Chemotherapy followed by low dose radiotherapy in childhood Hodgkin's disease: retrospective analysis of results and prognostic factors

PURPOSE: To report the treatment results and prognostic factors of childhood patients with Hodgkin's disease treated with chemotherapy (CT) followed by low dose radiotherapy (RT). PATIENTS AND METHODS: This retrospective series analyzed 166 patients under 18 years old, treated from January 1985 to December 2003. Median age was 10 years (range 2–18). The male to female ratio was 2,3 : 1. Lymphonode enlargement was the most frequent clinical manifestation (68%), and the time of symptom duration was less than 6 months in 55% of the patients. In histological analysis Nodular Sclerosis was the most prevalent type (48%) followed by Mixed Celularity (34.6%). The staging group according Ann Arbor classification was: I (11.7%), II (36.4%), III (32.1%) and IV (19.8%). The standard treatment consisted of chemotherapy multiple drug combination according the period of treatment protocols vigent: ABVD in 39% (n-65) of the cases, by VEEP in 13 %(n-22), MOPP in 13 %(n-22), OPPA-13 %(n-22) and ABVD/OPPA in 22 %(n-33). Radiotherapy was device to all areas of initial presentation of disease. Dose less or equal than 21 Gy was used in 90.2% of patients with most part of them (90%) by involved field (IFRT) or mantle field. RESULTS: The OS and EFS in 10 years were 89% and 87%. Survival according to clinical stage as 94.7%, 91.3%, 82.3% and 71% for stages I to IV(p = 0,005). The OS was in 91.3% of patients who received RT and in 72.6% of patients who did not (p = 0,003). Multivariate analysis showed presence of B symptoms, no radiotherapy and advanced clinical stage to be associated with a worse prognosis. CONCLUSION: This data demonstrating the importance of RT consolidation with low dose and reduced volume, in all clinical stage of childhood HD, producing satisfactory ten years OS and EFS. As the disease is highly curable, any data of long term follow-up should be presented in order to better direct therapy, and to identify groups of patients who would not benefit from radiation treatment

Assessment of Outcomes Among Patients With Venous Thromboembolism With and Without Chronic Kidney Disease

Importance: Patients with venous thromboembolism (VTE) and concomitant chronic kidney disease (CKD) have been reported to have a higher risk of thrombosis and major bleeding complications compared with patients without concomitant CKD. The use of anticoagulation therapy is challenging, as many anticoagulant medications are excreted by the kidney. Large-scale data are needed to clarify the impact of CKD for anticoagulant treatment strategies and clinical outcomes of patients with VTE. Objective: To compare clinical characteristics, treatment patterns, and 12-month outcomes among patients with VTE and concomitant moderate to severe CKD (stages 3-5) vs patients with VTE and mild to no CKD (stages 1-2) in a contemporary international registry. Design, Setting, and Participants: The Global Anticoagulant Registry in the Field-Venous Thromboembolism (GARFIELD-VTE) study is a prospective noninterventional investigation of real-world treatment practices. A total of 10 684 patients from 415 sites in 28 countries were enrolled in the GARFIELD-VTE between May 2014 and January 2017. This cohort study included 8979 patients (6924 patients with mild to no CKD and 2055 patients with moderate to severe CKD) who had objectively confirmed VTE within 30 days before entry in the registry. Chronic kidney disease stages were defined by estimated glomerular filtration rates. Data were extracted from the study database on December 8, 2018, and analyzed between May 1, 2019, and July 30, 2020. Exposure: Moderate to severe CKD vs mild to no CKD. Main Outcomes and Measures: The primary outcomes were all-cause mortality, recurrent VTE, and major bleeding. Event rates and 95% CIs were calculated and expressed per 100 person-years. Hazard ratios (HRs) were estimated with Cox proportional hazards regression models and adjusted for relevant confounding variables. All-cause mortality was considered a competing risk for other clinical outcomes in the estimation of cumulative incidences. Results: Of the 10 684 patients with objectively confirmed VTE, serum creatinine data were available for 8979 patients (84.0%). Of those, 4432 patients (49.4%) were female and 5912 patients (65.8%) were White; 6924 patients (77.1%; median age, 57 years; interquartile range [IQR], 44-69 years) were classified as having mild to no CKD, and 2055 patients (22.9%; median age, 70 years; IQR, 59-78 years) were classified as having moderate to severe CKD. Calculations using the equation from the Modification of Diet in Renal Disease study indicated that, among the 6924 patients with mild to no CKD, 2991 patients had stage 1 CKD, and 3933 patients had stage 2 CKD; among the 2055 patients with moderate to severe CKD, 1650 patients had stage 3 CKD, 190 patients had stage 4 CKD, and 215 patients had stage 5 CKD. The distribution of VTE presentation was comparable between groups. In total, 1171 patients (57.0%) with moderate to severe CKD and 4079 patients (58.9%) with mild to no CKD presented with deep vein thrombosis alone, 547 patients (26.6%) with moderate to severe CKD and 1723 patients (24.9%) with mild to no CKD presented with pulmonary embolism alone, and 337 patients (16.4%) with moderate to severe CKD and 1122 patients (16.2%) with mild to no CKD presented with both pulmonary embolism and deep vein thrombosis. Compared with patients with mild to no CKD, patients with moderate to severe CKD were more likely to be female (3259 women [47.1%] vs 1173 women [57.1%]) and older than 65 years (2313 patients [33.4%] vs 1278 patients [62.2%]). At baseline, the receipt of parenteral therapy alone was comparable between the 2 groups (355 patients [17.3%] with moderate to severe CKD vs 1253 patients [18.1%] with mild to no CKD). Patients with moderate to severe CKD compared with those with mild to no CKD were less likely to be receiving direct oral anticoagulant therapy, either alone (557 patients [27.1%] vs 2139 patients [30.9%]) or in combination with parenteral therapy (319 patients [15.5%] vs 1239 patients [17.9%]). Patients with moderate to severe CKD had a higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.44; 95% CI, 1.21-1.73), major bleeding (aHR, 1.40; 95% CI, 1.03-1.90), and recurrent VTE (aHR, 1.40; 95% CI, 1.10-1.77) than patients with mild to no CKD. Conclusions and Relevance: In this study of patients with VTE, the presence of moderate to severe CKD was associated with increases in the risk of death, VTE recurrence, and major bleeding compared with the presence of mild to no CKD

Short term outcome after left atrial appendage occlusion with the AMPLATZER Amulet and WATCHMAN device: results from the ORIGINAL registry (saxOnian RegIstry analyzinG and followINg left atrial Appendage cLosure)

Background: Various randomized multicenter studies have shown that percutaneous left atrial appendage closure (LAAC) is not inferior in stroke prevention compared to vitamin K antagonists (VKA) and can be performed safely and effectively. Aims: The prospective multicenter ORIGINAL registry in the Free State of Saxony (saxOnian RegIstry analyzinG and followINg left atrial Appendage cLosure) investigated the efficiency and safety of LAAC with Watchman or Amulet device in a real word setting. A special focus was put on the influence of LAAC frequency on periprocedural efficiency and safety. Methods and results: The total of 482 consecutive patients (Abbott Amulet N = 93 and Boston Scientific Watchman N = 389) were included in the periinterventional analyses. After 6 weeks, 353 patients completed the first follow-up including transoesophageal echocardiography (TEE) (73.2%). Successful LAAC could be performed in more than 94%. The complication rate does not significantly differ between device types (p = 0.92) according to Fischer test and comprised 2.2% in the Amulet and 2.3% in the Watchman group. The kind of device and the frequency of LAAC per study center had no influence on the success and complication rates. Device related thrombus could be revealed more frequently in the Watchman group (4.5%) than in the Amulet group (1.4%) but this difference is still not significant in Fisher test (p = 0.14). Same conclusion can be made about residual leakage 1.1% versus 0% [not significant in Fisher test (p = 0.26)]. Dual antiplatelet therapy followed the intervention in 64% and 22% of patients were discharged under a combination of an anticoagulant (VKA/DOAC/Heparin) and one antiplatelet agent. Conclusions: The ORIGINAL registry supports the thesis from large, randomized trials that LAAC can be performed with a very high procedural success rate in the everyday clinical routine irrespective of the used LAA device (Watchman or Amulet). The postprocedural antithrombotic strategy differs widely among the participating centers

Isolated Distal Deep Vein Thrombosis: Perspectives from the GARFIELD-VTE Registry

Isolated distal deep vein thrombosis (IDDVT) represents up to half of all lower limb DVT. This study investigated treatment patterns and outcomes in 2,145 patients with IDDVT in comparison with those with proximal DVT (PDVT; n = 3,846) and pulmonary embolism (PE; n = 4,097) enrolled in the GARFIELD-VTE registry. IDDVT patients were more likely to have recently undergone surgery (14.6%) or experienced leg trauma (13.2%) than PDVT patients (11.0 and 8.7%, respectively) and PE patients (12.7 and 4.5%, respectively). Compared with IDDVT, patients with PDVT or PE were more likely to have active cancer (7.2% vs. 9.9% and 10.3%). However, influence of provoking factors on risk of recurrence in IDDVT remains controversial. Nearly all patients (IDDVT, PDVT, and PE) were given anticoagulant therapy. In IDDVT, PDVT, and PE groups the proportion of patients receiving anticoagulant therapy was 61.4, 73.9, and 81.1% at 6 months and 45.8, 54.7, and 61.9% at 12 months. Over 12 months, the incidence of all-cause mortality, cancer, and recurrence was significantly lower in IDDVT patients than PDVT patients (hazard ratio [HR], 0.61 [95% confidence interval [CI], 0.48-0.77]; sub-HR [sHR], 0.60 [95% CI, 0.39-0.93]; and sHR, 0.76 [95% CI, 0.60-0.97]). Likewise, risk of death and incident cancer was significantly (both p < 0.05) lower in patients with IDDVT compared with PE. This study reveals a global trend that most IDDVT patients as well as those with PDVT and PE are given anticoagulant therapy, in many cases for at least 12 months

Assessment of Outcomes Among Patients With Venous Thromboembolism With and Without Chronic Kidney Disease

Importance: Patients with venous thromboembolism (VTE) and concomitant chronic kidney disease (CKD) have been reported to have a higher risk of thrombosis and major bleeding complications compared with patients without concomitant CKD. The use of anticoagulation therapy is challenging, as many anticoagulant medications are excreted by the kidney. Large-scale data are needed to clarify the impact of CKD for anticoagulant treatment strategies and clinical outcomes of patients with VTE. Objective: To compare clinical characteristics, treatment patterns, and 12-month outcomes among patients with VTE and concomitant moderate to severe CKD (stages 3-5) vs patients with VTE and mild to no CKD (stages 1-2) in a contemporary international registry. Design, Setting, and Participants: The Global Anticoagulant Registry in the Field–Venous Thromboembolism (GARFIELD-VTE) study is a prospective noninterventional investigation of real-world treatment practices. A total of 10 684 patients from 415 sites in 28 countries were enrolled in the GARFIELD-VTE between May 2014 and January 2017. This cohort study included 8979 patients (6924 patients with mild to no CKD and 2055 patients with moderate to severe CKD) who had objectively confirmed VTE within 30 days before entry in the registry. Chronic kidney disease stages were defined by estimated glomerular filtration rates. Data were extracted from the study database on December 8, 2018, and analyzed between May 1, 2019, and July 30, 2020. Exposure: Moderate to severe CKD vs mild to no CKD. Main Outcomes and Measures: The primary outcomes were all-cause mortality, recurrent VTE, and major bleeding. Event rates and 95% CIs were calculated and expressed per 100 person-years. Hazard ratios (HRs) were estimated with Cox proportional hazards regression models and adjusted for relevant confounding variables. All-cause mortality was considered a competing risk for other clinical outcomes in the estimation of cumulative incidences. Results: Of the 10 684 patients with objectively confirmed VTE, serum creatinine data were available for 8979 patients (84.0%). Of those, 4432 patients (49.4%) were female and 5912 patients (65.8%) were White; 6924 patients (77.1%; median age, 57 years; interquartile range [IQR], 44-69 years) were classified as having mild to no CKD, and 2055 patients (22.9%; median age, 70 years; IQR, 59-78 years) were classified as having moderate to severe CKD. Calculations using the equation from the Modification of Diet in Renal Disease study indicated that, among the 6924 patients with mild to no CKD, 2991 patients had stage 1 CKD, and 3933 patients had stage 2 CKD; among the 2055 patients with moderate to severe CKD, 1650 patients had stage 3 CKD, 190 patients had stage 4 CKD, and 215 patients had stage 5 CKD. The distribution of VTE presentation was comparable between groups. In total, 1171 patients (57.0%) with moderate to severe CKD and 4079 patients (58.9%) with mild to no CKD presented with deep vein thrombosis alone, 547 patients (26.6%) with moderate to severe CKD and 1723 patients (24.9%) with mild to no CKD presented with pulmonary embolism alone, and 337 patients (16.4%) with moderate to severe CKD and 1122 patients (16.2%) with mild to no CKD presented with both pulmonary embolism and deep vein thrombosis. Compared with patients with mild to no CKD, patients with moderate to severe CKD were more likely to be female (3259 women [47.1%] vs 1173 women [57.1%]) and older than 65 years (2313 patients [33.4%] vs 1278 patients [62.2%]). At baseline, the receipt of parenteral therapy alone was comparable between the 2 groups (355 patients [17.3%] with moderate to severe CKD vs 1253 patients [18.1%] with mild to no CKD). Patients with moderate to severe CKD compared with those with mild to no CKD were less likely to be receiving direct oral anticoagulant therapy, either alone (557 patients [27.1%] vs 2139 patients [30.9%]) or in combination with parenteral therapy (319 patients [15.5%] vs 1239 patients [17.9%]). Patients with moderate to severe CKD had a higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.44; 95% CI, 1.21-1.73), major bleeding (aHR, 1.40; 95% CI, 1.03-1.90), and recurrent VTE (aHR, 1.40; 95% CI, 1.10-1.77) than patients with mild to no CKD. Conclusions and Relevance: In this study of patients with VTE, the presence of moderate to severe CKD was associated with increases in the risk of death, VTE recurrence, and major bleeding compared with the presence of mild to no CKD

The influence of anemia on clinical outcomes in venous thromboembolism: Results from GARFIELD-VTE.

INTRODUCTION: Clinical characteristics and outcomes of venous thromboembolism (VTE) patients with concomitant anemia are unclear. This study compares baseline characteristics, treatment patterns, and 24-month outcomes in patients with and without anemia within GARFIELD-VTE. MATERIALS AND METHODS: GARFIELD-VTE (ClinicalTrials.gov: NCT02155491) is a global, prospective, non-interventional registry of real-world treatment practices. Of the 10,679 patients enrolled in GARFIELD-VTE, 7698 were eligible for analysis. Primary outcomes were all-cause mortality, recurrent VTE, and major bleeding in VTE patients with or without concomitant anemia over 24-months after diagnosis. Event rates and 95% confidence intervals were estimated using Poisson regression. Adjusted hazard ratios were calculated using Cox proportional hazard models. RESULTS: Distribution of VTE events in 2771 patients with anemia and 4927 without anemia was similar (deep-vein thrombosis alone: 61·1% vs. 55·9%, pulmonary embolism ± deep vein thrombosis: 38·9% vs. 44·0%, respectively). Patients with anemia were older (62.6 year vs. 58.9 years) than those without. At baseline, VTE risk factors that were more common in patients with anemia included hospitalization (22·0% vs. 6·8%), surgery (19·2% vs. 8·2%), cancer (20·1% vs. 5·6%) and acute medical illness (8·3% vs. 4·2%). Patients with anemia were more likely to receive parenteral anticoagulation therapy alone than those without anemia (26·6% vs. 11·7%) and less likely to receive a direct oral anticoagulant (38·5% vs. 53·5%). During 24-months of follow-up, patients with anemia had a higher risk (adjusted hazard ratio [95% confidence interval]) of all-cause mortality (1·84 [1·56-2·18]), major bleeding (2·83 [2·14-3·75]). Among anemia patients, the risk of all-cause mortality and major bleeding remained higher in patients with severe anemia than in those with mild/moderate anemia, all-cause mortality: HR 1·43 [95% CI: 1·21-1·77]; major bleeding: HR 2·08 [95% CI: 1·52-2·86]). CONCLUSIONS: VTE patients with concomitant anemia have a higher risk of adverse clinical outcomes compared with those without anemia. Further optimization of anticoagulation therapy for VTE patients with anemia is warranted

Pregnancy-Associated Venous Thromboembolism: Insights from GARFIELD-VTE.

Introduction  The risk of venous thromboembolism (VTE) increases during pregnancy and the puerperium such that VTE is a leading cause of maternal mortality. Methods  We describe the clinical characteristics, diagnostic strategies, treatment patterns, and outcomes of women with pregnancy-associated VTE (PA-VTE) enrolled in the Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE. Women of childbearing age (<45 years) were stratified into those with PA-VTE ( n  = 183), which included pregnant patients and those within the puerperium, and those with nonpregnancy associated VTE (NPA-VTE; n  = 1,187). Patients with PA-VTE were not stratified based upon the stage of pregnancy or puerperium. Results  Women with PA-VTE were younger (30.5 vs. 34.8 years), less likely to have pulmonary embolism (PE) (19.7 vs. 32.3%) and more likely to have left-sided deep vein thrombosis (DVT) (73.9 vs. 54.8%) compared with those with NPA-VTE. The most common risk factors in PA-VTE patients were hospitalization (10.4%), previous surgery (10.4%), and family history of VTE (9.3%). DVT was typically diagnosed by compression ultrasonography (98.7%) and PE by chest computed tomography (75.0%). PA-VTE patients more often received parenteral (43.2 vs. 15.1%) or vitamin K antagonists (VKA) (9.3 vs. 7.6%) therapy alone. NPA-VTE patients more often received a DOAC alone (30.2 vs. 13.7%). The risk (hazard ratio [95% confidence interval]) of all-cause mortality (0.59 [0.18-1.98]), recurrent VTE (0.82 [0.34-1.94]), and major bleeding (1.13 [0.33-3.90]) were comparable between PA-VTE and NPA-VTE patients. Uterine bleeding was the most common complication in both groups. Conclusion  VKAs or DOACs are widely used for treatment of PA-VTE despite limited evidence for their use in this population. Rates of clinical outcomes were comparable between groups

Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry.

AIMS: Vitamin K antagonists (VKAs) need to be individually dosed. International guidelines recommend a target range of international normalised ratio (INR) of 2.0-3.0 for stroke prevention in atrial fibrillation (AF). We analysed the time in this therapeutic range (TTR) of VKA-treated patients with newly diagnosed AF in the ongoing, global, observational registry GARFIELD-AF. Taking TTR as a measure of the quality of patient management, we analysed its relationship with 1-year outcomes, including stroke/systemic embolism (SE), major bleeding, and all-cause mortality. METHODS AND RESULTS: TTR was calculated for 9934 patients using 136,082 INR measurements during 1-year follow-up. The mean TTR was 55.0%; values were similar for different VKAs. 5851 (58.9%) patients had TTR<65%; 4083 (41.1%) TTR≥65%. The proportion of patients with TTR≥65% varied from 16.7% in Asia to 49.4% in Europe. There was a 2.6-fold increase in the risk of stroke/SE, 1.5-fold increase in the risk of major bleeding, and 2.4-fold increase in the risk of all-cause mortality with TTR<65% versus ≥65% after adjusting for potential confounders. The population attributable fraction, i.e. the proportion of events attributable to suboptimal anticoagulation among VKA users, was 47.7% for stroke/SE, 16.7% for major bleeding, and 45.4% for all-cause mortality. In patients with TTR<65%, the risk of first stroke/SE was highest in the first 4 months and decreased thereafter (test for trend, p = 0.021). In these patients, the risk of first major bleed declined during follow-up (p = 0.005), whereas in patients with TTR≥65%, the risk increased over time (p = 0.027). CONCLUSION: A large proportion of patients with AF had poor VKA control and these patients had higher risks of stroke/SE, major bleeding, and all-cause mortality. Our data suggest that there is room for improvement of VKA control in routine clinical practice and that this could substantially reduce adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01090362

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. METHODS AND RESULTS: 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. CONCLUSIONS: Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate &gt;20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations