High cholesterol secondary prevention

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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 NCEP recommendations are mentioned here, in addition to recent evidence.

Therapy goals

NCEP ATP III guidelines recommended a 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. An update by the NCEP committee in 2004 based on new trial data recommended 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

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 in patients with CHD. Some of the important trials with positive and negative findings will be reviewed here.

  • 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 Lovastatin Restenosis Trial Study (1994)[5],PREDICT trial (1997)[6] and FLARE (1999)[7] 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

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[8].

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[9].

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[10].

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[11].

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[12].

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 [13].

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 16% reduction in all-cause mortality with statins 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[14].


  • 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[15].

Intensive versus moderate lowering of LDL

There is no clear consensus for intensive LDL lowering based on the available data. The data supporting intensive versus moderate LDL lowering in CHD patients will be reviewed here. In addition, recently FDA issued a black box warning about the increased risk of myopathy with high dose Simvastatin (80 mg) in patients who were never on it. This warning was based on the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial which showed a significantly increased risk of myopathic complications in the patients treated with simvastatin 80 mg as compared to 20 mg dose.

Meta-analysis

Statins in the setting of ACS

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. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "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.
  9. ↑ 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.
  10. ↑ "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.
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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).
  15. ↑ 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

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