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Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis.
Luo, W, Li, C, Zhang, Y, Du, M, Kou, H, Lu, C, Mei, H, Hu, Y
BMC cancer. 2022;(1):98
Abstract
BACKGROUND Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. METHODS We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. RESULTS Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68-89%), 61% (95% CI: 49-73%), and 68% (95%CI: 54-80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49-70%), 33% (95% CI: 27-40%), and 32% (95%CI: 25-40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. CONCLUSION CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.
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Increased bleeding events with the addition of apixaban to the dual anti-platelet regimen for the treatment of patients with acute coronary syndrome: A meta-analysis.
Jin, J, Zhuo, X, Xiao, M, Jiang, Z, Chen, L, Devi Shamloll, Y
Medicine. 2021;(12):e25185
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Abstract
BACKGROUND Dual anti-platelet therapy (DAPT) with aspirin and clopidogrel has been the mainstay of treatment for patients with acute coronary syndrome (ACS). However, the recurrence of thrombotic events, potential aspirin and clopidogrel hypo-responsiveness, and other limitations of DAPT have led to the development of newer oral anti-thrombotic drugs. Apixaban, a new non-vitamin K antagonist, has been approved for use. In this meta-analysis, we aimed to compare the bleeding outcomes observed with the addition of apixaban to DAPT for the treatment of patients with ACS. METHODS Online databases including EMBASE, Cochrane Central, http://www.ClinicalTrials.gov, MEDLINE and Web of Science were searched for English based publications comparing the use of apixaban added to DAPT for the treatment of patients with ACS. Different categories of bleeding events and cardiovascular outcomes were assessed. The analysis was carried out by the RevMan software version 5.4. Odds ratios (OR) with 95% confidence intervals (CI) were used to represent the data following analysis. RESULTS This research analysis consisted of 4 trials with a total number of 9010 participants. Thrombolysis in myocardial infarction (TIMI) defined major bleeding (OR: 2.45, 95% CI: 1.45-4.12; P = .0008), TIMI defined minor bleeding (OR: 3.12, 95% CI: 1.71-5.70; P = .0002), International society of thrombosis and hemostasis (ISTH) major bleeding (OR: 2.49, 95% CI: 1.80-3.45; P = .00001) and Global Use of Strategies to Open Occluded Arteries (GUSTO) defined severe bleeding (OR: 3.00, 95% CI: 1.56-5.78; P = .01) were significantly increased with the addition of apixaban to DAPT versus DAPT alone in these patients with ACS. However fatal bleeding (OR: 10.96, 95% CI: 0.61-198.3; P = .11) was not significantly different. CONCLUSIONS Addition of the novel oral anticoagulant apixaban to the DAPT regimen significantly increased bleeding and therefore did not show any beneficial effect in these patients with ACS. However, due to the extremely limited data, we apparently have to rely on future larger studies to confirm this hypothesis.
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Comparison of non-vitamin K antagonist oral anticoagulants on bleeding and thrombosis.
Liu, Z, Ma, L, Zhang, H, Mu, G, Xie, Q, Zhou, S, Wang, Z, Wang, Z, Hu, K, Gong, Y, et al
Journal of clinical pharmacy and therapeutics. 2021;(6):1729-1742
Abstract
WHAT IS KNOWN AND OBJECTIVE Limited data are available for the comparison between different non-vitamin K antagonist oral anticoagulants (NOACs) on clinical outcomes. We aimed to provide evidence of different NOACs for patients with non-valvular atrial fibrillation (NVAF). METHODS Electronic databases were searched from inception through 22 March 2020 to identify eligible studies in which clinical outcomes (stroke, systemic embolism [SE], bleeding or death events) were directly compared between different NOACs. RESULTS 29 real-world studies enrolled more than 700,000 patients were included. Compared with dabigatran, apixaban had higher risk of death (OR 1.07), major bleeding (1.43), GI bleeding (1.64), ischaemic stroke and stroke/SE events (1.10); rivaroxaban had higher risk of death (1.28), major bleeding (1.24), GI bleeding (1.14) and ischaemic stroke (1.08). Compared with rivaroxaban, apixaban had lower risk of death (0.8), major bleeding (0.56) and ischaemic stroke events (0.71). Compared with edoxaban, rivaroxaban had higher risk of major bleeding (2.83), GI bleeding (5.18) and ischaemic stroke (2.28). WHAT IS NEW AND CONCLUSION In view of the global burden of disease and the routine use of NOACs worldwide, the findings have immediate and important implications. Our data suggested that apixaban might be the priority choice in prevention of bleeding and stroke and dabigatran could be the priority choice in prevention of death events. TRIAL REGISTRATION This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and was registered with PROSPERO (CRD42019140553).
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Details on the effect of very short dual antiplatelet therapy after drug-eluting stent implantation in patients with high bleeding risk: insight from the STOPDAPT-2 trial.
Watanabe, H, Domei, T, Morimoto, T, Natsuaki, M, Shiomi, H, Toyota, T, Ohya, M, Suwa, S, Takagi, K, Nanasato, M, et al
Cardiovascular intervention and therapeutics. 2021;(1):91-103
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Previously we briefly reported the effect of 1-month dual antiplatelet therapy (DAPT) for patients with high bleeding risk (HBR) receiving percutaneous coronary intervention (PCI) in the STOPDAPT-2 trial, but full analysis data have not been available. We conducted post hoc subgroup analysis regarding the effect of very short DAPT for HBR patients in STOPDAPT-2 trial. The primary endpoint was a 1-year composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and bleeding (TIMI major/minor bleeding) outcomes. Major secondary endpoints were 1-year cardiovascular composite endpoint and bleeding endpoint. HBR was defined by the academic research consortium (ARC) HBR criteria. Among the 3009 study patients, 1054 (35.0%) were classified as HBR and 1955 (65.0%) were as non-HBR. There were no significant interactions between HBR/non-HBR subgroups and the assigned DAPT group on the primary endpoint (HBR; 3.48% vs. 5.98%, HR 0.57, 95% CI 0.32-1.03, and non-HBR; 1.81% vs. 2.36%, HR 0.78, 95% CI 0.42-1.45; P for interaction = 0.48), the major secondary cardiovascular endpoint (HBR; 3.07% vs. 4.03%, HR 0.77, 95% CI 0.40-1.48, and non-HBR; 1.41% vs. 1.61%, HR 0.89, 95% CI 0.43-1.84; P for interaction = 0.77), and the major secondary bleeding endpoint (HBR; 0.41% vs. 2.71%, HR 0.15, 95% CI 0.03-0.65, and non-HBR; 0.40% vs. 0.85%, HR 0.48, 95% CI 0.14-1.58; P for interaction = 0.22). In conclusion, the effects of 1-month DAPT for the primary and major secondary endpoints were consistent in HBR and non-HBR patients without any significant interactions. The benefit of 1-month DAPT in reducing major bleeding was numerically greater in HBR patients.Clinical trial registration Short and optimal duration of dual antiplatelet therapy after everolimus-eluting cobalt-chromium stent-2 [STOPDAPT-2]; NCT02619760.
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Left Ventricular Thrombus Therapy With Direct Oral Anticoagulants Versus Vitamin K Antagonists: A Systematic Review and Meta-Analysis.
Saleiro, C, Lopes, J, De Campos, D, Puga, L, Costa, M, Gonçalves, L, Teixeira, R
Journal of cardiovascular pharmacology and therapeutics. 2021;(3):233-243
Abstract
BACKGROUND Current guidelines recommend vitamin K antagonists (VKAs) for left ventricular thrombus (LVT) resolution. Direct oral anticoagulants (DOACs) are increasingly evaluated as alternatives to the standard of care in anticoagulation. METHODS We performed a systematic review and meta-analysis to assess the use of DOACs vs VKAs for LVT treatment. The occurrence of LVT resolution, systemic embolism (SE) or stroke, and bleeding events were compared during follow-up using random-effects analysis. RESULTS The 5 included studies were all observational (a total of 828 patients). Of these, 284 patients (34%) were treated with DOACs, and 544 (66%) treated with VKAs. Thrombus resolution was similar for both methods (pooled odds ratio [OR], 0.91; 95% CI, 0.47-1.75; I2 = 63%; P = .78). The incidence of SE or stroke was also similar (pooled OR, 1.59; 95% CI, 0.85-2.97; I2 = 0%; P = .14). Clinically relevant bleeding incidence was similar for both groups (pooled OR, 0.66; 95% CI, 0.31-1.40; I2 = 0%; P = .28), although all bleeding events were less frequent in the DOAC group (pooled OR, 0.49; 95% CI, 0.26-0.90; I2 = 0%; P = .02). CONCLUSION Our systematic review and meta-analysis suggests DOACs were as effective as VKAs for LVT resolution, with a similar risk of systemic embolism/stroke and clinically relevant bleeding. These results, obtained from observational studies, are not definitive and hence randomized controlled trials are needed. Nevertheless, our analysis identifies key experimental features required in future studies.
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Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.
Khan, F, Tritschler, T, Kimpton, M, Wells, PS, Kearon, C, Weitz, JI, Büller, HR, Raskob, GE, Ageno, W, Couturaud, F, et al
Annals of internal medicine. 2021;(10):1420-1429
Abstract
BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO CRD42019128597).
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Safety and Efficacy of Vitamin K Antagonists versus Rivaroxaban in Hemodialysis Patients with Atrial Fibrillation: A Multicenter Randomized Controlled Trial.
De Vriese, AS, Caluwé, R, Van Der Meersch, H, De Boeck, K, De Bacquer, D
Journal of the American Society of Nephrology : JASN. 2021;(6):1474-1483
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BACKGROUND In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown. METHODS In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding. RESULTS Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68; P=0.0006) in the rivaroxaban group and 0.34 (95% CI, 0.19 to 0.61; P=0.0003) in the rivaroxaban and vitamin K2 group, compared with the VKA group. Death from any cause, cardiac death, and risk of stroke were not different between the treatment arms, but symptomatic limb ischemia occurred significantly less frequently with rivaroxaban than with VKA. After adjustment for competing risk of death, the hazard ratio for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17 to 0.90; P=0.03) in the rivaroxaban group, 0.48 (95% CI, 0.22 to 1.08; P=0.08) in the rivaroxaban and vitamin K2 group and 0.44 (95% CI, 0.23 to 0.85; P=0.02) in the pooled rivaroxaban groups. CONCLUSIONS In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Oral Anticoagulation in Hemodialysis, NCT03799822.
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Rivaroxaban Versus Warfarin in Patients with Mechanical Heart Valves: Open-Label, Proof-of-Concept trial-The RIWA study.
Duraes, AR, de Souza Lima Bitar, Y, Schonhofen, IS, Travassos, KSO, Pereira, LV, Filho, JAL, Neto, MG, Junior, RA, Roever, L
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2021;(3):363-371
Abstract
BACKGROUND AND PURPOSE To date, vitamin K antagonists are the only available oral anticoagulants in patients with mechanical heart valves. In this way, we developed a pilot trial with rivaroxaban. METHODS The RIWA study was a proof-of-concept, open-label, randomized clinical trial and was designed to assess the incidence of thromboembolic and bleeding events of the rivaroxaban-based strategy (15 mg twice daily) in comparison to dose-adjusted warfarin. Patients were randomly assigned in a 1:1 ratio and were followed prospectively for 90 days. RESULTS A total of 72 patients were enrolled in the present study. Of these, 44 patients were randomized: 23 patients were allocated to the rivaroxaban group and 21 to the warfarin group. After 90 days of follow-up, the primary outcome occurred in one patient (4.3%) in the rivaroxaban group and three patients (14.3%) in the warfarin group (risk ratio [RR] 0.27; 95% confidence interval [CI] 0.02-2.85; P = 0.25). Minor bleeding (without discontinuation of medical therapy) occurred in six patients (26.1%) in the rivaroxaban group versus six patients (28.6%) in the warfarin group (RR 0.88; 95% CI 0.23-3.32; P = 0.85). One patient in the warfarin group died from myocardial infarction. No cases of hemorrhagic stroke, valve thrombosis, peripheral embolic events, or new intracardiac thrombus were related in both groups. CONCLUSIONS In this pilot study, rivaroxaban 15 mg twice daily had thromboembolic and bleeding events similar to warfarin in patients with mechanical heart valves. These data confirm the authors' proof-of-concept and suggest that a larger trial with a similar design is not unreasonable. CLINICALTRIAL. GOV IDENTIFIER NCT03566303.
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Direct oral anticoagulants for extended treatment of venous thromboembolism: insights from the EINSTEIN CHOICE study.
Imberti, D, Pomero, F, Mastroiacovo, D
Blood transfusion = Trasfusione del sangue. 2020;(1):49-57
Abstract
The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.
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Bleeding in anticoagulated patients with atrial fibrillation: practical considerations.
Undas, A, Drabik, L, Potpara, T
Polish archives of internal medicine. 2020;(1):47-58
Abstract
Major bleeding (especially intracranial hemorrhage) is the most feared adverse event observed in patients with atrial fibrillation (AF) receiving oral anticoagulation. Clinical risk factor-based scores have modest ability to predict major or clinically relevant bleeds, and blood biomarkers are increasingly implemented to improve bleeding prognostication in patients with AF on life‑long anticoagulation. To improve the safety of anticoagulation in the era of non-vitamin K antagonist oral anticoagulants (NOACs, or direct oral anticoagulants [DOACs], including dabigatran, rivaroxaban, apixaban, and edoxaban), specific demographic, clinical, and laboratory variables should be considered. The current review summarizes practical challenges in the management of oral anticoagulation with emphasis on the risk assessment tools, elderly or underweight patients, cancer patients, impact of chronic kidney disease, liver cirrhosis, and thrombocytopenia in the context of bleeding risk in patients with AF.