Primary Outcome Event Rate Research Articles

Association Between Hospital Policy on Local Versus General Anesthesia, and Outcomes of Carotid Endarterectomy

BACKGROUND Carotid endarterectomy (CEA) is an established procedure for the treatment of extracranial internal carotid artery stenosis. However, the type of anesthesia during elective CEA is still under debate. This study analyzes the association between the hospital policy on local anesthesia (LA) versus general anesthesia, and the outcome of elective CEA in German hospitals. METHODS This retrospective analysis is based on the nationwide German statutory carotid quality assurance database for the years 2012 to 2016. Research was funded by Germany's Federal Joint Committee Innovation Fund (funding reference number 01VSF19016). Emergency CEA and carotid stenting procedures were excluded from the analysis. A total of 119 800 patients remained in the analysis. Hospitals were classified on a yearly basis as routine general anesthesia (<10% LA), selective LA (10%–90% LA), or routine LA centers (>90% LA). The primary outcome event was the combined in‐hospital rate of stroke or death. Secondary outcome events were in‐hospital stroke, major stroke or death, death, myocardial infarction, and major adverse cardiovascular events. Univariate and multivariable regression analyses were performed to analyze associations between the primary outcome event and the hospital policy on LA versus general anesthesia as well as clinical or procedural variables. RESULTS Patient characteristics did not differ significantly between the groups (age, degree of stenosis, and rate of symptomatic patients). Raw primary outcome event rates were 1.9%, 2.1%, and 1.6% in routine general anesthesia, selective LA, and routine LA centers, respectively. Multivariable analysis revealed a significant lower rate of the primary outcome event for CEA operated under LA (adjusted odds ratio, 0.47 [95% CI, 0.33–0.67]; P <0.001). Stratified multivariable analysis revealed that the beneficial effect of LA was only present in routine LA centers. CONCLUSION LA is associated with a lower risk of in‐hospital stroke or death after CEA in centers that use LA routinely.

Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial

BackgroundStereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75–85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation.ObjectiveA single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk.MethodsPatients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D.DiscussionDEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure.Trial registrationNCT05594368.

Efficacy of a Newly Developed Guidewire for Selective Biliary Cannulation: A Multicenter Randomized Controlled Trial.

Various guidewires are used for biliary cannulation, and each one has its own characteristics affecting its effectiveness. This study aimed to measure the basic properties and evaluate the effectiveness of a newly developed 0.025-inch guidewire for selective biliary cannulation. A total of 190 patients at five referral hospitals were randomly allocated to undergo selective biliary cannulation using the newly developed guidewire (NGW group, n = 95) or a conventional guidewire (CGW group, n = 95). The primary outcome was the selective biliary cannulation rate in naïve papillae. The secondary outcome was to measure the NGW basic properties, compare them with those of the CGW, and analyze the importance of basic property differences. There were no significant differences between the groups in the baseline characteristics. The primary outcome (75.8% vs. 84.2%, p = 0.102) and adverse event rate (6.3% vs. 4.2%, p = 0.374) were similar in both groups. However, compared with the CGW group, the NGW group showed a higher number of ampulla contacts (2.58 vs. 2.02, p = 0.011) and longer cannulation time (216.5 vs. 135.1 s, p = 0.016). Furthermore, the NGW group had higher maximum friction (34.6 ± 1.34 vs. 30.2 ± 4.09), lower stiffness, and better elastic resiliency. In the multivariate analysis, a curved-tip GW (OR = 0.26, 95% CI 0.11-0.62, p = 0.002) and normal papillary shape (OR = 0.39, 95% CI 0.17-0.86, p = 0.021) were contributing factors for successful selective biliary cannulation. The NGW group had high friction and low stiffness, characteristics affecting biliary cannulation. Clinically, the NGW group had similar success and adverse event rates as the CGW, but they showed a higher number of ampulla contacts and longer cannulation time.

Recency of Heart Failure Hospitalization, Outcomes, and the Effect of Empagliflozin: An EMPEROR-Pooled Analysis

BackgroundPatients with a recent heart failure (HF) hospitalization have a high risk of rehospitalization and mortality. Early treatment may have a substantial impact on patient outcomes. ObjectivesThis study sought to study the outcomes and effect of empagliflozin according to timing of prior HF hospitalization. MethodsEMPEROR-Pooled (EMPEROR-Reduced [EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction] and EMPEROR-Preserved [EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction] combined) included 9,718 HF patients who were grouped according to the recency of HF hospitalization (none, <3 months, 3-6 months, 6-12 months, >12 months). The primary outcome was a composite of time to first of HF hospitalization or cardiovascular death, over a median follow-up of 21 months. ResultsThe primary outcome event rates (per 100 person-years) in the placebo group were 26.7, 18.1, 13.7, and 2.8 for patients hospitalized within 3 months, 3-6 months, 6-12 months, and >12 months, respectively. The relative risk reduction of primary outcome events with empagliflozin was similar across HF hospitalization categories (P interaction = 0.67). The primary outcome absolute risk reduction was more pronounced among patients with a recent HF hospitalization but without statistical heterogeneity of treatment effect: −6.9, −5.5, −0.8, and −0.6 events prevented per 100 person-years for patients hospitalized within <3 months, 3-6 months, 6-12 months, and >12 months, respectively, and −2.4 events prevented per 100 person-years of follow-up in those without a prior HF hospitalization (P interaction = 0.64). Empagliflozin was safe irrespective of HF hospitalization recency. ConclusionsPatients with a recent HF hospitalization have a high risk of events. Empagliflozin reduced HF events regardless of HF hospitalization recency.

Association between dosing of spironolactone and outcomes in heart failure with preserved ejection fraction patients combined with chronic kidney disease------Balance of efficacy and risk.

Aims: Few studies have compared the association between dosing of spironolactone and outcomes in patients with heart failure with preserved ejection fraction (HFpEF), and whether spironolactone dose could significantly affect the prognosis of HFpEF patients combined with chronic kidney disease (CKD) remains unclear. Our aim was to directly compare 'high vs. low' doses of spironolactone in an attempt to find a benefit-risk-balanced point, and infer an adequate dose for HFpEF with CKD patients. Methods: Overall, 4,321 symptomatic heart failure inpatients were initially screened from January 2013 to December 2019, and all enrolled patients were followed-up for 36months; After including patients who meet the diagnostic criteria of HFpEF and CKD with ejection fraction > 45% and estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2, a total of 387 patients was selected. Primary outcome was a composite of all-cause death, heart failure (HF) hospitalization and non-fatal stroke. The key safety outcome was hyperkalemia rates during the follow-up period. Results: The primary outcome event rates in patients with or without spironolactone were 12.74 and 21.45 per 100 person-years, respectively. Compared with patients not taking spironolactone, the adjusted hazard ratio (HR) [95% confidence interval (CI)] was 0.55 (0.38-0.79) with spironolactone group for primary outcomes. After grouped by the daily dose of spironolactone, low-dose group (≤ 40mg) was associated with lower relative risk for the primary efficacy outcome [adjusted HR (95% CI) was 0.43 (0.23-0.81), 0.50 (0.33-0.76) and 0.74 (0.36-2.79) with < 40mg, 40mg and >40mg, respectively]. During 3-year follow-up, the risk for hyperkalemia was amplified in the higher dose group (>40mg) while showed no significant difference compared with low dose group (p = 0.425). Conclusion: HFpEF with CKD patients using spironolactone had lower risk of adverse cardiovascular outcomes. And the use of low-dose spironolactone (≤ 40mg) showed the best efficacy and safety, therefore we may recommend ≤ 40mg as the optimal initial dose for these patients. However, this was a relatively small sample size, retrospective study, and further adequately powered randomized trials are needed to verify these results.

Comparative effectiveness of metformin versus sulfonylureas on kidney function decline or death among patients with reduced kidney function: a retrospective cohort study.

Diabetes often causes kidney disease. In this study, we sought to evaluate if metformin use was associated with death or kidney events in patients with diabetes and concurrent reduced kidney function. We used data from the Veterans Health Administration, Medicare and National Death Index databases to assemble a national retrospective cohort of veterans who were using metformin or sulfonylureas from 2001 through 2016 and who began follow-up at an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2. The primary composite outcome was a kidney event (i.e., 40% decline in eGFR or end-stage renal disease) or death. The secondary outcome was a kidney event (eGFR decline or end-stage renal disease). We weighted the cohort using propensity scores and used Cox proportional models to estimate the cause-specific hazard of outcomes and of treatment nonpersistence as a competing risk. We stratified follow-up into 2 periods, namely the first 360 days from the start of follow-up, and 361 days and beyond. In the first 360 days, the propensity score-weighted cohort included 24 883 patients who used metformin and 24 998 who used sulfonylureas. There were 33.5 (95% confidence interval [CI] 30.9-36.3) and 43.0 (95% CI 40.1-46.0) deaths or kidney events per 1000 person-years for patients who used metformin or sulfonylureas, respectively (hazard ratio [HR] 0.78, 95% CI 0.71-0.85). For the secondary outcome of kidney events, the HR was 0.94 (95% CI 0.67-1.33). In the second period from 361 days onward, the primary outcome event rate was 26.5 (95% CI 24.7-28.5) per 1000 person-years for those who used metformin, compared with 36.3 (95% CI 34.2-38.6) per 1000 person-years for those who used sulfonylureas (HR 0.73, 95% CI 0.67-0.79). Results were consistent for kidney events alone (HR 0.73, 95% CI 0.59-0.91). Metformin use for 361 days or longer after reaching an eGFR of less than 60 mL/min/1.73 m2 was associated with decreased likelihood of kidney events or death in patients with diabetes, compared with use of sulfonylureas. Metformin provided end-organ protection, in addition to glucose control.

Contribution of hypertriglyceridemia to ischemic cardiovascular disease in Korean women: A nationwide population-based study

The independent effect of serum triglyceride levels on the development of ischemic cardiovascular disease (CVD) remains inconclusive, which might be due to heterogeneity among study populations. To evaluate the effect of triglyceride levels on ischemic CVD and mortality in Korean women, with stratification according to the menopausal status, diabetes mellitus, or low-density lipoprotein cholesterol levels (LDL-C). We retrospectively investigated Korean women aged 40-69 years who underwent health examination in 2009 and were followed up until 2018 using nationwide claim data. The subjects were divided according to triglyceride quartiles (Q): Q1 <70 mg/dL, Q2 71-99 mg/dL, Q3 100-142 mg/dL, and Q4 ≥143 mg/dL. The primary outcome was the incidence of CVD defined as a composite of myocardial infarction and ischemic stroke. Among 2,208,347 women, primary outcome occurred in 62,255 (2.8%) subjects. As triglyceride levels increased, the event rate of primary outcome increased in both premenopausal and postmenopausal women in the fully adjusted model (hazard ratio [HR] per 1 Q, 1.10 [95% confidence interval (CI), 1.08-1.12] and 1.08 [95% CI, 1.07-1.09], respectively), which was maintained on further stratification according to diabetes or LDL-C (P<0.05 in all). Higher triglyceride levels were more significantly associated with the primary outcome, MI, and stroke risk among women with optimal non-high-density lipoprotein cholesterol levels (non-HDL-C) <130 mg/dL, but only weakly with stroke for women with non-optimal non-HDL-C. Triglyceride is an independent prognosticator in the development of ischemic CVD in Korean women aged 40-69 years.

Eight-year post-trial follow-up of morbidity and mortality of telephone health coaching

BackgroundHealth coaching is a patient-centred approach to supporting self-management for the chronic conditions. However, long-term evidence of effectiveness of health coaching remains scarce. The object of this study was to evaluate the long-term effect of telephone health coaching (THC) on mortality and morbidity among people with type 2 diabetes (T2D), coronary artery disease (CAD) and congestive heart failure (CHF)..Methods1535 T2D, CAD and CHF patients with unmet treatment targets were randomly allocated into an intervention group (n = 1034) and control group (n = 501). Intervention group received monthly individual strength-based, autonomy supportive THC sessions (average 30 min) for behavior change with a specially trained nurse for 12 months additional to usual health care. Control group received usual health care services. The primary outcome was a composite of death from cardiovascular causes or non-fatal stroke or non-fatal myocardial infarction (AMI) or unstable angina pectoris (UAP) during a follow-up of 8 years Three other composite endpoints with distinct combinations of fatal and non-fatal cardiovascular events and death from any cause were used as secondary outcomes. Other outcomes followed were the most relevant components of the composite endpoints. Randomized controlled trial (RCT) data was linked to Finnish national health and social care registries and electronic health records (EHR). Post-trial eight-year evaluation was conducted using intention-to-treat (ITT) and per-protocol (PP) analysis.ResultsThe composite primary outcome event rate per 100 person years was lower in the intervention group (3.45) than in control group (3.88) in ITT -analysis, but the difference was not statistically significant (hazard ratio in the intervention group 0.87; 95% CI, 0.71 to 1.07; P = 0.19). In the subgroup (T2D, CAD/CHF) analysis, there were no statistically significant effects. The secondary PP-analysis showed statistically significant benefits for those who participated in the study.ConclusionsNo statistically significant effect of health coaching on mortality and morbidity was found in intention to treat analysis. The per protocol results suggest, however, that the intervention may be effective among patients who are willing and able to participate in health coaching. More research is needed to identify patients most likely to benefit from low-intensity health coaching.Trial registrationNCT00552903 (registration date: the 1st of November 2007, updated the 3rd of February 2009).

Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke

Prior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup. To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5). The THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021. Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after symptom onset. All patients received aspirin, 300 to 325 mg, on day 1 followed by aspirin, 75 to 100 mg, daily on days 2 to 30. Patients were observed for 30 additional days. The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding. In total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke group, 1293 (39.0%) were female, and the mean (SD) age was 64.5 (10.8) years; of those in the less severe stroke group, 2518 (37.7%) were female, and the mean (SD) age was 64.8 (11.2) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129 of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and 5.7% (190 of 3312) for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66-1.01) (P for interaction = .88). Severe bleeding occurred in 8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16 patients (0.5%) and 3 patients (0.1%), respectively, with less severe stroke (P for interaction = .26). In this study, patients with a moderate ischemic stroke had consistent benefit from ticagrelor plus aspirin vs aspirin alone compared with patients with less severe ischemic stroke, with no further increase in the risk of intracranial bleeding or other severe bleeding events. ClinicalTrials.gov Identifier: NCT03354429.

438-P: Contribution of Hypertriglyceridemia to Cardiovascular Disease in Korean Women: A Nationwide Population-Based Study

Introduction: The independent effect of serum triglyceride (TG) level on the development of cardiovascular disease (CVD) has been inconclusive, which might be due to heterogeneity of study populations. We aimed to evaluate the effect of TG level on CVD and mortality in Korean women with stratification according to the menopausal status, diabetes mellitus (DM) or LDL cholesterol level (LDL-C). Method: We investigated Korean women aged 40-69 years who underwent health examination in 2009 and were followed up until 2018 using nationwide claim data covering 97.0% of the Korean population. The subjects were divided into four groups according to TG quartiles (Q): Q1 &amp;lt;70 mg/dL, Q2 71-99 mg/dL, Q3 100-142 mg/dL, Q4 ≥143 mg/dL. The primary outcome was the incidence of CVD defined as composite of myocardial infarction and ischemic stroke. Results: Among 2,208,347 women, primary outcome occurred in 62,255 (2.8%) subjects. As TG levels increased, the event rate of primary outcome increased in both premenopausal and postmenopausal women in the fully adjusted model (hazard ration [HR] per 1 Q, 1.10 [95% confidence interval (CI), 1.08-1.12] and 1.08 [95% CI, 1.07-1.09], respectively), which was maintained on further stratification according to DM or LDL-C (p&amp;lt;0.05 in all). In premenopausal women without diabetes and LDL-C of less than 130 mg/dL, even those in Q2 had a significantly higher CVD risk compared to subjects in Q1 (p&amp;lt;0.05), which was not found in the in subjects with diabetes or in the higher range of LDL-C. Conclusion: TG is an independent prognosticator in the development of CVD in the Korean women aged 40-69 years. The dose-response relationship is more significant in patients without diabetes when LDL-C&amp;lt;130mg/dL. These results imply that more emphasis should be set on TG when assessing women with elevated TG levels with otherwise few established risk factors. Disclosure H. Choe: None. M. Moon: None. B. Koo: None.

Rapid prediction of adverse outcomes for acute normotensive pulmonary embolism: derivation of the Calgary Acute Pulmonary Embolism score.

BackgroundAcute pulmonary embolism (PE) has a wide spectrum of outcomes, but the best method to risk-stratify normotensive patients for adverse outcomes remains unclear.MethodsA multicentre retrospective cohort study of acute PE patients admitted from emergency departments in Calgary, Canada, between 2012 and 2017 was used to develop a refined acute PE risk score. The composite primary outcome of in-hospital PE-related death or haemodynamic decompensation. The model was internally validated using bootstrapping and the prognostic value of the derived risk score was compared to the Bova score.ResultsOf 2067 patients with normotensive acute PE, the primary outcome (haemodynamic decompensation or PE-related death) occurred in 32 (1.5%) patients. In simplified Pulmonary Embolism Severity Index high-risk patients (n=1498, 78%), a multivariable model used to predict the primary outcome retained computed tomography (CT) right–left ventricular diameter ratio ≥1.5, systolic blood pressure 90–100 mmHg, central pulmonary artery clot and heart rate ≥100 beats·min−1 with a C-statistic of 0.89 (95% CI 0.82–0.93). Three risk groups were derived using a weighted score (score, prevalence, primary outcome event rate): group 1 (0–3, 73.8%, 0.34%), group 2 (4–6, 17.6%, 5.8%), group 3 (7–9, 8.7%, 12.8%) with a C-statistic 0.85 (95% CI 0.78–0.91). In comparison the prevalence (primary outcome) by Bova risk stages (n=1179) were stage I 49.8% (0.2%); stage II 31.9% (2.7%); and stage III 18.4% (7.8%) with a C-statistic 0.80 (95% CI 0.74–0.86).ConclusionsA simple four-variable risk score using clinical data immediately available after CT diagnosis of acute PE predicts in-hospital adverse outcomes. External validation of the Calgary Acute Pulmonary Embolism score is required.

Chronic coronary syndrome patients with polyarterial disease are a high risk but heterogenous subset of patients. Insights from the CLARIFY registry

Patients with chronic coronary syndrome (CCS) currently have overall a relatively low rate of long-term ischaemic events but some high risk subsets of patient still experience a worse prognosis such as polyarterial disease patients. Cigarette smoking and diabetes mellitus are strongly associated with polyarterial disease and may be associated with an additional increase in ischaemic outcomes. We aimed to determine the 5-year ischaemic risk of CCS outpatients according to arterial disease phenotype as well as diabetic and smoking status. We analyzed data from 32,703 consecutive CCS outpatients enrolled in the prospective observational CLARIFY registry. Subsets of patients were compared according to their vascular phenotypes: Coronary artery disease (CAD) alone, CAD with peripheral artery disease (PAD) or cerebrovascular disease (CVD) (CAD + 1), CAD with CVD and PAD (CAD + 2) and according to their diabetic and smoking status. The primary outcome was a composite of cardiovascular death, myocardial infarction or stroke, adjusted by age, sex and geographic origin at 5 years. The 5-year primary outcome event rate was 9.5% overall (95% confidence interval (CI) 9.3–9.7) increasing according to the number of diseased arterial beds: from 8.4% (95% CI 8.1–8.7) in patients with CAD alone to 17.4% (95% CI 16.9–17.8) for CAD + 2 patients ( P < 0.001). Subgroup analyzes according to diabetes and smoking status revealed an even greater variation of the primary outcome event rate ranging from 7% (95% CI 6.5–7.6) in non-diabetic, non-smoking CAD alone patients to 20.3% (95% CI 19.1–21.4) in diabetics and smokers CAD + 2 patients ( Fig. 1 ). CCS patients with polyarterial disease are a heterogeneous group of patients, in which the ischaemic risk varies not only according to the number of arterial beds involvement, but also according to smoking and diabetes status. These findings highlighted a very vulnerable population of CCS patients.

Design and Main Results of STURDY: A Randomized Clinical Trial of Four Vitamin D3 Doses to Prevent Falls in Older Adults

STURDY was a Bayesian, response-adaptive trial with dose-finding and confirmatory stages. Participants (n=688; ≥70years with serum 25(OH)D of 10-29ng/mL) were randomized to 200 (control), 1000, 2000, or 4000 IU/day of vitamin D3. The primary outcome was time to first fall or death over 2 years. During dose-finding, the best non-control dose was determined to be 1000IU/day based on higher primary outcome event rates in the 2000 and 4000IU/day doses than the 1000IU/day dose (posterior probability of being best dose=0.90; hazard ratios[HR] were 1.86 [95%CI: 1.16-2.97] and 1.68 [95%CI: 1.05-2.69], respectively). Participants were then switched from other non-control doses to 1000IU/day, and event rates did not differ between the pooled higher doses and control groups (HR=1.02, P=0.84). There was no heterogeneity by baseline 25(OHD). In conclusion, high-dose vitamin D supplementation ≥1000IU/day did not prevent falls. Whether vitamin D doses >2000IU/day increase the risk of falls is uncertain.

Ursodeoxycholic acid to reduce adverse perinatal outcomes for intrahepatic cholestasis of pregnancy: the PITCHES RCT

Background Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and raised serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment, but without an adequate evidence base. Objective We aimed to evaluate whether or not ursodeoxycholic acid reduces adverse perinatal outcomes in affected women. Design Multicentre, masked, randomised, placebo-controlled, two-arm, parallel-group trial. Setting Thirty-three UK maternity units. Participants Women with intrahepatic cholestasis of pregnancy aged ≥ 18 years, between 20+0 and 40+6 weeks’ gestation with a singleton or twin pregnancy and no known lethal fetal anomaly. Interventions Women were randomly assigned (1 : 1 allocation ratio) to take ursodeoxycholic acid tablets or matched placebo tablets, at an equivalent dose of 1000 mg daily, titrated as needed. Main outcome measures The primary outcome was a composite of perinatal death (in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (&lt; 37 weeks’ gestation) or neonatal unit admission for at least 4 hours (from birth until hospital discharge). Each infant was counted once within this composite. Analyses were by intention to treat. Results Between 23 December 2015 and 7 August 2018, 605 women were randomised, with 305 women allocated to the ursodeoxycholic acid arm and 300 women to the placebo arm. There was no evidence of a significant difference in the incidence of the primary outcome between the groups: 23.0% (74 out of 322 infants) in the ursodeoxycholic acid group compared with 26.7% (85 out of 318 infants) in the placebo group; adjusted risk ratio 0.85 (95% confidence interval 0.62 to 1.15). There was no evidence of a significant difference in total costs (maternal, infant and the cost of ursodeoxycholic acid) between the two trial groups. There were two serious adverse events in the ursodeoxycholic acid group and six in the placebo group. Limitations Limitations include a primary outcome event rate in the control group that was lower than that estimated for the sample size calculation, but the lack of evidence of effect in all analyses suggests that it is unlikely that the trial had insufficient power. Conclusions In this clinical trial of ursodeoxycholic acid in women with intrahepatic cholestasis of pregnancy, there is no evidence that it is effective in reducing a composite of adverse perinatal outcomes. Future work Future research should aim to elucidate the aetiology and pathophysiology of adverse perinatal outcomes, particularly stillbirth, in women with intrahepatic cholestasis of pregnancy to assist the development of an effective preventative treatment. Further exploratory analyses may identify groups of women who might respond to ursodeoxycholic acid treatment. Trial registration Current Controlled Trials ISRCTN91918806. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 9. See the NIHR Journals Library website for further project information.

Potential eligibility for low dose rivaroxaban treatment in a “real world” population of Spanish patients with stable coronary artery disease: a subanalysis of the CICCOR registry

Abstract Background In the COMPASS trial, low dose rivaroxaban (2.5 mg/12h) on top of aspirin showed a 26% reduction in major cardiovascular events in patients with stable coronary artery disease (sCAD). However, information about external applicability of these results is limited. Our objective was to assess potential eligibility for this treatment in a “real world” cohort of Spanish patients with sCAD and to evaluate the incidence of major events in the long-term follow up in this population. Methods The CICCOR registry (“Chronic ischemic heart disease in Cordoba”, in Spanish “Cardiopatía isquémica crόnica en Cordoba”) is a prospective, monocentric study. From February 1, 2000 to January 31, 2004, all consecutive patients with sCAD attended at two outpatient cardiology clinics in a city of the south of Spain were included in the study and prospectively followed. The COMPASS inclusion and exclusion criteria were applied to this cohort, and the proportion of patients potentially eligible for this trial was described. The rate of the main COMPASS end-point (the composite of acute myocardial infarction, stroke, or cardiovascular death), as well as mortality rates, were investigated in this subset of patients, and compared with those of sCAD patients included in the aspirin alone group of the COMPASS trial. Results From a total population of 1268 patients, 1246 subjects presented enough data to assess eligibility. Among these, 575 patients (46%) had exclusion criteria, and another 229 (18%) did not fulfill the inclusion criteria and were not eligible. The main reasons for exclusion were requirement for dual antiplatelet therapy within 1 year of an acute coronary syndrome or coronary stent implantation (70%), high-bleeding risk (33%), other non-aspirin antiplatelet therapy (13%), atrial fibrillation (12%), anticoagulant use (11%), history of ischemic stroke (5%) and heart failure with severe left ventricular dysfunction (4%). The reason for not fulfilling inclusion criteria was the absence of additional high risk factors in patients younger than 65 years. The potentially eligible population included 442 patients (35% of evaluable patients), with up to 17 years of follow-up (median 9 years, IQR 4–15 years, only 1 patient lost in follow-up, 4174 patients-years of observation). These patients experienced higher primary outcome event rates than coronary patients actually enrolled in the aspirin alone arm of COMPASS (5.1% versus 2.9% per year), and higher rates of cardiovascular (4.0% versus 1.1%) and all-cause mortality (6.3 versus 2.1%, p&amp;lt;0.00005 for all comparisons). Conclusion More than one third of “real world” patients with sCAD of this prospective Spanish registry could be potentially eligible for low dose rivaroxaban therapy, according to COMPASS inclusion and exclusion criteria. This population had a higher risk of cardiovascular events and mortality than COMPASS participants with sCAD in the reference aspirin group. Funding Acknowledgement Type of funding source: None

Prognostic Value of Stress CMR Perfusion Imaging in Patients With Reduced Left Ventricular Function

ObjectivesThe aim of this study was to investigate the prognostic value of stress cardiac magnetic resonance imaging (CMR) in patients with reduced left ventricular (LV) systolic function. BackgroundPatients with ischemic cardiomyopathy are at risk from both myocardial ischemia and heart failure. Invasive testing is often used as the first-line investigation, and there is limited evidence as to whether stress testing can effectively provide risk stratification. MethodsIn this substudy of a multicenter registry from 13 U.S. centers, patients with reduced LV ejection fraction (<50%), referred for stress CMR for suspected myocardial ischemia, were included. The primary outcome was cardiovascular death or nonfatal myocardial infarction. The secondary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, hospitalization for unstable angina or congestive heart failure, and unplanned late coronary artery bypass graft surgery. ResultsAmong 582 patients (mean age 62 ± 12 years, 34% women), 40% had a history of congestive heart failure, and the median LV ejection fraction was 39% (interquartile range: 28% to 45%). At median follow-up of 5.0 years, 97 patients had experienced the primary outcome, and 182 patients had experienced the secondary outcome. Patients with no CMR evidence of ischemia or late gadolinium enhancement (LGE) experienced an annual primary outcome event rate of 1.1%. The presence of ischemia, LGE, or both was associated with higher event rates. In a multivariate model adjusted for clinical covariates, ischemia and LGE were independent predictors of the primary (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.68 to 4.14; p < 0.001; and HR: 1.86; 95% CI: 1.05 to 3.29; p = 0.03) and secondary (HR: 2.14; 95% CI: 1.55 to 2.95; p < 0.001; and HR 1.70; 95% CI: 1.16 to 2.49; p = 0.007) outcomes. The addition of ischemia and LGE led to improved model discrimination for the primary outcome (change in C statistic from 0.715 to 0.765; p = 0.02). The presence and extent of ischemia were associated with higher rates of use of downstream coronary angiography, revascularization, and cost of care spent on ischemia testing. ConclusionsStress CMR was effective in risk-stratifying patients with reduced LV ejection fractions. (Stress CMR Perfusion Imaging in the United States [SPINS] Study; NCT03192891)

Efficacy and safety of an antithrombotic regimen for atrial fibrillation patients with acute coronary syndrome or those undergoing percutaneous coronary intervention: a meta-analysis.

This study evaluated the benefit of dual therapy in reducing ischemic events in atrial fibrillation (AF) patients presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). We searched PubMed, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing dual and triple therapies (oral anticoagulation plus aspirin and P2Y12 inhibitor) for AF patients with ACS or those undergoing PCI. The composite primary outcome included all-cause death, myocardial infarction (MI), stent thrombosis (ST), or stroke. Relative risk (RR) and the corresponding 95% confidence interval (CI) was used as the measure of effect size. Four RCTs with 10,969 patients were included. Dual therapy had a higher event rate of primary outcome than triple therapy (RR, 1.15; 95%CI, 1.03–1.28; P<0.0001). Dual therapy was associated with significantly higher MI risk, insignificantly higher ST risk, and significantly lower major bleeding risk than triple therapy (RR1.23, 95%CI 1.01–1.49, P = 0.036; RR 1.43, 95 %CI 0.98–2.09, P = 0.064; and RR0.58, 95%CI 0.45–0.76, P<0.0001, respectively). Dual antithrombotic therapy was associated with higher ischemic risk but lower major bleeding risk than triple therapy. The data suggest that antithrombotic regimens should be based on tradeoffs between ischemia and bleeding risk.

403-P: Impact of Diabetes-Related Factors and Background Antihyperglycemic Therapy on the Efficacy and Safety of Ticagrelor Added to Aspirin: Insights from the THEMIS Trial

In the THEMIS trial of 19,220 patients with stable CAD and T2DM without prior MI or stroke followed for a median of 39.9 months, ticagrelor plus aspirin (ASA) lowered ischemic CV events but increased major bleeding events compared with placebo plus ASA, with a more favorable net clinical benefit in those with prior PCI. We now report the efficacy and safety by diabetes-related factors and background antihyperglycemic therapy. While the incidence of the primary efficacy outcome (CV death, MI, stroke; MACE) event rates (overall 8.1%) was higher with increasing diabetes duration (11.1% &amp;gt;20 years vs. 6.7% ≤5 years) and A1c (11.8% &amp;gt;10% vs. 6.4% ≤6%), the relative benefits of ticagrelor on MACE reduction (overall HR 0.90; p=0.04) did not differ across these various subgroups (p-values for interaction=0.83 and 0.16, respectively). In contrast, the primary safety outcome (TIMI major bleeding) event rate (overall 1.6%) did not vary by diabetes duration or A1c and was similarly increased by ticagrelor in all of these subgroups (overall HR=2.32 [1.82,2.94]; p&amp;lt;0.01). The impact of diabetes duration and A1c were similar in the prior PCI subgroup. Regardless of treatment assignment, patients treated with insulin vs. not had a higher risk for MACE (HR=1.65 [1.49, 1.83]; p&amp;lt;0.01) with no difference in major bleeding (HR=0.92 [0.71, 1.19]; p=0.52), while those treated with sulfonylurea vs. not had no difference in risk for MACE (HR=1.00 [0.91,1.11]; p=0.93) or major bleeding (HR=1.12 [0.89,1.41]; p=0.34) endpoints. The efficacy and safety of ticagrelor did not differ based on background antihyperglycemic therapy. These data suggest that, in general, the relative benefits and risks of ticagrelor added to aspirin are consistent regardless of T2DM duration, A1c, or background antihyperglycemic therapy. NCT01991795. Disclosure L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp &amp; Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. K. Fox: Other Relationship; Self; AstraZeneca, Servier. T. Simon: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Servier. Board Member; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc. Consultant; Self; Air Liquide, Sanofi. S. Mehta: Research Support; Self; AstraZeneca. E. Lev: None. R.G. Kiss: Speaker’s Bureau; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Pfizer Inc. A.J. Dalby: None. H. Bueno: Advisory Panel; Self; AstraZeneca, Bayer AG, Novartis AG. Consultant; Self; Amgen, Bristol-Myers Squibb, Pfizer Inc. Research Support; Self; AstraZeneca, Novartis AG. W. Ridderstråle: Employee; Self; AstraZeneca. A. Himmelmann: Employee; Self; AstraZeneca. J. Prats: Other Relationship; Self; AstraZeneca. Y. Liu: None. J.J. Lee: None. J. Amerena: None. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P.G. Steg: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Idorsia, Mylan, Novartis AG, Pfizer Inc., Sanofi, Servier. Research Support; Self; Amarin Corporation. Speaker’s Bureau; Self; Novo Nordisk A/S.

Ten-year outcomes in adult patients with congenital heart disease and implantable cardioverter-defibrillators

BackgroundAdult congenital heart disease (ACHD) patients may be at risk of sudden cardiac death and be candidates for an implantable cardioverter-defibrillator (ICD). We evaluated the long-term rates of ventricular arrhythmias requiring treatment and mortality in these patients. MethodsA single-center retrospective case-series identified ACHD patients with an ICD and were evaluated for the primary outcome of appropriate ICD intervention or ablation for ventricular tachyarrhythmias. Secondary endpoints were mortality and complication rates. Survival analyses to generate Kaplan-Meier curves for the primary and secondary outcomes were performed. ResultsThere were 125 adult patients (median age 35.5 years, 68.8% male) with congenital heart disease and an ICD. The median follow-up was 6.4 years (interquartile range 2.8–9.1 years). Transposition of the Great Arteries (TGA) was present in 62 patients (49.6%) and Tetralogy of Fallot (ToF) in 33 (26.4%). The indication for an ICD was primary prevention in 90 patients (72%) and secondary prevention in 35 patients (28%). The primary endpoint occurred in 44 patients (35.2%). Time dependent analyses demonstrated a continual risk of the primary outcome (event rates of 23.8% at 5 years, 45.5% at 8 years, 47.9% at 10 years; p < 0.001). Death occurred in 20 patients (16.0%) and was most commonly from congestive heart failure (CHF). ConclusionsLong-term follow-up of ACHD patients with an ICD experience a persistent risk of ventricular arrhythmias. Mortality was most commonly attributed to CHF. These data provide insight into the clinical course and may guide shared clinical decision making in this complex patient population.

Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial (CAP-IT)

IntroductionCommunity-acquired pneumonia (CAP) is a common indication for antibiotic treatment in young children. Data are limited regarding the ideal dose and duration of amoxicillin, leading to practice variation which may...