Composite Clinical Endpoint Research Articles

POS0446 FILGOTINIB-TREATED RHEUMATOID ARTHRITIS PATIENTS WITH HIGH BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO SHOW BETTER CLINICAL RESPONSE RATES AND PATIENT-REPORTED OUTCOMES

Background:Rheumatoid arthritis (RA) is a systemic inflammatory disease which includes increased innate and myeloid immune cell activation. Filgotinib (FIL), an oral JAK1 inhibitor, has shown safety and efficacy in three phase 3 studies (FINCH1-3) in adults with moderately-to-severely active RA. The baseline (BL) neutrophil-to-lymphocyte ratio (NLR) in RA has been associated with a positive response to anti-tumor necrosis factor (TNF) therapy1 and a negative response to DMARD triple therapy2. We previously reported a BL signature of clinical response in the FINCH2 (bDMARD-IR) population which included a neutrophil component3.Objectives:We conducted a post-hoc analysis to explore whether the BL NLR was associated with response to treatment in the FINCH studies.Methods:Clinical data of 3273 RA patients (pts) enrolled in the FINCH clinical trials (FINCH3, methotrexate (MTX)-naïve: NCT02886728; FINCH1, MTX-Inadequate Responder (IR): NCT02889796; FINCH2, bDMARD-IR: NCT02873936) were retrospectively analyzed for a relationship between the BL NLR and composite clinical endpoints (ACR-N, DAS28CRP, or CDAI) or PROs (Pain VAS, FACIT Fatigue, HAQ-DI) through week 24. Pts were classified as High or Low BL NLR using a cutpoint (2.7) identified as an independent predictor of treatment failure in a published RA study2. Adjusted clinical outcomes were estimated based on mixed effects linear regression models including geographic region and demographics covariates.Results:57% of pts enrolled in the FINCH trials were classified as BL NLR-High (Table 1) and FINCH3 NLR-High pts showed higher BL DAS28(CRP). FINCH1 and FINCH3 FIL+MTX-arm NLR-High pts demonstrated significantly better DAS28(CRP) response compared to NLR-Low pts (Figure 1). DAS28(CRP) differences between NLR-High and NLR-Low were detectable as early as Week 2 for FIL200mg + MTX and were sustained through Week 24. FINCH1 and FINCH3 FIL200mg + MTX NLR-High pts also demonstrated sustained clinical and PRO improvements over NLR-Low, including CDAI, ACR-N, Pain VAS, FACIT Fatigue, and HAQ-DI. The strength of these associations was dose-dependent; pts that received FIL100mg + MTX demonstrated weaker but directionally consistent trends in both populations. No significant association between NLR subgroup and clinical efficacy was observed in FINCH2 FIL+MTX-arm pts, FIL-monotherapy (FINCH3) pts, or adalimumab+MTX (FINCH1) pts.Conclusion:In FINCH1 (MTX-IR) and FINCH3 (MTX-naïve), FIL200mg + MTX -arm NLR-High pts demonstrate better sustained clinical response and PRO scores compared to NLR-Low pts. These data are the first to report an association between the BL NLR and therapeutic response in large randomized RA clinical trials. Future studies on pathobiologies reflected by the NLR biomarker may clarify its potential to guide RA disease management.

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects

Results of the First Pilot Randomized Controlled Trial of Fecal Microbiota Transplant In Pediatric Ulcerative Colitis: Lessons, Limitations, and Future Prospects

Impact of Antecedent Aspirin Use on Infarct Size, Bleeding and Composite Endpoint in Patients with de Novo Acute Myocardial Infarction.

BackgroundThe study aimed to evaluate the impact of antecedent aspirin use on infarct size, bleeding and composite endpoint in patients with de novo acute myocardial infarction.Patients and MethodsA total of 562 consecutive patients with de novo acute myocardial infarction were included in this prospective cohort study. Patients were assigned into two groups based on presence (n=212) and absence (n=350) of prior aspirin use. Primary endpoint was myocardial infarct size, as estimated by troponin I peak. In-hospital mortality, bleeding and composite clinical endpoint including cardiogenic shock, stroke, in-hospital mortality and major bleeding were also evaluated.ResultsAlthough GRACE and CRUSADE scores were higher, troponin I peak was lower in prior aspirin users. This result was maintained after adjustment for baseline ischemic risk profile and other major confounders including MI type and location. Despite high CRUSADE score, there was no increase in major and minor bleeding. Minimal bleeding was higher in antecedent aspirin users. When it was adjusted for the CRUSADE score, a similar risk was reported.ConclusionPatients with de novo acute myocardial infarction using aspirin for primary prevention have an unexpectedly smaller infarct size and similar bleeding rates.

Clinical Impact of FFR-Guided PCI Compared to Angio-Guided PCI From the France PCI Registry

Background: Fractional Flow Reserve (FFR) has become the invasive gold standard to quantify myocardial ischemia generated by a coronary stenosis in patients with chronic coronary syndrome, but in clinical practice it is still underutilised to guide percutaneous coronary intervention (PCI) compared to angiography (angio). Methods: We sought to compare, in a national French registry (France PCI), the clinical impact of FFR-guided PCI compared with angio-guided PCI at one year. We extracted from the France PCI database all chronic coronary syndrome patients treated with PCI for coronary stenosis <90% between 2014 and 2019. Our composite clinical endpoint was the rate of major adverse clinical events (MACE) defined as the composite of the following endpoints: rates of death, myocardial infarction, stent thrombosis, revascularisation, stroke, and bleeding with a BARC score ≥ 3. Findings: 14384 patients with one-year clinical follow-up were included. Among them, 13125 had angio-guided PCI (91%) and 1259 (9%) had FFR-guided PCI. We observed a significantly higher rate of MACE in the angio-guided group versus the FFR-guided group: 1478 (11·3%) versus 100 (7·9%) (p<0·0001), respectively, with Hazard Ratio (HR) of 1·440, 95% confidence Interval (CI) [1·211-1·713] (p=0·0004). This result was driven by the higher occurrence of death in the angio-guided group versus the FFR-guided-group: 506 (3·9%) versus 17 (1·4%) (p<0·0001), respectively, with HR of 2·845, 95% CI [2·099-3·856] (p<0·0001). After adjustment for potential confounding factors, HRs were 1·287, 95% CI [1·028-1·613] (p=0·028) for MACE and 2·527, 95% CI [1·452-4·399] (p=0·001) for death. No significant differences between angio-guided PCI and FFR-guided PCI were observed for other clinical endpoints. Interpretation: Our study showed that FFR was the most important predictor of death after adjustment for confounding factors. PCI guided with FFR improves outcome at one year compared to angio-guided PCI with a reduction of 64M of death at one year. Funding: None Declaration of Interest: The authors do not have any conflict of interest to report related to this manuscript. Ethical Approval: The French Persons Protection Committee (IR3888) approved the study protocol (no. 15-231). Data file collection and storage were approved by the French National Commission for Data Protection and Liberties (no. 2014-073).

Physiological Evaluation of Anomalous Aortic Origin of a Coronary Artery Using Computed Tomography–Derived Fractional Flow Reserve

BackgroundWith the emergence of coronary computed tomography (CT) angiography, anomalous aortic origin of a coronary artery (ANOCOR) is more frequently diagnosed. Fractional flow reserve derived from CT (FFRCT) is a noninvasive functional test providing anatomical and functional evaluation of the overall coronary tree. These unique features of anatomical and functional evaluation derived from CT could help for the management of patients with ANOCOR. We aimed to retrospectively evaluate the physiological and clinical impact of FFRCT analysis in the ANOCOR registry population.Methods and ResultsThe ANOCOR registry included patients with ANOCOR detected during invasive coronary angiography or coronary CT angiography between January 2010 and January 2013, with a planned 5‐year follow‐up. We retrospectively performed FFRCT analysis in patients with coronary CT angiography of adequate quality. Follow‐up was performed with a clinical composite end point (cardiac death, myocardial infarction, and unplanned revascularization). We obtained successful FFRCT analyses and 5‐year clinical follow‐up in 54 patients (average age, 60±13 years). Thirty‐eight (70%) patients had conservative treatment, and 16 (30%) patients had coronary revascularization after coronary CT angiography. The presence of an ANOCOR course was associated with a moderate reduction of FFRCT value from 1.0 at the ostium to 0.90±0.10 downstream the ectopic course and 0.82±0.11 distally. No significant difference in FFRCT values was identified between at‐risk and not at‐risk ANOCOR. After a 5‐year follow‐up, only one unplanned percutaneous revascularization was reported.ConclusionsThe presence of ANOCOR was associated with a moderate hemodynamic decrease of FFRCT values and associated with a low risk of cardiovascular events after a 5‐year follow‐up in this middle‐aged population.

Epidemiological, demographic, laboratory, clinical management, and outcome data of symptomatic bradyarrhythmia in COVID-19 patients

BackgroundCardiovascular manifestations are an important cause of mortality and morbidity in COVID-19 infections. Conduction system abnormality in the form of symptomatic bradyarrhythmia is underreported in the literature. AimTo evaluate epidemiological, demographic, laboratory, clinical management, and outcome data of symptomatic bradyarrhythmia in COVID-19 patients. MethodsThis was a retrospective, observational study including all the adult patients (>18 years) who were diagnosed with COVID-19 infection and had complete heart block (CHB) or symptomatic high-grade Atrio-Ventricular (AV) block requiring a temporary pacemaker insertion (TPI). Epidemiological, demographic, laboratory, clinical management, and outcome data were extracted from all the enrolled patients and studied for the primary clinical composite endpoint of all-cause death. ResultsThe study population included 15 patients, including 14 patients with CHB and 1 patient with 2:1 AV block. Syncope was the most common presentation. The clinical endpoint in the form of death was seen in 5 patients (33.3%), 3 patients reverted to sinus rhythm, and 7 patients required permanent pacemaker implantation. The markers of inflammation were raised in all patients; however trend toward more inflammation was seen in patients reaching the primary clinical endpoint. 3 out of 7 patients with narrow QRS rhythm reverted to normal sinus rhythm, while all 8 patients with broad complex QRS either died or required a permanent pacemaker insertion. ConclusionSymptomatic bradyarrhythmia is associated with a high inflammatory state, and high mortality in COVID-19 infection and a transient conduction block in patients with narrow QRS rhythm may suggest local subclinical myocardial inflammation.

Oral anticoagulants in extremely-high-risk, very elderly (>90 years) patients with atrial fibrillation

The prevalence and incidence of atrial fibrillation (AF) increase with age. However, older patients often are denied oral anticoagulation (OAC), especially if they are "very elderly" (age ≥90 years) and perceived to be high risk for bleeding, for example, those with a history of intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), or chronic kidney disease. The purpose of this study was to investigate the effectiveness and safety of OAC in this high-risk, very elderly group. We used the Taiwan National Health Insurance Research Database to identify high-risk, very elderly subjects taking OAC, either warfarin or a non-vitamin K antagonist oral anticoagulant (NOAC), and compared them to non-OAC users for the composite net clinical endpoint of ischemic stroke, ICH, major bleeding, or mortality. We studied 7362 subjects (mean age 92.5 years), of whom 1737 were taking NOACs, 670 warfarin, and 4955 non-OACs. Compared to non-OACs, warfarin was associated with a higher risk of the composite endpoint (adjusted hazard ratio [aHR] 1.163; 95% confidence interval [CI] 1.052-1.287), whereas NOACs were associated with a lower risk (aHR 0.763; 95% CI 0.702-0.830). After propensity matching, NOACs were associated with a lower risk of events compared to non-OACs or warfarin, whereas warfarin had a similar risk compared to non-OACs. Warfarin was associated with a similar or even higher risk of composite clinical outcomes compared to non-OACs. NOACs were associated with a lower risk of composite endpoint compared to warfarin or non-OACs, and their use still should be considered in these high-risk, very elderly AF patients.

No association between use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID-19 in the COvid MEdicaTion (COMET) study.

Since the outbreak of SARS‐CoV‐2, also known as COVID‐19, conflicting theories have circulated on the influence of angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID‐19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID‐19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID‐19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality.

Determination of the optimal on-treatment diastolic blood pressure range using automated office measurements in patients without cardiovascular disease.

Optimal diastolic blood pressure (DBP) during antihypertensive treatment in patients without a history of cardiovascular disease (CVD) remains unknown. This post‑hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) data aimed to determine the optimal DBP evaluated using automated office blood pressure measurements (AOBPM) in hypertensive patients without a history of CVD. Data of 1470 patients with CVD and 7117 patients without CVD were used. Clinical composite endpoint (CE) was defined as the occurrence of myocardial infarction, acute coronary syndrome other than myocardial infarction, decompensation of heart failure, stroke, or cardiovascular death. Two different approaches based on the hazard ratio plot were used to identify the optimal DBP range. The first approach was to determine the 10 mm Hg-wide DBP range with the lowest risk for CE. In the second approach, it was assumed that the hazard ratio of CE at the boundary points of the optimal DBP range should be the same in patients with and without CVD. Two ranges of on-treatment DBP were proposed: 73.7 to 83.7 mm Hg (first approach) and 63.6 to 95.8 mm Hg (second approach). The risk for CE was increased by 3% and 20% at the boundary points of the range, respectively, depending on the method of DBP determination. Due to the fact that the range determined by the second method was wide and substantially different from the one recommended by the European Society of Cardiology (70-79 mm Hg), we have concluded that a DBP range of 73.7 to 83.7 mm Hg, measured using AOBPM, should be considered optimal in patients without CVD.

Eosinophilic heart disease: diagnostic and prognostic assessment by cardiac magnetic resonance.

Eosinophilic heart disease (EHD) is a rare cardiac condition with a wide spectrum of phenotypes. The diagnostic and prognostic value of cardiac magnetic resonance (CMR) in EHD remains unknown. This was a retrospective analysis of 250 patients with eosinophilia referred for a CMR scan (period 2000-2020). CMR data sets and clinical/laboratory data were collected. Patients were followed up for a mean of 24 months (range 1-224) for the composite endpoint of death, acute coronary syndrome, hospitalization for acute heart failure, malignant ventricular arrhythmias, or the need for implantable cardiac defibrillator/pacemaker. The main objectives were to explore the diagnostic value of CMR in EHD; relationships between cardiac function, late gadolinium enhancement (LGE), and EHD phenotypes; and the prognostic value of fibrosis and oedema by CMR. The prevalence of findings compatible with EHD was 39% (patients with cardiac symptoms: 57% vs. screening: 20%, P < 0.001). EHD phenotypes included subendocardial LGE (n = 58), mid-wall/subepicardial LGE (n = 26), pericarditis (n = 5) or dilated cardiomyopathy (n = 8). Myocardial oedema was present in 10% of patients. Intracardiac thrombi (7%) were associated with EHD phenotype (χ2=47.3, P = 1.3×10-8). LGE extent correlated with LVEDVi (rho = 0.268, P = 5.3×10-5) and LVEF (rho=-0.415, P = 8.6×10-11). A CMR scan positive for EHD [hazard ratio (HR) = 5.61, 95% confidence interval (CI): 1.82-17.89, P = 0.0026] or a subendocardial LGE pattern (HR = 5.13, 95% CI: 1.29-20.38, P = 0.020) were independently associated with the composite clinical endpoint. The diagnostic yield of CMR screening in patients with persistent eosinophilia, even if asymptomatic, is high. The extent of subendocardial fibrosis correlates with LV remodelling and independently predicts clinical outcomes in patients with eosinophilia.

Abstract 14781: Computational Prediction of Protein Subdomain Stability as a Novel Approach to Cardiac Myosin Binding ProteinC Variant Adjudication and Clinical Risk Stratification in Hypertrophic Cardiomyopathy

Introduction: Patients with HCM and a pathogenic sarcomere variant have a higher risk of adverse clinical outcomes compared to those without a sarcomere gene variant. Pathogenic truncating variants in MYBPC3 (encoding cardiac myosin binding protein C, MYBP-C) cause loss-of-function and are the most common genetic cause of HCM. However, a substantial number of patients carry missense variants in MYBPC3 that cannot be clearly classified as either pathogenic or benign. Interpretation of these variants of uncertain significance (VUS) remain a significant challenge. Hypothesis: We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on subdomain protein folding, will enable clinical risk stratification of patients with HCM and a MYBPC3 VUS. Methods and Results: Among the 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry (SHaRe), 19 unique missense pathogenic variants and 120 missense VUSs in MYBPC3 were identified. Within SHaRe and GnomAD, 110 benign missense variants (allele frequency &gt; 4e-05) were identified. Following structural modeling of each MyBP-C domain, variants were predicted to cause subdomain misfolding if ΔΔG &lt; = -1.2 kcal/mol (STRUM+). 93% of benign variants were predicted to be STRUM (-). Time-event analysis for an overall composite clinical endpoint [defined as the first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation (AF), or stroke] demonstrated that patients carrying a STRUM+ MYBPC3 VUS exhibited a higher rate of adverse events compared to those with a STRUM- VUS (Hazard Ratio=2.29, P=0.0282). Of the 120 missense VUSs, 34 (28%) were STRUM+. In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants predicted to cause subdomain misfolding. Conclusions: STRUM is capable of clinically risk stratifying HCM patients with a MYBPC3 VUSs . These findings support the routine use of STRUM in variant interpretation algorithms and clinical decision making.

Abstract 16009: Sex Differences in Patients With Suspected Cardiac Sarcoidosis

Introduction: Cardiac sarcoidosis is increasingly recognized as a cause of cardiomyopathy and mortality. However, there are no data on sex differences in patients with suspected cardiac sarcoidosis. Hypothesis: We hypothesized that sex differences exist in the clinical presentation, cardiac involvement, and long-term clinical outcomes of patients with suspected cardiac sarcoidosis. Methods: We performed a retrospective cohort study to examine sex differences in presenting features, CMR findings, and the long-term incidence of adverse clinical outcomes among consecutive patients with histologically proven sarcoidosis and suspected cardiac involvement investigated by cardiovascular magnetic resonance imaging (CMR). The primary composite clinical endpoint was all-cause mortality or significant ventricular arrhythmia. The secondary endpoints were all-cause mortality and significant ventricular arrhythmia. Results: Among 324 patients, 163 (50.3%) were women and 161 (49.7%) were men. Women reported a greater prevalence of chest pain and palpitations than men, but not dyspnea, presyncope, or syncope. Women were less likely to have LGE or meet the criteria for a clinical diagnosis of cardiac sarcoidosis, indicating lesser cardiac involvement. The long-term incidence of the primary composite endpoint (hazard ratio for women 1.36; 95% confidence interval 0.77-2.43; p = 0.29; Figure 1 ) or the cause of death between women and men (p = 0.62). However, women had a significantly lower cumulative incidence of significant ventricular arrhythmia compared with men (4.3% vs. 13.0%; log-rank p = 0.022). Conclusions: There were distinct sex differences in patients with histologically proven sarcoidosis and suspected cardiac involvement. A paradox was noted wherein women had a greater prevalence of chest pain and palpitations than men, but had lesser cardiac involvement, and a similar long-term incidence of all-cause death or significant ventricular arrhythmia.

The impact of resting heart rate measured on cardiovascular events in subject with hypertension

Abstract Background Available evidence does not indicate whether resting heart rate (RHR) is an independent risk factor or just marker of elevated risk. None of the studies assessed impact of RHR on cardiovascular events, when RHR was measured using automated blood pressure measurements (AOBPM). Purpose To assess the relationship between RHR (measured using AOBPM) and cardiovascular events risk in subjects with hypertension. Methods The data of SPRINT trial obtained via NHLBI were used to perform the analysis. SPRINT trial assessed intensive lowering of systolic BP to a target &amp;lt;120 mm Hg in comparison to standard goal (&amp;lt;140 mm Hg). RHR was measured using AOBPM device and calculated as an average of 3 measurements during the baseline visit of the study. Clinical composite endpoint (CE) of the study was defined as: myocardial infarction, acute coronary syndrome, decompensation of heart failure, stroke or cardiovascular death. The relationship between RHR and CE was assessed according to presence of cardiovascular disease (CVD) in past medical history. The statistical methods included t-test and chi-square test, Cox proportional risk models. The Cox models were adjusted for adjusted for age, sex, current smoking status and mean SBP during the trial. Restricted cubic splines were used to describe the relationship between RHR and hazard ratio. Results Data of 1877 participants with CVD and 7484 participants without CVD were analyzed. Subjects with cardiovascular disease were older (69.7±9.5 vs 67.5 years ± 9.4, p&amp;lt;0.001), more often were men (72.8% vs 62.3%, p&amp;lt;0.001) and had prior chronic kidney disease (34.3% vs 26.8%, p&amp;lt;0.001) than subjects without CVD. CE was more than twice often when CVD was present (10.9% vs 4.8%, p&amp;lt;0.001). RHR was lower in subjects with CVD disease than in subjects without CVD (63.6±11 vs 66.9±11.6 bpm, p=0&amp;lt;00.1). Elevated RHR was associated with increased risk both in subjects with and without CVD (Figure 1). The multivariable Cox proportional hazard risk model revealed that RHR&amp;gt;80 bpm is an independent risk factor for CE in subjects without CVD (hazard ratio 1.37, 95% CI 1.01–1.85, p=0.043) while not in subjects with CVD (hazard ratio 0.99, 95% CI 0.57–1.71, p=0.98). Conclusion Elevated RHR (&amp;gt;80 bpm) measured using AOBPM is an independent risk factor for cardiovascular events in subjects with hypertension and without CVD. Figure 1. Heart ratio vs hazard ratio. Funding Acknowledgement Type of funding source: None

The utility of coronary artery calcium in non-gated high resolution CT thorax scans in predicting cardiac events as compared to the Framingham risk score: a retrospective study

Abstract Background There is existing evidence to suggest a correlation between coronary artery calcification (CAC) measured using ECG-triggered chest computed tomography and cardiovascular disease. Further evidence has emerged to suggest a correlation between CAC measured using non-gated CT scans and cardiovascular disease. Herein, we sought to ascertain the utility of incidental findings of CAC on non-triggered high resolution CT (HRCT) thorax used for patients undergoing lung cancer screening or follow-up for interstitial lung disease and Framingham risk score (FRS) in predicting cardiovascular events. Methods The Computerised Radiology Information Service (CRIS) database was manually searched to determine all HRCT scans performed in a single trust from 05/2015 to 05/2016. The reports issued by Radiologists and images of selected studies were reviewed. For patients with CAC, we calculated the calcium score for patients using the Agatston method. Clinical events were determined from the electronic medical record without knowledge of patients' CAC findings. For these patients, the Framingham Risk Score (FRS) was also calculated. The primary end point of the study was composite of all-cause mortality and cardiac events (non-fatal myocardial infarction, coronary revascularization, new atrial fibrillation or heart failure episode requiring hospitalization). Results We selected 300 scans from a total of approximately 2000 scans performed over this time. Data at follow up was available for 100% of the patients, with a median duration of follow up of 1.6 years. Moderate to severe CAC was found in 35% of people. Multivariable analysis showed good concordance between CAC and FRS in predicting composite clinical end point. The Odds Ratio for cardiac events in patients with moderate to severe CAC was 5.3 (p&amp;lt;0.01) and for composite clinical end point was 3.4 (p&amp;lt;0.01). This is similar to the OR predicted by the FRS: 4.8; p&amp;lt;0.01 and 3.1; p&amp;lt;0.01 respectively. Only 6.2% of patients with moderate to severe CAC were currently statin treated. Conclusion In this retrospective study of patients with respiratory disease attending for HRCT scanning, co-incidentally detected CAC predicts cardiac events, with good concordance with the FRS. The incidental finding of CAC on non-gated CT scanning should be reported with Agatston score calculation allowing consideration of intervention to mitigate cardiovascular risk and optimize. Further multi-centre prospective studies of this strategy, with a larger patient cohort should be conducted to clarify the utility of CAC as a prediction tool to modify cardiac risk. Funding Acknowledgement Type of funding source: None

Triple therapy in the elderly patients and women – results from the MUNICH triple cohort in patients with AF undergoing PCI

Abstract Introduction Approximately 20% of patients with atrial fibrillation (AF) are suffering from coronary artery disease (CAD), requiring percutaneous coronary intervention (PCI) and stenting over time. These patients are in need of a so-called “triple therapy” (TT) for prevention of stent thrombosis and stroke. Prospective and randomized trials examined risk for bleeding in TT and compared it to a dual regimen, but in majority excluded elderly patients. Moreover, in all to date presented triple therapy trials women represent a minority of included patients (mostly &amp;lt;30%). This raises the question, why female and elderly patients are underrepresented and these groups have a different outcome then younger and male patients, when treated with a guideline recommended TT. Methods The objective of our retrospective cohort study was to determine the number of women and elderly patients with the indication for TT and to evaluate the differences in medical treatment. Furthermore, we evaluated safety, represented by bleeding (BARC ≥2 bleedings) and efficacy endpoints (composite clinical endpoint: all-cause-death, myocardial infarction, stent thrombosis, stroke and other systemic thromboembolism) in women vs. men, and elderly vs. younger patients. Moreover, we investigated the influence of NOAC (new oral anticoagulant) vs. VKA (vitamin K antagonist) treatment. Follow-ups were performed via phone-calls or in-hospital visits. Results In total, we included 928 patients with AF, that underwent PCI and stenting. Mean follow-up was 464 days. 627 patients were &amp;lt;80 years old (mean age: 72±7 years), 301 were ≥80 years old (mean age: 84±4 years). Only 27.9% of all patients were female. The number of men and women receiving TT was comparable (83.0% vs. 82.2%, p=0.78), while in the younger group significantly more patients received TT (537 (85.6%) vs. 228 (74.7%) (p&amp;lt;0.001). The incidence of BARC ≥2 bleedings in patients with TT was not significantly different in younger vs. older patients and in men vs. women. Also, the incidence of the composite clinical endpoint did not differ significantly in both comparisons. Conclusion In our real-life cohort female sex represents around a quarter of TT patients in line with large RCTs. But, unlike the large RCTs, 1/3 of our included patients were older then 80 years and seem to be underrepresented in randomized TT trials. TT seems to be safe in elderly as well as in female patients. As they both represent an important group, future trials should focus more on including a well balanced patient cohort to improve the applicability of the results. Funding Acknowledgement Type of funding source: None

Cardiovascular magnetic resonance to predict clinical outcome in chronic total coronary artery occlusion

Abstract Background Chronic total coronary artery occlusions (CTOs) are present in approximately 20–30% of patients undergoing invasive angiography. Despite their prevalence, the optimum management strategy of CTOs remains uncertain. A potential limitation in published trials of CTO revascularisation is their failure to incorporate systematic assessment of ischaemia/viability in informing revascularisation decisions. Aim We sought to determine the prognostic utility of ischaemia/viability assessment by cardiovascular magnetic resonance (CMR) in a large, contemporaneous, real-world CTO population. Methods We retrospectively studied consecutive adult patients with≥1angiographically identified CTO who were referred for clinical CMR imaging during a consecutive 8-year period in our centre (2010–2018). Multi-parametric CMR comprised functional assessment, adenosine-stress perfusion and scar imaging. For perfusion assessment, images were analysed qualitatively with a concurrent examination of scar images. Myocardial segments were assigned to CTO or non-CTO territories according to standard criteria, taking into account coronary dominance. Significant ischaemia was defined as ≥10% and/or ≥2 contiguous myocardial segments with hibernation. Angiographic collateral flow to the CTO territory was graded using the Rentrop classification and the Collateral Connection (CC) Score. Significant CAD in non-CTO vessels was defined angiographically as ≥50% stenosis in any epicardial coronary artery/branch with diameter ≥2mm. The composite clinical endpoint comprised all-cause mortality, myocardial infarction and heart failure hospitalisation. Results From a total of 27,201 invasive angiograms performed during the study period, 389 patients were diagnosed with CTO and underwent CMR imaging (mean age 65.0±11.0 years, 84% male). CTO was present most frequently in the right coronary artery (59% of subjects, 229/389), with left circumflex (LCx) artery involvement in 29% (112/389) and left anterior descending (LAD) artery in 29% (111/389). Collaterals with CC grade ≥2 were identified in 186 subjects (48%), and Rentrop score ≥2 in 300 (77%). Significant ischaemia was present in 61% of patients, and infarction in 71% (median infarction 8.6% [interquartile range (IQR) 4.5–14.1]. With a median follow-up time of 3.30 years [IQR 0.04–8.64], 65 (17%) met the composite endpoint. On multivariate analysis, neither significant ischaemia nor infarction was associated with the composite endpoint. However, non-CTO territory ischaemia was independently predictive of adverse outcome (hazard ratio 1.93; 95% CI 1.16–3.21; p=0.0113). Conclusion CTO-territory ischaemia and infarction are not predictive of adverse clinical outcome, challenging the assertion that CTO revascularisation may be guided by ischaemia assessment. The finding that non-CTO territory ischaemia is associated with adverse cardiovascular events warrants further investigation. Kaplan-Meier curves_CTO Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Oral anticoagulants in extremely high risk very elderly (&amp;gt;90 years) patients with Atrial Fibrillation

Abstract Background The prevalence and incidence of atrial fibrillation (AF) increases with age, resulting in a high mortality and morbidity, especially from stroke and systemic thromboembolism (SSE). Nonetheless, the elderly are often denied oral anticoagulants (OACs), especially if they are “very elderly” (age ≥90 years) and perceived to be “high risk” of bleeding, for example, those with a history of intracranial haemorrhage (ICH), gastrointestinal bleeding or chronic kidney disease. We aimed to investigate the effectiveness and safety of OAC in this “high risk” very elderly group. Methods We used the Taiwan National Insurance Database to identify “high risk” very elderly subjects taking OACs, whether warfarin or non-vitamin K antagonist OACs (NOACs), who were compared to non-OAC users for the composite clinical endpoint of “ischemic stroke, ICH, major bleeding or mortality”. Propensity score matching was used for comparisons of the treatment groups. Results We studied 7,362 subjects (48.4% males; mean age 92.5 years, SD 2.78), of which 1737 were taking NOACs, 670 warfarin and 4955 were non-OAC users. Using non-OAC users as the reference group, warfarin use in “high risk” very elderly patients was associated with a higher risk of the composite endpoint (adjusted hazard ratio [aHR] 1.163, 95% CI 1.052–1.287), while NOACs were associated with a lower risk (aHR 0.763, 0.702–0.830). After propensity matching, NOACs were associated with a lower risk of events compared to “non-OAC use” or “warfarin”, while warfarin had a similar risk compared to non-OAC use (Figure). Conclusions Warfarin was associated with a similar (after propensity matching) or higher (Cox model before matching) risk of the composite clinical outcome compared to non-OAC use. NOACs were associated with a significantly lower risk of the composite clinical outcome compared to warfarin or non-OAC use. NOACs should be considered as the preferred OAC strategy in these “high risk” very elderly AF patients. Funding Acknowledgement Type of funding source: None

The Association Between Switching from Synthroid® and Clinical Outcomes: US Evidence from a Retrospective Database Analysis.

IntroductionClinical guidelines recommend levothyroxine as the standard of care for hypothyroidism and that patients should be treated with a consistent preparation of synthetic levothyroxine without switching among formulations. This study examines the likelihoods of negative clinical outcomes between continuous users of Synthroid® (AbbVie, Inc.) and patients who switch from Synthroid® to an alternative formulation of levothyroxine.MethodsThis retrospective cohort analysis utilized data from Optum Clinformatics™ DataMart covering May 1, 2000 to March 30, 2016. After 6 months of consistent use of Synthroid®, patients were categorized as continuous users or as switchers (by filling a prescription for an alternative formulation). Key outcomes included the likelihood of a thyroid-stimulating hormone (TSH) laboratory value out of a guideline recommended range and/or an adverse clinical composite endpoint identified by ICD codes in the patient’s claims data over the following 2 years for any of the following: chronic kidney disease, depression, fatigue, heart failure, hyperlipidemia, hypertension, or obesity. Individual components of the composite endpoint were also examined. Outcomes were analyzed using multivariable logistic models on propensity score matched cohorts. Analyses controlled for patient characteristics using SAS 9.4 software. Chi-square and t tests were employed and P < 0.05 was pre-specified as statistically significant.ResultsPropensity score matching resulted in a sample of 9925 continuous users and 9925 switchers. Switchers were significantly more likely than continuers to have a TSH laboratory value out-of-range in the post-period [odds ratio (OR) 1.15; 95% confidence interval (CI) (1.08–1.23)]. Switchers were also more likely to have the composite clinical endpoint [OR 1.23; CI (1.12–1.37)] and to have individual diagnoses of chronic kidney disease, depression, fatigue, hypertension, or obesity in the post-period.ConclusionsResults of this large retrospective study over an extended time horizon support clinical guideline recommendations that switching among alternative formulations of synthetic levothyroxine should generally be avoided. Continuous use of Synthroid® was associated with a significantly higher likelihood of maintaining the TSH laboratory value within a guideline recommended range and a significantly lower likelihood of being diagnosed with adverse clinical outcomes.

Evolución de pacientes tratados con armazones coronarios bioabsorbibles liberadores de everolimus tras su disolución completa

Introduction and objectivesLong-term outcomes of unselected patients treated with bioresorbable vascular scaffold (BVS) implantation are lacking, especially for the period after complete dissolution of the BVS. This study sought to evaluate 5-year outcomes in patients treated with BVS in routine practice. MethodsConsecutive patients who underwent implantation of everolimus-eluting BVS during routine clinical practice at 2 high-volume centres in Germany were studied. The patients were followed-up for up to 5 years. The primary endpoints of interest were the composite of death, myocardial infarction and target lesion revascularization, as well as definite scaffold thrombosis. ResultsA total of 419 patients (mean age 66.6 ± 10.9 years; 31.5% had diabetes) were included, of whom 38.9% presented with an acute coronary syndrome. Of the 527 lesions treated, 49.0% were classified as complex and 13.1% were bifurcation lesions. At 5 years, the composite clinical endpoint occurred in 33.1% of patients and definite scaffold thrombosis occurred in 4.7%. Most definite scaffold thrombosis occurred within 2 years after BVS implantation. ConclusionsIn patients treated with BVS implantation in routine clinical practice the rates of adverse clinical events at 5 years were high, including a considerable incidence of scaffold thrombosis.

Novel composite clinical endpoints and risk scores used in clinical trials in pulmonary arterial hypertension.

This manuscript on endpoints incorporates the broad experience of members of Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It reviews our current understanding of endpoints used in phase 2 and 3 trials for pulmonary hypertension and discusses in detail the value of newer approaches. These include the roles of composite endpoints and how these can be developed and validated. The newer concept of risk analysis is also discussed, including how such risk scores might be utilised as endpoints in clinical trials.