Statins Prevent Stroke Recurrences… But Can They Improve Stroke Outcome?
See related article, pages 3526–3531.
First, multiple studies firmly established the value of statins in reducing the risk of ischemic stroke among patients with cardiovascular disease.1 Then the truly seminal Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed that high-dose atorvastatin reduced the risk of subsequent stroke in patients without known coronary artery disease who had a recent stroke or transient ischemic attack before enrollment.2 Now, in this issue of Stroke, the SPARCL investigators present data suggesting that high-dose statin might also reduce the severity of recurrent strokes.3 Can it be true that statins may not only prevent progression of vascular disease, but also be neuroprotectants or enhance recovery from neurological injury?
There is convincing experimental evidence indicating that statins have various potentially neuroprotective properties, including amelioration of glutamate-mediated excitotoxicity, attenuated production of reactive oxygen species, upregulation of endothelial nitric oxide synthase with favorable effects on the microcirculation, diminished inflammatory reaction by modulation of the cytokine response, and promotion of angiogenesis, which could improve the availability of collateral vessels.4–9⇓⇓⇓⇓⇓ Flow in the microcirculation could also be enhanced by statins due to antiplatelet and profibrinolytic effects.10,11⇓ Furthermore, statins could positively impact brain regeneration by stimulating neurogenesis and angiogenesis.4
However, the promise of neuroprotection and improved neurological recovery from these pleiotropic actions of statin drugs has not been consistently supported by the results of observational studies assessing the effect of previous statin treatment on ischemic stroke outcome. Although some studies suggested that previous statin therapy could improve functional outcome12–14⇓⇓ or early mortality15 after a stroke, others did not show such an effect16 or found a benefit only in specific subgroups of patients.17 Still, retrospective studies may have been contaminated by selection biases, which could have affected the results on either direction (eg, patients treated with a statin may have had more severe vascular disease or, conversely, their vascular disease may have been more aggressively treated before the stroke).
The SPARCL population provides a unique opportunity to study the effect of previous statin therapy (in this case high-dose atorvastatin) on subsequent stroke outcome. Yet, the results of the analysis presented by the SPARCL investigators need to be carefully interpreted. The reductions in recurrent ischemic strokes of different severities were actually comparable in patients treated with atorvastatin and those treated with placebo. There was only a trend toward lesser severity of the recurrent ischemic strokes in the atorvastatin groups as measured by the modified Rankin Score, but no differences were noted when stroke severity was evaluated using the Barthel Index (arguably a more sensitive measure of functional outcome) or the National Institutes of Health Stroke Scale. The major difference between the 2 groups was the one we already know: patients on statin have a lower incidence of recurrent brain infarction. It was this reduction in stroke recurrence that led to the finding that patients on statin had a significant benefit in the overall combined end point, which included not only the severity of recurrent strokes, but also stroke-free outcomes.3
Hence, it is still unclear if high-dose atorvastatin may reduce the severity of recurrent ischemic strokes. However, the SPARCL trial has shown that high-dose atorvastatin decreases the risk of recurrent ischemic strokes and major cardiovascular events in men and women,6 young and old,18 with and without carotid stenosis,19 and regardless of initial stroke mechanism (although patients with identified sources of cardiac embolism were excluded from the trial)20 or baseline low-density lipoprotein cholesterol levels.21 Consequently, statins should be prescribed to all patients with ischemic stroke or transient ischemic attack caused by atherosclerosis.22 The challenge in practice is to optimize the timely prescription of statins and the adherence to therapy, which are currently inadequate.23 After all, it would be useful to patients if statins reduced the severity of recurrent strokes, but it is even more useful to them that statins can definitely diminish their risk of having recurrent strokes (and coronary events) in the first place. That is the message we need to transmit loudly and clearly to our patients.
The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
- ↵Goldstein LB, Amarenco P, Zivin J, Messig M, Altafullah I, Callahan A, Hennerici M, MacLeod MJ, Sillesen H, Zweifler R, Welch KMA; on behalf of the SPARCL Investigators. Statin treatment and stroke outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. 2009; 40: 3526–3531.
- ↵Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998; 95: 8880–8885.
- ↵Goldstein LB, Amarenco P, Lamonte M, Gilbert S, Messig M, Callahan A, Hennerici M, Sillesen H, Welch KM. Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Stroke. 2008; 39: 2444–2448.
- ↵Kawashima S, Yamashita T, Miwa Y, Ozaki M, Namiki M, Hirase T, Inoue N, Hirata K, Yokoyama M. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke. 2003; 34: 157–163.
- ↵Ovbiagele B, Saver JL, Starkman S, Kim D, Ali LK, Jahan R, Duckwiler GR, Vinuela F, Pineda S, Liebeskind DS. Statin enhancement of collateralization in acute stroke. Neurology. 2007; 68: 2129–2131.
- ↵Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, Endres M. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke. 2000; 31: 2442–2449.
- ↵Marti-Fabregas J, Gomis M, Arboix A, Aleu A, Pagonabarraga J, Belvis R, Cocho D, Roquer J, Rodriguez A, Garcia MD, Molina-Porcel L, Diaz-Manera J, Marti-Vilalta JL. Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke. 2004; 35: 1117–1121.
- ↵Moonis M, Kane K, Schwiderski U, Sandage BW, Fisher M. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005; 36: 1298–1300.
- ↵Elkind MS, Flint AC, Sciacca RR, Sacco RL. Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology. 2005; 65: 253–258.
- ↵Bushnell CD, Griffin J, Newby LK, Goldstein LB, Mahaffey KW, Graffagnino CA, Harrington RA, White HD, Simes RJ, Califf RM, Topol EJ, Easton JD. Statin use and sex-specific stroke outcomes in patients with vascular disease. Stroke. 2006; 37: 1427–1431.
- ↵Reeves MJ, Gargano JW, Luo Z, Mullard AJ, Jacobs BS, Majid A. Effect of pretreatment with statins on ischemic stroke outcomes. Stroke. 2008; 39: 1779–1785.
- ↵Chaturvedi S, Zivin J, Breazna A, Amarenco P, Callahan A, Goldstein LB, Hennerici M, Sillesen H, Rudolph A, Welch MA. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack. Neurology. 2009; 72: 688–694.
- ↵Sillesen H, Amarenco P, Hennerici MG, Callahan A, Goldstein LB, Zivin J, Messig M, Welch KM. Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2008; 39: 3297–3302.
- ↵Amarenco P, Benavente O, Goldstein LB, Callahan A III, Sillesen H, Hennerici MG, Gilbert S, Rudolph AE, Simunovic L, Zivin JA, Welch KM. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes. Stroke. 2009; 40: 1405–1409.
- ↵Amarenco P, Goldstein LB, Callahan A III, Sillesen H, Hennerici MG, O'Neill BJ, Rudolph AE, Simunovic L, Zivin JA, Welch KM. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis. 2009; 204: 515–520.
- ↵Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008; 39: 1647–1652.
- ↵Ovbiagele B, Saver JL, Bang H, Chambless LE, Nassief A, Minuk J, Toole JF, Crouse JR. Statin treatment and adherence to national cholesterol guidelines after ischemic stroke. Neurology. 2006; 66: 1164–1170.