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Abstract

Aims

Lowering the low-density lipoprotein cholesterol level reduces the risk of stroke, but it has not been clear whether the stroke risk would continuously decrease by lowering low-density lipoprotein cholesterol to a very low level. The purpose of this study was to evaluate the association between achieved low-density lipoprotein cholesterol levels and stroke risk.

Methods and results

A systematic search of MEDLINE, EMBASE and Cochrane Library databases was conducted to identify randomised controlled trials that tested cholesterol-lowering pharmacological therapies and reported both achieved low-density lipoprotein cholesterol levels and stroke outcomes. A meta-regression analysis was conducted to assess the linear association between the achieved low-density lipoprotein cholesterol levels and stroke risk. In addition, we evaluated pooled estimates of low-density lipoprotein cholesterol-lowering effect stratified by achieved low-density lipoprotein cholesterol levels of active arms. A total of 222,149 participants in 23 trials (52 arms of 26 studies) were included. The meta-regression analysis showed that each 1 mmol/L decrease in the achieved low-density lipoprotein cholesterol level (down to 0.78 mmol/L) was associated with a significant reduction of 23.5% (slope 0.235, 95% confidence interval 0.007–0.464, P = 0.044) in stroke risk. Irrespective of achieved low-density lipoprotein cholesterol levels in the active arms, the effects of lowering the low-density lipoprotein cholesterol level on stroke risk were significant and consistent (test for subgroup difference, P = 0.23, I² = 31%). However, there was no significant increase in haemorrhagic stroke risk with lower achieved low-density lipoprotein cholesterol levels.

Conclusion

In this meta-analysis of randomised controlled trials, the stroke risk monotonically reduced with lowering of low-density lipoprotein cholesterol to very low levels.

Keywords

Stroke LDL-cholesterol statin PCSK9 inhibitor meta-analysis

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References

Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376: 1670–1681.

Silverman

Ference

et al.

Association Between Lowering LDL-C and Cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016; 316: 1289–1297.

Amarenco

Labreuche

. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8: 453–463.

Liberati

Altman

Tetzlaff

et al.

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: 264–269.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22.

Cannon

Blazing

Giugliano

et al.

Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387–2397.

Ridker

Revkin

Amarenco

et al.

Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017; 376: 1527–1539.

Pedersen

Faergeman

Kastelein

et al.

High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294: 2437–2445.

Koren

Hunninghake

. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol 2004; 44: 1772–1779.

10.

The ALLHAT Officers and Coordinators for 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 (ALLHAT-LLT). JAMA 2002; 288: 2998–3007.

11.

Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231–1239.

12.

Holdaas

Fellstrom

Jardine

et al.

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361: 2024–2031.

13.

Amarenco

Bogousslavsky

Callahan

III et al.

High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559.

14.

Hosomi

Nagai

Kohriyama

et al.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): a Multicenter, Randomized, Open-label, Parallel-group Study. EBioMedicine 2015; 2: 1071–1078.

15.

Shepherd

Blauw

Murphy

et al.

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–1630.

16.

Sever

Dahlof

Poulter

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 multicentre randomised controlled trial. Drugs 2004; 64(Suppl. 2): 43–60.

17.

de Lemos

Blazing

Wiviott

et al.

Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307–1316.

18.

Colhoun

Betteridge

Durrington

et al.

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685–696.

19.

Cannon

Braunwald

McCabe

et al.

Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–1504.

20.

LaRosa

Grundy

Waters

et al.

Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425–1435.

21.

Knopp

d'Emden

Smilde

et al.

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 2006; 29: 1478–1485.

22.

Clearfield

. Rosuvastatin in older patients with systolic heart failure. Curr Atheroscler Rep 2009; 11: 5–6. 8.

23.

Ridker

Danielson

Fonseca

et al.

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–2207.

24.

Fellstrom

Jardine

Schmieder

et al.

Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360: 1395–1407.

25.

Baigent

Landray

Reith

et al.

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181–2192.

26.

Robinson

Farnier

Krempf

et al.

Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489–1499.

27.

Sabatine

Giugliano

Keech

et al.

Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713–1722.

28.

Schwartz

Steg

Szarek

et al.

Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379: 2097–2107.

29.

Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–1278.

30.

Davignon

. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109(23 Suppl. 1): III39–III43. .

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Achieved low-density lipoprotein cholesterol level and stroke risk: A meta-analysis of 23 randomised trials

Abstract

Aims

Methods and results

Conclusion

Keywords

Get full access to this article

References

Supplementary Material