Need For Long-term Anticoagulation Research Articles

Takotsubo pathophysiology and complications: what we know and what we do not know.

Takotsubo cardiomyopathy or stress cardiomyopathy (SCM), was first described in 1990 and initially, it was thought to be only associated with short-term complications and mortality with a benign long-term prognosis comparable to a healthy population. However recent investigations have proven otherwise and have shown SCM patients might have comparable long-term morbidity and mortality to ST-elevation myocardial infarction (STEMI) patients. Many emotional, or physical stressors can trigger SCM, and have been able to describe an interplay of neurohormonal and inflammatory mechanisms as the pathophysiology of this disease. Additionally, given the significantly higher prevalence of SCM in post-menopausal women, estrogen levels have been thought to play a role in the pathogenesis of this disease. Furthermore, there is an elusive disparity in prognosis depending upon different triggers. Currently, many questions remain unanswered regarding the long-term management of these patients to reduce morbidity, mortality, and improve quality of life, such as the need for long-term anticoagulation. In this paper, we review the findings of most recent published investigations regarding etiologies, pathophysiology, diagnostic criteria, prognosis, short-term and in more detail, long-term complications of SCM. Finally, we will discuss what future research is needed to learn more about this disease to improve the long-term prognosis, even though as of now, data for long-term management is still lacking.

Ibrutinib Added to Standard Conditioning and As Consolidation Therapy Following Autologous Hematopoietic Stem Cell Transplantation (AutoHCT) for Relapsed/Refractory Activated-B-Cell Subtype Diffuse Large B-Cell Lymphoma (ABC-DLBCL): Primary Analysis of the US Intergroup Double-Blind Randomized Phase III Study Alliance A051301/BMT-CTN 1201

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org

Abstract P2137: Comparative Effectiveness And Safety Of Rivaroxaban Versus Warfarin In Valvular Atrial Fibrillation: A Systematic Review And Meta-Analysis

Introduction: Patients with valvular atrial fibrillation (AF), which refers to moderate to severe mitral stenosis or mechanical prosthetic heart valves, have an increased risk of ischemic stroke and systemic embolism, which mandates the need for long-term anticoagulation. Still, there are no clear consensus guidelines on the indications of anticoagulation therapy in valvular AF. We aimed to compare the effectiveness of rivaroxaban, a common direct-acting oral anticoagulant (DOAC), to warfarin for preventing thromboembolism in valvular AF patients. Methods: We performed a systematic search of the following databases; PubMed, Cochrane Library, Google Scholar, and EMBASE from inception until February 06, 2023. Results: After screening 389 studies, 8 studies with 68,847 patients have been included in the final analysis. Our meta-analysis did not reveal a significant difference in the occurrence of all-cause mortality between patients who received rivaroxaban and those who received warfarin [RR, 0.97 (95% CI: 0.53-1.76]), p =0.91]. On analysis of the individual studies, rivaroxaban was non-inferior to warfarin with a lower risk of bleeding events [RR, 0. 80 (95% CI: 0.62-1.04), p =0.72], myocardial infarction [RR, 0.56 (95% CI: 0.13-2.47), p =0.44], and stroke/systemic embolism [RR, 0.54 (95% CI: 0. 11-2.55), p = 0.43]. But there was no statistically significant difference between the two groups. Conclusions: With a decreased risk for major adverse events, rivaroxaban appears to have a favorable safety profile, making them a promising alternative to warfarin in treating patients with valvular AF. However, more randomized clinical trials are imperative.

Abstract 14225: Atrial Tachycardias After Surgical Left Atrial Appendage Exclusion

Introduction: Surgical left atrial appendage exclusion (LAA-Ex) is often performed to eliminate the need for long-term anticoagulation either as a stand-alone or concomitant procedure during cardiac surgery. A modified MAZE procedure is also usually performed during surgical LAA-Ex. Residual arrhythmogenic foci within the LAAA and/or zones of slow conduction along the stump of the LAA may contribute to recurrent atrial tachycardias (AT) after LAA-Ex. The purpose of this study was to determine the role of the LAA in recurrent atrial tachycardias (ATs) after surgical LAA-Ex. Methods: Catheter ablation (CA) was performed to eliminate ATs in 21 patients with history of AF (persistent in 18/21, 86%) 25±26 months after surgical LAA-Ex. There were 3 women; mean age was 66±9 years; and the left atrial diameter was 54±8 mms. A concomitant MAZE procedure and CA was performed previously, in 16 and 9 patients, respectively. Two patients had neither maze nor catheter ablation. There was residual blood flow into the LAA in 1/21 patient. Results: A reentrant AT involving the stump of the LAA was identified in 5/21 (24%) patients. Focal ablation on a critical isthmus within a zone of slow conduction along the LAA stump terminated AT in 3/5 patients. In the remaining 2 patients a linear lesion set from the stump to an existing line of block (left atrial roof line and anterior mitral annulus) terminated the macroreentrant AT revolving around the LAA stump. During 16±13 months of follow-up 10/21 patients (48%) remained free from recurrent ATs without antiarrhythmic drug therapy. A repeat ablation was performed in 3 patients, the mechanism of the AT was epicardial, perimitral, and multifocal but did not involve the LAA. Conclusions: After surgical LAA-Ex recurrent ATs are not uncommon and can involve the LAA stump, Although these ATs can be successfully identified and ablated, other ATs may recur and prompt additional antiarrhythmic or ablative therapy.

Fondaparinux as an Alternative Anticoagulant Treatment in Patients with Left Ventricular Assist Devices and Recurrent Gastrointestinal Bleeding: Case Series

Gastrointestinal bleeding (GIB) can occur in patients after left ventricular assist device (LVAD) implantation. In cases of recurrent GIB, the management of anticoagulation treatment represents a challenging situation in which the risk of bleeding recurrence and the need for long-term anticoagulation must be balanced. This case series describes the successful management of anticoagulation in three patients with recurrent GIB using fondaparinux. To our knowledge, these are the first reported cases of recurrent GIB in which a single dose of subcutaneous fondaparinux was used instead of oral anticoagulation. None of the patients presented with signs of pump thrombosis or arterial embolism. If confirmed by larger studies, the substitution of oral anticoagulation with subcutaneous, single-dose fondaparinux could represent a safe alternative treatment in a select group of patients with recurrent GIB.

Chapter 4 - Neurologic complications of nonrheumatic valvular heart disease

Valvular heart disease (VHD) is frequently associated with neurologic complications. Cerebral embolism is the most common, since thrombus formation results from the abnormalities in the valvular surfaces and the anatomic and physiologic changes associated with valve dysfunction, including atrial or ventricular enlargement, intracardiac thrombi, and cardiac dysrhythmias. Prosthetic heart valves, particularly mechanical valves, are very thrombogenic, which explains the high risk of thromboembolism and the need for long-term anticoagulation. Transcatheter aortic valve replacement (TAVR) has emerged as a nonoperative alternative to surgical aortic valve replacement for patients with intermediate or high surgical risk, and the procedure also has a risk of cerebral ischemia. In addition, anticoagulation, the mainstay of treatment to prevent cerebral embolism, has known potential for hemorrhagic complications. The emergence of new oral anticoagulants with similar effectiveness to warfarin and a better safety profile has facilitated the management of patients with atrial fibrillation. However, their application in patients with mechanical heart valves is still evolving. The prevention and management of these complications requires an understanding of their natural history to balance the risks posed by valvular heart disease, as well as the risks and benefits associated with the treatment.

Mitral Valve Surgery in Neonates, Infants, and Children: Surgical Approach, Outcomes, and Predictors

The surgical treatment of mitral disease in pediatrics is challenging. Managing diversity in patient anatomy, growth, and the need for long-term anticoagulation requires trade-offs between imperfect solutions. We sought to assess our approach to pediatric mitral valve surgery and identify predictors associated with mortality and recurrent mitral disease. The medical records, echocardiograms, and operative reports of all patients who underwent surgical intervention on the mitral valve from January 2000 to April 2016 were reviewed. A total of 143 patients underwent mitral valve surgery, 64 of which were neonates or infants (ages 10-355 days) and 79 of which were children (ages 1-17.8 years). Neonates and infants had a higher preoperative New York Heart Association heart failure classification in comparison to children (P < 0.001) with a less severe degree of mitral valve insufficiency (P = 0.007). Postoperative outcomes for primary repair patients (n = 133) demonstrated significant differences in recurrence of mitral valve disease, with 38% of neonates/infants and 21% of children affected (P = 0.028). Five-year rates of mortality or transplant were 22% (8%, 33%) in neonates and infants compared to 4% (0%, 10%) in children, P = 0.013. Mitral valve surgery in neonates and infants is particularly high risk and is associated with higher rate of recurrence and reintervention early. However, if successful early, mitral valve repair in neonates and infants can result in a durable freedom from reintervention that parallels freedom from reintervention in older children undergoing repair. Further understanding of mechanisms of failure and better matching of anatomic substrate to strategy is needed.

The Effect of Anticoagulant Choice on Venous Thromboembolism Recurrence and Bleeding in Sickle Cell Disease

Patients with sickle cell disease (SCD) experience accelerated morbidity and mortality. Venous thromboembolism (VTE), a risk factor for early mortality in SCD, occurs in 11-12% of patients with SCD by the age of 40. While indefinite anticoagulation is indicated in the SCD population, there is limited understanding of comparative efficacy and hemorrhagic risk of individual anticoagulation agents in this population. We reviewed the use of anticoagulation for treatment of VTE in patients with SCD at our institution to begin to address these questions. A retrospective chart review of all patients with SCD 18 years of age and older (currently alive or deceased) who received care at Boston Medical Center/Boston University between 2003 and 2018 was performed. VTE was defined as deep venous thrombosis (DVT) diagnosed by duplex ultrasound or pulmonary embolism (PE) diagnosed by either ventilation-perfusion scanning or computed tomography angiography. The primary efficacy outcome was the number of VTE events which occurred while the patient was receiving anticoagulation. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Hemostasis 2005 guidelines. The medical records of 233 patients with SCD were reviewed; VTE was identified in 55 (23.6%) patients. Sixty-five percent were female. In these 55 patients, a total of 94 VTE events occurred. Fifteen (16.0%) were catheter-associated upper extremity DVTs. For the first event, initial outpatient treatment consisted of warfarin in 56%, low-molecular-weight heparin (LMWH) in 18.2%, rivaroxaban in 9.1%, apixaban in 5.5%, and fondaparinux in 3.6%. The median length of treatment was 7.3 (median: 6, IQR: 3-12) months. Recurrent VTEs occurred in 27 (49%) patients with a total of 39 recurrent events. Among the recurrent events, thirteen (33.0%) were treatment failures occurring during anticoagulation therapy (see Table 1): 7 of 37 (18.9%) on warfarin, 2 of 20 (10.0%) on LMWH, and 4 of 15 (26.7%) on rivaroxaban. Death from recurrent VTE occurred in two patients; one occurred while a patient was therapeutic on warfarin. Major bleeding occurred in two patients (3.6%); in both cases, this was intracranial hemorrhage while on warfarin. In this retrospective study, there was a high rate of VTE recurrence despite anticoagulation in patients with SCD. Treatment failure was highest with warfarin and rivaroxaban, although adherence was difficult to assess. Risk of hemorrhage and death appears higher in those prescribed warfarin. These data affirm the need for long-term anticoagulation in most patients with SCD with a VTE and support the use of direct oral anticoagulants as a first-line agent. Disclosures Sloan: Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy; Merck: Other: endpoint review commitee.

High prevalence of inherited thrombophilia and antiphospholipid syndrome in myocardial infarction with non-obstructive coronary arteries: Comparison with cryptogenic stroke

BackgroundA role of thrombophilia in myocardial infarction with non-obstructive coronary arteries (MINOCA) is unclear. We investigated thrombophilic factors in MINOCA patients versus those following cryptogenic stroke (CS), a well-established indication for thrombophilia screening. MethodsIn a prospective cross-sectional study, we assessed 84 consecutive patients (median age: 45.5 years) at least 3 months after MINOCA. Age-matched CS patients (n = 84) and published data on general population served as controls. Thrombophilia screening involved inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, deficiency of protein C, protein S or antithrombin), antiphospholipid syndrome (APS), along with factor VIII >150%, homocysteine ≥15 μM and lipoprotein (a) >30 mg/dl. ResultsCompared to CS, MINOCA were more often males (60.7 vs 33.3%, P < 0.001), obese (34.5 vs 17.9%, P = 0.014), smokers (51.2 vs 35.7%, P = 0.043) and had family history of myocardial infarction (27.4 vs 6.0%, P < 0.001). Inherited thrombophilia occurred in 20 (23.8%) MINOCA patients and in 13 (15.5%) with CS (P = 0.17), without any difference in the parameters except for elevated lipoprotein (a) that was less common in MINOCA (21.4 vs 39.3%, P = 0.012). APS was found in 13 (15.5%) of MINOCA patients, mostly in a single-positive form. APS was diagnosed less frequently in STEMI (2.5 vs 27.3% for NSTEMI, P = 0.002) and MINOCA patients aged ≤50 years (5.7 vs 32.3% for older subjects, P = 0.003). ConclusionsMINOCA patients exhibit high prevalence of thrombophilia including APS, similar to that in CS. Our first comprehensive thrombophilia testing in MINOCA supports its clinical relevance and the need for long-term anticoagulation for some abnormalities, especially APS.

High detection rates of antithrombin deficiency and antiphospholipid syndrome in outpatients aged over 50 years using the standardized protocol for thrombophilia screening

IntroductionThrombophilia screening has limited detection efficiency. We assessed the detection rate when a standardized approach to thrombophilia-screened outpatients was used. MethodsWe analyzed 1185 patients (36.5% males, median age: 43 years [IQR 33-54]) referred to a single center from January 2014 to October 2017 with 11 different clinical indications for thrombophilia screening, which was performed in the adherence to published guidelines. Factor V Leiden, prothrombin G20210A mutation, antithrombin (AT), protein C, protein S deficiencies and antiphospholipid syndrome (APS) were determined. ResultsThe overall positivity rate was 37.1% (95% CI 34.3%–39.7%). The highest positivity rate was found in women following VTE during pregnancy/childbirth (64.1%) and provoked VTE patients with positive family history (52.9%). In patients aged >50 years (32.5%), APS was found at a similar rate as in younger subjects (11.4% vs 10.1%), while AT deficiency was detected more frequently in the older group (5.7% vs 2.4%, p = 0.003). ConclusionsStandard indications for thrombophilia screening lead to detection rates of 37% or more. Frequent detection of APS and AT deficiency among older patients, which often implies a need for long-term anticoagulation and could impact clinical practice patterns, suggests a benefit of thrombophilia screening in this population in selected clinical circumstances.

Real World Experience of Leadless LV Endocardial CRT with the WiSE CRT Pacing System; An International Study

IntroductionBiventricular endocardial pacing (BiV ENDO) is a potential therapy for heart failure patients who either cannot receive transvenous, epicardial CRT (BiV EPI) or who have failed to respond. BiV ENDO is traditionally delivered via trans-septal pacing leads, mandating lifelong anti-coagulation due to thromboembolic complications. The introduction of a new wireless LV endocardial pacing system (WiSE-CRT System, EBR Systems, Sunnyvale, California) avoids the need for long-term anticoagulation.ObjectiveWe sought to assess the safety & efficacy of the WiSE-CRT system during real world clinical use in an international registry.MethodsRegistry of centres implanting the WiSE-CRT system as part of the WICS Post Market Surveillance Registry (Clinical trial study number NCT02610673)ResultsA total of 68 patients across the 12 centers underwent implantation with the WiSE-CRT system, the largest series of leadless LV endocardial CRT yet reported. Patients were predominantly male with a mean age of 68.3± 10.4 years, a mean LVEF of 31% ± 9.1 and a mean QRS duration of 195.8 ± 120.0ms. Ischemic etiology was present in 37.5% of patients. Successful implantation and chronic delivery of BiV ENDO pacing via the WiSE-CRT system was achieved in 97% of patients. Acute (<24hrs) and 30 day complications rates were 5.9% and 23.5% respectively.ConclusionThis is the largest international series of the WiSE-CRT pacing system to date. In a real-world setting, leadless LV endocardial CRT proved technically feasible with a high success rate and similar complication rate to that previously described. BiV ENDO is a safe and effective therapeutic option for patients who fail to improve following transvenous, epicardial CRT. Biventricular endocardial pacing (BiV ENDO) is a potential therapy for heart failure patients who either cannot receive transvenous, epicardial CRT (BiV EPI) or who have failed to respond. BiV ENDO is traditionally delivered via trans-septal pacing leads, mandating lifelong anti-coagulation due to thromboembolic complications. The introduction of a new wireless LV endocardial pacing system (WiSE-CRT System, EBR Systems, Sunnyvale, California) avoids the need for long-term anticoagulation. We sought to assess the safety & efficacy of the WiSE-CRT system during real world clinical use in an international registry. Registry of centres implanting the WiSE-CRT system as part of the WICS Post Market Surveillance Registry (Clinical trial study number NCT02610673) A total of 68 patients across the 12 centers underwent implantation with the WiSE-CRT system, the largest series of leadless LV endocardial CRT yet reported. Patients were predominantly male with a mean age of 68.3± 10.4 years, a mean LVEF of 31% ± 9.1 and a mean QRS duration of 195.8 ± 120.0ms. Ischemic etiology was present in 37.5% of patients. Successful implantation and chronic delivery of BiV ENDO pacing via the WiSE-CRT system was achieved in 97% of patients. Acute (<24hrs) and 30 day complications rates were 5.9% and 23.5% respectively. This is the largest international series of the WiSE-CRT pacing system to date. In a real-world setting, leadless LV endocardial CRT proved technically feasible with a high success rate and similar complication rate to that previously described. BiV ENDO is a safe and effective therapeutic option for patients who fail to improve following transvenous, epicardial CRT.

Risk of reoperation in bioprosthetic valve patients with indication for long-term anticoagulation. Results from the observational retrospective multicentre PLECTRUM study

ObjectiveSeveral factors should be considered when a prosthetic heart valve, bioprosthetic valve (BV) or mechanical valve is to be implanted: thrombogenicity, life expectancy and the risk of reoperation.MethodsWe conducted an...

Embolizing Massive Right Atrial Thrombus in a HIV-Infected Patient.

The risk of thromboembolism is increased when associated with the human immunodeficiency viral (HIV) infection. Various factors are involved in promoting thrombosis, and the presence of a patent foramen ovale augments the potential for a paradoxical embolism. We describe the case of a 56-year-old man receiving antiretroviral therapy with features of right heart failure and pulmonary embolism. Due to the high incidence of life-threatening thromboembolism in the HIV-infected group, the need for long-term anticoagulation has to be evaluated.

WITHDRAWN: Electrical cardioversion for atrial fibrillation and flutter.

Atrial fibrillation increases stroke risk and adversely affects cardiovascular haemodynamics. Electrical cardioversion may, by restoring sinus rhythm, improve cardiovascular haemodynamics, reduce the risk of stroke, and obviate the need for long-term anticoagulation. To assess the effects of electrical cardioversion of atrial fibrillation or flutter on the risk of thromboembolic events, strokes and mortality (primary outcomes), the rate of cognitive decline, quality of life, the use of anticoagulants and the risk of re-hospitalisation (secondary outcomes) in adults (>18 years). We searched the Cochrane CENTRAL Register of Controlled Trials (1967 to May 2004), MEDLINE (1966 to May 2004), Embase (1980 to May 2004), CINAHL (1982 to May 2004), proceedings of the American College of Cardiology (published in Journal of the American College of Cardiology 1983 to 2003), www.trialscentral.org, www.controlled-trials.com and reference lists of articles. We hand-searched the indexes of the Proceedings of the British Cardiac Society published in British Heart Journal (1980 to 1995) and in Heart (1995 to 2002); proceedings of the European Congress of Cardiology and meetings of the Joint Working Groups of the European Society of Cardiology (published in European Heart Journal 1983-2003); scientific sessions of the American Heart Association (published in Circulation 1990-2003). Personal contact was made with experts. Randomised controlled trial or controlled clinical trials of electrical cardioversion plus 'usual care' versus 'usual care' only, where 'usual care' included any combination of anticoagulants, antiplatelet drugs and drugs for 'rate control'. We excluded trials which used pharmacological cardioversion as the first intervention, and trials of new onset atrial fibrillation after cardiac surgery. There were no language restrictions. For dichotomous data, odds ratios were calculated; and for continuous data, the weighted mean difference was calculated. We found three completed trials of electrical cardioversion (rhythm control) versus rate control, recruiting a total of 927 participants (Hot Cafe; RACE; STAF) and one ongoing trial (J-RHYTHM). There was no difference in mortality between the two strategies (OR 0.83; CI 0.48 to 1.43). There was a trend towards more strokes in the rhythm control group (OR 1.9; 95% CI 0.99 to 3.64). At follow up, three domains of quality of life (physical functioning, physical role function and vitality) were significantly better in the rhythm control group (RACE 2002; STAF 2003). Electrical cardioversion (rhythm control) led to a non-significant increase in stroke risk but improved three domains of quality of life.

Ironclad: A randomized phase III study of ibrutinib (Ibr) or no consolidation following autologous hematopoietic stem cell transplantation (AutoHCT) for relapsed/refractory activated-B-cell (ABC) subtype diffuse large B-cell lymphoma (DLBCL).

TPS7566 Background: Relapsed DLBCL in the rituximab era portends a poor prognosis with only about 25% of patients achieving long-term disease control following 2ndline therapy and AutoHCT. Patients with the ABC subtype have an inferior prognosis at diagnosis than those with GC and are overrepresented at relapse. In order to improve outcomes in ABC-DLBCL, we designed a study targeting disease pathobiology at the time of AutoHCT. Ibr has a safety profile allowing combination with cytotoxic chemotherapy and has single-agent activity with a 37% response rate in patients with relapsed/refractory ABC-DLBCL. Methods: This is an intergroup, randomized, placebo-controlled phase III study combining Ibr or placebo with high-dose chemotherapy during conditioning with AutoHCT and for 12 months following AutoHCT. Pts with relapsed or refractory DLBCL have tissue submitted centrally for real-time review and subtype assignment by GEP (Frederick Laboratory). Key eligibility criteria include no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no progression on prior Ibr. Pts with chemosensitive ABC-DLBCL are randomized to Ibr 560 mg or placebo with BEAM or CBV chemotherapy until day 0. After engraftment, pts receive Ibr 560 mg daily or placebo for 12 additional cycles. Pts with progressive disease on placebo can cross over to Ibr monotherapy. An initial safety cohort of 6 pts is being enrolled to evaluate the tolerability of Ibr with concurrent BEAM and CBV therapy. The primary endpoint is superior 2-year PFS (Ha/H0: 67% vs 50%). Secondary endpoints include time to count recovery, post-transplant response rates, OS, PFS, and incidence of 2arymalignancies. In correlative studies, we will assess the prognostic and predictive role of pre-transplant FDG-PET in the setting of Ibr or placebo therapy, the role of emergent BCR pathway mutations, double hit genetics, and pharmacogenetic determinants on treatment outcome and toxicities. We expect to accrue 296 patients over 4 years. An Alliance/BMT-CTN study: NCT02443077 Clinical trial information: NCT02443077.

A retrospective review of pediatric antiphospholipid syndrome and thrombosis outcomes.

: Pediatric antiphospholipid syndrome (APS) is characterized by vascular thromboses and multisystem involvement associated with persistently positive antiphospholipid antibodies testing. There is limited literature regarding risk factors for development of thrombosis and long-term thrombotic outcomes in pediatric APS. The objective of our study was to review our institutional experience with pediatric APS and thrombosis outcomes. We conducted a 20-year retrospective review to study the clinical features, management, and long-term outcomes of patients between ages 6 months and 18 years diagnosed with APS. Seventeen patients (7 female; 10 male), with median age at first thrombosis being 15.3 years (range: 0.63-17.98 years) were included. The median follow-up period was 4.3 years (range: 0.8-16.9 years). Venous thrombosis was noted in 11 patients (64.7%) with arterial events occurring in six patients (35.3%). Nine (53%) patients were noted to have primary APS. Recurrent and/or progressive thrombotic events occurred in 10 patients (58.8%), which is higher than reported literature. The median time for recurrence/progression was 1.4 years (range: 0.37-11.85 years). At the time of recurrence/progression, only two (20%) patients were at therapeutic levels of anticoagulation. The high recurrence rate with majority of patients not being on therapeutic levels of anticoagulation at the time of the event along with 60% of recurrent events occurring at least 1 year from first vascular event suggests the possible need for long-term anticoagulation. However, larger pediatric studies are required to assess the need for long-term/indefinite anticoagulation.

Safety and Feasibility of Treatment with Rivaroxaban in Children for Non-Routine Indications: A Case Series Analysis

Background. Anticoagulation therapy is the cornerstone of acute treatment of venous thromboembolism (VTE) and for prevention of recurrent VTE. The need for anticoagulation is increasing in children, largely in part due to increasing VTE rates. Conventional anticoagulants, including heparin, low-molecular weight heparins (LMWH), Fondaparinux, and vitamin K antagonists (VKA) are widely used in children but have limitations. Standard of care management with these agents is plagued with the trade-off between daily or twice daily injections or frequent monitoring of therapeutic effect. The advent of direct oral anticoagulants (DOACs) have catalyzed significant changes in the therapeutic landscape of VTE management. DOACs have been evaluated for safety and efficacy in large, randomized controlled trials in the treatment and prevention of VTE in adults, with results that are comparable to conventional therapy. None of the current DOACs have FDA-approved indications and dosing in children yet. Off-label use of these agents is largely based on adult data and doses, and is increasing at many Children's Hospitals across US. Rivaroxaban, a DOAC, is a factor Xa inhibitor with predictable pharmacokinetic and pharmacodynamics properties. Methods. We describe a case series of 8 unique pediatric cases, treated with Rivaroxaban, for a variety of non-routine indications, due either to adverse effects, intolerability of LMWH or VKA or the need for ongoing, long term anticoagulation. Rivaroxaban was started after informed consent and assent from parents or patients respectively, and was initiated at a fixed dose but titrated to a final dose after monitoring of trough and peak Rivaroxaban levels (Aniara, West Chester,OH, USA). Results. The mean age of patients in this case series is 14 years (median: 16, range 3-17) (see Table). The most common indication to use Rivaroxaban was the need for long term anticoagulation after having completed therapeutic anticoagulation, except in two patients, one of whom developed warfarin skin necrosis due to protein C deficiency and another with heparin induced thrombocytopenia. Only two patients needed dose adjustments to achieve target trough and peak drug levels. The mean duration of follow-up is 9 months (median= 5.5; range 3-24) (see Table) at this time. None of the patients developed recurrent VTE while on Rivaroxaban. A soft tissue traumatic bleed occurred in one patient which was treated with holding off the drug for 48 hours. No other bleeding complications were observed. Conclusions. Clinical application of DOACs in a real world clinical setting, including strong thrombophilia and malignancy, results in treatment profile of high efficacy and safety in children; however, larger studies are needed to validate these findings. Disclosures Sarode: CSL Behring: Consultancy, Honoraria.

Composite valve graft implantation for the treatment of aortic valve and root disease: Results in 1045 patients

ObjectivesAortic root replacement using a composite graft is the treatment of choice for a large variety of aortic root conditions with a diseased aortic valve. The objective of the current study was to evaluate the long-term results of this procedure. MethodsBetween 1978 and 2010, 1045 patients aged 58.7 ± 13.6 years underwent aortic root composite graft replacement using the following techniques: 95 Bentall operation; 926 the “button technique;” 24 the Cabrol technique. A mechanical composite valve graft was implanted in 69.6% of the patients. Six-hundred and thirty-five patients (62.3%) had annuloaortic ectasia and 162 (15.5%) had aortic dissection. ResultsEarly mortality was 5.3% (55/1045). Independent risk factors for early mortality at logistic regression analysis were age ≥70 years (P = .051; odds ratio [OR], 2.97), New York Heart Association III-IV (P = .052; OR, 1.88), reoperation (P = .021; OR, 2.36), urgency/emergency (P = .003; OR, 3.09), mitral valve replacement (P = .001; OR, 6.01), or coronary artery bypass grafting (CABG) (P < .001; OR, 4.39); while bicuspid aortic valve (BAV) (P = .013; OR, 0.21), and time of operation 2001-2011 (P = .025; OR, 0.60) were protective predictors for early mortality. Overall survival at 5, 10, and 20 years was 84.1% ± 1.3%, 65.5% ± 2.6%, and 40.7% ± 4.6%, respectively. Multivariate analysis revealed chronic renal insufficiency (P = .001; hazard ratio [HR], 3.48), chronic obstructive pulmonary disease (P = .027; HR, 1.94), aortic dissection (P = .001; HR, 2.63), Cabrol technique (P = .009; HR, 15.34), and CABG (P = .016; HR, 2.02) to be significant predictors of late death, and BAV (P = .010; HR, 0.43) to be a significant protective predictor. Freedom from thromboembolism, bleeding complications, and endocarditis was 93.7% ± 2.6%, 90.3% ± 3.1%, and 98.4% ± 1% at 20 years, respectively. Freedom from aortic reoperation was 91.8% ± 2.1% at 20 years and was significantly lower in patients with aortic dissection. ConclusionsWithin the limitations of this retrospective study, we can conclude that aortic root replacement for aortic root aneurysms can be performed with low morbidity and mortality and with satisfactory long-term results. Few late serious complications were related to the need for long-term anticoagulation or a prosthetic valve. Reoperation on the proximal or in the distal aorta was most commonly performed in patients with aortic dissection.

OUP accepted manuscript

Extensive upper extremity deep venous thrombosis and compartment syndrome secondary to operative tourniquet application are rare outcomes of established practice. We present the case of a 54-year-old female who underwent elective removal of a right olecranon plate under general anaesthetic with brief application of a tourniquet. In recovery, she developed a swollen and erythematous forearm, without significant pain and paraesthesia. An urgent dual-phase computed tomography angiogram identified no venous outflow proximal to the axillary vein. Concern for early compartment syndrome necessitated emergency fasciotomies of the right forearm and hand, precluding thrombolysis. Thrombosis was found in the superficial and deep veins throughout the forearm, but the muscles were healthy. The patient commenced anticoagulation therapy early and made good recovery. Further haematology review concluded that she had a ‘provoked thrombosis’ and no need for long-term anticoagulation.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries