Incident Intracerebral Hemorrhage Research Articles

Risk of stroke in women using levonorgestrel-releasing intra-uterine device (IUD) for contraception.

Background: The commonly used combined hormonal contraceptives with progestins and ethinylestradiol are associated with an increased risk of ischemic stroke (IS). Progestin-only preparations, including levonorgestrel-releasing intra-uterine devices (LG-IUD), are not associated with an increased risk, and in smaller studies, the risk is even reduced. The risk of intracerebral hemorrhage (ICH) has never been investigated. We studied the risk of IS and ICH in women using LG-IUDs compared to women not using hormonal contraceptives. Methods: In this Danish historical cohort study (2004-2021) we followed non-pregnant women (18-49 years) registering incident IS and ICH in relation to use of LG-IUD/non-use of hormonal contraceptives utilizing Danish high-quality registries with nation-wide coverage. Poisson regression models adjusting for age, ethnicity, education, calendar-year, and medication use for risk factors were applied. Results: A total of 1,681,611 non-pregnant women contributed 11,971,745 person-years (py) of observation. Mean age at inclusion was 30.0 years; mean length of follow-up was 7.1 years; 2916 women (24.4 per 100,000 py) had IS; 367 (3.1 per 100,000 py) had ICH. Of these 364,784 were users of LG-IUD contributing 1,720,311 py to the investigation; mean age at start of usage was 34.6 years. Non-users of hormonal contraceptives contributed 10,251,434 py; mean age at inclusion was 30.0 years. Incidence rate of IS/ICH among LG-IUD users was 19.2/3.0 and among non-users it was 25.2/3.1 per 100,000 py. After adjustment incidence rate ratio for IS was 0.78 (CI: 0.70; 0.88), and for ICH it was 0.94 (CI: 0.69; 1.28). Conclusions:Use of LG-IUD was associated with a 22% lower incidence rate of IS without raising incidence rate of ICH. The finding raises the question of whether levonorgestrel, in addition to its contraceptive properties, could have the potential to prevent IS.

Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity

Stroke risk varies by systolic blood pressure (SBP), race, and ethnicity. The association between cumulative mean SBP and incident stroke type is unclear, and whether this association differs by race and ethnicity remains unknown. To examine the association between cumulative mean SBP and first incident stroke among 3 major stroke types-ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)-and explore how these associations vary by race and ethnicity. Individual participant data from 6 US longitudinal cohorts (January 1, 1971, to December 31, 2019) were pooled. The analysis was performed from January 1, 2022, to January 2, 2024. The median follow-up was 21.6 (IQR, 13.6-31.8) years. Time-dependent cumulative mean SBP. The primary outcome was time from baseline visit to first incident stroke. Secondary outcomes consisted of time to first incident IS, ICH, and SAH. Among 40 016 participants, 38 167 who were 18 years or older at baseline with no history of stroke and at least 1 SBP measurement before the first incident stroke were included in the analysis. Of these, 54.0% were women; 25.0% were Black, 8.9% were Hispanic of any race, and 66.2% were White. The mean (SD) age at baseline was 53.4 (17.0) years and the mean (SD) SBP at baseline was 136.9 (20.4) mm Hg. A 10-mm Hg higher cumulative mean SBP was associated with a higher risk of overall stroke (hazard ratio [HR], 1.20 [95% CI, 1.18-1.23]), IS (HR, 1.20 [95% CI, 1.17-1.22]), and ICH (HR, 1.31 [95% CI, 1.25-1.38]) but not SAH (HR, 1.13 [95% CI, 0.99-1.29]; P = .06). Compared with White participants, Black participants had a higher risk of IS (HR, 1.20 [95% CI, 1.09-1.33]) and ICH (HR, 1.67 [95% CI, 1.30-2.13]) and Hispanic participants of any race had a higher risk of SAH (HR, 3.81 [95% CI, 1.29-11.22]). There was no consistent evidence that race and ethnicity modified the association of cumulative mean SBP with first incident stroke and stroke type. The findings of this cohort study suggest that cumulative mean SBP was associated with incident stroke type, but the associations did not differ by race and ethnicity. Culturally informed stroke prevention programs should address modifiable risk factors such as SBP along with social determinants of health and structural inequities in society.

Predictive value of 8-year blood pressure measures in intracerebral hemorrhage risk over 5 years.

The relationships between long-term blood pressure (BP) measures and intracerebral hemorrhage (ICH), as well as their predictive ability on ICH, were unclear. We aimed to investigate the independent associations of multiple BP measures with subsequent 5-year ICH risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. We included 12,398 participants from the China Kadoorie Biobank (CKB) who completed three surveys every four to five years. The following long-term BP measures were calculated: mean, minimum, maximum, standard deviation, coefficient of variation, average real variability, and cumulative BP exposure (cumBP). Cox proportional hazard models were used to examine the associations between these measures and ICH. The potential incremental value of these measures in ICH risk prediction was assessed using Harrell's C statistics, continuous net reclassification improvement (cNRI), and relative integrated discrimination improvement (rIDI). The hazard ratios (95% confidence intervals) of incident ICH associated with per SD increase in cumSBP and cumDBP were 1.62 (1.25, 2.10) and 1.59 (1.23, 2.07), respectively. When cumBP was added to the conventional 5-year ICH risk prediction model, the C-statistic change was 0.009 (-0.001, 0.019), the cNRI was 0.267 (0.070, 0.464), and the rIDI was 18.2% (5.8%, 30.7%). Further subgroup analyses revealed a consistent increase in cNRI and rIDI in men, rural residents, and participants without diabetes. Other long-term BP measures showed no statistically significant associations with incident ICH and generally did not improve model performance. The nearly 10-year cumBP was positively associated with an increased 5-year risk of ICH and could significantly improve risk reclassification for the ICH risk prediction model that included single-point BP measurement.

Abstract TMP79: Magnetic Resonance Imaging Elements Predict Incident Intracerebral Hemorrhage

Introduction: Incident intracerebral hemorrhage (ICH) is an uncommon medical event that can lead to devastating outcomes, including death. Small vessel disease (SVD), as measured by cerebral microbleeds (CMBs) and white matter hyperintensities (WMH), has been associated with risk factors and might be a predictor of incident ICH. CMBs result from irregularities in brain vessel structure due to chronic hypertension and cerebral amyloid angiopathy. These microhemorrhages are a possible risk factor for ICH. Methods: A cohort of ARIC (Atherosclerosis Risk in Communities) participants underwent 3T MRI at visit 5 (2011-2013). CMBs were assessed using a T2* gradient echo. CMBs are homogenous hypointense lesions ≤10 mm in diameter. WMH volumes were derived from FLAIR images using an automated program to measure the volumetric burden of leukoaraiosis. During 10 years of follow-up, incident ICH was noted in 7 (0.4%) out of 1,656 participants were dichotomized based on the presence of CMB and the median of WMH volume. Results: ARIC subjects (n=1656, mean age=76±5 years; 40% men; 26% African American race) underwent MRI. CMBs were present in 385 (23.25%) patients out of 1656. ICH occurred in 0.16% and 1.30% of patients without CMBs and with CMBs, respectively. Kaplan Meier (KM) survival analysis between CMBs and ICH was significant (logrank p=0.002). Cox Regression yielded a significant crude hazards ratio (HR 8.7, 95% CI 1.7-44.7, p=0.010). Adjustment for age, gender, race, and hypertension was also significant (HR 9.9, 95% CI 1.9-52.0, p=0.07). KM survival analysis between WMH median (11.68 cm 3 ) and ICH was significant (logrank p=0.006). Figure 1 displays the KM curves of those with and without CMBs and the incidence of ICH as well as those below and above WMH median and incidence of ICH. Conclusion: CMBs and WMH detected by MRI appear to be an important predictor for the occurrence of incident ICH. Further research is needed to observe if MRI could be used to screen subjects at high-risk for elevated risk of incident ICH.

Lack of association between nonalcoholic fatty liver disease and intracerebral hemorrhage: A community-based cohort study

BackgroundThe association between nonalcoholic fatty liver disease (NAFLD) and intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether NAFLD and its severity predict incident ICH. MethodsParticipants free of other liver diseases, prior stroke, myocardial infarction, cancer, or alcohol abuse in the Kailuan cohort were enrolled in this study. Abdominal ultrasonography was used to diagnose NAFLD and assess its severity. Participants were stratified into different groups including nonfatty liver, mild, moderate and severe NAFLD. Multivariable Cox proportional hazards regression models were used to evaluate the hazard ratios (HRs) and 95% CIs of ICH events in the 11-year follow-up. ResultsA total of 77,461 participants were enrolled in our study. Among them, NAFLD was diagnosed in 23,890 (30.83 %) participants, including 15,581 (20.11 %) with mild NAFLD, 6839 (8.83 %) with moderate NAFLD and 1470 (1.90 %) with severe NAFLD. We documented 692 ICH events during 848,579 person years of follow-up. Patients with more severe NAFLD tended to be older, had higher levels of BMI, higher proportions of hypertension, diabetes and other known risk factors for cerebrovascular disease. However, there was no significant associations between NAFLD, its severity and incident ICH events. Relative to nonfatty liver participants, the HRs for participants with mild NAFLD, moderate and severe NAFLD were 0.98 (95 % CI, 0.80 to 1.20), 1.19 (95 % CI, 0.92 to 1.54) and 1.29 (95 % CI, 0.81 to 2.06), respectively. ConclusionsNAFLD and its severity did not appear to be significantly associated with ICH after adjustment for potential risk factors.

The impact of bilateral brachial-ankle pulse wave velocity difference on cardiovascular disease and all-cause mortality.

This study aims to investigate the association between an elevated bilateral pulse wave velocity difference (BPWVD) and cardiovascular diseases (CVDs) and all-cause mortality. This study included a total of 38,356 participants. A multivariable Cox proportional hazards regression was used to assess the association between high BPWVD and the increased risk of CVDs and all-cause mortality by calculating hazard ratios (HRs) with 95% confidence intervals. A total of 1,213 cases of CVDs were identified over a mean duration of 6.19 years, including 886 cases of cerebral infarction (CI), 105 cases of intracerebral hemorrhage (ICH), and 222 cases of myocardial infarction (MI), along with 1,182 cases of all-cause mortality. The median BPWVD was 42 cm/s (19-80 cm/s). After adjusting for all confounders and baseline brachial-ankle PWV (baPWV), our analysis revealed a significant correlation between a higher risk of CVDs, MI, and all-cause mortality with an increase in BPWVD per standard deviation. HRs (95% confidence interval) were found to be 1.06 (1.01-1.11), 1.11 (1.02-1.21), and 1.07 (1.04-1.10), respectively. Among the participants with higher baPWV on the left side, the HRs (95% confidence interval) were 1.08 (1.02-1.14) for CVDs, 1.27 (1.10-1.46) for incident ICH, 1.16 (1.00-1.24) for incident MI, and 1.10 (1.07-1.15) for all-cause mortality, for per standard deviation increase in BPWVD. Our findings reveal a significant correlation between elevated BPWVD and the risks of developing CVDs and all-cause mortality. This highlights the importance of thoroughly evaluating BPWVD as a means of detecting individuals at risk for CVDs and mortality.

Association between systolic blood pressure variability and severity of cerebral amyloid angiopathy in incident intracerebral hemorrhage

IntroductionThe role of systolic blood pressure (SBP) variability in the pathogenesis of cerebral amyloid angiopathy (CAA) as an underlying cause of intracerebral hemorrhage (ICH) is unknown. We studied SBP variability before ICH according to CAA severity at autopsy.MethodsWe collected office (primary care or hospital clinic) BP readings during 10 years before first-ever ICH onset in adults who died and had brain research autopsy in the Lothian IntraCerebral Hemorrhage, Pathology, Imaging, and Neurological Outcome (LINCHPIN), prospective, population-based, inception cohort study. A neuropathologist assessed CAA severity using a histopathological rating scale, masked to BP readings. Functional principal component analysis was used to model SBP levels by time before ICH, and logistic regression models assessed associations of SBP variability indices with CAA severity (moderate-severe vs. absent-mild) adjusted for age, gender, and mean SBP.ResultsAmong 72 adults (median age 81 [interquartile range 76–86], 56% female, median number of SBP readings 11 [3–19]), patients with moderate-severe CAA had similar mean SBP (143 vs. 145 mmHg, P = 0.588) but lower SBP variability (SBP standard deviation [SD] 14 vs. 17 mmHg, P = 0.033) compared with patients with absent-mild CAA, and their SBP trajectories seemed to differ over 10 years before ICH. The odds of moderate-severe CAA were higher with lower maximum SBP (adjusted OR per 10 mmHg lower: 1.53, 95% confidence interval [CI] 1.09–2.15; P = 0.015) and lower SBP range (1.29 [1.03–1.61]; P = 0.028), but not SBP SD (1.95 [0.87–4.38]; P = 0.11).DiscussionCompared with absent-mild autopsy-verified CAA, moderate-severe CAA is associated with lower maximum and range of pre-morbid SBP.

Modification of green space on the associations between long-term road traffic noise exposure and incident intracerebral hemorrhage: A prospective cohort study

BackgroundIntracerebral hemorrhage (ICH) is a subtype of stroke that would cause high mortality and disability. Environmental factors may play an important role in the incident risk of ICH. Evidence on how long-term road traffic noise exposure affects incident ICH is still scarce, and whether green space has a modification effect is unknown. We conducted a prospective analysis based on UK Biobank to assess the longitudinal association between road traffic noise exposure and incident ICH, and the potential modification of green space. MethodsAlgorithms based on medical records and linkage were utilized to identify ICH incident cases in the UK Biobank. The Common Noise Assessment Methods in Europe noise model was used to calculate the road traffic noise exposure at the residential level. The relationship between weighted average 24-h road traffic noise level (Lden) and incident ICH was assessed using Cox proportional hazard models, and the modification effect of green space was examined using stratified analysis with interaction terms. ResultsOver a median follow-up of 12.5 years, 1 459 incident ICH cases were ascertained in the 402 268 baseline individuals. After adjustment for potential confounders, Lden was significantly related to an elevated risk of incident ICH with a hazard ratio (HR) of 1.14 (95% CI: 1.01, 1.28) for a 10 dB [A] increment. The detrimental influence of Lden on ICH remained stable after adjustment for air pollution. Furthermore, green space modified the association between Lden exposure and incident ICH (Pinteraction = 0.035), and no association was found for higher green space. ConclusionsLong-term residential road traffic noise exposure was associated with an increased risk of ICH, but only for those who live in areas with less green space, indicating that green space may alleviate the negative impacts of road traffic noise exposure on ICH.

Dental Caries a Risk Factor for Intracerebral Hemorrhage

Introduction: Streptococcus mutans is a known cause of dental caries that contains a collagen-binding protein, Cnm, and exhibits inhibition of platelet aggregation and matrix metalloproteinase-9 activation. This strain has been linked to aggravation of experimental intracerebral hemorrhage (ICH) and may be a risk factor for ICH. The purpose of this study was to test the association between dental caries and incident ICH. Methods: The presence of dental caries and periodontal disease was assessed in subjects from the Dental Atherosclerosis Risk in Communities (DARIC) study without prior stroke or ICH. This cohort was followed for incident ICH over a period of 10 years. Cox regression was used to compute crude and adjusted hazards ratio from the dental assessment. Results: Among 6,315 subjects, dental surface caries and/or root caries were recorded in 1,338 (27%) subjects. Of those, 7 (0.5%) had incident ICH over a period of 10 years following the visit 4 assessment. Of the remaining 4,977 subjects, 10 (0.2%) had incident ICH. Those with dental caries versus those without dental caries were slightly younger (mean age 62.0 ± 5.7 vs. 62.4 ± 5.6, p = 0.012), had a greater proportion of males (51 vs. 44%, p < 0.001), African Americans (44 vs. 10%, p < 0.001), and were hypertensive (42 vs. 31%, p < 0.001). The association between caries and ICH was significant (crude HR 2.69, 95% CI 1.02–7.06) and strengthened after adjustment for age, gender, race, education level, hypertension, and periodontal disease (adjusted HR 3.88, 95% CI 1.34–11.24). Conclusion: Dental caries is a potential risk for incident ICH after caries detection. Future studies are needed to determine if treatment of dental caries can reduce the risk of ICH.

March 2023 Stroke Highlights.

March 2023 Stroke Highlights.

A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors. We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years). One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants. We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.

Genetic Risk Score Improves Risk Stratification for Anticoagulation-Related Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the most devastating adverse outcome for patients on anticoagulants. Clinical risk scores that quantify bleeding risk can guide decision-making in situations when indication or duration for anticoagulation is uncertain. We investigated whether integration of a genetic risk score into an existing risk factor-based CRS could improve risk stratification for anticoagulation-related ICH. We constructed 153 genetic risk scores from genome-wide association data of 1545 ICH cases and 1481 controls and validated them in 431 ICH cases and 431 matched controls from the population-based UK Biobank. The score that explained the largest variance in ICH risk was selected and tested for prediction of incident ICH in an independent cohort of 5530 anticoagulant users. A CRS for major anticoagulation-related hemorrhage, based on 8/9 components of the HAS-BLED score, was compared with a combined clinical and genetic risk score incorporating an additional point for high genetic risk for ICH. Among anticoagulated individuals, 94 ICH occurred over a mean follow-up of 11.9 years. Compared with the lowest genetic risk score tertile, being in the highest tertile was associated with a two-fold increased risk for incident ICH (hazard ratio, 2.08 [95% CI, 1.22-3.56]). Although the CRS predicted incident ICH with a hazard ratio of 1.24 per 1-point increase (95% CI [1.01-1.53]), adding a point for high genetic ICH risk led to a stronger association (hazard ratio of 1.33 per 1-point increase [95% CI, 1.11-1.59]) with improved risk stratification (C index 0.57 versus 0.53) and maintained calibration (integrated calibration index 0.001 for both). The new clinical and genetic risk score showed 19% improvement in high-risk classification among individuals with ICH and a net reclassification improvement of 0.10. Among anticoagulant users, a prediction score incorporating genomic information is superior to a clinical risk score alone for ICH risk stratification and could serve in clinical decision-making.

Nonalcoholic fatty liver disease and risk of intracerebral hemorrhage

Background and aimsThis study aimed to investigate the association between the steatosis severity of nonalcoholic fatty liver disease (NAFLD) and future intracerebral hemorrhage (ICH) risk. Methods and resultsWe used data from the Kailuan study. Participants without a history of stroke, myocardial infarction, cancer, other liver diseases or alcohol abuse were enrolled. NAFLD and the severity of liver steatosis were assessed by abdominal ultrasonography. We stratified the participants into different groups according to the severity changes in liver steatosis status across the first 4-year follow-up period. The outcome was the first occurrence of ICH during the next 6-year follow-up period. Hazard ratios (HRs) and 95% CI of ICH were estimated using Cox models adjusted for potential risk factors. A total of 49,906 participants were enrolled in this study. During a median of 6.79 years of follow-up, 193 incident ICH cases were identified. Compared with persistent nonfatty liver participants, the hazard ratios (HRs) for participants with persistent mild steatosis, persistent moderate steatosis, persistent severe steatosis, alleviating steatosis, and aggravating steatosis were 1.28 (95% CI, 0.75–2.18), 2.33 (95% CI, 1.24–4.38), 1.63 (95% CI, 0.22–12.11), 1.41 (95% CI, 0.91–2.18), and 1.37 (95% CI, 0.94–2.00), respectively, in the fully adjusted model. ConclusionsNAFLD with persistent moderate steatosis was significantly related to an increased risk of future ICH, independent of other conventional risk factors.

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Risk of Cerebrovascular Events in Intracerebral Hemorrhage Survivors With Atrial Fibrillation: A Nationwide Cohort Study.

Background:In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF.Methods:We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year.Results:A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up.Conclusions:We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

The Impact of ApoE and FOXO3 Genotype on the Risk of Intracerebral Hemorrhage Among American Men of Japanese Ancestry

This study assessed the impact of APOE e2, e4 minor alleles and the FOXO3 longevity-associated genotype (carrier of SNP rs2802292 “G” allele) on 34-year incidence of intracerebral hemorrhage (ICH). Cox regression models were performed to assess the impact of the APOE e2, e4 and FOXO3 G alleles on the incidence of ICH. A total of 6483 participants were eligible for the analyses. 213 participants developed ICH. Cox-regression model showed neither APOE minor allele vs. common genotype (APOE e3/e3: RR 0.89, 95% CI: 0.64-1.22, p=0.46) nor FOXO3 G carrier status (RR 0.97, 95% CI: 0.72-1.29, p=0.82) was associated with incident ICH. Conversely, both hypertension (RR: 1.46, 95% CI: 1.07-2.00, p=0.02) and low cholesterol level (RR: 0.99, 95% CI: 0.99-1.00, p=0.001) were associated with incident ICH. Carriage of APOE e2 or E4 alleles and the FOXO3 G allele do not appear to impact risk of ICH over 34 years in this cohort.

Incident stroke in patients with Alzheimer’s disease: A meta‐analysis

AbstractBackgroundWe aimed to describe the risk of stroke in patients with Alzheimer´s disease (AD) and to compare it with matched controls without AD.MethodWe conducted a systematic review of all studies reporting incident stroke in AD patients according to the PRISMA guidelines. We included studies which: 1) reported ≥50 patients with a diagnosis of AD; 2) reported a retrospective or prospective follow‐up period; 3) specifically reported the occurrence of ischemic stroke and/or non‐traumatic ICH and/or stroke (all types) during the follow‐up period. We assessed the quality of studies using the Quality Assessment Tool for Observational Cohort and Cross‐Sectional Studies provided by the National Heart, Lung and Blood Institute. Using random effects meta‐analyses, we pooled the incidence rates and incidence rate ratios (IRR) of ischemic stroke, intracerebral hemorrhage (ICH) and stroke (all types) in AD patients.ResultTwenty‐nine (29) articles reporting incident ischemic stroke and/or incident ICH and/or incident stroke (all types) in patients with AD and were included in the meta‐analyses. The majority of studies was judged to have a fair quality. In patients with AD the incidence rates were 13.0 per 1000 person‐years for ischemic stroke, 3.4 per 1000 person‐years for ICH and 15.4 per 1000 person years for stroke (all types). When compared to matched controls without AD, incidence rate for ICH in AD patients was significantly higher (IRR 1.67, 95%CI 1.43‐1.96), but similar for ischemic stroke. Significant study heterogeneity was found in the meta‐analyses of incidence rates of ischemic stroke and stroke (all types) and moderate for studies reporting ICH.ConclusionIncident stroke is not a rare event in AD population. AD is associated with an increased risk of ICH which warrants further clarification. The significant risk of bias and heterogeneity among the studies, as well as the lack of information on possible confounding variables, does warrant the need for better quality studies on the overlap of the two neurological disorders with the highest disease burden worldwide.

Risk of cerebrovascular events in intracerebral haemorrhage survivors with atrial fibrillation: the Danish Stroke Registry

Abstract Background In patients with atrial fibrillation (AF), who have suffered an intracerebral haemorrhage (ICH), the optimal stroke prevention strategy is unclear. The PRESTIGE-AF trial is a multinational randomized controlled trial designed to investigate the optimal stroke prevention strategy in patients with AF who have recently suffered an ICH. Until the results of the PRESTIGE-AF trial becomes available, data on the risk of future cerebrovascular events in AF patient surviving an ICH are important to gain knowledge on the risk in this patient group and to support the clinician in this challenging situation. Purpose To investigate the risk of cerebrovascular events in a study population of ICH survivors with AF resembling the expected trial population of the PRESTIGE-AF trial. Methods We used the Danish nationwide registries to identify all patients presenting with incident ICH and prevalent AF between 2003–2018. To resemble the expected trial population of the PRESTIGE-AF trial, key inclusion and exclusion criteria of the PRESTIGE-AF trial were applied [Flowchart]. Patients were followed for up to one year in the Danish Stroke Registry, and outcomes (recurrent ICH, cerebrovascular ischaemic event, and all-cause death) were reported according to initiation/resumption of oral anticoagulant therapy (OAC) during follow-up. Results A total of 1,885 patients were included in the study. At one year after the incident ICH, we observed 40 recurrent ICH, 63 cerebrovascular ischaemic events, 88 all strokes, and 650 all-cause deaths [Figure]. When splitting the follow-up period according to initiation/resumption of OAC during follow-up, 526 patients initiated/resumed OAC during follow-up. The median time to initiation/resumption of OAC was 5.3 months (IQR: 1.1–12.0). For the subpopulation of patients not initiating/resuming OAC during follow-up, we observed a 2.6% risk of cerebrovascular ischaemic events, a 1.5% risk of recurrent ICH, and a 30.3% risk of all-cause death at one year after the incident ICH. For the subpopulation of patients initiating/resuming OAC during follow-up, we observed a 2.8% risk of recurrent ICH, a 3.2% risk of cerebrovascular ischaemic events, and a 22.0% risk of all-cause death at one year after the incident ICH. Conclusion In this observational cohort study, we identified a population of ICH survivors with concomitant AF mirroring the expected PRESTIGE-AF trial population. One year after the incident ICH, we observed more cerebrovascular ischaemic events than recurrent ICH events, which was also evident for the subpopulation of patients initiating/resuming OAC during follow-up. The results of the PRESTIGE-AF trial are warranted to determine optimal stroke prevention among ICH survivors with concomitant AF. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study has received funding from the European Union's Horizon 2020 research and innovation programme. FlowchartFigure

Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage.

Fibroblast growth factor 23 (FGF23) is an osteogenic hormone associated with chronic kidney disease and is an emerging risk factor for several cardiovascular diseases. The association of FGF23 with stroke is unclear. The aim of this study was to investigate the association of FGF23 with incident intracerebral hemorrhage (ICH). This was a nested case-control study of 220 ICH cases and 244 age- and sex-matched controls from the population-based Malmö Diet and Cancer Study (n=28,449). Incident ICH cases were ascertained using national registers and classified by bleeding location. Logistic regression was used to study the association of plasma levels of FGF23 with incident ICH, adjusting for potential ICH risk factors. Subgroup analyses were performed for lobar and non-lobar ICH, fatal ICH, ICH with large volume and ICH with poor functional outcome, respectively. Higher FGF23 levels at baseline were significantly associated with incident ICH. After multivariable adjustment, the odds ratio for the association with all ICH was 1.84 (95% confidence interval [CI] 1.25-2.71, p=0.002) per doubling of FGF23 concentration. For lobar and non-lobar ICH, odds ratios were 1.73 (95% CI 1.04-2.87, p=0.035) and 2.13 (95% CI 1.32-3.45, p=0.002), respectively. FGF23 was also significantly associated with fatal ICH, ICH with large volume and ICH with poor functional outcome. Higher FGF23 was associated with incident ICH in this nested case-control study. Further studies are required to explore whether the association is causal.

Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage.

Background: Growth differentiation factor 15 (GDF-15) has been associated with the risk of developing major bleedings, including but not restricted to intracranial hemorrhages, in patients on oral anticoagulants or dual antiplatelet therapy. We hypothesized that there may be an association of GDF-15 with incidence of hemorrhagic strokes in the general population, which has not been investigated before.Methods: Two different case-control studies, one for intracerebral hemorrhage (ICH) and one for subarachnoid hemorrhage (SAH), nested within the population-based Malmö Diet and Cancer cohort, were defined using the incidence density sampling method. GDF-15 was analyzed in frozen blood samples taken at the baseline examination in 1991–1996. The associations between GDF-15 and incident ICH (220 cases, 244 controls) and incident SAH (79 cases, 261 controls), respectively, were explored using conditional logistic regression adjusting for risk factors.Results: GDF-15 levels at baseline were higher in both incident ICH and SAH cases, compared with their respective control subjects. After adjustment for risk factors, significant relationships with high GDF-15 concentrations were observed both for incident ICH (odds ratio (OR) per 1 log2 unit: 2.27, 95% confidence interval (CI): 1.52–3.41; P = 7.1 × 10−5) and incident SAH (OR: 2.16, 95% CI: 1.29–3.59; P = 0.0032).Conclusions: High circulating GDF-15 levels were associated with incident ICH and incident SAH, independently of the main risk factors.