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Journal of Cardiovascular Translational Research

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01-02-2022 | PCSK9 Inhibitor | Review

A Less than Provocative Approach for the Primary Prevention of CAD

Authors: Robert Roberts, Jacques Fair

Published in: Journal of Cardiovascular Translational Research | Issue 1/2022

Abstract

Coronary artery disease (CAD) risk increases in proportion to the magnitude and duration of exposure to plasma low-density lipoprotein cholesterol (LDL-C), doubling every additional decade of exposure. Early primary prevention is three times more effective than initiated later. Several clinical trials show plasma LDL-C of 15–40 mg/dL is more effective and equally safe as the Current Cardiovascular Clinical Practice Guidelines (CCCPG) recommended target of 70mg/dL. The cholesterol in the blood is the excess synthesized by the cells and secreted into the blood for disposal in the liver. The CCCPG is inadequate since traditional risk factors (TRF) are not detectable until the sixth and seventh decade. The genetic risk score (GRS) evaluated in 1 million individuals as a risk stratifier for CAD is superior to TRF. Genetic risk for CAD was reduced by 30–50% by statin therapy, PCSK9 inhibitors, and lifestyle changes. The GRS does not change during one’s lifetime and is inexpensive. Incorporating genetic risk stratification into CCCPG would induce a paradigm shift in the primary prevention of CAD.

Murray, C. J., & Lopez, A. D. (2013). Measuring the global burden of disease. The New England Journal of Medicine, 369(5), 448–457.PubMedCrossRef

Benjamin, E. J., Virani, S. S., Callaway, C. W., Chamberlain, A. M., Chang, A. R., Cheng, S., et al. (2018). Heart disease and stroke statistics-2018 update: A report from the American Heart Association. Circulation, 137(12), e67–e492.

Grundy, S. M., Stone, N. J., Bailey, A. L., Craig, B., Birtcher Kim, K., Blumenthal Roger, S., et al. (2019). 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, 139(25), e1082–e1143.PubMed

Authors/Task Force Members. (2019). 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, 290, 140–205.CrossRef

Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., et al. (2020). Low-density lipoproteins cause atherosclerotic cardiovascular disease: Pathophysiological, genetic, and therapeutic insights: A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal, 41(24), 2313–2330.PubMedPubMedCentralCrossRef

Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2015). Heart disease and stroke statistics--2015 update: A report from the American Heart Association. Circulation, 131(4), e29–e322.

Ference, B. A., Ginsberg, H. N., Graham, I., Ray, K. K., Packard, C. J., Bruckert, E., et al. (2017). Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal, 38(32), 2459–2472.PubMedPubMedCentralCrossRef

Navar-Boggan, A. M., Peterson, E. D., D’Agostino, R. B., Neely, B., Sniderman, A. D., & Pencina, M. J. (2015). Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation, 131(5), 451–458.PubMedPubMedCentralCrossRef

Scandinavian Simvastatin Survival Study Group. (1994). Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). The Lancet, 344(8934), 1383–1389.

10.

Baigent, C., Keech, A., Kearney, P. M., Blackwell, L., Buck, G., Pollicino, C., et al. (2005). Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 366(9493), 1267–1278.CrossRef

11.

Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., et al. (2016). Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet, 388(10059), 2532–2561.CrossRef

12.

Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent, C., Blackwell, L., Emberson, J., Holland, L. E., Reith, C., et al. (2010). Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 376(9753), 1670–1681.CrossRef

13.

Ference, B. A., Yoo, W., Alesh, I., Mahajan, N., Mirowska, K. K., Mewada, A., et al. (2012). Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease. Journal of the American College of Cardiology, 60(25), 2631.PubMedCrossRef

14.

Swiger, K. J., Martin, S. S., Blaha, M. J., Toth, P. P., Nasir, K., Michos, E. D., et al. (2014). Narrowing sex differences in lipoprotein cholesterol subclasses following mid-life: The very large database of lipids (VLDL-10B). Journal of the American Heart Association, 3(2), e000851.PubMedPubMedCentralCrossRef

15.

Domanski, M. J., Tian, X., Wu, C. O., Reis, J. P., Dey, A. K., Gu, Y., Zhao, L., Bae, S., Liu, K., Hasan, A. A., Zimrin, D., Farkouh, M. E., Hong, C. C., Lloyd-Jones, D. M., & Fuster, V. (2020). Time course of LDL cholesterol exposure and cardiovascular disease event risk. Journal of the American College of Cardiology, 76(13), 1507–1516.PubMedCrossRef

16.

Zeitouni, M., Nanna, M. G., Sun, J.-L., Chiswell, K., Peterson, E. D., & Navar, A. M. (2020). Performance of guideline recommendations for prevention of myocardial infarction in young adults. Journal of the American College of Cardiology, 76(6), 653–664.PubMedPubMedCentralCrossRef

17.

Cohen, D. E. (2008). Balancing cholesterol synthesis and absorption in the gastrointestinal tract. Journal of Clinical Lipidology, 2(2), S1–S3.PubMedPubMedCentralCrossRef

18.

Tabas, I. (2002). Consequences of cellular cholesterol accumulation: Basic concepts and physiological implications. The Journal of Clinical Investigation, 110(7), 905–911.PubMedPubMedCentralCrossRef

19.

Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., et al. (2015). Ezetimibe added to statin therapy after acute coronary syndromes. The New England Journal of Medicine, 372(25), 2387–2397.PubMedCrossRef

20.

Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. The New England Journal of Medicine, 376(18), 1713–1722.PubMedCrossRef

21.

Giugliano, R. P., Pedersen, T. R., Park, J.-G., De Ferrari, G. M., Gaciong, Z. A., Ceska, R., et al. (2017). Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: A prespecified secondary analysis of the FOURIER trial. The Lancet, 390(10106), 1962–1971.CrossRef

22.

Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., et al. (2018). Alirocumab and cardiovascular outcomes after acute coronary syndrome. The New England Journal of Medicine, 379(22), 2097–2107.PubMedCrossRef

23.

Ference, B. A., Cannon, C. P., Landmesser, U., Lüscher, T. F., Catapano, A. L., & Ray, K. K. (2018). Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: An analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. European Heart Journal, 39(27), 2540–2545.PubMedCrossRef

24.

High-dose atorvastatin after stroke or transient ischemic attack - PubMed [Internet]. [cited 2020 Oct 22]. Available from: https://pubmed.ncbi.nlm.nih.gov/16899775/

25.

Kones, R., & Rumana, U. (2015). Current treatment of dyslipidemia: A new paradigm for statin drug use and the need for additional therapies. Drugs, 75(11), 1187–1199.PubMedCrossRef

26.

Fujita, H., Okada, T., Inami, I., Makimoto, M., Hosono, S., Minato, M., et al. (2008). Low– density lipoprotein profile changes during the neonatal period. Journal of Perinatology, 28(5), 335–340.PubMedCrossRef

27.

Pac-Kozuchowska, E. (2007). Evaluation of lipids, lipoproteins and apolipoproteins concentrations in cord blood serum of newborns from rural and urban environments. Annals of Agricultural and Environmental Medicine, 14(1), 25–29.PubMed

28.

Chan, L., & Boerwinkle, E. (1994). Gene-environment interactions and gene therapy in atherosclerosis. Cardiology in Review, 2, 130–137.CrossRef

29.

McPherson, R., Pertsemlidis, A., Kavaslar, N., Stewart, A., Roberts, R., Cox, D. R., et al. (2007). A common allele on chromosome 9 associated with coronary heart disease. Science, 316(5830), 1488–1491.PubMedPubMedCentralCrossRef

30.

Helgadottir, A., Thorleifsson, G., Manolescu, A., Gretarsdottir, S., Blondal, T., Jonasdottir, A., et al. (2007). A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science, 316(5830), 1491–1493.PubMedCrossRef

31.

Erdmann, J., Kessler, T., Munoz Venegas, L., & Schunkert, H. (2018). A decade of genome-wide association studies for coronary artery disease: The challenges ahead. Cardiovascular Research, 114(9), 1241–1257.PubMed

32.

Khera, A. V., Chaffin, M., Zekavat, S. M., Collins, R. L., Roselli, C., Natarajan, P., et al. (2019). Whole-genome sequencing to characterize monogenic and polygenic contributions in patients hospitalized with early-onset myocardial infarction. Circulation, 139(13), 1593–1602.PubMedPubMedCentralCrossRef

33.

Inouye, M., Abraham, G., Nelson, C. P., Wood, A. M., Sweeting, M. J., Dudbridge, F., et al. (2018). Genomic risk prediction of coronary artery disease in 480,000 adults. Journal of the American College of Cardiology, 72(16), 1883–1893.PubMedPubMedCentralCrossRef

34.

Davies, R. W., Dandona, S., Stewart, A. F., et al. (2010). Improved prediction of cardiovascular disease based on a panel of single nucleotide polymorphisms identified through genome-wide association studies. Circulation. Cardiovascular Genetics, 3(5), 468–474.PubMedPubMedCentralCrossRef

35.

Assimes, T. L., & Roberts, R. (2016). Genetics: Implications for prevention and management of coronary artery disease. Journal of the American College of Cardiology, 68(25), 2797–2818.PubMedCrossRef

36.

Khera, A. V., Chaffin, M., Aragam, K. G., Haas, M. E., Roselli, C., Choi, S. H., et al. (2018). Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature Genetics, 50(9), 1219–1224.PubMedPubMedCentralCrossRef

37.

Mega, J. L., Stitziel, N. O., Smith, J. G., Chasman, D. I., Caulfield, M., Devlin, J. J., et al. (2015). Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: An analysis of primary and secondary prevention trials. Lancet, 385(9984), 2264–2271.PubMedPubMedCentralCrossRef

38.

Natarajan, P., Young, R., Stitziel, N. O., Padmanabhan, S., Baber, U., Mehran, R., et al. (2017). Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation, 135(22), 2091–2101.PubMedPubMedCentralCrossRef

39.

Abraham, G., Havulinna, A. S., Bhalala, O. G., et al. (2016). Genomic prediction of coronary heart disease. European Heart Journal, 37(43), 3267–3278.PubMedPubMedCentralCrossRef

40.

Marston, N. A., Kamanu, F. K., Francesco, N., Yared, G., Carolina, R., Sever Peter, S., et al. (2020). Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score. Circulation, 141(8), 616–623.PubMedCrossRef

41.

Amy, D., Gabriel, S. P., Schwartz, G. G., Michael, S., Emil, H., Lina, B., et al. (2020). Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from alirocumab treatment in the ODYSSEY OUTCOMES trial. Circulation, 141(8), 624–636.CrossRef

42.

Elliott, J., Bodinier, B., Bond, T. A., et al. (2020). Predictive accuracy of a polygenic risk score–Enhanced prediction model vs a clinical risk score for coronary artery disease. JAMA, 323(7), 636–645.PubMedPubMedCentralCrossRef

43.

Mosley, J. D., Gupta, D. K., Tan, J., et al. (2020). Predictive accuracy of a polygenic risk score compared with a clinical risk score for incident coronary heart disease. JAMA, 323(7), 627–635.PubMedPubMedCentralCrossRef

44.

Aragam, K. G., Dobbyn, A., Judy, R., Chaffin, M., Chaudhary, K., Hindy, G., et al. (2020). Limitations of contemporary guidelines for managing patients at high genetic risk of coronary artery disease. Journal of the American College of Cardiology, 75(22), 2769.PubMedPubMedCentralCrossRef

45.

Wang, M., Menon, R., Mishra, S., Patel, A. P., Chaffin, M., Tanneeru, D., et al. (2020). Validation of a genome-wide polygenic score for coronary artery disease in South Asians. Journal of the American College of Cardiology, 76(6), 703–714.PubMedPubMedCentralCrossRef

46.

Khera, A. V., Emdin, C. A., Drake, I., Natarajan, P., Bick, A. G., Cook, N. R., et al. (2016). Genetic risk, adherence to a healthy lifestyle, and coronary disease. The New England Journal of Medicine, 375(24), 2349–2358.PubMedPubMedCentralCrossRef

47.

Tikkanen, E., Gustafsson, S., & Ingelsson, E. (2018). Associations of fitness, physical activity, strength, and genetic risk with cardiovascular disease: Longitudinal analyses in the UK Biobank study. Circulation., 137(24), 2583–2591.PubMedPubMedCentralCrossRef

Title: A Less than Provocative Approach for the Primary Prevention of CAD
Authors: Robert Roberts
Jacques Fair
Publication date: 01-02-2022
Publisher: Springer US
Keywords: PCSK9 Inhibitor
Arterial Diseases
Published in: Journal of Cardiovascular Translational Research / Issue 1/2022
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-021-10144-6

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