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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 -
Stroke Oct 2015Carotid angioplasty and stenting (CAS) is associated with higher risk of periprocedural stroke and death when compared with carotid endarterectomy (CEA). By contrast,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
Carotid angioplasty and stenting (CAS) is associated with higher risk of periprocedural stroke and death when compared with carotid endarterectomy (CEA). By contrast, the risk of myocardial infarction (MI) was higher after CEA than after CAS in randomized trials. However, numbers were small, and risk factors are unknown.
METHODS
We performed a systematic review and a meta-analysis of studies published from January 1980 to June 2014 and collected unpublished data. We extracted data on 9 predefined risk factors (age, contralateral carotid occlusion, coronary artery disease, diabetes mellitus, sex, hypertension, peripheral artery disease, type stenosis, and clinical presentation). We selected studies with data available on MI in at least 1 subgroup, calculated absolute and relative risks, and identified differential effects on risks of MI.
RESULTS
The 30-day absolute risk of MI was 0.87% (95% confidence interval, 0.69-1.07) after CEA and 0.70% (95% confidence interval, 0.54-0.88) after CAS (Pint=0.38). After CAS, patients with symptomatic stenosis and restenosis were at higher risk of MI, whereas men were at lower risk. After CEA, age, history of coronary artery disease, peripheral artery disease, and restenosis increased the risk of MI. Only the effect of sex differed between CAS and CEA with men being at lower risk of MI than women after CAS, whereas there was no difference between after CEA (Pint=0.01).
CONCLUSIONS
The risk of MI after CEA and CAS did not significantly differ. Risk factors for MI are overall similar in both techniques except that men are at lower risk of MI after CAS but not after CEA.
Topics: Angioplasty; Carotid Stenosis; Endarterectomy, Carotid; Female; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Postoperative Complications; Stents; Stroke
PubMed: 26286540
DOI: 10.1161/STROKEAHA.115.010052 -
American Heart Journal Jan 2018The use of the potent oral P2Y12 inhibitors prasugrel and ticagrelor in patients with acute coronary syndromes (ACS) has a favorable net clinical effect compared with... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of potent platelet P2Y12 receptor inhibitors in elderly versus nonelderly patients with acute coronary syndrome: A systematic review and meta-analysis.
BACKGROUND
The use of the potent oral P2Y12 inhibitors prasugrel and ticagrelor in patients with acute coronary syndromes (ACS) has a favorable net clinical effect compared with clopidogrel and is recommended as first-line therapy. However, the impact of these agents on ischemic and bleeding events in elderly ACS patients is not well defined.
METHODS
We performed a systematic review of articles comparing potent P2Y12 inhibitors to clopidogrel in elderly and nonelderly patients (defined according to each study) with ACS in terms of efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (major bleeding) end points.
RESULTS
A total of 7,860 elderly and 37,857 nonelderly patients from 7 studies (5 randomized control trials and 2 observational studies) were included. Potent P2Y12 inhibitors significantly reduced efficacy end point in nonelderly patients (relative risk [RR] 0.85, 95% CI 0.79-0.93) and less so in elderly patients (RR 0.95, 95% CI 0.86-1.05). No significant differences were found between potent P2Y12 inhibitors and clopidogrel in terms of safety end point in both elderly (RR 1.19, 95% CI 0.95-1.49) and nonelderly patients (RR 1.16, 95% CI 0.95-1.41). There were no significant interactions between age and treatment effect in both analyses (efficacy P=.16; safety P=.83).
CONCLUSIONS
The effect of more potent P2Y12 inhibitors compared with clopidogrel on efficacy and safety end points is consistent in elderly and younger patients. These data imply that potent P2Y12 inhibitors should not be withheld from eligible patients solely because of advanced age.
Topics: Acute Coronary Syndrome; Aged; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Treatment Outcome
PubMed: 29224649
DOI: 10.1016/j.ahj.2017.09.012 -
JAMA Network Open Nov 2021The currently recommended method for screening for retinopathy of prematurity (ROP) is binocular indirect ophthalmoscopy, which requires frequent eye examinations... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The currently recommended method for screening for retinopathy of prematurity (ROP) is binocular indirect ophthalmoscopy, which requires frequent eye examinations entailing a heavy clinical workload. Weight gain-based algorithms have the potential to minimize the need for binocular indirect ophthalmoscopy and have been evaluated in different setups with variable results to predict type 1 or severe ROP.
OBJECTIVE
To synthesize evidence regarding the ability of postnatal weight gain-based algorithms to predict type 1 or severe ROP.
DATA SOURCES
PubMed, MEDLINE, Embase, and the Cochrane Library databases were searched to identify studies published between January 2000 and August 2021.
STUDY SELECTION
Prospective and retrospective studies evaluating the ability of these algorithms to predict type 1 or severe ROP were included.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data. This meta-analysis was performed according to the Cochrane guidelines and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines.
MAIN OUTCOMES AND MEASURES
Ability of algorithms to predict type 1 or sever ROP was measured using statistical indices (pooled sensitivity, specificity, and summary area under the receiver operating characteristic curves, as well as pooled negative likelihood ratios and positive likelihood ratios and diagnostic odds ratios).
RESULTS
A total of 61 studies (>37 000 infants) were included in the meta-analysis. The pooled estimates for sensitivity and specificity, respectively, were 0.89 (95% CI, 0.85-0.92) and 0.57 (95% CI, 0.51-0.63) for WINROP (Weight, IGF-1 [insulinlike growth factor 1], Neonatal, ROP), 1.00 (95% CI, 0.88-1.00) and 0.60 (95% CI, 0.15-0.93) for G-ROP (Postnatal Growth and ROP), 0.95 (95% CI, 0.71-0.99) and 0.52 (95% CI, 0.36-0.68) for CHOP ROP (Children's Hospital of Philadelphia ROP), 0.99 (95% CI, 0.73-1.00) and 0.49 (95% CI, 0.03-0.74) for ROPScore, 0.98 (95% CI, 0.94-0.99) and 0.35 (95% CI, 0.22-0.51) for CO-ROP (Colorado ROP). The original PINT (Premature Infants in Need of Transfusion) ROP study reported a sensitivity of 0.98 (95% CI, 0.91-0.99) and a specificity of 0.36 (95% CI, 0.30-0.42). The pooled negative likelihood ratios were 0.19 (95% CI, 0.13-0.27) for WINROP, 0.0 (95% CI, 0.00-0.32) for G-ROP, 0.10 (95% CI, 0.02-0.53) for CHOP ROP, 0.03 (95% CI, 0.00-0.77) for ROPScore, and 0.07 (95% CI, 0.03-0.16) for CO-ROP. The pooled positive likelihood ratios were 2.1 (95% CI, 1.8-2.4) for WINROP, 2.5 (95% CI, 0.7-9.1) for G-ROP, 2.0 (95% CI, 1.5-2.6) for CHOP ROP, 1.9 (95% CI, 1.1-3.3) for ROPScore, and 1.5 (95% CI, 1.2-1.9) for CO-ROP.
CONCLUSIONS AND RELEVANCE
This study suggests that weight gain-based algorithms have adequate sensitivity and negative likelihood ratios to provide reasonable certainty in ruling out type 1 ROP or severe ROP. Given the implications of missing even a single case of severe ROP, algorithms with very high sensitivity (close to 100%) and low negative likelihood ratios (close to zero) need to be chosen to safely reduce the number of unnecessary examinations in infants at lower risk of severe ROP.
Topics: Algorithms; Birth Weight; Early Diagnosis; Female; Forecasting; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Neonatal Screening; Philadelphia; Prognosis; Prospective Studies; Retinopathy of Prematurity; Retrospective Studies; Risk Assessment; Risk Factors; Sensitivity and Specificity; Weight Gain
PubMed: 34812847
DOI: 10.1001/jamanetworkopen.2021.35879 -
Journal of the American Heart... Jan 2018Uncertainties remain about the current risk of myocardial infarction (MI) after ischemic stroke or transient ischemic attack. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Uncertainties remain about the current risk of myocardial infarction (MI) after ischemic stroke or transient ischemic attack.
METHODS AND RESULTS
We undertook a systematic review to estimate the long-term risk of MI, compared to recurrent stroke, with temporal trends in ischemic stroke/transient ischemic attack patients. Annual risks and 95% confidence intervals (95% CI) of MI and recurrent stroke were estimated using random-effect meta-analyses. We calculated incidence ratios of MI/recurrent stroke, for fatal and nonfatal events, using similar analyses. Rate ratios for MI in patients with potential risk factors compared to those without were calculated using Poisson regression.A total of 58 studies (131 299 patients) with a mean (range) follow-up of 3.5 (1.0-10.0) years were included. The risk of MI was 1.67%/y (95% CI 1.36-1.98, <0.001 for heterogeneity) and decreased over time (=0.021); 96% of the heterogeneity between studies was explained by study design, study period, follow-up duration, mean age, proportion of patients on antithrombotic therapy, and incident versus combined ischemic stroke/transient ischemic attack. The risk of recurrent stroke was 4.26%/y (95% CI 3.43-5.09, <0.001), with no change over time (=0.63). The risk of fatal MI was half the risk of recurrent strokes ending in fatality (incidence ratio=0.51, 95% CI 0.14-0.89, =0.58). The risk of nonfatal MI was 75% smaller than the risk of recurrent nonfatal stroke (incidence ratio=0.25, 95%CI 0.02-0.50, =0.68). Male sex, hypertension, coronary and peripheral artery diseases were associated with a doubled risk of MI.
CONCLUSIONS
After ischemic stroke/transient ischemic attack, the risk of MI is currently <2%/y, and recurrent stroke is a more common cause of death than MI.
Topics: Aged; Brain Ischemia; Cause of Death; Female; Humans; Incidence; Ischemic Attack, Transient; Male; Middle Aged; Myocardial Infarction; Prognosis; Recurrence; Risk Assessment; Risk Factors; Stroke; Time Factors
PubMed: 29348322
DOI: 10.1161/JAHA.117.007267 -
BMC Medicine Jul 2021Light-to-moderate alcohol consumption has been reported to be cardio-protective among apparently healthy individuals; however, it is unclear whether this association is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Light-to-moderate alcohol consumption has been reported to be cardio-protective among apparently healthy individuals; however, it is unclear whether this association is also present in those with disease. To examine the association between alcohol consumption and prognosis in individuals with pre-existing cardiovascular disease (CVD), we conducted a series of meta-analyses of new findings from three large-scale cohorts and existing published studies.
METHODS
We assessed alcohol consumption in relation to all-cause mortality, cardiovascular mortality, and subsequent cardiovascular events via de novo analyses of 14,386 patients with a previous myocardial infarction, angina, or stroke in the UK Biobank Study (median follow-up 8.7 years, interquartile range [IQR] 8.0-9.5), involving 1640 deaths and 2950 subsequent events, and 2802 patients and 1257 deaths in 15 waves of the Health Survey for England 1994-2008 and three waves of the Scottish Health Survey 1995, 1998, and 2003 (median follow-up 9.5 years, IQR 5.7-13.0). This was augmented with findings from 12 published studies identified through a systematic review, providing data on 31,235 patients, 5095 deaths, and 1414 subsequent events. To determine the best-fitting dose-response association between alcohol and each outcome in the combined sample of 48,423 patients, models were constructed using fractional polynomial regression, adjusting at least for age, sex, and smoking status.
RESULTS
Alcohol consumption was associated with all assessed outcomes in a J-shaped manner relative to current non-drinkers, with a risk reduction that peaked at 7 g/day (relative risk 0.79, 95% confidence interval 0.73-0.85) for all-cause mortality, 8 g/day (0.73, 0.64-0.83) for cardiovascular mortality and 6 g/day (0.50, 0.26-0.96) for cardiovascular events, and remained significant up to 62, 50, and 15 g/day, respectively. No statistically significant elevated risks were found at higher levels of drinking. In the few studies that excluded former drinkers from the non-drinking reference group, reductions in risk among light-to-moderate drinkers were attenuated.
CONCLUSIONS
For secondary prevention of CVD, current drinkers may not need to stop drinking. However, they should be informed that the lowest risk of mortality and having another cardiovascular event is likely to be associated with lower levels of drinking, that is up to approximately 105g (or equivalent to 13 UK units, with one unit equal to half a pint of beer/lager/cider, half a glass of wine, or one measure of spirits) a week.
Topics: Alcohol Drinking; Cardiovascular Diseases; Female; Health Surveys; Humans; Male; Morbidity; Myocardial Infarction
PubMed: 34311738
DOI: 10.1186/s12916-021-02040-2 -
Clinical Research in Cardiology :... Nov 2023The performance of modified balloons (namely cutting or scoring balloons) to prepare severely calcified lesions in patients undergoing percutaneous coronary intervention...
BACKGROUND
The performance of modified balloons (namely cutting or scoring balloons) to prepare severely calcified lesions in patients undergoing percutaneous coronary intervention (PCI) remains controversial. We investigated the clinical and imaging outcomes of patients undergoing PCI assigned to modified balloon therapy to prepare severely calcified coronary lesions before stent implantation.
METHODS
In this meta-analysis, we aggregated the study-level data from trials enrolling invasively treated patients who were randomly assigned to modified balloon or control therapy to prepare severely calcified lesions before stenting. The primary outcome was major adverse cardiac events (MACE), including death, myocardial infarction (MI), and repeat revascularization. The secondary outcomes included the individual components of the primary outcome, coronary perforation and final minimal stent area (MSA) as measured by intracoronary imaging.
RESULTS
A total of 648 participants in six trials were allocated to modified balloon therapy (n = 335) or control therapy (semi-compliant, non-compliant, or super high-pressure balloon, n = 313). The median follow-up was 11 months. Overall, MACE occurred in 8.96% of patients assigned to a modified balloon and 12.78% of patients assigned to control therapy [risk ratio = 0.70, 95% confidence interval (CI) 0.35-1.39; P = 0.24]. There was a significant treatment effect-by-modified balloon type interaction for the outcome MACE in patients assigned to cutting balloon compared with control therapy [RR = 0.40 (0.28-0.56), P for interaction (P) < 0.001]. Patients treated with a modified balloon compared with control therapy showed neither a significant difference for the other clinical outcomes nor for final MSA [standardized mean difference = 0.67 (- 0.71, 2.06); P = 0.26].
CONCLUSIONS
In patients treated with PCI for severely calcific coronary artery disease a strategy of lesion preparation with a modified balloon before stenting does not improve clinical or imaging outcomes compared with control therapy. The different performance of cutting and scoring balloons warrants further investigation.
PubMed: 37930402
DOI: 10.1007/s00392-023-02324-y -
Journal of Clinical GastroenterologyThe aim of this study was to summarize the optimal strategy for early feeding in patients with acute pancreatitis. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this study was to summarize the optimal strategy for early feeding in patients with acute pancreatitis.
METHODS
The search was undertaken in electronic databases, which compared early with delayed feeding in acute pancreatitis. The primary outcome was the length of hospital stay (LOHS). The second outcomes were intolerance of refeeding, mortality, and total cost of each patient. This meta-analysis followed the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guideline. Research is registered by PROSPERO, CRD42020192133.
RESULTS
A total of 20 trials involving 2168 patients were included, randomly assigned to the early feeding group (N = 1033) and delayed feeding group (N = 1135). The LOHS was significantly lower in the early feeding group than the delayed feeding group (mean difference: -2.35, 95% CI: -2.89 to -1.80; P < 0.0001), no matter the mild or severe subgroup ( Pint = 0.69). The secondary outcome of feeding intolerance and mortality were no significant difference (risk ratio: 0.96, 0.40 to 2.16, P = 0.87 and 0.91, 0.57 to 1.46, P = 0.69; respectively). Moreover, the hospitalization cost was significantly less in the early feeding group, resulting in an average savings of 50%. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial ( Pint = 0.001).
CONCLUSION
Early oral feeding can significantly reduce the LOHS and hospitalization costs in patients with acute pancreatitis without increasing feeding intolerance or mortality. In patients with severe pancreatitis, early feeding after 24 hours may be beneficial.
Topics: Humans; Infant, Newborn; Enteral Nutrition; Acute Disease; Pancreatitis; Hospitalization; Length of Stay; Randomized Controlled Trials as Topic
PubMed: 37428071
DOI: 10.1097/MCG.0000000000001886 -
Interventional Neuroradiology : Journal... Jun 2019In acute ischemic stroke patients with large-artery occlusion, uncertainties remain about whether clinically important outcomes are comparable between first-line contact... (Comparative Study)
Comparative Study Meta-Analysis
First-line contact aspiration vs stent-retriever thrombectomy in acute ischemic stroke patients with large-artery occlusion in the anterior circulation: Systematic review and meta-analysis.
BACKGROUND
In acute ischemic stroke patients with large-artery occlusion, uncertainties remain about whether clinically important outcomes are comparable between first-line contact aspiration and stent-retriever thrombectomy, although two trials have investigated whether one strategy should be preferred over another.
PURPOSE
The purpose of this article is to compare the efficacy and safety of first-line contact aspiration and stent-retriever thrombectomy in stroke patients with anterior circulation large-artery occlusion.
METHODS
We undertook a systematic review of studies of patients treated for large-artery occlusion, with the latest devices of either strategy, within six hours of stroke onset. We determined rates of final complete reperfusion (defined as modified Thrombolysis In Cerebral Infarction score = 3), periprocedural complications and 90-day functional independence (defined as modified Rankin Scale (mRS) score 0-2), and excellent outcome (defined as mRS score 0-1) after contact aspiration and after stent-retriever thrombectomy using random-effects meta-analyses. Any differential effects in rates between the two strategies were assessed using random-effects meta-regressions.
RESULTS
Fifteen studies (1817 patients) were included. There was no difference in rates of final complete reperfusion at the end of all endovascular procedures between contact aspiration and stent retrievers (51.1%, 95% confidence interval (CI) 39.3-62.9; vs 38.3%, 95% CI 28.6-48.0; p = 0.14), 90-day functional independence (45.0%, 40.7-49.2; vs 52.4%, 47.7-57.1; p = 0.45) and excellent outcome (32.1%, 25.7-38.5; vs 34.1%, 21.2-46.9; p = 0.94). Rates of periprocedural complications did not differ between the two strategies.
CONCLUSIONS
Current data suggest no difference in efficacy and safety between first-line contact aspiration and stent-retriever thrombectomy in stroke patients with large-artery occlusion.
Topics: Brain Ischemia; Cerebrovascular Circulation; Stents; Stroke; Suction; Thrombectomy
PubMed: 30864466
DOI: 10.1177/1591019918821074 -
European Heart Journal. Cardiovascular... Apr 2021Safety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical... (Meta-Analysis)
Meta-Analysis
Safety and efficacy of double vs. triple antithrombotic therapy in patients with atrial fibrillation with or without acute coronary syndrome undergoing percutaneous coronary intervention: a collaborative meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials.
AIMS
Safety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical presentation. We sought to compare double vs. triple antithrombotic therapy (DAT vs. TAT) in AF patients with or without acute coronary syndrome (ACS) undergoing PCI.
METHODS AND RESULTS
A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials. Data on subgroups of ACS or elective PCI were obtained by published reports or trial investigators. A total of 10 193 patients from four NOAC trials were analysed, of whom 5675 presenting with ACS (DAT = 3063 vs. TAT = 2612) and 4518 with stable coronary artery disease (SCAD; DAT = 2421 vs. TAT = 2097). The primary safety endpoint of ISTH major bleeding or clinically relevant non-major bleeding was reduced with DAT compared with TAT in both ACS (12.2% vs. 19.4%; RR 0.63, 95% CI 0.56-0.71; P < 0.0001; I2 = 0%) and SCAD (14.6% vs. 22.0%; RR 0.68, 95% CI 0.55-0.85; P = 0.0008; I2 = 66%), without interaction (P-int = 0.54). Findings were consistent for secondary bleeding endpoints, including intra-cranial haemorrhage. In both subgroups, there was no difference between DAT and TAT for all-cause death, major adverse cardiovascular events, or stroke. Myocardial infarction and stent thrombosis were numerically higher with DAT vs. TAT consistently in ACS and SCAD (P-int = 0.60 and 0.86, respectively). Findings were confirmed by multiple sensitivity analyses, including a separate analysis on dabigatran regimens and a restriction to PCI population.
CONCLUSIONS
DAT, compared with TAT, is associated with lower bleeding risks, including intra-cranial haemorrhage, and a small non-significant excess of cardiac ischaemic events in both patients with or without ACS.
Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic
PubMed: 33119069
DOI: 10.1093/ehjcvp/pvaa116