Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

INTRODUCTION: Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. MATERIALS AND METHODS: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. RESULTS: In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. DISCUSSION AND CONCLUSION: This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

Outcome after intracranial hemorrhage under dabigatran and reversal with idarucizumab versus under vitamin-K-antagonists - the RIC-ICH study.

Background: Intracranial hemorrhage (ICH) is a rare but serious side effect associated with the use of oral anticoagulants, such as dabigatran. The specific reversal agent for dabigatran, idarucizumab, is available for the management of individuals with ICH. The aim of this study was to provide real-world evidence on patients with ICH and effective treatment with dabigatran and reversal with idarucizumab in clinical routine compared to those under effective treatment with vitamin-K-antagonist (VKA). Methods: Registration of Idarucizumab for Patients with IntraCranial Hemorrhage (RIC-ICH) is a non-interventional study conducted in 22 German stroke units that prospectively enrolled dabigatran patients treated with idarucizumab. Retrospective data from VKA patients served as reference population. Main objective was in-hospital mortality. Further objectives included change in bleeding volume, stroke severity, and functional status. Result: In-hospital mortality was 26.7% in 15 dabigatran and 27.3% in 88 VKA patients (hazard ratio 1.00, 95% CI 0.29-2.60). In patients with bleeding volume > 60 ml, mortality was lower in the dabigatran group (N = 6, 33%) compared to the VKA group (N = 15, 67%; HR 0.24, 95% CI 0.04-0.96). No differences were observed in secondary endpoints between dabigatran and VKA patients. Conclusion: These results, based on data from routine clinical practice, suggest that in-hospital mortality after idarucizumab treatment is comparable to that in patients pretreated with VKA. Due to the low precision of estimates, the results must be interpreted with caution.

Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study.

BACKGROUND: The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications. AIMS: In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA. METHODS: PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. RESULTS: Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10-2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00-13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints. CONCLUSIONS: The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate.

Excess mortality due to Covid-19? A comparison of total mortality in 2020 with total mortality in 2016 to 2019 in Germany, Sweden and Spain.

INTRODUCTION: Excess mortality is a suitable indicator of health consequences of COVID-19 because death from any cause is clearly defined contrary to death from Covid-19. We compared the overall mortality in 2020 with the overall mortality in 2016 to 2019 in Germany, Sweden and Spain. Contrary to other studies, we also took the demographic development between 2016 and 2020 and increasing life expectancy into account. METHODS: Using death and population figures from the EUROSTAT database, we estimated weekly and cumulative Standardized Mortality Ratios (SMR) with 95% confidence intervals (CI) for the year 2020. We applied two approaches to calculate weekly numbers of death expected in 2020: first, we used mean weekly mortality rates from 2016 to 2019 as expected mortality rates for 2020, and, second, to consider increasing life expectancy, we calculated expected mortality rates for 2020 by extrapolation from mortality rates from 2016 to 2019. RESULTS: In the first approach, the cumulative SMRs show that in Germany and Sweden there was no or little excess mortality in 2020 (SMR = 0.976 (95% CI: 0.974-0.978), and 1.030 (1.023-1.036), respectively), while in Spain the excess mortality was 14.8% (1.148 (1.144-1.151)). In the second approach, the corresponding SMRs for Germany and Sweden increased to 1.009 (1.007-1.011) and 1.083 (1.076-1.090), respectively, whereas results for Spain were virtually unchanged. CONCLUSION: In 2020, there was barely any excess mortality in Germany for both approaches. In Sweden, excess mortality was 3% without, and 8% with consideration of increasing life expectancy.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study.

Background: The optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage. Aim: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation. Design and Methods: PRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death. Summary: PRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Calculating the number of undetected active SARS-CoV-2 infections from results of population-wide antigen tests.

Current European research estimates the number of undetected active SARS-CoV-2 infections (dark figure) to be two- to 130-fold the number of detected cases. We revisited the population-wide antigen tests in Slovakia and South Tyrol and calculated the dark figure of active cases in the vulnerable populations and the number of undetected active cases per detected active case at the time of the population-wide tests. Our analysis follows three steps: using the sensitivities and specificities of the used antigen tests, we first calculated the number of test-positive individuals and the proportion of actual positives in those who participated in the antigen tests. We then calculated the dark figure in the total population of Slovakia and South Tyrol, respectively. Finally, we calculated the ratio of the dark figure in the vulnerable population to the number of newly detected infections through PCR tests. Per one positive PCR result, another 0.15 to 0.71 cases must be added in South Tyrol and 0.01 to 1.25 cases in Slovakia. The dark figure was in both countries lower than assumed by earlier studies.

Excess mortality due to COVID-19 in Germany.

OBJECTIVES: The first wave of the SARS-CoV-2 pandemic in Germany lasted from week 10 to 23 in 2020. The aim is to provide estimates of excess mortality in Germany during this time. METHODS: We analyzed age-specific numbers of deaths per week from 2016 to week 26 in 2020. We used weekly mean numbers of deaths of 2016-2019 to estimate expected weekly numbers for 2020. We estimated standardized mortality ratios (SMR) and 95% confidence intervals. RESULTS: During the first wave observed numbers of deaths were higher than expected for age groups 60-69, 80-89, and 90+. The age group 70-79 years did not show excess mortality. The net excess number of deaths for weeks 10-23 was +8,071. The overall SMR was 1•03 (95%CI 1•03-1•04). The largest increase occurred among people aged 80-89 and 90+ (SMR=1•08 and SMR=1•09). A sensitivity analysis that accounts for demographic changes revealed an overall SMR of 0•98 (95%CI 0•98-0•99) and a deficit of 4,926 deaths for week 10-23, 2020. CONCLUSIONS: The excess mortality existed for two months. The favorable course of the first wave may be explained by a younger age at infection at the beginning of the pandemic, lower contact rates, and a more efficient pandemic management.

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max ) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4 . For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4 , and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.

Supporting data for positron emission tomography-based risk modelling using a fixed-instead of a relative thresholding method for total metabolic tumor volume determination.

Total metabolic tumor volume (TMTV) was measured in 510 patients with DLBCL participating in the PETAL trial. The present data provide information about the prognostic impact of total metabolic tumor volume using the fixed standardized uptake value (SUV4) instead of the relative SUV41max thresholding method. A Bland-Altman plot was created to compare both methods. For TMTV assessed by the SUV4 method a Cox regression was applied to determine its effect on time to progression, progression-free survival, and overall survival. Kaplan-Meier curves and corresponding hazard ratios were used to estimate the effect of TMTV alone or in combination with interim positron emission tomography response on patients' survival. The data relate to the research article entitled "Dynamic risk assessment based on positron emission tomography scanning in diffuse large B-cell lymphoma: post-hoc analysis from the PETAL trial" [1].

Dynamic risk assessment based on positron emission tomography scanning in diffuse large B-cell lymphoma: Post-hoc analysis from the PETAL trial.

BACKGROUND: Valid prognostic tools are needed to guide risk-adjusted treatment approaches in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We assessed total metabolic tumor volume (TMTV) and standardized uptake value (SUV)-based interim positron emission tomography (iPET) response in 510 patients with DLBCL participating in the positron emission tomography-guided therapy of aggressive non-Hodgkin lymphomas (PETAL) trial (NCT00554164). TMTV was analyzed with a relative (SUV41max) and a fixed thresholding method (SUV4), and iPET was evaluated using the ΔSUVmax procedure. We determined associations between TMTV and international prognostic index (IPI) factors using Welch's t-test, investigated effects of TMTV, iPET response, and the IPI factors on time to progression (TTP), progression-free survival (PFS), and overall survival (OS) by Cox regression, and estimated the outcome using Kaplan-Meier curves. FINDINGS: TMTV was associated with all IPI factors except age. Irrespective of the thresholding method used, TMTV and iPET response were correlated with TTP, PFS, and OS, and remained the only independent outcome predictors in Cox regression analysis. By dichotomizing TMTV (cut-off: 328 cm³ by SUV41max) and iPET response (cut-off: 66% SUVmax reduction), we defined three groups at different risk of treatment failure (low [57.1% of patients]: low TMTV/good iPET response; intermediate [37.8%]: high TMTV/good iPET response or low TMTV/poor iPET response; and high [5.1%]: high TMTV/poor iPET response), with corresponding 2-year probabilities of 93.8% vs. 67.3% vs. 38.5% for TTP, 90.9% vs. 62.5% vs. 29.9% for PFS, and 95.5% vs. 77.4% vs. 37.1% for OS. INTERPRETATION: The PET-based risk model proposed may help identify patients who may benefit from treatment modifications or novel approaches.

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.