Pieper, Karen S.

Background: Refractory angina(Ang) effects 150 –250,000 pts in the US alone. These individuals have exhausted options for revasc and continue to have lifestyle limiting ang despite optimal medical Rx. Pre-clinical studies provided evidence that human CD34+ cells(CD34) can stimulate new blood vessel formation in ischemic myocardium(Myo), improving perfusion and function. We performed a phase 2 study of intraMyo injection of autologous CD34 in pts with CCS Class 3 and 4 Ang to obtain evidence for feasibility, safety and bioactivity. Methods: A phase 2 randomized, double-blind, placebo-controlled clinical trial was performed at 26 centers in the United States. There were 3 treatment groups: placebo, low dose (1×10^5 CD34/kg body wt) and high dose (5×10^5 CD34/kg). All pts underwent mobilization with GCSF 5 mcg/kg/day SC for 5 d, followed by apheresis on d5 to collect mononuclear cells. On day 6 CD34 were purified from the collected cells using the Isolex 300i device. After lot release testing, CD34 were injected endocardially at 10 locations in the ischemic Myo using the Myostar catheter following NOGA mapping. Placebo injections consisted of identical volumes of the diluent only. Results: A total of 167 pts were randomized and completed the injection procedure and 162 completed the 6 mo evaluation. The mean age of subjects was 61.0±8.9, there were 22 female and 145 male subjects. Trop was elevated in 26 pts at baseline and in 71 at some point following GCSF or injection. At 6 mo CD34 treated pts showed more reduction in ang frequency (−8.6 placebo vs 14.2 low dose) and improved ETT time (+69 sec placebo vs. +138 low dose). At 12m CD34 treated continue to show more reduction in angina (−8.2 placebo vs. −15.0 low dose) and improved ETT (+58 sec placebo vs. + 139 sec low dose). For key endpoints the high dose group results were inferior to low dose. The 12m data set has been locked and is being analyzed and the results of the completed analysis will be presented. Conclusions: Autologous CD34 cell therapy was associated with improved exercise tolerance and reduced angina in no-option pts with intractable angina. Ongoing analysis will determine endpoints, sample size and suitability of this therapy for a phase III study in no-option pts with refractory angina.

Background Guidelines for patients with atrial fibrillation (AF) at high thromboembolic risk recommend oral anticoagulants (OACs) for preventing stroke and systemic embolism (SE). The reasons for guideline non-adherence are still unclear. Aim The aim is to identify clinical, demographic and non-patient characteristics associated with withholding OAC in patients with AF at high stroke risk. Methods Patients in the Global Anticoagulant Registry in the FIELD-AF, newly diagnosed with AF between March 2010 and August 2016, and with CHA2DS2-VASc Score≥2 (excluding sex), were grouped by OAC treatment at enrolment. Factors associated with OAC non-use were analysed by multivariable logistic regression. Results Of 40 416 eligible patients, 12 126 (30.0%) did not receive OACs at baseline. Globally, OAC prescription increased over time, from 60.4% in 2010–2011 to 74.7% in 2015–2016. Country of enrolment was the major predictor for OAC withholding (χ2−df=2576). Clinical predictors of OAC non-use included type of AF (χ2−df=404), history of bleeding (χ2−df=263) and vascular disease (χ2−df=99). OACs were used most frequently around the age of 75 years and decreasingly with younger as well as older age beyond 75 years (χ2−df=148). Non-cardiologists (χ2−df=201) and emergency room physicians (χ2−df=14) were less likely to prescribe OACs. OAC prescription correlated positively with country health expenditure. Conclusions Approximately one out of three AF patients did not receive OAC, while eligible according to the guidelines. Country of enrolment was the major determinant of anticoagulation strategy, while higher country health expenditure was associated with lower likelihood of withholding anticoagulation.

AbstractBackgroundAn unmet need exists to reliably predict the risk of intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs).HypothesisAn externally validated model improves ICH risk stratification.MethodsIndependent factors associated with ICH were identified by Cox proportional hazard modeling, using pooled data from the GARFIELD‐AF (Global Anticoagulant Registry in the FIELD‐Atrial Fibrillation) and ORBIT‐AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registries. A predictive model was developed and validated by bootstrap sampling and by independent data from the Danish National Patient Register.ResultsIn the combined training data set, 284 of 53 878 anticoagulated patients had ICH over a 2‐year period (0.31 per 100 person‐years; 95% confidence interval [CI]: 0.28–0.35). Independent predictors of ICH included: older age, prior stroke or transient ischemic attack, concomitant antiplatelet (AP) use, and moderate‐to‐severe chronic kidney disease (CKD). Vitamin K antagonists (VKAs) were associated with a significantly higher risk of ICH compared with non‐VKA oral anticoagulants (NOACs) (adjusted hazard ratio: 1.61; 95% CI: 1.25–2.08; p = .0002). The ability of the model to discriminate individuals in the training set with and without ICH was fair (optimism‐corrected C‐statistic: 0.68; 95% CI: 0.65–0.71) and outperformed three previously published methods. Calibration between predicted and observed ICH probabilities was good in both training and validation data sets.ConclusionsAge, prior ischemic events, concomitant AP therapy, and CKD were important risk factors for ICH in anticoagulated AF patients. Moreover, ICH was more frequent in patients receiving VKA compared to NOAC. The new validated model is a step toward mitigating this potentially lethal complication.

The management of atrial fibrillation (AF), the most common sustained arrhythmia, impacts healthcare resource utilization (HCRU). This study aims to estimate global resource use in AF patients, using the GARFIELD-AF registry. A prospective cohort study was conducted to characterize HCRU in AF patients enrolled in sequential cohorts from 2012 to 2016 in 35 countries. Components of HCRU studied were hospital admissions, outpatient care visits, and diagnostic and interventional procedures occurring during follow-up. AF-related HCRU was reported as the percentage of patients demonstrating at least one event and was quantified as rate-per-patient-per-year (PPPY) over time. A total of 49,574 patients was analyzed, having an overall median follow-up of 719 days. Almost all patients (99.5%) had at least one outpatient care visit, while hospital admissions were the second most frequent medical contact, with similar proportions in North America (37.5%) and Europe (37.2%), and slightly higher in the other GARFIELD-AF countries (42.0%; namely Australia, Egypt, and South Africa). Asia and Latin America showed lower percentages of hospitalizations, outpatient care visits, and diagnostic and interventional procedures. Analyses of GARFIELD-AF highlighted the vast AF-related HCRU, underlying significant geographical differences in the type, quantity, and frequency of AF-related HCRU. These differences were likely attributable to health service availability and differing models of care.

Abstract Background Atrial fibrillation is associated with considerable morbidity and mortality. Real-world reports on the effect of early rhythm control on patient outcomes in patient with recent onset atrial fibrillation are limited. Purpose To assess the effect of early rhythm versus rate control on clinical outcomes in patients with newly diagnosed non-valvular atrial fibrillation. Method The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is a non-interventional registry of adult (≥18 years) patients with newly diagnosed atrial fibrillation (≤ six weeks' duration) and at least one investigator determined risk factor for stroke. Patients were enrolled in 1317 participating sites in 35 countries between March 2010 and August 2016. Patients with permanent atrial fibrillation were excluded. Stratification to rhythm or rate control was based on treatment strategy initiated at baseline (≤48 days post enrolment). Rhythm control was defined as investigator reported initiation of rhythm control (antiarrhythmic drug(s), cardioversion, or ablation – alone or in combination with rate modifiers). Rate control was defined as investigator reported initiation of rate control and absence of rhythm control therapy. Overlap propensity weighting and Cox proportional-hazards models were used to evaluate effect on outcomes. Results Of 45,382 included patients, 23,858 (52.6%) received rhythm control and 21,524 (47.4%) rate control. Rates of rhythm control were similar throughout the study time period (52.7% in 2010/2011, 54.2% in 2015/2016). Patients in the rhythm control group were younger (median age (Q1; Q3) 68.0 (60.0; 76.0) versus 73.0 (65.0; 79.0)), had lower rates of prior stroke/transitory ischemic attack/systemic embolism (9.4% vs 13.0%), and a lower median GARFIELD death score (4.0 (2.3; 7.5) versus 5.1 (2.8; 9.2)). Median CHA2DS2-VASc Scores were 3.0 (2.0; 4.0) in both groups. Rate of anticoagulation treatment was similar in the rhythm and rate control group (66.0% versus 65.5%). After propensity score overlap weighting, patients of the two groups were well balanced on all observed characteristics. Event rates per 100 person-years (95% confidence interval [CI]) over two years follow-up in the rhythm and rate control group were 2.94 (2.78–3.10) versus 4.43 (4.22–4.64) for mortality, 0.84 (0.75–0.92) versus 1.16 (1.05–1.27) for non-haemorrhagic stroke/systemic embolism and 0.84 (0.76–0.93) versus 1.16 (1.06–1.27) for major bleeding. Adjusted hazard ratios (95% CI) for the same time period were 0.85 (0.79–0.92), 0.84 (0.72–0.97) and 0.9 (0.78–1.04). Conclusion In this large, internation registry, a rhythm control strategy was initiated at baseline in about half of the patients with newly diagnosed non-valvular atrial fibrillation. After adjustment for confounding factors, a significantly lower risk of all-cause mortality and non-haemorrhagic stroke/systemic embolism were observed for patients that received an early rhythm control strategy. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by the Thrombosis Research Institute (London, UK).

Abstract Background Many patients with atrial fibrillation (AF) have comorbid vascular disease. The effects of oral anticoagulation (OAC) in AF patients with vascular disease, however, have not been widely studied. Purpose To investigate the impact of OAC in AF patients with (Vasc) or without (nVasc) concomitant vascular disease. Methods GARFIELD-AF is the largest multinational, prospective AF registry. The study comprised 51,574 GARFIELD-AF patients with newly diagnosed AF, 13,365 Vasc and 38,209 nVasc patients. All patients who reported coronary artery disease, aortic or peripheral artery disease, acute coronary syndromes, myocardial infarction, stenting, or coronary artery bypass graft were classified as having vascular disease. Adjusted hazard ratios were obtained via Cox proportional-hazards models to quantify the association of vascular disease with selected endpoints. Comparative effectiveness analyses were restricted to patients enrolled from April 2013-September 2016 (when NOACs became widely available) and who were eligible for anticoagulation (CHA2DS2-VASc ≥2 excl. gender). To evaluate the safety and efficacy of different anticoagulation strategies in Vasc and nVasc patients, propensity score using an overlap weighting scheme was applied. Weights were applied to Cox proportional-hazards models to estimate the effects of OAC vs No OAC and NOAC vs VKA. Results Vasc patients were older (median (Q1; Q3): 72.0 (65.0; 79.0) vs 70.0 (62.0; 78.0) and more often male (62.0 vs 53.6%). Vasc patients had a higher rate of comorbidities including heart failure, hypertension, and diabetes. Vasc patients received less OAC (62.8 vs 68.3%). NOACs were less common compared with nVasc patients (23.8% vs 28.7%) but a similar proportion of VKAs was observed in both (39.0% vs 39.6%). Antiplatelet monotherapy was more common in Vasc (31%) than nVasc (18%) patients. At 2-years, Vasc was associated with a higher risk of all-cause (HR [95% CI]: 1.30 [1.16–1.47]) and cardiovascular mortality (1.59 [1.28–1.97]). OACs significantly lowered the risk of all-cause mortality and stroke in nVasc patients (0.72 [0.63–0.82] and 0.64 [0.49–0.84], respectively), but not in nVasc patients. OACs led to a numerical increase in major bleeding in Vasc patients (1.32 [0.90–1.93]) and a significant increase in major bleeding in nVasc patients (1.40 [1.03–1.90]) (Figure 1). Compared with VKAs, NOACs did not significantly improve the risk of outcomes in nVasc patients. In Vasc patients however, NOACs significantly lowered the risk of all-cause mortality (0.74 [0.61–0.90]) and major bleeding (0.45 [0.29–0.70]) compared with VKAs (Figure 2). Conclusion AF patients with vascular disease have worse long-term outcomes than those without. They receive less often OAC, specifically NOAC, and more antiplatelet agents. The beneficial effects of NOAC over VKA are much more pronounced in patients with than in those without vascular disease. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by the Thrombosis Research Institute (London, UK).

Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI. Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI <18.5 kg/m 2 ), 13 095 normal (BMI=18.5–24.9 kg/m 2 ), 15 043 overweight (BMI=25.0–29.9 kg/m 2 ), 7560 obese (BMI=30.0–34.9 kg/m 2 ) and 4081 extremely obese (BMI ≥35.0 kg/m 2 ). Restricted cubic splines quantified the association of BMI with outcomes. Comparative effectiveness of NOACs and vitamin K antagonists (VKAs) by BMI was performed using propensity score overlap-weighted Cox models. Results The median age of participants was 71.0 years (Q1; Q3 62.0; 78.0), and 55.6% were male. Those with high BMI were younger, more often had vascular disease, hypertension and diabetes. Within 2-year follow-up, a U-shaped relationship between BMI and all-cause mortality was observed, with BMI of ~30 kg/m 2 associated with the lowest risk. The association with new/worsening heart failure was similar. Only low BMI was associated with major bleeding and no association emerged for non-haemorrhagic stroke. BMI was similarly associated with outcomes in men and women. BMI did not impact the lower rate of all-cause mortality of NOACs compared with VKAs. Conclusions In the GARFIELD-AF registry, underweight and extremely obese AF patients have increased risk of mortality and new/worsening heart failure compared with normal or obese patients.

Abstract Introduction Non-vitamin-K oral anticoagulants (NOACs) were recommended in preference to oral vitamin K antagonists (VKAs) in the 2020 updated guidelines for stroke prevention in atrial fibrillation (AF), from the European Society of Cardiology (ESC). Rivaroxaban is a NOAC that is approved in many countries worldwide for reducing the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Purpose To explore the baseline characteristics, dosing and 2-year outcomes of patients with AF treated with rivaroxaban. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international, multicenter registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Results A total of 5043 patients were enrolled into RIVER between January 2015 and June 2017. Mean (SD) age at diagnosis was 69.5 (11.0) years and 55.7% were males. Caucasian patients represented the largest proportion of patients in RIVER (80.3%), followed by Asians (5.5%) and hispanic/latino (3.7%). Almost all patients (98.5%) were prescribed a single daily dose of rivaroxaban, most commonly 20 mg (77.3%) and 15 mg (20.4%), while a 10 mg dose was prescribed in only 2.3% of patients. During the 2-year follow-up, the rates (95% CI) of all-cause mortality, stroke/SE, and major bleeding were 2.75 (2.43 to 3.12), 0.89 (0.72; 1.11), and 1.26 (1.05 to 1.52) per 100 person years, respectively (Figure 1). The most common cardiovascular cause of death was congestive heart failure (30.4%) and myocardial infarction (11.4%). Leading non-cardiovascular causes of death were malignancy (27.4%), respiratory failure (18.9%) and infections/sepsis (13.2%). Over 2 years, 710 (14.1%) of patients discontinued rivaroxaban. The corresponding proportions at 6 months and 1 year were 7.8% and 10.8%, respectively. Out of all the patients who discontinued, 62 (8.7%) restarted rivaroxaban during their follow-up (Table 1). Conclusion During 2 years of follow up in the international, prospective RIVER registry, rivaroxaban treatment for AF was associated with low rates of stroke or major bleeding. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Abstract Introduction Rivaroxaban is recommended as an option for anticoagulation in patients with nonvalvular atrial fibrillation (AF) with one or more risk factors for stroke. The approved/recommended rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is solely based on renal function: 20 mg once daily (od) for patients with a creatinine clearance [CrCl] ≥50 ml/min and 15 mg od in patients with CrCl 15–49 mL/min). Purpose To assess the patterns of rivaroxaban prescription as per the creatinine clearances levels and to assess the impact of the rivaroxaban dosing on the rate of events at 2-year follow-up in patients with AF. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard model. Results Among 3402 patients with normal renal function (CrCl ≥50 mL/min), 82.1% were prescribed the recommended rivaroxaban dose of 20 mg (od) at baseline. Among 524 patients with moderate or severe renal impairment (CrCl 15–50 mL/min), 55.3% patients received rivaroxaban 15 mg (od), 39.9% received 20 mg (od) and 4.2% 10 mg (od). Non-recommended dosing was rare in patients younger than 70 (13.5%) but more frequent in older patients (28.8%). Non-recommended low dosing was more frequent in Asians (38.9%), compared to non-Asian patients (13.8%). Regarding clinical outcomes, adjusted hazards ratios (HR, presented with 95% confidence intervals) showed that the non-recommended low dosing (&lt;20 mg od) was associated with higher risk of non-cardiovascular mortality (HR 2.09 (1.16–3.77)) in patients with normal renal function. The non-recommended high dosing (&gt;15 mg od) was associated with lower risk of all-cause mortality (HR 0.63 (0.42–0.93)) and cardiovascular mortality (HR 0.32 (0.13–0.77)) and higher risk of major bleeding (HR 2.86 (1.49–5.50)) in patients with moderate to severe renal impairment (figure 1 and 2). Conclusion In patients with normal renal function, non-recommended low dose rivaroxaban was associated with increased cardiovascular mortality without reducing the risk of major bleeding compared to recommended dosing. In patients with CrCl &lt;50 ml/min, non-recommended high dose rivaroxaban was associated with reduced cardiovascular mortality but at the cost of increased major bleeding. These observational data largely support the reduction of rivaroxaban dosing according to renal function but educational strategies are needed to ensure that rivaroxaban is used appropriately. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the RIVER registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Introduction: Patient understanding of available therapies for atrial fibrillation (AF) is foundational to shared medical decision making and long term medication adherence. Yet, there is a paucity of data regarding the extent to which patients newly diagnosed with AF in routine community practice understand their options. Hypotheses: 1) Understanding of warfarin, novel oral anticoagulants (NOAC), rhythm control therapy, cardioversion and radio frequency ablation changes little from baseline to 6 months and 2) treatment rates at 6 months are associated with patient understanding of therapies at baseline. Methods: We analyzed survey data from SATELLITE, a substudy of new-onset AF patients enrolled at 56 US sites participating in the ORBIT-AF registry. Patients were surveyed at the baseline and 6 month follow up clinic visit using Likert scales. Agreement between time points was assessed with the McNemar test, and the relationship between understanding and treatment was assessed only for the subset not on treatment at baseline. Results: Of 1000 patients enrolled in SATELLITE, 506 had 6-month survey data (data collection is continuing). Among these, the median age was 69.0 years (IQR 63.0 - 76.0) and 93.7% (474 of 506) were white. There was evidence of improvement in the self-reported understanding of warfarin and NOACs from baseline to 6 months, but not for rhythm control, ablation or cardioversion. The proportion reporting high understanding improved significantly for warfarin (p<.0001) and NOACs (p<.0001) from 47% (223 of 474) and 51% (245 of 481) at baseline to 60% (284 of 474) and 69% (332 of 481) at 6 months respectively (Figure 1). Patients with high understanding of the benefits of ablation (p=0.0005) and options for ablation (p=0.0093) at baseline were more likely to have this therapy at the 6 month follow up (N=590), but improved understanding was not associated with increased use of warfarin/NOACs (N=83) or rhythm control (N=444). Conclusions: Patients with new-onset AF had improved self-reported understanding of some treatment options over the first 6-months from diagnosis; however, factors other than patient understanding may influence AF treatments received at 6 months. Patient understanding of AF treatments remains suboptimal at 6 months, and our results suggest a need for ongoing patient education.