Only a few clinical trials primarily addressed the question of whether statins may improve stroke outcome. However, there is not only promising but also controversial evidence from pilot studies and subgroup analysis of larger trials.
In the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) trial, 3086 patients with acute coronary syndrome were randomized within 24–96 h after admission to 80 mg atorvastatin daily or placebo and followed up for 16 wk for the primary end points death, nonfatal myocardial ischemia, resuscitated cardiac arrest, and recurrent symptomatic ischemia requiring rehospitalization. In addition to a significant reduction in the combined primary end point (14.8% vs 17.8%; relative risk 0.84; 95% CI, 0.7–1.0; P = 0.048), a substudy reported a significant reduced risk of the secondary end point nonfatal and fatal stroke. Nonfatal or fatal stroke was reported in 12 patients in the atorvastatin group and 24 patients in the placebo group (relative risk 0.49; 95% CI, 0.24–0.98; P = 0.04). However, the follow-up period only covered 16 wk, and the annualized stroke rate in the MIRACL trial appeared to be much higher in contrast to other trials.43
Recent data from the fast assessment of stroke and TIA to prevent early recurrence (FASTER) trial44 did not show a beneficial effect of statin treatment in acute stroke. In the FASTER trial, 392 patients with TIA or minor stroke were randomized to 40 mg/d simvastatin or placebo, and clopidogrel or placebo. Treatment was initiated within 24 h of admission, the follow-up period covered 90 days for the primary outcome total stroke (ischemic or hemorrhagic). The FASTER trial did not report a reduction in stroke risk in the simvastatin group. However, if a 50% RRR was to be shown as in the MIRACL study, and based a 7.3% incidence as reported in the control group of the FASTER study, more than 600 patients per group would be required to show a statistically significant difference for the outcome. The FASTER trial only had 392 patients.
The FASTER trial was stopped prematurely because of problems in recruitment, which at an earlier time point had already resulted in extending the time window for enrollment from 12 to 24 h.44 In fact, after the publication of the SPARCL trial, the investigators found it difficult to select patients who were not receiving chronic statin therapy.
The markers of inflammation after simvastatin in ischemic cortical stroke (MISTICS) trial was the first trial designed to study the effect and safety of statin treatment on outcome rather than on stroke incidence. In this double-blind, randomized, multicenter trial, 60 patients received either placebo or 40 mg simvastatin within 3–12 h after ischemic stroke. Treatment with recombinant tPA was a criterion for exclusion. Markers of inflammation served as primary end points, whereas functional outcome was chosen as the secondary end point. Both end points were measured at baseline, 1, 3, 5, 7, and 90 days after stroke. The evaluation of a number of biomarkers showed no significant difference between the two groups, but patients receiving simvastatin had significantly better functional outcome at different time points. In fact, approximately 47% of the simvastatin-treated patients showed an improvement of ≥4 in the National Institute of Health and Stroke Score at Day 3 compared with only 18% in the placebo group (P = 0.022). In addition, only the simvastatin group comprised patients with complete functional recovery at Day 90.
Similarly, the SPARCL trial also reported a reduction in the severity of secondary strokes in the atorvastatin group. In fact, the rate of fatal stroke was reduced by 43% (adjusted HR 0.57; 95% CI, 0.35–0.95; P = 0.03).35 Another observational study reported a favorable outcome at 90 days, in which statin therapy was initiated within 4 wk after stroke onset.45 Thus far, the MISTICS trial remains the only one dedicated to acute treatment and improvement of functional outcome after stroke. Although in the FASTER study, treatment was initiated within the acute phase, it was designed as an early secondary prevention rather than an outcome trial. The findings of the MISTICS trial suggest a protective effect of acute statin treatment, and this is supported by experimental and clinical data investigating the effects of statin discontinuation.
Presently, the neuroprotection with statin therapy for acute recovery trial (Neu-START trial) (ACTRN 12607000028404; www.anzctr.org.au) is investigating the effects of lovastatin given at escalating dosages (1, 3, 6, 8, and 10 mg/kg) for 3 days, starting within 24 h after stroke onset. The follow-up period comprises 30 days. The study is primarily designed to study safety and pharmacokinetics of high-dose statin treatment in the acute phase of stroke. Results are expected in 2009. Investigators from the MISTICS group are currently initiating a randomized controlled Phase III trial (personal communication, J. Montaner).
Evidence from experimental and clinical studies clearly demonstrated that sudden discontinuation of statin treatment may acutely impair vascular function. Data from in vivo and in vitro studies show that cessation of statin treatment is followed by a distinct transient decrease of NO production below baseline levels, indicating a rebound mechanism. In addition, antithrombotic effects are attenuated as well. For an explanation, in vitro studies have identified an overshoot activation of small G proteins such as Rho and Rac as the underlying molecular mechanism for this rebound phenomenon.
Chronic statin pretreatment in a murine model of transient focal cerebral ischemia confers a 40% reduction in infarct size, but protection was lost when statin therapy was stopped 2 days before the induction of cerebral ischemia. Discontinuation of statin therapy was followed by a significant downregulation of eNOS expression in the brain and aorta after 2 days.46 Conversely, platelet factor 4 and β-thromboglobulin, which were downregulated by statin therapy, showed an “overshoot” upregulation after statin withdrawal, reducing the antithrombotic effect of statin treatment (however, this was observed on Day 4 after discontinuation). Another study showed a 90% decrease in endothelial NO production (i.e., 32% below baseline levels), 2 days after cessation of statin treatment. After 4 days, NO production, as well as eNOS mRNA expression, returned to baseline levels.47 In a cell culture experiment using human endothelial cells derived from the umbilical vein, a 50% reduction in eNOS mRNA was shown, occurring within 24 h after statin treatment was stopped.48 Experiments studying cultured endothelial cells and aortas of mice have shown that eNOS mRNA stability is transiently decreased by Rho/Rho kinase-regulated modifications of the actin cytoskeleton.47
In a recently published placebo-controlled, double-blind study in young, normocholesteremic men, discontinuation of statin therapy resulted in a significant reduction (11% ± 4% vs 13% ± 5% at baseline, P < 0.01) in evoked flow velocity responses, assessed via transcranial Doppler sonography in the posterior cerebral artery.49 Presently, this is the first study that investigated cerebral vasoreactivity testing the statin discontinuation paradigm in men. An earlier study by Laufs et al.23 in healthy volunteers showed increased endothelium-dependent forearm blood flow after 24 h of treatment with high-dose atorvastatin, which reached its maximum at Day 4 and was abrogated 24 h after statin therapy was stopped. These observations are supported by other studies using different types and dosages of the statin class. A rebound effect on endothelial function preferentially occurred in patients who already showed impaired endothelium function at baseline.50–52 In all of these studies, changes in endothelial function appeared independently of inflammatory markers, such as high-sensitivity C-reactive protein and serum LDL-cholesterol levels.
One prospective clinical trial investigated the effect of statin discontinuation in the acute phase of ischemic stroke. Patients admitted within 24 h after stroke onset and with prior statin treatment were divided into either immediate treatment with 20 mg atorvastatin (n = 43) or discontinuation of statin treatment for the first 3 days (n = 46). In addition, 126 patients without prior statin treatment served as a reference control. Starting Day 4, all patients received statin therapy regardless of preexisting statin treatment. Patients receiving acute recombinant-tPA therapy were excluded. Primary outcome measures were death or dependency (defined as modified Rankin scale >2) at 3 mo. Lesion volume on computed tomography/magnetic resonance imaging determined between Days 4–7 and early neurological deterioration as defined by an increase of ≥4 points in the National Institute of Health Stroke Scale score between admission and any time within the first 48 h served as secondary outcome measures. In the withdrawal group, 27 (60%) patients versus only 16 (39%) in the immediate statin group died or were dependent at 90 days follow-up. In fact, discontinuation of statin therapy was associated with a significantly increased risk for death or dependency (odds ratio 4.66; 95% CI, 1.46–14.9; P < 0.05), when data were adjusted for age and baseline stroke severity at admission. The significant effects on the primary outcome were emphasized by the distinct impact on secondary outcome measures. Statin discontinuation was related to an 8.7- (95% CI, 3.05–24.63; P = 0.002) fold increase in the risk for early neurological deterioration and a significantly larger mean infarct volume (P < 0.001), compared with the nondiscontinuation group. Although in the discontinuation group no significant difference in primary outcome measures was reported compared with the reference group, a significant difference in secondary outcome measures was detected. Early neurological deterioration occurred more frequently in the statin withdrawal group (odds ratio 19.01; 95% CI, 1.96–184.09; P = 0.01) and mean infarct volume increase was reported to be higher as well (P < 0.048).53
Previously, a study reported significant improvement in neurological outcome after tPA treatment in patients with prior statin use. Preexisting statin treatment was observed as an independent predictor of improved functional outcome (odds ratio 5.26; 95% CI, 1.48–18.72; P = 0.027).54 Given this result, the authors proposed extending further studies for the effect of acute statin therapy to the therapeutic window for thrombolysis. In support of these results, a number of observational and retrospective studies have demonstrated improved neurological outcome and reduced mortality at 3 mo follow-up in patients with preexisting statin therapy before the event.55,56
In addition, there is evidence from experimental and clinical studies suggesting that statins act directly via profibrinolytic mechanisms and effects on microvascular integrity.
Surgery is a typical situation leading to abrupt cessation of statin therapy, and there are a number of reasons for a delay in continuing or readministering statin therapy after surgery. Considering the available evidence for a rebound effect, whenever possible, statins should not be discontinued perioperatively in patients at high-vascular risk.62,63 In addition, there is evidence for a protective effect of initiating statin therapy before surgery.64–66 In fact, endothelial dysfunction is an important pathologic phenomenon occurring early after vascular surgery and is associated with the release of inflammatory cytokines,67 physical damage to the endothelium and decreased NO levels and an oxidative burst.68 In turn, this might account for postoperative complications, including atrial fibrillation, myocardial infarction, and direct organ injury (e.g., renal failure). However, evidence is now predominantly derived from observational data.66 Only one randomized controlled trial has investigated the impact of short-term statin treatment before surgery in statin naive patients at vascular risk. The combined end point of cardiac death, myocardial infarction, ischemic stroke, or unstable angina at 6 mo after surgery was significantly reduced in the treatment group (P = 0.03).64 An earlier study showed improved endothelial function measured as flow-mediated dilations of the brachial artery in patients after coronary bypass surgery who received statin treatment before surgery.
Beyond the negative impact of abrupt statin discontinuation, the negative impact of statin cessation on 12 mo mortality has also been reported in a multicenter, prospective cohort study that investigated medication discontinuation after discharge from hospital in 1521 enrolled patients who had suffered myocardial infarction.69 Interestingly, discontinuation of statin treatment was associated with the highest risk of death (HR 2.86; 95% CI, 1.47–5.55) compared with discontinuation of aspirin and β blocker.
In addition to stroke, there is recent experimental and clinical evidence from other fields, suggesting that acute delivery of statins exerts beneficial effects in critically ill patients and in patients at acute vascular risk.
There are as yet only limited data from randomized controlled trials on the effect of statin therapy in SAH. However, a meta-analysis of the available literature (until 2007) gave evidence for a protective effect of statin therapy in patients suffering from SAH.74 The primary outcome was the incidence of angiographically confirmed vasospasm; the incidence of DINDs and mortality served as secondary outcome measures. Statin treatment significantly reduced the incidence of vasospasm (RR 0.73, 95% CI, 0.54–0.99), DINDs (RR 0.38; 95% CI, 0.17–0.83), and mortality (RR 0.22, 95% CI, 0.06–0.82). For these outcomes, the number needed to treat was 6.25, 5, and 6.7. A recent randomized controlled pilot study by Chou et al.75 did not support this result; however, a trend toward lower mortality in the statin-treated group was reported. To clarify, the efficacy and safety of statin treatment in SAH larger trials are needed.74,75 A multicenter, randomized controlled Phase III trial (SimvaSTatin for Aneurysmal Subarachnoid Hemorrhoage, STASH) is currently recruiting patients. Driven by the promising results of a Phase II trial,72,73 in the STASH trial, 1600 patients will be randomized to either 40 mg simvastatin or placebo within the first 96 h for 3 wk and followed up for the primary outcome Modified Rankin Disability Score at 6 mo. Secondary outcome measures are acute clinical course, discharge destination, and socioeconomic outcome.
Moreover, a number of experimental studies have suggested a beneficial effect of statins in models for intracerebral hemorrhage (ICH).78–80 Although there is evidence for a protective effect from preclinical studies, it remains unclear whether chronic statin use improves outcome in patients with ICH. Naval et al.81,82 retrospectively investigated the effect of prior statin use in a cohort of ICH patients. Statin treatment was associated with a reduction in 30-day mortality (adjusted OR 0.08; 95% CI, 0.0063–1.0184; P = 0.05) and decreased perihematomal edema (mean edema volume 13.2 ± 9.2 mL vs 22.3 ± 18.3 mL, P = 0.035). Improvement in functional outcome was not reported.81 A larger study, investigating the data of 629 consecutive ICH patients enrolled in a prospective cohort study, did not report a difference in outcomes in patients with prior statin use.83 Randomized controlled trials are desperately needed because a possible beneficial impact of statin therapy could offer a therapeutic intervention for this disease. Yet, because pleiotropic effects of statins include effects on platelet activation (platelet factor-4, β-thromboglobulin47) and coagulation factors (t-PA, PAI1) (vide supra), there are concerns that statins could enhance hematoma expansion or increase the incidence of hemorrhagic stroke. In contrast to cumulative evidence from several randomized controlled trials,29,34 an exploratory post hoc analysis of the SPARCL data reported a small but significant increase in the incidence of hemorrhagic strokes in the statin group36 (vide supra). The study by FitzMaurice et al.83 did not find an association between prior or poststatin use and the incidence of ICH.
Endothelial dysfunction occurs early and plays a key role in the progression and course of sepis and systemic inflammatory response syndrome (SIRS). The endothelium is the primary target for the development of capillary leaks, coagulatory processes, and migration of inflammatory cells. Given the multimodal vasoprotective effects of statins, statin therapy appears to be a promising candidate for additive treatment in sepsis and SIRS.
Experimental studies in different animal models for sepsis have shown that statins exert rapid protective effects on the microcirculation and microvascular integrity.84 There is also clinical evidence suggesting protective effects of statin therapy in sepsis and SIRS. Randomized controlled trials for sepsis are missing, which might clarify the promising data from observational studies. Currently, there are several ongoing trials, testing the safety and efficacy of statins as additive treatment in sepsis in a randomized controlled study design.84–86
The most important adverse events related to statin therapy are myopathy and increase of liver enzymes. Notably, after several fatal cases of rhabdomyolysis,87 cerivastatin (Lipobay, Bayer, Germany) was withdrawn from the market in 2001, which raises questions about the overall safety of HMG-CoA reductase inhibitors.
Statin-induced muscle toxicity is dose dependent and a class effect, likely related to the inhibition of HMG-CoA reductase within myocytes. Although the exact mechanism remains unclear, several hypotheses have been considered: reduction of cholesterol synthesis and resultant decreased cholesterol content in the myocyte wall; decrease in coenzyme Q10 (ubiquinone) levels, which results in impaired mitochondrial enzyme activity; and apoptosis of myofibers induced by the depletion of isoprenoid levels.88
All statins are metabolized in the liver and several statins are predominantly metabolized by the cytochrome P450 system isoenzyme CYP3A4 (lovastatin, simvastatin, atorvastatin). Hence, CYP3A4 inhibitors (e.g., cyclosporines, macrolide antibiotics, serotonin reuptake inhibitors, or grapefruit juice89,90) can interact with statin metabolism. Moreover, fibrates (especially gemfibrozil) can increase statin levels by inhibiting the glucuronidation and subsequent biliary excretion of statins.91 Recently, a genomewide scan identified a strong association of the rs4149056 single-nucleotide polymorphism located within SLCO1B1 and statin-induced myopathy.92 Hepatic uptake of statins is mediated by the organic anion transporter polypeptide, which is encoded on SLCO1B1. Patients carrying the C allele of polymorphism develop higher circulating plasma levels of statins. Hence, drug interactions, nutrients, and genetic polymorphisms can all lead to increased statin plasma concentrations, and substantially increase the risk of statin-induced myopathy.90
Except for cerivastatin, the incidence of statin-induced myopathy is very low, which has been shown by a number of systematic reviews and meta-analyses.91,93,94 A systematic review by Kashani et al.94 analyzed the data of 74,102 patients enrolled in 35 randomized controlled trials. It did not show a significant absolute increase in the risks of myalgias (defined as muscoskeletal pain/symptoms without creatine kinase [CK] elevation) and rhabdomyolysis (defined as Ck elevation ≥10 times upper limit of normal [ULN]).94 In this analysis, the end point “myalgia” is reported in 15.4% in patients taking statins (except cerivastatin) versus 18.7% in patients taking placebo, showing no significant difference between the groups (incidence risk difference IRD 2.7; 95% CI, −3.2 to 8.7; P = 0.37). CK elevations <10 times ULN were only reported in 0.9% of the statin group and 0.4% of the placebo group. The incidence of rhabdomyolysis was even lower (0.2% statin group vs 0.1% placebo).94 Using standard doses of statins, the estimated statin-related risk of myopathy is only about 11 per 100,000 person/year, and the estimated risk for rhabdomyolysis is 3 per 100,000 person/year.29,91,92 However, with higher doses, the risk increases.92,95 In more than 50% of all cases of statin-related rhabdomyolysis, the presence of drugs that interact with statin metabolism was reported.91,94
According to the National Lipid Association’s (NLA) muscle expert panel, routine monitoring of CK is not recommended for asymptomatic patients.90,96 Data on muscle toxicity and liver function during the perioperative period are very limited. Meta-analyses did not report significant increases in CK levels in statin-treated patients versus patients receiving placebo.66,97 There are as yet no specific concerns for the perioperative period. Nevertheless, in the perioperative period, patients might be at higher risk for statin-induced myopathy than in ambulatory practice, considering the use of concomitant medications in the perioperative setting and postoperative impairment of renal function. In addition, analgesia and sedation could mask symptoms of myopathy.
Because of the very rare incidence of muscle-related adverse events of statins, many individual clinical trials reporting these events are underpowered. Furthermore, as stated by the NLA Muscle Safety Expert Panel,90 the definitions for muscle complaints from myalgia, myopathy, and myositis to rhabdomyolysis are often used inconsistently throughout clinical trials and clinical practice, thus making it difficult to compare results among studies. Especially mild symptoms, with only little or no CK elevation, might get lost and not be reported, as a standardized definition for muscle complaints is missing. Thus, the reporting of muscle-related adverse events has to be read carefully. The SPARCL trial, for example, stated that “there was no preset definition of rhabdomyolysis.”35 For future clinical trials with statins, a standardized definition for muscle complaints needs to be established.
The association of statin treatment and a significant elevation of liver transaminases (defined as >3 times ULN at least at two consecutive measurements) has been reported (for all statins) in individual statin trials and is supported by a number of meta-analysis and systematic reviews.94,98–100 Although asymptomatic elevations in liver enzymes are quite common in patients using statins, clinically significant liver damage is very rare99 and neither a causality nor precise mechanism of direct hepatotoxicity of statins has been established.98 The Liver Expert Panel of the NLA does not recommend routine monitoring of liver enzymes in asymptomatic patients receiving statins.98,100
Experimental and clinical studies have identified both vaso- and cerebroprotective effects of statin treatment that occur before and in addition to cholesterol lowering. Large clinical trials and meta-analyses have demonstrated that statin therapy safely reduces the incidence of cardio- and cerebrovascular events. At present, statin therapy is not only recommended in hypercholesteremic patients but also for secondary prevention of CHD and stroke in patients with average cholesterol levels. Moreover, statin therapy should be initiated as soon as possible for early secondary prevention.
In addition, there is experimental evidence that statin treatment improves stroke outcome, even when administered after the event. Recently, the MISTICS trial has reported improved neurological outcome in stroke patients, when statin treatment was initiated within 3–12 h after stroke onset. Conversely, adverse effects of abrupt statin discontinuation have been demonstrated by Blanco et al.53 Furthermore, there is experimental and clinical data from observational trials, suggesting a protective effect of statins when coadministered with tPA treatment. Future trials will have to clarify whether acutely administered statins can improve stroke outcome.
A number of experimental and clinical studies have suggested a protective effect of statin therapy in patients suffering from SAH. At present, strength of evidence is limited but, given the limited therapeutic options and the good safety profile of statins, early initiation of statin therapy is promising for the treatment of SAH patients. A multicenter Phase III trial is currently investigating the efficacy and safety of statin therapy in SAH patients.
Regarding the safety and efficacy of perioperative statin therapy and possible related adverse events, the body of evidence from randomized controlled trials is very small, but suggests a positive impact of statin treatment.62,63,101 At present, recommending routine use of statins for the perioperative period would be premature. Nevertheless, we think, in patients at high-vascular risk, preoperative initiation of statin therapy can be considered.62,63,66 In patients chronically treated with statins, treatment should be continued throughout the perioperative period.62,63,66 This would imply administering the drug via nasogastric tubes in patients who are unable to swallow.
In summary, statin therapy reduces the incidence of cardio- and cerebrovascular events and is recommended for early secondary prevention of CHD and stroke. Considering the multitargeted vasoprotective effects of statins, statin therapy may be beneficial to various conditions in which acute and subacute endothelial dysfunction plays a key role. Vice versa, abrupt interruption of statin therapy after acute cardio- or cerebrovascular events or surgery may impede vascular function and increase morbidity and mortality. Pilot trials and meta analyses have reported promising results of acute statin therapy and statin pretreatment in stroke, SAH, perioperative medicine, and sepis or SIRS. These findings have to be confirmed by larger clinical trials. For future studies, the development of an IV statin formulation for acute treatment protocols is warranted.102 Hydrophilic statins, such as pravastatin or rosuvastatin, are ideally suited for the development of an IV compound. Rosuvastatin has been safely administered IV in healthy volunteers.103 However, it is not known whether established side effects of statins (e.g., myopathy) are amplified by an IV formulation. Of course, appropriate trials and standard regulatory approval are needed before clinical use of an IV statin formulation in humans.102
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