2 Minute Medicine Rewind June 8, 2020

Migraines During Pregnancy and the Risk of Maternal Stroke

1. Women with migraines are at an increased risk of stroke during and after pregnancy compared to those without migraines.

Evidence Rating Level: 2 (Good)

Increased risk of maternal stroke is associated with migraines during the perinatal period, with the belief that hypertension and related disorders mediate this relationship. However, this relationship has not been formally quantified in a research setting. This retrospective cohort study of 3 million live, singleton births between January 2007 and December 2012 sought to determine the degree to which hypertensive disorders impact the association between maternal stroke (ischemic and hemorrhagic) and migraines. A total of 2,866,316 births fell into the no migraine group and 26,440 births fell into the migraine group (≥1 ICD-9 migraine code). Hispanic women were the majority ethnic group in the no migraine group (48.9%) while non-Hispanic whites (41.0%) and Hispanics (34.7%) were the most represented in the migraine group. A total of 843 women experienced strokes, with 58% being ischemic strokes. Women experiencing stroke were more likely to have private insurance, use drugs or alcohol, have diabetes and/or obesity, have a pre-existing mental health condition, and be non-Hispanic. Women with migraines were also more likely to have a hypertensive disorder, including preeclampsia (difference 8.1%, adjusted RR 1.6, 95% CI 1.6 to 1.7), have a stroke during pregnancy or delivery (difference 0.14%, adjusted RR 6.8, 95% CI 4.7 to 9.8), or have a postpartum stroke (difference 0.04%, adjusted RR 2.1, 95% CI 1.2 to 3.7). Effects were noted as twice as strong among models for ischemic stroke compared to hemorrhagic stroke, given the small numbers. Mediation analysis suggested that hypertensive disorders mediated 21% of stroke risk during pregnancy and delivery and 27% of stroke risk postpartum. Overall, this study demonstrates that migraines significantly increase the risk of stroke in women during and after pregnancy, such that the identification of modifiable risk factors is important in prenatal care.

Carotid Endarterectomy vs Initial Medical Therapy In Asymptomatic Carotid Stenosis

1. Absolute risk reduction of stroke in asymptomatic carotid stenosis was significantly lower than it was two decades ago.

2. Advances in stroke prevention suggest that medical therapy may be an acceptable treatment strategy for this population.

Evidence Rating Level: 2 (Good)

Carotid endarterectomy (CEA) has been shown effective in both asymptomatic and symptomatic patients with carotid stenosis. However, the clinical trials upon which we have relied for this information may not reflect the advances made in primary stroke prevention. For this reason, revascularization may not be the preferred method of intervention among patients with carotid stenosis. This comparative effectiveness study used databases of the U.S. Veterans Affairs to investigate the differences between initial medical therapy and CEA in preventing strokes among patients with asymptomatic carotid stenosis. Patients without a carotid imaging report, those with a history of stroke within six months of index imaging, and those with carotid stenosis of less than 50% or hemodynamically insignificant stenosis were excluded from subsequent analyses. Of the 5,221 patients included, 51.9% received CEA (M [SD] age = 73.6 [6.0] years, 1.2% female) and 48.1% received initial medical therapy (M [SD] age = 73.6 [ 6.0] years, 1.2% female) within one year of the index carotid imaging. Perioperative complications in the form of stroke or death within 30 days among the CEA group was 2.5% (95% CI 2.0 to 3.1). Although the five-year risk of strokes, both fatal and nonfatal, was lower among individuals randomized to CEA compared to initial medical therapy (difference 2.2%, risk difference -2.3%, 95% CI -4.0 to -0.3), differences in risk were not significant when incorporating competing risk of death (risk difference -0.8%, 95% CI -2.1 to 0.5). Among those who met full RCT inclusion criteria, the five-year risk of strokes was 5.5% among the CEA group (95% CI 4.5 to 6.5) and 7.6% among the initial medical therapy group (95% CI 5.7 to 9.5) with a risk difference of -2.1 (95% CI -4.4 to -0.2). Competing risk analysis resulted in a non-significant finding (risk difference -0.9%, 95% CI -2.9 to 0.7). This study highlights that the absolute reduction in stroke risk associated with early CEA was significantly lower than the risk difference from two decades ago, with a lack of significance when competing risks were accounted for. Therefore, improvements in stroke prevention may suggest that medical therapy is an acceptable treatment in patients with asymptomatic carotid stenosis.

Effects of Non-Pharmaceutical Interventions on COVID-19 Cases, Deaths, and Demand For Hospital Services In the UK: A Modelling Study

1. School closures, physical-distancing, shielding older adults ≥70 years, and quarantining symptomatic COVID-19 patients were all likely to reduce the basic reproduction number (R₀).

2. R₀ reductions were insufficient across individual intervention methods to avoid overwhelming healthcare systems.

3. Periods of lockdown was the only intervention to reduce R₀ to ≤1, and projected to be necessary over the majority of the coming year to prevent exceeding healthcare capacity.

Evidence Rating Level: 2 (Good)

Infectious disease models and projections have been essential in determining public policy to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. This age-structured transmission dynamic modelling study conducted in the United Kingdom aimed to determine the potential effects of four control measures for reducing COVID-19 burden through a stochastic, age-structured transmission model: (1) school closures, (2) physical-distancing, (3) shielding of older adults ≥70 years, and (4) quarantining of symptomatic patients. Each of these control measures, as well as in combination, were utilized to project new cases, patients requiring inpatient care, deaths, and the basic reproduction number (R₀). In the United Kingdom, by December 2021, this study projected a median unmitigated burden of 23 million cases and 350,000 COVID-19-related deaths. While each of the four interventions were likely to decrease R₀, which is a critical value in determining actionable steps during this pandemic, these reductions were insufficient to avoid exceeding health service capacity. School closures alone for example, had little effect on projections, despite them being a core part of many national strategies to reduce spread. A combination of these interventions was most effective in reducing R₀ but only periods of lockdown were found to adequately reduce R₀ to ≤1. The strictest of these lockdown periods resulted in an estimated 120,000 cases and 50,000 deaths, significantly lower than the unmitigated projections. Overall, this modelling study suggests that lockdown periods, while detrimental to health in many ways (e.g., psychological), may be necessary for the larger part of the coming year to avoid overwhelming healthcare systems and reducing R₀ to the degree possible.

Effect of Aspirin vs Placebo On the Prevention Of Depression In Older People: A Randomized Clinical Trial

1. Aspirin (100mg daily) was not found to be effective in preventing depression in healthy older adults.

Evidence Rating Level: 2 (Good)

Depression is a common mental health condition, accounting for a significant portion of disability cases in both young and older populations. Due to the confirmed role of immune system function in the pathogenesis of depression, preclinical data suggests that aspirin may serve an antidepressant role. This double-blind, placebo-controlled randomized clinical trial aimed to determine whether or not low-dose aspirin (100mg) could reduce depression risk among healthy older adults, as a substudy within the Aspirin in Reducing Events in the Elderly (ASPREE) trial. Included were Australians aged ≥70 years, U.S. Caucasians ≥65 years, and U.S. Black and Hispanic individuals ≥65 years. These 19,114 participants were randomly assigned to aspirin (100mg daily) or placebo with median (IQR) follow-up of 4.7 (3.5 to 5.6) years. A total of 9,525 were assigned to the aspirin group (M [SD] age = 75.2 [4.0] years) and 9,589 were assigned to the placebo group (M [SD] age = 75.1 [4.5] years). No differences in demographics were found between the groups. Each participant completed the Center for Epidemiologic Studies Depression Scale Revised (CES-D-10; M measurements = 4.2). Those scoring ≥8 did not differ proportionally. Incidence rates of increased CES-D-10 scores to ≥8 was 69.1 per 1,000 person-years in the placebo group and 70.4 per 1,000 person-years in the aspirin group (HR 1.02, 95% CI 0.96 to 1.08, p = 0.54). Overall, this study did not find aspirin to be effective in preventing depression in healthy older adults despite its rationale.

39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial

1. In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature as a threshold for fever is non-inferior to 38·5°C for safety and appeared efficacious.

Evidence Rating Level: 1 (Excellent)

Febrile neutropenia is the most frequent complication of chemotherapy. Currently, the temperature limit defined for children varies across different treatment centres, which may lead to unnecessary medical intervention for patients spontaneously recovering from fever when thresholds are set too low. In this cluster-randomised, multiple crossover, non-blinded, non-inferiority trial, Swiss researchers sought to determine whether a fever threshold of 39•0°C as a fever limit would be non-inferior to 38•5°C in terms of safety. Two hundred and sixty nine patients aged 1 to 18 with a malignancy treated by myelosuppressive chemotherapy were repeatedly randomly assigned to monthly limits of either 39•0°C or 38•5°C ear temperature limits for diagnosis in neutropenia. To assess non-inferiority, the primary outcome was rate of febrile neutropenia with safety relevant events (SRE) per chemotherapy year, with a non-inferiority margin of 1.33 for safety, and a superiority margin of 1.00 for superiority. Following 2547 total randomization periods and 195 chemotherapy years, SREs were diagnosed in 72 (20%) of 360 febrile neutropenia episodes, consisting of 16 ICU admissions, 22 cases of severe sepsis, and 56 cases of bacteremia. In 92 chemotherapy years randomised to the higher fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year), compared to 209 diagnosed episodes (2·03 per year), and 50 cases (24%) with SRE (0·49 per year) in the 38•5°C group. In mixed Poisson regression analysis, the rate ratio of febrile neutropenia was 0.83 when comparing the 39•0°C to the 38•5°C group, with the RR for febrile with SRE at 0.56 (upper limit of 95% CI, 0.72), well within limits of noninferiority. Findings suggest that setting a higher fever limit for children on chemotherapy treatment was both safe and efficacious, which may be recommended as the new standard to prevent unnecessary medical intervention. Further investigation will be needed to improve generalizability of findings however, in different nations and for patients with acute myeloid leukemia or hematopoietic stem cell transplantation.

Image: PD

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