High-Dose Statin for Every Stroke
The Good, the Bad, and the Unknown
Statins exert neuroprotective, microvascular, and anti-inflammatory beneficial effects in animal stroke models, independent of their lipid-lowering capabilities. These are seen at the highest doses with a dose–response effect. Observational studies show that statin use is associated with improved outcome in patients with ischemic stroke, presumably a result of the pleiotropic effects suggested in animal studies. This prompted an ongoing debate as to whether statins should be used in every patient with ischemic stroke regardless of the stroke mechanism and whether maximum doses should be used on initiation of therapy. Our experts firmly hold opposing and widely divergent views.
So, let us address the following questions. Is there sufficient evidence that statins have neuroprotective effects in patients with stroke? First, we point out that interpretation of clinical studies linking statins to improved stroke outcome, which were mostly retrospective, is difficult due to variability in patient population and follow-up periods and insufficient power to fully adjust for confounding variables. Few randomized trials of statins in acute stroke have been performed with inconclusive results. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, while it demonstrated the benefit of high-dose atorvastatin for secondary stroke prevention, it did not provide evidence of neuroprotective benefits. However, patients in SPARCL began their treatment within 30 to 60 days after the stroke. In another pilot study, randomization to simvastatin at 40 mg/day within 12 hours and for 72 hours after stroke onset was associated with improvement in neurological function by Day 3 compared with placebo, but this did not persist at Day 90.2
Should all patients with stroke be started on high-dose statins? Is there an association between dose and response? The answers are presently unknown. The SPARCL study reliably showed that high-dose atorvastatin at 80 mg/day reduces the risk of recurrent stroke and other cardiovascular events in patients with stroke without known coronary disease, classified as having large-vessel disease, small-vessel disease, or stroke of unknown cause. It is, however, unclear in the absence of randomized comparisons in patients with stroke if lower doses of atorvastatin are equally or less effective than the high-dose regimen. Although the Medical Research Council/British Heart Foundation Heart Protection Study (HPS) showed no obvious reduction in stroke recurrence among those with a history of stroke with simvastatin at 40 mg/day, these results do not necessarily imply that atorvastatin in doses <80 mg/day would have been less effective in SPARCL given the differences in medical comorbidities between HPS and SPARCL participants. The dose–response analyses in the North Dublin Population Stroke Study were exploratory, and the observed association between atorvastatin's dose and outcome was largely driven by worse outcome in atorvastatin-untreated patients.
There is randomized evidence that atorvastatin at 80 mg/day provides significant reductions in the risks of cardiovascular events and stroke beyond that afforded by a 10-mg dose in patients with coronary disease.1 In the Treating to New Targets (TNT) trial, high-dose atorvastatin significantly reduced total cholesterol and triglycerides levels compared with the 10-mg dose. However, the high-dose regimen was associated with significantly more frequent adverse events (8.1% versus 5.8%), higher rate of discontinuation of treatment due to treatment-related adverse events (7.2% versus 5.3%), and greater incidence of persistent elevations in liver enzymes (1.2% versus 0.2%). As Dr Furie points out, the benefit of high-dose atorvastatin in SPARCL occurred with a greater incidence in cerebral hemorrhage (2.3% versus 1.4% in placebo-treated patients); and the treatment was associated with elevations in liver enzymes and creatine kinase levels (2.2% versus 1.4%) and a discontinuation rate of 15.4%. Recently, the Food and Drug Administration issued a warning regarding increased risk of myopathy in patients taking simvastatin at 80 mg/day, especially if taken concomitantly with calcium channel blockers, which are not uncommonly used by patients with stroke. Needless to say, most insurance companies in the United States and primary care physicians in Europe substitute atorvastatin with generic simvastatin. Here rests the conundrum! Interestingly, the recent American Heart Association/American Stroke Association guidelines for prevention of stroke in patients with stroke or transient ischemic attack cleverly state “Statin-therapy with intensive lipid-lowering effects is recommended” without specifically advocating a high-dose regimen.
Although the SPARCL results support the use of high-dose atorvastatin for secondary stroke prevention, it is unclear whether the highest currently approved doses of statins are able elicit neuroprotective effects in patients. The Phase 1B dose-escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART) investigated 4 doses of lovastatin; 1 mg/kg, 3 mg/kg, 6 mg/kg, and 8 mg/kg (found to be the maximum tolerated dose) daily for 3 days initiated within 24 hours of stroke onset followed by 20 mg/day for 27 days. There was no effect on C-reactive protein, interleukin-6, or tumor necrosis factor levels within the 30-day study period at any of the tested doses.3 Therefore, we advise caution. We need further reassurance that the benefit outweighs the risks before advocating routine use of high-dose statins to all patients with stroke.
The premise of statins' potential neuroprotective effects in animals and observational studies should be considered hypothesis-generating prompting further clinical studies and not the basis to render therapy that may not only be not indicated, but also costly and potentially harmful, prematurely. There are several other issues that require further investigations. What is the optimal “neuroprotective” dose? What is the optimal duration of treatment for neuroprotection? What is the optimal timing to initiate treatment?
“There are known knowns; these are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know, but there are also unknown unknowns—these are things we do not know we don't know.”
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 3 of a 3-part article. Parts 1 and 2 appear on pages 1992 and 1994, respectively.
This paper was presented in part at the International Stroke Conference 2012.
- Received January 13, 2012.
- Accepted January 18, 2012.
- © 2012 American Heart Association, Inc.