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Josep Rodés-Cabau,
Harold L Dauerman,
Mauricio G Cohen,
Roxana Mehran,
Eric M Small,
Susan S Smyth,
Marco A Costa,
Jessica L Mega,
Michelle L O'Donoghue,
E Magnus Ohman, Richard C Becker
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ABSTRACT: Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic alternative for patients with symptomatic aortic stenosis at high or prohibitive surgical risk. However, patients undergoing TAVI are also at high risk for both bleeding and stroke complications, and specific mechanical aspects of the procedure itself can increase the risk of these complications. The mechanisms of periprocedural bleeding complications seem to relate mainly to vascular/access site complications (related to the use of large catheters in a very old and frail elderly population), whereas the pathophysiology of cerebrovascular events remains largely unknown. Further, although mechanical complications, especially the interaction between the valve prosthesis and the native aortic valve, play a major role in events that occur during TAVI, postprocedural events might also be related to a prothrombotic environment or state generated by the implanted valve, the occurrence of atrial arrhythmias, and associated comorbidities. Antithrombotic therapy in the setting of TAVI has been empirically determined, and unfractionated heparin during the procedure followed by dual antiplatelet therapy with aspirin (indefinitely) and clopidogrel (1-6 months) is the most commonly recommended treatment. However, bleeding and cerebrovascular events are common; these may be modifiable with optimization of peri- and post-procedural pharmacology. Further, as the field of antiplatelet and anticoagulant therapy evolves, potential drug combinations will multiply, introducing variability in treatment. Randomized trials are the best path forward to determine to determine the balance between the efficacy and risks of antithrombotic treatment in this high risk population.
Journal of the American College of Cardiology 04/2013; · 14.16 Impact Factor
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Renato D Lopes, Richard C Becker,
L Kristin Newby,
Eric D Peterson,
Elaine M Hylek,
Robert Giugliano,
Christopher B Granger,
Kenneth W Mahaffey,
Antonio C Carvalho,
Otavio Berwanger, [......],
Gilson Soares Feitosa-Filho,
Marcia M Barbosa,
Maria da Consolacao V Moreira,
Renato A K Kalil,
Marildes Freitas,
Joao Carlos de Campos Guerra,
Marcio Vinicius Lins Barros,
Thiago da Rocha Rodrigues,
Antonio C Lopes,
David A Garcia
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ABSTRACT: To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fifth International Symposium of Thrombosis and Anticoagulation was held in Belo Horizonte, Minas Gerais, Brazil, on October 18-19, 2012. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.
Journal of Thrombosis and Thrombolysis 03/2013; · 1.48 Impact Factor
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Jonathan P Piccini,
Susanna R Stevens,
Yuliya Lokhnygina,
Manesh R Patel,
Jonathan L Halperin,
Daniel E Singer,
Graeme J Hankey,
Werner Hacke, Richard C Becker,
Christopher C Nessel,
Kenneth W Mahaffey,
Keith A A Fox,
Robert M Califf,
Günter Breithardt
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ABSTRACT: OBJECTIVES: To investigate outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban. BACKGROUND: There are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors. METHODS: We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post-hoc analysis of ROCKET AF. RESULTS: Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n=321) (1.44 [n=161] in the warfarin arm, 1.46 [n=160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio [HR] 1.38; 95% confidence interval [CI] 0.61-3.11), cardiovascular death (HR 1.57; CI 0.69-3.55), and death from all causes (HR 1.75; 95% CI 0.90-3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR 2.01; CI 1.51-2.68), but there was no evidence of a differential effect by randomized treatment (p for interaction=0.58). The incidence of stroke or systemic embolism (1.88 vs 1.86%) and death (1.88 vs. 3.73%).were similar in the rivaroxaban- and warfarin-treated groups. CONCLUSIONS: Despite an increase in hospitalization, there was no difference in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin.
Journal of the American College of Cardiology 03/2013; · 14.16 Impact Factor
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Manesh R Patel,
Anne S Hellkamp,
Yuliya Lokhnygina,
Jonathan P Piccini,
Zhongxin Zhang,
Surya Mohanty,
Daniel E Singer,
Werner Hacke,
Günter Breithardt,
Jonathan L Halperin,
Graeme J Hankey, Richard C Becker,
Christopher C Nessel,
Scott D Berkowitz,
Robert M Califf,
Keith A A Fox,
Kenneth W Mahaffey
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ABSTRACT: The purpose of this study was to understand the possible risk of discontinuation in the context of clinical care.
Rivaroxaban is noninferior to warfarin for preventing stroke in atrial fibrillation patients. Concerns exist regarding possible increased risk of stroke and non-central nervous system (CNS) thromboembolic events early after discontinuation of rivaroxaban.
We undertook a post-hoc analysis of data from the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation, n = 14,624) for stroke or non-CNS embolism within 30 days after temporary interruptions of 3 days or more, early permanent study drug discontinuation, and end-of-study transition to open-label therapy.
Stroke and non-CNS embolism occurred at similar rates after temporary interruptions (rivaroxaban: n = 9, warfarin: n = 8, 6.20 vs. 5.05/100 patient-years, hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 0.49 to 3.31, p = 0.62) and after early permanent discontinuation (rivaroxaban: n = 42, warfarin: n = 36, 25.60 vs. 23.28/100 patient-years, HR: 1.10, 95% CI: 0.71 to 1.72, p = 0.66). Patients transitioning to open-label therapy at the end of the study had more strokes with rivaroxaban (n = 22) versus warfarin (n = 6, 6.42 vs. 1.73/100 patient-years, HR: 3.72, 95% CI: 1.51 to 9.16, p = 0.0044) and took longer to reach a therapeutic international normalized ratio with rivaroxaban versus warfarin. All thrombotic events within 30 days of any study drug cessation (including stroke, non-CNS embolism, myocardial infarction, and vascular death) were similar between groups (HR: 1.02, 95% CI: 0.83 to 1.26, p = 0.85).
In atrial fibrillation patients who temporarily or permanently discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar with rivaroxaban or warfarin. An increased risk of stroke and non-CNS embolism was observed in rivaroxaban-treated patients compared with warfarin-treated patients after the end of the study, underscoring the importance of therapeutic anticoagulation coverage during such a transition.
Journal of the American College of Cardiology 02/2013; 61(6):651-8. · 14.16 Impact Factor
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Daniel E Singer,
Anne S Hellkamp,
Jonathan P Piccini,
Kenneth W Mahaffey,
Yuliya Lokhnygina,
Guohua Pan,
Jonathan L Halperin, Richard C Becker,
Günter Breithardt,
Graeme J Hankey,
Werner Hacke,
Christopher C Nessel,
Manesh R Patel,
Robert M Califf,
Keith A A Fox
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ABSTRACT: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.
TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals.
Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.
URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
Journal of the American Heart Association. 01/2013; 2(1):e000067.
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Jonathan P Piccini,
Susanna R Stevens,
Yuchiao Chang,
Daniel E Singer,
Yuliya Lokhnygina,
Alan S Go,
Manesh R Patel,
Kenneth W Mahaffey,
Jonathan L Halperin,
Günter Breithardt,
Graeme J Hankey,
Werner Hacke, Richard C Becker,
Christopher C Nessel,
Keith A A Fox,
Robert M Califf
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ABSTRACT: BACKGROUND: We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS: In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R(2)CHADS(2)) improved net reclassification index (NRI) by 6.2% when compared with CHA(2)DS(2)VASc (C-statistic=0.578) and 8.2% when compared with CHADS(2) (C-statistic=0.575). The inclusion of estimated glomerular filtration rate <60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R(2)CHADS(2) in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS(2). CONCLUSIONS: In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Unique identifier: NCT00403767.
Circulation 12/2012; · 14.74 Impact Factor
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Axel Akerblom,
Lars Wallentin,
Agneta Siegbahn, Richard C Becker,
Andrzej Budaj,
Jay Horrow,
Steen Husted,
Hugo Katus,
Marc J Claeys,
Robert F Storey,
Nils Asenblad,
Stefan K James
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ABSTRACT: To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS).
Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I.
Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P < .0005), 1 month (1.00 mg/L and 0.98 mg/L) (P = .12), and 6 months (1.00 mg/L and 0.99 mg/L) (P = .17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively.
Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.
American heart journal 11/2012; 164(5):728-34. · 4.65 Impact Factor
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ABSTRACT: The anticoagulant properties of a novel RNA aptamer that binds FIXa depend collectively on the intensity of surface contact activation of human blood plasma, aptamer concentration, and its binding affinity for FIXa. Accordingly, anticoagulation efficiency of plasma containing any particular aptamer concentration is low when coagulation is strongly activated by hydrophilic surfaces compared to the anticoagulation efficiency in plasma that is weakly activated by hydrophobic surfaces. Anticoagulation efficiency is lower at hypothermic temperatures possibly because aptamer-FIXa binding decreases with decreasing temperatures. Experimental results demonstrating these trends are qualitatively interpreted in the context of a previously established model of anticoagulation efficiency of thrombin-binding DNA aptamers that exhibit anticoagulation properties similar to the FIXa aptamer. In principle, FIXa aptamer anticoagulants should be more efficient and therefore more clinically useful than thrombin-binding aptamers because aptamer binding to FIXa competes only with FX that is at much lower blood concentration than fibrinogen (FI) that competes with thrombin-binding aptamers. Our findings may have translatable relevance in the application of aptamer anticoagulants for clinical conditions in which blood is in direct contact with non-biological surfaces such as those encountered in cardiopulmonary bypass circuits.
Journal of Thrombosis and Thrombolysis 10/2012; · 1.48 Impact Factor
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Christoph Varenhorst,
Ulrica Alström,
Benjamin M Scirica,
Charles W Hogue,
Nils Asenblad,
Robert F Storey,
Ph Gabriel Steg,
Jay Horrow,
Kenneth W Mahaffey, Richard C Becker,
Stefan James,
Christopher P Cannon,
Gunnar Brandrup-Wognsen,
Lars Wallentin,
Claes Held
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ABSTRACT: This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial.
In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality.
In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death.
Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively).
The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872).
Journal of the American College of Cardiology 09/2012; 60(17):1623-30. · 14.16 Impact Factor
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Steen Husted,
Stefan James, Richard C Becker,
Jay Horrow,
Hugo Katus,
Robert F Storey,
Christopher P Cannon,
Magda Heras,
Renato D Lopes,
Joao Morais,
Kenneth W Mahaffey,
Richard G Bach,
Daniel Wojdyla,
Lars Wallentin
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ABSTRACT: Background- Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age. Methods and Results- The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction. Conclusions- The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
Circulation Cardiovascular Quality and Outcomes 09/2012; 5(5):680-688. · 4.91 Impact Factor
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Jan H Cornel, Richard C Becker,
Shaun G Goodman,
Steen Husted,
Hugo Katus,
Anwar Santoso,
Gabriel Steg,
Robert F Storey,
Marius Vintila,
Jie L Sun,
Jay Horrow,
Lars Wallentin,
Robert Harrington,
Stefan James
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ABSTRACT: Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.
Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.
Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).
In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.
American heart journal 09/2012; 164(3):334-342.e1. · 4.65 Impact Factor
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Thomas J Povsic,
John P Vavalle,
Laura H Aberle,
Jaroslaw D Kasprzak,
Mauricio G Cohen,
Roxana Mehran,
Christoph Bode,
Christopher E Buller,
Gilles Montalescot,
Jan H Cornel,
Andrzej Rynkiewicz,
Michael E Ring,
Uwe Zeymer,
Madhu Natarajan,
Nicolas Delarche,
Steven L Zelenkofske, Richard C Becker,
John H Alexander
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ABSTRACT: AimsWe sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined.Methods and resultsNon-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively.Conclusion
At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation. Clinical Trials Registration: ClinicalTrials.gov NCT00932100.
European Heart Journal 08/2012; · 10.48 Impact Factor
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ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome initiated by heparin exposure and characterized by thrombocytopenia and paradoxical thrombophilia. HIT is mediated by the formation of antibodies against the platelet factor 4/heparin complex, which leads to platelet activation, thrombin generation, and potentially fatal thrombotic sequelae. The clinical presentation of HIT is variable and can be easily overlooked. Although a number of functional and antigen-based immunoassays have been developed to detect the presence of HIT antibodies, initial diagnosis is often based on recognition of thrombocytopenia in the appropriate clinical context and later confirmed with immunologic testing. Given the serious clinical consequences of HIT, immediate cessation of heparin products and administration of non-heparin anticoagulants are crucial components of treatment. We provide a review of the clinical syndrome and practical summary of treatment recommendations from the most recent 2012 American College of Chest Physicians evidence-based guidelines for the treatment and prevention of HIT.
Journal of Thrombosis and Thrombolysis 07/2012; 34(4):552-61. · 1.48 Impact Factor
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ABSTRACT: Oral anticoagulation with vitamin K antagonists has served as the primary treatment for the prevention of stroke and systemic embolization in patients with atrial fibrillation (AF) for decades. Over the past several years, multiple novel oral anticoagulants targeting key mediators of coagulation, including thrombin and factor Xa, have been developed. Specifically, agents targeting thrombin (dabigatran) and factor Xa (apixaban and rivaroxaban) have either reached late stages of clinical development (apixaban) or have received approval (dabigatran, rivaroxaban) by the US Food and Drug Administration for use in patients with nonvalvular AF. The promising results derived from large-scale clinical trials with these agents compared to warfarin expand the available therapeutic options for the prevention of stroke and systemic embolization in this rapidly increasing patient population. Here we present a general guidance pathway for the initiation and selection of oral anticoagulants in patients with AF.
Critical pathways in cardiology 06/2012; 11(2):55-61.
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Stefan K James,
Robert F Storey,
Nardev S Khurmi,
Steen Husted,
Matyas Keltai,
Kenneth W Mahaffey,
Juan Maya,
Joao Morais,
Renato D Lopes,
Jose C Nicolau,
Prem Pais,
Dimitar Raev,
Jose L Lopez-Sendon,
Susanna R Stevens, Richard C Becker
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[hide abstract]
ABSTRACT: Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages.
We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively).
Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.
URL: http://www.clinicatrials.gov. Unique identifier: NCT00391872.
Circulation 05/2012; 125(23):2914-21. · 14.74 Impact Factor
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Dominick J Angiolillo,
David J Schneider,
Deepak L Bhatt,
William J French,
Matthew J Price,
Jorge F Saucedo,
Tamaz Shaburishvili,
Kurt Huber,
Jayne Prats,
Tiepu Liu,
Robert A Harrington, Richard C Becker
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ABSTRACT: Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.
Journal of Thrombosis and Thrombolysis 05/2012; 34(1):44-55. · 1.48 Impact Factor
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Richard C. Becker,
Kenneth W. Mahaffey,
Hongqiu Yang,
A. J. Marian,
Mark I. Furman,
A. Michael Lincoff,
Stanley L. Hazen,
John L. Petersen,
Craig J. Reist,
Neal S. Kleiman,
SYNERGY Investigators
[show abstract]
[hide abstract]
ABSTRACT: Heparin compounds, to include fractionated and unfractionated preparations, exert both antithrombotic and antiinflammatory
effects through combined inhibition of factor Xa and thrombin. The contribution of modulated platelet activity in vivo is
less clearly defined. The SYNERGY library was a prospectively designed repository for candidate clinical, hemostatic, platelet,
and molecular biomarkers from patients participating in SYNERGY—a large-scale, randomized clinical trial evaluating the comparative
benefits of unfractionated heparin (UFH) and enoxaparin in high-risk patients with acute coronary syndrome (ACS). Samples
were collected from 201 patients enrolled at 26 experienced, participating sites and shipped to established core laboratories
for analysis of platelet, endothelium-derived, inflammatory and coagulation activity biomarkers. Tissue factor pathway inhibitor
(TFPI)—a vascular endothelial cell-derived factor Xa regulatory protein—correlated directly with plasma anti-Xa activity (unadjusted:
r=0.23, P<0.0001; adjusted: β=0.10; P=0.001), as did TFPI–fXa complexes (unadjusted: r=0.34, P<0.0001; adjusted: β=0.38; P=<0.0001). In contrast, there was a direct and inverse relationship between anti-Xa activity and two platelet-derived biomarkers—plasminogen
activator inhibitor-1 (unadjusted: r=−0.18, P=0.0012; adjusted: β=−0.10; P=0.021) and soluble CD40 ligand (unadjusted: r=−0.11, P=0.05; adjusted: β=−0.13; P=0.049). All measured analyte relationships persisted after adjustment for age, creatinine clearance, weight, sex, and duration
of treatment. Differences in biomarkers between patients receiving UFH and those randomized to enoxaparin were not observed.
The ability of heparin compounds to affect the prothrombotic and proinflammatory states which characterize ACS may involve
factor Xa-related modulation of platelet activation and expression. Whether this potentially beneficial effect is direct or
indirect and achieved, at least in part, through the release of endothelial cell-derived coagulation regulatory proteins will
require further investigation.
KeywordsHeparin compounds–Platelets–Antithrombin–Factor Xa inhibition
Journal of Thrombosis and Thrombolysis 04/2012; 31(2):146-153. · 1.48 Impact Factor
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Renato D. Lopes, Richard C. Becker,
David Garcia,
Elaine M. Hylek,
Christopher B. Granger,
Dayse M. Lourenço,
Helena B. Nader,
Francisco H. A. Maffei,
Fernando H. Y. Cesena,
José C. Nicolau,
Ari Timmerman,
Ana T. Rocha,
Edison F. de Paiva,
Helio P. Guimaraes,
Antonio C. Carvalho,
Elbio A. D’Amico,
Carlos A. Moreira-Filho,
José M. Aldrighi,
Antonio C. Lopes
[show abstract]
[hide abstract]
ABSTRACT: The importance of thrombosis and anticoagulation in clinical practice is rooted firmly in several fundamental constructs that
can be applied both broadly and globally. Awareness and the appropriate use of anticoagulant therapy remain the keys to prevention
and treatment. However, to assure maximal efficacy and safety, the clinician must, according to the available evidence, choose
the right drug, at the right dose, for the right patient, under the right indication, and for the right duration of time.
The first International Symposium of Thrombosis and Anticoagulation in Internal Medicine was a scientific program developed by clinicians for clinicians. The primary objective of the meeting was to educate, motivate
and inspire internists, cardiologists and hematologists by convening national and international visionaries, thought-leaders
and dedicated clinician-scientists in Sao Paulo, Brazil. This article is a focused summary of the symposium proceedings.
Journal of Thrombosis and Thrombolysis 04/2012; 28(1):106-116. · 1.48 Impact Factor
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Jesse W Rowley,
Aloke V Finn,
Patricia A French,
Lisa K Jennings,
Danny Bluestein,
Peter L Gross,
Jane E Freedman,
Steven R Steinhubl,
Guy A Zimmerman, Richard C Becker,
Harold L Dauerman,
Susan S Smyth
Circulation Cardiovascular Interventions 04/2012; 5(2):296-304. · 6.06 Impact Factor
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Renato D Lopes, Richard C Becker,
L Kristin Newby,
Eric D Peterson,
Elaine M Hylek,
Christopher B Granger,
Mark Crowther,
Tracy Wang,
Antonio C Carvalho,
Otavio Berwanger, [......],
Jorge Pinto Ribeiro,
Eduardo Darze,
Renato A K Kalil,
Marianna Andrande,
Fabio Villas Boas,
Jadelson Andrade,
Ana Thereza Rocha,
Robert A Harrington,
Antonio C Lopes,
David A Garcia
[show abstract]
[hide abstract]
ABSTRACT: To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.
Journal of Thrombosis and Thrombolysis 03/2012; 34(1):143-63. · 1.48 Impact Factor
