High cholesterol primary prevention

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Template:Hypercholesterolemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753; Associate Editor(s)-In-Chief: Kashish Goel, M.D.

Overview

Primary prevention is the most effective means of reducing the global burden of cardiovascular disease. NCEP recommends population-based and clinical-based approaches for primary prevention. Physicians should establish short-term and long-term goals for their patients based on risk factors and 10-year CHD risk. Therapeutic lifestyle changes and LDL lowering are both advocated.

Therapeutic lifestyle changes

Therapeutic lifestyle changes should be recommended to every individual to reduce long-term risk. These include cessation of smoking, dietary modifications, weight control and physical inactivity. A previous meta-analysis showed that dietary lowering of cholesterol was associated with CHD risk reduction similar to drug therapy[1]. A recent randomized controlled trial by Jenkins et al. showed that cholesterol lowering diets were associated with a significant reduction in LDL and 10-year CHD risk at 6 monhts, as compared to control diet[2]. ATP III recommends a multifaceted lifestyle approach to reduce risk for CHD. The essential features of this approach designated as therapeutic lifestyle changes are:

“

1. Reduced intakes of saturated fats (<7% of total calories) and cholesterol (<200 mg per day).

2. Therapeutic options for enhancing LDL lowering such as plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day)

3. Weight reduction

4. Increased physical activity

”


LDL lowering drug therapy

LDL lowering therapy for primary prevention has been evaluated in numerous trials. If therapeutic lifestyle changes do not achieve the desired LDL goal, then drug therapy should be considered. Statins are usually the 'first choice' medications. Trials evaluating the role of statin therapy in primary prevention are detailed here.

Meta-analyses

  • A recently published Cochrane meta-analysis including 14 randomized controlled trials (34,272 participants) showed a significant reduction in all-cause mortality, combined fatal and non-fatal CVD endpoints and revascularizations with statin therapy in subjects without cardiovascular disease. However, they reported heterogeneity of effects between studies[3].
  • Another meta-analysis evaluating the role of statins in primary prevention of cardiovascular disease showed a significant reduction in major coronary events, major cerebrovascular events and revascularizations in 42, 848 participants, however no change in coronary heart disease mortality or overall mortality was noted[4].


Randomized Controlled Trials of Hypolipidemic Strategies in Primary Prevention

WOSCOPS (1995)

Treatment with pravastatin 40 mg daily in 6595 men with hypercholesterolemia resulted in a significant reduction in the incidence of fatal and non-fatal myocardial infarction and death from cardiovascular causes, without a difference in the deaths due to non-cardiovascular causes in a follow-up period of 4.9 years[5].

AFCAPS/TexCAPS (1998)

Lovastatin 20-40 mg daily (in addition to low-saturated ad low-colesterol diet) reduced the incidence of first major acute cardiovascular event (MACE) during a follow-up of 5.2 years, in this study involving 5608 men and 997 women with average total cholesterol and LDL levels and low HDL levels[6].

PROSPER (2002)

Pravastatin 40 mg daily reduced the incidence of non-fatal MI and CHD death during a follow-up of 3.2 years, in this trial involving the 2804 elderly men and 3000 women with a history of, or risk factors for vascular disease. This trial extended the treatment strategies to elderly population[7].

ALLHAT-LLT (2002)

No significant difference was observed on CHD mortality in the group treated with pravastatin 40 mg daily as compared to the usual care group with well controlled hypertension and moderately elevated LDL. Possible explanations for failure to observe a significant reduction included a modest reduction in total cholesterol, unblinded study with no placebo group and a large crossover of high risk subjects[8]

ASCOT-LLA (2003)

Hypertensive patients (n=10305) with total cholesterol < 251 mg/dL were randomly assigned to atorvastatin 10 mg daily and a significant reduction in non-fatal MI, fatal CHD and stoke (fatal and non-fatal) was noticed. No significant difference was observed on all-cause mortality. The trial was stopped earlier than expected of 5 years because of beneficial treatment[9].

HPS (2003)

In the sub-group of 5963 patients with diabetes without known occlusive vascular disease, simvastatin 40 mg daily significantly reduced the rate of first major vascular events during a follow-up period of 4.8 years[10].

CARDS (2004)

Atorvastatin 10 mg daily significantly reduced the occurrence of primary end-point of MACE and secondary end-points of CHD events, coronary revascularizations and stroke during a median follow-up of 3.9 years in 2838 patients with type 2 diabetes and LDL < 160 mg/dL. Trial was stopped 2 years earlier than expected[11].

ASPEN (2006)

In 1905 patients with diabetes and no prior CHD, the composite/primary end-point and secondary end-points of CV mortality, fatal/non-fatal MI, revascularizations, strokes or hospitalization for angina were similar in the treatment group (atorvastatin 10 mg daily) and placebo[12].

MEGA (2006)

A total of 3966 Japanese subjects with hypercholesterolemia were randomized to diet alone or diet plus pravastatin 10-20 mg daily during a mean follow-up of 5.3 years. Low dose pravastatin significantly reduced the occurence of CHD in this ethnicity-specific study[13].

JUPITER (2008)

This most recent trial randomly assigned 17,802 healthy subjects with LDL < 130 mg/dL and high-sensitivity CRP > 2 g/L to Rosuvastatin 20 mg daily or placebo. A significant reduction in the composite and individual components of the primary end-point of myocardial infarction, stroke, arterial revascularization hospitalization for unstable angina or death from cardiovascular causes and all-cause mortality was noted and trial was stopped earlier at 1.9 years (maximum of 5 years)[14].

References

  1. ↑ Gordon DJ.Cholesterol lowering reduces mortality:the statins. In: Grundy SM, ed. Cholesterol-lowering therapy: evaluation of clinical trial evidence. New York:Marcel Dekker Inc., 2000:299-311
  2. ↑ Jenkins DJ, Jones PJ, Lamarche B, Kendall CW, Faulkner D, Cermakova L; et al. (2011). "Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial". JAMA. 306 (8): 831–9. doi:10.1001/jama.2011.1202. PMID 21862744.
  3. ↑ Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP; et al. (2011). "Statins for the primary prevention of cardiovascular disease". Cochrane Database Syst Rev (1): CD004816. doi:10.1002/14651858.CD004816.pub4. PMID 21249663.
  4. ↑ Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK (2006). "Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials". Arch Intern Med. 166 (21): 2307–13. doi:10.1001/archinte.166.21.2307. PMID 17130382. Review in: J Fam Pract. 2007 Mar;56(3):174
  5. ↑ Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW; et al. (1995). "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group". N Engl J Med. 333 (20): 1301–7. doi:10.1056/NEJM199511163332001. PMID 7566020.
  6. ↑ Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA; et al. (1998). "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study". JAMA. 279 (20): 1615–22. PMID 9613910.
  7. ↑ Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM; et al. (2002). "Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial". Lancet. 360 (9346): 1623–30. PMID 12457784. Review in: ACP J Club. 2003 Jul-Aug;139(1):9
  8. ↑ ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002). "Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)". JAMA. 288 (23): 2998–3007. PMID 12479764. Review in: ACP J Club. 2003 Jul-Aug;139(1):10
  9. ↑ Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M; et al. (2003). "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 multicentre randomised controlled trial". Lancet. 361 (9364): 1149–58. doi:10.1016/S0140-6736(03)12948-0. PMID 12686036. Review in: ACP J Club. 2003 Nov-Dec;139(3):57
  10. ↑ Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group (2003). "MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial". Lancet. 361 (9374): 2005–16. PMID 12814710. Review in: ACP J Club. 2004 Jan-Feb;140(1):1
  11. ↑ Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ; et al. (2004). "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial". Lancet. 364 (9435): 685–96. doi:10.1016/S0140-6736(04)16895-5. PMID 15325833. Review in: ACP J Club. 2005 Mar-Apr;142(2):29
  12. ↑ Knopp RH, d'Emden M, Smilde JG, Pocock SJ (2006). "Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN)". Diabetes Care. 29 (7): 1478–85. doi:10.2337/dc05-2415. PMID 16801565. Review in: ACP J Club. 2006 Nov-Dec;145(3):62
  13. ↑ Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T; et al. (2006). "Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial". Lancet. 368 (9542): 1155–63. doi:10.1016/S0140-6736(06)69472-5. PMID 17011942.
  14. ↑ Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ; et al. (2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". N Engl J Med. 359 (21): 2195–207. doi:10.1056/NEJMoa0807646. PMID 18997196. Review in: Evid Based Med. 2009 Apr;14(2):48 Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-4

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