Hylek, Elaine M.

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.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Introduction: Higher body mass index (BMI) is an independent risk factor for incident atrial fibrillation (AF). However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear. Methods: The study cohort included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry from June 2010 through August 2011. Participants with BMI > 18.5 kg/m2 were stratified into normal (18.5 - 25 kg/m2), overweight (25 - 30 kg/m2), Class I obese (30 - 35 kg/m2), Class II obese (35 - 40 kg/m2), and Class III obese (>40 kg/m2) categories. Unadjusted and adjusted Cox frailty models were constructed to assess the categorical and continuous association of BMI with AF progression, mortality, and incidence of thromboembolic events. Results: We evaluated 9,606 patients with AF (mean age: 74 + 11 years; 42% women) from 174 US ORBIT participating practices. Patients in the higher BMI categories were younger and had a higher prevalence of comorbidities such as diabetes, hypertension, and obstructive sleep apnea. AF symptom burden was greatest among patients in extreme BMI categories. Proportional use of anticoagulation, antiarrhythmic drugs, and invasive rhythm control strategies was significantly greater among patients in higher BMI categories. Rates for mortality and stroke/non-CNS embolism decreased in a near linear fashion across successively higher BMI categories (P<0.001; Table). After multivariable adjustment, higher BMI categories were associated with lower risk for mortality (p = 0.0002), with the lowest risk observed among overweight patients [Hazard Ratio (HR) (95% CI): 0.65 (0.54 - 0.79) ref. group: normal weight]. For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 6% lower [HR (95% CI): 0.94 (0.89 - 0.98)]. In contrast, the association between BMI and risk for stroke/non-CNS embolism was significant on unadjusted analysis (P <0.001) but attenuated after adjustment for risk factors (P = 0.78; Table). No significant association was observed between BMI and AF progression rates in either unadjusted (P = 0.35) or adjusted analyses (P = 0.17). Conclusion: Among patients with AF, higher BMI was associated with a greater use of anticoagulation, rhythm control strategies, and lower mortality risk.

Background: Dabigatran is a novel oral anticoagulant approved in October 2010 for thromboprophylaxis in atrial fibrillation (AF), yet patterns of adoption of this novel agent in clinical practice are unknown. Methods: Using the ORBIT-AF Registry, a national outpatient prospective AF registry involving 170 sites, we examined patterns of those switching to dabigatran from warfarin from 2010 to 2012. Results: Of 7,066 patients with AF receiving warfarin at baseline, 511 (7%) were switched to dabigatran during follow-up. Patients switched to dabigatran were younger (median age 73 vs. 76, p<0.0001), more likely to be White (94% vs. 89%, p=0.001), and had better kidney function (median creatinine clearance (CrCl) 77 mL/min vs. 69 mL/min, p<0.0001), but less likely to have a history of anemia, (14% vs. 18%, p=0.009) or history of any cerebrovascular disease (14% vs. 17%, p=0.04) or CAD (22% vs. 34%, p<0.0001) or be followed in an anticoagulation clinic (36% vs. 45%, p<0.0001). Patients switched to dabigatran were more likely to have been recently diagnosed with AF (5.3% vs. 3.0%, p=0.03), and their CHADS 2 scores were significantly lower (p<0.0001). Conclusions: Patients receiving warfarin who were switched to dabigatran were younger, with lower CHADS 2 scores, better kidney function, and less concomitant cardiovascular disease than those not switched. This conservative transition pattern suggests greater physician emphasis on bleeding avoidance than on stroke risk reduction.

Background. Oral anticoagulation therapy (OAC) reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The frequencies of and factors associated with contraindications to OAC therapy in clinical practice are not well-described. Methods. We used data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. OAC contraindications were uniformly collected at study enrollment by site personnel. Patient and provider characteristics were compared between participants with documented OAC contraindications at baseline and those without OAC contraindications. Results. From June 2010 to August 2011, 10124 patients ≥18 years old with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1409 (13.9%) had OAC contraindications documented at the baseline visit: prior bleed (26.2%), patient refusal/preference (26.0%), high bleeding risk (22.6%), frequent falls/frailty (16.6%), other (11.9%), need for dual antiplatelet therapy (9.8%), unable to adhere/monitor warfarin (5.7%), comorbid illness (5.0%), prior intracranial hemorrhage (4.7%), allergy (2.3%), occupational risk (0.8%), and pregnancy (0.2%). Compared to patients without contraindications, those with contraindications had higher stroke risk (CHADS2>2) and were older, more likely to be female, more likely to be seen by a cardiologist and less likely to be seen by an electrophysiologist (Table 1). Among those patients with reported contraindications, 28.4% were taking warfarin. Conclusions. Contraindications to OAC therapy among AF patients are common and often due to high bleeding risk. Furthermore, many patients with reported contraindications are taking warfarin, suggesting that many contraindications to warfarin therapy are minor, relative, or temporary.

Background: Little information exists on clinical characteristics and treatment patterns of patients with atrial fibrillation (AF) following a major bleeding event in clinical practice. Methods: We used data from a large, national outpatient registry, ORBIT-AF (2010 – 2011), to evaluate event characteristics and oral anticoagulation (OAC) management following a major bleeding event. Major bleeds were defined according to ISTH criteria. We compared baseline characteristics among patients who persisted on OAC therapy at the first clinic visit following a major bleed and those in whom OAC was discontinued using chi-squared tests. Results: Of 10135 patients enrolled in ORBIT-AF, n=791 (7.8%) bleeding events occurred during 2 years of follow-up. Among patients who were receiving OA, n=632 (3.5 per 100 person years) experienced a major bleed. Of these, 67.3% experienced a fall in hemoglobin and 46.8% required transfusion of 2 of more units of red blood cells. Critical site bleeding occurred in 150 OAC patients, with the majority of these classified as intracranial bleeding (n= 89), followed by retroperitoneal (n=25) and intraocular (n=17). Fatal bleeds occurred in 37 patients (5.9% of all major bleeds). Nearly one-third of patients (31.0%) discontinued OAC therapy following the major bleeding event. Compared with those who persisted on OAC, patients who discontinued OAC were more likely to have hypertension and CKD. Those who discontinued OAC were more likely to have gastrointestinal or CNS site bleeding compared with those who persisted (Table). Conclusions: One in three patients who experienced a major bleed were no longer optimally anticoagulated after the event. Those who discontinued OAC had a greater comorbidity burden and more likely to have bleeding in a critical site those who persisted on OAC.

Background: The use of evidence-based therapies to treat cardiovascular comorbidities and risk factors in patients with AF in outpatient clinical practice has not been well characterized. Methods: Using a large, community-based registry of patients with AF in the United States, the prevalence of cardiovascular comorbidities and corresponding use of evidence-based therapies were determined. Results: Among 9,589 enrolled patients with AF, the median age was 75 years; 57.8% were male; 10.7% were non-white; 69.9% had Medicare or Medicaid; 31.8% had coronary heart disease, 32.2% had heart failure, 13.0% had peripheral vascular disease, and 29.5% had diabetes mellitus. Among eligible patients, 62.8% of 3,612 were prescribed an antiplatelet agent, 72.1% of 4,674 were prescribed a β-blocker, 59.7% of 5,121 were prescribed an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 15.7% of 624 were prescribed an aldosterone antagonist, 70.1% of 6,914 were prescribed a statin, 94.7% of 8,329 were prescribed an antihypertensive, 58.3% of 504 had an ICD, and 44.5% of 9,589 received all indicated evidence-based therapies ( Table ). Conclusion: Cardiovascular comorbidities and risk factors in patients with AF are often inadequately treated with evidence-based therapies in the outpatient practice setting, underscoring opportunities to improve care for patients with AF.

Introduction: Warfarin and non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran are effective for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). However, few analyses have compared persistence rates of warfarin vs. dabigatran-treated patients. Methods: The ORBIT-AF registry enrolled patients with AF from 173 clinical practices across the US. One-year persistence of warfarin vs. dabigatran was defined as treatment at baseline visit and at 1-year follow-up. Multivariable logistic regression analysis was used to identify characteristics associated with warfarin or NOAC persistent use. Results: At baseline, 6.4% (N=459/7,150) were treated with dabigatran and 93.6% (N=6,691/7,150) with warfarin. Patients treated with warfarin at baseline were older (74 vs. 71, p<.0001), had more NYHA class III/IV heart failure (7 vs. 5, p=.0007), lower creatinine clearance (77 vs. 88, p<.0001), higher CHA2DS2-VASc risk scores, and more prior CVA/TIA events (16 vs. 11, p=.003). Patients treated with dabigatran had more severe symptoms (EHRA class III: 20 vs. 14, p<.0001), higher rates of treatment with a rhythm control strategy (42.7 vs. 28.2, p<.0001), more attempts at cardioversion (38.3 vs. 32.1, p<.006), and catheter ablation of AF (9.8 vs. 5.2, p<.0001). At 12 months, adjusted persistence rates for warfarin were higher than dabigatran [82% (80-84) vs. 67% (61-73) p<.0001]. Factors independently associated with one year persistence were: African American race (OR 1.53, 95% C.I. 1.07-2.19, p=0.02), Hispanic race (OR 1.66, 95% C.I. 1.06-2.60), paroxysmal AF (vs. new onset) (OR 1.68, 95% C.I. 1.21-2.33, p=.002), LVH (OR 1.40, 95% C.I. 1.08-1.81, p=.01), persistent AF (vs. new onset) (OR 1.91, 95% C.I. 1.35-2.69, p=.0002), and CHA2DS2-VASc risk scores ≥ 2 (OR 1.94, 95% C.I. 1.18-3.19, p=.009). Conclusion: Persistence rates for warfarin were higher at one year than those on dabigatran. In addition, factors associated with persistence of warfarin include: African American and Hispanic race, type of AF including permanent and persistent, LVH, and CHA2DS2-VASc risk scores ≥ 2.

Background: Novel therapies for stroke prevention in atrial fibrillation (AF) are emerging. However, data on use and outcomes of these agents in the community are limited, particularly in patients newly diagnosed with AF or recently transitioned to a novel anticoagulant. Methods: Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF II) is a multicenter, national, AF registry. We are enrolling 15,000 patients with new-onset AF, or those with known AF recently-transitioned to a novel anticoagulant. The primary objective is to evaluate the safety of novel anticoagulants, with specific focus on use, transitions, and management around invasive procedures and bleeding events. An adaptive design is used to ensure diversity of enrollment across geographic, provider, and treatment groups. The primary outcomes are major bleeding and thromboembolic events. Results: Of 1,011 patients in ORBIT-AF II, the median age was 73, 44% were female, 23% had a history of heart failure, 34% had a prior MI, and 11% had a prior stroke/TIA. The mean CHADS2 score was 2. Overall, 76% had AF new-onset, and a range of anticoagulant strategies was used in these patients (Figure). Among the 24% with known AF transitioned to a novel agent, 66% received rivaroxaban, versus 8.1% dabigatran, and 26% apixaban. Compared with patients having new-onset AF, those with known AF recently-transitioned to a novel anticoagulant were slightly older (median age 74 vs. 72), had higher CHADS2 scores (>2 in 70% vs. 62%), but less severe kidney disease (0 vs. 1.7%). Conclusions: Patients with new-onset AF are frequently treated with novel anticoagulants and these patients have lower risk scores than those with known AF transitioned to a novel drug. These data will provide insights into clinical management and patient centered outcomes among those treated with novel anticoagulants in real world practice settings.

Objective: Time in the therapeutic range (TTR) of INR 2.0-3.0 is an important measurement of warfarin anticoagulation quality. There are few reports on TTR in United States (US) clinical practice. Methods: Using the US ORBIT AF registry, we analyzed TTR for patients on warfarin with at least 5 recorded INR measurements. The Rosendaal method of linear interpolation was used between each pair of measured INR values. Patients were stratified into quartiles based on TTR. Results: We studied 5,451 patients treated at 169 US sites with 48% of patients being followed at an anticoagulation clinic. Patients had a median age of 76 years [interquartile range (IQR) 68-82 years] and median follow-up was 18.9 months [IQR 12.7-23.3 months], and patients were 42% women. The median number of INR draws was 21 [IQR 12-30]. Patients had an overall median TTR of 68% [IQR 52-80%]. The median TTR by quartile was 40%, 60%, 73%, and 87%. Patients were more likely to be subtherapeutic (median time of 17%) than supratherapeutic (median time of 10%). Patients age 61-80 years and those with a college education had the highest TTRs. Patients with their INR followed at an anticoagulation clinic were more likely to be in the highest TTR quartile than in the lowest (27% vs 23%, p=0.0002). Patients with worsening renal function and higher risk for bleeding (ATRIA) or stroke (CHADS2 score) had lower TTR (p<0.0001 for all) (Figure). Conclusions: In US clinical practices, warfarin patients have therapeutic INR levels about 2/3 of the time. Those at highest risk for stroke and bleeding paradoxically were the least likely to be in the therapeutic range.