Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

Objective To study the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin in anticoagulant naïve patients with atrial fibrillation.

Design Observational nationwide cohort study.

Setting Three Danish nationwide databases, August 2011 to October 2015.

Participants 61 678 patients with non-valvular atrial fibrillation who were naïve to oral anticoagulants and had no previous indication for valvular atrial fibrillation or venous thromboembolism. The study population was distributed according to treatment type: warfarin (n=35 436, 57%), dabigatran 150 mg (n=12 701, 21%), rivaroxaban 20 mg (n=7192, 12%), and apixaban 5 mg (n=6349, 10%).

Main outcome measures Effectiveness outcomes defined a priori were ischaemic stroke; a composite of ischaemic stroke or systemic embolism; death; and a composite of ischaemic stroke, systemic embolism, or death. Safety outcomes were any bleeding, intracranial bleeding, and major bleeding.

Results When the analysis was restricted to ischaemic stroke, NOACs were not significantly different from warfarin. During one year follow-up, rivaroxaban was associated with lower annual rates of ischaemic stroke or systemic embolism (3.0% v 3.3%, respectively) compared with warfarin: hazard ratio 0.83 (95% confidence interval 0.69 to 0.99). The hazard ratios for dabigatran and apixaban (2.8% and 4.9% annually, respectively) were non-significant compared with warfarin. The annual risk of death was significantly lower with apixaban (5.2%) and dabigatran (2.7%) (0.65, 0.56 to 0.75 and 0.63, 0.48 to 0.82, respectively) compared with warfarin (8.5%), but not with rivaroxaban (7.7%). For the combined endpoint of any bleeding, annual rates for apixaban (3.3%) and dabigatran (2.4%) were significantly lower than for warfarin (5.0%) (0.62, 0.51 to 0.74). Warfarin and rivaroxaban had comparable annual bleeding rates (5.3%).

Conclusion All NOACs seem to be safe and effective alternatives to warfarin in a routine care setting. No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin.

BMJ 2016;353:i3189


Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Objective To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation.

Design Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)—a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011.

Participants 18 201 ARISTOTLE trial participants.

Interventions In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years.

Main outcome measures Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country).

Results Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin.

Conclusions In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe.

Trial registration ARISTOTLE trial, NCT00412984.

BMJ 2016;353:i2868

Prediction of rates of thromboembolic and major bleeding outcomes with dabigatran or warfarin among patients with atrial fibrillation: new initiator cohort study

Objectives To compare stratified event rates from randomized controlled trials with predicted event rates from models developed in observational data, and assess their ability to accurately capture observed rates of thromboembolism and major bleeding for patients treated with dabigatran or warfarin as part of routine care.

Design New initiator cohort study.

Setting Data from United Health (October 2009 to June 2013), a commercial healthcare claims database in the United States.

Participants 21 934 adults with atrial fibrillation initiating dabigatran (150 mg dose only) or warfarin treatment as part of routine care.

Main outcome measures Predicted annual rates of thromboembolism or major bleeding, based on estimates from randomized controlled trials, models developed in routine care patients, and baseline risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED). Thromboembolism was a composite outcome, including primary inpatient diagnosis codes for ischemic or ill defined stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, and systemic embolism. Major bleeding was a composite outcome including codes occurring in an inpatient setting for hemorrhagic stroke; major upper, lower, or unspecified gastrointestinal bleed; and major urogenital or other bleed.

Results 6516 (30%) and 15 418 (70%) of patients initiated dabigatran and warfarin, respectively. Annual event rates per 100 patients were 1.7 for thromboembolism and 4.6 for major bleeding. For thromboembolism, calibration of estimates from randomized controlled trials was similar to calibration for model based predictions; however, trial estimates for major bleeding consistently underestimated the rate of bleeding among patients in routine care. Underestimation of bleeding rates was particularly pronounced in warfarin initiators with high HAS-BLED scores, where event rates were underestimated by up to 4.0 per 100 patient years. Harrell’s c indices for discrimination for thromboembolism or major bleeding in dabigatran and warfarin initiators ranged between 0.59 and 0.66 for randomized controlled trial predictions, and between 0.52 and 0.70 for cross validated model based predictions.

Conclusion Estimated rates of thromboembolism under dabigatran or warfarin treatment in randomized controlled trials were close to observed rates in routine care patients. However, rates of major bleeding were underestimated. Models developed in routine care patients can provide accurate, tailored estimates of risk and benefit under alternative treatment to enhance patient centered care.

BMJ 2016;353:i2607

Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis

Study question Is warfarin use associated with an increased risk of serious hypoglycemic events among older people treated with the sulfonylureas glipizide and glimepiride?

Methods This was a retrospective cohort analysis of pharmacy and medical claims from a 20% random sample of Medicare fee for service beneficiaries aged 65 years or older. It included 465 918 beneficiaries with diabetes who filled a prescription for glipizide or glimepiride between 2006 and 2011 (4 355 418 person quarters); 71 895 (15.4%) patients also filled a prescription for warfarin (416 479 person quarters with warfarin use). The main outcome measure was emergency department visit or hospital admission with a primary diagnosis of hypoglycemia in person quarters with concurrent fills of warfarin and glipizide/glimepiride compared with the rates in quarters with glipizide/glimepiride fills only, Multivariable logistic regression was used to adjust for individual characteristics. Secondary outcomes included fall related fracture and altered consciousness/mental status.

Summary answer and limitations In quarters with glipizide/glimepiride use, hospital admissions or emergency department visits for hypoglycemia were more common in person quarters with concurrent warfarin use compared with quarters without warfarin use (294/416 479 v 1903/3 938 939; adjusted odds ratio 1.22, 95% confidence interval 1.05 to 1.42). The risk of hypoglycemia associated with concurrent use was higher among people using warfarin for the first time, as well as in those aged 65-74 years. Concurrent use of warfarin and glipizide/glimepiride was also associated with hospital admission or emergency department visit for fall related fractures (3919/416 479 v 20 759/3 938 939; adjusted odds ratio 1.47, 1.41 to 1.54) and altered consciousness/mental status (2490/416 479 v 14 414/3 938 939; adjusted odds ratio 1.22, 1.16 to 1.29). Unmeasured factors could be correlated with both warfarin use and serious hypoglycemic events, leading to confounding. The findings may not generalize beyond the elderly Medicare population.

What this study adds A substantial positive association was seen between use of warfarin with glipizide/glimepiride and hospital admission/emergency department visits for hypoglycemia and related diagnoses, particularly in patients starting warfarin. The findings suggest the possibility of a significant drug interaction between these medications.

Funding, competing interests, data sharing JAR and DPG receive support from the National Institute on Aging, the Commonwealth Fund, and the Leonard D. Schaeffer Center for Health Policy and Economics at the University of Southern California. ABJ receives support from the NIH Office of the Director. No additional data are available.

John A Romley et al, BMJ 2015;351:h6223


Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study

Objective To examine the association between warfarin treatment and longitudinal outcomes after ischemic stroke in patients with atrial fibrillation in community practice.

Design Observational study.

Setting Hospitals (n=1487) participating in the Get With The Guidelines (GWTG)-Stroke program in the United States, from 2009 to 2011.

Participants 12,552 warfarin naive atrial fibrillation patients admitted to hospital for ischemic stroke and treated with warfarin compared with no oral anticoagulant at discharge, linked to Medicare claims for longitudinal outcomes.

Main outcome measures Major adverse cardiovascular events (MACE) and home time, a patient centered outcomes measure defined as the total number of days free from institutional care after discharge. A propensity score inverse probability weighting method was used to account for all differences in observed characteristics between treatment groups.

Results Among 12,552 survivors of stroke, 11,039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke.

Conclusions Among ischemic stroke patients with atrial fibrillation, warfarin treatment was associated with improved long term clinical outcomes and more days at home.

Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study by Ying Xian, et al. BMJ 2015; 351 :h3786