Systematic Review of Sex Differences in Ischemic Strokes Among Young Adults: Are Young Women Disproportionately at Risk?

BACKGROUND AND PURPOSE: Recent evidence suggests that young women (18-45 years) may be at higher risk of ischemic strokes than men of the same age. The goal of this systematic review is to reconcile and synthesize existing evidence of sex differences among young adults with ischemic strokes. METHODS: We searched PubMed from January 2008 to July 2021 for relevant articles and reviews and consulted their references. We included original studies that (1) were population based and (2) reported stroke incidence by sex or sex-specific incidence rate ratios of young adults ≤45 years. We excluded studies that (1) omitted measurements of error for incidence rates or incidence rate ratios, (2) omitted age adjustment, and (3) were not in English. Statistical synthesis was performed to estimate sex difference by age group (≤35, 35-45, and ≤45) and stroke type. RESULTS: We found 19 studies that reported on sex-specific stroke incidence among young adults, including 3 that reported on overlapping data. Nine studies did not find a statistically significant sex difference among young adults ≤45 years. Three studies found higher rates of ischemic stroke among men among young adults ≥30 to 35 years. Four studies found more women with ischemic strokes among young adults ≤35 years. Overall, in young adults ≤35 years, the estimated effect size favored more ischemic strokes in women (incidence rate ratio, 1.44 [1.18-1.76], I2=82%) and a nonsignificant sex difference in young adults 35 to 45 years (incidence rate ratio, 1.08 [0.85-1.38], I2=95%). CONCLUSIONS: Overall, there were 44% more women ≤35 years with ischemic strokes than men. This gap narrows in young adults, 35 to 45 years, and there is conflicting evidence whether more men or women have ischemic strokes in the 35 to 45 age group.

Young Women Had More Strokes Than Young Men in a Large, United States Claims Sample.

BACKGROUND AND PURPOSE: Cardiovascular risk factors, which are overall more prevalent in men, are considered the major risk factors for strokes among young adults. However, recent European data found the incidence of strokes to be higher in young women. Using a large US claims sample, we examined sex differences in the index stroke rate of young adults. METHODS: We performed a retrospective cohort study of enrollees in a 10% random sample of PharMetrics, a nationally representative claims database of insured Americans from 2001 to 2014. Outcomes were index ischemic stroke events, based on inpatient admissions using International Classification of Diseases-Ninth Revision codes. The index stroke rate was estimated from Poisson rate models with time varying covariates for 2-year periods, stratified by sex and age groups. RESULTS: We identified 20 554 index strokes (50.4% women; mean age 63) including 5198 in young adults ages 15 to 54. There was no difference by sex in the index stroke rate in the extremes of age groups 15 to 24 and ≥75 years old. However, in the 25 to 34 and 35 to 44 year age groups, more women had strokes than men (incidence rate ratio: men:women, 0.70 [95% CI, 0.57-0.86]; 0.87 [95% CI, 0.78-0.98], respectively). In contrast, in the 45 to 54, 55 to 64, and 65 to 74 year age groups, more men had strokes (incidence rate ratio, 1.25 [95% CI, 1.16-1.33]; 1.41 [95% CI, 1.18-1.34]; 1.18 [95% CI, 1.12-125], respectively). CONCLUSIONS: More young women than men have strokes, suggesting possible importance of sex-mediated etiologies of stroke. Understanding these drivers is critical to stroke treatment and prevention efforts in young adults.

Cost-Effectiveness of Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Stroke Prevention.

BACKGROUND AND PURPOSE: Percutaneous transcatheter closure of patent foramen ovale (PFO closure) plus antiplatelet therapy has been shown to reduce the risk of recurrent stroke compared with medical therapy alone in carefully selected patients after cryptogenic stroke presumed to be from paradoxical embolism. Our objective was to determine the cost-effectiveness of PFO closure after cryptogenic stroke compared with conservative medical management from a US healthcare payer perspective. METHODS: A decision analytic Markov model estimated the 15-year cost and outcomes associated with the additional benefit of PFO closure compared with medical management alone. Model inputs were obtained from published literature, national databases, and a meta-analysis of 5 published randomized clinical trials on PFO closure. Health outcomes were measured in quality-adjusted life years (QALY). Cost-effectiveness used the incremental cost per QALY gained, whereas the net monetary benefit assumed a willingness to pay of $150 000/QALY. One-way and probabilistic sensitivity analyses estimated the uncertainty of model results. RESULTS: At 15 years, PFO closure compared with medical therapy alone improved QALY by 0.33 at a cost saving of $3568, representing an incremental net monetary benefit of $52 761 (95% interval -$8284 to $158 910). When the meta-analysis hazard ratio for stroke was increased to the 95% interval's upper bound of 0.77, one-way sensitivity analyses suggested that PFO closure's cost-effectiveness was $458 558 per additional QALY. Probabilistic sensitivity analysis suggested cost-effectiveness in 90% of simulation runs. CONCLUSIONS: PFO closure for cryptogenic strokes in the right setting is cost-effective, producing benefit in QALYs gained and potential cost savings. However, patient selection remains vitally important as marginal declines in treatment effectiveness can dramatically affect cost-effectiveness.

The Addition of Endovascular Intervention for Dural Venous Sinus Thrombosis: Single-Center Experience and Review of Literature.

BACKGROUND: Dural venous sinus thrombosis (DVST) is a cause of infarction and intracranial hemorrhage (ICH) that can lead to significant morbidity. Endovascular therapy has emerged as an adjunctive therapy in select cases but has been associated with increased hemorrhagic complications. We present our experience with a large single-center cohort of DVST cases treated with current-generation thrombectomy devices. MATERIALS AND METHODS: In this retrospective cohort study, a chart review was performed to compare presentations and outcomes of patients treated with anticoagulation alone with those treated with additional interventional therapy, using the modified Rankin Scale (mRS) score at discharge and at 90 days' follow-up. RESULTS: A total of 66 patients were included; 37 were treated with anticoagulation alone, and 29 underwent additional interventional therapy. Patients presenting with ICH or infarction had a significantly greater likelihood of disability at the time of discharge (odds ratio [OR] of 64.5 and 45.8, respectively; P < .0001) and at 90 days (OR of 28.4 and 22.8, respectively; P < .0001). Patients presenting with ICH or infarction were more likely to be selected for endovascular therapy (P < .05). Endovascular therapy was typically performed within 24 hours of admission; 9 patients (31%) had post-treatment hemorrhage, with 2 being (6.9%) symptomatic. There were fewer patients with slight disability (mRS score ≤1) in the endovascular group compared with the anticoagulation group at discharge (P = .05), but outcomes were not significantly different at 90 days (P = .19). CONCLUSIONS: Despite a higher rate of ICH or infarction at presentation in the endovascular group and an increased risk of postprocedural ICH, both treatment groups had similarly good functional outcomes at 90 days.

Cost-Effectiveness of Intra-Arterial Treatment as an Adjunct to Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The objective of this study was to determine the cost-effectiveness of intra-arterial treatment within the 0- to 6-hour window after intravenous tissue-type plasminogen activator within 0- to 4.5-hour compared with intravenous tissue-type plasminogen activator alone, in the US setting and from a social perspective. METHODS: A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intra-arterial therapy compared with standard treatment with intravenous tissue-type plasminogen activator alone. Model inputs were obtained from published literature, the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study, and claims databases in the United States. Health outcomes were measured in quality-adjusted life years (QALYs). Treatment benefit was assessed by calculating the cost per QALY gained. One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results. RESULTS: The addition of intra-arterial therapy compared with standard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $9911, which resulted in a cost of $14 137 per QALY. Multivariable sensitivity analysis predicted cost-effectiveness (≤$50 000 per QALY) in 97.6% of simulation runs. CONCLUSIONS: Intra-arterial treatment after intravenous tissue-type plasminogen activator for patients with anterior circulation strokes within the 6-hour window is likely cost-effective. From a societal perspective, increased investment in access to intra-arterial treatment for acute stroke may be justified.

Association of Traditional and Nontraditional Risk Factors in the Development of Strokes Among Young Adults by Sex and Age Group: A Retrospective Case-Control Study.

BACKGROUND: Despite women having fewer traditional risk factors (eg, hypertension, diabetes), strokes are more common in women than men aged ≤45 years. This study examined the contributions of traditional and nontraditional risk factors (eg, migraine, thrombophilia) in the development of strokes among young adults. METHODS: This retrospective case-control study used Colorado's All Payer Claims Database (2012-2019). We identified index stroke events in young adults (aged 18-55 years), matched 1:3 to stroke-free controls, by (1) sex, (2) age±2 years, (3) insurance type, and (4) prestroke period. All traditional and nontraditional risk factors were identified from enrollment until a stroke or proxy-stroke date (defined as the prestroke period). Conditional logistic regression models stratified by sex and age group first assessed the association of stroke with counts of risk factors by type and then computed their individual and aggregated population attributable risks. RESULTS: We included 2618 cases (52% women; 73.3% ischemic strokes) and 7827 controls. Each additional traditional and nontraditional risk factors were associated with an increased risk of stroke in all sex and age groups. In adults aged 18 to 34 years, more strokes were associated with nontraditional (population attributable risk: 31.4% men and 42.7% women) than traditional risk factors (25.3% men and 33.3% women). The contribution of nontraditional risk factors declined with age (19.4% men and 27.9% women aged 45-55 years). The contribution of traditional risk factors peaked among patients aged 35 to 44 years (32.8% men and 39.7% women). Hypertension was the most important traditional risk factor and increased in contribution with age (population attributable risk: 27.8% men and 26.7% women aged 45 to 55 years). Migraine was the most important nontraditional risk factor and decreased in contribution with age (population attributable risk: 20.1% men and 34.5% women aged 18-35 years). CONCLUSIONS: Nontraditional risk factors were as important as traditional risk factors in the development of strokes for both young men and women and have a stronger association with the development of strokes in adults younger than 35 years of age.

Thalamic Volume Loss Is Greater in Children Than in Adults Following Middle Cerebral Artery Territory Arterial Ischemic Stroke.

Background: Younger stroke patients may suffer worse outcomes than older patients; however, the extent to which age at stroke impacts remote areas of the brain remains unclear. The objective of this study was to determine thalamic volume changes ipsilateral to middle cerebral artery territory strokes based on age at acute ischemic stroke onset. Methods: Acute ischemic stroke patients <9 years, 9-18 years, and >18 years old were retrospectively recruited from a large quaternary care system. Each subject underwent an acute (<72 hours from AIS) and chronic (>90 days) magnetic resonance imaging (MRI) scan. Manual thalamic segmentation was performed. Results: Younger and older children had significantly greater stroke-side thalamic volume loss compared to adults (48.2%, P = .022; 40.7%, P = .044, respectively). Conclusions: Stroke-side thalamic volumes decreased across the age spectrum but to a greater degree in pediatric patients. This observation can affect functional and cognitive outcomes post stroke and warrants further research.

Relationship between early follow-up and readmission within 30 and 90 days after ischemic stroke.

OBJECTIVE: To examine whether early follow-up with primary care or neurology is associated with lower all-cause readmissions within 30 and 90 days after acute ischemic stroke admission. METHODS: We performed a retrospective cohort study of patients who were discharged home after acute ischemic stroke, identified by ICD-9 and ICD-10 codes, using PharMetrics, a nationally representative claims database of insured Americans from 2009 to 2015. The primary predictor was outpatient primary care or neurology follow-up within 30 and 90 days of discharge, and the primary outcome was all-cause 30- and 90-day readmissions. Multivariable Cox models were used with primary care and neurology visits specified as time-dependent covariates, with adjustment for patient demographics, comorbid conditions, and stroke severity measures. RESULTS: The cohort included 14,630 patients. Readmissions within 30 days occurred in 7.3% of patients, and readmissions within 90 days occurred in 13.7% of patients. By 30 days, 59.3% had a primary care visit, and 24.4% had a neurology visit. Primary care follow-up was associated with reduced 30-day readmissions (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.72-0.98). Primary care follow-up before 90 days did not reach significance (HR 0.92, 95% CI 0.83-1.03). Neurology follow-up was not associated with reduced readmissions within 30 or 90 days (HR 1.05, 95% CI; HR 1.00, 95% CI, respectively). CONCLUSION: Early outpatient follow-up with primary care is associated with a reduction in 30-day hospital readmissions. Early outpatient follow-up may represent an important opportunity for intervention after acute stroke admissions.

Is Prevalence of Atherosclerotic Risk Factors Increasing Among Young Adults? It Depends on How You Ask.

Background Incidence of cardiovascular disease in young adults is unabated. Increased prevalence of self-reported atherosclerotic risk factors may be driving this trend. The goal of this study was to examine whether the prevalence of atherosclerotic risk factors in young adults is increasing over time using both self-report and standard clinical criteria. Methods and Results Data from young adults, aged 20 to 45 years, in the National Health and Nutrition Examination Survey from 1999/2000 to 2013/2014 were analyzed. Risk factor prevalence of hypertension, diabetes mellitus, and hyperlipidemia was measured using clinical criteria and self-report. Smoking was based on self-report only, and obesity was based clinically on body mass index and waist to height ratio. Prevalence by survey was adjusted for age, sex, and race/ethnicity. By clinical criteria, adjusted prevalence of any 3 risk factors (hypertension, diabetes mellitus, and hyperlipidemia) declined slightly from 21.8% to 18.9% ( P for trend=0.05). However, by self-report, the adjusted prevalence of any 3 risk factors increased from 17.8% to 26.5% ( P<0.01). Hypertension was unchanged by clinical criteria ( P=0.32) but increased by self-report ( P<0.08). Diabetes mellitus, by clinical diagnosis and self-report, remained unchanged ( P=0.35 and P=0.29, respectively). Hyperlipidemia, by clinical criteria, declined over time ( P<0.01), but increased by self-report ( P<0.01). Smoking declined ( P<0.01), and obesity increased by both body mass index ( P<0.01) and waist/height ratio ( P<0.01). Conclusions The perception that young adult risk factors are increasing is consistent with increasing self-reported risk factors. However, evidence does not suggest that clinical risk factor prevalence overall has increased in young adults.