Differences in Stroke Recurrence Risk Between Atrial Fibrillation Detected on ECG and 14-Day Cardiac Monitoring.

BACKGROUND: Ischemic stroke and transient ischemic attack (TIA) standard-of-care etiological investigations include an ECG and prolonged cardiac monitoring (PCM). Atrial fibrillation (AF) detected after stroke has been generally considered a single entity, regardless of how it is diagnosed. We hypothesized that ECG-detected AF is associated with a higher risk of stroke recurrence than AF detected on 14-day Holter (PCM-detected AF). METHODS: We conducted a retrospective, registry-based, cohort study of consecutive patients with ischemic stroke and TIA included in the London Ontario Stroke Registry between 2018 and 2020, with ECG-detected and PCM-detected AF lasting ≥30 seconds. We quantified PCM-detected AF burden. The primary outcome was recurrent ischemic stroke, ascertained by systematically reviewing all medical records until November 2022. We applied marginal cause-specific Cox proportional hazards models adjusted for qualifying event type (ischemic stroke versus TIA), CHA2DS2-VASc score, anticoagulation, left ventricular ejection fraction, left atrial size, and high-sensitivity troponin T to estimate adjusted hazard ratios for recurrent ischemic stroke. RESULTS: We included 366 patients with ischemic stroke and TIA with AF, 218 ECG-detected, and 148 PCM-detected. Median PCM duration was 12 (interquartile range, 8.8-14.0) days. Median PCM-detected AF duration was 5.2 (interquartile range, 0.3-33.0) hours, with a burden (total AF duration/total net monitoring duration) of 2.23% (interquartile range, 0.13%-12.25%). Anticoagulation rate at the end of follow-up or at the first event was 83.1%. After a median follow-up of 17 (interquartile range, 5-34) months, recurrent ischemic strokes occurred in 16 patients with ECG-detected AF (13 on anticoagulants) and 2 with PCM-detected AF (both on anticoagulants). Recurrent ischemic stroke rates for ECG-detected and PCM-detected AF groups were 4.05 and 0.72 per 100 patient-years (adjusted hazard ratio, 5.06 [95% CI, 1.13-22.7]; P=0.034). CONCLUSIONS: ECG-detected AF was associated with 5-fold higher adjusted recurrent ischemic stroke risk than PCM-detected AF in a cohort of ischemic stroke and TIA with >80% anticoagulation rate.

Stroke Prevention: Little-Known and Neglected Aspects.

Combining available therapies has the potential to reduce the risk of stroke by 80% or more. A comprehensive review of all aspects of stroke prevention would be very lengthy; in this narrative review, we focus on some aspects of stroke prevention that are little-known and/or neglected. These include the following: (1) implementation of a Mediterranean diet; (2) B vitamins to lower homocysteine; (3) coordinated approaches to smoking cessation; (4) intensive lipid-lowering therapy; (5) lipid lowering in the elderly; (6) physiologically individualized therapy for hypertension based on renin/aldosterone phenotyping; (7) avoiding excessive blood pressure reduction in patients with stiff arteries; (8) treatment of insulin resistance with pioglitazone in stroke patients with prediabetes and diabetes; (9) impaired activation of clopidogrel in patients with variants of CYP2C19; (10) aspirin pseudoresistance due to enteric coating; (11) rationale for anticoagulation in patients with embolic stroke of unknown source; (12) pharmacologic properties of direct-acting oral anticoagulants that should be considered when choosing among them; (13) the identification of which patients with asymptomatic carotid stenosis are at a high enough risk to benefit from carotid endarterectomy or stenting; and (14) the importance of age in choosing between endarterectomy and stenting. Stroke prevention could be improved by better recognition of these issues and by implementation of the principles derived from them.

Stroke Prevention in Older Adults: Recent Advances.

The risks of stroke and dementia increase steeply with age, and both are preventable. At present, the best way to preserve cognitive function is to prevent stroke. Therapeutic nihilism based on age is common and unwarranted. We address recent advances in stroke prevention that could contribute greatly to prevention of stroke and dementia at a time when the aging of the population threatens to markedly increase the incidence of both. Issues discussed: (1) old patients benefit even more from lipid-lowering therapy than do younger patients; (2) patients with stiff arteries are at risk from a target systolic blood pressure <120 mm Hg; (3) the interaction of the intestinal microbiome, age, and renal function has important dietary implications for older adults; (4) anticoagulation with direct-acting oral anticoagulants should be prescribed more to old patients with atrial fibrillation; (5) B vitamins to lower homocysteine prevent stroke; and (6) most old patients in whom intervention is warranted for carotid stenosis would benefit more from endarterectomy than from stenting. An 80-year-old person has much to lose from a stroke and should not have effective therapy withheld on account of age. Lipid-lowering therapy, a more plant-based diet, appropriate anticoagulation or antiplatelet therapy, appropriate blood pressure control, B vitamins to lower homocysteine, and judicious intervention for carotid stenosis could do much to reduce the growing burden of stroke and dementia.

Choosing the right therapy for a patient with asymptomatic carotid stenosis.

Introduction: Most patients with asymptomatic carotid stenosis (ACS) now have a lower risk with intensive medical therapy than with stenting (CAS) or endarterectomy (CEA); the annual risk of stroke or death with intensive medical therapy is ~ 0.5%, vs. a periprocedural risk with CAS of ~ 2.5-4.1% with CAS, and ~ 1.4-1.8% with CEA. The excess risk of CAS is greater in older patients.Areas covered: Discussed are the need for intensive medical therapy, the nature of intensive medical therapy, approaches to identifying the few patients with ACS who could benefit from CEA or CAS, and which patients would be better suited to CEA vs. CAS.Expert opinion: All patients with ACS are at high risk of cardiovascular events, soshould receive intensive medical therapy including lifestyle modification, intensive lipid-lowering, B vitamins to lower homocysteine (using methylcobalamin rather than cyanocobalamin), and appropriate antithrombotic therapy. High-risk patients who could benefit from intervention can be identified by clinical and imaging features including transcranial Doppler embolus detection, ulceration, intraplaque hemorrhage, reduced cerebrovascular reserve, plaque echolucency, silent infarction on brain imaging, and progression of stenosis. Most patients whose risk of stroke warrants intervention would be better treated with CEA than with CAS.

Invasive Crooke cell adenoma in a patient with diffuse large B-cell lymphoma.

Crooke cell adenoma (CCA) is an aggressive corticotroph subtype of pituitary adenoma often with cyclically elevated blood adrenocorticotropic hormone (ACTH), which preoperative diagnosis is challenging especially in the context of a functionally silent invasive tumor and a history of high-stage malignancy such as diffuse large B-cell lymphoma (DLBCL). Here, we report the first case of invasive CCA in a patient with DLBCL. A 71 year-old previously healthy man was recently diagnosed with DLBCL that was treated with CHOP-R chemotherapy. Within one week of completing his first cycle of chemotherapy, he had a frontal headache that progressed to right-sided proptosis. Cranial MRI showed a heterogeneously enhancing mass with invasion into the sellar and suprasellar compartment, compression of the optic chiasm, as well as extension into the clivus, bilateral cavernous sinuses, and the prepontine cistern. He underwent a partial resection for the pituitary tumor debulking. Pathological examination revealed CCA with invasion into the adjacent tissue. The patient had no history of Cushing disease or syndrome, but his blood ACTH was found to be elevated on the operation day. Our present case and literature review suggest that comorbidity of CCA or ACTH-producing adenoma and B-cell lymphoma deserves awareness in our clinical practice, as these two diseases and/or their therapies may interact substantially. CAA should be considered in the major differential diagnosis for an invasive sellar tumor, even without blood ACTH elevation and/or with a history of malignant lymphoma.

Vitamin B 12 deficiency and hyperhomocysteinaemia in outpatients with stroke or transient ischaemic attack: a cohort study at an academic medical centre.

OBJECTIVE: We sought to assess the current magnitude of the opportunity for secondary stroke prevention with B vitamins. DESIGN: A cohort study. SETTING: The Urgent TIA (Transient Ischaemic Attack) Clinic at an academic medical centre. MAIN OUTCOME MEASURES: We assessed the prevalence of biochemical vitamin B12 deficiency (B12Def, serum B12 <156 pmol/L), hyperhomocysteinaemia (HHcy; plasma total homocysteine [tHcy] >14 µmol/L) and metabolic B12 deficiency (MetB12Def, serum B12 <258 pmol/L and HHcy) between 2002 and 2017, by age group and by stroke subtype. RESULTS: Data were available in 4055 patients. B12Def was present in 8.2% of patients overall; it declined from 10.9% of patients referred before 2009 to 5.4% thereafter (p=0.0001). MetB12Def was present in 10.6% of patients, and HHcy was present in 19.1% of patients. Among the patients aged ≥80 years, MetB12Def was present in 18.1% and HHcy in 35%. Among the 3410 patients whose stroke subtype was determined, HHcy was present in 18.4% of patients: 23.3% of large artery atherosclerosis, 18.1% of cardioembolic, 16.3% of small vessel disease, 10.8% of other unusual aetiologies and 13.6% of undetermined subtypes (p=0.0001). CONCLUSIONS: Despite a decline in our referral area since 2009, B12Def, MetB12Def and HHcy remain common in patients with stroke/TIA. Because these conditions are easily treated and have serious consequences, all patients with stroke/TIA should have their serum B12 and tHcy measured.

Moderate Renal Impairment and Toxic Metabolites Produced by the Intestinal Microbiome: Dietary Implications.

OBJECTIVE: Toxic metabolites produced by the intestinal microbiome from animal proteins, carnitine (mainly from red meat), or phosphatidylcholine (mainly from egg yolk), have important adverse effects on cardiovascular disease. These are renally eliminated and may be termed gut-derived uremic toxins (GDUT). We hypothesized that even moderate renal impairment and intake of nutrient precursors would raise plasma levels of GDUT. DESIGN: A cohort study. SETTING: Academic medical center. SUBJECTS: Patients attending stroke prevention clinics at a university medical center were recruited. MAIN OUTCOME MEASURE: Nutrient intake was assessed by the 131-item Harvard Food Frequency Questionnaire; estimated glomerular filtration rate (eGFR) was caculated using the Chronic Kidney Disease-Epidemiology (EPI) equations. Plasma levels of trimethylamine n-oxide, p-cresyl sulfate, hippuric acid, p-cresyl glucuronide, pheny acetyl glutamine, and phenyl sulfate were measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Among 316 patients recruited, the mean (standard deviation [SD]) age was 66.74 (10.42) years; 59.7% were men. Mean eGFR was 76.03 ± 20.01; 57 (18%) had eGFR<60 mL/min/1.73 m2. Plasma levels of all GDUT were significantly higher even with moderate reduction of eGFR. Nutrient intake affected plasma levels of some GDUT; the effects differed by eGFR above and below 60 mL/min/1.73 m2. Plasma levels were obtained fasting, so we probably underestimated the effect of nutrient intake. CONCLUSIONS: Even moderate impairment of renal function was associated with higher plasma levels of GDUT. This has dietary implications for patients at risk of atherosclerosis, particularly in those with impaired renal function (including the elderly): they should limit intake of animal protein, red meat, and egg yolk. It also points the way to novel approaches to vascular prevention, including more intensive dialysis, renal transplantation, and modification of the intestinal microbiome with probiotics or fecal transplantation.

Mediterranean Diet Score: Associations with Metabolic Products of the Intestinal Microbiome, Carotid Plaque Burden, and Renal Function.

Metabolic products of the intestinal microbiome such as trimethylamine N-oxide (TMAO) that accumulate in renal failure (gut-derived uremic toxins, GDUTs) affect atherosclerosis and increase cardiovascular risk. We hypothesized that patients on a Mediterranean diet and those consuming lower amounts of dietary precursors would have lower levels of GDUTs. Patients attending vascular prevention clinics completed a Harvard Food Frequency Questionnaire (FFQ) and had plasma levels of TMAO, p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresyl glucuronide, phenyl acetyl glutamine, and phenyl sulfate measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Carotid plaque burden was measured by ultrasound; CKD-Epi equations were used to estimate the glomerular filtration rate. In total, 276 patients completed the study. Even moderate renal function significantly increased plasma GDUTs, which were significantly associated with higher carotid plaque burden. There was no significant difference in plasma levels of any GDUT associated with a Mediterranean diet score or with intake of dietary precursors. In omnivorous patients with vascular disease, the intake of dietary precursors of intestinal metabolites or adherence to a Mediterranean diet did not change plasma GDUT. Approaches other than diet, such as probiotics and repopulation of the intestinal microbiome, may be required to mitigate the adverse effects of GDUTs.

Data on the gut and saliva microbiota from a cohort of atherosclerosis patients determined by 16S rRNA gene sequencing.

This work was conducted to characterize the 16S rRNA gene profile of a cohort of patients with traditional risk factors for developing atherosclerosis. The patients in the cohort were divided into two extremes; those predicted to develop extreme atherosclerosis who did not (Protected), and those predicted not to develop atherosclerosis who did (Unexplained). Bacterial DNA was isolated from stool and saliva and this was used to determine the V4 variable region of the 16S rRNA gene sequence composition of the samples in triplicate.

Metabolic products of the intestinal microbiome and extremes of atherosclerosis.

BACKGROUND AND AIMS: There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area. METHODS: Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <-2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure - gut-derived uremic toxins (GDUT) - were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden. CONCLUSIONS: The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

Effects of Eplerenone on Resistance to Antihypertensive Medication in Patients with Primary or Secondary Hyperaldosteronism.

BACKGROUND AND OBJECTIVES: Resistant hypertension is an important problem; nearly half of diagnosed hypertensives are not controlled to target blood pressure levels, and approximately 90% of strokes occur among patients with resistant hypertension. Primary aldosteronism accounts for approximately 20% of resistant hypertension, but the role of secondary hyperaldosteronism in resistant hypertension is seldom considered. We assessed the effects of eplerenone in patients with hypertension and either primary or secondary hyperaldosteronism. METHODS: Patients with a history of resistant hypertension and a supine plasma aldosterone level ≥ 360 pmol/L were randomized to eplerenone versus placebo in a fully blinded study for one year. A medication intensity score was developed to assess the resistance of hypertension to medication (blood pressure × medication intensity). We assessed the effects of eplerenone on blood pressure and on resistance to concomitant medication. RESULTS: Final results were available in 37 patients (19 on eplerenone and 18 on placebo). Resistance to medication, as assessed by the intensity of concomitant medication required to maintain blood pressure control, was markedly reduced by eplerenone: medication intensity scores declined by -0.50 ± 1.04 (SD) on placebo versus -2.11 ± 1.45 with eplerenone (P = 0.0001), the Systolic Resistance Score declined by -80.00 ± 122.93 on placebo versus -334.05 ± 21.73 on eplerenone (P = 0.0001), and the Diastolic Resistance Score increased by 1.28 ± 31.65 on placebo and declined by -40.74 ± 57.08 on eplerenone (P = 0.009). CONCLUSIONS: Eplerenone significantly reduced resistance to concomitant antihypertensive medication in both primary and secondary hyperaldosteronism.

Association of homocysteine and smoking with cerebral microemboli in patients with mechanical heart valves: a transcranial Doppler study.

Objectives: Microembolic signals (MES) on transcranial Doppler (TCD) predict stroke and cognitive decline. Plasma levels of total homocysteine (tHcy), a prothrombotic factor, are higher in patients with microemboli in carotid stenosis and in patients with paradoxical embolism. In this study we assessed the association between the level of tHcy and the number of MES in patients with mechanical heart valves (MHVs). Methods: TCD monitoring was performed to detect MES before and after breathing 100% oxygen and repeated every 2-4 weeks up to six times. Results: Twenty-five patients with MHVs (mean age: 63.60±10.15 years) participated in this study; 15 were men (66.47±7.25 years) and 10 were women (59.30±12.60 years). In total, there were 126 study visits. In multiple regression, higher tHcy was associated with more MES in both preoxygenation (OR 1.34 (95% CI 1.07 to 1.68, P=0.009)) and postoxygenation (OR 1.40 (95% CI 1.07 to 1.83, P=0.01)) phases. Current smoking and the length of time between the operation and monitoring also correlated with a higher number of MES before and after breathing oxygen, particularly in women. Conclusions: Higher tHcy and smoking were associated with a higher MES count in both preoxygenation and postoxygenation phases. Because smoking can be stopped and hyperhomocysteinaemia is treatable, these are clinically important findings.

Transcranial Doppler is Complementary to Echocardiography for Detection and Risk Stratification of Patent Foramen Ovale.

BACKGROUND: In patients with patent foramen ovale (PFO), strategies are needed to identify patients at higher risk, who might benefit from PFO closure. METHODS: We studied the frequency of detection of a right-to-left shunt (RLS) using transesophageal echocardiography (TEE) among patients with cryptogenic stroke and transcranial Doppler (TCD) to detect RLS, and analyzed the prediction of recurrent stroke according to TCD shunt grade, by detection of RLS on TEE, and by atrial septal aneurysm or mobility. RESULTS: Among 334 patients with TCD, 69.8% were female, with a mean (SD) age of 53 (14) years, with a median follow-up of 420 days. There were 284 cases with TCD and TEE; 54 (19%) had atrial septal aneurysm or mobility. Echocardiography failed to show a RLS in 43 (15.1%) of the patients who had TCD and TEE, even in some patients with high-grade shunts on TCD: 18 (42%) were grade 3 or higher on TCD. Survival free of stroke or transient ischemic attack was predicted significantly by TCD shunt grade < 2 (P = 0.028), shunt grade < 3 (P = 0.03), and shunt grade < 4 (P < 0.0001); this was attenuated by adjustment for risk factors in Cox regression (P = 0.08). Neither RLS on TEE (P = 0.47), or atrial septal aneurysm or mobility (P = 0.08), predicted events. CONCLUSIONS: Our findings suggest that TCD might be more sensitive than TEE for detection of RLS, which misses some cases with substantial RLS, and might be valuable for prediction of recurrent stroke or transient ischemic attack in patients with PFO. TCD complements TEE for management of suspected paradoxical embolism.

Risk of Stroke at the Time of Carotid Occlusion.

IMPORTANCE: Many patients with asymptomatic carotid stenosis are offered carotid stenting for the prevention of carotid occlusion. However, this treatment may be inappropriate if the risk of stroke is low at the time of occlusion and with intensive medical therapy. OBJECTIVES: To determine the risk resulting from progression to occlusion among patients with asymptomatic carotid stenosis and to assess the role of severity of carotid stenosis or the presence of contralateral occlusion as factors that may predict the risk of stroke or death after occlusion of a previously asymptomatic carotid stenosis. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of data collected from patients at the Stroke Prevention Clinic of Victoria Hospital from January 1, 1990 (when annual surveillance with carotid ultrasonography first began), through December 31, 1995, or the Stroke Prevention at University Hospital from January 1, 1995, through December 31, 2012. The last date of follow-up was August 26, 2014. EXPOSURES: A new carotid occlusion during annual monitoring with carotid duplex ultrasonography (index occlusion). MAIN OUTCOMES AND MEASURES: Ipsilateral stroke or transient ischemic attack, death from ipsilateral stroke, or death from unknown cause. RESULTS: Among 3681 patients in our clinic database with data on sequential annual carotid ultrasonographic examinations during the study period, 316 (8.6%) were asymptomatic before an index occlusion that occurred during observation. Most of the new occlusions (254 of 316 [80.4%]) occurred before 2002, when medical therapy was less intensive; the frequency decreased by quartile of years (P < .001, χ2 test). Only 1 patient (0.3%) had a stroke at the time of the occlusion, and only 3 patients (0.9%) had an ipsilateral stroke during follow-up (all before 2005). In Kaplan-Meier survival analyses, neither severity of stenosis (P = .80, log-rank test) nor contralateral occlusion (P = .73) predicted the risk of ipsilateral stroke or transient ischemic attack, death from stroke, or death from unknown cause at a mean (SD) follow-up of 2.56 (3.64) years. In Cox proportional hazards regression analyses, only age (P = .02), sex (P = .01), and carotid plaque burden (P = .006) significantly predicted risk of those events. CONCLUSIONS AND RELEVANCE: The risk of progression to carotid occlusion is well below the risk of carotid stenting or endarterectomy and has decreased markedly with more intensive medical therapy. Preventing carotid occlusion may not be a valid indication for stenting.

Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Recurrent cerebrovascular events are frequent in medically treated patients with patent foramen ovale (PFO), but it still remains unclear whether PFO is a causal or an incidental finding. Further uncertainty exists on whether the size of functional shunting could represent a potential risk factor. The aim of the present study was to evaluate if the presence of PFO is associated with an increased risk of recurrent stroke or transient ischemic attack and to investigate further if this relationship is related to the shunt size. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of all available prospective studies reporting recurrent cerebrovascular events defined as cryptogenic stroke and transient ischemic attacks in medically treated patients with PFO diagnosed by echocardiography or transcranial sonography. RESULTS: We identified 14 eligible studies including a total of 4251 patients. Patients with stroke with PFO did not have a higher risk of the combined outcome of recurrent stroke/transient ischemic attack (risk ratio=1.18; 95% confidence interval=0.78-1.79; P=0.43) or in the incidence of recurrent strokes (risk ratio =0.85; 95% confidence interval=0.59-1.22; P=0.37) in comparison with stroke patients without PFO. In addition, PFO size was not associated with the risk of recurrent stroke or transient ischemic attack. We also documented no evidence of heterogeneity across the included studies. CONCLUSIONS: Our findings indicate that medically treated patients with PFO do not have a higher risk for recurrent cryptogenic cerebrovascular events, compared with those without PFO. No relation between the degree of PFO and the risk of future cerebrovascular events was identified.

Secular trends in ischemic stroke subtypes and stroke risk factors.

BACKGROUND AND PURPOSE: Early diagnosis and treatment of a stroke improves patient outcomes, and knowledge of the cause of the initial event is crucial to identification of the appropriate therapy to maximally reduce risk of recurrence. Assumptions based on historical frequency of ischemic subtypes may need revision if stroke subtypes are changing as a result of recent changes in therapy, such as increased use of statins. METHODS: We analyzed secular trends in stroke risk factors and ischemic stroke subtypes among patients with transient ischemic attack or minor or moderate stroke referred to an urgent transient ischemic attack clinic from 2002 to 2012. RESULTS: There was a significant decline in low-density lipoprotein cholesterol and blood pressure, associated with a significant decline in large artery stroke and small vessel stroke. The proportion of cardioembolic stroke increased from 26% in 2002 to 56% in 2012 (P<0.05 for trend). Trends remained significant after adjusting for population change. CONCLUSIONS: With more intensive medical management in the community, a significant decrease in atherosclerotic risk factors was observed, with a significant decline in stroke/transient ischemic attack caused by large artery atherosclerosis and small vessel disease. As a result, cardioembolic stroke/transient ischemic attack has increased significantly. Our findings suggest that more intensive investigation for cardiac sources of embolism and greater use of anticoagulation may be warranted.

SPARKLE (Subtypes of Ischaemic Stroke Classification System), incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes.

BACKGROUND: Previous classification systems of acute ischemic stroke (Causative Classification System, CCS, of acute ischemic stroke, Trial of Org 10172 in Acute Stroke Treatment, TOAST) established the diagnosis of large artery disease (LAD) based on the presence or absence of carotid stenosis. However, carotid plaque burden is a stronger predictor of cardiovascular risk than stenosis. Our objective was to update definitions of ischemic stroke subtypes to improve the detection of LAD and to assess the validity and reliability of a new classification system: SPARKLE (Subtypes of Ischaemic Stroke Classification System). METHODS: In a retrospective review of clinical research data, we compared three stroke subtype classifications: CCS, TOAST and SPARKLE. We analyzed a random sample of 275 patients presenting with minor stroke or transient ischemic attack (TIA) in an Urgent TIA Clinic in London, Ont., Canada, between 2002 and 2012. RESULTS: There was substantial overall agreement between SPARKLE and CCS (κ = 0.75), with significant differences in the rate of detection of LAD, cardioembolic and undetermined causes of stroke or TIA. The inter-rater reliability of SPARKLE was substantial (κ = 0.76) and the intra-rater reliability was excellent (κ = 0.91). CONCLUSION: SPARKLE is a valid and reliable classification system, providing advantages compared to CCS and TOAST. The incorporation of plaque burden into the classification of LAD increases the proportion of cases attributable to LAD and reduces the proportion classified as being of 'undetermined' etiology.

Ezetimibe and regression of carotid atherosclerosis: importance of measuring plaque burden.

BACKGROUND AND PURPOSE: There has been recent controversy over failure of ezetimibe to reduce carotid intima-media thickness. Much of this is based on failure to understand important differences among ultrasound phenotypes of atherosclerosis. METHODS: We analyzed the effect of adding ezetimibe to the regimen of patients being followed in vascular prevention clinics where measurement of carotid plaque burden (total plaque area) is used to guide therapy. RESULTS: There were complete data in 231 patients with total plaque area for 2 years before and 2 years after initiation of ezetimibe. In the 2 years before and after initiation of ezetimibe, total cholesterol decreased significantly before (P<0.0001) and after initiation of ezetimibe (P<0.0001); low-density lipoprotein cholesterol declined significantly before (P<0.0001) and after (P=0.003) initiation of ezetimibe. Triglycerides declined significantly before ezetimibe (P<0.0001) but did not change after addition of ezetimibe (P=0.48). High-density lipoprotein cholesterol did not change significantly before (P=0.87) but declined significantly after ezetimibe (P=0.03). Despite the decline in low-density lipoprotein cholesterol before addition of ezetimibe, there was a significant mean increase in within-individual total plaque area in the 2 years before addition of ezetimibe by 6.89±39.57 mm(2) (SD); after addition of ezetimibe, despite the decline in high-density lipoprotein, plaque area decreased by -3.05±SD 38.18 mm(2) SD (P<0.01). CONCLUSIONS: Ezetimibe appears to regress carotid plaque burden. To assess effects of antiatherosclerotic therapies, it is important to measure plaque burden. These findings should be tested in a clinical trial.