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Aims: Previous studies show a reduced incidence of first myocardial infarction and stroke 1-3 months after influenza vaccination, but it is unclear how underlying cardiovascular risk impacts the association., Methods and Results: The study used linked Clinical Practice Research Datalink, Hospital Episode Statistics Admitted Patient Care and Office for National Statistics mortality data from England between 1 September 2008 and 31 August 2019. From the data, individuals aged 40-84 years with a first acute cardiovascular event and influenza vaccination occurring within 12 months of each September were selected. Using a self-controlled case series analysis, season-adjusted cardiovascular risk stratified incidence ratios (IRs) for cardiovascular events after vaccination compared with baseline time before and >120 days after vaccination were generated. 193 900 individuals with a first acute cardiovascular event and influenza vaccine were included. 105 539 had hypertension and 172 050 had a QRISK2 score ≥10%. In main analysis, acute cardiovascular event risk was reduced in the 15-28 days after vaccination [IR 0.72 (95% CI 0.70-0.74)] and, while the effect size tapered, remained reduced to 91-120 days after vaccination [0.83 (0.81-0.88)]. Reduced cardiovascular events were seen after vaccination among individuals of all age groups and with raised and low cardiovascular risk., Conclusions: Influenza vaccine may offer cardiovascular benefit among individuals at varying cardiovascular risk. Further studies are needed to characterize the populations who could derive the most cardiovascular benefits from vaccination., Competing Interests: Conflict of interest: A.B. has received grants from Astra Zeneca, UK Research and Innovation (UKRI), British Medical Association and the NIHR. C.W.-G. has received speaker fees from Sanofi Pasteur and participated in a Data Safety Monitoring Board for an investigator-led trial of the effect of influenza vaccination after heart attack on future cardiovascular prognosis (NCT02831608) from January 2019 to April 2020. H.I.M is funded by the National Institute for Health Research (NIHR) Health Protection Research Unit in Vaccines and Immunisation was an invited expert to the Commission on Human Medicines (CHM) COVID-19 Vaccine Safety Surveillance Methodologies Expert Working Group. I.D. has received unrestricted research grants from Glaxo Smith Kline. C.L. has received lecturer fees from Astra Zeneca and participated in a Data Safety Monitoring Board for the Université de Clermont-Ferrand (NCT03892148). J.A.D is funded by the British Heart Foundation through the grant received by C.W.-G. E.H. is funded by a NIHR postdoctoral fellowship. All other authors declare no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF)., Methods: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications., Results: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses., Conclusions: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs., Competing Interests: Competing interests: LS reports grants from Wellcome, Medical Research Council, National Institute of Health Research, Glaxo Smith Kline, the British Heart Foundation and Diabetes UK, outside the submitted work and is a Trustee of the British Heart Foundation. CW-G reports grants from Wellcome, during the conduct of the study and grants from British Heart Foundation and the Alzeinher’s Society, outside the submitted work. SLC, EP, AYW and KW have nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

BackgroundSeveral studies have investigated a possible association between respiratory infection and acute myocardial infarction (MI). As both influenza and pneumococcal infections are vaccine preventable, understanding the populations affected by virus-induced cardiovascular complications is important to guide public health and clinical practice.AimThis observational study aimed to quantify the association between laboratory-confirmed respiratory bacteria or virus infections and risk of first MI or stroke, by using self-controlled case series (SCCS) analysis of anonymised linked electronic Danish health records.MethodsThe SCCS method was used to determine the relative incidence of the first event of MI and stroke occurring within 28 days after laboratory-confirmed respiratory infections compared with the baseline time period.ResultsIn the age and season adjusted analyses for first acute MI, the incidence ratios (IR) of a MI event occurring during the risk period were significantly elevated following a Streptococcus pneumoniae infection with values of 20.1, 11.0 and 4.9 during 1-3, 4-7 and 8-14 days, respectively and following respiratory virus infection with values of 15.2, 4.5 and 4.4 during 1-3, 8-14 and 15-28 days, respectively. The significantly elevated IRs for stroke following an S. pneumoniae infection were 25.5 and 6.3 during 1-3 and 8-14 days, respectively and following respiratory virus infection 8.3, 7.8 and 6.2 during 1-3, 4-7 and 8-14 days, respectively.ConclusionThis study suggested a significant cardiovascular event triggering effect following infection with S. pneumoniae and respiratory viruses (mainly influenza), indicating the importance of protection against vaccine-preventable respiratory infections.

Introduction: The UK has over 1.2 million stroke survivors. Stroke is a major risk factor for dementia, and along with other risk factors such as hypertension and diabetes, is more common among Black, Asian and other ethnic minorities (BAME). We aimed to explore whether diagnosed dementia differed by ethnicity among adult stroke survivors., Methodology: Using the UK Clinical Practice Research Datalink and linked hospital data, we conducted a cohort study among patients aged ≥40 years who had an incident stroke between 2005 and 2016. We fitted multivariable Cox proportional hazard models to estimate ethnic differences in the risk of poststroke dementia, adjusting for major clinical and social confounders., Results: Our cohort comprised 45 474 stroke survivors (mean age 72.6 years, 49% female), of whom 95.7% were White, 2.0% South Asian, 1.2% Black and 1.1% of Mixed/Other ethnicity. Of these, 4624 (10.2%) were diagnosed with poststroke dementia over a median follow-up of 3.26 years. Compared with the White ethnic group, those of Black ethnicity were 42% more likely to be diagnosed with dementia (adjusted HR 1.42, 95% CI 1.05 to 1.93). There was no association between any other ethnic group and poststroke dementia diagnosis., Discussion: There was good evidence that those of Black ethnicity had higher risk of diagnosed dementia poststroke. Further understanding of the mechanisms of this relationship could help target interventions at communities most at risk of dementia poststroke., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Cardiovascular diseases (CVDs) are among the leading causes of death globally. Electronic health records (EHRs) provide a rich data source for research on CVD risk factors, treatments and outcomes. Researchers must be confident in the validity of diagnoses in EHRs, particularly when diagnosis definitions and use of EHRs change over time. Our systematic review provides an up-to-date appraisal of the validity of stroke, acute coronary syndrome (ACS) and heart failure (HF) diagnoses in European primary and secondary care EHRs., Methods and Analysis: We will systematically review the published and grey literature to identify studies validating diagnoses of stroke, ACS and HF in European EHRs. MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library, OpenGrey and EThOS will be searched from the dates of inception to April 2019. A prespecified search strategy of subject headings and free-text terms in the title and abstract will be used. Two reviewers will independently screen titles and abstracts to identify eligible studies, followed by full-text review. We require studies to compare clinical codes with a suitable reference standard. Additionally, at least one validation measure (sensitivity, specificity, positive predictive value or negative predictive value) or raw data, for the calculation of a validation measure, is necessary. We will then extract data from the eligible studies using standardised tables and assess risk of bias in individual studies using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data will be synthesised into a narrative format and heterogeneity assessed. Meta-analysis will be considered when a sufficient number of homogeneous studies are available. The overall quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation tool., Ethics and Dissemination: This is a systematic review, so it does not require ethical approval. Our results will be submitted for peer-review publication., Prospero Registration Number: CRD42019123898., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Herpesviruses induce a range of inflammatory effects potentially contributing to an increased risk of stroke., Objectives: To investigate whether patients with infection, or reactivation of, human herpesviruses are at increased stroke risk, compared to those without human herpesviruses., Data Sources: Six medical databases and grey literature sources from inception to January 2017., Study Eligibility Criteria: Studies where the exposure was any human herpesvirus and the outcome was stroke. We included randomised controlled trials, cohort, case-control, case-crossover and self-controlled case series designs., Methods: Meta-analyses when sufficiently homogeneous studies were available. Quality of evidence across studies was assessed., Results: We identified 5012 publications; 41 met the eligibility criteria. Across cohort and self-controlled case series studies, there was moderate quality evidence that varicella infection in children was associated with a short-term increased stroke risk. Zoster was associated with a 1.5-fold increased stroke risk four weeks following onset (summary estimate: 1.55, 95%CI 1.46-1.65), which resolved after one year. Subgroup analyses suggested post-zoster stroke risk was greater among ophthalmic zoster patients, younger individuals and those not prescribed antivirals. Recent infection/reactivation of cytomegalovirus and herpes simplex viruses, but not past infection, was associated with increased stroke risk; however the evidence across studies was mainly derived from small, very low quality case-control studies., Conclusions: Our review shows an increased stroke risk following zoster and suggests that recent infection or reactivation of other herpesviruses increases stroke risk, although better evidence is needed. Herpesviruses are common and potentially preventable; these findings may have implications for reducing stroke burden., Competing Interests: The authors have declared that no competing interests exist.

Routine data from electronic health records (EHRs) provide insights into links between herpes zoster (HZ) and cardiovascular complications such as stroke or myocardial infarction (MI) in different populations worldwide. Evidence from large EHR studies using both self-controlled case series and traditional cohort designs suggests that there is a transient increase in the risk of stroke after HZ, which gradually resolves over 6-12 months. In these studies, herpes zoster ophthalmicus was associated with a higher risk of stroke than HZ at other sites. A larger effect size was seen in people aged under 40 years. Existing studies also suggest that HZ may have a triggering effect on MI, although fewer studies examined this outcome. Further evidence is needed on the effectiveness and cost-effectiveness of vaccine and antiviral drugs to reduce cardiovascular complications after HZ from studies that are designed to minimize selection biases and confounding by indication.

Background: Acute respiratory infections are associated with increased risk of myocardial infarction (MI) and stroke; however, the role of different organisms is poorly characterized., Methods: Time-series analysis of English hospital admissions for MI and stroke (age-stratified: 45-64, 65-74, ≥75 years), laboratory-confirmed viral respiratory infections, and environmental data for 2004-2015. Weekly counts of admissions were modeled using multivariable Poisson regression with weekly counts of respiratory viruses (influenza, parainfluenza, rhinovirus, respiratory syncytial virus [RSV], adenovirus, or human metapneumovirus [HMPV]) investigated as predictors. We controlled for seasonality, long-term trends, and environmental factors., Results: Weekly hospital admissions in adults aged ≥45 years averaged 1347 (interquartile range [IQR], 1217-1541) for MI and 1175 (IQR, 1023-1395) for stroke. Respiratory infections ranged from 11 cases per week (IQR, 5-53) for influenza to 55 (IQR, 7-127) for rhinovirus. In the adjusted models, all viruses except parainfluenza were significantly associated with MI and ischemic stroke admissions in those aged ≥75. Among 65- to 74-year-olds, adenovirus, rhinovirus, and RSV were associated with MI but not ischemic stroke admissions. Respiratory infections were not associated with MI or ischemic stroke in people aged 45-64 years, nor with hemorrhagic stroke in any age group. An estimated 0.4%-5.7% of MI and ischemic stroke admissions may be attributable to respiratory infection., Conclusions: We identified small but strongly significant associations in the timing of respiratory infection (with HMPV, RSV, influenza, rhinovirus, and adenovirus) and MI or ischemic stroke hospitalizations in the elderly., Clinical Trials Registration: NCT02984280.

While acute respiratory tract infections can trigger cardiovascular events, the differential effect of specific organisms is unknown. This is important to guide vaccine policy.Using national infection surveillance data linked to the Scottish Morbidity Record, we identified adults with a first myocardial infarction or stroke from January 1, 2004 to December 31, 2014 and a record of laboratory-confirmed respiratory infection during this period. Using self-controlled case series analysis, we generated age- and season-adjusted incidence ratios (IRs) for myocardial infarction (n=1227) or stroke (n=762) after infections compared with baseline time.We found substantially increased myocardial infarction rates in the week after Streptococcus pneumoniae and influenza virus infection: adjusted IRs for days 1-3 were 5.98 (95% CI 2.47-14.4) and 9.80 (95% CI 2.37-40.5), respectively. Rates of stroke after infection were similarly high and remained elevated to 28 days: day 1-3 adjusted IRs 12.3 (95% CI 5.48-27.7) and 7.82 (95% CI 1.07-56.9) for S. pneumoniae and influenza virus, respectively. Although other respiratory viruses were associated with raised point estimates for both outcomes, only the day 4-7 estimate for stroke reached statistical significance.We showed a marked cardiovascular triggering effect of S. pneumoniae and influenza virus, which highlights the need for adequate pneumococcal and influenza vaccine uptake. Further research is needed into vascular effects of noninfluenza respiratory viruses., Competing Interests: Conflict of interest: H. Whitaker has received grants from the MRC (methodology grant MR/L009005/1) and IMI/EFPIA (ADVANCE), outside the submitted work., (Copyright ©ERS 2018.)

Introduction: After primary infection, human herpesviruses establish latency and persist lifelong. Periodic virus reactivation can lead to serious inflammatory complications. Recent research suggests that herpesvirus reactivation may also be linked to acute stroke. An improved understanding of this relationship is vital to inform public health prevention strategies. We will review the evidence regarding the role of human herpesviruses in triggering stroke., Methods and Analysis: A systematic literature review of published and grey literature studies with a human herpesvirus (infection or reactivation) as an exposure and stroke as an outcome will be carried out. Randomised controlled trials, cohort, case-control, case crossover and self-controlled case series designs will be eligible; no restrictions will be placed on publication status, language and geographical or healthcare setting. The Cochrane Central Register of Controlled Trials, Embase, Global Health, Medline, Scopus and Web of Science will be searched from dates of inception to January 2017. A prespecified search strategy of medical subject headings and free text terms (in the title and abstract) for human herpesviruses AND stroke will be used. Two reviewers will independently screen titles and abstracts for eligible studies, followed by full-text screening. The reviewers will then extract data from the eligible studies using standardised, pilot-tested tables and assess risk of bias in individual studies, in line with the Cochrane Collaboration approach. The data will be synthesised in a narrative format, and meta-analyses considered where there are sufficient data. Quality of evidence will be assessed in line with theGrading of Recommendations, Assessment, Development and Evaluation (GRADE) approach., Ethics and Dissemination: As this is a systematic review, ethical approval is not required. The results will be submitted for peer-review publication and presented at national conferences. A lay and short summary will be disseminated on appropriate webpages., Prospero Registration Number: CRD42017054502., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background Associations between human herpesviruses (HHVs) and cardiovascular disease/mortality have been reported, but evidence is inconsistent. We investigated associations between 3 common herpesviruses and (1) incident stroke or myocardial infarction (MI) and (2) all-cause mortality. Methods We included participants from the UK Biobank Infectious Disease pilot study with valid serum antibody (IgG) measurements taken at cohort entry (2006–2010) for herpes simplex virus type 1 (HSV1), varicella zoster virus (VZV), and cytomegalovirus (CMV). Linked hospital and mortality records up to December 30 2019 provided information on rates of (1) incident first stroke or MI and (2) all-cause mortality. Hazard ratios (HRs) from Cox proportional hazards regression models were used to assess relationships between (1) HHV seropositivity, (2) HHV titer and incident stroke/MI, and death outcomes. Fully adjusted models accounted for sociodemographic information (age, sex, ethnicity, education, deprivation quintile, birthplace, population density), baseline comorbidities (including diabetes and hypertension), smoking status, body mass index, and serum cholesterol. Results Of 9429 study participants (56% female, 95% White, median age 58 years), 41% were seropositive for all 3 HHVs. Human herpesvirus seropositivity was not associated with stroke/MI (fully adjusted HRs and 95% confidence intervals [CIs]: HSV1 = 0.93 [CI, 0.72–1.22], VZV = 0.78 [CI, 0.51–1.20], CMV = 0.91 [CI, 0.71–1.16]) or all-cause mortality (HSV1 = 1.21 [CI, 1.00–1.47], VZV = 0.79 [CI, 0.58–1.07], CMV = 0.90 [CI, 0.76–1.06]). Human herpesvirus titers were not associated with outcomes. Conclusions In this mostly White UK Biobank subset, neither HHV seropositivity nor titers were associated with stroke/MI or all-cause mortality. [ABSTRACT FROM AUTHOR]

Background: Electronic health records are widely used in cardiovascular disease research. We appraised the validity of stroke, acute coronary syndrome and heart failure diagnoses in studies conducted using European electronic health records. Methods: Using a prespecified strategy, we systematically searched seven databases from dates of inception to April 2019. Two reviewers independently completed study selection, followed by partial parallel data extraction and risk of bias assessment. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value estimates were narratively synthesized and heterogeneity between sensitivity and PPV estimates were assessed using I2. Results: We identified 81 studies, of which 20 validated heart failure diagnoses, 31 validated acute coronary syndrome diagnoses with 29 specifically recording estimates for myocardial infarction, and 41 validated stroke diagnoses. Few studies reported specificity or negative predictive value estimates. Sensitivity was ≤ 66% in all but one heart failure study, ≥ 80% for 91% of myocardial infarction studies, and ≥ 70% for 73% of stroke studies. PPV was ≥ 80% in 74% of heart failure, 88% of myocardial infarction, and 70% of stroke studies. PPV by stroke subtype was variable, at ≥ 80% for 80% of ischaemic stroke but only 44% of haemorrhagic stroke. There was considerable heterogeneity (I2 > 75%) between sensitivity and PPV estimates for all diagnoses. Conclusion: Overall, European electronic health record stroke, acute coronary syndrome and heart failure diagnoses are accurate for use in research, although validity estimates for heart failure and individual stroke subtypes were lower. Where possible, researchers should validate data before use or carefully interpret the results of previous validation studies for their own study purposes. [ABSTRACT FROM AUTHOR]

Background: The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction. Methods: We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006–2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 329 community-dwelling participants from Finland (baseline 1986–2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and death registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk. Results: In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the type of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36–9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40–1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82–10.03] during the first month; HR, 1.41 [95% CI, 1.34–1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort. Conclusions: Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded. [ABSTRACT FROM AUTHOR]