Effect of Previous INR Control during VKA Therapy on Subsequent DOAC Adherence and Persistence, in Patients Switched from VKA to DOAC.

INTRODUCTION: Current guideline suggests a switch from vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) in patients with low time in therapeutic range (TTR < 70%). Poor international normalized ratio (INR) control may be the result of poor compliance, and might therefore be associated with subsequent DOAC intake. Therefore, this study evaluates the effect of previous TTR and other measures of INR control on DOAC nonadherence and nonpersistence, in patients who switched from VKA to DOAC. METHODS: A total of 437 patients who switched from VKA to DOAC between 2012 and 2019 were included using data from Certe Thrombosis Service, IADB.nl pharmacy community database University Groningen, and Statistics Netherlands. DOAC prescriptions were used to determine nonadherence and nonpersistence. INR control (i.e., TTR, time under therapeutic range [TUR], and INR variability) was assessed during the last 180 days of VKA use. Multivariable regression models were applied to determine the association between INR control and DOAC nonpersistence/nonadherence. RESULTS: On VKA, 67.7% of the patients had a TTR below 70%. DOAC nonpersistence was 39.8% (95% confidence interval [CI]: 33.4-45.5%) during a median follow-up of 34.4 months (interquartile range: 19.1-49.2). Approximately 80% of persistent patients were DOAC-adherent. Low TTR was not associated with DOAC nonpersistence (hazard ratio: 1.14, 95% CI: 0.69-1.87) and DOAC nonadherence (odds ratio: 1.38, 95% CI: 0.67-2.84), nor were TUR and INR variability. CONCLUSION: Previous INR control during VKA therapy is not associated with subsequent DOAC nonadherence and nonpersistence. This study suggests that INR control on VKA cannot, and therefore should not, be used for predicting DOAC adherence or persistence.

Exploring heterogeneity in reported venous thromboembolism risk in COVID-19 and comparison to other viral pneumonias: a systematic review and meta-regression.

Background: Sources of heterogeneity in venous thromboembolism (VTE) risk in COVID-19 are unclear and comparisons to other viruses are lacking. Objectives: To describe VTE risk in patients with COVID-19, explore sources of heterogeneity, and make comparisons with other viral pneumonia. Methods: PubMed and Embase data were searched on March 14, 2021, for studies on VTE in adults hospitalized with viral pneumonia. VTE risk estimates were pooled in a random effects meta-analysis stratified by virus type. Heterogeneity in COVID-19 was explored in multivariable meta-regression. Results: Seventy studies in COVID-19 (intensive care [ICU] [47] vs ward [23]), 4 studies in seasonal influenza (ICU [3] vs ward [1]), 2 ICU studies in H1N1 and 1 ICU study in SARS-CoV-1 were included. For COVID-19 ICU, pooled VTE risk was 19.6% (95% confidence interval [CI], 16.2%-23.5; I2 = 92.8%) for nonscreening studies and 30.0% (95% CI, 17.9%-45.7%; I2 = 81.9%) for screening studies. For COVID-19 ward, pooled VTE risk was 3.4% (95% CI, 2.4%-4.7%; I2 = 91.3%) and 22.5% (95% CI, 10.2%-42.7%; I2 = 91.6%) for nonscreening and screening studies, respectively. Higher sample size was associated with lower VTE risk. Pooled VTE risk in seasonal influenza and H1N1 at ICU were 9.0% (95% CI, 5.6%-14.2%; I2 = 39.7%) and 29.2% (95% CI, 8.7%-64.2%; I2 = 77.9%), respectively. At ward, VTE risk of seasonal influenza was 2.4% (95% CI, 2.1%-2.7%). In SARS-CoV-1, VTE risk was 47.8% (95% CI, 34.0-62.0). Conclusion: Pooled risk estimates in COVID-19 should be interpreted cautiously as a high degree of heterogeneity is present, which hinders comparison to other viral pneumonia. The association of VTE risk in COVID-19 to sample size suggests publication bias.

Long-Term Trends of Coagulation Parameters in People Living With HIV Treated With Combined Antiretroviral Therapy.

Trends of coagulation parameters during long-term treatment with combination antiretroviral therapy (cART) are unclear. We followed 40 male subjects living with human immunodeficiency virus (HIV). Plasma levels of procoagulant parameters, factor VIII, von Willebrand factor and D-dimer, and anticoagulant parameter Protein S (PS), were measured before start and 3 months, 1 year, and 9 years after. Analyses were adjusted for cardiovascular risk factors (age, smoking, and hypertension) at baseline. At baseline, procoagulant parameters were markedly elevated and PS was in the lower range of normal. CD4/CD8-ratio improved during the complete follow-up period. In the first year, procoagulant parameters were decreasing, but at year 9 an increase was observed. After correction for cardiovascular risk factors, this increase was no longer present. PS remained stable during the first year and slightly increased from one to 9 years. This study indicates that decreasing immune activation by cART reverses the procoagulant state in HIV partially during the first year. These parameters increase in the long term despite an on-going decrease in immune activation. This increase might be related to established cardiovascular risk factors.

Recurrence risk of venous thromboembolism associated with systemic lupus erythematosus: A retrospective cohort study.

Background: Recurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. Aim: To determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares. Methods: A multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. Results: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE. Conclusion: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk.

Impact of a Vancomycin-Induced Shift of the Gut Microbiome in a Gram-Negative Direction on Plasma Factor VIII:C Levels: Results from a Randomized Controlled Trial.

BACKGROUND: Inflammation is present in several conditions associated with risk of venous thromboembolism. The gut microbiome might be a source of systemic inflammation and activation of coagulation, by translocation of lipopolysaccharides from gram-negative bacteria to the systemic circulation. OBJECTIVE: To investigate whether a vancomycin-induced shift of the gut microbiome in a gram-negative direction influences systemic inflammation and plasma factor (F) VIII procoagulant activity (FVIII:C). METHODS AND RESULTS: We performed a randomized controlled trial including 43 healthy volunteers aged 19 to 37 years. Twenty-one were randomized to 7 days of oral vancomycin intake and 22 served as controls. Feces and blood were sampled at baseline, the day after the end of intervention, and 3 weeks after intervention. Gut microbiome composition was assessed by amplicon sequencing. FVIII: C was measured using an activated partial thromboplastin time-based assay, cytokines were measured using multiplex technology, complement activation was measured using the enzyme-linked immunosorbent assay, and high-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay. Vancomycin intake reduced gut microbiome diversity and increased the abundance of gram-negative bacteria. Change in FVIII:C in the intervention group was +4 IU/dL versus -6 IU/dL (p = 0.01) in the control group. A similar change was observed for log-transformed CRP (+0.21 mg/dL vs. -0.25 mg/dL, p = 0.04). The cytokines and complement activation markers remained similar in the two groups. CONCLUSION: The found slight increases in FVIII:C and CRP levels might support the hypothesis that a vancomycin-induced gram-negative shift in the gut microbiome could induce increased systemic inflammation and thereby a procoagulant state.

Predictors, time course, and outcomes of persistence patterns in oral anticoagulation for non-valvular atrial fibrillation: a Dutch Nationwide Cohort Study.

AIMS: Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We investigated the persistence with oral anticoagulants (OACs) and its association with prognosis among a nationwide cohort of NVAF patients. METHODS AND RESULTS: DOAC-naive NVAF patients who started to use DOACs for ischaemic stroke prevention between 2013 and 2018 were included using Dutch national statistics. Persistence with OACs was determined based on the presence of a 100-day gap between the last prescription and the end of study period. In 93 048 patients, 75.7% had a baseline CHA2DS2-VASc score of ≥2. The cumulative incidence of persistence with OACs was 88.1% [95% confidence interval (CI) 87.9-88.3%], 82.6% (95% CI 82.3-82.9%), 77.7% (95% CI 77.3-78.1%), and 72.0% (95% CI 71.5-72.5%) at 1, 2, 3, and 4 years after receiving DOACs, respectively. Baseline characteristics associated with better persistence with OACs included female sex, age range 65-74 years, permanent atrial fibrillation, previous exposure to vitamin K antagonists, stroke history (including transient ischaemic attack), and a CHA2DS2-VASc score ≥2. Non-persistence with OACs was associated with an increased risk of the composite outcome of ischaemic stroke and ischaemic stroke-related death [adjusted hazard ratio (aHR) 1.79, 95% CI 1.49-2.15] and ischaemic stroke (aHR 1.58, 95% CI 1.29-1.93) compared with being persistent with OACs. CONCLUSION: At least a quarter of NVAF patients were non-persistent with OACs within 4 years, which was associated with poor efficacy of ischaemic stroke prevention. The identified baseline characteristics may help identify patients at risk of non-persistence.

Risk of recurrent venous thromboembolism in patients with HIV infection: A nationwide cohort study.

BACKGROUND: Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. METHODS AND FINDINGS: PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. CONCLUSIONS: Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE.

Risk of Recurrent Venous Thromboembolism in Autoimmune Diseases: A Systematic Review of the Literature.

Despite an abundance of literature on the risk of a first venous thromboembolic event (VTE) in autoimmune diseases, specific recommendations about managing VTE in autoimmune diseases are lacking. This article aimed to collect evidence on the risk of recurrent VTE in patients with autoimmune diseases. The authors searched PubMed/Embase for studies including patients with VTE and autoimmune diseases as an exposure or studies including patients with autoimmune diseases in which recurrent VTE was one of the outcomes. Eleven articles were selected from 4,739 unique abstracts. Of the 11 studies, 3 reported time-dependent rates. Two studies collected rates of recurrence in Behcet's disease, reporting a 5-year recurrence risk between 35 and 40%. However, the 5-year recurrence risk was lower than 10% in patients treated with immunosuppressant medication, while two studies suggested frequent recurrence in patients on only anticoagulant therapy. The other study reporting time-dependent incidence concerned patients with inflammatory bowel disease and index VTE. The 5-year risk of recurrent VTE was 33.4%, yielding a hazard ratio of 1.7 versus controls. All studies were retrospective and therefore risk may overestimate recurrence risk in comparison with known prospective cohort studies. There are insufficient data to make confident recommendations about the management of recurrent VTE prevention in patients with autoimmune diseases in general. The overall VTE risk profile, lower effectiveness of anticoagulants, and the observation that immunosuppression lowered risk of recurrence in patients with Behcet's disease seem to warrant immunosuppressant therapy over anticoagulation as a first consideration when preventing VTE recurrence in these patients.

Antibiotic use as a marker of acute infection and risk of first and recurrent venous thrombosis.

A role for transient infections in the aetiology of venous thrombosis (VT) has been suggested. This study aimed to determine whether individuals who receive antibiotic treatment (as a proxy for infections) have an increased risk of first and recurrent VT and whether infections should be seen as a provoking risk factor for VT. We used the self-controlled case series method to study the risk of first VT during antibiotic prescriptions. The risk of recurrent VT during antibiotic use was estimated by of time-dependent Cox-regression. A total of 2547 patients with a first VT were included and followed for a median of 5·9 years for recurrence (1999-2010), in whom 114 first events occurred during antibiotic use. We found a five-fold increased risk of first VT during antibiotic treatment: [incidence-rate-ratio 5·0; 95% confidence interval (CI), 4·0-6·1]. Antibiotic use was associated with a 2·0-fold (95% CI, 1·1-4·0) increased risk of recurrent VT. Patients with an unprovoked first VT who used antibiotics shortly before this event, had a similar risk of recurrence as patients with a provoked first VT (adjusted hazard ratio 1·1; 95% CI, 0·7-1·7). Individuals who receive antibiotics have an increased risk of first and recurrent VT and infections should be considered a provoking risk factor for VT.

A Retrospective Comparison of Ultrasound-Assisted Catheter-Directed Thrombolysis and Catheter-Directed Thrombolysis Alone for Treatment of Proximal Deep Vein Thrombosis.

BACKGROUND: Recent studies have suggested that catheter-directed thrombolysis (CDT) reduces development of post-thrombotic syndrome (PTS). Ultrasound-assisted CDT (USCDT) might enhance the efficiency of thrombolysis. We aimed to compare USCDT with CDT on efficacy, safety, development of PTS, and quality of life after long-term follow-up. METHODS: We describe a retrospective case series of 94 consecutive patients admitted with iliofemoral or more proximal deep vein thrombosis (DVT) to the University Hospital from 2002 to 2011, treated either with CDT or USCDT. Scheduled follow-up visits took place between April 2013 and January 2014. Venography measured the degree of residual luminal obstruction of the affected veins. Each patient completed the Short Form 36-item health survey assessment and the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms questionnaires. PTS was assessed using the Villalta scale. RESULTS: Risk factors of DVT were equally distributed between groups. In the USCDT group, we observed a significant decline in the duration of thrombolytic treatment (<48 h: 27 vs. 10 %), shortened hospital stay (median 6.0 days (IQR 5.0-9.0) vs. 8.0 (IQR 5.8-12.0)), and less implantation of (intravenous) stents (30 vs. 55 %). There was no difference in patency (76 vs. 79 % fully patent), prevalence of PTS (52 vs. 55 %), or quality of life between groups after long-term follow-up (median 65 months, range: 15-141). CONCLUSIONS: In this observational study, USCDT was associated with shortened treatment duration, shorter hospital stay, and less intravenous stenting, compared to CDT alone without affecting the long-term prevalence of PTS or quality of life.

The acute phase reaction explains only a part of initially elevated factor VIII:C levels: a prospective cohort study in patients with venous thrombosis.

We determined in a prospective cohort of patients treated with vitamin K antagonists for venous thrombosis, the course of factor VIII (FVIII:C), C-reactive protein (CRP) and fibrinogen levels, to assess the influence of the acute phase reaction on FVIII:C levels. Second, we hypothesized that patients with preceding infectious symptoms might have higher levels of FVIII:C at baseline than patients without those. We included 75 patients. Blood was sampled at baseline, once during treatment (t=1) and at the end of treatment (t=2). Mean levels of FVIII:C were 207, 186 and 175IU/dL (p for trend 0.003) at baseline, t=1 and t=2 respectively. Eight-eight percent of patients had an elevated FVIII:C at baseline, 75% at t=1 and 72% at t=2 (p for trend 0.045). Mean levels of FVIII:C were not different in patients with or without preceding infectious symptoms (206 versus 205IU/dL respectively). A baseline CRP level below 62mg/L could best distinguish between patients who will keep an elevated FVIII:C and those who will drop below 150IU/dL. We conclude that FVIII:C levels are partially influenced by the acute phase reaction, especially in patients who keep a persistent elevated FVIII:C during treatment. Preceding infectious symptoms did not influence baseline FVIII:C levels.

FDG hepatic superscan caused by massive breast cancer invasion.

A 46-year-old woman who was treated in the past for locally advanced breast cancer, presented with signs of acute liver failure. FDG PET revealed a massive hot liver with increased activity without any pathologic FDG uptake elsewhere in the body. Therefore, the term hepatic superscan was chosen because intense diffuse hepatic FDG uptake was seen in combination with a surprisingly low cardiac and in minor degree of low brain uptake, similar to the superscan pattern encountered in conventional skeletal scintigraphy. This very unusual finding was the indicator of extensive hepatic involvement caused by breast cancer.