Small Steps on Statins in Stroke Research Show Big Promise but Momentum Is Key


Statins, alone or in combination with other agents, promote angiogenesis and significantly enhance neuroregeneration in the aftermath of brain injury, including stroke, according to Michael Chopp, PhD, professor and vice chair of the Department of Neurology at Henry Ford Health Sciences Center in Detroit.

Statins, alone or in combination with other agents, promote angiogenesis and significantly enhance neuroregeneration in the aftermath of brain injury, including stroke, according to Michael Chopp, PhD, professor and vice chair of the Department of Neurology at Henry Ford Health Sciences Center in Detroit. Chopp chaired a symposium on the role of statins in stroke at the International Stroke Conference (ISC) 2007 held February 7 to 9 in San Francisco.

In his summarial presentation, Chopp lauded statins, which are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as agents that work through multiple mechanisms to boost the neuroregenerative process. Chopp and colleagues have conducted experimental as well as clinical studies that have demonstrated the dose-dependent value of these agents before and after both ischemic and hemorrhagic stroke, in combination with tissue plasminogen activator (tPA) after stroke, and in traumatic brain injury (TBI).

Although the prophylactic value of statins in cardiovascular and coronary heart disease is well known, little exists in the way of randomized controlled clinical trials that specifically look at statins and their mechanisms of action in patients post-stroke, particularly their value in enhancing brain recovery, according to Chopp. He and other researchers who also have been at the forefront of experimental and clinical research on the use of statins in stroke presented data at the ISC symposium.

Research by Chopp's team at the Henry Ford Health Sciences Center has shown that statins promote angiogenesis, neurogenesis, and synaptogenesis in rat models in the aftermath of ischemic and hemorrhagic stroke as well as in TBI1,2 and that the agents can enhance the effects of tPA while staving off tPA's deleterious effects when given outside of the therapeutic window.3,4

In a study performed by clinical neurologist and researcher Jieli Chen, MD, Chopp, and coinvestigators showed for the first time that statins had neurorestorative properties post-stroke and that the effect was dose-dependent.1 Rat models of ischemic stroke were given atorvastatin 1, 3, or 8 mg/kg or placebo for 7 days. A subset of rats also were treated with simva- statin, either 1 or 8 mg/kg, to decipher whether superiority between commonly used statins could be determined. Therapy began 24 hours after induction of stroke, which consisted of subjecting adult male Wistar rats to 2 hours of middle cerebral artery (MCA) occlusion. The animals were sacrificed 14 days after MCA occlusion and their brain tissue was studied.

"Neurological dysfunction was maintained in the control animals, but a significant functional improvement was seen in animals given 1 mg/kg of a statin. If given a higher dose of 8 mg/kg, no functional improvement was seen. So, you have to give the right dose," reported Chopp.

For the treatment of stroke, the investigators found no difference in effect between atorvastatin and simvastatin. Histological studies of the rats treated with low-dose statins-either 1 or 3 mg/kg-showed increased neurogenesis and endothelial cell proliferation in the ipsilateral hemisphere indicative of angiogenesis. Vascular endothelial growth factor was significantly increased in the ischemic boundary area. The investigators also confirmed that low-dose statins promoted corneal neurorevascularization; cell proliferation in the ipsilateral subventricular zone and dentate gyrus; and expression of synaptophysin, a marker for presynaptic plasticity and synaptogenesis.

Benefit was only achieved when the statin was given at low doses. In their studies on statins and tPA1,4 Chopp and coinvestigators demonstrated that when a statin is given with tPA outside of tPA's 3-hour therapeutic window, tight junction proteins, such as occludin, are up-regulated, helping to preserve the microvasculature and inhibit spread of infarction.

"tPA results in a substantial increase in MMP9 [matrix metalloproteinase 9], which chews up collagen and, in turn, causes leakiness of the blood-brain barrier," explained Chopp. "However, if you give a combination of a tPA and a statin, you get a significant reduction in expression of MMP9. Collagen 4 is more intact when the combination of tPA and a statin is given."

In another rat study, members of Chopp's team showed that administration of tPA 4 hours after stroke caused a significant increase in messenger RNA levels of protease-activated receptor 1 and tissue factor over that incited by the index ischemic event in cerebral endothelial cells.5 Levels were increased "nearly 1000-fold at the core and 500-fold in the boundary [zone]" 30 hours after stroke in experimental animals, compared with control animals. MMP2 and MMP9 levels also were significantly increased in the boundary and core zones. However, when atorvastatin was administered with tPA 4 hours after stroke, MMP2 and MMP9 up-regulation was completely inhibited. The study authors added that statins given as monotherapy 4 hours after stroke did not have a significant effect on MMP levels.

Because of their effect on cholesterol, statins are thought to help prevent stroke in persons with cardiovascular disease, but the relationship between stroke and cholesterol levels may be a bit more complicated. "Meta-analysis from 45 prospective cohorts, inclusive of 450,000 patients, with a mean of 16 years of follow-up that examined 13,397 strokes found little to no relationship between total cholesterol and stroke risk," related Larry Goldstein, MD, director of the Duke Center for Cerebrovascular Disease and the Duke Stroke Center at Duke University in Durham, North Carolina, during his presentation. He was referring to a pivotal study published in Lancet 12 years ago that showed that although cholesterol levels impacted cardiovascular disease, no significant connection could be drawn between cholesterol levels and stroke.6

"There are a bunch of paradoxes between lipids and stroke. This is one of them," Goldstein remarked. He added, as did the investigators of the study in Lancet, that the trial's failure to distinguish between type of stroke-embolic or hemorrhagic-might have been at least partially responsible for the study's findings.

A study that was published a few years before this meta-analysis, however, did look at the impact of cholesterol in stroke according to subtype.7 It also was a large study, including 350,977 middle-aged men (35 to 57 years) who had a history of heart disease; researchers followed up with participants for 6 years.

"These researchers found that lower levels of total cholesterol were associated with an increased risk of subarachnoid hemorrhage [SAH]," said Goldstein. "The association was even more pronounced in relation to intracerebral hemorrhage [ICH]." Indeed, the 6-year risk of ICH was 3 times higher in patients with serum cholesterol levels of less than 4.14 mmol/L than in those with higher levels. Nuances in diastolic blood pressure, however, played a role in risk of ICH-related death. Patients at risk were those with a diastolic blood pressure of 90 mm Hg or higher.

"When you look at ischemic stroke, however, cholesterol lowering is salutary in a way similar to that seen in coronary heart disease," Goldstein continued in his analysis of the study. "That is to say, low cholesterol levels are associated with hemorrhagic stroke, higher levels are associated with ischemic stroke."

He cited a more recent study of coronary artery disease that found that statin use was responsible for a 20% to 21% relative risk reduction of stroke.8 "It works out that 156 patients needed to be treated to prevent 1 event," Goldstein remarked. "But these were patients who needed to be treated with statins anyway because they had coronary heart disease. The study showed that protection against stroke provided by the statin was a bonus."

In terms of trials on the use of statins for secondary prevention, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial is probably the most salient, according Goldstein, who was a coinvestigator. It is notable because it is the first randomized double-blind study to exclusively look at the effect of statins in stroke prevention and in doing so, excluded patients with coronary heart disease.9

"Over the first month, there was a pretty dramatic 53% reduction in LDL [low-density lipoprotein] cholesterol levels in patients receiving the statin," reported Goldstein. LDL cholesterol levels in the placebo group remained unchanged.

In this study, 4731 patients who had a stroke or transient ischemic attack within 1 to 6 months before study entry, had LDL cholesterol levels of 100 to 190 mg/dL, and had no known coronary heart disease, were randomly selected to receive either atorvastatin 80 mg/d or placebo. The large majority of patients also took aspirin or another antiplatelet agent.

During a 4.9-year follow-up, intention-to-treat analysis showed that either fatal or nonfatal stroke occurred in 265 (11.2%) patients who were randomly selected to receive active treatment and 311 (13.1%) patients who were randomly selected to receive placebo. After prespecified adjustment for baseline factors, a 16% risk reduction in fatal or nonfatal stroke was seen in association with statin use.

The researchers estimated that 46 patients would need to receive prophylactic statin therapy for 5 years to prevent 1 stroke. Because of drop-ins to open-label statin use in the study, the researchers commented that the effect of statins on stroke prevention might be greater than that reflected in the study's intention-to-treat analysis.

Although statins pose a slight chance of aggravating hemorrhagic stroke, they may be quite useful in preventing vasospasm following SAH, according to Daniel Laskowitz, MD, associate professor of medicine (neurology), neurobiology, and anesthesiology at Duke University Medical Center. "Average incidence of aneurysmal SAH is about 12 per 100,000 and the morbidity and mortality of SAH remains very high. A significant minority of patients will not survive the trip to the hospital after aneurysm rupture. Of those who make it to the hospital, approximately one third will develop clinical vasospasm, which is the most feared delayed medical complication of SAH, and may result in stroke and increased mortality," Laskowitz reported. He and colleagues theorized that statins might be useful in preventing vasospasm because they might up-regulate endothelial nitric oxide synthase (eNOS) without inducing hypotension.

Laskowitz and his colleagues proved the validity of their hypothesis in an experimental study published in Stroke in 200210 and in a pilot randomized clinical trial published in Stroke in 2005.11 Their findings also were confirmed in a recently published retrospective case series analysis.12

The double-phase experimental study10 involved (1) treating mice with either simvastatin or vehicle for 2 weeks and then endovascularly perforating the right anterior cerebral artery or performing sham surgery, and (2) inducing rupture of the cerebral artery or performing sham surgery and then treating the mice with either the study drug or vehicle. Three days after the surgical procedures the mice were evaluated for neurological deficits, MCA diameter, and eNOS protein levels.

"We found that luminal diameter increases with simvastatin treatment," Laskowitz said. Indeed, neurological deficits were decreased and MCA diameter and eNOS levels were increased in mice pretreated with the statin. Promising results, although not as dramatic, were seen in mice treated postinjury. Neurological deficits were reduced and a modest increase (about 11µ) in MCA diameter was seen in statin-treated mice (postinjury) over that seen in vehicle-treated mice. eNOS protein levels, however, were not significantly affected by treatment.

Laskowitz mentioned 2 other, more recent trials in animal models-one in rabbits13 and the other in dogs14-in which it was shown that simvastatin, given after experimental SAH, ameliorated basilar artery vasospasm. (The study in dogs also showed that the addition of cyclosporine to a statin does not enhance treatment outcome and may interfere with the statin's vasodilatory effect.)

"Based on work in mice, we moved into the ICU," remarked Laskowitz. He and a team from Duke and Johns Hopkins University performed a trial wherein patients were randomly selected to begin 2 weeks of prophylactic therapy with either simvastatin 80 mg/d or placebo within 48 hours of SAH symptom onset.11

"These patients were clinically deteriorated at baseline. They had new onset of overall neurological deficit thought to represent vasospasm, and they had angiographic or transcranial Doppler ultrasonographic confirmation of vasospasm," reported Laskowitz. "We found a 4-fold increased rate of vasospasm in placebo versus statin-treated patients. We also looked at transcranial Doppler velocities as a circuit of vasospasm and found that the velocities were much higher in placebo patients than in treated patients."

The team also found that treatment reduced levels of S100ß-a marker for astrocytic activation-throughout the 14-day course of treatment, suggesting that statins reduced CNS inflammation.

"Statins down-regulate the inflammatory response," explained Laskowitz. "We don't know what the optimal statin is or what the optimal dose and time window are. A lot of it is guesswork. Our experimental research was done with super-therapeutic doses. The maximal FDA-approved dose is 80 mg," he said, urging that more experimental studies and especially more clinical trials need to be set in motion promptly. "A large, multi-institutional study is required. If we lose this window of opportunity, there is a chance that statins won't become a standard of care, and we may lose the opportunity to test them."


REFERENCES1. Chen J, Zhang ZG, Li Y, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003;53:743-751.
2. Seyfried D, Han Y, Lu D, et al. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg. 2004;101:104-107.
3. Lu D, Goussev A, Chen J, et al. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma. 2004;21:21-32.
4. Zhang L, Zhang ZG, Ding GL, et al. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation. 2005;112:3486-3494.
5. Liu XS, Zhang ZG, Zhang L, et al. Atorvastatin downregulates tissue plasminogen activator-aggravated genes mediating coagulation and vascular permeability in single cerebral endothelial cells captured by laser microdissection. J Cereb Blood Flow Metab. 2006;26:787-796.
6. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet. 1995;346:1647-1653.
7. Iso H, Jacobs DR Jr, Wentworth D, et al. 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;320:904-910.
8. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:2902-2909.
9. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
10. McGirt MJ, Lynch JR, Parra A, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33:2950-2956.
11. Lynch JR, Wang H, McGirt MJ, et al. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke. 2005;36:2024-2026.
12. McGirt MJ, Blessing R, Alexander MJ, et al. Risk of cerebral vasospasm after subarachnoid hemorrhage reduced by statin therapy: a multivariate analysis of an institutional experience. J Neurosurg. 2006;105:671-674.
13. McGirt MJ, Pradilla G, Legnani FG, et al. Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery. 2006;58:945-951.
14. Bulsara KR, Coates JR, Agrawal VK, et al. Effect of combined simvastatin and cyclosporine compared with simavastin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model. Neurosurg Focus. 2006;21:E11.

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