Trends in Atrial Fibrillation Incidence Rates Within an Integrated Health Care Delivery System, 2006 to 2018.

Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and multiple studies have reported increasing AF incidence rates over time, although the underlying explanations remain unclear. Objectives: To estimate AF incidence rates from 2006 to 2018 in a community-based setting and to investigate possible explanations for increasing AF by evaluating the changing features of incident AF cases and the pool of patients at risk for AF over time. Design, Setting, and Participants: This cohort study included 500 684 patients who received primary care and other health care services for more than 2 years through a single integrated health care delivery network in Pennsylvania. Data collection was conducted from January 2003 to December 2018. The base study population had no documentation of AF in the electronic medical record for at least 2 years prior to baseline. Data analysis was conducted from May to December 2019. Main Outcomes and Measures: Incident AF cases were identified through diagnostic codes recorded at inpatient or outpatient encounters. Age- and sex-adjusted AF incidence rates were estimated by calendar year from 2006 to 2018 both overall and across subgroups, including according to diagnostic setting (inpatient vs outpatient) and priority (primary vs secondary diagnosis). Results: Among 514 293 patients meeting criteria for the base study population, the mean (SD) age at baseline was 47 (18) years and 282 103 (54.9%) were women; 13 609 (2.6%) met AF diagnostic criteria on or prior to the baseline date and were excluded. Among 500 684 patients free of AF at baseline, standardized AF incidence rates from 2006 to 2018 increased from 4.74 (95% CI, 4.58-4.90) to 6.82 (95% CI, 6.65-7.00) cases per 1000 person-years, increasing significantly over time (P < .001). Incidence rates increased in all age and sex subgroups, although absolute rate increases were largest among those aged 85 years or older. The fraction of incident AF cases among individuals aged 85 years or older increased from 135 of 1075 (12.6%) in 2006 to 451 of 2427 (18.6%) in 2017. Patients with incident AF were more likely over time to have high body mass index (1351 of 3389 patients [39.9%] in 2006-2008 vs 4504 of 9214 [48.9%] in 2015-2018; P < .001), hypertension (2764 [81.6%] in 2006-2008 vs 7937 [86.1%] in 2015-2018; P < .001), and ischemic stroke (328 [9.7%] in 2006-2008 vs 1455 [15.8%] in 2015-2018; P < .001), but less likely to have coronary artery disease (1533 [45.2%] in 2006-2008 vs 3810 [41.4%] in 2015-2018; P < .001). Among 22 077 new cases of AF, 9146 (41.4%) were diagnosed as inpatients and 5731 (26.0%) as the primary diagnosis. Incidence rates of AF increased significantly in all diagnostic setting and priority pairings (eg, inpatient, primary: rate ratio, 1.07; 95% CI, 1.06-1.08; P < .001). Among patients at risk for AF, high BMI and hypertension increased over time (BMI: 71 433 of 198 245 [36.0%] in 2007 to 130 218 of 282 270 [46.1%] in 2017; hypertension: 79 977 [40.3%] in 2007 to 134 404 [47.6%] in 2017). Documentation of short-term ECG increased over time (23 297 of 207 349 [11.2%] in 2008 to 45 027 [16.0%] in 2017); however, long-term ECG monitoring showed no change (1871 [0.9%] in 2007 to 4036 [1.4%] in 2017). Conclusions and Relevance: In this community-based study, AF incidence rates increased significantly during the study period. Concurrent increases were observed in AF risk factors in the at-risk population and short-term ECG use.

Warfarin interactions with antibiotics in the ambulatory care setting.

IMPORTANCE: The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability. OBJECTIVE: To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls). DESIGN, SETTING, AND PARTICIPANTS: A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation. EXPOSURES: Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics. MAIN OUTCOMES AND MEASURES: Primary outcomes were the proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR. RESULTS: The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more. CONCLUSIONS AND RELEVANCE: Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. METHODS: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban RESULTS: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. CONCLUSIONS: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.

Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS(2) [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS(2) score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS(2) score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. CONCLUSIONS: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS(2) score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.

Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans Affairs Study to Improve Anticoagulation (VARIA).

BACKGROUND: Oral anticoagulation is safer and more effective when patients receive high-quality care. However, there have been no prior efforts to measure quality of oral anticoagulation care or to risk adjust it to ensure credible comparisons. Our objective was to profile site performance in the Veterans Health Administration (VA) using risk-adjusted percent time in therapeutic range (TTR). METHODS AND RESULTS: We included 124 551 patients who received outpatient oral anticoagulation from 100 VA sites of care for indications other than valvular heart disease from October 1, 2006, to September 30, 2008. We calculated TTR for each patient and mean TTR for each site of care. Expected TTR was calculated for each patient and each site based on the variables in the risk adjustment model, which included demographics, comorbid conditions, medications, and hospitalizations. Mean TTR for the entire sample was 58%. Site-observed TTR varied from 38% to 69% or from poor to excellent. Site-expected TTR varied from 54% to 62%. Site risk-adjusted performance ranged from 18% below expected to 12% above expected. Risk adjustment did not alter performance rankings for many sites, but for other sites, it made an important difference. For example, the site ranked 27th of 100 before risk adjustment was one of the best (risk-adjusted rank, 7). Risk-adjusted site rankings were consistent from year to year (correlation between years, 0.89). CONCLUSIONS: Risk-adjusted TTR can be used to profile the quality of outpatient oral anticoagulation in a large, integrated health system. This measure can serve as the basis for quality measurement and quality improvement efforts.

Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study.

STUDY OBJECTIVE: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. DESIGN: Retrospective, matched cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. MEASUREMENTS AND MAIN RESULTS: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). CONCLUSION: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.

Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study.

OBJECTIVES: To assess whether older age is independently associated with hemorrhage risk in patients with atrial fibrillation, whether or not they are taking warfarin therapy. DESIGN: Cohort study. SETTING: Integrated healthcare delivery system. Thirteen thousand five hundred fifty-nine adults with nonvalvular atrial fibrillation. MEASUREMENTS: Patient data were collected from automated clinical and administrative databases using previously validated search algorithms. Medical charts were reviewed from patients hospitalized were for major hemorrhage (intracranial, fatal, requiring >or=2 units of transfused blood, or involving a critical anatomic site). Age was categorized into four categories (<60, 60-69, 70-79, and >or=80), and multivariable Poisson regression was used to assess whether major hemorrhage rates increased with age, stratified by warfarin use and adjusted for other clinical risk factors for hemorrhage. RESULTS: A total of 170 major hemorrhages were identified during 15,300 person-years of warfarin therapy and 162 major hemorrhages during 15,530 person-years off warfarin therapy. Hemorrhage rates rose with older age, with an average increase in hemorrhage rate of 1.2 (95% confidence interval (CI) 1.0-1.4) per older age category in patients taking warfarin and 1.5 (95% CI=1.3-1.8) in those not taking warfarin. Intracranial hemorrhage rates were significantly higher in those aged 80 and older (adjusted rate ratio=1.8, 95% CI=1.1-3.1 for those taking warfarin, adjusted rate ratio=4.7, 95% CI=2.4-9.2 for those not taking warfarin) than in those younger than 80. CONCLUSION: Older age increases the risk of major hemorrhage, particularly intracranial hemorrhage, in patients with atrial fibrillation, whether or not they are taking warfarin. Hemorrhage rates were generally comparable with those reported in previous randomized trials, indicating that carefully monitored warfarin therapy can be used with reasonable safety in older patients.

Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?

CONTEXT: Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in randomized trials, but its effectiveness and safety in clinical practice is less clear. OBJECTIVE: To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage, and death in atrial fibrillation within a usual care setting. DESIGN: Cohort study assembled between July 1, 1996, and December 31, 1997, and followed up through August 31, 1999. SETTING: Large integrated health care system in Northern California. PATIENTS: Of 13,559 adults with nonvalvular atrial fibrillation, 11,526 were studied, 43% of whom were women, mean age 71 years, with no known contraindications to anticoagulation at baseline. MAIN OUTCOMES: Ischemic stroke, peripheral embolism, hemorrhage, and death according to warfarin use and comorbidity status, as determined by automated databases, review of medical records, and state mortality files. RESULTS: Among 11,526 patients, 397 incident thromboembolic events (372 ischemic strokes, 25 peripheral embolism) occurred during 25,341 person-years of follow-up, and warfarin therapy was associated with a 51% (95% confidence interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) after adjusting for potential confounders and likelihood of receiving warfarin. Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke. A nested case-control analysis estimated a 64% reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy. Warfarin was also associated with a reduced risk of all-cause mortality (adjusted hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon, but the rate was moderately higher among those taking vs those not taking warfarin (0.46 vs 0.23 per 100 person-years, respectively; P =.003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However, warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage. The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications (total cohort of 13,559). CONCLUSIONS: Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small. Results of randomized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation.