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Journal of the American Heart... Feb 2024There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin low-density lipoprotein-cholesterol (LDL-C)- and triglyceride-lowering therapies.
METHODS AND RESULTS
We performed a systematic review of large randomized clinical trials (≥1000 patients with ≥2 years follow-up) of LDL-C-lowering therapy (statin, ezetimibe, and PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitor) and triglyceride-lowering therapy (omega-3 supplements and fibrate) that reported hemorrhagic stroke as an outcome. We searched MEDLINE, Embase, and Cochrane Library up to July 2, 2021 and updated a meta-analysis of cardiovascular statin trials published in 2012. Among our several subgroup analyses, we looked at difference depending on stroke status and also depending on age. We identified 37 trials for LDL-C lowering (284 301 participants) and 11 for triglyceride lowering (120 984 participants). Overall, we found a higher risk of hemorrhagic stroke for LDL-C lowering, risk ratio (RR) 1.16 (95% CI, 1.01-1.32, =0.03). For statins (33 trials, 216 258 participants), RR=1.17 (95% CI, 1.01-1.36); for PCSK-9 inhibitors (2 trials, 46 488 participants), RR=0.86 (95% CI, 0.43-1.74); and for ezetimibe (2 trials, 21 555 participants), RR=1.14 (95% CI, 0.64-2.03). In statin trials of patients with previous stroke/transient ischemic attack, RR was 1.46 (95% CI, 1.05-2.04), and in trials with mean age ≥65 years old, RR=1.34 (95% CI, 1.04-1.73) (=0.14 and =0.23 respectively); for triglyceride lowering (11 trials, 120 984 participants), RR=1.05 (95% CI, 0.86-1.30).
CONCLUSIONS
We found evidence for a small increased risk of hemorrhagic stroke events with LDL-C-lowering therapies but no clear evidence for triglyceride-lowering therapies.
REGISTRATION
URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021275363.
Topics: Humans; Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Cholesterol, LDL; Hemorrhagic Stroke; Cardiovascular Diseases; Randomized Controlled Trials as Topic; Ezetimibe; Stroke; Triglycerides
PubMed: 38323514
DOI: 10.1161/JAHA.123.030714 -
Chinese Medical Journal Jun 2023There is still uncertainty regarding whether diabetes mellitus (DM) can adversely affect patients undergoing carotid endarterectomy (CEA) for carotid stenosis. The aim... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There is still uncertainty regarding whether diabetes mellitus (DM) can adversely affect patients undergoing carotid endarterectomy (CEA) for carotid stenosis. The aim of the study was to assess the adverse impact of DM on patients with carotid stenosis treated by CEA.
METHODS
Eligible studies published between 1 January 2000 and 30 March 2023 were selected from the PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials databases. The short-term and long-term outcomes of major adverse events (MAEs), death, stroke, the composite outcomes of death/stroke, and myocardial infarction (MI) were collected to calculate the pooled effect sizes (ESs), 95% confidence intervals (CIs), and prevalence of adverse outcomes. Subgroup analysis by asymptomatic/symptomatic carotid stenosis and insulin/noninsulin-dependent DM was performed.
RESULTS
A total of 19 studies (n = 122,003) were included. Regarding the short-term outcomes, DM was associated with increased risks of MAEs (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 5.1%), death/stroke (ES = 1.61, 95% CI: [1.13-2.28], prevalence = 2.3%), stroke (ES = 1.55, 95% CI: [1.16-1.55], prevalence = 3.5%), death (ES = 1.70, 95% CI: [1.25-2.31], prevalence =1.2%), and MI (ES = 1.52, 95% CI: [1.15-2.01], prevalence = 1.4%). DM was associated with increased risks of long-term MAEs (ES = 1.24, 95% CI: [1.04-1.49], prevalence = 12.2%). In the subgroup analysis, DM was associated with an increased risk of short-term MAEs, death/stroke, stroke, and MI in asymptomatic patients undergoing CEA and with only short-term MAEs in the symptomatic patients. Both insulin- and noninsulin-dependent DM patients had an increased risk of short-term and long-term MAEs, and insulin-dependent DM was also associated with the short-term risk of death/stroke, death, and MI.
CONCLUSIONS
In patients with carotid stenosis treated by CEA, DM is associated with short-term and long-term MAEs. DM may have a greater impact on adverse outcomes in asymptomatic patients after CEA. Insulin-dependent DM may have a more significant impact on post-CEA adverse outcomes than noninsulin-dependent DM. Whether DM management could reduce the risk of adverse outcomes after CEA requires further investigation.
Topics: Endarterectomy, Carotid; Humans; Carotid Stenosis; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Risk Factors
PubMed: 37334731
DOI: 10.1097/CM9.0000000000002730 -
BMC Emergency Medicine Jun 2022The worldwide burden of stroke remains high, with increasing time-to-treatment correlated with worse outcomes. Yet stroke subtype determination, most importantly between... (Review)
Review
BACKGROUND
The worldwide burden of stroke remains high, with increasing time-to-treatment correlated with worse outcomes. Yet stroke subtype determination, most importantly between stroke/non-stroke and ischemic/hemorrhagic stroke, is not confirmed until hospital CT diagnosis, resulting in suboptimal prehospital triage and delayed treatment. In this study, we survey portable, non-invasive diagnostic technologies that could streamline triage by making this initial determination of stroke type, thereby reducing time-to-treatment.
METHODS
Following PRISMA guidelines, we performed a scoping review of portable stroke diagnostic devices. The search was executed in PubMed and Scopus, and all studies testing technology for the detection of stroke or intracranial hemorrhage were eligible for inclusion. Extracted data included type of technology, location, feasibility, time to results, and diagnostic accuracy.
RESULTS
After a screening of 296 studies, 16 papers were selected for inclusion. Studied devices utilized various types of diagnostic technology, including near-infrared spectroscopy (6), ultrasound (4), electroencephalography (4), microwave technology (1), and volumetric impedance spectroscopy (1). Three devices were tested prior to hospital arrival, 6 were tested in the emergency department, and 7 were tested in unspecified hospital settings. Median measurement time was 3 minutes (IQR: 3 minutes to 5.6 minutes). Several technologies showed high diagnostic accuracy in severe stroke and intracranial hematoma detection.
CONCLUSION
Numerous emerging portable technologies have been reported to detect and stratify stroke to potentially improve prehospital triage. However, the majority of these current technologies are still in development and utilize a variety of accuracy metrics, making inter-technology comparisons difficult. Standardizing evaluation of diagnostic accuracy may be helpful in further optimizing portable stroke detection technology for clinical use.
Topics: Emergency Medical Services; Humans; Intracranial Hemorrhages; Stroke; Time-to-Treatment; Triage
PubMed: 35710360
DOI: 10.1186/s12873-022-00663-z -
Journal of the American Heart... Oct 2023BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants...
BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations.
Topics: Humans; Coronary Artery Disease; Diabetes Mellitus, Type 2; Mendelian Randomization Analysis; Risk Factors; Stroke; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37804188
DOI: 10.1161/JAHA.122.029040 -
Journal of Stroke and Cerebrovascular... Apr 2024Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention.
BACKGROUND
PCSK9i reduce low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (LpA) levels. Their efficacy in reducing the risk of major cardiovascular events has been shown in multiple randomized clinical trials (RCT). However, clinical equipoise remains on the magnitude and mechanisms by which PCSK9i decrease the risk of stroke.
METHODS
We performed a systematic search of biomedical databases from inception to January 15, 2024, to identify RCTs that investigated the efficacy of PCSK9i versus placebo for major cardiovascular event prevention. The primary outcome was total stroke. The safety outcome was the risk of adverse neurological events, as defined by each trial. Effect size was represented by risk ratio (RR), and analysis was done using random-effects meta-analysis. Heterogeneity was assessed by I and Cochrane Q statistics. Meta-regression analyses were performed to assess the association between LDL-C and LpA reduction and stroke risk.
RESULTS
Overall, 20 studies with 93,093 patients were included. The quality of the evidence was moderate and heterogeneity for all comparisons was low (I < 25 %). The mean age was 60.1 years for the PCSK9i group and 59.6 years for the placebo group, with a mean follow-up time of 60.1 weeks. PCSK9i reduced the LDL-C levels by 11 % and LpA levels by 8 %. PCSK9i were associated with a significant reduction in stroke risk (RR 0.75, 95 % CI 0.66-0.86, I = 0 %), without an increase in mortality (RR 0.97, 95 % CI 0.87-1.08, I = 0 %). The risk of adverse neurological events was similar between groups (RR 0.99, 95 % CI 0.84-1.18, I = 11 %). In meta-regression analyses, the stroke risk was not associated with the magnitude of the effect of PCSK9i on LDL-C (LDL C β = -0.01, 95 % CI = -0.03-0.02) and LpA (β = -0.01, 95 % CI = -0.06-0.04) levels.
CONCLUSIONS
PCSK9i significantly reduced the stroke risk, without increasing mortality or the risk of adverse neurological events. Our findings also suggest that the beneficial effect of PCSK9i on stroke risk is mediated by LDL-C- and LpA-independent mechanisms.
Topics: Humans; Middle Aged; PCSK9 Inhibitors; Cholesterol, LDL; Antibodies, Monoclonal, Humanized; Stroke; Anticholesteremic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Proprotein Convertase 9
PubMed: 38336118
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107633 -
PloS One 2021Stroke is a major contributor to the global burden of disease. Although numerous modifiable risk factors (RF) for stroke have been identified, some remain unexplained.... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Stroke is a major contributor to the global burden of disease. Although numerous modifiable risk factors (RF) for stroke have been identified, some remain unexplained. Increasing studies have investigated stroke risk in arthritis, but their results are inconsistent. We aimed to synthesize, quantify, and compare the risk of stroke for the major types of arthritis in cohort studies by using a systematic review and meta-analysis approach.
METHODS
We searched Chinese and English databases to identify relevant studies from inception to April 30, 2020. Only studies adjusting at least for age and sex were included. We calculated pooled effect estimates for relative risk (RR) and 95% confidence interval (CI) and identified potential sources of heterogeneity and publication bias.
RESULTS
A total of 1,348 articles were retrieved, and after an preliminary screening of titles and abstracts, 69 were reviewed for full text, and finally, 32 met the criteria for meta-analysis. Stroke risk in arthritis was significantly increased in studies adjusting for age and sex (RR = 1.36, 95% CI: 1.27-1.46) and for at least one traditional risk factor (RR = 1.40, 95% CI: 1.28-1.54). The results of studies stratified by stroke subtype were consistent with the main finding (ischemic stroke: RR = 1.53, 95% CI: 1.32-1.78; hemorrhagic stroke: RR = 1.45, 95% CI: 1.15-1.84). In subgroup analysis by arthritis type, stroke risk was significantly increased in rheumatoid arthritis (RR = 1.38, 95% CI: 1.29-1.48), ankylosing spondylitis (RR = 1.49, 95% CI: 1.25-1.77), psoriatic arthritis (RR = 1.33, 95% CI: 1.22-1.45), and gout (RR = 1.40, 95% CI: 1.13-1.73) but not osteoarthritis (RR = 1.03, 95% CI: 0.91-1.16). Age and sex subgroup analyses indicated that stroke risk was similar by sex (women: RR = 1.47, 95% CI: 1.31-1.66; men: RR = 1.44, 95% CI: 1.28-1.61); risk was higher with younger age (<45 years) (RR = 1.46, 95% CI: 1.17-1.82) than older age (≥65 years) (RR = 1.17, 95% CI: 1.08-1.26).
CONCLUSIONS
Stroke risk was increased in multiple arthritis and similar between ischemic and hemorrhagic stroke. Young patients with arthritis had the highest risk.
Topics: Adult; Age Factors; Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cohort Studies; Female; Gout; Humans; Male; Risk Factors; Sex Factors; Spondylitis, Ankylosing; Stroke
PubMed: 33725018
DOI: 10.1371/journal.pone.0248564 -
Disability and Rehabilitation Jun 2022Finding and accessing social services and community resources are a challenge for stroke survivors and care partners. The purpose of this systematic review was to...
PURPOSE
Finding and accessing social services and community resources are a challenge for stroke survivors and care partners. The purpose of this systematic review was to identify and review interventions that aimed to increase access and use of such services and resources post stroke.
METHOD
A systematic review of the published literature was performed using MEDLINE, CINAHL, PsycINFO, and ProQuest Nursing and Allied Health (January 2008 to May 2020). Studies were included if they were quantitative designs and reported on outcomes of interventions addressing post-stroke access to social services or community resources. Results were synthesised narratively.
RESULTS
3566 titles and abstracts were reviewed. Ten articles met the inclusion criteria. The interventions included in this review varied in terms of target group, timing, and type of support provided (passive or active tailored information provision, referral service, navigation assistance). Outcome measures, for social service and community resource access, included discharge preparedness measures, service counts, observations, satisfaction evaluations, interviews, and open-ended questions.
CONCLUSION
Overall, interventions demonstrated some improvements in information received and access to social services and community resources following stroke. Future research should focus on carrying out high quality studies that examine the effectiveness of various social service and community resource interventions, and on setting valid and reliable outcome measures.IMPLICATIONS FOR REHABILITATIONStroke survivors and care partners have unmet social service and community resource needs.Stroke survivors and care partners can benefit from interventions that provide information, referrals, and ongoing support to access services and resources.Clearly identifying social service and community resource needs is important for tailoring interventions to individual situations.Interventions should ideally be provided throughout the hospital stay, in acute care and rehabilitation, and continue on in the community.
Topics: Community Resources; Health Services Accessibility; Humans; Social Work; Stroke; Stroke Rehabilitation; Survivors
PubMed: 33280453
DOI: 10.1080/09638288.2020.1851780 -
Frontiers in Neurology 2020As the world witnessed the devastation caused by the coronavirus disease 2019 (COVID-19) outbreak, a growing body of literature on COVID-19 is also becoming...
As the world witnessed the devastation caused by the coronavirus disease 2019 (COVID-19) outbreak, a growing body of literature on COVID-19 is also becoming increasingly available. Stroke has increasingly been reported as a complication of COVID-19 infection. However, a systematic synthesis of the available data has not been conducted. Therefore, we performed a systematic review and meta-analysis of currently available epidemiological, clinical, and laboratory data related to both stroke and COVID-19 infection. We systematically searched Medline, Cinahl, and PubMed for studies related to stroke and COVID-19 from inception up to June 4, 2020. We selected cohort studies, case series, and case reports that reported the occurrence of stroke in COVID-19 patients. A fixed-effects model was used to estimate the pooled frequency of stroke in COVID-19 patients with a 95% confidence interval (CI). Twenty-eight studies were included in the systematic review and seven studies for the meta-analysis. The pooled frequency of stroke in COVID-19 patients was 1.1% (95% CI: 0.8, 1.3). The heterogeneity was low ( = 0.0%). Even though the frequency of stroke among patients having COVID-19 infection was low, those with concomitant COVID-19 infection and stroke suffered from a more severe infection and eventually had a poorer prognosis with a higher mortality rate (46.7%) than COVID-19 alone. Many COVID-19 patients shared the common traditional risk factors for stroke. We noted that ischemic stroke involving the anterior circulation with large vessels occlusion is the most common type of stroke with more strokes seen in multi-territorial regions, suggesting systemic thromboembolism. An elevated level of D-dimers, C-reactive protein, ferritin, lactic acid dehydrogenase, troponin, ESR, fibrinogen, and a positive antiphospholipid antibody were also noted in this review. The occurrence of stroke in patients with COVID-19 infection is uncommon, but it may pose as an important prognostic marker and indicator of severity of infection, by causing large vessels occlusion and exhibiting a thrombo-inflammatory vascular picture. Physicians should be made aware and remain vigilant on the possible two-way relationship between stroke and COVID-19 infection. The rate of stroke among patients with COVID-19 infection may increase in the future as they share the common risk factors.
PubMed: 33123082
DOI: 10.3389/fneur.2020.579070 -
Acta Diabetologica Dec 2023To investigate the lowering BP effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on the risk of... (Meta-Analysis)
Meta-Analysis
Blood pressure-lowering effects of SGLT2 inhibitors and GLP-1 receptor agonists for preventing of cardiovascular events and death in type 2 diabetes: a systematic review and meta-analysis.
AIMS
To investigate the lowering BP effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on the risk of major cardiovascular event stratified by glucose-lowering drugs, baseline BP, glycated hemoglobin (HbA), and history of cardiovascular disease in patients with type 2 diabetes.
METHODS
We performed a systematic review of the MEDLINE and EMBASE databases search up to December 31, 2022, (PROSPERO, CRD42023400899) to identify all large-scale cardiovascular outcomes (CVO) trials of SGLT2i and GLP-1 RAs in which more than 1,000 patient-years of follow-up in each randomized group. Outcomes included all-cause mortality, major adverse cardiovascular event (MACE) and its component (cardiovascular death, myocardial infarction [MI], and stroke), heart failure, and renal failure. A random-effects meta-analyses were used to pool the estimates.
RESULTS
Eighteen CVOTs (ten for SGLT2i and eight for GLP-1 RAs) with 127,606 patients with type 2 diabetes were included. Over 2.5 years median follow-up, the average reduction of systolic BP was 2.2 mmHg (mean difference [MD] - 2.2; 95% CI - 2.7 to - 1.7) with more important reduction (P = 0.001) with SGLT2 inhibitors (- 2.9; - 3.4 to - 2.5) than with GLP-1 RAs (- 1.4; - 1.8 to - 1). With SGLT2i, every 5-mmHg reduction in systolic BP was associated with a significantly lower risk of mortality (hazard ratio[HR], 0.77; 95% CI 0.65-0.90), MACE (HR 0.81 [0.74-0.89]), cardiovascular death (HR 0.72 [0.59-0.88]), MI (HR 0.82 [0.71-0.95]), heart failure (HR 0.49 [0.42-0.57]), and renal failure (HR 0.46 [0.38-0.55]), while the association was not significant for stroke (HR 0.91 [0.69-1.19]). The corresponding effects for every 5-mmHg reduction in SBP with GLP-1 RAs were 0.65 (0.51-0.84) for all-cause mortality, 0.65 (0.56-0.76) for MACE, 0.62 (0.45-0.85) for CV death, 0.71 (0.52-0.76) for MI, 0.49 (0.35-0.69) for stroke, and 0.49 (0.35-0.66) for renal failure, while the association was not significant for heart failure (HR 0.82 [0.63-1.08]).
CONCLUSION
In patients with type 2 diabetes, the hypotensive effects of SGLT2i and GLP-1 RAs were significantly associated with a reduction in mortality and cardiorenal events. These findings suggest that the lowering BP effect could be seen as an additive indicator of cardiovascular protection by SGLT2i and GLP-1 RAs drugs.
Topics: Humans; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor; Blood Pressure; Cardiovascular Diseases; Heart Failure; Myocardial Infarction; Glucagon-Like Peptide 1; Stroke; Renal Insufficiency; Hypoglycemic Agents
PubMed: 37439858
DOI: 10.1007/s00592-023-02154-4 -
European Journal of Preventive... Dec 2023It is unclear whether the future risk of cardiovascular events in breast cancer (Bc) survivors is greater than in the general population. This meta-analysis quantifies... (Meta-Analysis)
Meta-Analysis
AIMS
It is unclear whether the future risk of cardiovascular events in breast cancer (Bc) survivors is greater than in the general population. This meta-analysis quantifies the risk of cardiovascular disease development in Bc patients, compared to the risk in a general matched cancer-free population, and reports the incidence of cardiovascular events in patients with Bc.
METHODS AND RESULTS
We searched PubMed, Scopus, and Web of Science databases (up to 23 March 2022) for observational studies and post hoc analyses of randomized controlled trials. Cardiovascular death, heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), and stroke were the individual endpoints for our meta-analysis. We pooled incidence rates (IRs) and risk in hazard ratios (HRs), using random-effects meta-analyses. Heterogeneity was reported through the I2 statistic, and publication bias was examined using funnel plots and Egger's test in the meta-analysis of risk. One hundred and forty-two studies were identified in total, 26 (836 301 patients) relevant to the relative risk and 116 (2 111 882 patients) relevant to IRs. Compared to matched cancer-free controls, Bc patients had higher risk for cardiovascular death within 5 years of cancer diagnosis [HR = 1.09; 95% confidence interval (CI): 1.07, 1.11], HF within 10 years (HR = 1.21; 95% CI: 1.1, 1.33), and AF within 3 years (HR = 1.13; 95% CI: 1.05, 1.21). The pooled IR for cardiovascular death was 1.73 (95% CI 1.18, 2.53), 4.44 (95% CI 3.33, 5.92) for HF, 4.29 (95% CI 3.09, 5.94) for CAD, 1.98 (95% CI 1.24, 3.16) for MI, 4.33 (95% CI 2.97, 6.30) for stroke of any type, and 2.64 (95% CI 2.97, 6.30) for ischaemic stroke.
CONCLUSION
Breast cancer exposure was associated with the increased risk for cardiovascular death, HF, and AF. The pooled incidence for cardiovascular endpoints varied depending on population characteristics and endpoint studied.
REGISTRATION
CRD42022298741.
Topics: Humans; Female; Cardiovascular Diseases; Breast Neoplasms; Stroke; Brain Ischemia; Cancer Survivors; Myocardial Infarction; Coronary Artery Disease; Heart Failure; Atrial Fibrillation
PubMed: 37499186
DOI: 10.1093/eurjpc/zwad243