Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population

Background:Serum calciprotein particle maturation time (T50), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T50 and study their association with cardiovascular disease and mortality.Methods:We performed a genome-wide association study of serum T50 in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T50 on cardiovascular outcomes. Finally, we examined associations between T50 loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study.Results:We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10−101), rs2077119 (p = 3.34 × 10−18), and rs9870756 (p = 3.10 × 10−8), together explaining 18.3% of variation in serum T50. MR did not demonstrate a causal effect of T50 on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T50, was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01–1.28)] and all-cause mortality alone [1.14 (1.00–1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06–1.84), relative excess risk due to interaction 0.54 (0.01–1.08)].Conclusions:We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T50 levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.

A ortic V alve Repl A cemen T versus Conservative Treatment in A symptomatic Seve R e Aortic Stenosis: The AVATAR Trial

Background: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. Methods: The Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR) trial is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm 2 with aortic jet velocity >4 m/s or a mean trans-aortic gradient ≥40 mm Hg), and with normal LV function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite endpoint of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure, as compared to a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. Results: Between June 2015 and September 2020, 157 patients (mean age 67 years, 57 % men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in conservative treatment group. In the early surgery group, 72 patients (92.3 %) underwent SAVR with operative mortality of 1.4 %. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite endpoint than those in the conservative arm (HR 0.46, 95 % CI 0.23-0.90, p=0.02). There was no statistical difference in secondary endpoints, including all-cause mortality, first heart failure hospitalizations, major bleeding or thromboembolic complications, but trends were consistent with the primary outcome. Conclusions: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms.

Comparison of Prasugrel and Ticagrelor for Patients with Acute Coronary Syndrome: A Systematic Review and Meta-analysis

Introduction: There has been inconsistent data on the direct comparison of prasugrel and ticagrelor. This meta-analysis was conducted to summarise the current available evidence. Methods: We performed a meta-analysis (PROSPERO-registered CRD42020166810) of randomized trials up to Feb 2020 that compared prasugrel and ticagrelor in acute coronary syndrome with respect to the composite endpoint of myocardial infarction (MI), stroke or cardiovascular death, and secondary endpoints including MI, stroke, cardiovascular death, major bleeding (Bleeding Academic Research Consortium (BARC) type 2 or above), stent thrombosis, all-cause death and other safety outcomes. Results: Of the 11 eligible RCTs with 6098 patients randomized to prasugrel (n=3050) or ticagrelor (n=3048), 180 and 207 had the composite endpoint events in the prasugrel arm and the ticagrelor arm respectively over a weighted mean follow up period of 11±2 months. Compared with prasugrel, the ticagrelor group had similar risk in the primary composite endpoint (Risk Ratio (RR)= 1.17; 95% CI=0.96-1.42; p=0.12, I2=0%). Compared to prasugrel, there was no significant difference associated with the use of ticagrelor groups with respect to stroke (RR=1.05; 95% CI=0.66-1.67; p=0.84, I2=0%); cardiovascular death (RR=1.01; 95% CI=0.75-1.36; p=0.95, I2=0%); BARC type 2 or above bleeding (RR=1.16; 95% CI =0.89-1.52; p=0.26, I2=0%); stent thrombosis (RR=1.58; 95% CI =0.90-2.76; p=0.11, I2=0%); all cause death (RR=1.10; 95% CI =0.86-1.43; p=0.45, I2=0%) except MI (RR=1.38; 95% CI=1.05-1.81; p=0.02, I2=0%) Conclusion: Compared with prasugrel, ticagrelor did not reduce the primary composite endpoint of MI, stroke and cardiovascular death at a weighted mean follow up of 11 months. There was no significant difference between the secondary outcomes except myocardial infarction.

Clinical Characteristics and Risk Factors of Poor Prognosis in 83 Cases of Coronavirus Disease 2019

Objective Since December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan city and rapidly spread throughout the world. The clinical characteristics of patients with COVID-19 have been reported, but risk factors for prognosis have not been well described.Methods A total of 83 patients with COVID-19 were included in this retrospective study. All cases were divided into severe and nonsevere groups according to the severity of the disease. The primary composite endpoint was admission to an intensive care unit (ICU), use of mechanical ventilation or high-flow oxygen, or death. We used univariable and multivariable logistic regression methods to explore the risk factors associated with the primary composite endpoint.ResultsThe median age of patients was 46 years; a total of 48.2% of the patients were male. Of these patients, 17 were in the severe group (20.5%), and 66 were in the nonsevere group (79.5%).ln the severe group, the proportions of basic diseases, including hypertension, diabetes, and malignant tumors, were significantly higher than those in the nonsevere group(all P<0.05), and patients in the severe group were significantly older than those in the nonsevere group (P<0.05).The primary composite endpoint occurred in 13(15.7%) patients, including 10(12.0%) who underwent mechanical ventilation, 3(3.6%) who were treated with high-flow oxygen, 5(6.0%) who were admitted to the ICU,and 5(6.0%) who died. Multivariable regression showed that an increase in high-sensitivity C-reactive protein (1.063,1.02-1.108;P=0.004) or having diabetes (735.985,7.111-8444.318;P=0.002) was an independent risk factor for COVID-19 patients with poor prognosis; however,higher hemoglobin was associated with lower odds of poor prognosis(0.912, 0.856-0.97;P=0.004).CondusionMore than 20% ofpatients with COVID-19 developed severe conditions with a poor prognosis. The potential risk factors of high-sensitivity C-reactive protein, diabetes andlow hemoglobin content could help clinicians identify COVID-19 patients with poor prognosis on admission.

Time to percutaneous coronary intervention in patients with ST-elevation myocardial infarction undergoing successful systemic fibrinolysis: does early or late make a difference?

Funding Acknowledgements Type of funding sources: None. OnBehalf PHASE-MX Background/Introduction: Early routine angiography with subsequent Percutaneous Coronary Intervention (PCI) (if needed) after fibrinolysis reduced the rates of reinfarction and recurrent ischemia compared with a ‘watchful waiting’ strategy. A crucial issue is the optimal time delay between successful lysis and PCI, there is a wide variation in delay in trials from a median of 1.3 h to 17h (CAPITAL AMI, GRACIA-1 and STREAM trials). At present a time window of 2-24h after successful lysis is recommended. Purpose To analyze the incidence of major cardiovascular outcomes in patients with ST-segment elevation myocardial infarction (STEMI) according to the timing of PCI after lysis (pharmacoinvasive strategy, less/more than 24h). Methods A retrospective analysis of the PHASE-MX study (ClinicalTrials.gov Identifier: NCT03974581) including patients with STEMI whom underwent pharmacoinvasive strategy during the first 12h since symptom onset. Patients were further stratified according to the time from the use of fibrinolysis to sheat insertion (&lt;24h or &gt;24h) in the completion of pharmacoinvasive strategy. The primary composite endpoint included the occurrence of cardiovascular death, cardiogenic shock, recurrent myocardial infarction or congestive heart failure at 30 days of follow-up. Results A total of 171 patients were included, of whom 34 underwent PCI after fibrinolysis in less than 24 hours and 137 underwent PCI in more than 24 hours (95% CI 24-120h). Mostly were male (86.4%), mean age was 56.4 ±12.1 years. The primary composite endpoint occurred in 2 patients (5.8%) in PCI &lt; 24 hours and 12 patients (8.6%) in PCI &gt;24 hours (p 0.58). PCI in &lt;24h after lysis was not associated with a reduced risk of the primary endpoint (HR 0.66 95%CI: 0.14-2.97). Conclusion In patients with successful fibrinolysis undergoing to PCI the first 24 h was not associated with a reduced risk of cardiovascular death, cardiogenic shock, recurrent MI or congestive heart failure at 30 days comparing with PCI after 24 h. Abstract Figure. Kaplan-Meier in primary endpoint

Efficacy and safety of pharmacoinvasive strategy compared with primary PCI in patients with STEMI presenting to non-PCI hubs: A real world study

Funding Acknowledgements Type of funding sources: None. Background Primary percutaneous coronary intervention (PPCI) is the treatment of choice for ST-elevation myocardial infarction (STEMI). Clinical practice guidelines recommend performing pPCI &lt;120 minutes after the diagnosis of STEMI. Nevertheless, in a real world model this treatment is not always the fastest option. This is mostly due to the transfer delays when patients arrive to non-PCI capable hubs. These delays can decrease the benefits of the PPCI. Regional networks have been created to speed up these times and administer reperfusion therapy as early as possible. The pharmacoinvasive strategy (PIs) consists of the administration of fibrinolytic drugs in the non-pPCI setting followed by the immediate transfer of the patient to a pPCI center. Purpose To compare the efficacy and safety of pharmacoinvasive strategy compared with referral for primary PCI in patients with STEMI presenting to non PCI hubs. Methods A retrospective analysis of the PHASE-MX study (ClinicalTrials.gov Identifier: NCT03974581) including patients with STEMI whom initially presented to non-PCI hospitals and underwent either systemic fibrinolysis followed by pharmaco-invasive strategy or were transfer to perform primary PCIc according to the decision made by the doctor in the non-PCI center, the ease of referring the patient and the proximity of the PCI center. The primary composite endpoint included the occurrence of cardiovascular death, cardiogenic shock, recurrent MI or congestive heart failure at 30 days of follow-up. Results A total of 448 patients were included, of whom 273 (60.9%) underwent PIs and 175 (39.0%) were transfered for pPCI. Mean age was 58+-10 years, and most patients (86.8%) were male. No statistically significant differences in risk factors and other clinically meaningful variables were found. There was a 40% reduction in the risk of the primary composite endpoint (HR 0.60 for PIs: 95% CI:0.36-0.99; p = 0.048) for those undergoing PIs compared with pPCI, (Figure 1). Conclusion The pPCI main limitation is the impossibility to use it in the entire population due to its limited geographic availability and the delays involved in the transfer of patients from non-pPCI centers to reference hospitals. Through the PIs patients who arrive at non-PCI hospitals with STEMI and receive thrombolysis and then are redirect to PCI center there was a 40% reduction in the risk of a major endpoint occurring. Abstract Figure 1

Risk factors and cardiovascular outcomes in patients with coronary artery ectasia presented with st elevation myocardial infarction

Funding Acknowledgements Type of funding sources: None. OnBehalf PHASE-MX Background Coronary artery ectasia (CAE), defined as "a dilatation greater than 1.5 times the diameter of the adjacent normal coronary arteries", is an uncommon finding in patients with acute coronary syndrome with a reported prevalence from 0.3 to 4.9% in different series. Because its low frequency, at present time there is lack of evidence and consensus of treatment strategies in those patients. Purpose To identify differences in risk factors, treatment strategies and cardiovascular outcomes among population with and without CAE presented with STEMI. Methods A retrospective, observational, comparative study was conducted in a tertiary-level cardiovascular center. We included hospitalized patients between 2018 and 2020 diagnosed with STEMI who had received reperfusion treatment within 12 hours of symptom onset. Coronary angiography was performed in the setting of primary PCI or pharmacoinvasive strategy. The primary composite endpoint was the time to first occurrence of either cardiovascular death, cardiogenic shock, recurrent MI or congestive heart failure at 30 days of follow-up according to the presence or absence of coronary artery ectasia. Results We identified 539 patients with a STEMI diagnosis, of those 56 (10.3%) were diagnosed with CAE and 483 without CAE (89.7%). The median age of population was 57.9 (±10.9 SD) with no differences between groups and most of them were male (94.6% vs 85.7%, p 0.08). Among risk factors we identified a lower prevalence of type 2 diabetes mellitus in patients with CAE (14.2% vs 36.4%, p 0.001), no difference was observed in prevalence of hypertension (44.6% vs. 43.4%, p 0.86), obesity (26.7% vs 23.4%, p 0.57), dyslipidemia (26.7% vs 18.8%, p 0.35) or smoking (35.7% vs 45.1%, p 0.17). In angiographic findings of patients diagnosed with CAE the infarction culprit artery had ectasia in 83.9% (n = 47) of the patients. According to the Markis classification, type 1 was the most common type, with the right coronary artery presenting the greatest involvement (72.7%, n= 40), followed by the anterior descending artery (67.2%, n= 37) and finally by circumflex artery (54.5%, n= 30). There were no differences in reperfusion strategies performed between both groups, pharmacoinvasive strategy (43.6% vs 50.6%, p 0.32) or PCI (56.4% VS 49.4%, P 0.12). There was no difference in the primary composite endpoint of MACE over a period of 30 days of follow up (8.93% vs 10.3%, p 0.73) Figure 1. There was also no difference in major or minor bleeding between groups (5.4% vs 3.6%, p 0.78; and 3.5% vs 1.6%, p 0.37). Conclusion CAE is a disease with a higher prevalence in México than reported in other countries. There are no identifiable risk factors in our study that predicts the presence of CAE in patients diagnosed with STEMI. Both reperfusion strategies used (Pharmacoinvasive strategy and primary PCI) could be safe with no differences in cardiovascular outcomes or bleeding at 1 month of follow-up. Abstract Figure.

Utility of Abdominal Drain in Gastrectomy (ADiGe) Trial: study protocol for a multicenter non-inferiority randomized trial

Background Prophylactic use of abdominal drain in gastrectomy has been questioned in the last 15 years, and a 2015 Cochrane meta-analysis on four RCTs concluded that there was no convincing evidence to the routine drain placement in gastrectomy. Nevertheless, the authors evidenced the moderate/low quality of the included studies and highlighted how 3 out of 4 came from Eastern countries. After 2015, only retrospective studies have been published, all with inconsistent results. Methods ADiGe (Abdominal Drain in Gastrectomy) Trial is a multicenter prospective randomized non-inferiority trial with a parallel design. It aimed to verify whether avoiding routine use of abdominal drain is burdened with complications, particularly an increase in postoperative invasive procedures. Patients with gastric cancer, scheduled for subtotal or total gastrectomy with curative intent, are eligible for inclusion, irrespective of previous oncological treatment. The primary composite endpoint is reoperation or percutaneous drainage procedures within 30 postoperative days. The primary analysis will verify whether the incidence of the primary composite endpoint is higher in the experimental arm, avoiding routine drain placement, than control arm, undergoing prophylactic drain placement, in order to falsify or support the null hypothesis of inferiority. Secondary endpoints assessed for superiority are overall morbidity and mortality, Comprehensive Complications Index, incidence and time for diagnosis of anastomotic and duodenal leaks, length of hospital stay, and readmission rate. Assuming one-sided alpha of 5%, and cumulative incidence of the primary composite endpoint of 6.4% in the control arm and 4.2% in the experimental one, 364 patients allow to achieve 80% power to detect a non-inferiority margin difference between the arm proportions of 3.6%. Considering a 10% drop-out rate, 404 patients are needed. In order to have a balanced percentage between total and subtotal gastrectomy, recruitment will end at 202 patients for each type of gastrectomy. The surgeon and the patient are blinded until the end of the operation, while postoperative course is not blinded to the patient and caregivers. Discussion ADiGe Trial could contribute to critically re-evaluate the role of prophylactic drain in gastrectomy, a still widely used procedure. Trial registration Prospectively registered (last updated on 29 October 2020) at ClinicalTrials.gov with the identifier NCT04227951.

Utility of Abdominal Drain in Gastrectomy (ADiGe) Trial: study protocol for a multicenter non-inferiority randomized trial

Background: Prophylactic use of abdominal drain in gastrectomy has been questioned in the last 15 years and a 2015 Cochrane meta-analysis on four RCTs concluded that there was no convincing evidence to the routine drain placement in gastrectomy. Nevertheless, the Authors evidenced the moderate/low quality of the included studies and highlighted how 3 out of 4 came from Eastern countries. After 2015 only retrospective studies have been published, all with inconsistent results.Methods: ADiGe (Abdominal Drain in GastrEctomy) Trial is a multicenter prospective randomized non-inferiority trial with a parallel design. It aimed to verify whether avoiding routine use of abdominal drain is burdened with complications, particularly an increase in postoperative invasive procedures. Patients with gastric cancer, scheduled for subtotal or total gastrectomy with curative intent, are eligible for inclusion, irrespective of previous oncological treatment. The primary composite endpoint is reoperation or percutaneous drainage procedures within 30 postoperative days. The primary analysis will verify whether the incidence of the primary composite endpoint is higher in the experimental arm, avoiding routine drain placement, than control arm, undergoing prophylactic drain placement, in order to falsify or support the null hypothesis of inferiority. Secondary endpoints assessed for superiority are overall morbidity and mortality, Comprehensive Complications Index, incidence and time for diagnosis of anastomotic and duodenal leaks, length of hospital stay, readmission rate.Assuming one-sided alpha of 5%, and cumulative incidence of the primary composite endpoint of 6.4% in control arm and 4.2% in the experimental one, 364 patients allow to achieve 80% power to detect a non-inferiority margin difference between the arm proportions of 3.6%. Considering a 10% drop-out rate, 404 patients are needed. In order to have a balanced percentage between total and subtotal gastrectomy, recruitment will end at 202 patients for each type of gastrectomy. The surgeon and the patient are blinded until the end of the operation, while postoperative course is not blinded to patient and caregivers.Discussion: ADiGe Trial could contribute to critically re-evaluate the role of prophylactic drain in gastrectomy, a still widely used procedure.Trial registration: Prospectively registered (last updated on October 29, 2020) at Clinicaltrials.gov with the identifier NCT04227951, https://clinicaltrials.gov/ct2/show/NCT04227951.

healthcareCOVID: a national cross-sectional observational study identifying risk factors for developing suspected or confirmed COVID-19 in UK healthcare workers

Objective To establish the prevalence, risk factors and implications of suspected or confirmed coronavirus disease 2019 (COVID-19) infection among healthcare workers in the United Kingdom (UK). Design Cross-sectional observational study. Setting UK-based primary and secondary care. Participants Healthcare workers aged ≥18 years working between 1 February and 25 May 2020. Main outcome measures A composite endpoint of laboratory-confirmed diagnosis of SARS-CoV-2, or self-isolation or hospitalisation due to suspected or confirmed COVID-19. Results Of 6,152 eligible responses, the composite endpoint was present in 1,806 (29.4%) healthcare workers, of whom 49 (0.8%) were hospitalised, 459 (7.5%) tested positive for SARS-CoV-2, and 1,776 (28.9%) reported self-isolation. Overall, between 11,870 and 21,158 days of self-isolation were required by the cohort, equalling approximately 71 to 127 working days lost per 1,000 working days. The strongest risk factor associated with the presence of the primary composite endpoint was increasing frequency of contact with suspected or confirmed COVID-19 cases without adequate personal protective equipment (PPE): ‘Never’ (reference), ‘Rarely’ (adjusted odds ratio 1.06, (95% confidence interval: [0.87–1.29])), ‘Sometimes’ (1.7 [1.37–2.10]), ‘Often’ (1.84 [1.28–2.63]), ‘Always’ (2.93, [1.75–5.06]). Additionally, several comorbidities (cancer, respiratory disease, and obesity); working in a ‘doctors’ role; using public transportation for work; regular contact with suspected or confirmed COVID-19 patients; and lack of PPE were also associated with the presence of the primary endpoint. A total of 1,382 (22.5%) healthcare workers reported lacking access to PPE items while having clinical contact with suspected or confirmed COVID-19 cases. Conclusions Suspected or confirmed COVID-19 was more common in healthcare workers than in the general population and is associated with significant workforce implications. Risk factors included inadequate PPE, which was reported by nearly a quarter of healthcare workers. Governments and policymakers must ensure adequate PPE is available as well as developing strategies to mitigate risk for high-risk healthcare workers during future COVID-19 waves.