Lp(a):A Toolkit for Health Care Professionals Novartis is proud to support the American Heart Association’s Lp(a) Awareness and Testing Initiative.
2 Contents: 3 ................ Contributing Authors 5 ................ Lp(a) at a Glance 6 ................ How High Is Too High? 7 ................ Elevated Lp(a): What Are the Risks? 8 ................ How Does Lp(a) Work? 8 ................ The Challenge 9 ................ In Whom Should Lp(a) Be Measured? 10 ............... What to Know When Managing Your Patients’ Risk 12 ............... Recent Approaches to Lowering Lp(a): What the Studies Show 15................ The Importance of Shared Decision-Making 16 ............... What Does the Future Hold? 18 ............... 2018 AHA/ACC Cholesterol Guidelines Top 10 Takeaways 21................ References
3 Publisher’s Note The Lp(a): A Toolkit for Health Care Professionals is published by Ascend Media, LLC 401 SW Ward Road, Suite 210, Lee’s Summit, MO 64081 © 2024 American Heart Association, Inc., a 501(c)(3) not-for-profit. All rights reserved. Unauthorized use prohibited. All references and data are as of September 2024 Contributing Authors Marlys Koschinsky PhD, FAHA, is professor, physiology and pharmacology, and scientist at Robarts Research Institute, Schulich School of Medicine & Dentistry at Western University in Ontario, Canada. She is a recognized leader in the Lp(a) field and has unraveled many mysteries of this unique lipoprotein. She has national and international collaborations with many stakeholder groups and has helped translate knowledge from the basic biochemistry of Lp(a) to preclinical, clinical and R&D applications. Joseph L. Witztum, MD, is a Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism at the University of California in San Diego. For more than 40 years, Dr. Witztum has made major contributions to the field of atherosclerosis and lipoprotein metabolism. He has been actively involved in basic and clinical studies to develop novel therapies for unmet needs, especially in the context of hypertriglyceridemia and elevated Lp(a) levels. His research has resulted in more than 500 manuscripts. Cindy Lamendola, MSN, ANP, FAHA, FPCNA, is an adult nurse practitioner and clinical research nurse manager at Stanford University School of Medicine in Stanford, California. She has focused on risk management of cardiovascular disease and type 2 diabetes. Areas of research include insulin resistance, type 2 diabetes and relationship to cardiovascular disease and lipid abnormalities, including Lpa. She is a founding member of the Preventive Cardiovascular Nurses Association, and member and fellow of AHA. Leslie L. Davis, PhD, APRN, FAAN, FAANP, FACC, FAHA, FPCNA, is an associate professor at the University of North Carolina at Chapel Hill. She also maintains a part-time nurse practitioner practice with the Division of Cardiology at the UNC Chapel Hill School of Medicine. A cardiovascular expert, Dr. Davis is a certified hypertension clinician and a fellow in the American Academy of Nursing, the American Association of Nurse Practitioners, the American College of Cardiology, the American Heart Association and the Preventive Cardiovascular Nurses Association. Disclosures Marlys Koschinsky PhD, FAHA Professional Services and Activities – Employment: University of Western Ontario Professional Services and Activities – Other Professional Activities: Amgen; Eli Lilly and Company; Novartis Joseph L. Witztum, MD Professional Services and Activities – Other Professional Activities: Ionis Financial Stake – Other Business: Oxitope, Kleanthi Diagnostic Intellectual Property – Patent: Patents and patent applications Cindy Lamendola, MSN, ANP, FAHA, FPCNA Professional Services and Activities – Employment: School of Medicine, Stanford University Professional Services and Activities – Other Professional Activities: Alnylam Pharmaceuticals, Inc.; Novo Nordisk; Novartis Pharmaceuticals Corporation; Novartis Leslie L. Davis, PhD, APRN, FAAN, FAANP, FACC, FAHA, FPCNA Professional Services and Activities – Employment: University of North Carolina at Chapel Hill Professional Services and Activities – Other Professional Activities: American Association of Nurse Practitioners; American College of Cardiology; Kentucky Association of Nurse Practitioners and Nurse Midwives; Nurse Practitioners Associates for Continuing Education; Preventive Cardiovascular Nurses Association; Skin, Bones, Hearts, and Private Parts; University of North Carolina at Chapel Hill Intellectual Property – Copyright: Journal for Nurse Practitioners Intellectual Property – Other Intellectual Property: Nursing Clinics of North America
4 An estimated 20% to 30% of people worldwide have high levels of plasma lipoprotein(a) An estimated 20% to 30% of people worldwide have elevated levels of plasma lipoprotein(a) [Lp(a)] which is independently associated with increased risk of cardiovascular disease (CVD) including myocardial infarction (MI), peripheral arterial disease (PAD), and stroke. In addition, elevated Lp(a) is a strong predictor of the presence and progression of calcific aortic valve disease (CAVD). Yet, Lp(a) gets the least attention among clinicians compared with the three other major classes of lipid disorders: z elevated low-density-lipoprotein cholesterol (LDL-C) z low high-density-lipoprotein cholesterol (HDL-C) z elevated triglycerides1 ,2 It’s important for clinicians to incorporate comprehensive guidelines for diagnosing, treating, and managing elevated Lp(a) into patient evaluation and risk assessment. The clinical relevance of Lp(a) as a risk-enhancing factor and the importance of patient-health care professional risk discussions is detailed in the 2018 Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. The guidelines also have implications for reducing CVD risk through cholesterol management.3 Scan to view a video on the impact of Lp(a).
5 Lp(a) at a Glance z Lp(a) is independently associated with CVD risk. z Lp(a) levels are established in early childhood and remain relatively consistent over an individual’s lifetime. z Lp(a) is composed of apolipoprotein(a) [apo(a)] covalently bound to an apolipoprotein B (apoB)-100-containing lipoprotein particle and is the preferential carrier of proinflammatory oxidized phospholipids in plasma. z Although definitive data are lacking, Lp(a) likely increases cardiovascular risk through multiple mechanisms, including those attributed both to its LDL-like moiety, as well as its unique apo(a) protein. The latter may confer prothrombotic and/or additional proinflammatory effects that can cause vascular cell dysfunction.4 z Lp(a) is approximately 6 times more atherogenic than LDL on a per particle basis.5 z Up to 90% of Lp(a) plasma concentration is determined by genetics.4,6 z Other factors that influence Lp(a) levels include age, sex, ethnicity7 and comorbid conditions, such as Familial Hypercholesterolemia8 and liver or kidney disease.7 z Lp(a) levels are approximately 10-15% higher in women than men.9 Distribution of Lp(a) levels may also vary by population-specific percentiles, due to differences in the distribution of Lp(a) levels among ancestry groups.10 z There is limited evidence that heart-healthy eating and regular physical activity reduce Lp(a) levels. However, commitment to both will improve overall cardiovascular health.7 z Statins are ineffective in lowering Lp(a). To the contrary, research shows statins can modestly increase Lp(a) levels by, on average, approximately 10-15%.11 The mechanism is not understood. z PCSK9 inhibitors can modestly lower Lp(a) levels.12 Up to 90% of Lp(a) plasma concentration is determined by genetics4,8 Other factors that influence Lp(a) levels include age, sex, ethnicity7 and comorbid conditions, such as Familial Hypercholesterolemia8 and liver or kidney disease.7 Lp(a): A Toolkit for Health Care Professionals Scan to view a video on Lp(a) at a glance.
6 How High Is Too High? Meta-analyses have shown increased risk of CVD in individuals with Lp(a) levels above 50 mg/dL. According to AHA/ACC cholesterol guidelines, Lp(a) levels greater than/equal to 50 mg/dL constitute a risk enhancing factor.3 Lp(a) increases ASCVD risk, especially at higher levels. How Common Is It? 20%30% to of the global population10 Elevated levels prevalent in Black people have the highest median Lp(a) levels, followed by South Asian, Hispanic and East Asian peoples. Native American people have the lowest Lp(a) levels.13 What Causes High Lp(a) Levels? The major cause of high Lp(a) levels is genetics, mostly reflecting differences in the size of the gene encoding apo(a).4
7 Elevated Lp(a): What Are the Risks? People who have clinical CVD (including atherosclerosis-based cardiovascular diseases (ASCVD) such as acute coronary syndrome; stable angina or a history of MI or coronary or other arterial revascularization; stroke or transient ischemic attack; or PAD, including aortic aneurysm), are at higher risk for future events if Lp(a) is elevated. Elevated Lp(a) is also associated with onset14,15 and progression14 of CAVD, and progression to symptomatic heart failure.16 In the general population, Lp(a) levels greater than 50 mg/dL (~125 nmol/L) are associated with an approximately 20% increased risk of cardiovascular events: each 3.5-fold increase in Lp(a) is associated with a 16% increase of risk of events.20* People with borderline or slightly elevated LDL-C are three to four times more likely to have CVD events than those with low LDL-C.21 Lp(a) can pose increased risk for acute coronary syndrome when LDL-C is elevated.22** * Treatment strategy: Consider implementation of aggressive LDL-C lowering strategies in patients with elevated Lp(a). ** Treatment strategy: Maximally manage treatable risk factors in patients with elevated Lp(a). Lp(a): A Toolkit for Health Care Professionals In people with established CVD, elevated Lp(a) levels significantly increase the risk of future cardiovascular events, particularly in those with LDL-C ≥ 130 mg/dL.19 Elevated Lp(a) seems to be associated with atherosclerotic renal artery stenosis in hypertensive patients with low LDL-C.17 Elevated Lp(a) values represent an independent risk factor for ischemic stroke (more relevant in patients who have a stroke at a young age), PAD and aortic and mitral valve stenosis.18 Of Note … Patients with elevated Lp(a) are at risk even if their LDL-C is optimally controlled by statins.6 In particular, residual risk conferred by Lp(a) for a recurrent event is about 10% even when statins and other lipid-lowering therapies (i.e., PCSK9 inhibitors) are used to lower LDL-C.23
8 How Does Lp(a) Work? Despite the link between Lp(a) level and a variety of CVD events, the exact pathophysiological roles of Lp(a) are not clear. Lp(a) accumulates in the blood vessel wall, where it appears to be retained more avidly than LDL.24 Recent evidence suggests that proinflammatory oxidized phospholipids present on Lp(a) promote the processes of endothelial dysfunction, inflammation and calcification in vasculature.24 The role of Lp(a) as a prothrombotic factor is controversial, with evidence both for and against this possibility.25 The Challenge • Lifestyle therapy, including heart-healthy eating and regular physical activity, has no significant effect on Lp(a) levels.7 • Statin therapy doesn’t decrease Lp(a) levels. Patients with a history of CVD who are taking statins and have an Lp(a) ≥50 mg/dL are at increased risk for vascular events, independent of other risk factors.6 • Niacin lowers Lp(a); yet, to date, there are no randomized trials in people with high Lp(a) to determine if this is beneficial or not. In other randomized trials, use of niacin has been associated with enhanced side effects and even adverse events.6 • It is suggested by post hoc analyses that PCSK9 inhibitors lower Lp(a) to a modest degree, but the specific contribution of Lp(a) reduction in lowering CVD risk in treated patients remains unclear. • Lipoprotein apheresis (LA) is currently the only FDAapproved treatment for lowering Lp(a). FDA approved for Lp(a) lowering when: • Patient has heterozygous familial hypercholesterolemia and • LDL-C > 100mg/dL and • Patient has established coronary artery disease or peripheral artery disease and • Lp(a) > 60 mg/dL26
9 In Whom Should Lp(a) Be Measured? Because the majority of Lp(a) plasma concentration (up to 90%) is influenced by genetics through the LPA gene4, relative indications for its measurements are: z Family history of premature CVD (men, age <45 years; women, age <55 years). z A personal history of premature CVD. z Individuals with Familial Hypercholesterolemia. z Individuals with family history of elevated Lp(a). Although the 2018 ACC/AHA guidelines3 and the 2019 NLA statement on Lp(a)6 have not recommended measurement of Lp(a) in all individuals, most27-30 but not all31,32, subsequent statements/guidelines contain recommendations for Lp(a) screening in all individuals at least once in a lifetime. However, despite recent guidelines suggesting measurement of Lp(a) in all adults, the testing rate for Lp(a) remains very low. If a decision is made to measure Lp(a), an Lp(a) ≥50 mg/dL or ≥125nmol/L may be considered a risk-enhancing factor for CVD events. Lp(a): A Toolkit for Health Care Professionals Scan to view a video on Lp(a) measurement.
10 What to Know When Managing Your Patients’ Lp(a) Risk z In patients already on statin therapy, high Lp(a) is associated with residual CVD risk. z In primary prevention for adults ages 40-75 with a 10-year CVD risk of 7.5% to 19.9%, risk-enhancing factors favor initiation of statin therapy. If measured, an Lp(a) ≥50 mg/dL or ≥125 nmol/L may be considered a risk-enhancing factor. z In high-risk or very-high-risk patients with LDL-C ≥70 mg/dL (non–HDL-C ≥100 mg/dL) and a Lp(a) ≥50 mg/dL or ≥100 nmol/L on maximally tolerated statin treatment, it’s reasonable to consider more intensive therapies (such as ezetimibe and/or PCSK9 inhibitors) to lower LDL-C (and non–HDL-C) to better reduce CVD risk.6 z The presence of an elevated Lp(a) in patients with very-high-CVD risk and baseline LDL-C ≥70 mg/ dL or non–HDL-C ≥100 mg/dL despite maximally tolerated statin and ezetimibe therapies may be used as a factor favoring a PCSK9 inhibitor. z Although niacin and hormone replacement therapy can reduce Lp(a) levels, these drugs are not recommended because they haven’t demonstrated benefit and may be harmful, according to the NLA scientific statement.6 z Maximize treatment of modifiable risk factors. z Good adherence to various LDLlowering diets will reduce LDL-C levels by 10% to >15%. Moderateintensity statins can be expected to reduce LDL-C levels by an additional 30% to 49%, and highintensity statins by ≥50%. Adding ezetimibe or bile acid sequestrants to statin therapy typically provides an additional 13% to 30% reduction in LDL-C. Much greater additive reductions occur by adding a PCSK9 inhibitor to statin plus ezetimibe, providing a 43% to 64% reduction.3
11 z In clinical practice, lifestyle modifications and statin therapy are commonly introduced together. The maximum percentage change will occur by four to 12 weeks after starting a statin or combined therapy.3 z Review the need for lifestyle adjustments in eating habits and level of physical activity to maintain a healthy weight or body mass index, and the elimination of tobacco use. Promote a heart healthy lifestyle and provide relevant advice, educational materials or referrals as needed.3 Access the American Heart Association’s Life’s Essential 8™ heart.org/lifes8 The AHA/ACC 2018 Guideline on the Management of Blood Cholesterol recommends assessing 10-year ASCVD risk and focusing on reducing LDL-C, primarily through the use of statin therapy. It advocates for more aggressive lowering of LDL-C on a percentage basis, (e.g., <50%). The AHA/ACC guidelines include a value statement regarding cost considerations for PCSK9 inhibitors.3 Lp(a): A Toolkit for Health Care Professionals Scan to view a video on Life’s Essential 8 and Lp(a).
Recent Approaches to Lowering Lp(a): What the Studies Show Approaches that result in lowering of both Lp(a) and LDL Lipoprotein Apheresis (LA): Moriarty and colleagues reported that lipoprotein apheresis (LA) therapy can effectively reduce both LDL and Lp(a), with a significant reduction in future CVD events (94% reduction in major adverse cardiovascular events over a mean treatment period of 48 months).33 In the Pro(a)LiFe-Study (Lipoprotein Apheresis for Lipoprotein(a)- Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization)34, it was shown that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)- hyperlipidemia. Mean Lp(a) concentration was reduced in a single LA treatment by 68.1% on average and a significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter. PCSK9 inhibitors reduce LDL-C by 43% to 64% and lower Lp(a) by 20% to 30%. Analysis of the ODYSSEY OUTCOMES and FOURIER outcomes trials showed enhanced benefit from PCSK9 inhibitor therapy in patients with elevated Lp(a) despite more modest (16-22%) Lp(a) percent lowering in this group.12 Inclisiran, a small interfering RNA molecule that targets PCSK9 messenger RNA, has been evaluated in people with high risk for CVD and elevated LDL-C. Compared with placebo, inclisiran reduced Lp(a) by 25.6% in the ORION-10 trial evaluating inclisiran in patients with ASCVD and by 18.6% in the ORION-11 trial that enrolled subjects with an ASCVD equivalent.35 12
Emerging Therapies that specifically and effectively lower Lp(a) There are three compounds (pelacarsen, olpasiran and lepodisiran) that are in Phase 3 clinical trials. Pelacarsen is an antisense oligonucleotide (ASO) that targets apo(a) messenger RNA and lowers Lp(a) by ~80%. This compound is currently being tested in a Phase 3 cardiovascular outcomes trial ( Lp(a) HORIZON; NCT04023552). z 8323 participants; randomized, double-blind, placebo-controlled trial z Key inclusion criteria: Lp(a) ≥ 70 mg/dL; pre-existing ASCVD z Primary endpoint: time to expanded MACE (Lp(a) ≥ 70 mg/dL or ≥ 90 mg/dL) z Anticipated study completion date is May 2025 Olpasiran is a silencing RNA compound (siRNA) that targets apo(a) messenger RNA and lowers Lp(a) by >90%. This compound is currently being tested in a Phase 3 cardiovascular outcomes trial (OCEAN(a); NCT05581303) z 7297 participants; randomized, double-blind, placebo-controlled trial z Key inclusion criteria: Lp(a) ≥ 200 nmol/L; history of ASCVD z Primary endpoint: time to CHD death, myocardial infarction, or urgent coronary revascularization z Anticipated study completion date is December 2026 Lp(a): A Toolkit for Health Care Professionals 13 Two RNA-targeting drugs that lower Lp(a) >80% are in Phase 3 cardiovascular outcomes trials. Scan to view a video on what the future holds for Lp(a).
Lepodisaran is a silencing RNA compound that targets apo(a) messenger RNA. It is being tested in a Phase 3 cardiovascular outcomes trial (ACCLAIM-Lp(a); NCT06292013 (currently recruiting)) with an anticipated study completion date of March 2029. Other Lp(a)-specific lowering drugs in the pipeline: There are several additional compounds that are in earlier stages of development.36 These include zerlasiran, another siRNA compound against apo(a) mRNA (Phase 2 completed; up to 96% Lp(a) lowering), and a small molecule (muvalaplin) that disrupts Lp(a) formation and is in Phase 2 (NCT05563246), with up to 65% Lp(a) reduction observed in Phase 1. 14
15 The Importance of Shared Decision-Making Clinicians and patients should work in tandem to arrive at an informed treatment decision. Consider these important factors: z Because cholesterol-lowering therapy is intended to be prescribed for a lifetime, patients should be involved in shared decision-making about treatment options to encourage better health outcomes, better health care experiences and lower costs. z Discuss recommendations for lifestyle modifications, pharmacological treatment and therapy goals. z Explain the patient’s risk of clinical CVD and how the treatment recommendations reduce CVD risk. z Encourage patients to verbalize values, attitudes, abilities, concerns, and personal goals for making lifestyle changes and taking medications, including concerns about cost or side effects. z Use a guide to facilitate shared decision-making with the patient.3 Access to the American Heart Association’s Lp(a) Discussion Guide at heart.org/lpa Of Note… Evidence indicates that measuring Lp(a) may reclassify CVD risk and aid in pharmacotherapy decision-making. Repeat measurement of Lp(a) isn’t recommended as the clinical value of serial measurements hasn’t been established.6 AHA/ACC guidelines characterize Lp(a) >50 mg/dL (≥125 nmol/L) as a risk-enhancing factor, with assessment of Lp(a) indicated in women with hypercholesteremia and in people with a family history of premature CVD.3 Lp(a): A Toolkit for Health Care Professionals Scan to view a video on shared decisionmaking.
16 What part will artificial intelligence and machine learning play in risk assessment that will expedite patient diagnosis and treatment? What Does the Future Hold? Much is now known about Lp(a) and its role in CVD. But more evidence is needed to inform future recommendations for clinical practice. For Lp(a) to be accepted as a risk factor for intervention, randomized outcome trials of specific Lp(a) lowering that demonstrate reduction in CVD risk are required. The results of these trials will provide the initial answers as to the benefits of Lp(a) lowering but many important unanswered questions are likely to remain, requiring further investigation.
17 z Will earlier measurement of Lp(a) and effective interventions to lower it help to improve outcomes? z Is it reasonable to recommend universal testing of Lp(a) in all individuals in early adulthood regardless of family history or health status? z How will Lp(a) screening inform clinical decisionmaking for more aggressive management of cardiovascular risk in high Lp(a) patients? z What will be the benefit of medical interventions that target Lp(a) lowering, and how will such therapies change outcomes of people at risk and those currently affected by CVD? z Will Lp(a)-lowering therapy be effective in people with low LDL-C, in light of new promising LDL-C–lowering therapies beyond statins, ezetimibe and PCSK9 inhibitors? z What role will LA continue to play in reduction of LDL and Lp(a) in people with FH? z What part will artificial intelligence and machine learning play in risk assessment that will expedite patient diagnosis and treatment? To answer these and myriad other questions, it’s encouraging that randomized, placebo-controlled, double blind cardiovascular outcomes trials of pelacarsen, olpasiran and lepodisaran that specifically and effectively reduce Lp(a), are ongoing and due to report between 2025 and 2029. In addition, there are several other potential therapies in earlier stages of development. This underscores an urgent need for better standardization of Lp(a) measurement and an improved understanding of Lp(a) metabolism, physiology and the pathologic mechanisms by which Lp(a) and oxidized phospholipids on Lp(a) lead to CVD. Finally, the knowledge gaps for unique populations need to be addressed, including the possible relationship of high Lp(a) with stroke in children and to better define the unmet medical needs for Lp(a) reduction in people of all ancestries. Lp(a): A Toolkit for Health Care Professionals
18 Top 10 Takeaways Currently, there is no treatment for elevated Lp(a), but clinicians can make sure their patients’ LDL levels and triglycerides are well controlled according to the current guidelines. For all people, emphasize a heart-healthy lifestyle, which reduces ASCVD risk at all ages. In younger people, a heart-healthy lifestyle can lower risk of developing factors and is the foundation of ASCVD risk reduction. In young adults 20 to 39 years of age, assessing lifetime risk facilitates the clinician– patient risk discussion (see No. 6) and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome. In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy. The more LDL-C is reduced on statin therapy, the greater subsequent risk reduction. Use a maximally tolerated statin to lower LDL-C levels by ≥50%. In very-high-risk ASCVD, use an LDL-C threshold of 70 mg/ dL (1.8 mmol/L) to consider addition of non-statins to statin therapy. Very high risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions. In very-high-risk ASCVD patients, it’s reasonable to add ezetimibe to maximally tolerated statin therapy when the LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L). In patients at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable, although the long-term safety (>3 years) is uncertain and cost effectiveness is low at mid-2018 list prices. It is reasonable to consider LA when other measures are insufficient to reach LDL threshold. 2018 AHA/ACC Cholesterol Guidelines 1 2 3
19 In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin highintensity statin therapy. If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable. If the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered. However, the long-term safety (>3 years) is uncertain, and economic value is uncertain at mid-2018 list prices. It is reasonable to consider LA when other measures are insufficient to reach LDL threshold. In patients 40 to 75 years old with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk. In patients with diabetes mellitus at higher risk, especially those with multiple risk factors or those 50 to 75 years old, it’s reasonable to use a high-intensity statin to reduce the LDL-C level by ≥50%. In adults 40 to 75 years old evaluated for primary ASCVD prevention, have a clinician–patient risk discussion before starting statin therapy. Risk discussion should include a review of major risk factors (e.g., cigarette smoking, elevated blood pressure, LDL-C, hemoglobin A1C [if indicated], and calculated 10year risk of ASCVD); the presence of risk-enhancing factors (see No. 8); the potential benefits of lifestyle and statin therapies; the potential for adverse effects and drug–drug interactions; consideration of costs of statin therapy; and patient preferences and values in shared decision-making. In adults 40 to 75 years old without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderateintensity statin if a discussion of treatment options favors statin therapy. Risk-enhancing factors favor statin therapy (see No. 8). If risk status is uncertain, consider using coronary artery calcium (CAC) to improve specificity (see No. 9). If statins are indicated, reduce LDL-C levels by ≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%. 4 6 7 5 Lp(a): A Toolkit for Health Care Professionals
20 In adults 40 to 75 years old without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), riskenhancing factors favor initiating statin therapy (see No. 7). Riskenhancing factors include family history of premature ASCVD; persistently elevated LDL-C levels ≥160 mg/dL (≥4.1 mmol/L); metabolic syndrome; chronic kidney disease; history of preeclampsia or premature menopause (age <40 years); chronic inflammatory disorders (eg, rheumatoid arthritis, psoriasis or chronic HIV); high-risk ethnic groups (e.g., South Asian); persistent elevations of triglycerides ≥175 mg/dL (≥1.97 mmol/L); and, if measured in selected individuals, apolipoprotein B ≥130 mg/dL, highsensitivity C-reactive protein ≥2.0 mg/L, ankle-brachial index <0.9 and lipoprotein (a) ≥50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5 to 7.5% (borderline risk). In adults 40 to 75 years old without diabetes mellitus and with LDL-C levels ≥70 mg/dL to 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring coronary artery calcium. If CAC is zero, treatment with statin therapy may be withheld or delayed, except in persons who smoke tobacco, people with diabetes mellitus and those with a strong family history of premature ASCVD. A CAC score of 1 to 99 favors statin therapy, especially in those ≥55 years old. For any patient, if the CAC score is ≥100 Agatston units or ≥75th percentile, statin therapy is indicated unless otherwise deferred by the outcome of clinician–patient risk discussion. Assess adherence and percentage response to LDL-C–lowering medications and lifestyle modifications with repeat lipid measurement four to 12 weeks after statin initiation or dose adjustment, repeated every three to 12 months as needed. Define responses to lifestyle and statin therapy by percentage reductions in LDL-C levels compared with baseline. In very-high-risk ASCVD patients, triggers for adding non-statin drug therapy are defined by threshold LDL-C levels ≥70 mg/ dL (≥1.8 mmol/L) on maximal statin therapy (see No. 3). 8 9 10 Check Out Patient Education Resources at heart.org/lpa
21 REFERENCES 1. Tsimikas S, Stroes ESG. The dedicated “Lp(a) clinic”: A concept whose time has arrived? Atherosclerosis. 2020;300:1-9. doi: 10.1016/j.atherosclerosis.2020.03.003 2. Tsimikas S. Lipoprotein(a) in the Year 2024: A Look Back and a Look Ahead. Arterioscler Thromb Vasc Biol. 2024;44:1485-1490. doi: 10.1161/ATVBAHA.124.319483 3. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, 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. Circulation. 2019;139:e1082-e1143. doi: 10.1161/CIR.0000000000000625 4. Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, Lloyd-Jones DM, Marcovina SM, Yeang C, Koschinsky ML, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e48-e60. doi: 10.1161/ ATV.0000000000000147 5. Bjornson E, Adiels M, Taskinen MR, Burgess S, Chapman MJ, Packard CJ, Boren J. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. J Am Coll Cardiol. 2024;83:385-395. doi: 10.1016/j.jacc.2023.10.039 6. Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ, Nordestgaard BG, Orringer CE. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol. 2019;13:374-392. doi: 10.1016/j.jacl.2019.04.010 7. Enkhmaa B, Berglund L. Non-genetic influences on lipoprotein(a) concentrations. Atherosclerosis. 2022;349:53-62. doi: 10.1016/j. atherosclerosis.2022.04.006 8. Durrington PN, Bashir B, Bhatnagar D, Soran H. Lipoprotein (a) in familial hypercholesterolaemia. Curr Opin Lipidol. 2022;33:257263. doi: 10.1097/MOL.0000000000000839 9. Varvel S, McConnell JP, Tsimikas S. Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States. Arterioscler Thromb Vasc Biol. 2016;36:2239-2245. doi: 10.1161/ATVBAHA.116.308011 10. Tsimikas S, Marcovina SM. Ancestry, Lipoprotein(a), and Cardiovascular Risk Thresholds: JACC Review Topic of the Week. J Am Coll Cardiol. 2022;80:934-946. doi: 10.1016/j.jacc.2022.06.019 11. Tsimikas S, Gordts P, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2020;41:2275-2284. doi: 10.1093/eurheartj/ehz310 12. Schwartz GG, Ballantyne CM. Existing and emerging strategies to lower Lipoprotein(a). Atherosclerosis. 2022;349:110-122. doi: 10.1016/j.atherosclerosis.2022.04.020 13. Wang W, Hu D, Lee ET, Fabsitz RR, Welty TK, Robbins DC, Yeh JL, Howard BV. Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease. The Strong Heart Study. Ann Epidemiol. 2002;12:107-114. doi: 10.1016/s10472797(01)00273-3 14. Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JG, Tam JW, Teo KK, Mahmut A, Yang X, et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015;66:1236-1246. doi: 10.1016/j.jacc.2015.07.020 15. Kaiser Y, van der Toorn JE, Singh SS, Zheng KH, Kavousi M, Sijbrands EJG, Stroes ESG, Vernooij MW, de Rijke YB, Boekholdt SM, Bos D. Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification. Eur Heart J. 2022;43:3960-3967. doi: 10.1093/eurheartj/ehac377 16. Januzzi JL, Jr., van Kimmenade RRJ, Liu Y, Hu X, Browne A, Plutzky J, Tsimikas S, Blankstein R, Natarajan P. Lipoprotein(a), Oxidized Phospholipids, and Progression to Symptomatic Heart Failure: The CASABLANCA Study. J Am Heart Assoc. 2024;13:e034774. doi: 10.1161/JAHA.124.034774 17. Hu X, Yang X, Li X, Luo D, Zhou Y, Dong H. Lipoprotein (a) as a residual risk factor for atherosclerotic renal artery stenosis in hypertensive patients: a hospital-based cross-sectional study. Lipids Health Dis. 2020;19:173. doi: 10.1186/s12944-020-01272-0 18. Bucci M, Tana C, Giamberardino MA, Cipollone F. Lp(a) and cardiovascular risk: Investigating the hidden side of the moon. Nutr Metab Cardiovasc Dis. 2016;26:980-986. doi: 10.1016/j. numecd.2016.07.004 19. O’Donoghue ML, Morrow DA, Tsimikas S, Sloan S, Ren AF, Hoffman EB, Desai NR, Solomon SD, Domanski M, Arai K, et al. Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol. 2014;63:520-527. doi: 10.1016/j. jacc.2013.09.042 20. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412-423. doi: 10.1001/jama.2009.1063
22 21. Duncan MS, Vasan RS, Xanthakis V. Trajectories of Blood Lipid Concentrations Over the Adult Life Course and Risk of Cardiovascular Disease and All-Cause Mortality: Observations From the Framingham Study Over 35 Years. J Am Heart Assoc. 2019;8:e011433. doi: 10.1161/JAHA.118.011433 22. Afshar M, Pilote L, Dufresne L, Engert JC, Thanassoulis G. Lipoprotein(a) Interactions With Low-Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS). J Am Heart Assoc. 2016;5. doi: 10.1161/JAHA.115.003012 23. Dhindsa DS, Sandesara PB, Shapiro MD, Wong ND. The Evolving Understanding and Approach to Residual Cardiovascular Risk Management. Front Cardiovasc Med. 2020;7:88. doi: 10.3389/ fcvm.2020.00088 24. Koschinsky ML, Boffa MB. Oxidized phospholipid modification of lipoprotein(a): Epidemiology, biochemistry and pathophysiology. Atherosclerosis. 2022;349:92-100. doi: 10.1016/j. atherosclerosis.2022.04.001 25. Boffa MB. Beyond fibrinolysis: The confounding role of Lp(a) in thrombosis. Atherosclerosis. 2022;349:72-81. doi: 10.1016/j. atherosclerosis.2022.04.009 26. Safarova MS, Moriarty PM. Lipoprotein Apheresis: Current Recommendations for Treating Familial Hypercholesterolemia and Elevated Lipoprotein(a). Curr Atheroscler Rep. 2023;25:391-404. doi: 10.1007/s11883-023-01113-2 27. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-188. doi: 10.1093/ eurheartj/ehz455 28. Pearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P, Dayan N, Francis GA, Genest J, Gregoire J, Grover SA, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021;37:1129-1150. doi: 10.1016/j. cjca.2021.03.016 29. Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, Dweck MR, Koschinsky M, Lambert G, Mach F, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925-3946. doi: 10.1093/eurheartj/ehac361 30. Koschinsky ML, Bajaj A, Boffa MB, Dixon DL, Ferdinand KC, Gidding SS, Gill EA, Jacobson TA, Michos ED, Safarova MS, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. 2024;18:e308-e319. doi: 10.1016/j. jacl.2024.03.001 31. Cegla J, Neely RDG, France M, Ferns G, Byrne CD, Halcox J, Datta D, Capps N, Shoulders C, Qureshi N, et al. HEART UK Medical, Scientific Research, Committee. HEART UK consensus statement on Lipoprotein(a): A call to action. Atherosclerosis. 2019;291:62-70. doi: 10.1016/j.atherosclerosis.2019.10.011 32. Ward NC, Watts GF, Bishop W, Colquhoun D, Hamilton-Craig C, Hare DL, Kangaharan N, Kostner KM, Kritharides L, O’Brien R, et al. Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations. Heart Lung Circ. 2023;32:287-296. doi: 10.1016/j.hlc.2022.11.015 33. Moriarty PM, Gray JV, Gorby LK. Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease. J Clin Lipidol. 2019;13:894-900. doi: 10.1016/j.jacl.2019.09.010 34. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Leebmann J, Lehmacher W, Kamstrup PR, Nordestgaard BG, et al. Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization. Arterioscler Thromb Vasc Biol. 2016;36:2019-2027. doi: 10.1161/ATVBAHA.116.307983 35. Chan DC, Watts GF. The Promise of PCSK9 and Lipoprotein(a) as Targets for Gene Silencing Therapies. Clin Ther. 2023. doi: 10.1016/j. clinthera.2023.07.008 36. Nicholls SJ. Therapeutic Potential of Lipoprotein(a) Inhibitors. Drugs. 2024;84:637-643. doi: 10.1007/s40265-024-02046-z
RkJQdWJsaXNoZXIy MjI2NjI=