[Show abstract][Hide abstract] ABSTRACT: Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or
No preview · Article · Dec 2015 · Journal of Thrombosis and Thrombolysis
[Show abstract][Hide abstract] ABSTRACT: Background:
Whether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making.
To determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365days after incident ICH.
We conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH.
There were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up.
Resumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality.
No preview · Article · Oct 2015 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Oral anticoagulants are highly efficacious for the prevention of stroke in atrial fibrillation, and are the preferred treatment by current guidelines. The purpose of our study was to assess the utilization of antithrombotic drugs in atrial fibrillation patients at the time of ischemic stroke and the factors associated with their use.
We enrolled 759 consecutive patients admitted with ischemic stroke at Boston Medical Center, Geisinger Health System, and the University of Alabama. To be eligible, patients had to have electrocardiographically-confirmed atrial fibrillation at the time of admission or within 6months of the index stroke. All stroke events and electrocardiograms were validated by study physicians. Patients with newly diagnosed atrial fibrillation were not eligible.
The mean age was 78years, 43% were male, 19% black, and the mean CHADS2 score is 3.0. Atrial fibrillation was paroxysmal in 31%. At presentation, 181 (24%) patients were taking warfarin only, 96 (13%) both warfarin and aspirin, 294 (39%) aspirin alone, and 189 (25%) no antithrombotic therapy. The mean international normalized ratio was 1.6. Among patients with paroxysmal atrial fibrillation, one in five was taking warfarin. Although increasing stroke risk was associated with a greater likelihood of warfarin use, only 39% of highest risk CHADS2 3-6 were taking warfarin at the time of stroke.
Among high-risk individuals with atrial fibrillation, only 37% were taking warfarin at the time of stroke. Paroxysmal atrial fibrillation was associated with the highest risk of not receiving warfarin.
No preview · Article · Sep 2015 · International journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: Background:
Most patients with atrial fibrillation (AF) require rate control; however, the optimal target heart rate remains under debate. We aimed to assess rate control and subsequent outcomes among patients with permanent AF.
Methods and results:
We studied 2812 US outpatients with permanent AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. Resting heart rate was measured longitudinally and used as a time-dependent covariate in multivariable Cox models of all-cause and cause-specific mortality during a median follow-up of 24 months. At baseline, 7.4% (n=207) had resting heart rate <60 beats per minute (bpm), 62% (n=1755) 60 to 79 bpm, 29% (n=817) 80 to 109 bpm, and 1.2% (n=33) ≥110 bpm. Groups did not differ by age, previous cerebrovascular disease, heart failure status, CHA2DS2-VASc scores, renal function, or left ventricular function. There were significant differences in race (P=0.001), sinus node dysfunction (P=0.004), and treatment with calcium-channel blockers (P=0.006) and anticoagulation (P=0.009). In analyses of continuous heart rates, lower heart rate ≤65 bpm was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.15 per 5-bpm decrease; 95% CI, 1.01 to 1.32; P=0.04). Similarly, increasing heart rate >65 bpm was associated with higher all-cause mortality (adjusted HR, 1.10 per 5-bpm increase; 95% CI, 1.05 to 1.15; P<0.0001). This relationship was consistent across endpoints and in a broader sensitivity analysis of permanent and nonpermanent AF patients.
Among patients with permanent AF, there is a J-shaped relationship between heart rate and mortality. These data support current guideline recommendations, and clinical trials are warranted to determine optimal rate control.
Clinical trial registration:
URL: http://clinicaltrials.gov/. Unique identifier: NCT01165710.
Preview · Article · Sep 2015 · Journal of the American Heart Association
[Show abstract][Hide abstract] ABSTRACT: Idarucizumab, a Fab fragment directed against dabigatran, produced rapid and complete reversal of the anticoagulation effect of dabigatran in animals and in healthy volunteers. The Study of the REVERSal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD™) is a global phase 3 prospective cohort study aimed at investigating idarucizumab in dabigatran-treated patients who present with uncontrollable or life-threatening bleeding, and in those requiring urgent surgery or intervention. We describe the rationale for, and design of the trial (clinicaltrials.gov NCT02104947).
Full-text · Article · May 2015 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment and outcomes associated with AF.
Full-text · Article · Mar 2015 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Thrombosis is a common pathology underlying ischaemic heart disease, ischaemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischaemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low, middle and high income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalisation was the leading cause of disability-adjusted-life-years (DALYs) lost in low and middle income countries, and second in high income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low, middle, and high income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilisation of preventive measures will reduce the burden.
No preview · Article · Nov 2014 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: Background:
Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability.
To review the literature on the global burden of disease caused by VTE.
Approach and results:
We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events.
VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.
Full-text · Article · Oct 2014 · Arteriosclerosis Thrombosis and Vascular Biology