain ApoB- 100 a d b c Lp(a) serum level is associated with atherosclerotic cardiovascular diseases including stroke, myocardial infarction (MI), and PAD. Lp(a) is also a significant independent risk factor for PAD and is associated with more severe forms of PAD in specific populations.11 Regulation Genetics Ethnicity/ Race Medical conditions Environment Lp(a) concentration (high variability) Defining Lp(a): and why it matters Continued
10 Lp(a) is an independent risk factor for coronary heart disease, PAD, cerebrovascular disease, and aortic stenosis. Why Is Lp(a) Important to Know Beyond LDL? Lp(a) is an additional way to identify risk for ASCVD ... 13 in absence of other major risk factors. in patients with personal or family history of early ASCVD.13 in patients with progression or recurrence of PAD after appropriate medical management. a) Exercise b) Diet c) Statins Lp(a) is not impacted as much by:
Who to test? How to Interpret Lp(a) Test Results Guidelines and expert statements encourage Lp(a) measurement in individuals with strong family history of premature ASCVD.16, 17, 18, 19 Raising Awareness of Lp(a) Once an individual’s Lp(a) levels are tested, do they need to be retested? Given their stable values throughout an individual’s lifetime, recent data favor one-time measurement of Lp(a) instead of repeated measurements. 14, 15 Beware of different testing mechanisms and reporting as international standardization has not occurred.21 Lp(a) levels20 < 30 mg/dL Normal Risk 30 - 50 mg/dL Intermediate Risk 51 - 180 mg/dL Elevated Risk > 180 mg/dL Extremely Elevated Risk Those with borderline ASCVD risk to aid in discussion of risk modification therapies Family or personal history of high Lp(a), heart disease, or premature cardiovascular disease Diagnosis of familial hypercholesterolemia (FH) - an inherited condition 13 11 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management REPEAT
12 4x Intersection of Lp(a) With PAD MALE occurs up to 80%sooner in those with elevated Lp(a). 26 A retrospective study showed the prevalence of TransAtlantic Inter-Society Consensus (TASC) II class D and severe calcification of femoropopliteal lesions was higher in patients with high Lp(a) than those with low Lp(a).28 Lp(a) levels correspond to MALE risk. 24, 25 Lp(a) predicts PAD and severity. MALE is 4 times more common in patients with elevated Lp(a). 27 Lp(a) predicts Major Adverse Cardiovascular Event (MACE) Elevated Lp(a) levels are independently associated with incident MACE and MALE in patients with PAD treated with revascularization irrespective of LDL-cholesterol (LDL-C) level and statin administration. 22, 23 Higher Lp(a) levels are independently associated with an increased risk of MALE in hospitalized patients.3
High Lp(a) Is Associated With Increased Adverse PAD Events Plasma Lp(a) is independently associated with first and consecutive MALE after iliofemoral endarterectomy. 29 Lp(a) is a significant residual risk factor for pure leg events, cardiovascular-related death, all-cause death, and MACE in PAD patients.30 13 33% higher risk of lower extremity revascularization. 32 Elevation of Lp(a) incurs a 67.9% Elevated Lp(a) increases risk for MALE postrevascularization in of PAD patients at 5 years regardless of LDL level and statin use (HR 4.15). 31 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management
PCSK9 Inhibitors reduce Lp(a) up to 30%37 FOURIER trial: The PCSK9 inhibitor (PCSK9i) evolocumab lowered Lp(a) by a median of 27% at 48 weeks. 16, 38 ODYSSEY OUTCOMES trial: 18,924 patients with recent acute coronary syndrome who were taking high-intensity statin demonstrated that the PCSK9i alirocumab reduced Lp(a) by 23% after 4 months.39 ORION-11 (inclisiran) trial: 40 The placebo-corrected percentage reduction in Lp(a) levels from baseline to Day 540 was 28.5%. Lipoprotein Apheresis lowers Lp(a) by 50-85%21 14 Mipomersen inhibits Lp(a) production Current Therapies for Lp(a) Approved by FDA for use in homozygous familial hyperlipidemia (HoFH) 37 In combination with lipid-lowering medications and diet, mipomersen is indicated to reduce LDL-C in patients with HoFH. FDA approved for FH patients with Lp(a) > 60 mg/dL and LDL-C > 100 mg/dL with PAD to be true to the indication.21 Decreases Lp(a) in high-risk patients who cannot be treated effectively with drugs.33 Results in improved circulation, pain level, and walking distance in those with elevated Lp(a) and severe PAD.34 Reduces CV events in FH patients with elevated Lp(a) ≥60 mg/dL. 35,36
15 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Small interfering RNA (siRNA) a. Olpasiran - dose-dependent reduction with ASCVD 41 b. SLN360 – dose-dependent reduction of Lp(a) without CVD 42 c. Lepodisiran – dose-dependent, long-duration reductions in serum Lp(a) concentrations without CVD 43 Emerging Therapies for Lp(a)
16 What Can Health Care Professionals (HCPs) Do Now? Shared Decision Making 44 Consider regional access to testing and treatment options. Consider insurance coverage of testing and treatments. Discuss new therapies in development.
17 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Diet and exercise have not been shown to reduce Lp(a) levels.4, 45 Treat modifiable risk factors Medical therapy and lifestyle changes include targeting diabetes (enhanced glucose control), smoking cessation, treating HTN and/or high LDL-C, and increasing physical activity.5 Initiate or increase statin intensity with elevated Lp(a) even if LDL-C is at goal. Prevention is difficult Lp(a) levels are 90% genetically influenced. 5 Knowing Lp(a) levels could lead to cascade testing in families for early modification of ASCVD risk factors or new therapies 21 Point to the Guidelines 2019 AHA/ACC primary prevention of CVD.5 An Lp(a) ≥50 mg/dL or ≥125 nmol/L is considered a risk-enhancing factor.46 Check Lp(a) once in a lifetime to assess for degree of elevation at age 40 or any age with ASCVD risk factors.20
18 Call to Action Here are things HCPs can do now in anticipation of Lp(a) therapies to come in the next several years: Screen high-risk patients. Identify patients with ongoing or recurrent events despite optimal LDL-C control or high intensity statin therapy. Enquire if there is a family history of elevated Lp(a). All adults at least once Clinical ASCVD (premature or recurrent) despite evidence-based LDL-C lowering Inadequate response to evidence-based LDL-C lowering therapy Established family history of familial hypercholesterolemia, very high Lp(a), or premature/recurrent ASCVD Established diagnosis of calcific aortic valve disease Use of elevated Lp(a) as riskenhancing factor to promote lifestyle modification and guide pharmacotherapy to reduce ASCVD risk, including statins and other lipid-lowering therapies Consideration of lipoprotien apheresis in patients with Lp(a) ≥60 mg/dL or ≥150 nmol/L Increased frequency of clinical examination and aortic valve surveillance Prioritize use of PCSK9 inhibitors Risk factor assessment, lifestyle modification, and evidence-based primary prevention strategies Aggressive LDL-C lowering and lifestyle modification in patients with Lp(a) ≥50 mg/dL or ≥125 nmol/L Borderline/intermediate 10-year ASCVD risk Secondary Prevention Lp(a) Testing Primary Prevention Lp(a) Testing Cascade Lp(a) Testing Proposed Action Plan for Practicing Clinicians Positive family history of premature ASCVD
19 Lp(a) and PAD Toolkit: Emerging Diagnosis and Management Top Takeaways Lp(a) is largely determined by genetics. Once an individual’s Lp(a) levels are tested, there is usually not a need to repeat the test. Lp(a) is elevated in approximately 20-25% of the general population. Elevated Lp(a) is overrepresented in the Black community. Lp(a) elevation is known to drive atherosclerosis and intravascular inflammation, increasing the risk for ASCVD and PAD. Patients with elevated Lp(a) have poor outcomes related to PAD and high incidence of MALE. PAD patients should be screened for elevated Lp(a) if they have a family history of ASCVD or recurrence of MALE despite optimal medical therapy. Current treatment options include PCSK9 inhibitors and lipoprotein apheresis. New therapies to reduce Lp(a) levels are in development. 1 2 3 4 5 6 7
Glossary Apo(a) . . . . . . . Apolipoprotein(a) ASCVD . . . . . . . Atherosclerotic cardiovascular disease FH . . . . . . . . . Familial hypercholesterolemia HCP . . . . . . . . Health Care Professionals HoFH . . . . . . . . Homozygous familial hyperlipidemia LDL-C . . . . . . . . Low density lipoprotein cholesterol Lp(a) . . . . . . . . Lipoprotein(a) (pronounced L-P-little-A) 47 MACE . . . . . . . . Major adverse cardiovascular event MALE . . . . . . . . Major adverse limb event PAD......... Peripheral artery disease PVD......... Peripheral vascular disease PCSK9 inhibitors . . . PCSK9 monoclonal antibody siRNA . . . . . . . . Small interfering RNA TASC . . . . . . . TransAtlantic Inter-Society Consensus For more information on Lp(a), scan the QR code to download Lp(a): A Toolkit for Health Care Professionals. Lp(a):A Toolkit for Health Care Professionals Novartis is proud to support the American Heart Association’s Lp(a) Awareness and Testing Initiative. 20
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22 Notes:
This publication was funded by the Kaneka Corporation.
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