[Show abstract][Hide abstract] ABSTRACT: Worldwide there is a tremendous need for affordable anticoagulants that do not require monitoring. The advent of the non-warfarin oral anticoagulant drugs represents a major advance for stroke prevention in atrial fibrillation (AF). The objectives of this review are to 1) identify gaps in our current knowledge regarding use of these single target anticoagulant drugs; 2) outline the potential implications of these gaps for clinical practice, and thereby, 3) highlight areas of research to further optimise their use for stroke prevention in AF.
Thrombosis and Haemostasis 02/2014; 111(5). · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF) is an independent risk factor for thromboembolism and stroke. Women with AF are at a higher overall risk for thromboembolic stroke when compared to men with AF. Recent evidence suggests that female sex, after adjusting for stroke risk profile and sex differences in utilisation of anticoagulation, is an independent stroke risk factor in AF. The inclusion of female sex has improved the accuracy of the CHADS2 stroke risk stratification schema (Congestive heart failure, Hypertension, Age 75 years or greater, Diabetes mellitus, and prior Stroke or TIA). The newly revised and validated schema, CHA2DS2-VASc, dichotomises age and incorporates female sex and vascular disease history. The pathophysiological mechanisms to explain this increased risk in women are not well understood. According to Virchow's triad, thrombosis that leads to stroke in AF should arise from three co-existing phenomena: structural abnormalities, blood stasis, and a hypercoagulable state. Herein, we explore the sex differences in the biological processes that lead to thrombus formation as applied to Virchow's Triad. The objective of this review is to describe the potential mechanisms behind the increased risk of stroke in AF associated with female sex.
Thrombosis and Haemostasis 12/2013; 111(3). · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Warfarin is the mainstay of anticoagulation for patients with mechanical heart valves. However, warfarin has well-known limitations, including interactions with food and drugs and the requirement for lifelong monitoring of the international normalized ratio (INR).(1) Variability of the INR is the strongest independent predictor of reduced survival after mechanical valve replacement.(2) Thus, there is a pressing need for alternatives to warfarin, and the advent of the target-specific oral anticoagulants has been highly anticipated. Eikelboom et al.(3) now report in the Journal the results of a study whose primary aim was to validate a new dosing regimen for dabigatran, as compared . . .
New England Journal of Medicine 08/2013; · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify older adults with comorbidities or poor functional status at high risk of postoperative venous thromboembolism (VTE).
Retrospective cohort study.
Veterans Affairs Medical Center (VAMC).
Older adults who underwent total hip and knee replacement (THR and TKR) from 2002 to 2009.
Using multivariate logistic regression, the independent effect of cardiopulmonary comorbidities and diabetes on VTE was analyzed. Functional status expressed in a summary physical component score (PCS) was also analyzed in a subset of individuals in whom information on it was available.
There were 23,326 THR and TKR surgeries performed at the VAMC during the study period. Individuals with chronic obstructive pulmonary disease (COPD) had a 25% greater risk of VTE (odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.06-1.48), whereas those with coronary artery disease, congestive heart failure, and cerebrovascular disease did not have a greater risk of VTE. Individuals with diabetes mellitus had a lower risk of VTE (OR = 0.77, 95% CI = 0.64-0.92). Individuals with low PCS, which were available for 3,169 patients, had a 62% greater risk, although the effect did not reach statistical significance (lowest vs highest quartile OR = 1.62, 95% CI = 0.93-2.80).
Individuals with COPD had slightly greater risk of VTE, whereas low functional status had a larger effect that did not reach statistical significance. The constraints of administrative data analysis and sample size available for PCS limit conclusions about the role of these comorbidities and functional status.
Journal of the American Geriatrics Society 04/2013; 61(4):590-601. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.
Journal of Thrombosis and Thrombolysis 03/2013; · 1.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
Journal of the American College of Cardiology 06/2012; 60(7):569-80. · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anticoagulation clinics (ACCs) can improve anticoagulation control and prevent adverse events. However, ACCs vary widely in their performance on anticoagulation control. Our objective was to compare the organization and management of top-performing with that of bottom-performing ACCs.
Three high outlier and three low outlier ACCs in the Veterans Health Administration (VA).
Site visits with qualitative data collection and analysis.
We conducted semi-structured interviews with ACC staff regarding work flow, staffing, organization, and quality assurance efforts. We also observed ACC operations and collected documents, such as the clinic protocol. We used grounded thematic analysis to examine site-level factors associated with high and low outlier status.
High outlier sites were characterized by (1) adequate (pharmacist) staffing and effective use of (nonpharmacist) support personnel; (2) innovation to standardize clinical practice around evidence-based guidelines; (3) the presence of a quality champion for the ACC; (4) higher staff qualifications; (5) a climate of ongoing group learning; and (6) internal efforts to measure performance. Although high outliers had all of these features, no low outlier had more than two of them.
The top-performing ACCs in the VA system shared six relatively recognizable characteristics. Efforts to improve performance should focus on these domains.
Health Services Research 02/2012; 47(4):1541-60. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2-3. A patient's mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR).
To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care.
We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site-level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk-adjusted TTR.
Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites' proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (P < 0.001).
Proportion of patients with mean INR near 2.5 is a site-level 'signature' of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.
Journal of Thrombosis and Haemostasis 01/2012; 10(4):590-5. · 6.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are exciting new developments in several areas of atrial fibrillation (AF) management that carry the hope of improving outcomes in AF patients. This paper is an executive summary that summarises the proceedings from the 3rd AFNET/EHRA consensus conference on atrial fibrillation, held in Sophia Antipolis from November 7th to 9th 2010, shortly after the release of the new ESC guidelines on AF. The conference was jointly organised by the German Atrial Fibrillation competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). This executive summary report covers four sections: 1. Risk factors and risk markers for AF, 2. Pathophysiological classification of AF, 3. Relevance of monitored AF duration for AF-related outcomes, and 4. Perspectives and needs for implementing better antithrombotic therapy.
Thrombosis and Haemostasis 11/2011; 106(6):1012-9. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this executive summary of a Consensus Document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in atrial fibrillation (AF) patients. The main aim of the document was to summarise 'best practice' in dealing with bleeding risk in AF patients when approaching antithrombotic therapy, by addressing the epidemiology and size of the problem, and review established bleeding risk factors. We also summarise definitions of bleeding in the published literature. Patient values and preferences balancing the risk of bleeding against thromboembolism as well as the prognostic implications of bleeding are reviewed. We also provide an overview of published bleeding risk stratification and bleeding risk schema. Brief discussion of special situations (e.g. periablation, peri-devices such as implantable cardioverter defibrillators [ICD] or pacemakers, presentation with acute coronary syndromes and/or requiring percutanous coronary interventions/stents and bridging therapy) is made, as well as a discussion of the prevention of bleeds and managing bleeding complications. Finally, this document puts forwards consensus statements that may help to define evidence gaps and assist in everyday clinical practice.
Thrombosis and Haemostasis 11/2011; 106(6):997-1011. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prothrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8-2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0-3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0-2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9-16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.
Thrombosis and Haemostasis 07/2011; 106(3):429-38. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.
[Show abstract][Hide abstract] ABSTRACT: Despite the clear net clinical benefit of oral anticoagulation (OAC) in atrial fibrillation (AF) patients at risk for stroke, major bleeding events (especially intra-cranial bleeds) may be devastating events when they do occur. The decision for OAC is often based on a careful assessment of both stroke risk and bleeding risk, but clinical scores for bleeding risk estimation are much less well validated than stroke risk scales. Also, the estimation of bleeding risk is rendered difficult since many of the known factors that increase bleeding risk overlap with stroke risk factors. As well as this, many factors that increase bleeding risk are transient, such as variable international normalized ratio values, operations, vascular procedures, or drug-drug and food-drug interactions. In this Position Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in AF patients, with a view to summarizing 'best practice' when approaching antithrombotic therapy in AF patients. We address the epidemiology and size of the problem of bleeding risk in AF and review established bleeding risk factors. We also summarize definitions of bleeding in the published literature. Patient values and preferences balancing the risk of bleeding against thrombo-embolism is reviewed, and the prognostic implications of bleeding are discussed. We also review bleeding risk stratification and currently published bleeding risk schema. A brief discussion of special situations [e.g. peri-ablation, peri-devices (implantable cardioverter-defibrillator, pacemakers) and presentation with acute coronary syndromes and/or requiring percutaneous coronary interventions/stents and bridging therapy], as well as a discussion of prevention of bleeds and managing bleeding complications, is made. Finally, this document also puts forwards consensus statements that may help to define evidence gaps and assist in everyday clinical practice. Bleeding risk is almost inevitably lower than stroke risk in patients with atrial fibrillation. Nonetheless, identification of patients at high risk of bleeding and delineation of conditions and situations associated with bleeding risk can help to refine antithrombotic therapy to minimize bleeding risk.
[Show abstract][Hide abstract] ABSTRACT: The use of generic drugs has become increasingly common in clinical practice. However, for drugs with a narrow therapeutic index, such as warfarin, there may be some concern regarding the definition of bioequivalence. Clinical studies that compared brand name and generic warfarin products provided conflicting results. Therefore, we performed a systematic review of the literature to better assess the characteristics of each generic warfarin product. Several sources were searched, including MEDLINE and EMBASE, electronic records of meetings' abstracts, and reference lists of included articles. Articles were considered relevant if they were original studies, enrolled patients receiving oral anticoagulant treatment, and compared any approved generic warfarin with brand name warfarin in at least one clinical, laboratory, or management outcome. Eleven studies, with a total of more than 40,000 patients, were included; five were randomized controlled trials, and six were observational studies. In three crossover trials evaluating the mean difference of the international normalized ratio (INR) after switching to the alternate formulation of warfarin, no statistically significant difference was found between patients randomly assigned to receive brand name or generic warfarin. The two other randomized trials found no significant differences in the magnitude or number of dosage changes between patients switched to brand name or generic warfarin. The results of the observational studies are more conflicting, suggesting different features for different generic warfarin products. In these observational studies, the time in the therapeutic range and the number of thromboembolic and hemorrhagic complications were similar in studies that compared the anticoagulation control before and after the switch to a generic warfarin product. In one observational study, however, a change in therapeutic INR control after the switch to generic warfarin was reported at the individual patient level. The results of our systematic review suggest that generic warfarin products may be as safe and effective as brand name products and that patients may be safely treated with these products. However, closer monitoring may be reasonable when switching brands, as variations in individual INR response may be seen.
[Show abstract][Hide abstract] ABSTRACT: In patients receiving oral anticoagulation, improved control can reduce adverse outcomes such as stroke and major hemorrhage. However, little is known about patient-level predictors of anticoagulation control.
To identify patient-level predictors of oral anticoagulation control in the outpatient setting.
We studied 124,619 patients who received oral anticoagulation from the Veterans Health Administration from October 2006 to September 2008. The outcome was anticoagulation control, summarized using percentage of time in therapeutic International Normalized Ratio range (TTR). Data were divided into inception (first 6 months of therapy; 39,447 patients) and experienced (any time thereafter; 104,505 patients). Patient-level predictors of TTR were examined by multivariable regression.
Mean TTRs were 48% for inception management and 61% for experienced management. During inception, important predictors of TTR included hospitalizations (the expected TTR was 7.3% lower for those with two or more hospitalizations than for the non-hospitalized), receipt of more medications (16 or more medications predicted a 4.3% lower than for patients with 0-7 medications), alcohol abuse (-4.6%), cancer (-3.1%), and bipolar disorder (-2.9%). During the experienced period, important predictors of TTR included hospitalizations (four or more hospitalizations predicted 9.4% lower TTR), more medications (16 or more medications predicted 5.1% lower TTR), alcohol abuse (-5.4%), female sex (- 2.9%), cancer (-2.7%), dementia (-2.6%), non-alcohol substance abuse (-2.4%), and chronic liver disease (-2.3%).
Some patients receiving oral anticoagulation therapy are more challenging to maintain within the therapeutic range than others. Our findings can be used to identify patients who require closer attention or innovative management strategies to maximize benefit and minimize harm from oral anticoagulation therapy.
Journal of Thrombosis and Haemostasis 10/2010; 8(10):2182-91. · 6.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation is a common condition that increases the risk of stroke in many patients. Although warfarin has been shown to reduce the risk of stroke, many patients who might benefit from anticoagulation do not receive this therapy. Fear of bleeding is the most often cited reason. Several new anticoagulant medications are being studied to determine their efficacy and safety relative to warfarin. Unlike earlier trials that established the superiority of warfarin over placebo, recent trials in atrial fibrillation have enrolled a disproportionate number of patients already taking warfarin. This review suggests that the risk of both haemorrhage and stroke are highest when atrial fibrillation is newly diagnosed and during the initiation of anticoagulant medication. Randomised controlled trials designed to evaluate the safety and efficacy of new anti-thrombotic agents should include substantial numbers of patients without prior exposure to anticoagulation since these individuals are at the highest risk for bleeding and thromboembolism.
Thrombosis and Haemostasis 09/2010; 104(6):1099-105. · 5.76 Impact Factor