Ravinder-Jeet Singh, MBBS, DM
Several observational studies have investigated the effects of serum cholesterol levels (or its subfractions) on cardiovascular health and disease. These studies have shown that increased serum cholesterol is a strong risk factor for coronary artery disease, though association with stroke is less clear.(1-3) The inconsistent association between cholesterol and stroke could partly be explained by the difference in the effects of total cholesterol levels or its subfractions (especially LDL cholesterol) on the risk of ischemic vs hemorrhagic stroke, which are often combined in many epidemiologic studies. High total cholesterol is associated with higher risk of ischemic stroke, while low total cholesterol increases hemorrhagic stroke risk, and similar observations are noted with LDL cholesterol (LDL-C) levels as well.(2-6) Nonetheless, control of serum LDL-C levels constitutes standard recommendation for primary and secondary stroke prevention.(7)
Use of high-dose statins after a recent TIA or stroke was shown to reduce the incidence of stroke and other cardiovascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, despite a small increase in the incidence of hemorrhagic stroke.(8) Further, multiple clinical trials and their meta-analysis showed that more intensive LDL-C lowering is associated with greater reduction in cardiovascular events.(9) Whether intensive LDL-C lowering among patients with recent TIA/stroke lowers future stroke risk was not assessed in the previous trials. In the January issue of NEJM, Amarenco et al. reported the results of the Treat Stroke to Target (TST) trial, which compared two LDL-C targets after recent TIA and ischemic stroke.
In the TST trial, patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days were randomized to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All patients also had evidence of atherosclerotic disease (aortic, extracranial or intracranial atherosclerosis or prior coronary artery disease) on vascular imaging. Primary outcome was composite end point of major cardiovascular events, which included nonfatal stroke, nonfatal MI, unstable angina with urgent coronary-artery revascularization, TIA with urgent carotid revascularization, or cardiovascular or sudden death.
A total of 2860 patients were included and had a median follow-up of 3.5 years. Mean LDL-C was 65 mg/dl (1.7 mmol/L) in the lower-target and 96 mg/dl (2.5 mmol/L) in the higher-target group. Primary end point occurred in 8.5% in lower-target and 10.9% in the higher-target group (adjusted hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). Non-fatal stroke occurred in 5.7% in the former and 7.0 % in the latter group. Though overall mortality was similar, the mortality due to cardiovascular cause was lower in the lower-target group (1.5 vs 2.2 % in higher-target group) but did not achieve statistical significance. Intracranial hemorrhage occurred more frequently in the lower target group than the higher target group (1.3 vs 0.9%; HR 1.38, 95% CI 0.68-2.82) as also new diagnosis of diabetes (7.2 vs 5.7; HR 1.27, 95% CI 0.95–1.70).
The trial confirms that achieving lower LDL-C target leads to reduction in stroke and cardiovascular events among patients with recent ischemic stroke or TIA and evidence of atherosclerosis. This could be accomplished with the use of high-dose statins or adding ezetimibe when needed, as done in the trial. It remains unclear if patients with cardioembolic stroke or those with lacunar stroke benefit to a similar extent in the absence of large vessel atherosclerosis. Similarly, the treatment benefit in younger patients with lesser prevalence of atherosclerotic disease remains undefined. Of note, most patients included were over the age of 60 years in the trial. Although not acknowledged by the authors, it is interesting to note that most patients were enrolled early (median 6 days) after the TIA/stroke, suggesting that early intensive cholesterol lowering/statins could be more effective in improving cardiovascular outcomes. The observation is reminiscent of dual antiplatelet therapy, which is more effective if started early after TIA/minor stroke. The period after TIA/stroke is phase of plaque instability with high risk of ischemic events in different vascular beds due to activation of hemostatic system, systemic inflammation and endothelial dysfunction. Statin could reduce inflammation and endothelial dysfunction and improve plaque stability; similarly, lower cholesterol could benefit by plaque modification. Major limitation: the trial was stopped prematurely due to lack of funding and was underpowered to allow statistical testing of several secondary end points, therefore, remains inconclusive in that regard.
In conclusion, intensive LDL cholesterol reduction, statin therapy or both initiated early after the TIA or stroke and maintained in the long term reduces major cardiovascular events.
References:
1. Peters SA, Singhateh Y, Mackay D, Huxley RR, Woodward M. Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: A systematic review and meta-analysis. Atherosclerosis. 2016;248:123-31.
2. Yaghi S, Elkind MS. Lipids and Cerebrovascular Disease: Research and Practice. Stroke. 2015;46:3322-8.
3. Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M; Asia Pacific Cohort Studies Collaboration. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol. 2003;32:563-72.
4. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320:904-10.
5. Wang X, Dong Y, Qi X, Huang C, Hou L. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke. 2013;44:1833-9.
6. Pikula A, Beiser AS, Wang J, Himali JJ, Kelly-Hayes M, Kase CS, Yang Q, Seshadri S, Wolf PA. Lipid and lipoprotein measurements and the risk of ischemic vascular events: Framingham Study. Neurology. 2015;84:472-9.
7. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754-832.
8. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-59.
9. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.
