Xiaoxi Yao

Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation

Background In comparison to warfarin, non–vitamin K antagonist oral anticoagulants (NOACs) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation. Methods and Results We performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow‐up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients (P<0.001). Patients with CHA 2 DS 2‐VASc (risk based on the presence of congestive heart failure, hypertension age 65–74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (1–3 months: hazard ratio [HR] 1.96, 3–6 months: HR 2.64, ≥6 months: HR 3.66; all P<0.001). Patients with CHA 2 DS 2‐VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months (HR 2.73, P<0.001). In these patients with CHA 2 DS 2‐VASc score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA 2 DS 2‐VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding. Conclusions Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA 2 DS 2‐VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA 2 DS 2‐VASc score 0 or 1.

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation

Background The introduction of non–vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Methods and Results Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46–0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76–1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72–1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34–0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67–0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90–1.20], P=0.60). All non–vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. Conclusions In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin.

Non–Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction

BACKGROUND Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk, whereas dose reductions without a firm indication may decrease the effectiveness of stroke prevention. OBJECTIVES The goal of this study was to investigate NOAC dosing patterns and associated outcomes, i.e., stroke (ischemic stroke and systemic embolism) and major bleeding in patients treated in routine clinical practice. METHODS Using a large U.S. administrative database, 14,865 patients with AF were identified who initiated apixaban, dabigatran, or rivaroxaban between October 1, 2010, and September 30, 2015. We examined use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication is not present (potential underdosing). Cox proportional hazards regression was performed in propensity score-matched cohorts to investigate the outcomes. RESULTS Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication. CONCLUSIONS In routine clinical practice, prescribed NOAC doses are often inconsistent with drug labeling. These prescribing patterns may be associated with worse safety with no benefit in effectiveness in patients with severe kidney disease and worse effectiveness with no benefit in safety in apixaban-treated patients with normal or mildly impaired renal function.

Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013.

OBJECTIVE To examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Using claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18–44, 45–64, 65–74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more). RESULTS From 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36). CONCLUSIONS During the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged.

Intensive Treatment and Severe Hypoglycemia Among Adults With Type 2 Diabetes.

IMPORTANCE Intensive glucose-lowering treatment among patients with non-insulin-requiring type 2 diabetes may increase the risk of hypoglycemia. OBJECTIVES To estimate the prevalence of intensive treatment and the association between intensive treatment, clinical complexity, and incidence of severe hypoglycemia among adults with type 2 diabetes who are not using insulin. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of administrative, pharmacy, and laboratory data from the OptumLabs Data Warehouse from January 1, 2001, through December 31, 2013. The study included nonpregnant adults 18 years or older with type 2 diabetes who achieved and maintained a hemoglobin A1c (HbA1c) level less than 7.0% without use of insulin and had no episodes of severe hypoglycemia or hyperglycemia in the prior 12 months. MAIN OUTCOMES AND MEASURES Risk-adjusted probability of intensive treatment and incident severe hypoglycemia, stratified by patient clinical complexity. Intensive treatment was defined as use of more glucose-lowering medications than recommended by practice guidelines at specific index HbA1c levels. Severe hypoglycemia was ascertained by ambulatory, emergency department, and hospital claims for hypoglycemia during the 2 years after the index HbA1c test. Patients were categorized as having high vs low clinical complexity if they were 75 years or older, had dementia or end-stage renal disease, or had 3 or more serious chronic conditions. RESULTS Of 31 542 eligible patients (median age, 58 years; interquartile range, 51-65 years; 15 483 women [49.1%]; 18 188 white [57.7%]), 3910 (12.4%) had clinical complexity. The risk-adjusted probability of intensive treatment was 25.7% (95% CI, 25.1%-26.2%) in patients with low clinical complexity and 20.8% (95% CI, 19.4%-22.2%) in patients with high clinical complexity. In patients with low clinical complexity, the risk-adjusted probability of severe hypoglycemia during the subsequent 2 years was 1.02% (95% CI, 0.87%-1.17%) with standard treatment and 1.30% (95% CI, 0.98%-1.62%) with intensive treatment (absolute difference, 0.28%; 95% CI, -0.10% to 0.66%). In patients with high clinical complexity, intensive treatment significantly increased the risk-adjusted probability of severe hypoglycemia from 1.74% (95% CI, 1.28%-2.20%) with standard treatment to 3.04% (95% CI, 1.91%-4.18%) with intensive treatment (absolute difference, 1.30%; 95% CI, 0.10%-2.50%). CONCLUSIONS AND RELEVANCE More than 20% of patients with type 2 diabetes received intensive treatment that may be unnecessary. Among patients with high clinical complexity, intensive treatment nearly doubles the risk of severe hypoglycemia.

Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment

Objective To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism. Design Retrospective cohort study. Setting Large US administrative database between 1 January 2010 and 31 December 2014. Participants 5405 pregnant women with subclinical hypothyroidism, defined as untreated thyroid stimulating hormone (TSH) concentration 2.5-10 mIU/L. Exposure Thyroid hormone therapy. Main outcome measure Pregnancy loss and other pre-specified maternal and fetal pregnancy related adverse outcomes. Results Among 5405 pregnant women with subclinical hypothyroidism, 843 with a mean pre-treatment TSH concentration of 4.8 (SD 1.7) mIU/L were treated with thyroid hormone and 4562 with a mean baseline TSH concentration of 3.3 (SD 0.9) mIU/L were not treated (P<0.01). Pregnancy loss was significantly less common among treated women (n=89; 10.6%) than among untreated women (n=614; 13.5%) (P<0.01). Compared with the untreated group, treated women had lower adjusted odds of pregnancy loss (odds ratio 0.62, 95% confidence interval 0.48 to 0.82) but higher odds of preterm delivery (1.60, 1.14 to 2.24), gestational diabetes (1.37, 1.05 to 1.79), and pre-eclampsia (1.61, 1.10 to 2.37); other pregnancy related adverse outcomes were similar between the two groups. The adjusted odds of pregnancy loss were lower in treated women than in untreated women if their pre-treatment TSH concentration was 4.1-10 mIU/L (odds ratio 0.45, 0.30 to 0.65) but not if it was 2.5-4.0 mIU/L (0.91, 0.65 to 1.23) (P<0.01). Conclusion Thyroid hormone treatment was associated with decreased risk of pregnancy loss among women with subclinical hypothyroidism, especially those with pre-treatment TSH concentrations of 4.1-10 mIU/L. However, the increased risk of other pregnancy related adverse outcomes calls for additional studies evaluating the safety of thyroid hormone treatment in this patient population.

Patterns of Anticoagulation Use and Cardioembolic Risk After Catheter Ablation for Atrial Fibrillation

Background There is significant practice variation in oral anticoagulation (OAC) use following catheter ablation for atrial fibrillation. It is not clear whether the risk of cardioembolism increases after discontinuation of OAC following catheter ablation. Methods and Results We identified 6886 patients within a large national administrative claims database who underwent catheter ablation for atrial fibrillation between January 1, 2005, and September 30, 2014. We assessed the effect of time off of OAC by CHA 2 DS 2‐VASc score (after adjusting for other comorbidities) on risk of cardioembolism, using Cox proportional hazards models. There was an increase in the use of non–vitamin K OAC after ablation from 0% in 2005 to 69.8% in 2014. OAC discontinuation was high, with only 60.5% and 31.3% of patients remaining on OAC at 3 and 12 months, respectively. The rate of discontinuation was higher in low‐risk patients (82% versus 62.5% at 12 months for CHA 2 DS 2‐VASc 0–1 versus ≥2, respectively; P<0.001). Stroke occurred in 1.4% of patients with CHA 2 DS 2‐VASc ≥2 and 0.3% of those with CHA 2 DS 2‐VASc 0 or 1 over the study follow‐up. The risk of cardioembolism in the first 3 months after ablation was increased among those with any time off OAC (hazard ratio 8.06 [95% CI 1.53–42.3], P<0.05). The risk of cardioembolism beyond 3 months was increased with OAC discontinuation among high‐risk patients (hazard ratio 2.48 [95% CI 1.11–5.52], P<0.05) but not low‐risk patients. Conclusion The overall risk of stroke in postablation patients is low; however, OAC discontinuation after ablation is common and is associated with increased risk of cardioembolism for all patients within the first 3 months and for high‐risk patients in the long term. Continuing OAC for at least 3 months in all patients and indefinitely in high‐risk patients appears to be the safest strategy.

Trends and predictors of repeat catheter ablation for atrial fibrillation.

BACKGROUND Atrial fibrillation (AF) ablation is superior to pharmacologic therapy in achieving maintenance of normal sinus rhythm in selected patient populations. However, the procedure is resource intensive, and repeat ablations are sometimes required. We examined the predictors and trends of repeat ablation using a large national administrative claims database. METHODS Privately insured and Medicare Advantage patients who underwent catheter ablation for AF between January 1, 2004, and September 30, 2014, were included in the study. The primary outcome was repeat AF ablation during enrollment. We examined the associations between repeat ablation and patient demographics (age, gender, socioeconomic demographics), comorbid conditions (CHA2DS2-Vasc score and Charlson index), and year of the index ablation. Cox proportional hazard models were used to identify predictors of repeat ablation. RESULTS We included 8,648 adult patients in the analysis. Median age was 61.0 (interquartile range [IQR] 54-68) years, and 70.9% were men. Median follow-up was 1.1 (IQR 0.5-2.3) years. A total of 1,263 patients underwent repeat ablation (14.6%) over a total of 14,280 person-years (12.1% at 1 year). The hazard ratio (HR) for repeat ablation was higher in younger patients (HR 0.75 [0.61-0.91; P < .01] for age 65-75 and 0.55 [0.4-0.75; P < .001] for age ≥ 75 compared with age 18-54), those with higher household income (HR 1.24 [1-1.54; P < .05] for household income ≥

Incidence and Early Outcomes of Heart Failure in Commercially Insured and Medicare Advantage Patients, 2006 to 2014

100,000 compared with household income <

Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA Risk Scores in Predicting Non–Vitamin K Antagonist Oral Anticoagulants-Associated Bleeding in Patients With Atrial Fibrillation

40,000), patients treated in the south (HR 1.15 [1-1.31]; P < .05), and those on antiarrhythmic medications (HR 1.15 [1.01-1.31]; P < .05). In particular, younger patients (ages 18-54 years) continued to undergo repeat ablations over the entire follow-up period, and the cumulative rate was approximately 40% among those followed for 5 years. Clinical characteristics including those included in the CHA2DS2-Vasc score and Charlson index did not predict likelihood of repeat ablation. The rate of repeat ablation remained constant over the available follow-up. CONCLUSION Approximately 1 in 8 patients treated with catheter ablation for AF will undergo a second procedure within 1 year, although the rate is as high as 40% in young patients at 5 years. The rate of repeat ablation appears to be associated with demographic characteristics (younger age and higher household income) rather than medical comorbidities.