Effect of atorvastatin versus no Statin Treatment on major clinical events in Acute CardioEmbolic stroke patients without a definite indication for statin therapy: protocol for the STACE trial

Background: There is no specific recommendation on statin therapy for cardioembolic stroke (CES) patients in current stroke guidelines. We evaluated the effect of statin on major vascular events following acute ischemic stroke in patients with CES and no other indications for statin. Methods: Using a prospective multicenter stroke registry database, we identified acute ischemic stroke patients who were hospitalized between 2008 and 2015 and were categorized into CES according to the Trial of Org 10172 in Acute Stroke Treatment classification. Patients who had established indications for statin in accordance with the recent stroke guidelines were excluded. Primary outcome measure was a major vascular event, a composite of stroke recurrence, myocardial infarction and vascular death; and secondary outcome measures were stroke recurrence and all-cause death. We performed frailty model analysis to estimate hazard ratios (HRs) of statin therapy on outcomes accounting for variation in quality of care among centers. Stabilized inverse probability of treatment weighting method with propensity scores was used to remove baseline imbalances between statin users and non-users. Results: Of the 6124 CES patients, 2987 patients (male, 52%; mean age, 73±12 years) met the eligibility criteria; and 2125 (71%) of 2987 patients were on statin at discharge. Compared to the non-users, the statin users were more likely to arrive at hospitals later, have milder neurologic deficits at presentation, be on stain prior to index stroke and have hyperlipidemia and were less likely to have atrial fibrillation and occlusion of relevant cerebral arteries. During the median follow-up of 364 days, major vascular events were observed in 118 patients (5.6%) among the statin users and 177 patients (20.5%) among the non-users, respectively (p<0.001 on log rank test); the adjusted HR of statin therapy was 0.35 (95% confidence interval, 0.27-0.46). The adjusted HRs of statin therapy were 0.71 (0.49-1.04) for stroke recurrence and 0.55 (0.46-0.66) for all-cause death, respectively. Conclusion: This study suggests that statin therapy may reduce major vascular events and all-cause death in cardioembolic stroke patients without definite indications for statin.

Interactions Between Statins, Exercise, and Health: A Clinical Update

Compelling evidence suggest a key role of immune system in the development and progression of ischemic stroke. Although the balance between proinflammatory CD4 + T helper (Th)-1 lymphocytes, expressing T-bet transcription factor, and anti-inflammatory Th2 cells expressing GATA3 seems to influence the outcome in experimental stroke, the role of peripheral immune response in acute stroke patients is poorly understood. We aimed to evaluate the peripheral Th1/Th2 balance in acute atherothrombotic (ATHS) and cardioembolic stroke (CES) patients and in age- and sex-matched healthy subjects. Using flow cytometry, we analyzed the percentage of CD4 + T-bet + T cells and CD4 + GATA3 + T cells from peripheral blood of ATHS and CES patients (2,4 and 7 days after stroke onset). Patients and controls were screened for infectious conditions, autoimmune, inflammatory, or cancerous diseases. On day 2 circulating CD4 + T-bet + T cells were significantly higher in stroke patients compared to controls, and in ATHS compared to CES and controls. On day 7, we observed a significant increase of CD4 + T-bet + T cells in both ATHS and CES patients compared to baseline. No difference was observed in circulating CD4 + GATA3 + T cells among ATHS, CES patients, and controls. These data suggest that circulating CD4 + T-bet + T cells could be useful marker indicating atherothrombotic genesis of stroke and provide new insight into the peripheral adaptive immune response in acute stroke.

It is uncertain whether patients with cardioembolic stroke and without a guidance-based indication for statin therapy should be administered a statin for prevention of subsequent vascular events. This study was performed to determine whether the statin therapy is beneficial in preventing major vascular events in this population. Using a prospective multicenter stroke registry database, we identified patients with acute cardioembolic stroke who were hospitalized between 2008 and 2015. Patients who had other established indications for statin therapy according to current guidelines were excluded. Major vascular event was defined as a composite of stroke recurrence, myocardial infarction, and vascular death. We performed frailty model analysis with the robust sandwich variance estimator using the stabilized inverse probability of treatment weighting method to estimate hazard ratios of statin therapy on outcomes. Of 6,124 patients with cardioembolic stroke, 2,888 (male 44.6%, mean age 75.3 years, 95% confidence interval [CI] 74.8-75.8) were eligible, and 1,863 (64.5%) were on statin therapy during hospitalization. After a median follow-up of 359 days, cumulative incidences of major vascular events were 9.3% in the statin users and 20.5% in the nonusers (p < 0.001 by log-rank test). The adjusted hazard ratios of statin therapy were 0.39 (95% CI 0.31-0.48) for major vascular events, 0.81 (95% CI 0.57-1.16) for stroke recurrence, 0.28 (95% CI 0.21-0.36) for vascular death, and 0.53 (95% CI 0.45-0.61) for all-cause death. Starting statin during the acute stage of ischemic stroke may reduce the risk of major vascular events, vascular death, and all-cause death in patients with cardioembolic stroke with no guidance-based indication for statin.

To determine whether the plasma level of free fatty acid (FFA) could be associated with recurrent stroke in cardioembolic (CE) stroke patients. We analyzed data from 669 acute ischemic stroke patients and examined the association between FFA concentration and recurrent stroke in CE stroke patients compared with non-CE stroke patients. The baseline plasma FFA concentration (mEq/L) was approximately 1.5-fold higher in CE stroke patients (1.01 ± 0.63) than in non-CE stroke patients (0.72 ± 0.51). Multivariate logistic analysis showed that an increased level of FFA was significantly associated with CE stroke (hazard ratio [HR] 2.124, confidence interval [CI] 1.492-3.024). During the mean follow-up period of 25.4 months, a total of 56 (8.4%) patients experienced a stroke recurrence. The recurrence rate did not differ between patients with CE (10.5%) and non-CE (8.0%) stroke (p = 0.396). In CE stroke patients, an elevated baseline FFA concentration was independently associated with stroke recurrence (HR 2.711, CI 1.056-6.959). However, there was no association between FFA and stroke recurrence in non-CE stroke patients. In this retrospective registry-based observational study, CE stroke seemed to be associated with elevated plasma level of FFA. In addition, the present study suggested that an elevated FFA concentration could be a useful indicator for predicting recurrent stroke in CE stroke patients.

Background: Atrial fibrillation is the most common arrhythmia in older adults and a common cause of stroke. Patients with acute cardio-embolic stroke from atrial fibrillation are at high risk for recurrence with up to 50% of recurrent stroke occurring within 2 weeks of the index event. Anti-coagulation with heparinoids within 48 hours of stroke has been shown to increase risk of symptomatic intracranial hemorrhage (ICH) with no clear benefit on early stroke recurrence. Methods: This study was a retrospective chart review of consecutive patients who were admitted to the stroke service at the Foothills Medical Centre between 2009 and 2011. All patients with an acute stroke with a cardio-embolic etiology and a diagnosis of atrial fibrillation either by history or on electrocardiogram within two years of stroke were reviewed. We hypothesized that anti-coagulation within two weeks of stroke, appropriately begun because of a diagnosis of atrial fibrillation, decreased rates of recurrent stroke without causing an increase in rates of symptomatic ICH. Results: During the three-year period 324 patients were identified with cardio-embolic stroke secondary to atrial fibrillation. Within two weeks of stroke onset 63.0% (203/324) of patients were therapeutic on anti-coagulation with warfarin being the most common anti-coagulant used (67.6%). Patients who were anti-coagulated had a smaller mean stroke volume (18.9 cc vs 49 cc) and lower mean NIHSS at presentation (7 vs 9) but otherwise did not differ in baseline characteristics. Three (0.9%) patients had a clinically significant ICH; only one patient was actively anti-coagulated at the time of ICH, one was taking aspirin only and one was on aspirin and low dose enoxaparin for prevention of deep vein thrombosis. Recurrent stroke occurred in 16 patients (4.9%) within the two-week period. Anti-coagulation did not significantly reduce the risk of recurrent stroke (RR 0.67 95% CI 0.19 - 2.36). Conclusion: Anti-coagulation within 2 weeks of acute stroke in patients with atrial fibrillation appears to be safe among patients with smaller infarcts. Large studies would be needed to show if anticoagulation actually reduced the rate of early recurrent cardioembolic stroke.

Association of serum uric acid and cardioembolic stroke in patients with acute ischemic stroke

Introduction: Although statin therapy reduces cardiovascular events, statin use is associated with the risk of new-onset diabetes mellitus (NODM). Using a linked dataset, we evaluated the effect of statin treatment on vascular outcomes and NODM development in patients with ischemic stroke. Methods: From the dataset, we identified 20,250 patients with acute ischemic stroke who had neither a prior history of DM nor a previous history of statin use before the index stroke. Patients were divided into statin users and non-users. The outcomes were NODM and vascular outcomes, including recurrent ischemic stroke and acute myocardial infarction (AMI). Results: Of the 20,250 patients, 13,706 (67.7%) received statin treatment after the index stroke. For the risk of NODM, a time-response relationship was observed between the use of statins and NODM; a longer post-stroke follow-up duration substantially increased the risk of NODM. Among those with ischemic strokes exceeding 3 years, statin users had an approximately 1.7-fold greater risk of NODM than statin non-users. Statin therapy significantly reduced the risk of recurrent ischemic stroke by 54% (HR 0.46, 95% CI, 0.43–0.50, p < 0.001) across all stroke subtypes. Conclusion: Statin therapy following ischemic stroke increased the occurrence of NODM in patients over a period of 3 years. Despite the increased risk of NODM, statin therapy shows a beneficial effect in reducing major cardiovascular events such as recurrent ischemic stroke and AMI in patients with ischemic stroke.

Statin Therapy Improves Multiple Myeloma (MM) Specific Surviva

Background: The efficacy of statin therapy in the prevention of recurrent stroke and major adverse cardiovascularevents (MACE) was clearly established by the SPARCL trial; but SPARCL excluded patients whose index stroke was due to a presumed cardioembolic mechanism. As such, it remains unclear whether statins are beneficial in cardioembolic stroke patients, particularly those with atrial fibrillation (AF). Objective: To evaluate the relationship between statin use and future vascular risk reduction among recent ischemic stroke patients with AF Methods: We analyzed the Taiwan National Health Insurance registry which comprises beneficiaries aged ≥ 18 years. Code ICD-9 was used to identify a primary hospitalization diagnosis of ischemic stroke and AF among subjects encountered between 2003 and 2009. Follow-up was from time of the index stroke to admission for recurrent stroke or myocardial infarction; withdrawal from the registry; and last medical claim before 1/1/2011. Patients were divided into 2 groups based on whether statin was prescribed (at least 30 days vs. never used) during the follow-up period. Patients were excluded if they did not take any antithrombotic agent within 30 days before an endpoint. Primary endpoint was MACE (composite of stroke and myocardial infarction) and a key secondary endpoint was any recurrent stroke. Multivariate-adjusted hazard ratio (HR) and 95% CI for the development of events were estimated using Cox models. Model was adjusted for baseline age, gender, hypertension, diabetes, prior stroke, prior myocardial infarction, hyperlipidemia, hospital level, and antithrombotic agent during follow-up. Results: Among 4455 eligible patients, mean age was 71 years and mean follow-up duration was 2.8 years.Compared to non-statin use, statin use was associated with a significantly lower occurrence of MACE (adjusted HR 0.84, 95% CI 0.72 to 0.99, P=0.04) and recurrent stroke (adjusted HR 0.82, 0.69 to 0.97, P=0.02). Statin use was also linked to lower ischemic stroke risk, but had neutral effects on intracranial hemorrhage and myocardial infarction. Conclusion: Among patients with an index ischemic stroke and AF, statin use is associated with a lower risk of recurrent vascular events including stroke.

The objective of this study was to investigate the potential benefits of statin therapy on mortality and stroke recurrence after cardioembolic stroke. In this retrospective observational study, we analyzed data from 535 patients with first-ever cardioembolic stroke. Patients were classified into nonstatin, low-potency statin, and high-potency statin groups. The primary outcomes were time to mortality and time to recurrent stroke. The mean duration of follow-up was 22.2 months. The cumulative mortality rate was 7% at the end of the first year and 10% at the end of the third year. Statin therapy was independently associated with reduced mortality (hazard ratio, 0.237; 95% confidence interval, 0.080-0.703 for nonstatin versus low-potency statin; hazard ratio, 0.158; 95% confidence interval, 0.037-0.686 for nonstatin versus high-potency statin). Statin treatment did not affect the incidence of recurrent stroke in patients with cardioembolic stroke. Statin therapy could be associated with reduced mortality in patients with cardioembolic stroke.

Background and Objectives：An ischemic brain stroke following acute myocardial infarction (AMI) has a poor clinical prognosis, which primarily results from a thromboembolism. We determined the risk factors of acute cardioembolic brain stroke events that developed concurrently with, or soon after, the onset of AMI. Subjects and Methods：We evaluated 38 AMI patients, who developed subsequent acute cardioembolic brain stroke during their index admission, by comparing their clinical and angiographic characteristics with those of 1,443 consecutive patients that had not experienced a brain stroke. Strokes that occurred between the onset of the AMI and patient discharge were analyzed. The incidences of cardiovascular risk factors, and the clinical and angiographic characteristics, of patients admitted to Ewha Womans University Mokdong Hospital, with a diagnosis of AMI over a 10-year period, were compared. Results：In the univariate analysis, the frequencies of atrial fibrillation (21% vs. 4%, p=0.011) and hypertension (71% vs. 48%, p=0.030), and a left ventricular ejection fraction <40% (52% vs. 33%, p=0.039) were significantly higher in patients that had had an acute cardioembolic brain stroke. In a logistical regression analysis, atrial fibrillation was found to be a significant contributor to the subsequent development of an acute cardioembolic brain stroke in the AMI patients (p=0.023, β=2.025, odds ratio=7.6). Mean follow-up period, which was mainly determined as the time to death after the AMI, was shorter in the acute cardioembolic brain stroke patients (8.5 month vs. 24.3 month, p=0.002). The death rate during the mean follow-up period was much higher in these patients (50% vs. 29%). Conclusion：We found that the presence of atrial fibrillation at the time of admission for an AMI was associated with an increased risk of a subsequent acute cardioembolic brain stroke. (Korean Circulation J 2005;35:353-356)

Vasculocentricity Versus Cerebrocentricity: What Stroke-Related Baroreceptor Reflex Sensitivity Changes Might Be Telling Us

Introduction: Stroke is the fifth leading cause of death in the US and a major cause of disability. Atrial fibrillation (AF) increases the risk of ischemic stroke fivefold. Cardioembolic stroke in patients with AF is associated with high mortality. The association of elevated cardiac troponin with mortality in patients with acute ischemic stroke has been studied previously; however, there is limited data in subgroups of ischemic stroke etiology. We sought to determine the association of troponin elevation at presentation with 90-day all-cause mortality in patients with acute ischemic stroke and AF. Methods: The I nitiation of A nticoagulation after C ardioembolic Stroke (IAC) study is a multicenter cohort drawn from eight US Stroke Centers. We included consecutive patients hospitalized with acute ischemic stroke and AF between 2015-2018, who had an initial baseline cardiac troponin I (bcTnI) obtained at presentation. The primary outcome was all-cause mortality at 90 days from stroke onset. We undertook multivariable logistic regression to determine the association between elevated bcTnl (≥0.1 ng/mL) and 90-day mortality. Results: Of the 2084 patients enrolled in IAC, 1889 patients had 90-day follow-up of which 1461 patients had bcTnI available. 239 of the included patients (16.4%) had an elevated bcTnl, and death within 90-days occurred in 323 patients (22.1%). Elevated bcTnI was associated with 90-day mortality in univariable analysis (49.4% vs 24.9%; OR 1.71, 95% CI 1.17-2.50, p&lt;0.001). This association persisted after adjusting for potential confounders: age, NIHSS, coronary artery disease, congestive heart failure and initial systolic blood pressure (OR 1.71, 95% CI 1.17-2.50, p=0.006); and in sensitivity analysis adding CrCl to the adjusted model above (OR 1.57, 95% CI 1.03-2.39, p=0.037). Conclusion: In acute ischemic stroke patients with AF, elevated bcTnI was independently associated with 90-day all-cause mortality.

Background: Intra-arterial urokinase (IA-UK) thrombolysis is frequently given in Japan to selected patients with acute cerebral artery occlusion. However, it is not clear whether or not IA-UK thrombolysis has an efficacy for acute stroke patients. The purpose of this study was to assess the effects of IA-UK thrombolysis in acute cardioembolic stroke patients, by performing a case-control analysis using data from Japan’s Multicenter Stroke Investigator’s Collaboration (J-MUSIC). Methods: 16,922 acute ischemic stroke patients were enrolled into J-MUSIC. From these patients, we selected 91 patients (UK group) who met the following criteria: treatment with IA-UK; 20–75 years of age; cardioembolic stroke; presenting with a carotid stroke; admission within 4.5 h of symptom onset, and a National Institutes of Health Stroke Scale (NIHSS) score of 5–22 points on admission. A control group of 182 patients without IA-UK treatment and matched to the NIHSS score, gender, and age was chosen. We compared the modified Rankin scale (mRS) score at discharge and the mortality between the 2 groups. Results: In both groups, the mean age was 65 ± 8 years, and the median NIHSS score was 14. The mean interval between symptom onset and UK administration was 3.4 ± 1.3 h, and the IA-UK dose was 392,000 ± 200,000 units. The mRS score at discharge was lower in the UK group than in the control group (mean, SD, median; 2.8, 2.9, 2 in UK group vs. 3.3, 1.8, 4, in the control, respectively p = 0.031). A favorable outcome (mRS of 0–2) was more frequently observed in the UK group (50.5%) than in the control group (34.1%, p = 0.0124). No difference in the mortality rate was seen between the UK group (11.0%) and the control group (13.3%). As well, there was no difference in the length of hospital stay between the UK group (46 ± 41 days, mean ± SD) and the control group (42 ± 42 days, mean ± SD). Conclusions: IA-UK thrombolytic therapy may improve the outcome in hyperacute cardioembolic stroke patients.