Stroke Prevention By Aggressive Reduction In Cholesterol Levels Research Articles

Lipoprotein(a): A Residual Cardiovascular Risk Factor in Statin-Treated Stroke Survivors: Insights From the SPARCL Trial

BackgroundIn the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol levels) trial, atorvastatin (80 mg/d) was compared to placebo in patients with recent stroke or transient ischemic attack (TIA) and no known coronary artery disease. ObjectivesThis study aimed to assess the contribution of lipoprotein(a) [Lp(a)] to subsequent cerebrovascular and cardiovascular events in stroke/TIA survivors. MethodsLp(a) levels and apolipoprotein(a) [apo(a)] isoform size were determined by liquid-chromatography mass spectrometry in samples collected at baseline from 2,814 SPARCL participants (1,418 randomized to atorvastatin and 1,396 to placebo). Within each treatment arm, patients in the highest quartile (≥84.0 nmol/L) were compared with those in the lowest quartiles of Lp(a) concentrations. Patients in the lowest quartile (≤25.9 Kringle IV domains) of apo(a) isoform sizes were compared with those in the highest quartiles. Multivariable-adjusted HRs were calculated using Cox proportional regression models. ResultsThere was no significant association between Lp(a) concentrations or apo(a) isoform sizes and the risk of recurrent stroke, the primary outcome of SPARCL, or cerebrovascular events in patients randomized to atorvastatin or placebo. In contrast, in patients randomized to atorvastatin, elevated Lp(a) concentrations and short apo(a) isoforms were positively and independently associated with an increased risk of coronary events (HR: 1.607 [95% CI: 1.007-2.563] and HR: 2.052 [95% CI: 1.303-3.232]). No such association was found in patients randomized to placebo (HR: 1.025 [95% CI: 0.675-1.555] and HR: 1.097 [95% CI: 0.735-1.637]). ConclusionsLp(a) contributes to the residual coronary artery disease risk of statin-treated stroke/TIA survivors, paving the way for use of therapies targeting Lp(a) in this population with stroke. (Lipitor In The Prevention Of Stroke, For Patients Who Have Had A Previous Stroke [SPARCL]; NCT00147602)

Atorvastatin

Atorvastatin

Cerebrovascular Disease and Statins.

Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment.

Atorvastatin Reduces First and Subsequent Vascular Events Across Vascular Territories: The SPARCL Trial

BackgroundIn the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, atorvastatin was compared with placebo in 4,731 participants with recent stroke or transient ischemic attack and no known coronary heart disease. Atorvastatin reduced the first occurrence of stroke and the first occurrence of a composite of vascular events. ObjectivesThe aim of this post hoc analysis was to assess the occurrence of all (first and subsequent) vascular events and the effect of atorvastatin to reduce these events by vascular territory (cerebrovascular, coronary, or peripheral) in SPARCL. MethodsTreatment effects on total adjudicated vascular events, overall and by vascular territory, were summarized by marginal proportional hazards models. Vascular event rates were estimated for each treatment group with cumulative incidence functions. ResultsThe placebo group had an estimated 41.2 first and 62.7 total vascular events per 100 participants over 6 years. There were 164 fewer first and 390 fewer total vascular events in the atorvastatin group (total events hazard ratio: 0.68; 95% confidence interval: 0.60 to 0.77). The total events reduction included 177 fewer cerebrovascular, 170 fewer coronary, and 43 fewer peripheral events. Over 6 years, an estimated 20 vascular events per 100 participants were avoided with atorvastatin treatment. ConclusionsIn participants with recent stroke or transient ischemic attack, the total number of vascular events prevented with atorvastatin was more than twice the number of first events prevented. Total event reduction provides a comprehensive metric to capture the totality of atorvastatin clinical efficacy in reducing disease burden after stroke or transient ischemic attack. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602)

Reader response: Association of statin use with spontaneous intracerebral hemorrhage: A cohort study.

The article by Saliba et al.1 further informs the debate on the important topic of statin use and spontaneous intracerebral hemorrhage. In our original Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial report (atorvastatin 80 mg/d vs placebo for secondary stroke prevention),2 we indicated that our analysis of the type of outcome stroke (ischemic, hemorrhagic, or unclassified) was unplanned and that the small numbers of participants with a baseline brain hemorrhage precluded meaningful conclusions in this population. A meta-analysis (17,000 participants; 26 randomized trials) found that more vs less intensive statin therapy reduced first ischemic strokes (risk ratio [RR] 0.84, 99% confidence interval [CI] 0.71–0.99; p = 0.005) and nonsignificantly increased hemorrhagic strokes (RR 1.21, 99% CI 0.76–1.91; p = 0.3).3 The meta-analysis did not address the risks of high-intensity statins for secondary stroke prevention. In the current analysis,1 statin dose was categorized as an average atorvastatin equivalent daily dose (AAEDD) of 20 mg/d. Although no interaction between AAEDD and previous stroke/TIA was found, given that the limited initial and subsequent exploratory SPARCL analyses prompted much of the debate regarding statin risk for secondary stroke prevention,2,4,5 it would be helpful to provide an analysis for participants with prior stroke who received an AEDD of 80 mg/d.

Author response: Association of statin use with spontaneous intracerebral hemorrhage: A cohort study.

We appreciate Prof. Goldstein's response to our article.1 As mentioned in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, high-dose statins use was associated with increased risk of intracerebral hemorrhage (ICH) among patients with an investigator-designated cerebral small vessel disease (SVD) distribution stroke or ICH at entry.2 To our knowledge, ICH type was not assessed.

Editors' note: Association of statin use with spontaneous intracerebral hemorrhage: A cohort study

In “Association of statin use with spontaneous intracerebral hemorrhage: A cohort study,” Saliba et al. reviewed the risk of intracerebral hemorrhage (ICH) in patients in a large database who were recently started on statins and found that high-dose statin use was associated with decreased risk of ICH as compared with low-dose statin use. However, the authors noted a paradox in their data because they also found that low cholesterol levels were associated with increased risk of ICH. This protective effect of statins may be from other mechanisms besides simply lowering cholesterol. Dr. Goldstein notes that these findings add to those of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels ( SPARCL ) trial, which showed high-dose statins were beneficial for secondary stroke prevention in general, but did not provide meaningful conclusions for patients with ICH in particular, due to low numbers. Dr. Vilanilam commends the study's design, but points out that there have been conflicting data about the relationship between statin use and cerebral microbleeds, and comments that preclinical studies are needed to further clarify this relationship. Dr. Saliba et al. agree that preclinical studies and large prospective studies are needed to better assess the effect of statin use on ICH, with respect to both statin dose and ICH location. In “Association of statin use with spontaneous intracerebral hemorrhage: A cohort study,” Saliba et al. reviewed the risk of intracerebral hemorrhage (ICH) in patients in a large database who were recently started on statins and found that high-dose statin use was associated with decreased risk of ICH as compared with low-dose statin use. However, the authors noted a paradox in their data because they also found that low cholesterol levels were associated with increased risk of ICH.

Oxidized Phospholipids on Apolipoprotein B-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack

BackgroundBiomarkers to predict recurrent stroke and targets of therapy to prevent stroke are lacking. ObjectivesThis study evaluated whether patients with prior cerebrovascular events and elevated levels of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), but without prior coronary artery disease (CAD), are at risk for recurrent stroke and CAD events following high-dose statin therapy. MethodsIn the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, OxPL-apoB levels were measured in 4,385 patients with stroke or transient ischemic attack at baseline and in 3,106 patients at 5 years following randomization to placebo or 80 mg atorvastatin. The primary endpoint was the time from randomization to a second nonfatal or fatal stroke. Secondary endpoints included first major coronary events and any cardiovascular event. ResultsPatients with recurrent stroke had higher baseline median OxPL-apoB levels than patients without (15.5 nmol/l vs. 11.6 nmol/l; p < 0.0001). After multivariable adjustment, elevated baseline OxPL-apoB predicted recurrent stroke (hazard ratio [HR]: 4.3; p < 0.0001), first major coronary events (HR: 4.0; p < 0.0001), and any cardiovascular event (HR: 4.4; p < 0.0001). These comparisons for any endpoint did not differ by treatment, shown as a nonsignificant interaction test. The net reclassification improvement, integrated discrimination improvement, and area under the receiver-operating characteristic curve (AUC) were all significantly improved by adding OxPL-apoB to the models, with ΔAUC +0.0505 (p < 0.0001) for recurrent stroke, ΔAUC +0.0409 (p < 0.0001) for first major coronary event, and ΔAUC +0.0791 (p < 0.0001) for any cardiovascular event. ConclusionsElevated OxPL-apoB levels predicted recurrent stroke and first major coronary events in patients with prior stroke or transient ischemic attack. The lack of statin–OxPL-apoB treatment interaction suggested that OxPLs might be statin-independent therapeutic targets to reduce risk of cardiovascular events. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602)

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

GPi vs STN deep brain stimulation for Parkinson disease: Three-year follow-up.

Editors' Note: In reference to “GPi vs STN deep brain stimulation for Parkinson disease: Three-year follow-up,” Drs. Sidiropoulos and LeWitt suggest that the study findings could be due to suboptimal globus pallidus internus (GPi) programming and targeting imprecision. Odekerken et al., authors of the study, disagree and offer several arguments to support their findings, which showed superiority of subthalamic nucleus (STN) over GPi deep brain stimulation. Commenting on “Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke,” Dr. Goldstein further discusses the benefit of statin on cerebrovascular events and functional outcome, citing 2 exploratory analyses based on data from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Tsivgoulis et al., authors of the study, suggest further research to establish the safety and efficacy of early statin treatment on the …

Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke.

The article by Tsivgoulis et al.1 focused on the potential effect of statin pretreatment on outcomes in patients with large artery atherosclerosis. We conducted 2 relevant exploratory analyses based on data from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, in which patients with noncardioembolic stroke were randomized to high-dose atorvastatin (80 mg/day) or placebo.2 In the first, we hypothesized that the …

2013 Cholesterol Guidelines Revisited: Percent LDL Cholesterol Reduction or Attained LDL Cholesterol Level or Both for Prognosis?

BackgroundThe 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol recommends moderate- to high-intensity statins for patients with atherosclerotic cardiovascular disease but departs from the traditional treat-to-target approach. Whether percent low-density lipoprotein cholesterol (LDL-C) reduction or attained LDL-C levels add incremental prognostic value to statin dose is not known. MethodsPatients in the Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patient-level data) randomized to a statin arm (atorvastatin 80 mg/10 mg or simvastatin 20 mg) were chosen. Patients were divided into groups based on attained LDL-C levels (≤70 vs >70 mg/dL) and percent LDL-C reduction (≥50% vs <50%). Primary outcome was major cardiovascular event defined as death due to coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. Incremental prognostic value was assessed by using a forward conditional Cox proportional hazards model. Two models were tested: Model 1: Step 1 statin dose; Step 2 add attained LDL-C levels (continuous variable); Step 3 add percent LDL-C reduction (continuous variable). Model 2: Steps 2 and 3 were reversed. ResultsAmong 13,937 patients included in this study, percent LDL-C reduction added incremental prognostic value over both statin dose and attained LDL-C levels (global chi-square increased from 3.64 to 26.1 to 47.5; P <.0001). However, attained LDL-C level did not provide incremental prognostic value over statin dose and percent LDL-C reduction (global chi-square increased from 3.64 to 47.5 to 47.5; P <.0001 and .94, respectively). Among patients with attained LDL-C ≤70 mg/dL, those with percent LDL-C reduction of <50% had a significantly higher risk of primary outcome (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.16-1.97; P = .002) and stroke (HR, 2.07; 95% CI, 1.46-2.93; P <.0001) and a numerically higher risk of death (HR, 1.37; 95% CI, 0.98-1.90; P = .06) when compared with the group with percent LDL-C reduction of ≥50%. ConclusionsIn patients with atherosclerotic cardiovascular disease, percent LDL-C reduction provides incremental prognostic value over statin dose and attained LDL-C levels. However, the attained LDL-C level does not provide additional prognostic value over statin dose and percent LDL-C reduction.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Trial: Where to Now?

The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Trial: Where to Now?

Impact of Female Sex on Lipid Lowering, Clinical Outcomes, and Adverse Effects in Atorvastatin Trials

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial.

Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100-190 mg/dL). We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. http://www.clinicaltrials.gov. Unique identifier: NCT00147602.

Safety Profile of High-Dose Statin Therapy in Geriatric Patients with Stroke

Use of high-dose statin therapy (HDST) in patients with stroke became standard clinical practice after the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, in which the mean age of the study population was approximately 63 years. Little data are available on the adverse effects of statins when used in high doses in adults older than 65 years. The objective of this study was to assess the magnitude of adverse effects of HDST in geriatric patients. This single-center, retrospective, case-control study was conducted at Upstate Medical University, Syracuse, New York. All patients older than 65 years admitted between 2008 and 2011 to the hospital's Upstate Stroke Center with acute stroke were eligible. Electronic medical records of 200 eligible patients were reviewed to collect demographic, clinical, and laboratory data. Patients on HDST (cases) were compared with those on low doses (controls) using the χ, Fisher exact (two-sided), and Student t tests. One hundred cases (mean age 80.5 ± 7.7 years) were compared with 100 controls (mean age 78.9 ± 6.4 years). Sixty-seven percent were taking simvastatin. Ninety percent of the cases compared with 81% of the controls had ischemic stroke. The prevalence of elevated alanine aminotransferase (13%) and myositis (4%) was significantly higher in the cases than in the controls. Fourteen percent of the cases reported myalgias, 9% had nausea, and 6% had diarrhea. Seventy-three cases had low-density lipoprotein levels <100 mg% and 41% of the cases had mean glycated hemoglobin levels ≥ 6.5%. The use of HDST in older adult patients with acute stroke is associated with a significantly increased burden of liver enzyme elevation and myalgias.

Clinical determinants of incident aortic valve stenosis in patients treated with atorvastatin: results from three large randomized clinical trials

Background: Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world, and may share some risk factors with coronary heart disease (CHD). Clinical trials have failed to show a benefit for statin therapy in delaying the progression of AVS among asymptomatic individuals with known AVS. Whether statin therapy may decrease the incidence of AVS in populations enriched with CHD risk factors is unknown. Our objective was to compare the incidence rates of AVS among patients treated with high- versus low-dose statin or placebo and to identify clinical risk factors associated with the risk of AVS. Methods and results: Results from three large-scale atorvastatin trials were included in this study, the Treating to New Targets (TNT) trial, in which 80 mg and 10 mg/day of atorvastatin were compared in patients with stable coronary disease, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial, in which atorvastatin 80 mg was compared to simvastatin 20 mg/day in post-myocardial infarction patients, and the Stroke Prevention by Aggressive Reduction in Cholesterol levels (SPARCL) trial, in which 80 mg/day of atorvastatin was compared to placebo in patients with a recent stroke or transient ischemic attack. All patients with known AVS at baseline were excluded from this analysis. During the follow-up (median=4.9 years), 45 patients developed AVS in TNT, 28 in IDEAL and 9 in SPARCL. Among the 82 patients who developed AVS, 39 (47.6%) patients were treated with atorvastatin 80 mg and 43 (52.4%) were treated with low-dose statin or placebo (hazard ratio [HR]=0.91 [95% CI, 0.59-1.41], p=0.67). Risk factors that showed a significant association in univariate regression analyses were entered into a multivariate model. These risk factors included age, height, weight, body mass index, diabetes, angina, previous coronary artery bypass grafting, peripheral vascular disease, warfarin and antiplatelets use, prior use of statins and calcium channel blockers use. In multivariate analyses forcing treatment, sex and race into the model, age (hazard ratio [HR]=2.24 [95% CI, 1.66-3.02], p<0.0001 per 1-SD increment), diabetes (HR=1.69 [1.00-2.82], p=0.05), warfarin and antiplatelets use (HR=2.89 [1.80-4.62], p<0.0001) and prior statin use (HR=2.56 [1.48-4.44], p=0.03) were significantly associated with the onset of AVS. Conclusions: In this study, high-dose statin therapy did not impact the incidence of AVS. We found that age, diabetes, warfarin and antiplatelets use and prior use of statins were significant predictors of incident AVS in these high-risk patients.

Should Statins Be Paused or Discontinued After Thrombolysis or Acute Intracerebral Hemorrhage? No!

A 78-year-old male patient arrives at the emergency department 3 hours after sudden onset of aphasia and right-sided sensorimotor hemiparesis (National Institutes of Health Stroke Scale=8). There is a medical history of coronary artery disease, hypertension, and hyperlipidemia. Prior medication consists of 100 mg aspirin, 5 mg bisoprolol, and 40 mg simvastatin. Initial blood glucose is 5.6 mmol/L and blood pressure is 150/90 mm Hg. Computed tomography does not reveal any pathology. Intravenous recombinant tissue-plasminogen activator (rt-PA) is rapidly administered 225 minutes after symptom onset. There is uncertainty about how to proceed with preexisting statin treatment in the acute setting of thrombolysis. Several studies linked statin treatment with an increased risk of intracerebral hemorrhage (ICH) after stroke, and additional studies recently indicated an increased risk for ICH after thrombolysis.1–4 This is in line with earlier epidemiological evidence showing an inverse correlation of cholesterol and ICH risk.5,6 Should statin treatment be discontinued following the principle “primum nil nocere” (Latin: first of all, do not harm)? On the contrary, there is strong evidence that discontinuation of statin therapy during acute vascular events, including ischemic as well as hemorrhagic stroke, impairs vascular function and dramatically decreases the chances of good outcome and survival.7–10 In this opinion article, we would like to make a strong case that preexisting statin treatment should not be paused or abruptly discontinued, either in acute ischemic stroke patients receiving rt-PA or in patients with acute ICH. What is the evidence that stroke patients on statins have a higher risk of ICH? The evidence for risks and benefits of statins after stroke are mainly derived from the Heart Protection Study and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.1,2 A subgroup analysis of the Heart …

Letter by Goldstein Regarding Article, “Statins and Intracerebral Hemorrhage”

To the Editor: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial enrolled subjects with recent (within 1–6 months) transient ischemic attack or stroke, reporting more frequent brain hemorrhages among those randomly assigned to a statin (hazard ratio=1.66; 95% CI, 1.08–2.55).1 Hackam et al2 write that this finding has “led to some uncertainty regarding the balance of benefits and risks of statins, particularly in patients with a history of cerebrovascular disease.” Notwithstanding their exhaustive meta-analysis, the reason for this concern is not clear. The SPARCL trial, the only randomized trial designed to evaluate a statin in a cerebrovascular population, found a treatment-related reduction in all strokes (hazard ratio=0.84; 95% …

High-Dose Statin for Every Stroke

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 …