This activity will you improve your knowledge, awareness, competency, and strategies for women with or at high risk of atherosclerotic cardiovascular disease (ASCVD). Topics covered include the recent AHA/ACC/Multisociety Blood Cholesterol Guidelines. Also discussed are the new options for lowering LDL-C, and how treatment for patients with hypertriglyceridemia has redefined lipid management. The faculty, Drs. Erin Michos and Eliot Brinton, expertly review information on managing women with risk of ASCVD.
Prevention of ASCVD in Women Through Lipid Management in the New Era
Prevention of ASCVD in Women Through Lipid Management in the New Era
The American Heart Association’s cardiovascular disease mortality statistics show that CV events were rising in women during the late 1980s and 1990s in the United States.1 This increase in women continued until 1999 when the first women-specific cardiovascular prevention guidelines were released, followed shortly thereafter by the launch of the Go Red for Women campaign. Since that time, there has been a steep decline in cardiovascular disease mortality. Now there is a slight uptick in cardiovascular mortality in both men and women, likely due to the epidemic of obesity, diabetes, and cardiometabolic disease. A larger rise of 7% can be seen in middle-aged women between 45 and 64.1,2
Traditional cardiovascular risk factors such as diabetes and smoking confer greater risk in women than they do in men, but there are also unique risk factors that women experience related to menarche, menopause, hormones, and pregnancy. It is important to discuss these factors with women because these can be red flags that may identify a woman who is at a higher cardiovascular risk.3 It is also important to discuss these factors at any age because excess cardiovascular risk from hypertensive disorders in pregnancy, such as preeclampsia and preterm delivery, can extend more than 10 years out from the adverse pregnancy.4 Putting together pooled data from many cohorts shows that preeclampsia is associated with a 4-fold increased risk of heart failure and a 2-fold increased risk of coronary disease, stroke, and cardiovascular death; preterm delivery is associated with a 2-fold increased risk of cardiovascular disease, especially if it occurred before 32 weeks.5 Cohort data from France showed that even after adjustment, a history of gestational diabetes was associated with a 25% increased risk of a subsequent cardiovascular disease event.6 The UK Biobank data found that premature menopause before the age of 40 is associated with a 36% increased risk of a subsequent cardiovascular event even after accounting for traditional cardiovascular risk factors.7
To lower cardiovascular risk, the reduction of LDL-C is very important, but all traditional risk factors should be assessed because prevention is a multifaceted approach. The most important way to prevent cardiovascular disease is to emphasize a healthy lifestyle throughout one’s life.8 While there are many healthy dietary patterns, a Mediterranean-style diet is associated with the most evidence for a reduction of myocardial infarction.
In addition to diet, it is important to underscore the importance of physical activity. The guidelines recommend physical activity of moderate to vigorous intensity for 150 minutes a week, which averages 30 minutes a day for 5 days a week.8 Most of the cardiometabolic benefits occur with a moderate-level intensity activity like a brisk walk, and all patients should be encouraged to make time to exercise.
The AHA/ACC guidelines still emphasize statins as the first-line treatment. While statins are also indicated for first-line use in secondary prevention, they should be used for primary prevention of cardiovascular disease in patients with elevated LDL-C above 190 mg/dL.8 These patients should be given a high-intensity statin to lower their LDL-C by more than 50% regardless of their 10-year risk score. Similarly, patients with diabetes who are between 40 and 75 years old should be recommended for a moderate-intensity statin regardless of their 10-year risk score, as should other patients in primary prevention who are deemed to be of sufficient atherosclerotic cardiovascular disease (ASCVD) risk after a clinician-patient risk discussion.
The guidelines recommend beginning the treatment decision-making process by using the Pooled Cohort Equation to determine a 10-year risk score for individuals 40-75 years old who do not have diabetes and who have an LDL-C 70-189 mg/dL. These patients would automatically be indicated for statins above that range.8 The 10-year risk score sorts patients into 4 groups. Patients with a 10-year risk of less than 5% are low-risk individuals, and in general, lifestyle modifications are enough for prevention. Those with a 10-year risk score of more than 20% are in the high-risk category where statins are recommended in addition to lifestyle changes with the goal of reducing LDL-C by more than 50%. In between these extremes are the borderline risk group with scores ranging from 5%-7.5% and the intermediate risk group, with scores from 7.5%-20%. Statins are generally recommended for patients with a 10-year risk score above 7.5%, but this is not a mandated statin prescription. Rather, this is the start of a shared decision conversation with your patient.
The guidelines acknowledge that even after the 10-year risk is estimated, there can still be risk uncertainty, so it is recommended that risk-enhancing factors be reviewed with the patient. These are factors that are already known about the patient clinically, such as traditional ASCVD risk factors and diabetes-specific risk enhancers, such as duration of diabetes, albuminuria, CKD, retinopathy, neuropathy, or a low ankle-brachial index. For borderline- or intermediate-risk individuals, these additional factors would strengthen the decision to start a statin or intensify the statin if one is already being taken.
The guidelines further recognize that there can still be clinical indecision about the benefits of preventive pharmacotherapy even after 10-year risk is estimated and risk-enhancing factors are considered. In these cases, the guidelines state that it may be reasonable to determine a coronary artery calcium score to refine risk up or down to guide shared decision-making.8,9 A score of 0 puts a patient into a much lower risk category. On the other hand, if the score is greater than 0, atherosclerosis is present, and a statin would generally be recommended. A score of 100 or higher, which is the 75th percentile or above, puts patients into a higher-risk category where they would likely derive benefit from statins for primary prevention.
Statins are safe, efficacious, and well tolerated, and in clinical trials there really is no difference in myalgias between statin-treated and placebo patients. In clinical practice, however, up to 20%-30% of patients report statin-associated muscle symptoms, which may be a nocebo effect.10-11 Accordingly, it is important to educate patients about how effective statins are at reducing events, both for primary and secondary prevention, across all LDL-C levels. The risk of serious adverse events is very low. For instance, the risk of a serious muscle injury, including rhabdomyolysis, is less than 0.1%, and the risk of serious hepatotoxicity is ~0.001%.11 There is a very modest increased risk of newly diagnosed diabetes mellitus, but this is in patients who were already glucose intolerant and prediabetic; statins do still provide this group with the benefit of reduced vascular events. Unfortunately, a large proportion of patients stop their statins within 1 to 2 years after initiation, and this is associated with increased cardiovascular risk. If patients cannot use the recommended intensity or cannot tolerate it, the maximum-tolerated statin dose should be used.
Triglycerides (TGs) also must be added into the treatment equation because even a small elevation of TGs despite appropriate statin therapy can substantially elevate ASCVD risk. The most recent data and guidelines now support managing elevated TGs as a biomarker and therapeutic target to reduce ASCVD events. The optimal TG level is less than 100 mg/dL.12 In the 100-200 mg/dL range, the risk of ASCVD events begins to increase, and there is a considerable increase when the level reaches 200-500 mg/dL. Lab tests for nonfasting TG levels are sufficient, but the measurement is slightly more precise when fasting.
Management of elevated TG levels has been challenging, and fibrate and niacin trials have not shown a statistically significant benefit in reducing ASCVD events. The data for ASCVD reduction with these 2 drug classes added to a statin is not very robust and is not recommended by current guidelines.8
Notable trials of omega-3 fatty acids to lower TGs include ASCEND and VITAL, each of which used 1 gram a day of EPA (eicosapentaenoic acid) plus DHA (docosahexaenoic acid) and failed to meet their primary endpoint.13,14 These trials used a combination of EPA plus DHA at low doses, which was more of a dietary supplement dose and not a prescription dose of 4 grams a day.
The first major indication of omega-3 benefit as an adjunct to statin therapy was the JELIS trial.15 JELIS recruited patients with high LDL-C and treated everybody with a statin according to Japanese guidelines. Patients were then randomly assigned to receive 1.8 grams of pure EPA or control. There was a 19% relative risk reduction in the patients receiving EPA and an even higher relative risk reduction of 53% in the subgroup of patients with high TGs and low HDL-C levels.16
More recently, the REDUCE-IT trial used a full dose of 4 grams a day of a virtually identical pure EPA ethyl ester called icosapent ethyl in patients who were already on a statin.17 The study population (N=8,179) was selected for elevated TGs of 135-500 mg/dL, and subjects were followed for up to 5 years. The results were very dramatic, showing a 25% relative risk reduction of the primary endpoints (nonfatal MI, stroke, CV death, coronary revascularization, hospitalization for unstable angina) and a very similar reduction with key secondary hard endpoints (nonfatal MI, stroke, CV death).17 Further analysis of the REDUCE-IT data showed a reduction in total mortality and impressive ASCVD recurrent event reductions that were achieved by simply treating patients with 4 grams a day of icosapent ethyl for 5 years.18 This translates into preventing hundreds of thousands of events by just implementing icosapent ethyl in patients who already have their LDL-C controlled on a statin but have a slightly elevated TG level.
On-treatment TG levels in REDUCE-IT decreased less than 20%, and the relative risk reduction was similar if the patients’ levels got below 150 mg/dL compared to those whose levels were ≥150 mg/dL. There was a comparable benefit across the entire spectrum of baseline TGs.19
REDUCE-IT also showed interesting data on the relationship of plasma EPA and ASCVD benefit. The higher the achieved EPA level during the trial, the greater the relative risk reduction.20
There are stark differences between prescription-only icosapent ethyl (IPE) and over-the-counter dietary supplement omega-3s, which are not regulated by the FDA. Studies show that up to 36% of the content in supplements may be saturated fat, the EPA and DHA content may often be overstated, oxidation of the omega-3 fatty acid content tends to be high, and contamination risks exist.21-24 While the supplements may not be harmful taken in small doses, fish oil supplements are not recommended to treat disease, especially ASCVD.25
As a result of the REDUCE-IT study, icosapent ethyl is now indicated by the FDA for ASCVD reduction.26 There are also many professional societies that have recommended its use as an adjunct to statin therapy for high-risk patients with TG levels 135-500 mg/dL.27-31 They recommend using 4 grams of IPE a day on top of appropriate statin therapy for patients with TGs either >135 mg/dL fasting or >150 mg/dL nonfasting. The recommendation is to get the LDL-C to the goal level with a statin and then add IPE if the TGs remain slightly elevated in the 135-500 mg/dL or 150-500 mg/dL range, depending on fasting or nonfasting levels. 32-33 The first step is to optimize statin therapy. If further LDL lowering is needed, ezetimibe can be prescribed, followed by the PCSK9 inhibitors or newly approved bempedoic acid. If a patient’s LDL-C is controlled on the statin therapy, the LDL cholesterol may not need to be further reduced, but icosapent ethyl is indicated if the TGs are elevated.
A final point is a reminder not to give up on statins. The data from REDUCE-IT was from patients who were on statins. Patients who initially cannot tolerate statins often can when rechallenged. Ezetimibe or other LDL-C adjuncts can be used as needed, and icosapent ethyl should be used to treat elevated TG.
- Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139-e596.
- Curtin SC. Trends in cancer and heart disease death rates among adults aged 45–64: United States, 1999–2017. Natl Vital Stat Rep. 2019;68(5):1-9.
- Elder P, Sharma G, Gulati M, Michos ED. Identification of female-specific risk enhancers throughout the lifespan of women to improve cardiovascular disease prevention. Am J Preventive Cardiol. 2020. doi:10.1016/j.ajpc.2020.100028
- Ying W, Catov JM, Ouyang P. Hypertensive disorders of pregnancy and future maternal cardiovascular risk. J Am Heart Assoc. 2018;7(17):e009382.
- Wu P, Haththotuwa R, Kwok CS, et al. Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2017;10(2):e003497.
- Goueslard K, Cottenet J, Mariet AS, et al. Early cardiovascular events in women with a history of gestational diabetes mellitus. Cardiovasc Diabetol. 2016;15:15. doi: 10.1186/s12933-016-0338-0
- Honigberg MC, Zekavat SM, Aragam K, et al. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA. 2019. doi:10.1001/jama.2019.19191
- 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. Circulation. 2019;139(25):e1082-e1143.
- ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140-205.
- Toth PP, Patti AM, Giglio RV, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018;18(3):157-173.
- Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: A scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38-e81.
- Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-333.
- ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540-1550.
- Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23-32.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369(9567):1090-1098.
- Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200(1):135-140.
- Bhatt D, Steg, G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
- Bhatt DL, Steg PG, Miller M, et al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019;73(22):2791-2802.
- Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol. 2019;74(8):1159-1161.
- Bhatt DL. EPA Levels and cardiovascular outcomes in the Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial. Abstract presented at: ACC.20/WCC Virtual Meeting; March 30, 2020.
- Mason RP, Sherratt SCR. Omega-3 fatty acid fish oil dietary supplements contain saturated fats and oxidized lipids that may interfere with their intended biological benefits. Biochem Biophys Res Commun. 2017;483(1):425-429.
- Rundblad A, Holven KB, Ottestad I, et al. High-quality fish oil has a more favourable effect than oxidised fish oil on intermediate-density lipoprotein and LDL subclasses: a randomised controlled trial. Br J Nutr. 2017;117(9):1291-1298.
- Albert BB Derraik JG, Cameron-Smith D, et al. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA. Sci Rep. 2015;5:7928.
- Merkle S, Giese E, Rohn S, et al. Impact of fish species and processing technology on minor fish oil components. Food Control. 2017;73(Part B):1379-1387.
- American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care. 2017;40(Suppl 1):S1-S135.
- Vascepa. Prescribing information. Amarin Pharma, Inc. 2019. https://amarincorp.com/docs/Vascepa-PI.pdf
- American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S103–S123.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188.
- Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia. a science advisory from the American Heart Association. Circulation. 2019;140(12):e673-e691.
- Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation. 2020;141(19):e779-e806.
- Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 Executive Summary. Endocr Pract. 2020;26(1):107-139.
- Trivedi K, Le V, Nelson JR. The case for adding eicosapentaenoic acid (icosapent ethyl) to the ABCs of cardiovascular disease prevention. Postgrad Med. 2020;1-14. Published online August 6, 2020. doi:10.1080/00325481.2020.1783937
- Orringer CE. Icosapent ethyl: where will it fit into guideline-based medical therapy for high risk atherosclerotic cardiovascular disease? Trends Cardiovasc Med. 2020;30(3):151-157.
In accordance with the ACCME Standards for Commercial Support, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. GLC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Eliot A. Brinton, MD, FAHA, FNLA, FACE
Utah Lipid Center
Salt Lake City, UT
Consulting Fees: Amarin, Esperion, Kowa
Commercial Interest Speakers Bureau: Amarin, Amgen, Boehringer Ingelheim, Kowa, Merck, Nova, Regeneron, Sanofi
Erin D. Michos, MD, MHS, FACC, FAHA, FASE
Associate Professor of Medicine and Epidemiology
Director of Women's Cardiovascular Health
Associate Director of Preventive Cardiology
Associate Faculty of the Welch Center for Prevention, Epidemiology, and Clinical Research
Division of Cardiology
Johns Hopkins University School of Medicine
No relationships reported
- Ben Caref, PhD, has nothing to disclose.
- Sue Grossman has nothing to disclose.
- Kathy Wickman has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Screen and diagnose female patients at high risk of cardiovascular events during their annual visit
- Describe the importance of triglyceride management in ASCVD risk assessment and management
- Apply evidence-based guidelines and recent randomized clinical trial evidence of icosapent ethyl in addition to statin therapy to manage women at risk of ASCVD events
This course is designed to meet the educational needs of physicians, nurse practitioners, physician assistants, nurses, and certified nurse midwives in the fields of obstetrics and gynecology, family practice, and internal medicine.
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This activity is supported by an independent educational grant from Amarin Pharma, Inc.
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Javed Butler, MD, MPH, MBAPeer