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The Evolution or Revolution of Statin Therapy in Primary Prevention: Where Do We Go From Here?

Abstract

CHD morbidity and mortality rates have more than halved since their peak in the 1960s and 1970s. This trend is a result of many factors; however, primary prevention provides the bulk of this benefit. Despite this tremendous progress, cardiovascular disease remains the major cause of death and this trend is projected to persist given the continuous growth in those aged 65 years or greater. Although statin therapy has been a main contributor to a primary prevention strategy, there is still controversy about exposing a large healthy population to long-term statin therapy. Advocates contend the mortality benefits from an aggressive statin approach would remove heart disease from its perch as the greatest killer of Americans and stroke mortality would drop from third to fifth place. Those advocating a much more conservative approach contend the data are not available to expose a healthy population to lifelong statin therapy given limited data on mortality, potential adverse events, and considerable costs. Given these opposing views, this summary of the evolution of statin therapy for the primary prevention of cardiovascular disease will review the major factors fueling this debate.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–7.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Downs JR, Clearfield MB, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–22.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    National Cholesterol Education Program (NCEP) Expert Panel on Detection. Evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;106:3143–421.

    Google Scholar 

  4. 4.

    Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet. 2002;360:1623–30.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    The ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid lowering treatment to prevent heart attack trial. JAMA. 2002;288:2998–3007.

    Article  Google Scholar 

  6. 6.

    Sever PS, Dalhof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet. 2003;361:1149–58.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomized placebo controlled trial. Lancet. 2003;361:2005–16.

    PubMed  Article  Google Scholar 

  8. 8.

    Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS); multicenter randomized placebo controlled trial. Lancet. 2004;364:685–96.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Thavendiranathan P, Bagai A, Brookhart MA, et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Int Med. 2006;166:2307–13.

    Article  CAS  Google Scholar 

  10. 10.

    Nakamuro H, Arakawa K, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomized controlled trial. Lancet. 2006;368:1155–63.

    Article  Google Scholar 

  11. 11.

    Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–65.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical public health practice. A statement for health care professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.

    PubMed  Article  Google Scholar 

  13. 13.

    Murphy SA, Cannon CP, Wiviott, et al. Effect of intensive lipid lowering therapy on mortality after acute coronary syndrome (a patient level analysis of the Aggrastat to Zocor and pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 trials). Am J Cardiol. 2007;100:1047–51.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Ridker PM, Danielson E, Fonseca AF, for the JUPITER study group, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2197–207.

    Article  Google Scholar 

  16. 16.

    Ridker PM, Danielson E, Fonseca F, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–83.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    • Hsia J, MacFadyen JG, Monyak J. Cardiovascular event reduction and adverse events among subjects attaining LDL-C < 50 mg/dl with rosuvastatin. J Am Coll Cardiol. 2011;57:1666–75. This substudy of JUPITER demonstrated those subjects treated with rosuvastatin who achieved LDL-C levels below 50 mg/dl continued to have lower rates of cardiovascular events without an increase in the rates of statin-induced adverse events.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Lee KH, Jeong MH, Kim HM, et al. Benefit of early statin therapy in patients with acute myocardial infarction who have extremely low LDL-C. J Am Coll Cardiol. 2011;58:1664–71.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Ray KK, Seshasai S, Erqou S, et al. Statins and all-cause mortality in high risk primary prevention. Arch Intern Med. 2010;170:1024–31.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, et al. The benefits of statins in people without established cardiovascular disease but with cardiac risk factor: meta-analysis of randomized controlled trials. BMJ. 2009;338:b2376. doi:10.1136/bmj.b2376.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816

  22. 22.

    Grammer TB. Are statins really useless in primary prevention? Recent Cochrane meta-analysis revisited. Int J Clin Pharmacol Ther. 2011;49:293–6.

    PubMed  CAS  Google Scholar 

  23. 23.

    Goldfine AB. Statins: is it really time to reassess benefits and risk? NEJM. 2012;366(19):1752–5.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Minder CM, Blaha MJ, Horne A, et al. Evidence based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125(5):440–6.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    •• Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376:1670–11681. This is the most comprehensive meta-analysis on statin therapy for the prevention of cardiovascular disease. This analysis demonstrated there was no evidence for any threshold within the cholesterol range studied and suggested reductions in LDL-C levels by 2–3 mmol/l could reduce the risk of cardiovascular disease by 40-50%.

    Article  Google Scholar 

  26. 26.

    •• Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL-C with statin therapy in people at low risk of vascular disease: a meta-analysis of individual data from 27 randomized trials. Lancet. 2012;380:581–90. This meta-analysis evaluating subjects at low risk of vascular disease demonstrated continued cardiovascular benefits from statins in lower-risk subgroups currently not recommended for statin therapy.

    Google Scholar 

  27. 27.

    Redberg RF, Katz M, Grady D. To make the case: evidence is required. Comment on “making the case for selective use of statins in the primary prevention setting.”. Arch Int Med. 2011;171:1594.

    Article  Google Scholar 

  28. 28.

    Steinberg D. Earlier intervention in the management of hypercholesterolemia. What are we waiting for? J Am Coll Cardiol. 2010;56:627–9.

    PubMed  Article  Google Scholar 

  29. 29.

    Roberts WC. It’s the cholesterol, stupid! Am J Cardiol. 2010;106:1364–6.

    PubMed  Article  Google Scholar 

  30. 30.

    Forrester JS. Redefining normal low-density cholesterol. A strategy to unseat coronary disease as the Nation’s leading killer. J Am Coll Cardiol. 2010;56:630–6.

    PubMed  Article  Google Scholar 

  31. 31.

    • Domanski M, Lloyd-Jones D, Fuster V, Grundy S. Can we dramatically reduce the incidence of coronary heart disease? Nat Rev Cardiol. 2011;8:721–5. This article outlines the feasibility and basic design for a new clinical trial to further assess an LDL-C-lowering strategy in men aged 35–50 years and women aged 35–59 years.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study. Am J Cardiol. 2004;93:136–41.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Clearfield M, Downs JR, Lee M, et al. Implications from the Air Force/Texas Coronary Atherosclerosis Prevention Study for the Adult Treatment Panel III guidelines. Am J Cardiol. 2005;96:1674–80.

    PubMed  Article  Google Scholar 

  34. 34.

    Clearfield M. Statins and the primary prevention of cardiovascular events. Curr Atheroscler Reports. 2006;8:390–96.

    Article  CAS  Google Scholar 

  35. 35.

    Ridker PM, MacFadyen JG, Nordestgaard BG, et al. Rosuvstatin for primary prevention among individuals with elevated high sensitivity C-reactive protein and 5% to 10% and 10% to 20% 10 year risk. Circ Cardiovasc Qual Outcomes. 2010;3:447–52.

    PubMed  Article  Google Scholar 

  36. 36.

    Sniderman A, Thanassoulis G, Couture P, et al. Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists’ Collaboration meta-analysis for LDL-C lowering. J Clin Lipidology. 2012;6:303–9.

    Article  Google Scholar 

  37. 37.

    Lloyd-Jones D, Adams R, Carnethon M, American Heart Association Statistics Committee and Stroke statistics subcommittee, et al. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke statistics subcommittee. Circulation. 2009;119(3):e21–e181.

    PubMed  Article  Google Scholar 

  38. 38.

    Culver AL, Balasubramanian R, Olendzki BC, et al. Statin use and risk diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Int Med. 2012;172:144–52.

    Article  Google Scholar 

  39. 39.

    Preiss D, Seshasai RK, Welsh P, et al. Risk of incident diabetes with intensive dose compared with moderate dose statin therapy. A meta-analysis. JAMA. 2011;305:2556–64.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol lowering therapy in 18,686 people with diabetes in 14 randomized trials of statins: a meta-analysis. Lancet. 2008;371:117–25.

    Article  Google Scholar 

  41. 41.

    • Ridker PM, Pradham A, MacFaden JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–71. The JUPITER analysis noted an increased risk of new onset of diabetes in those treated with rosuvastatin versus placebo; however, this risk was almost entirely isolated to those with risk factors for diabetes or in a prediabetic state.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Wang KL, Liu CJ, Chao TF, et al. Statins, Risk of diabetes and implications on outcome in the general population. J Am Coll Cardiol. 2012;60:1231–8.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    • Kizer JR, Madias C, Wilner B, et al. Relation of different measures of LDL-C to risk of coronary artery disease and death in a meta-regression analysis of large scale trials of statin therapy. Am J Cardiol. 2010;105:11289–1296. This analysis suggests the absolute reduction in LDL-C level by comparing the control and treatment groups was the predominant determinant for mortality reduction from treatment with statins.

    Article  Google Scholar 

  44. 44.

    Lloyd-Jones DM, Dyer AR, Wang R, et al. Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death. (Chicago Heart Association Detection Project in Industry). Am J Cardiol. 2007;99:535–40.

    PubMed  Article  Google Scholar 

  45. 45.

    Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791–8.

    PubMed  Article  Google Scholar 

  46. 46.

    Cohen JC, Boerwinkle E, Mosely TH, Hobbs HH. Sequence variations in PCSK9, low LDLand protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Martin SS, Metkus TS, Horne A, et al. Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations. Am J Cardiol. 2012;110:307–13.

    PubMed  Article  Google Scholar 

  48. 48.

    • Kostis WJ, Moreyra AE, Cheng JQ, et al. Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid lowering therapy. J Clin Lipidology. 2011;5:97–104. A meta-analysis of eight lipid-lowering trials (including five statin trials) showed a continuous cardiovascular benefit after the trials concluded and suggested a legacy effect may be possible where curves continued to diverge after discontinuation of the blinded therapy.

    Article  Google Scholar 

  49. 49.

    Simpson RJ, Mendys P. The effect of adherence and persistence on clinical outcomes in patients treated with statins: A systematic review. J Clin Lipidiology. 2010;4:462–71.

    Article  Google Scholar 

  50. 50.

    LaRosa JC, Deedwania PC, Shepherd JM, et al. Comparison of 80 vs 10 mg of atorvastatin on occurrence of cardiovascular events after first event (from the Treating to New Targets [TNT] trial). Am J Cardiol. 2010;105:283–87.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Choudhry NK, Patrick AR, Glynn RJ, et al. The cost-effectiveness of C-reactive protein and rosuvastatin treatment for patients with normal cholesterol. J Am Coll Cardiol. 2011;57:784–91.

    PubMed  Article  Google Scholar 

  52. 52.

    Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid lowering. Ann Intern Med. 2009;150:243–54.

    PubMed  Google Scholar 

  53. 53.

    LaRosa JC, Grundy SM, Kastelein JP, et al. Safety and efficacy of atorvastatin induced very low LDL-C levels patients with coronary heart disease (a post hoc analysis of the Treating to New Target (TNT) study. Am J Cardiol. 2007;100:747–52.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Sever P, Poulter NR, Chang C, et al. Evaluation of CRP prior to and on-treatment as a predictor of benefit from the Anglo-Scandanavian Cardiac Outcomes Trial. Eur Heart J. 2012;33:486–94.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Braunwald E. Creating controversy where none exists: the important role of CRP in CARE, AFCAPS/TexCAPS, PROVE-IT, REVERSAL, A to A, JUPITER, HEART PROTECTION and ASCOT trials. Eur Heart J. 2012;33:430–2.

    PubMed  Article  Google Scholar 

  56. 56.

    Mottillo SM, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk: A systemic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–32.

    PubMed  Article  Google Scholar 

  57. 57.

    Robinson JG, Smith B, Maheshwari, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 2005;46:1855–62.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Robinson JG. Models for describing relations among various statin drugs, lowering LDL-C, pleiotropic effects, and cardiovascular risk. Am J Cardiol. 2008;101:1009–15.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Genest J. C-reactive protein: risk factor, biomarker and/or therapeutic target? Can J Cardiol. 2010;26:A41–4.

    Article  Google Scholar 

  60. 60.

    Ridker P. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial. (CIRT). J Thrombo Heamost. 2009;7 Suppl 1:332–9.

    Article  CAS  Google Scholar 

  61. 61.

    Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597–605.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Young F, Capewell S, Ford E, et al. Coronary mortality declines in the U.S. between 1980 and 2000. Quantifying the contributions from primary and secondary prevention. Am J Prev Med. 2010;39:228–34.

    PubMed  Article  Google Scholar 

  63. 63.

    Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first priority in cardiovascular risk management be those with prior cardiovascular disease? Heart. 2009;95:125–9.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Roger VL, Go AS, Lloyd-Jones, et al. Executive summary: heart disease and stroke statistics-2102 update. A report from the American Heart Association. Circ. 2012;125:188–97.

    Article  Google Scholar 

  65. 65.

    Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JP, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters D, Shear CL, Revkin JH, Buhr KA, Fisher M, Tall AR, Brewer B, for the ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. New Engl J Med. 2007;357:2109–22.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. New Engl J Med. 2010;362:1563–74.

    Article  Google Scholar 

  67. 67.

    Cannon CP, Shah S, Dansky HM, Davidson M, Brinton E, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P, for the DEFINE investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. New Engl J Med. 2010;363:2406–15.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Ridker PM, Fonseca F, Genest J, et al. Baseline characteristics of participants in the JUPITER, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low LDL-C and elevated hs-CR. Am J Cardiol. 2007;100:1659–64.

    PubMed  Article  Google Scholar 

  69. 69.

    Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average LDL-C levels: exploratory analysis of a randomized trial. Ann Int Med. 2010;152:488–96.

    PubMed  Google Scholar 

  70. 70.

    Rahilly-Tierney CR, Lawler EV, Scranton RE, Gaziano M. Cardiovascular benefit of magnitude of LDL-C reduction. A comparison of subgroups by age. Circulation. 2009;120:1491–7.

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJP, Hutten BA. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007;116:664–8.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Vermissen J, Oosterveer D, Yazdanpanah M, Defesche JC, Basart D, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JP, Sijbrands EJ. Efficacy of statins in familial hypercholesterolemia: a long term cohort study. BMJ. 2008;337:a2423. doi:10.1136/bmj.a2423.

    Article  Google Scholar 

  73. 73.

    Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol. 2009;25(10):567–79.

    PubMed  Article  CAS  Google Scholar 

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Disclosure

P. Rehfield: none, C. Kopes-Kerr: none, and M. Clearfield: consultancy, honoraria received from and has travel/accommodation expenses covered or reimbursed by Astra Zeneca and Daiichi Sankyo.

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Correspondence to Michael Clearfield.

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This article is part of the Topical Collection on Statin Drugs

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Rehfield, P., Kopes-Kerr, C. & Clearfield, M. The Evolution or Revolution of Statin Therapy in Primary Prevention: Where Do We Go From Here?. Curr Atheroscler Rep 15, 298 (2013). https://doi.org/10.1007/s11883-012-0298-0

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Keywords

  • Statin
  • Primary prevention
  • LDL target
  • C-reactive protein