High cholesterol secondary 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

Patients with CHD or newly diagnosed acute coronary syndrome are at a high risk of recurrent coronary events. In addition to modification of lifestyle factors, LDL lowering has been shown to reduce recurrent events, cardiovascular deaths and all-cause mortality in these patients. According to the NCEP ATP III guidelines, LDL cholesterol of < 100 mg/dL is the goal in patients with CHD and CHD risk equivalents. The complete NCEP recommendations are reviewed here, in addition to the data supporting these recommendations.

Therapy goals

NCEP ATP III guidelines recommended an LDL goal < 100 mg/dL for CHD or CHD risk equivalents, however drug therapy was considered optional between a LDL of 100 to <130 mg/dL. A 2004 update based upon new trial data recommends starting drug therapy simultaneously with therapeutic lifestyle changes in CHD patients with LDL < 100 mg/dL. An optional goal of LDL < 70 mg/dL was recommended in high risk patients.

LDL Lowering for Secondary Prevention In Patients with Coronary Heart Disease

Progression of coronary atherosclerosis

In the 90's, a number of clinical trials were performed to evaluate the role of statin therapy on coronary atherosclerosis progression in patients with CHD. Some of the important trials with positive and negative findings are as follows:

  • The MAAS (1994)[1], PLAC-I (1995)[2] and REGRESS (1995)[3] trials showed that statins slowed the progression of focal and diffuse coronary atherosclerosis. Another European trial, Coronary Intervention Study (CIS) (1997) reported a significant reduction in progression of angiographically-determined CHD as assessed by mean global scores and mean luminal diameter. The reduction in LDL levels was significantly correlated with these angiographic parameters[4].
  • On the other hand, the Harvard Atherosclerosis Regression Project (HARP) (1994) [5], Lovastatin Restenosis Trial Study (1994)[6],PREDICT trial (1997)[7] and FLARE (1999)[8] trials reported no affect of statin therapy on the rate of restenosis or angiographic disease progression as assessed by mean luminal diameter.

Randomized Double Blind Trials In Secondary Prevention

The role of LDL lowering in patients with CHD or CHD risk equivalents is well established. Multiple trials have shown that addition of statin therapy to secondary risk reduction reduces all-cause mortality (13-30%), cardiovascular mortality (18-42%), major cardiovascular events (24-35%), revascularization (24-37%). Four major clinical trials have compared statins to placebo directly, in addition to smaller clinical trials.

Scandinavian Simvastatin Survival Study (4S) trial (1994)

One of the first trial to evaluate the role of statin therapy in secondary prevention. Treatment with simvastatin was associated with a significant reduction in all-cause mortality, cardiovascular mortality, major coronary events, revascularizations and stroke in 4444 patients during a mean follow-up of 5.4 years[9].

Cholesterol and Recurrent Events (CARE) trial (1996)

In this study involving 4159 patients with myocardial infarction, treatment with pravastatin significantly reduced the risk of fatal/non-fatal myocardial infarctions and revascularizations without any significant effect on all-cause mortality or mortality from non-cardiovasular causes. This study showed that LDL lowering therapy is beneficial in coronary heart disease patients with average cholesterol levels[10].

Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial (1998)

Pravastatin therapy reduced coronary heart disease mortality (risk reduction 24%), overall mortality (risk reduction 22%) and all cardiovascular outcomes (risk reduction 19-29%) in 9014 patients with a history of myocardial infarction or unstable angina during a mean follow-up of 6.1 years. This study was the third large trial after 4S and CARE to provide evidence for cholesterol lowering therapy in coronary heart disease patients. However, all these trials did not enroll patients within first 3 months of an acute coronary event and results were just extrapolated[11].

Heart Protection Study (HPS) (2002)

In this clinical trial involving 20,536 patients with history of coronary artery disease, other occlusive arterial disease, or diabetes, subjects were randomized to 40 mg simvastatin daily or placebo. A significant reduction in death due to vascular causes (7.6% vs. 9.1%), all-cause mortality (12.9% vs. 14.7%), major coronary went (8.7% vs. 11.8%), any stroke (4.3% vs. 5.7%) and revascularization (9.1% vs. 11.7%) was noted after a mean follow-up of 5 years. On selecting the patients with CHD only, a significant reduction in the risk of any major vascular event was also noticed in the simvastatin arm. The annual risk of myopathy was 0.01%. There was no significant adverse effects on cancer incidence or hospitalization for any other non-vascular cause[12].

PROSPER (2002)

The investigators performed a sub-group analysis in elderly patients with history of vascular disease (about 40% of the study population) and reported a 22% relative reduction in the coronary heart disease death or non-fatal myocardial infarction or fatal/non-fatal stroke. This study extended the safety profile and benefits of statins to the patients above 70 years[13].

LIPS (2002)

This was the first prospective randomized double-blind trial exclusively in patients undergoing their first PCI and was based on the FLARE trial, which did not show any change in restenosis rate. In addition, patients received statin therapy early after the event, as compared to previous trials. Treatment with fluvastatin in this study of 1677 patients significantly reduced the first major acute cardiovascular events after percutaneous coronary intervention during a mean follow-up of 3.9 years [14].

Meta-Analyses

  • An important meta-analysis of 25 clinical trials including 69,511 individuals showed a 25% risk reduction in CHD mortality and non-fatal MI, and a 16% reduction in all-cause mortality associated with statin administration as compared to placebo. Reductions in cardiovascular events occurred within 2 years of statin initiation and was applicable over a wide range of baseline LDL levels[15].
  • Another meta-ananlysis limited to elderly patients with an age range of 65 to 82 years reported significant reductions in all-cause mortality (↓ 22%), [[CHD] mortality (↓ 30%), non-fatal MI (↓ 26%), revascularization (↓ 30%) and stroke (↓ 25%) with statin therapy. This meta-analysis included data from 4 published trials and 5 unpublished trials and included 19,569 patients. The beneficial effect of statins reported in this meta-analysis was substantially higher than previously reported. The number needed to treat to save 1 life in the pooled meta-analysis was only 28[16].

Intensive versus moderate lowering of LDL

Most of the studies comparing intensive statin therapy with standard dose statin therapy have shown significant reduction of LDL to below 80 mg/dL and reduction in non-fatal MI with trend towards decreased mortality. The data supporting intensive versus moderate LDL lowering in CHD patients are reviewed here. These data provide substantial evidence in the favor of intensive statin therapy and a goal of LDL lowering to <70 mg/dL in patients with CHD or ACS. However, these recommendations have not yet been adopted in clinical guidelines.

Randomized Controlled trials

Intensive LDL Lowering in Patients with ACS

PROVE-IT

In this trial of 4162 patients who were hospitalized for an ACS within the last 10 days, treatment with high-dose atorvastatin (80 mg) reduced the primary/composite end-point by 16% as compared to standard-dose pravastatin (40 mg). In the secondary end-points, a significant reduction of 29% in recurrent unstable angina, 14% reduction in revascularization and a non-signficant reduction in all-cause mortality was noted. No effect was noted on death from CHD. Another significant finding of the study was that the mean LDL level in the high-dose statin arm was 62 mg/dL as compared to 95 mg/dL in standard dose arm, giving rise to the concept of an optimal LDL goal of < 70 mg/dL in ACS patients. Investigators also reported that the benefits of statin therapy were observed as early as 30 days after initiation of therapy[17].

A-Z

This trial established the role of early initiation of statin therapy after ACS. Early initiation of standard dose statin therapy followed by high dose statin was associated with a significant reduction in the secondary end-points of cardiovascular mortality and congestive heart failure. In addition, a significant increase in the incidence of myopathy (creatine kinase > 10 times the normal) was noted in the sub-group of patients receiving 80 mg simvastatin.

Intensive LDL Lowering in Stable CHD

IDEAL

IDEAL study enrolled 8888 patients with previous MI and randomized the patients to high doses atorvastatin (80 mg) or usual dose simvastatin (20 mg). During a mean follow-up of 4.8 years, a non-significant reduction in the primary end-point was noted. A significant reduction in non-fatal acute myocardial infarction and composite of any CHD event and major or any cardiovascular events was noted. The mean LDL level in the atorvastatin arm was 81 mg/dL as compared to 104 mg/dL in the usual dose simvastatin group. A significant increase in elevated transaminases and myalgias was also noted in the high dose group, without serious myopathic complications or rhabdomyolysis[18].

REVERSAL

In this trial of 654 patients who had intravascular ultrasound examinations at baseline and 18 months after treatment, treatment with high dose atorvastatin resulted in a significant reduction of atheroma volume and reduced the progression of coronary atherosclerosis, as compared to standard dose pravastatin. A significant drop in LDL and CRP levels was also noted in the high dose group[19].

TNT

A total of 10,001 stable CHD patients were randomized to 80 mg atorvastatin versus 10 mg atorvastatin. During a mean follow-up of 4.9 years, high dose statin therapy reduced the incidence of first MACE by 22%, however there was no affect on all-cause mortality. The reduction of LDL levels to 77 mg/dL in the high dose arm was considered as a significant evidence for lowering the LDL goal in CHD patients[20].

SAGE

Intensive therapy with high dose atorvastatin resulted in significant reductions in all-cause mortality and a trend towards fewer MACE, as compared to standard dose pravastatin in elderly patients 65 to 85 years of age and past history of MI. SAGE study extended the benefits of intensive statin therapy in older patients[21].

SEARCH

High dose simvastatin (80 mg) reduced the incidence of first major vascular events by 6% (non-significant) in 12.064 patients with history of MI during a mean follow-up of 6.7 years as compared to 20 mg simvastatin daily. However, a significant increase in the cases of myopathy (0.9% vs. 0.03%) was noted in the patients on high dose simvastatin. This study formed the basis of the FDA black box warning in new patients[22].

Vascular Basis

This study evaluated the role of intensive statin therapy in patients with stable CHD and a positive exercise treadmill test. Intensive lowering of LDL to 80 mg/dL did not have an effect on angina frequency, ambulatory ischemia, exercise time to onset of ischemia or any clinical outcomes[23].

Meta-analysis

  • The most recent meta-analysis of 10 randomized controlled trials including 41,778 patients with CHD reported that intensive statin therapy led to a significant reduction of 18% in non-fatal MI, 14% reduction in fatal and non-fatal stroke and a non-significant trend towards reduced all-cause mortality. In the sub-group of ACS trials, there was a 25% relative reduction in all-cause mortality and a 26% relative reduction in cardiovascular mortality.
  • In one meta-analysis, intensive statin therapy may be associated with new onset diabetes mellitus. In this pooled analysis of 5 trials enrolling 32,752 participants, a significant hazards ratio of 1.12 for new onset [diabetes mellitus]] and 0.84 for cardiovascular events was reported with intensive statin therapy as compared to moderate-dose statin therapy. The number needed to harm for intensive-dose statin therapy was 498 per year for new-onset diabetes mellitus. On the other hand, number needed to treat was 155 per year to prevent one cardiovascular event. This meta-analysis confirmed the observations in previous trials that statins may pose a risk towards development of new-onset diabetes mellitus[24].

Statin Therapy Precautions

Drug Interactions

  • Cyclosporin co-administration is associated with a higher rate of myositis among statin users as a result of inhibition of CYP3A4. The exception is pravastatin in which this is not a problem.

Myositis

Reducing non-myositis Muscle Pain

  • Coenzyme Q can be used to reduce the incidence of non-myositis muscle pain. Several weeks of coenzyme Q should be administered prior to trying the combination of the agent with statin therapy.

References

  1. ↑ "Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS)". Lancet. 344 (8923): 633–8. 1994. PMID 7864934.
  2. ↑ Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME (1995). "Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation". J Am Coll Cardiol. 26 (5): 1133–9. PMID 7594023.
  3. ↑ Jukema JW, Bruschke AV, van Boven AJ, Reiber JH, Bal ET, Zwinderman AH; et al. (1995). "Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS)". Circulation. 91 (10): 2528–40. PMID 7743614.
  4. ↑ Bestehorn HP, Rensing UF, Roskamm H, Betz P, Benesch L, Schemeitat K; et al. (1997). "The effect of simvastatin on progression of coronary artery disease. The Multicenter coronary Intervention Study (CIS)". Eur Heart J. 18 (2): 226–34. PMID 9043838.
  5. ↑ Sacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH (1994). "Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Harvard Atherosclerosis Reversibility Project (HARP) Group". Lancet. 344 (8931): 1182–6. PMID 7934538.
  6. ↑ Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King SB, Ivanhoe R; et al. (1994). "Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group". N Engl J Med. 331 (20): 1331–7. doi:10.1056/NEJM199411173312002. PMID 7935702.
  7. ↑ Bertrand ME, McFadden EP, Fruchart JC, Van Belle E, Commeau P, Grollier G; et al. (1997). "Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty". J Am Coll Cardiol. 30 (4): 863–9. PMID 9316510.
  8. ↑ Serruys PW, Foley DP, Jackson G, Bonnier H, Macaya C, Vrolix M; et al. (1999). "A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial". Eur Heart J. 20 (1): 58–69. PMID 10075142.
  9. ↑ "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet. 344 (8934): 1383–9. 1994. PMID 7968073.
  10. ↑ Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG; et al. (1996). "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators". N Engl J Med. 335 (14): 1001–9. doi:10.1056/NEJM199610033351401. PMID 8801446.
  11. ↑ "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group". N Engl J Med. 339 (19): 1349–57. 1998. doi:10.1056/NEJM199811053391902. PMID 9841303.
  12. ↑ Heart Protection Study Collaborative Group (2002). "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial". Lancet. 360 (9326): 7–22. doi:10.1016/S0140-6736(02)09327-3. PMID 12114036. Review in: ACP J Club. 2003 Jan-Feb;138(1):2-3
  13. ↑ 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
  14. ↑ Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M; et al. (2002). "Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial". JAMA. 287 (24): 3215–22. PMID 12076217. Review in: ACP J Club. 2003 Jan-Feb;138(1):1
  15. ↑ Wilt TJ, Bloomfield HE, MacDonald R, Nelson D, Rutks I, Ho M; et al. (2004). "Effectiveness of statin therapy in adults with coronary heart disease". Arch Intern Med. 164 (13): 1427–36. doi:10.1001/archinte.164.13.1427. PMID [ 15249352 [ Check |pmid= value (help).
  16. ↑ Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ (2008). "Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis". J Am Coll Cardiol. 51 (1): 37–45. doi:10.1016/j.jacc.2007.06.063. PMID 18174034. Review in: ACP J Club. 2008 May 20;148(3):3 Review in: J Fam Pract. 2008 Apr;57(4):1 p following 220
  17. ↑ Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R; et al. (2004). "Intensive versus moderate lipid lowering with statins after acute coronary syndromes". N Engl J Med. 350 (15): 1495–504. doi:10.1056/NEJMoa040583. PMID 15007110. Review in: ACP J Club. 2004 Sep-Oct;141(2):33
  18. ↑ Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I; et al. (2005). "High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial". JAMA. 294 (19): 2437–45. doi:10.1001/jama.294.19.2437. PMID 16287954.
  19. ↑ Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA; et al. (2004). "Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial". JAMA. 291 (9): 1071–80. doi:10.1001/jama.291.9.1071. PMID 14996776.
  20. ↑ LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC; et al. (2005). "Intensive lipid lowering with atorvastatin in patients with stable coronary disease". N Engl J Med. 352 (14): 1425–35. doi:10.1056/NEJMoa050461. PMID 15755765. Review in: ACP J Club. 2005 Sep-Oct;143(2):38
  21. ↑ Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D; et al. (2007). "Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE)". Circulation. 115 (6): 700–7. doi:10.1161/CIRCULATIONAHA.106.654756. PMID 17283260.
  22. ↑ Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K; et al. (2010). "Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial". Lancet. 376 (9753): 1658–69. doi:10.1016/S0140-6736(10)60310-8. PMC 2988223. PMID 21067805.
  23. ↑ Stone PH, Lloyd-Jones DM, Kinlay S, Frei B, Carlson W, Rubenstein J; et al. (2005). "Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study". Circulation. 111 (14): 1747–55. doi:10.1161/01.CIR.0000160866.90148.76. PMID 15809368.
  24. ↑ Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD; et al. (2011). "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis". JAMA. 305 (24): 2556–64. doi:10.1001/jama.2011.860. PMID 21693744.

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