Prospective International Multicenter Study Research Articles

Validation of the Canadian syncope risk score in a large prospective international multicenter study

Abstract Background Management and risk stratification of patients with syncope in the emergency department (ED) is often challenging. In an effort to support ED physicians in disposition decisions, the Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes. Methods The CSRS was developed in a Canadian multicenter study and contains nine predictors: predisposition to vasovagal syncope, heart disease, systolic pressure <90 or >180mmHg in the ED, troponin level >99th percentile, abnormal QRS axis, QRS duration >130ms, QTc interval >480ms and an ED diagnosis of vasovagal or cardiac syncope. Patients can achieve a CSRS score between −3 and +11 points. We validated the CSRS in a large prospective international multicenter study recruiting patients 40 years or older presenting to the ED with a syncopal event within the last 12 hours. Recruitment centers contained smaller provincial hospitals, as well as big University Hospitals in eight countries on three continents. Primary outcome measure were 30-day serious arrhythmic and non-arrhythmic adverse events, as defined by the authors of the original score. Results 1581 patients were eligible for this analysis. The population in this validation cohort was older (mean age 68 vs 54 years) and had a considerably higher rate of serious outcomes compared to the derivation cohort (n=186 (11.8%) vs n=147 (3.6%)). The area under the receiver operating characteristic curve (AUC) for the CSRS was 0.88 (95% confidence interval (CI) 0.86–0.91) and significantly higher compared to the validated OESIL score (AUC 0.75, 95% CI 0.71–0.78, p<0.001). Calibration curve analysis showed an underestimation of risk in patients with a low CSRS and an overestimation in patients with a high CSRS. The rate of observed serious outcomes within 30d increased from 0.8% in the very low risk group (CSRS equal to or below −2) to 48% in the (very) high risk group (CSRS equal to or above 4, Hazard ratio 79.4, 95% CI 11.1–570.9). A Kaplan-Meier plot was used to visualize rates of serious outcomes in three different risk groups (Figure). Conclusion This is the first validation of the Canadian Syncope Risk Score in a large international syncope cohort. The prognostic discrimination of the CSRS for 30-day serious outcomes was very good in our validation cohort and comparable to that of the Canadian derivation study. Despite suboptimal calibration, prognostic analysis showed a high rate of serious outcomes in the CSRS (very) high risk group and a low rate of serious outcomes in the very low risk group. Allowing the clinical judgement of the ED physician in the form of suspected syncope etiology to be a part of the score seems to largely contribute to the high performance of the CSRS. Additional validation studies might be needed to further increase the accuracy of the CSRS in different patient populations with a different incidence of outcomes in settings outside of Canada. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation; Swiss Heart Foundation

Incidence, characteristics, determinants and prognostic impact of recurrent syncope

Abstract Background The incidence, characteristics, determinants, and prognostic impact of recurrent syncope are largely unknown, causing uncertainty for both patients and physicians. Methods We characterized recurrent syncope including sex-specific aspects and its impact on death and major adverse cardiovascular events (MACE) in a large prospective international multicenter study enrolling patients ≥40 years presenting with syncope to the emergency department (ED). Syncope etiology was centrally adjudicated by two independent and blinded cardiologists using all information becoming available during syncope work-up and 12-month follow-up. MACE were defined as a composite of all-cause death, acute myocardial infarction, surgical or percutaneous coronary intervention, life-threatening arrhythmia including cardiac arrest, pacemaker or implantable cardioverter defibrillator implantation, valve intervention, heart-failure, gastrointestinal bleeding or other bleeding requiring transfusion, intracranial hemorrhage, ischemic stroke or transient ischemic attack, sepsis and pulmonary embolism. Results Incidence of recurrent syncope among 1790 patients was 20% (95%-confidence interval (CI) 18% to 22%) within 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95%-CI 1.11 to 2.01) or syncope of unknown etiology even after central adjudication (HR 2.11, 95%-CI 1.54 to 2.89) had an increased risk for syncope recurrence (Figure). LASSO regression fit on all patient information available early in the ED identified more than three previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95%-CI 1.64 to 2.75). Recurrent syncope within the first 12 months after the index event carried an increased risk for all-cause death (HR 1.59, 95%-CI 1.06 to 2.38) and MACE (HR 2.24, 95%-CI 1.67 to 3.01), whereas recurrences after 12 months did not have a significant impact on outcome measures. Conclusion Recurrence rates of syncope are substantial and vary depending on syncope etiology. There seem to be no reliable patient characteristics available early on the ED that allow for the prediction of recurrent syncope with only a history of more than three previous syncope being associated with a higher risk for future recurrences. Importantly, recurrent syncope within the first 12 months carries an increased risk for death and MACE. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation

Application of the ESC and AHA guidelines for admission of syncope patients presenting to the ED

Abstract Background Syncope in the ED is linked with high diagnostic and prognostic uncertainty, leading to an extremely high rate of admissions. These often inappropriate admissions are costly and expose patients to unnecessary testing. The recent ESC and AHA guidelines aim at reducing these admissions by stratifying patients in high- and low-risk groups. Methods The BASEL IX Syncope study is a large prospective international multicenter study recruiting patients 40 years presenting to the ED with syncope within the last 12 hours in eight countries on three continents. Cardiac syncope was centrally adjudicated by two physicians using all data collected up to 1-y follow-up. We classified patients as requiring admission or being judged safe for discharge according to the ESC and AHA guidelines criteria and compared these with the physician's decision regarding hospitalization. We assessed the consequence of these decisions on 30-day serious cardiac events and mortality. We validated our findings in a large American cohort recruiting syncope patients >60 years in 11 EDs. Results 1977 patients were eligible for this analysis. 215 (10.8%) experienced 30-day Major Adverse Cardiovascular Events (MACE). The ESC and AHA guidelines would have admitted a largely different number of patients (75.9% vs 29.6%) and provided different safety regarding adverse events and death at 30 days (Figure). The validation in the US cohort provided similar results, however US ED physicians decided to admit more patients (84%) as compared with the international derivation cohort (46.6%). Conclusion The AHA and ESC syncope guidelines recommend admission based on very different criteria and for a largely different number of patients. While the most recent ESC guidelines were written with the aim to limit the number of patients admitted, they still classify a large majority of an ED syncope cohort as high risk and warranting admission. The large discrepancy between the two guidelines is based on the criteria used for the classification: While the ESC guidelines consider risk factors, previous cardiac history, physical examination and ECG criteria, the AHA guidelines focus on serious conditions previously known or diagnosed in the ED. Figure: Percentage of the overall cohort admitted (green) or discharged (red) according to the AHA and ESC guidelines and to the decision of the physician in the BASEL-IX cohort. Patients experiencing a cardiac syncope, a 30-day MACE or death are represented for both the discharged and admitted groups. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University hospital Basel

Validation of the FAINT risk score in a large prospective international multicenter study

Abstract Background Risk stratification of older patients presenting to the Emergency Department (ED) with syncope remains an unmet clinical need. The FAINT Score was derived in a large American cohort in an attempt to predict 30-day serious cardiac outcomes in patients >60y.o. While a FAINT score of 0 showed high sensitivity to exclude death and serious outcomes at 30 days in the derivation cohort, it remains unvalidated. Methods We validated the FAINT score (History of heart failure, history of arrhythmia, initial ECG result abnormal, elevate NT-proBNP, elevated hs-troponin T) in a large prospective international multicenter study recruiting patients 40 years presenting to the ED with syncope within the last 12 hours in eight countries on three continents. Main outcome measure was 30-day serious cardiac events or mortality. We assessed the performance and calibration of the FAINT score for validation and compared it to the OESIL score (Age >64y, cardiovascular disease history, syncope without prodromes, abnormal ECG). Results 1885 patients were eligible for this validation analysis. 169 (8.9%) patients experienced 30-day serious adverse events. A FAINT score of 0 was present for 378 patients (20% of the cohort) and allowed for a sensitivity of 0.97 to rule out adverse events and death at 30-days. A FAINT score of 0 or 1 was present for 626 patients (33% of the cohort) and allowed for a sensitivity of 0.92. The area under the receiver operating characteristic curve (AUC) for the FAINT score was 0.75 (95%, Confidence Interval (CI) 0.72–0.79), which was comparable to the performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or high-sensitivity Troponin T (hs-cTnT) alone, which are two biomarkers used in the FAINT score. The score did not outperform the OESIL score. A calibration curve showed that the score was extremely well calibrated for low-risk patients. Conclusion This is the first validation of the FAINT score in a large international syncope cohort. The safety of a FAINT score of 0 or 1 was good and comparable to the results obtained in the derivation cohort. While the score is suitable to highlight low-risk patients and calibrates well in an external cohort, its discrimination for higher risk patients is not better than biomarkers alone or an older, less complex risk score. Figure 1. Area under the Receiver Operating Curve (ROC) for the FAINT score and for NT-proBNP and hs-cTnT as continuous markers as well as for the OESIL score. CI = Confidence Interval. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University Hospital Basel, Switzerland

External validation of a clinical decision rule to identify patients at low risk for acute coronary syndrome who do not need objective coronary artery disease testing

Abstract Background Rapid high-sensitivity cardiac troponin (hs-cTn) based algorithms have substantially improved the early rule-out of acute myocardial infarction (AMI) and thereby facilitated the selection of patients eligible for outpatient management. However, it remains unclear, which patients after rule-out of AMI should still undergo objective anatomic or functional cardiac testing for the detection of relevant coronary artery disease. A pilot study has derived a clinical decision rule for the selection of patients who do not need objective anatomic or functional cardiac testing for coronary artery disease (“No Objective Testing” (NOT) rule). Purpose To externally validate the performance of the NOT-rule in a multicentre study. Methods Patients presenting to the ED with symptoms suggestive of an acute coronary syndrome (ACS) were enrolled in a large prospective international multicentre study at 12 study sites in five European countries. Two independent cardiologists centrally adjudicated the final diagnosis using all clinical data including cardiac imaging and at least 90-day follow-up. The NOT-rule is applied in patients, in whom a 2h accelerated diagnostic protocol (using hs-cTnI concentrations at 0h/2h and ECG data) has ruled-out AMI and based on clinical variables. In brief, the first rule is a weighted score derived from independent predictors of ACS that classifies patients as low-risk if they score ≤4 points. The second rule was simplified and ruled patients out if they were younger than 50 years, had no history of an AMI or known CAD, and no prescribed nitrates. The third rule equals the second except nitrate use was omitted. Primary objective was the safety and efficacy of the NOT-rules for rule-out of major adverse cardiac events (MACE) including AMI, unstable angina pectoris, urgent or emergency revascularisation or cardiovascular death at 30-days of follow-up. Secondary objective was the safety and efficacy for rule-out of MACE at 2-years. Results Out of 3188 enrolled patients, 2162 (68%) had hs-cTnI concentrations at 0h and 2h below the 99th centile as well as a non-diagnostic ECG and were therefore eligible for the analysis. MACE at 30-days occurred in 302 (14%) patients. The second and third rule offered highest safety and efficacy for rule-out of MACE at 30-days. Both identified 492 (23%) patients at low-risk with a sensitivity of 99.7% (95% CI 98.2–99.9%) and a negative predictive value (NPV) of 99.8% (95% CI 98.6–99.9%). One MACE was missed within 30-days (revascularisation of a one-vessel CAD). Sensitivity 98.9% (95% CI 97.1–99.7%) and NPV 99.2% (95% CI 97.8–99.7) were also very high for 1-year MACE, as well as 2-year MACE 98.4% (95% CI 96.5–99.4%) and 98.4% (95% CI 96.5–99.3%), respectively. Conclusions The NOT rules proved to be a safe tool that identifies nearly one-fourth of patients at very low risk for MACE, who may not need objective anatomic or functional cardiac testing for coronary artery disease. Performance of NOT rules Funding Acknowledgement Type of funding source: Other. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel, the University Hospital Basel

Incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope

Abstract Background Cardiac syncope has been shown to carry the highest hazard for all-cause death compared to other causes of syncope including vasovagal and orthostatic syncope. However, little is known about the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Purpose To evaluate the incidence, characteristics and prognosis of different cardiac etiologies underlying cardiac syncope. Methods We enrolled patients presenting to the emergency department (ED) with syncope in a large prospective international multicentre study. The cause of syncope (cardiac vs non-cardiac) including the detailed cardiac aetiology (if cardiac) was centrally adjudicated by two independent cardiologists based on detailed in-hospital as well as outpatient cardiac work-up during 360 days following presentation. Cardiac syncope was classified into four groups: bradyarrhythmia, tachyarrhythmia, structural disease and other (cardiopulmonary and great vessels), as recommended in the ESC Syncope Guidelines. All-cause death during 2-years follow-up was the primary outcome. Results Among 2025 patients presenting with syncope to the ED, cardiac syncope was the final adjudicated diagnoses in 318 (15.7%) patients. The incidence rate of all-cause death among cardiac syncope patients was 103 cases per 1000 person-years. Bradyarrhythmia was the most frequent primary cause of cardiac syncope (n=146, 45.9%) followed by tachyarrhythmia (n=75, 23.6%), structural disease (n=64, 20.1%) and other cardiac (n=26, 8.2%). Patients were 37% female with a median age of 77 years (IQR 67–83) showing no statistically significant difference between subgroups. Clinical characteristics differed significantly among the four subgroups. E.g. syncope occurred during exercise in 12 patients (8.2%) with bradyarrhythmia, 10 patients (13.3%) with tachyarrhythmia, 16 patients (25%) with structural disease, and 5 patients (19%) with other cardiac (p<0.01). Likely of most importance, long-term mortality differed significantly among the four different cardiac subgroups. The multivariable-adjusted hazard ratios (HR) among patients with bradyarrhythmia, tachyarrhythmia, structural disease and other cardiac as compared to patients with vasovagal syncope, the HR were 1.3 (95% CI 0.7–2.5), 4.6 (95% CI 2.3–9.1), 3.1 (95% CI 1.5–6.4) and 5.9 (95% CI 2.3–15.2), respectively (Figure 1). Conclusions Bradyarrhythmia, tachyarrhythmia, and structural cardiac disease are the dominant causes of cardiac syncope. Interestingly, with the appropriate therapy initiated long-term mortality of bradyarrhythmia is comparable to that of vasovagal syncope, while long-term mortality of tachyarrhythmia and structural cardiac disease were substantially increased 3 to 5 fold. Figure 1. Kaplan-Meier curve Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Swiss National Science Foundation, the Swiss Heart Foundation, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel and the University Hospital Basel.

Evaluation of Surgical Learning Curve Effect on Obstructive Sleep Apnea Outcomes in Upper Airway Stimulation.

An increasing number of facilities offer Upper Airway Stimulation (UAS) with varying levels of experience. The goal was to quantify whether a surgical learning curve exists in operative or sleep outcomes in UAS. International multi-center retrospective review of the ADHERE registry, a prospective international multi-center study collecting UAS outcomes. ADHERE registry centers with at least 20 implants and outcomes data through at least 6-month follow-up were reviewed. Cases were divided into two groups based on implant order (the first 10 or second 10 consecutive implants at a given site). Group differences were assessed using Mann-Whitney U-tests, Chi-squared tests, or Fisher's Exact tests, as appropriate. A Mann-Kendall trend test was used to detect if there was a monotonic trend in operative time. Sleep outcome equivalence between experience groups was assessed using the two one-sided tests approach. Thirteen facilities met inclusion criteria, contributing 260 patients. Complication rates did not significantly differ between groups (P = .808). Operative time exhibited a significant downward trend (P < .001), with the median operative time dropping from 150 minutes for the first 10 implants to 134 minutes for the subsequent 10 implants. The decrease in AHI from baseline to 12-month follow-up was equivalent between the first and second ten (22.8 vs 21.2 events/hour, respectively, P < .001). Similarly, the first and second ten groups had equivalent ESS decreases at 6 months (2.0 vs 2.0, respectively, P < .001). ESS outcomes remained equivalent for those with data through 12-months. Across the centers' first 20 implants, an approximately 11% reduction operative time was identified, however, no learning curve effect was seen for 6-month or 12-month AHI or ESS over the first twenty implants. Ongoing monitoring through the ADHERE registry will help measure the impact of evolving provider and patient specific characteristics as the number of implant centers increases.

Do Knee Osteoarthritis Patterns Affect Patient-Reported Outcomes in Total Knee Arthroplasty? Results From an International Multicenter Prospective Study With 3-Year Follow-Up

BackgroundThe aim of this multicenter study is to answer (1) Does patellofemoral osteoarthritis (OA) affect preoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) scores in total knee arthroplasty (TKA)? and (2) Do different OA patterns affect preoperative and postoperative KOOS scores in TKA? MethodsThis international, multicenter prospective study examined 384 TKA patients. Compartmental OA was divided into (1) medial, (2) medial + patellofemoral, (3) lateral, (4) lateral + patellofemoral, (5) medial + lateral (bicompartmental), and (6) medial + lateral + patellofemoral (tricompartmental), based on preoperative anterior-posterior and lateral ± skyline radiographs with Kellgren-Lawrence grade III-IV and joint space width <2.5 mm. KOOS was collected preoperatively, 1 year postoperatively, and 3 years postoperatively. Higher KOOS score represented better clinical state, for example, higher KOOS Pain score indicated less pain. ResultsPatellofemoral OA had no effect on preoperative KOOS scores (P > .15). Compared to medial ± patellofemoral OA patients, bicompartmental/tricompartmental OA patients had less preoperative pain (KOOS Pain 7.4, P = .03) and higher daily function (KOOS-ADL [Activities of Daily Living] 7.1, P = .05), and higher 1-year postoperative daily function (KOOS-ADL 9.2, P = .03) and sports activity (KOOS Sports & Recreation Function 15.0, P = .04), while lateral ± patellofemoral OA patients had more symptoms (KOOS-Symptoms 7.0, P < .01), more pain (KOOS-Pain 7.5, P = .01), lower daily function (KOOS-ADL 9.3, P < .01), and lower quality of life (KOOS-QOL 9.0, P = .04), at 3 years postoperatively. ConclusionPatellofemoral OA does not affect medial ± lateral OA patients’ preoperative KOOS scores, challenging the importance of patellofemoral OA in TKA. Lateral ± patellofemoral OA patients have lower postoperative KOOS scores than medial/more progressed compartmental OA patients, indicating that patients with less common OA patterns present with unique surgical challenges. Further development of indications for and correct timing of TKA surgery in different patient subgroups is needed.

Safety and efficacy of non-vitamin K antagonist oral anticoagulants for prevention of thromboembolism in adults with systemic right ventricle: Results from the NOTE international registry

BackgroundPatients with systemic right ventricle (sRV), including transposition of great arteries (TGA) after atrial switch procedure and congenitally corrected transposition of great arteries (ccTGA), may require anticoagulation for thromboembolism (TE) prevention. In the absence of data on non-vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonists (VKAs) remain the agent of choice. We investigated the safety, efficacy and feasibility of NOACs treatment in adults with sRV in a worldwide study. MethodsThis is an international multicentre prospective study, using data from the NOTE registry on adults with sRV taking NOACs between 2014 and 2019. The primary endpoints were TE and major bleeding (MB). The secondary endpoint was minor bleeding. ResultsA total of 76 patients (42.5 ± 10.0 years, 76% male) with sRV (74% TGA, 26% ccTGA) on NOACs were included in the study. During a median follow-up of 2.5 years (IQR1.5–3.9), TE events occurred in 3 patients (4%), while no MB episodes were reported. Minor bleeding occurred in 9 patients (12%). NOAC treatment cessation rate was 1.4% (95%CI:0.3–4%) during the first year of follow-up. All the patients with TE events had a CHA2DS2-VASc score ≥ 2 and impaired sRV systolic function at baseline. The total incidence of major events during follow-up was significantly lower compared to historical use of VKAs or aspirin before study inclusion (1.4% (95%CI:0.29–4%) vs 6,9% (95%CI:2.5–15.2%); p = .01). ConclusionsIn this prospective study, NOACs appear to be well-tolerated, with excellent efficacy and safety at mid-term in patients with sRV.

C-reactive protein trajectory to predict colorectal anastomotic leak: PREDICT Study.

Anastomotic leak is a common complication after colorectal surgery, associated with increased morbidity and mortality, and poorer long-term survival after oncological resections. Early diagnosis improves short-term outcomes, and may translate into reduced cancer recurrence. Multiple studies have attempted to identify biomarkers to enable earlier diagnosis of anastomotic leak. One study demonstrated that the trajectory of C-reactive protein (CRP) levels was highly predictive of anastomotic leak requiring intervention, with an area under the curve of 0·961. The aim of the present study was to validate this finding externally. This was a prospective international multicentre observational study of adults undergoing elective colorectal resection with an anastomosis. CRP levels were measured before operation and for 5 days afterwards, or until day of discharge if earlier than this. The primary outcome was anastomotic leak requiring operative or radiological intervention. Between March 2017 and July 2018, 933 patients were recruited from 20 hospitals across Australia, New Zealand, England and Scotland. Some 833 patients had complete CRP data and were included in the primary analysis, of whom 41 (4·9 per cent) developed an anastomotic leak. A change in CRP level exceeding 50 mg/l between any two postoperative days had a sensitivity of 0·85 for detecting a leak, and a high negative predictive value of 0·99 for ruling it out. A change in CRP concentration of more than 50 mg/l between either days 3 and 4 or days 4 and 5 after surgery had a high specificity of 0·96-0·97, with positive likelihood ratios of 4·99-6·44 for a leak requiring intervention. This study confirmed the value of CRP trajectory in accurately ruling out an anastomotic leak after colorectal resection.

Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study.

SummaryHealthcare workers involved in aerosol‐generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID‐19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID‐19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self‐reporting. The primary endpoint was the incidence of laboratory‐confirmed COVID‐19 diagnosis or new symptoms requiring self‐isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure‐related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow‐up of 32 (18–48 [0–116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID‐19 subsequently reported a COVID‐19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID‐19 transmission.

Myocardial Edema, Myocyte Injury, and Disease Severity in Fabry Disease.

Background Cardiovascular magnetic resonance can demonstrate myocardial processes in Fabry disease (FD), such as low native T1 (sphingolipid storage) and late gadolinium enhancement (LGE, scar). Recently, high T2 (edema) has been observed in the basal inferolateral wall along with troponin elevation. We hypothesized that edema and myocyte injury would be chronically associated and have electrical, mechanical, and disease associations in FD. Methods A prospective international multicenter study was conducted on 186 consecutive FD patients (45.2±1.1 years, 58% females). Additionally, 28 patients with hypertrophic cardiomyopathy, 30 with chronic myocardial infarction and 59 healthy volunteers were included. All study participants underwent comprehensive cardiovascular magnetic resonance with T1 and T2 mapping, cines, and LGE imaging. Results LGE in the basal inferolateral wall in FD had T2 elevation (FD 58.2±5.0 ms versus hypertrophic cardiomyopathy 55.6±4.3 ms, chronic myocardial infarction 53.7±3.4 ms and healthy volunteers 48.9±2.5 ms, P<0.001), but when LGE was present there was also global T2 elevation (53.1±2.9 versus 50.6±2.2 ms, P<0.001). Thirty-eight percent of FD patients had high troponin. The strongest predictor of increased troponin was high basal inferolateral wall T2 (odds ratio, 18.2 [95% CI, 3.7-90.9], P<0.0001). Both T2 and troponin elevations were chronic over 1 year. High basal inferolateral wall T2 was associated with baseline global longitudinal strain impairment (P=0.005) and electrocardiographic abnormalities (long PR, complete bundle branch block, left ventricular hypertrophy voltage criteria, long QTc, and T-wave inversion, all P<0.05) and predicted clinical worsening after 1 year (Fabry stabilization index >20%, P=0.034). Conclusions LGE in Fabry has chronic local T2 elevation that is strongly associated with chronic troponin elevation. In addition, there is slight global T2 elevation. Both are associated with ECG and mechanical changes and clinical worsening over 1 year.

Mitral and aortic paravalvular leaks closure: Insights from the prospective international multicenter FFPP cohort study

Percutaneous paravalvular leak closure (PVLc) has emerged as an alternative to surgery. It remains a technically challenging procedure. We aim to compare outcomes after mitral and aortic PVLc. We analyzed data from PVLc procedures performed over the 2 first years of inclusion in the FFPP (Fermeture de Fuite Périprothétique) study, a prospective observational industry-independent cohort study which started in January 2017. We analyzed 147 PVLc (99 mitral–48 aortic), performed in 127 patients (1 procedure in 109 patients, 2 in 16 and 3 in 2) included in 22 centers among 3 countries (France, Poland and Belgium). Age (69 ± 10 versus 69 ± 11 yo), left ventricular ejection fraction (56 versus 51%), Euroscore2 (9 versus 7.6) and rate of mechanical valve (56.7% versus 41.7%, P = 0.1) were not significantly different among mitral and aortic groups. All patients had heart failure and/or hemolytic anemia. Hemolysis was more common in mitral PVL (62 versus 43%, P = 0.04). A mean of 1.4 (min 1, max 3) and 1.8 (min 1 max 5) devices were respectively required for technically successful aortic and mitral PVLc. No complication was reported in procedures with failure of device implantation. Aortic PVLc were faster than mitral PVLc (1h18 versus 2h20), with a trend towards a higher rate of technical success (96% versus 87%, P = 0.1) and fewer rate of major adverse events (worsening hemolysis, stroke, life threatening events and deaths; 2% versus 14%, P = 0.02). At 1 month follow-up, events were reported in 2% of patients (blood transfusion for hemolysis) versus 26.2% (deaths 3.3%; hemolysis 14.8%; heart failure 3.3%; heart failure and hemolysis 4.9%) after successful aortic and mitral PVLc respectively, P = 0.6. Mitral PVLc is a more complex procedure than aortic PVLc, with a lower success rate and a higher risk of peri-procedural and one-month severe adverse events. Longer follow-up data are expected and will be available from this on-going study.

Responsiveness of quality-of-life measures in patients with peripheral vascular malformations: the OVAMA project.

SummaryBackgroundThe OVAMA (Outcome Measures for Vascular Malformations) project determined quality of life (QoL) as a core outcome domain for patients with vascular malformations. In order to measure how current therapeutic strategies alter QoL in these patients, a patient‐reported outcome measurement (PROM) responsive to changes in QoL is required.ObjectivesTo assess the responsiveness of two widely used generic QoL PROMs, the Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29, in adult patients with vascular malformations.MethodsIn an international multicentre prospective study, treated and untreated patients completed the SF‐36 and Skindex‐29 at baseline and after a follow‐up period of 6–8 weeks. Global rating of change (GRC) scales assessing various QoL‐related outcome domains were additionally completed. Per subscale, responsiveness was assessed using two methods: by testing hypotheses on expected correlation strength between change scores of the questionnaires and the GRC scales, and by calculating the area under the receiver operating characteristics curve (AUC). The questionnaires were considered responsive if ≥ 75% of the hypotheses were confirmed or if the AUC was ≥ 0·7.ResultsEighty‐nine participants were recruited in three centres in the Netherlands and the U.S.A., of whom 67 completed all baseline and follow‐up questionnaires. For all subscales of the SF‐36 and Skindex‐29, < 75% of the hypotheses were confirmed and the AUC was < 0·7.ConclusionsOur findings suggest that the SF‐36 and Skindex‐29 seemed unresponsive to change in QoL. This suggests that alternative PROMs are needed to measure – and ultimately improve – QoL in patients with vascular malformations. What's already known about this topic? Quality of life is often impaired in patients with vascular malformations.Quality of life is considered a core outcome domain for evaluating treatment of vascular malformations.To measure the effect of treatment on quality of life, a patient‐reported outcome measure is required that is responsive to changes in quality of life. What does this study add? This is the first study assessing the responsiveness of quality‐of‐life measures in patients with vascular malformations.The results seem to indicate that the Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29 are not responsive to changes in quality of life in patients with vascular malformations. What are the clinical implications of this work? Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29 are not ideal to assess the effect on quality of life over time, of treatment strategies for peripheral vascular malformations.

A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was ‘programming/stimulation’ (in 26 patients), followed by ‘New illness, injury, condition’ (13 patients) and ‘pre-existing condition, worsening or exacerbation’ (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation - a prospective, non-interventional study of the EBMT Transplant Complication Working Party.

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0–2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7–4.7, P<0.0001) and progression free survival (HR 1.6, 95% CI: 1.1–2.4, P=0.025). Non-relapse mortality was significantly increased in alloSCT recipients with high uric acid levels (HR 2.7, 95% CI: 1.4–5.0, P=0.003). Finally, the incidence of relapse after alloSCT was increased in patients with higher uric acid levels (HR 1.6, 95% CI: 1.0–2.5, P=0.04). We conclude that high uric acid levels before the start of conditioning correlate with increased mortality after alloSCT.

2409ALERT-CS - Development of an ECG-based cardiac syncope risk calculator

Abstract Background Syncope is a common symptom with rising incidence, often leading to emergency department (ED) visits. Early determination of diagnosis is often difficult in patients with syncope and there is an unmet clinical need for tools that can support physicians in their decision making. We hypothesized that an electrocardiogram (ECG)-based cardiac syncope risk calculator might create a simple and attractive clinical decision tool for the diagnosis and risk stratification of patients with syncope. Methods Based on a large prospective diagnostic international multicenter study enrolling patients who presented to the ED with syncope, we derived a cardiac syncope risk calculator by penalized stepwise backward-selection and multivariable logistic regression utilizing predefined ECG criteria. Primary diagnostic endpoint was cardiac syncope, as adjudicated by two independent physicians taking into account all available information including cardiac work-up and 12-month follow-up. Major adverse cardiac events (MACE) including life-threatening arrhythmias, myocardial infarction, pulmonary embolism, stroke, transient ischemic attack, valvular surgery, and death within 30 days were the prognostic endpoint. Results Median age in our cohort was 71 years and 40% of patients were women. Of all 2007 patients enrolled, 1696 patients were eligible for the prognostic analysis and 1550 patients were eligible for the diagnostic analysis. We identified seven ECG criteria (rhythm, heart rate, corrected QT-interval, ST-segment depression, atrioventricular-block, bundle-branch-block and ventricular extrasystole/non-sustained ventricular tachycardia) as significant predictors for cardiac syncope and combined them into the bAseL Ecg Risk calculaTor for Cardiac Syncope (ALERT-CS). Diagnostic accuracy for cardiac syncope, as quantified by the area under the receiver operating characteristic curve (AUC), was high (AUC 0.80, 95%-confidence interval (CI) 0.77 to 0.83), and significantly higher compared to that of the EGSYS score (AUC 0.73, 95%-CI 0.70 to 0.76, p&lt;0.001). Prognostic verification of the ALERT-CS to predict 30-day overall MACE showed similar accuracy (AUC 0.75, 95%-CI 0.71 to 0.79). Comparison of diagnostic discrimination Conclusion Combining seven ECG criteria within a simple risk calculator for cardiac syncope may aid physicians in the diagnosis and risk stratification of patients presenting to the ED with syncope. Acknowledgement/Funding Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University Basel

248Real-world Outcome of the ESC 0/1-hour Algorithm when Routinely Applied in Early Presenters

Abstract Background The European Society of Cardiology (ESC) recommends the use of a 0/1h-algorithm for rapid triage of patients with suspected non-ST-elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin (hs-cTn). Concerns were articulated about its efficacy and particularly safety when applied in patients presenting early (≤3 hours) after chest pain onset, as hs-cTn concentrations might still be very low or even undetectable in these high-risk patients. Purpose We aimed to assess the real-world effectiveness, efficacy, and ultimately safety of the ESC 0/1h-algorithm when routinely applied in early presenters. Methods In a prospective international multicenter study enrolling unselected patients presenting with suspected NSTEMI to the ED, patients were assessed according to the ESC 0/1h-algorithm using high-sensitivity cardiac troponin T embedded in routine clinical care. Patients with ST-segment elevation myocardial infarctions were excluded. Safety was quantified by the 30-day incidence of major adverse cardiac events (MACE, defined as the composite of cardiovascular death and myocardial infarction including the index event) in the rule-out group and in outpatients. Results Among 2296 patients, 819 (36%) were early presenters. NSTEMI prevalence in early presenters was 11%. Effectiveness was very high as 97% of patients triaged towards rule-out by the ESC 0/1h-algorithm did not require additional cardiac investigations including hs-cTnT measurements at later time points (e.g. 3–12h) or coronary CT-angiography in the ED. Median time to discharge or transfer from the ED was 150 minutes [q1130, q3215]. Efficacy of the ESC 0/1h-algorithm was very high: 67% of patients were triaged towards rule-out and 14% towards rule-in of NSTEMI. Overall, 75% of early presenters underwent outpatient management. Safety of rule-out and outpatient management were excellent in early presenters with a 30-day MACE incidence of both 0% and comparable with 0.3% and 0.1% in late presenters, respectively (p=ns). Conclusions These real-world data document for the first time the excellent effectiveness, efficacy and particularly safety of the ESC 0/1h-algorithm when routinely applied in early presenters. No differences in safety could be observed when compared with late presenters.

P1579Impact of Renal Dysfunction on Real-world Outcome of the ESC 0/1-hour Algorithm

Abstract Background The ESC recommends the use of a 0/1h-algorithm for rapid triage of patients with suspected non-ST-elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. Patients with renal dysfunction (RD, defined as a GFR &lt;60ml/min) are at higher risk of NSTEMI and are presenting more often with elevated levels of hs-cTn even in absence of NSTEMI, which may contribute to an impaired efficacy and safety of the ESC 0/1h-algorithm. Purpose We aimed to assess and directly compare the real-world adherence, effectiveness, efficacy, and ultimately safety of the ESC 0/1h-algorithm when applied in patients with RD and normal renal function. Methods In a prospective international multicenter study enrolling unselected patients presenting with suspected NSTEMI to the ED, patients were assessed according to the ESC 0/1h-algorithm embedded in routine clinical care. Safety was quantified by the 30-day incidence of major adverse cardiac events (MACE, defined as the composite of cardiovascular death and myocardial infarction including the index event) in the rule-out group and in outpatients. Results Among 2296 enrolled patients, RD was present in 129 (6%) patients. NSTEMI prevalence was substantially higher in RD as compared with normal renal function (19% versus 9%, p&lt;0.001). Adherence to the ESC 0/1h-algorithm protocol was excellent with no violations observed in patients with RD as compared with 132 (6%) violations in patients with normal renal function (p=0.004). Effectiveness was very high in RD and comparable to normal renal function: 94% of patients triaged towards rule-out by the ESC 0/1h-algorithm did not require additional cardiac investigations including hs-cTnT measurements at later time points (e.g. 3–12h) or coronary CT-angiography in the ED as compared with 98% in normal renal function. Median time to discharge or transfer from the ED was significantly longer in RD (285 minutes [q1174, q3392]) as compared with normal renal function (150 minutes [q1132, q3222]). Efficacy of the ESC 0/1h-algorithm was lower in RD as it triaged 13% of patients towards rule-out and 34% towards rule-in of NSTEMI as compared with 65% and 12% in normal renal function, respectively (p&lt;0.001). Overall, 30% of patients with RD underwent outpatient management as compared with 73% in normal renal function (p&lt;0.001). Safety of rule-out and outpatient management were excellent in RD with a 30-day MACE incidence of both 0% and comparable with 0.2% and 0.1% in normal renal function, respectively (p=0.010). Conclusions These real-world data document for the first time the excellent adherence, effectiveness, and safety of the ESC 0/1h-algorithm when routinely applied in patients with RD. Compared with patients with normal renal function, fewer patients with RD could be triaged towards rule-out or were treated as outpatients, most likely due to the higher prevalence of NSTEMI and comorbidities in RD.

P5673Combination of high-sensitivity cardiac troponin and B-Type natriuretic peptide (BNP) for diagnosis and risk-stratification of syncope

Abstract Background While high-sensitivity cardiac troponin (hs-cTn) and B-Type natriuretic peptide (BNP) have been assessed separately for the diagnosis and risk-stratification of patients with syncope, their combined accuracy is unknown. Methods We assessed the diagnostic and prognostic accuracy of the combination of hs-cTnI and BNP in a prospective international multicenter study enrolling patients 40 years and older presenting with syncope to the emergency department (ED). Hs-cTnI (Architect) and BNP (Architect) concentrations were measured in a blinded fashion. Cardiac syncope, as adjudicated by two independent physicians using all available clinical information including one year follow-up, was the diagnostic endpoint. MACE were defined as death, resuscitation, life-threatening arrhythmia, implantation of a pacemaker or implantable cardioverter defibrillator (ICD), acute myocardial infarction, pulmonary embolism, stroke/transient ischemic attack (TIA), intracranial bleeding or valvular intervention. Patients were classified in three risk groups (low (&lt;10%), medium (10–30%), high (&gt;30%)) for cardiac syncope based on hs-cTnI and BNP levels. Results Among 1533 patients, cardiac syncope was the adjudicated final diagnosis in 233 (15.2%). Hs-cTnI and BNP concentrations both remained independent predictors of cardiac syncope in multivariable models. The diagnostic accuracy of the combination hs-cTnI/BNP for cardiac syncope was good with an area under the curve (AUC) of 0.81 (95%-CI 0.78–0.84) and significantly better than each biomarker separately or a set of clinical variables (each p&lt;0.001). The classification of patients in three risk groups, depending on the probability for cardiac syncope based on their hs-cTnI and BNP values, translated well in predictions for MACE (AUC 0.79, 95%-CI 0.77–0.82) and death (AUC 0.78, 95%-CI 0.74–0.82) at 2 years follow-up. Based on these results, we designed a visual tool allowing convenient patient-specific diagnostic and prognostic risk evaluation based solely on hs-cTnI and BNP concentrations (Figure). Risk stratification based on hs-cTnI/BNP Conclusion The combination hs-cTnI/BNP may have clinical utility in patients presenting to the ED with syncope as it allows good diagnostic as well as prognostic discrimination. Acknowledgement/Funding Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University Basel