Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

COVID-19 pandemic and STEMI: pathway activation and outcomes from the pan-London heart attack group.

OBJECTIVES: To understand the impact of COVID-19 on delivery and outcomes of primary percutaneous coronary intervention (PPCI). Furthermore, to compare clinical presentation and outcomes of patients with ST-segment elevation myocardial infarction (STEMI) with active COVID-19 against those without COVID-19. METHODS: We systematically analysed 348 STEMI cases presenting to the PPCI programme in London during the peak of the pandemic (1 March to 30 April 2020) and compared with 440 cases from the same period in 2019. Outcomes of interest included ambulance response times, timeliness of revascularisation, angiographic and procedural characteristics, and in-hospital clinical outcomes RESULTS: There was a 21% reduction in STEMI admissions and longer ambulance response times (87 (62-118) min in 2020 vs 75 (57-95) min in 2019, p<0.001), but that this was not associated with a delays in achieving revascularisation once in hospital (48 (34-65) min in 2020 vs 48 (35-70) min in 2019, p=0.35) or increased mortality (10.9% (38) in 2020 vs 8.6% (38) in 2019, p=0.28). 46 patients with active COVID-19 were more thrombotic and more likely to have intensive care unit admissions (32.6% (15) vs 9.3% (28), OR 5.74 (95%CI 2.24 to 9.89), p<0.001). They also had increased length of stay (4 (3-9) days vs 3 (2-4) days, p<0.001) and a higher mortality (21.7% (10) vs 9.3% (28), OR 2.72 (95% CI 1.25 to 5.82), p=0.012) compared with patients having PPCI without COVID-19. CONCLUSION: These findings suggest that PPCI pathways can be maintained during unprecedented healthcare emergencies but confirms the high mortality of STEMI in the context of concomitant COVID-19 infection characterised by a heightened state of thrombogenicity.

Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice.

RATIONALE: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. OBJECTIVE: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. METHODS AND RESULTS: Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia. CONCLUSIONS: Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.

Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anticoagulation therapy: a systematic review and economic modelling.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of self-testing and self-management of oral anticoagulation treatment compared with clinic-based monitoring. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: A systematic review was undertaken of relevant data from selected studies. Results about complication events and deaths were pooled in meta-analyses using risk difference (RD) as the outcome statistic. Heterogeneity across trials and possible publication bias were statistically measured. Subgroup analyses (post hoc) were conducted to compare results of self-testing versus self-management, low versus high trial quality, trials conducted in the UK versus trials in other countries and industry versus other sponsors. A Markov-type, state-transition model was developed. Stochastic simulations using the model were conducted to investigate uncertainty in estimated model parameters. RESULTS: In the 16 randomised and eight non-randomised trials selected, patient self-monitoring of oral anticoagulation therapy was found to be more effective than poor-quality usual care provided by family doctors and as effective as good-quality specialised anticoagulation clinics in maintaining the quality of anticoagulation therapy. There was no significant RD of major bleeding events between patient self-monitoring and usual care controls and pooled analyses found that compared with primary care or anticoagulation control (AC) clinics, self-monitoring was statistically significantly associated with fewer thromboembolic events. However, the reduction in complication events and deaths was not consistently associated with the improvement of AC; in some trials this may be due to alternative explanations, including patient education and patient empowerment. Also, the improved AC and the reduction of major complications and deaths by patient self-monitoring were mainly observed in trials conducted outside the UK. According to UK-specific data, for every 100 eligible patients, 24% would agree to conduct self-monitoring, 17 of the 24 patients (70%) could be successfully trained and able to carry out self-monitoring and only 14 of these (80%) would conduct long-term self-monitoring. Seven cost-effectiveness studies were identified and the study that provided the most relevant UK data found that patient self-management was more expensive than current routine care (417 pounds versus 122 pounds per patient-year) and concluded that using a cost-effectiveness threshold of 30,000 pounds per quality-adjusted life-year (QALY) gained, patient self-management does not appear to be cost-effective. De novo modelling for this report found that the incremental cost per QALY gained by patient self-monitoring is 122,365 pounds over 5 years and 63,655 pounds over 10 years. The estimated probability that patient self-monitoring is cost-effective (up to 30,000 pounds/QALY) is 44% over a 10-year period. Wide adoption of patient self-monitoring of anticoagulation therapy would cost the NHS an estimated additional 8-14 million pounds per year. CONCLUSIONS: For selected and successfully trained patients, self-monitoring is effective and safe for long-term oral anticoagulation therapy. In general, patient self-management (PSM) is unlikely to be more cost-effective than the current specialised anticoagulation clinics in the UK; self-monitoring may enhance the quality of life for some patients who are frequently away from home, who are in employment or education, or those who find it difficult to travel to clinics. Further research is needed into alternative dosing regimes, the clinical effectiveness and cost-effectiveness of patient education and training in long-term oral anticoagulation therapy, UK-relevant cost-effectiveness, the effectiveness of PSM in children, and the potential future developments of near-patient testing devices.

Vascular complications of transsphenoidal surgery.

Vascular complication of transsphenoidal surgery can lead to mortality and serious morbidity. In a series of 3,061 transsphenoidal operations for pituitary disease, 24 such complications were encountered, seven of which were fatal. The anatomic substrate for such complications is discussed, along with technical aspects of surgery and other methods for the avoidance of vascular complications.

Influence of plasma fibronectin on the response to infusion of thrombin and adenosine diphosphate.

An important physiological anti-thrombotic function has been suggested for plasma fibronectin and the reticuloendothelial system. The current study evaluated the effects of specific immunological fibronectin depletion and fibronectin supplementation upon resistance to infusion of thrombin and ADP in terms of mortality, mean arterial blood pressure and circulating levels of platelets, fibrinogen and fibrin degradation products. Mortality data indicated that rats with reduced fibronectin levels had reduced resistance to thrombin or adenosine diphosphate infusion. The increased lethality was characterized by reduced circulating levels of fibrinogen and platelets while fibrin degradation product levels rose. The infusion of ADP or thrombin in fibronectin supplemented rats failed to elicit higher mortality or reduce fibrinogen or platelet levels further. These data are consistent with the hypothesis that resistance to excessive coagulation and/or platelet aggregation is correlated to circulating plasma fibronectin levels. It is suggested that by direct effects and/or acting as an opsonin for RES phagocytosis, plasma fibronectin acts as an important anti-thrombotic mechanism.