Treatment patterns of venous thromboembolism in a real-world population: The Q-VTE study cohort

Background

Few studies have assessed treatment patterns of acute venous thromboembolism (VTE) in a real-world population. We aimed to describe anticoagulant treatment patterns for acute VTE using healthcare databases of Québec, Canada.

Methods

We used linked healthcare databases of the province of Québec, Canada to identify all incident cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) between 2000 and 2009. We formed two patient cohorts, one with definite cases (definite VTE cohort, N = 40,776) and the other including cases with definite or probable VTE (any VTE cohort, N = 54,803) that were followed until death, end of health coverage, or end of study (December 31, 2009).

Results

In the definite cohort, 73.6% of subjects were dispensed an anticoagulant following the diagnosis of VTE. Of those who were dispensed a vitamin K antagonist (VKA), median duration of use was 61 days (interquartile range 89). VKA initiation was more likely in patients with pulmonary embolism than deep vein thrombosis alone (HR 1.62, 95% CI (1.58-1.66)). Among outpatients, those managed initially in the outpatient setting were less likely to initiate VKA therapy (HR 0.75, 95% CI (0.68-0.77)), while those requiring admission to hospital for VTE management were more likely to initiate (HR 1.81, 95% CI (1.76-1.87)). Findings were similar in the any VTE cohort.

Conclusion

Our study describes VTE treatment patterns in a real-world setting and suggests that there may be important gaps. These may include significant numbers of patients who did not initiate oral anticoagulant therapy, particularly in the outpatient setting, and shorter duration of oral anticoagulant use than recommended.     

Population-based epidemiology of postoperative venous thromboembolism in Taiwanese patients receiving hip or knee arthroplasty without pharmacological thromboprophylaxis

Introduction

Population-based evaluation on the incidence of postoperative venous thromboembolism (VTE) has not yet been reported for Asians receiving arthroplasty. In Taiwan, thromboprophylaxis was not commonly applied for patients. The population-based cohort study aimed to investigate the epidemiology, and to determine the risk factors VTE for patients receiving hip or knee replacement without pharmacological thromboprophylaxis in Taiwan.

Materials and Methods

We retrospectively acquired patients’ data from National Health Insurance databases representing more than 99% of about 23 million Taiwanese citizens. The primary outcome was the incidence of composite symptomatic VTE within 28 days after receiving hip or knee replacement surgery.

Results

During 2002 to 2006, there were 114,026 patients undergoing hip (n = 61,460) or knee (n = 52,566) replacement surgery. The occurrence rate of overall postoperative VTE was 0.44%. The incidence of pulmonary embolism was four in 10,000 patients receiving hip replacement or seven in 10,000 individuals undergoing knee replacement. The weekly cumulative incidence of VTE was persistently rising up to 28 days after surgery. Dramatic increase in risk of post-surgical VTE was associated with prior disease history of PE (p < 0.001 for hip replacement, p = 0.01 for knee replacement) or DVT (p = 0.004 for hip replacement, p < 0.001 for knee replacement). Prior claim of congestive heart failure was an independent risk factor associated with patients receiving knee arthroplasty (p = 0.01).

Conclusion

Life-threatening PE occurred and increased cumulatively up to 28 days after hip or knee arthroplasty in Asians. Proper prophylaxis for patients with the exposure of high risks needs to be scrutinized.     

Incidence and risk factors associated with in-hospital venous thromboembolism after aneurysmal subarachnoid hemorrhage

Our purpose was to determine the incidence and risk factors associated with in-hospital venous thromboembolism (VTE) in patients with aneurysmal subarachnoid hemorrhage (aSAH). The Nationwide Inpatient Sample database was queried from 2002 to 2010 for hospital admissions for subarachnoid hemorrhage or intracerebral hemorrhage and either aneurysm clipping or coiling. Exclusion criteria were age <18, arteriovenous malformation/fistula diagnosis or repair, or radiosurgery. Primary outcome was VTE (deep vein thrombosis [DVT] or pulmonary embolus [PE]). Multivariate logistic regression was used to assess association between risk factors and VTE. Secondary outcomes were in-hospital mortality, discharge disposition, length of stay and hospital charges. A total of 15,968 hospital admissions were included. Overall rates of VTE (DVT or PE), DVT, and PE were 4.4%, 3.5%, and 1.2%, respectively. On multivariate analysis, the following factors were associated with increased VTE risk: increasing age, black race, male sex, teaching hospital, congestive heart failure, coagulopathy, neurologic disorders, paralysis, fluid and electrolyte disorders, obesity, and weight loss. Patients that underwent clipping versus coiling had similar VTE rates. VTE was associated with pulmonary/cardiac complication (odds ratio [OR] 2.8), infectious complication (OR 2.8), ventriculostomy (OR 1.8), and vasospasm (OR 1.3). Patients with VTE experienced increased non-routine discharge (OR 3.3), and had nearly double the mean length of stay (p < 0.001) and total inflation-adjusted hospital charges (p < 0.001). To our knowledge, this is the largest study evaluating the incidence and risk factors associated with the development of VTE after aSAH. The presence of one or more of these factors may necessitate more aggressive VTE prophylaxis.     

Elevated risk of venous thromboembolism among post-traumatic brain injury patients requiring pharmaceutical immobilization

Traumatic brain injury (TBI) patients are known to have a high rate of venous thromboembolism (VTE), and additional neuromuscular blockade or barbiturate coma therapy has the theoretical risk of exacerbating baseline hemostasis and elevating the incidence of thromboembolic events. We conducted a single-institution retrospective review of patients surviving severe TBI, as determined by need for intracranial pressure (ICP) monitoring, who further required paralytics or barbiturate therapy to maintain ICP control. Patients were administered VTE prophylaxis as clinically appropriate. Predictors for VTE were subsequently determined with univariate and logistic multivariate regression analyses. The main cohort includes 144 patients, 34 of whom received pharmaceutical immobilization for ICP control. Mean ISS and GCS at intake were 31.9 and 5.2, respectively. Among those receiving vs not-receiving paralytics and/or barbiturate therapy, there was a statistical difference of 12/34 (35.3%) vs 18/110 (16.4%, p = 0.0280) in VTE events, at a mean time greater than two weeks from the time of trauma. Multivariate logistics regression indicated 3.2 times increased odds of developing a VTE (log odds = 1.17, p = 0.023). No pediatric patients were positive for an event (0/12 vs 7/22, p = 0.0356), and infections were only documented among those with VTE (0/22 vs 4/12, p = 0.0107). Overall, paralytics and barbiturate therapy were correlated with a higher incidence of VTE among TBI patients. Although the need for ICP control will outweigh an increase in thromboembolic risk, there is value for increased surveillance and screening during the prolonged inpatient stay of these patients.     

Factors associated with the timing of diagnosis of venous thromboembolism: results from the MASTER registry

INTRODUCTION: Signs and symptoms of venous thromboembolism (VTE) are non-specific and thus can make diagnosis difficult, even for an experienced clinician. We aimed to evaluate the timing of diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in Italian hospitals and to identify individual and clinical predictors of timely or delayed diagnosis. MATERIAL AND METHODS: MASTER is a multicenter prospective registry of patients with acute DVT and PE. Information on clinical presentation and diagnostic methods, temporary and permanent risk factors, were captured by an electronic data network at the time of the index event. RESULTS: Data on 2047 patients (1024 males), 1505 with DVT and 542 with PE, were analysed. Delayed diagnosis (i.e. more than 10 days from onset of symptoms) was observed in 340 (22.6%) patients with DVT and in 88 (16.2%) with PE, respectively. In DVT patients, factors associated with earlier diagnosis were the presence of multiple signs or symptoms (p=0.014), the presence of pain (p=0.049), and previous venous thrombosis (p=0.016). Neither the presence of other known risk factors nor ongoing prophylaxis influenced the timing of diagnosis. In PE patients, only multiple signs or symptoms at presentation (p=0.014) and the presence of transient risk factors (p=0.001) were significantly associated with earlier diagnosis. CONCLUSIONS: Substantial delays occur when diagnosing both DVT and PE. The severity of presentation, but not patient risk profile are associated with earlier diagnosis, even in patients with signs or symptoms of PE.     

神经外科领域的静脉血栓栓塞症

肺栓塞症(PTE)和深部静脉血栓症(DVT)近年来有增高的倾向,其原因尚不明确。在美国发病率为270～400人/100万人。一般认为东方人本病发病率较低,被认为是一种比较少见的疾病,但近10年其发病增加了约3倍。所以,对PTE及DVT作为重症合并症不断增加的倾向要给予足够的认识。我们报道10例临床病例,对神经外科领域的PTE及DVT的特征进行探讨。     

Exclusion of venous thromboembolism: evaluation of D-Dimer PLUS for the quantitative determination of D-dimer

The objective of this study was to evaluate if D-Dimer PLUS (Dade Behring, USA), a rapid fully automated assay, could be used as an initial screening test in the diagnosis of venous thromboembolism (VTE). Samples from 274 consecutive symptomatic patients with suspected pulmonary embolism (n=229; 79% outpatients, 21% inpatients), deep venous thrombosis (n=37; 84% outpatients, 16% inpatients) or suspected for both complications (n=8) were tested with this D-dimer assay with a Sysmex CA-1500 Coagulation Analyzer. Clinical probability for pulmonary embolism (PE) or deep venous thrombosis (DVT) was staged according to a pretest risk score proposed by Wells. Final diagnosis of PE and/or DVT was established by spiral-computed tomography of the pulmonary arteries or compression ultrasonography, respectively. PE was diagnosed in 13.5% of the patients, whereas DVT was confirmed in 17.7% of the patients. The optimal cut-off value for exclusion of venous thromboembolism was 130 mug/l, and sensitivity, specificity and negative predictive value (NPV) were 95.0% (95% CI: 92.4-97.6), 30.4% (95% CI: 25.0-35.8) and 97.2% (95% CI: 95.2-99.2), respectively. In fact, two patient with PE were missed using D-Dimer PLUS; both cases were outpatients. In conclusion, this assay appears to be safe when implemented in an algorithm based on clinical assessment, D-dimer concentration, and radiological diagnostic techniques to stratify the risk for PE or DVT. However, higher sensitivities and negative predictive values were claimed in the scarce published reports for the D-Dimer PLUS assay than found in this study.     

A case-cohort study with propensity score matching to evaluate the effects of mannitol on venous thromboembolism

Mannitol has been shown to damage endothelial cells and activate coagulation pathways leading to intravascular thrombosis. Dehydration and hemagglutination have also been associated with mannitol use, although the risk of clinically evident venous thromboembolism (VTE) disease is not well-defined. The aim of this study was to compare the risk of VTE in critically ill neurological patients who received mannitol compared to only hypertonic saline. A case-cohort study design with propensity score matching was used to evaluate the risk of VTE among patients who received mannitol compared to those who received hypertonic saline alone. The odds of thrombosis were evaluated by the Cochran-Mantel-Haenszel method and conditional logistic regression was used to adjust for year of treatment. Ninety-one of 330 patients (27.6%; 95% confidence interval [CI] 23–33%) developed a VTE; however, the yearly proportion remained unchanged over the 8 year study period. Cumulative use of mannitol declined and use of hypertonic saline increased significantly. The odds of thrombosis for those exposed to mannitol compared to hypertonic saline alone was 1.11 (95% CI 0.65–1.73; p = 0.75). This remained insignificant after adjusting for year of injury. In conclusion, despite a significant change in the pattern of osmotic therapy used at our institution, the proportion of patients with VTE remained unchanged. We found no evidence that mannitol use was associated with VTE compared to hypertonic saline alone.     

Risk of venous thromboembolism during treatment with antipsychotic agents

The evidence to date on the relation between the risk of venous thromboembolic disease (VTE) and antipsychotic agents derives primarily from observational and case history studies. While an increased risk of VTE has been associated with first‐generation low‐potency antipsychotic agents, particularly clozapine, there appears to be a growing number of reports on the occurrence of this adverse reaction during the use of second‐generation antipsychotics, such as risperidone and olanzapine. The highest risk of pathological blood clotting emerges during the first 3 months after initiation of treatment with the product. Potential etiopathogenetic factors leading to VTE during treatment with antipsychotic agents include sedation, obesity, elevation of antiphospholipid antibodies, increased platelet activation and aggregation, hyperhomocysteinemia, and hyperprolactinemia. Diagnoses of schizophrenia and/or bipolar affective disorder, as well as hospitalization or stress with sympathetic activation and elevation of catecholamine levels, have been reported as known prothrombogenic factors. The present article contains the new version of the guideline for the prevention of VTE in psychiatric patients with limited mobility. Further prospective studies are necessary to elucidate the biological mechanisms of the relations between antipsychotic agents and VTE.     

神经外科术后静脉栓塞症发病率及早期诊断

目的对神经外科术后患者静脉栓塞症（深静脉血栓和肺栓塞）发病率及早期诊断进行前瞻性研究。方法37例神经外科术后患者均按照静脉血栓预防指南进行了弹力袜和（或）四肢间隙气动压迫的预防性治疗。在术后平均12d进行血管彩色超声检查,并通过增强CT扫描明确诊断。结果本组研究中下肢深静脉血栓发生率为13．5％,在发生深静脉血栓患者中肺栓塞发生率为60％,所有静脉血栓患者在临床上均没有症状。结论在神经外科术后患者中静脉血栓症的发病率很高,在采用了预防措施后部分患者依然不能避免,早期预防和早期发现对于减少神经外科术后静脉栓塞症非常重要。     

Variation in prophylactic anticoagulation for venous thromboembolism among acute stroke patients

Asians were known to have relatively lower incidence of deep vein thrombosis (DVT) compared with Caucasians. We aimed to evaluate rates of prophylactic anticoagulation among Korean acute stroke patients who are at high-risk for developing DVT. Of 1295 patients with acute ischemic stroke who were at high-risk for developing DVT, anticoagulation was used in only 21 patients (1.6%; 95% Confidence Interval, 0.9–2.3) during admission. The use of anticoagulation did not differ in relation to age, stroke severity, leg motor weakness, or functional outcomes at discharge. Prophylactic anticoagulation was rarely used in Korean stroke patients who were at high-risk for developing DVT.     

Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study

Introduction

Because the risk of venous thromboembolism (VTE) associated with progestin is uncertain, we tested oral contraceptives, estrogen and progestin as independent VTE risk factors.

Materials and Methods

Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN women with objectively-diagnosed incident VTE over the 13-year period, 1988-2000 (n = 726) and one to two Olmsted County women per case matched on age, event year and duration of prior medical history (n = 830), and reviewed their complete medical history in the community for previously-identified VTE risk factors (i.e., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, varicose veins and pregnancy/postpartum), and oral contraceptive, oral estrogen, and oral or injectable progestin exposure. Using conditional logistic regression we tested these hormone exposures as VTE risk factors, both unadjusted and after adjusting for previously-identified VTE risk factors.

Results

In unadjusted models, oral contraceptives, progestin alone, and estrogen plus progestin were significantly associated with VTE. Individually adjusting for body mass index (BMI) and previously-identified VTE risk factors, these effects remained essentially unchanged except that progestin alone was not associated with VTE after adjusting for active cancer. Considering only case-control pairs without active cancer, progestin alone was positively but non-significantly associated with VTE (OR = 2.49; p = 0.16). Adjusting for BMI and previously-identified VTE risk factors including active cancer, oral contraceptives, estrogen alone, and progestin with or without estrogen were significantly associated with VTE.

Conclusions

Oral contraceptives, estrogen alone, estrogen plus progestin, and progestin with or without estrogen are independent VTE risk factors.     

Seasonal variation in the occurrence of venous thromboembolism: A report from the Korean Venous Thromboembolism Working Party

There have been conflicting results on seasonal variation in the occurrence of venous thromboembolism (VTE). It also has never been studied in Asian population. To address these issues, we investigated seasonal changes of the incidence of VTE in Korean population using 1,495 patients with VTE between January 2001 and December 2010. VTE occurred most frequently in the winter and least frequently in the summer (χ2 = 11.83, P = 0.008). In the subset analyses, the same trend was shown in the PE ± DVT group, the unprovoked VTE group, and the VTE without malignancy group. The monthly occurrence rate peaked in December and was at its lowest in July (P = 0.004). In conclusion, our study provides evidence that there is an increased risk for VTE in Korean population in the winter season.     

The utility of routine head CT for hemorrhage surveillance in post-craniotomy patients undergoing anticoagulation for venous thromboembolism

Anticoagulation for postoperative venous thromboembolism (VTE) may infer a higher risk of intracranial hemorrhage. We treat patients with VTE using slowly titrating intravenous heparin drip without bolus. When PTT is greater than 60 s, a head CT is obtained to monitor for the development of a intracranial hemorrhage before transition to oral anticoagulation. We evaluated the utility of routine surveillance head CT to monitor for intracranial hemorrhage during anticoagulation. This is a case series of neurosurgical patients in an academic quaternary hospital who developed a VTE after cranial procedures between 2007 and 2017. Over 11,000 patients were screened for the study. Patients’ demographics data, surgical indication, PTT at the time of surveillance CT head, surveillance CT head findings, and patient’s clinical course were reviewed. A total of 83 patients were included. Three patients (3.6%) developed a new subclinical hemorrhage on CT head imaging while on heparin drip. Interval CT head showed stable hemorrhage in all patients. Heparin drip was stopped in two patients and they both progressed from DVT to pulmonary embolism: one patient died due to cardiac arrest, the other patient was transitioned to oral anticoagulation. In the third patient heparin drip was continued uneventfully and transitioned to oral anticoagulation with no further clinical sequalae. Surveillance CT while on heparin drip for VTE management detected subclinical intracranial hemorrhage in a small subset of patients. Patients whose anticoagulation was stopped had progression of VTE. Undertreatment of VTE in the presence of subclinical hemorrhage may lead to significant morbidity and mortality.     

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of venous thromboembolism in Chinese population

Introduction

Endothelium derived nitric oxide (NO) is a key mediator of vascular homeostasis. Endothelial nitric oxide synthase (eNOS) gene, by affecting the expression and functional activity of the eNOS enzyme, thereby reducing NO availability, may be implicated in venous thromboembolism (VTE). We investigated the eNOS G894T polymorphism in VTE patients in the Chinese population.

Materials and methods

A case-control study was conducted in a general hospital. Blood samples, collected from 462 consecutive patients with VTE and 462 healthy controls, were used for DNA extraction. Single nucleotide polymorphisms (SNP) of eNOS (894 G/T) were determined by allele specific-polymerase chain reaction (ARMS-PCR) analysis.

Results

The eNOS 894 G/T polymorphism alleles distribution was in agreement with the principle of Hardy-Weinberg equilibrium. The prevalence of homozygote, heterozygote and pathological homozygote for the eNOS G894T polymorphism in VTE patients was 79.7%, 18.1% and 2.2%, respectively (controls: 86.6%,12.3% and 1.1%). T allele distribution in the VTE (11.3%) and especially the male VTE patients (12.5%) was more common than in healthy controls (7.3%). The frequency of GT + TT genotype was significantly higher among the age ≤ 55 years patients in VTE group than in controls (20.1% vs. 12.2%, P = 0.033).

Conclusion

Our result demonstrates that the 894 G/T polymorphism variant of eNOS is a risk factor for VTE in Chinese population.     

Risk factors for hospital-sssociated venous thromboembolism in the neonatal intensive care unit

Objective

To determine hospital-associated venous thromboembolism (HA-VTE) risk factors in critically ill neonates.

Methods

We conducted a case-control study in the neonatal intensive care unit (NICU) of All Children’s Hospital Johns Hopkins Medicine (St. Petersburg, FL), from January 1, 2006 - April 10, 2013. We identified HA-VTE cases using electronic health record. Four NICU controls were randomly selected for each HA-VTE case. Associations between putative risk factors and HA-VTE were estimated using odds ratios (ORs) and ninety-five percent confidence intervals (95%CIs) from univariate and multivariate regression analyses.

Results

Twenty-three HA-VTE cases and 92 controls were included. The annual HA-VTE incidence was approximately 1.4 HA-VTE cases per 1,000 NICU admissions. In univariate analyses, mechanical ventilation (OR = 7.27, 95%CI = 2.02-26.17, P = 0.002), central venous catheter (CVC; OR = 52.95, 95%CI = 6.80-412.71, P < 0.001), infection (OR = 7.24, 95%CI = 2.66-19.72, P < 0.001), major surgery (OR = 5.60, 95%CI = 1.82-17.22, P = 0.003) and length of stay ≥ 15 days (OR = 6.67, 95%CI = 1.85-23.99, P = 0.004) were associated with HA-VTE. Only CVC (OR = 29.04, 95%CI = 3.18-265.26, P = 0.003) remained an independent risk factor in the multivariate analysis. Based on this result, the estimated risk of HA-VTE in NICU patients with a CVC was 0.9%.

Conclusion

This study identifies CVC as an independent risk factor for HA-VTE in critically ill neonates. However, the level of risk associated with CVC is below the conventional threshold for primary anticoagulation thromboprophylaxis. Larger studies are needed to substantiate these findings and identify novel putative risk factors to further distinguish NICU patients at highest HA-VTE risk.     

Prophylaxis of venous thromboembolism in physically restrained psychiatric patients

Objective: We analysed the rate of physical restraint in acute and chronic psychiatric patients and looked at the safety of waiving venous thromboembolic disease (VTE) prophylaxis in the case of restraining of less than 24?h.

Methods: We did a retrospective analysis of all episodes of restraining in 2012 and 2013, diagnosis of restrained patients, time of restraining and use of low molecular weight heparin (LMWH) for prophylaxis of VTE associated with restraining.

Results: Overall, 12 734 patients were hospitalised. The number of episodes of restraining was 1035 and involved 469 (7.4%) patients. Only 79 episodes of restraining lasted more than 24?h and affected only 36 (0.3%) individual patients. The most frequent psychiatric diagnoses were unstable borderline personality in 41 (52%) and schizophrenic or schizoaffective psychosis in 26 (33%) episodes. None of these prolonged restraints and none of the 956 episodes of restraining for less than 24?h were associated with clinical symptoms or signs of VTE that would have required additional diagnostic consequences.

Conclusion: The concept of waiving VTE prophylaxis within the first 24?h of restraining seems to be safe. On the other hand, LMWH sufficiently protected the small sample being restrained for more than 24?h.     

Increased venous versus arterial thrombosis in the Factor V Leiden mouse

BACKGROUND: Deep vein thrombosis (DVT) occurs with high prevalence in association with the Factor V Leiden (R506Q) mutation, whereas most evidence suggests no correlation with clinical arterial thrombosis. OBJECTIVE: This study compared arterial to venous thrombosis in the mutationally analogous Factor V Leiden mouse. METHODS: Three separate vascular thrombosis models were evaluated in Fv(+/+) (wild-type), Fv(Q/+) (heterozygous) and Fv(Q/Q) (homozygous) Factor V Leiden mice. RESULTS: In a FeCl(3)-induced arterial thrombosis model, no statistical differences among the three genotypes were found in the time to thrombotic occlusion. In contrast, Fv(Q/+) and Fv(Q/Q) mice demonstrated larger femoral vein thrombi at 30 and 60 min compared to wild-types, with Fv(Q/Q) mice having statistically larger thrombi than both wild-type and Fv(Q/+) mice at 10 and 60 min and 24 h (p<0.05). In a model of thrombotic occlusion following arterial and venous anastomotic repair, both Fv(Q/+) and Fv(Q/Q) mice had higher rates of venous thrombosis than wild-types, but only Fv(Q/Q) homozygotes showed a statistically greater arterial occlusion rate than wild-types. CONCLUSION: The Factor V Leiden mouse demonstrated a greater propensity for venous vs. arterial thrombosis, paralleling clinical epidemiologic findings and supporting its use for research on deep vein thrombosis.