Background and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We... Show moreBackground and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We investigated whetheraddition of these factors would improve the performance of prediction models for the risk ofstroke in women younger than 50 years.MethodsWe used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20–49 years without a history of cardiovasculardisease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportionalhazards models to predict stroke risk were developed, including traditional cardiovascularfactors, and compared with models that additionally included female-specific and psychosocialfactors. We compared the risk models using the c-statistic and slope of the calibration curve at afollow-up of 10 years. We developed an age-specific stroke risk prediction tool that may helpcommunicating the risk of stroke in clinical practice.ResultsWe included 409,026 women with a total of 3,990,185 person-years of follow-up. Strokeoccurred in 2,751 women (incidence rate 6.9 [95% CI 6.6–7.2] per 10,000 person-years).Models with only traditional cardiovascular factors performed poorly to moderately in all agegroups: 20–29 years: c-statistic: 0.617 (95% CI 0.592–0.639); 30–39 years: c-statistic: 0.615(95% CI 0.596–0.634); and 40–49 years: c-statistic: 0.585 (95% CI 0.573–0.597). After addingthe female-specific and psychosocial risk factors to the reference models, the model discrimi-nation increased moderately, especially in the age groups 30–39 (Dc-statistic: 0.019) and 40–49years (Dc-statistic: 0.029) compared with the reference models, respectively.DiscussionThe addition of female-specific factors and psychosocial risk factors improves the discrimina-tory performance of prediction models for stroke in women younger than 50 years. Show less
Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain... Show moreBackground: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association.Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine.Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS >= 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS >= 3 RR: 1.5; 95% CI: 1.0-2.1).Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings. Show less
Meij, A. van der; Walderveen, M.A.A. van; Kruyt, N.D.; Zwet, E.W. van; Liebler, E.J.; Ferrari, M.D.; Wermer, M.J.H. 2020
BackgroundSecondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models... Show moreBackgroundSecondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models, vagus nerve stimulation (VNS) inhibits these detrimental changes and thereby reduces tissue injury. The aim of this study is to investigate whether non-invasive cervical VNS (nVNS) in addition to the current standard treatment can improve penumbral recovery and limit final infarct volume.MethodsNOVIS is a single-center prospective randomized clinical trial with blinded outcome assessment. One hundred fifty patients will be randomly allocated (1:1) within 12h from clinical stroke onset to nVNS for 5 days in addition to standard treatment versus standard treatment alone. The primary endpoint is the final infarct volume on day 5 assessed with MRI.DiscussionWe hypothesize that nVNS will result in smaller final infarct volumes as compared to standard treatment due to improved penumbral recovery. The results of this study will be used to assess the viability and approach to power a larger trial to more definitively assess the clinical efficacy of nVNS after stroke.Trial registrationClinicalTrials.govNCT04050501. Registered on 8 August 2019 Show less
Mulder, I.A.; Li, M.; Vries, T. de; Qin, T.; Yanagisawa, T.; Sugimoto, K.; ... ; Ayata, C. 2020
Objective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We,... Show moreObjective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21,p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle,p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold,p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020 Show less
BackgroundPreeclampsia is a female-specific risk factor for the development of future cardiovascular disease. Whether early preventive cardiovascular disease risk screenings combined with risk... Show moreBackgroundPreeclampsia is a female-specific risk factor for the development of future cardiovascular disease. Whether early preventive cardiovascular disease risk screenings combined with risk-based lifestyle interventions in women with previous preeclampsia are beneficial and cost-effective is unknown.MethodsA micro-simulation model was developed to assess the life-long impact of preventive cardiovascular screening strategies initiated after women experienced preeclampsia during pregnancy. Screening was started at the age of 30 or 40 years and repeated every five years. Data (initial and follow-up) from women with a history of preeclampsia was used to calculate 10-year cardiovascular disease risk estimates according to Framingham Risk Score. An absolute risk threshold of 2% was evaluated for treatment selection, i.e. lifestyle interventions (e.g. increasing physical activity). Screening benefits were assessed in terms of costs and quality-adjusted-life-years, and incremental cost-effectiveness ratios compared with no screening.ResultsExpected health outcomes for no screening are 27.35 quality-adjusted-life-years and increase to 27.43 quality-adjusted-life-years (screening at 30 years with 2% threshold). The expected costs for no screening are euro9426 and around euro13,881 for screening at 30 years (for a 2% threshold). Preventive screening at 40 years with a 2% threshold has the most favourable incremental cost-effectiveness ratio, i.e. euro34,996/quality-adjusted-life-year, compared with other screening scenarios and no screening.ConclusionsEarly cardiovascular disease risk screening followed by risk-based lifestyle interventions may lead to small long-term health benefits in women with a history of preeclampsia. However, the cost-effectiveness of a lifelong cardiovascular prevention programme starting early after preeclampsia with risk-based lifestyle advice alone is relatively unfavourable. A combination of risk-based lifestyle advice plus medical therapy may be more beneficial. Show less
Objectives Compare the predictive performance of Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs) and Systematic COronary Risk Evaluation (SCORE) model between women with and without a... Show moreObjectives Compare the predictive performance of Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs) and Systematic COronary Risk Evaluation (SCORE) model between women with and without a history of hypertensive disorders of pregnancy (hHDP) and determine the effects of recalibration and refitting on predictive performance. Methods We included 29 751 women, 6302 with hHDP and 17 369 without. We assessed whether models accurately predicted observed 10-year cardiovascular disease (CVD) risk (calibration) and whether they accurately distinguished between women developing CVD during follow-up and not (discrimination), separately for women with and without hHDP. We also recalibrated (updating intercept and slope) and refitted (recalculating coefficients) the models. Results Original FRS and PCEs overpredicted 10-year CVD risks, with expected:observed (E:O) ratios ranging from 1.51 (for FRS in women with hHDP) to 2.29 (for PCEs in women without hHDP), while E:O ratios were close to 1 for SCORE. Overprediction attenuated slightly after recalibration for FRS and PCEs in both hHDP groups. Discrimination was reasonable for all models, with C-statistics ranging from 0.70-0.81 (women with hHDP) and 0.72-0.74 (women without hHDP). C-statistics improved slightly after refitting 0.71-0.83 (with hHDP) and 0.73-0.80 (without hHDP). The E:O ratio of the original PCE model was statistically significantly better in women with hHDP compared with women without hHDP. Conclusions SCORE performed best in terms of both calibration and discrimination, while FRS and PCEs overpredicted risk in women with and without hHDP, but improved after recalibrating and refitting the models. No separate model for women with hHDP seems necessary, despite their higher baseline risk. Show less
AimTo provide a comprehensive overview of cardiovascular disease (CVD) risk prediction models for women and models that include female-specific predictors.MethodsWe performed a systematic review of... Show moreAimTo provide a comprehensive overview of cardiovascular disease (CVD) risk prediction models for women and models that include female-specific predictors.MethodsWe performed a systematic review of CVD risk prediction models for women in the general population by updating a previous review. We searched Medline and Embase up to July 2017 and included studies in which; (a) a new model was developed, (b) an existing model was validated, or (c) a predictor was added to an existing model.ResultsA total of 285 prediction models for women have been developed, of these 160 (56%) were female-specific models, in which a separate model was developed solely in women and 125 (44%) were sex-predictor models. Out of the 160 female-specific models, 2 (1.3%) included one or more female-specific predictors (mostly reproductive risk factors). A total of 591 validations of sex-predictor or female-specific models were identified in 206 papers. Of these, 333 (56%) validations concerned nine models (five versions of Framingham, SCORE, Pooled Cohort Equations and QRISK). The median and pooled C statistics were comparable for sex-predictor and female-specific models. In 260 articles the added value of new predictors to an existing model was described, however in only 3 of these female-specific that no competing interests exist. predictors (reproductive risk factors) were added.ConclusionsThere is an abundance of models for women in the general population. Female-specific and sex-predictor models have similar predictors and performance. Female-specific predictors are rarely included. Further research is needed to assess the added value of female-specific predictors to CVD models for women and provide physicians with a well-performing prediction model for women. Show less
