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1.  Outcomes registry for better informed treatment of atrial fibrillation II: Rationale and design of the ORBIT-AF II registry 
American heart journal  2014;168(2):160-167.
Background
Recent clinical trials have demonstrated the safety and efficacy of several non–vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF). However, there are limited data on their use and outcomes in routine clinical practice, particularly among patients newly diagnosed as having AF and patients with AF recently transitioned to a NOAC.
Methods/Design
ORBIT-AF II is a multicenter, national registry of patients with AF that is enrolling up to 15,000 newly diagnosed patients with AF and/or those with AF recently transitioned to a NOAC from 300 US outpatient practices. These patients will be followed for up to 2 years, including clinical status, outcomes (major adverse cardiovascular events, bleeding), and management of anticoagulation surrounding bleeding events. In addition, detailed data regarding the use of these agents in and around cardiac procedures, their complications, and management of such complications will be collected.
Conclusions
The ORBIT-AF II registry will provide valuable insights into the safety and effectiveness of NOACs used in AF in community practice settings.
doi:10.1016/j.ahj.2014.04.005
PMCID: PMC4145241  PMID: 25066554
2.  Heart rate is associated with progression of atrial fibrillation, independent of rhythm 
Heart  2015;101(11):894-899.
Objective
Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described.
Methods
Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA2DS2VASc scores for identifying AF progression.
Results
Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12–24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS2 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64–80) vs 68(60–76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ≤80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA2DS2VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)).
Conclusions
Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.
doi:10.1136/heartjnl-2014-307043
PMCID: PMC4453487  PMID: 25732748
3.  Use and Outcomes of Antiarrhythmic Therapy in Patients with Atrial Fibrillation Receiving Oral Anticoagulation: Results from the ROCKET AF Trial 
Background
Antiarrhythmic drugs (AAD) and anticoagulation are mainstays of atrial fibrillation (AF) treatment.
Objective
We aimed to study the use and outcomes of AAD therapy in anticoagulated AF patients.
Methods
Patients in the ROCKET AF trial (n=14,264) were grouped by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across groups, as well as across treatment assignment (rivaroxaban or warfarin).
Results
Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone, 537 [3.8%] with other AADs). Amiodarone-treated patients were less-often female (38% vs. 48%), had more persistent AF (64% vs. 40%), and more concomitant heart failure (71% vs. 41%) than patients receiving other AADs. Patients receiving no AAD more closely-resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone versus no AAD (50% vs. 58%, p<0.0001). Compared with no AAD, neither amiodarone (adjusted HR 0.98, 95% CI 0.74–1.31, p=0.9) nor other AADs (adjusted HR 0.66, 95% CI 0.37–1.17, p=0.15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Rivaroxaban treatment effects in patients not on an AAD were consistent with the overall trial (primary endpoint adjusted HR 0.82, 95% CI 0.68–0.98, pinteraction=0.06; safety endpoint adjusted HR 1.12, 95% CI 0.90–1.24, pinteraction=0.33).
Conclusion
Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The influence of amiodarone on outcomes in patients receiving rivaroxaban requires further study.
doi:10.1016/j.hrthm.2014.03.006
PMCID: PMC4035424  PMID: 24833235
atrial fibrillation; antiarrhythmic drugs; rivaroxaban; warfarin; outcomes
4.  Lack of Concordance between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry 
Circulation  2014;129(20):2005-2012.
Background
Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. While empirical models have been developed to predict such risks, the degree to which these coincide with clinicians’ estimates is unclear.
Methods and Results
We examined 10,094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June, 2010 and August, 2011. Empirical stroke and bleeding risks were assessed using the CHADS2 and ATRIA scores, respectively. Separately, physicians were asked to categorize their patients’ stroke and bleeding risks: low- (<3%); intermediate- (3-6%); and high-risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. While 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.
Conclusions
There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, current divergence of anticoagulation treatment decisions from guideline recommendations.
doi:10.1161/CIRCULATIONAHA.114.008643
PMCID: PMC4050636  PMID: 24682387
atrial fibrillation; risk assessment; stroke; bleeding; anticoagulation
5.  Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) 
American heart journal  2014;167(5):735-742.e2.
Background
Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.
Methods
The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.
Results
Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ≥75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.
Conclusions
Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.
doi:10.1016/j.ahj.2014.02.003
PMCID: PMC4006943  PMID: 24766985
6.  Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial 
Background
In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.
Methods and Results
We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted.
Conclusions
TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
doi:10.1161/JAHA.114.001349
PMCID: PMC4392426  PMID: 25736441
anticoagulants; arrhythmia; embolism; prevention; risk factors
7.  Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial 
European Heart Journal  2013;35(4):233-241.
Aims
We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.
Methods and results
In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73–1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59–3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).
Conclusion
Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.
doi:10.1093/eurheartj/eht428
PMCID: PMC3896862  PMID: 24132190
Atrial fibrillation; Myocardial infarction; Coronary artery disease; Outcomes; Factor Xa; Rivaroxaban; Warfarin
8.  Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial 
Background
Premature cardiovascular disease limits the duration and quality of life on long‐term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.
Methods and Results
EVOLVE was a randomized, double‐blind, placebo‐controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.
Conclusions
Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.
Clinical Trials Registration
Unique identifier: NCT00345839. URL: ClinicalTrials.gov.
doi:10.1161/JAHA.114.001363
PMCID: PMC4338730  PMID: 25404192
atherosclerosis; cardiovascular diseases; heart failure; kidney; sudden death
9.  Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation 
Circulation  2014;129(18):1850-1859.
Background
During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.
Methods and Results
In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non–central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3–30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36–1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80–2.00]; P=0.32).
Conclusions
TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.
doi:10.1161/CIRCULATIONAHA.113.005754
PMCID: PMC4206548  PMID: 24552831
anticoagulation; atrial fibrillation; stroke
10.  Factors Associated With Major Bleeding Events 
Objectives
This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Background
The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.
Methods
The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.
Results
The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.
Conclusions
Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767)
doi:10.1016/j.jacc.2013.11.013
PMCID: PMC4206565  PMID: 24315894
anticoagulants; atrial fibrillation; hemorrhage
11.  Independent data monitoring committees: Preparing a path for the future 
American heart journal  2014;168(2):135-41.e1.
Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.
doi:10.1016/j.ahj.2014.05.003
PMCID: PMC4181557  PMID: 25066551
12.  Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial 
European Heart Journal  2014;36(5):288-296.
Aim
Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation.
Methods and results
Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6).
Conclusion
In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.
doi:10.1093/eurheartj/ehu359
PMCID: PMC4313363  PMID: 25209598
Atrial fibrillation; Paroxysmal; Persistent; Anticoagulation; Outcomes
13.  Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial 
European Heart Journal  2014;35(47):3377-3385.
Aims
We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.
Methods and results
ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban.
Conclusions
Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.
doi:10.1093/eurheartj/ehu305
PMCID: PMC4265383  PMID: 25148838
Fibrillation; Anticoagulants; Heart diseases; Regurgitation; Stenosis
14.  Use and Associated Risks of Concomitant Aspirin Therapy with Oral Anticoagulation in Patients with Atrial Fibrillation: Insights from the ORBIT-AF Registry 
Circulation  2013;128(7):721-728.
Background
The role of concomitant aspirin therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant aspirin use and its association with clinical outcomes among AF patients treated with OAC.
Methods and Results
The Outcomes Registry for Better Informed Treatment (ORBIT) of Atrial Fibrillation registry enrolled 10,126 AF patients from 176 US practices from June, 2010 through August, 2011. The study population was limited to those on OAC (n=7,347).
Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant aspirin therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% (n=2543) of AF patients on OAC also received aspirin (OAC+ASA). Patients receiving OAC+ASA were more likely male (66% vs. 53%, p<0.0001) and had more comorbid illness than those on OAC alone. Over one-third (39%) of OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated ATRIA bleeding risk scores (≥5). Major bleeding (adjusted HR 1.53, 95% CI 1.20–1.96) and bleeding hospitalizations (adjusted HR 1.52, 95% CI 1.17–1.97) were significantly higher in those on OAC+ASA versus OAC alone. Rates of ischemic events were low.
Conclusions
Patients with AF receiving OAC are often treated with concomitant aspirin, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant aspirin outweigh the risks in AF patients already on OAC.
doi:10.1161/CIRCULATIONAHA.113.002927
PMCID: PMC3908483  PMID: 23861512
atrial fibrillation; anticoagulants; aspirin; hemorrhage; outcomes research
15.  Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER 
Background
Clinical trials traditionally use time‐to‐first‐event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.
Methods and Results
TRACER randomized 12 944 patients with non‐ST‐segment elevation acute coronary syndromes to placebo or to protease‐activated receptor 1 antagonist vorapaxar with a median follow‐up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).
Conclusions
Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00527943.
doi:10.1161/JAHA.114.001032
PMCID: PMC4310394  PMID: 25012288
acute coronary syndromes; recurrent events; vorapaxar
16.  Prognostic Significance of Bleeding Location and Severity Among Patients With Acute Coronary Syndromes 
JACC. Cardiovascular interventions  2013;6(7):10.1016/j.jcin.2013.03.010.
Objectives
This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients.
Background
The prognostic significance of bleeding location among ACS patients undergoing cardiac catheterization is not well known.
Methods
We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model.
Results
A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio [HR]: 2.52 [95% confidence interval (CI): 2.16 to 2.94, and 1.40 [95% CI: 1.16 to 1.69], respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 [95% CI: 0.97 to 1.40], and 0.96 [95% CI: 0.82 to 1.12], respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 [95% CI: 3.80 to 7.29]), followed by systemic (HR: 4.48 [95% CI: 2.98 to 6.72]), and finally access-site bleeds (HR: 3.57 [95% CI: 2.35 to 5.40]).
Conclusions
Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management.
doi:10.1016/j.jcin.2013.03.010
PMCID: PMC3884698  PMID: 23866183
acute coronary syndrome; bleeding; percutaneous coronary intervention
17.  Use of Evidence-Based Primary and Secondary Cardiac Prevention Therapy Among Outpatients with Atrial Fibrillation 
The American journal of medicine  2013;126(7):625-32.e1.
Background
Patients with atrial fibrillation often have cardiovascular risk factors or known comorbid disease, yet the use of evidence-based primary and secondary prevention cardiac therapy among atrial fibrillation outpatients is unknown.
Methods
Using baseline data collected between June 2010 and August 2011 from 174 sites participating in ORBIT-AF, a US national registry of patients with atrial fibrillation coordinated from Durham, NC, USA, we examined professional guideline -recommended evidence-based therapy use for cardiovascular comorbid conditions and risk factors. Multivariable logistic regression was used to identify factors associated with receipt of all indicated evidence-based therapy.
Results
Among 10096 enrolled patients, 93.5% were eligible for one or more evidence-based therapy. Among those eligible, 46.6% received all indicated therapies: 62.3% received an antiplatelet agent, 72.3% received a β-blocker, 59.5% received an angiotensin converting enzyme or angiotensin receptor blocker, 15.3% received an aldosterone antagonist, 65.7% received a statin, and 58.8% received implantable cardioverter-defibrillator. A minority of patients with coronary artery disease, diabetes mellitus, heart failure, and peripheral vascular disease received all indicated therapies (25.1%, 43.2%, 42.5%, and 43.4%, respectively). A total of 52.4% of patients had controlled hypertension and 74.6% of patients with hyperlipidemia received a statin. Factors associated with non-receipt of all indicated therapies included frailty, comorbid illness, geographic region, and antiarrhythmic drug therapy.
Conclusions
The majority of eligible atrial fibrillation outpatients did not receive all guideline-recommended therapies for cardiovascular comorbid conditions and risk factors. This represents a potential opportunity to improve atrial fibrillation patients’ quality of care and outcomes.
doi:10.1016/j.amjmed.2013.01.037
PMCID: PMC4037289  PMID: 23787195
atrial fibrillation; evidence-based medicine; registry
18.  Rate versus rhythm control for management of atrial fibrillation in clinical practice: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry 
American heart journal  2013;165(4):622-629.
Background
All patients with atrial fibrillation (AF) require optimization of their ventricular rate. Factors leading to use of additional rhythm control in clinical practice have not been thoroughly defined.
Methods
The ORBIT-AF registry enrolled patients with AF from a broad range of practice settings and collected data on rate versus rhythm control, as indicated by the treating physician. Multivariable logistic regression analysis was performed to identify factors associated with each strategy.
Results
Of 10,061 patients enrolled, 6,859 (68%) were managed with rate only control versus 3,202 (32%) with rhythm control. Patients managed with rate control were significantly older and more likely to have hypertension, heart failure, prior stroke, and gastrointestinal bleeds. They also had fewer AF-related symptoms (41% with no symptoms vs 31% for rhythm control). Systemic anticoagulation was prescribed for 5,448 (79%) rate-control patients versus 2,219 (69%) rhythm-control patients (P < .0001). After multivariable adjustment, patients with higher symptom scores (severe symptoms vs. none, OR 1.62, 95% CI 1.41–1.87) and those referred to electrophysiologists (OR 1.64, 95% CI 1.45–1.85) were more likely to be managed with a rhythm control strategy.
Conclusions
In this outpatient registry of US clinical practice, the majority of patients with AF were managed with rate control alone. Patients with more symptoms and who were treated by an electrophysiologist were more likely to receive rhythm-control therapies. A significant proportion of AF patients, regardless of treatment strategy, were not treated with anticoagulation for thromboembolism prophylaxis.
doi:10.1016/j.ahj.2012.12.019
PMCID: PMC4074883  PMID: 23537981
19.  Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial 
Background
Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.
Methods and Results
TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger‐stick point‐of‐care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non‐central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower‐risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non‐major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.
Conclusions
The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.
doi:10.1161/JAHA.113.000521
PMCID: PMC4187517  PMID: 24755148
rivaroxaban; time in therapeutic range; warfarin
20.  Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment 
Peptic ulcer disease is a major cause of morbidity and mortality in the US with more than six million diagnoses annually. Ulcers are reported as the most common cause of hospitalization for upper gastrointestinal (GI) bleeding and are often a clinical concern due to the widespread use of aspirin and nonsteroidal anti-inflammatory drugs, both of which have been shown to induce ulcer formation. The finding that Helicobacter pylori infection (independent of aspirin use) is associated with the development of ulcers led to a more thorough understanding of the causes and pathogenesis of ulcers and an improvement in therapeutic options. However, many patients infected with H. pylori are asymptomatic and remain undiagnosed. Complicating matters is a current lack of understanding of the association between aspirin use and asymptomatic ulcer formation. Low-dose aspirin prescriptions have increased, particularly for cardioprotection. Unfortunately, the GI side effects associated with aspirin therapy continue to be a major complication in both symptomatic and asymptomatic patients. These safety concerns should be important considerations in the decision to use aspirin and warrant further education. The medical community needs to continue to improve awareness of aspirin-induced GI bleeding to better equip physicians and improve care for patients requiring aspirin therapy.
doi:10.2147/JMDH.S54324
PMCID: PMC3970722  PMID: 24741318
low-dose aspirin; cardioprotection; ulcers; Helicobacter pylori; gastrointestinal bleeding; cardiovascular disease
21.  Early Adoption of Dabigatran and Its Dosing in US Patients With Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation 
Background
Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown.
Methods and Results
We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new‐onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow‐up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001).
Conclusions
Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted.
Clinical Trial Registration
URL: Clinicaltrials.gov. Unique identifier: NCT01165710.
doi:10.1161/JAHA.113.000535
PMCID: PMC3886732  PMID: 24275632
anticoagulant; atrial fibrillation; dabigatran; dosing; pharmacoepidemiology
22.  Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients 
American heart journal  2012;164(4):607-615.
Background
Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.
Methods
From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS2) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.
Results
Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS2 ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS2 scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS2 ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.
Conclusions
Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.
doi:10.1016/j.ahj.2012.07.004
PMCID: PMC3777661  PMID: 23067921
23.  Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy 
Trials  2013;14:123.
Background
Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes.
Methods
Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days.
Results
In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials.
Conclusions
Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.
doi:10.1186/1745-6215-14-123
PMCID: PMC3662641  PMID: 23782531
Creatine kinase-MB; Infarct size; ST-segment elevation myocardial infarction; Clinical outcomes
24.  Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial 
Background
Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.
Methods and Results
TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals.
Conclusions
Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
doi:10.1161/JAHA.112.000067
PMCID: PMC3603243  PMID: 23525418
anticoagulants; arrhythmia; embolism; prevention; risk factors
25.  Inference on treatment effects from a randomized clinical trial in the presence of premature treatment discontinuation: the SYNERGY trial 
Biostatistics (Oxford, England)  2010;12(2):258-269.
The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) was a randomized, open-label, multicenter clinical trial comparing 2 anticoagulant drugs on the basis of time-to-event endpoints. In contrast to other studies of these agents, the primary, intent-to-treat analysis did not find evidence of a difference, leading to speculation that premature discontinuation of the study agents by some subjects may have attenuated the apparent treatment effect and thus to interest in inference on the difference in survival distributions were all subjects in the population to follow the assigned regimens, with no discontinuation. Such inference is often attempted via ad hoc analyses that are not based on a formal definition of this treatment effect. We use SYNERGY as a context in which to describe how this effect may be conceptualized and to present a statistical framework in which it may be precisely identified, which leads naturally to inferential methods based on inverse probability weighting.
doi:10.1093/biostatistics/kxq054
PMCID: PMC3062147  PMID: 20797983
Dynamic treatment regime; Inverse probability weighting; Potential outcomes; Proportional hazards model

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