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Introduction Infective endocarditis (IE) is associated with high mortality and morbidity. Multiple organ failure is the main cause of death after surgery for IE. Cardiopulmonary bypass (CPB) can cause a systemic inflammatory response. In a pilot study (REMOVE-pilot (Revealing mechanisms and investigating efficacy of hemoad-sorption for prevention of vasodilatory shock in cardiac surgery patients with infective endocarditis – a multicentric randomized controlled group sequential trial)), we found that plasma profiles of cytokines during and after CPB were higher in patients with IE compared with patients with non-infectious valvular heart disease. Sequential Organ Failure Assessment (SOFA) scores on the first and second postoperative days and in-hospital mortality were also higher in IE patients. This protocol describes the design of the REMOVE trial on cytokine-adsorbing columns, for example, CytoSorb, for non-selective removal of cytokines. The aim of the REMOVE study is to demonstrate efficacy of CytoSorb on the prevention of multiorgan dysfunction in patients with IE undergoing cardiac surgery. Methods and analysis The REMOVE study is an interventional randomised controlled multicenter trial with a group sequential (Pocock) design for assessing efficacy of CytoSorb in patients undergoing cardiac surgery for IE. The change in mean total SOFA (Δ SOFA) score between preoperative and postoperative care will be used as primary endpoint. Data on 30-day mortality, changes in cytokines levels, duration of mechanical ventilation, length of intensive care unit and hospital stay, and postoperative stroke will be collected as secondary endpoints. An interim analysis will be conducted after including 25 participating patients per study arm (with a focus on feasibility of the recruitment as well as differences in cytokines and cell-free DNA levels). Ethics and dissemination The protocol was approved by the institutional review board and ethics committee of the University of Jena as well as by the corresponding ethics committee of each participating study centre. The results will be published in a renowned international medical journal, irrespective of the outcomes of the study. [ABSTRACT FROM AUTHOR]

Objective: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH., Methods: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC., Results: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC., Conclusions: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention., Competing Interests: Competing interests: JBK reports grants from Covidien (Medtronic), personal fees from Bayer, Pfizer and Sanofi. ME reports grants and other from Bayer, other from Boehringer Ingelheim, BMS/Pfizer and Daiichi Sankyo during the conduct of the study; grants from DFG, BMBF, EU, Corona Foundation and Fondation Leducq, other from Amgen, GSK, Novartis, Sanofi and Covidien. KGH reports grants and personal fees from Bayer, personal fees from Daiichi Sankyo, BMS, Pfizer, Boehringer Ingelheim, Sanofi-Aventis and Edwards Lifesciences, non-financial support from Getemed, personal fees from EIP Pharma and Medtronic. JS reports personal fees from Bayer, Pfizer/BMS, Daiichi and Boehringer Ingelheim. PAR reports personal fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo and Pfizer. JCP reports personal fees from Boehringer Ingelheim and Pfizer. TR reports personal fees from BMS Pfizer, Bayer Healthcare, Daiichi Sankyo and Boehringer Ingelheim. JV reports grants from Medtronic and Boston Scientific and fees from Medtronic, St Jude, Boston Scientific, UCB, Merz, Allergan, Teva, Novartis and AbbVie. WM reports personal fees from Boehringer Ingelheim and Bayer Pharma. PK reports personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/Bristol-Myers Squibb. FE reports grants and personal fees from Boehringer Ingelheim, personal fees from Bayer Pharma, Pfizer Pharma, Bristol-Myers Squibb and Daiichi Sankyo. MN reports personal fees from Speaker’s fee Pfizer/BMS and Boehringer Ingelheim. PDS reports personal fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi and Medtronic. JG reports personal fees from Pfizer. UJK reports other from Daiichi Sankyo and Bayer. GRF reports personal fees from Bayer and Boehringer. CD reports speaking fees from Bayer, UCB, Daiichi Sankyo and Pfizer. JM reports personal fees from Boehringer Ingelheim and Bayer Healthcare. HN reports personal fees from Boehringer Ingelheim and Daiichi. JR reports personal fees from Bayer, Boehringer, Pfizer and Bristol Myers Squibb. MS reports grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and the European Union (EU) and fees from Bristol-Myers Squibb, GlaxoSmithKline, Merz Pharmaceuticals, Novartis Pharma, Orion Pharma, Pharmacia, Roche, Sanofi, Teva Pharma and UCB Pharma. GR reports personal fees from Boehringer Ingelheim, Pfizer and Bayer, grants from Daiichi. HB reports personal fees from Honoraria for lectures from Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi Sankyo. HS reports grants from Bayer Healthcare. FP reports personal fees from Pfizer/BMS, Bayer, Boehringer Ingelheim and Daiichi Sankyo. JCW reports personal fees from Boehringer Ingelheim Pharma GmbH & Co. KGH reports personal fees from Daiichi Sankyo Pharma. AG reports personal fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol-Myers Squibb/Pfizer. GFH reports participation in the Respect-ESUS trial. SS reports personal fees from Boehringer Ingelheim and grants from Daiichi. HBH reports personal fees from Boehringer Ingelheim, Daiichi Sankyo and Novartis, grants from Medtronic., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)