Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism.

The impact of residual pulmonary obstruction on the outcome of patients with pulmonary embolism is uncertain.We recruited 647 consecutive symptomatic patients with a first episode of pulmonary embolism, with or without concomitant deep venous thrombosis. They received conventional anticoagulation, were assessed for residual pulmonary obstruction through perfusion lung scanning after 6 months and then were followed up for up to 3 years. Recurrent venous thromboembolism and chronic thromboembolic pulmonary hypertension were assessed according to widely accepted criteria.Residual pulmonary obstruction was detected in 324 patients (50.1%, 95% CI 46.2-54.0%). Patients with residual pulmonary obstruction were more likely to be older and to have an unprovoked episode. After a 3-year follow-up, recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension developed in 34 out of the 324 patients (10.5%) with residual pulmonary obstruction and in 15 out of the 323 patients (4.6%) without residual pulmonary obstruction, leading to an adjusted hazard ratio of 2.26 (95% CI 1.23-4.16).Residual pulmonary obstruction, as detected with perfusion lung scanning at 6 months after a first episode of pulmonary embolism, is an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension.

The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation.

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial.

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

Low CD34(+) cells, high neutrophils and the metabolic syndrome are associated with an increased risk of venous thromboembolism.

The relationship between MetS (metabolic syndrome), levels of circulating progenitor/immune cells and the risk of VTE (venous thromboembolism) has not yet been investigated. We studied 240 patients with previous VTE and 240 controls. The presence of MetS was identified according to NCEP ATP III guidelines and flow cytometry was used to quantify circulating CD34(+) cells. VTE patients showed higher BMI (body mass index), waist circumference, triacylglycerol (triglyceride) levels, blood glucose, hs-CRP (high-sensitivity C-reactive protein) and lower HDL-C (high-density lipoprotein cholesterol) levels. The prevalence of MetS was significantly higher in VTE (38.3%) than in control individuals (21.3%) with an adjusted OR (odds ratio) for VTE of 1.96 (P=0.002). VTE patients had higher circulating neutrophils (P<0.0001), while the CD34(+) cell count was significantly lower among patients with unprovoked VTE compared with both provoked VTE (P=0.004) and controls (P=0.003). Subjects were also grouped according to the presence/absence of MetS (MetS(+) or MetS(-)) and the level (high/low) of both CD34(+) cells and neutrophils. Very high adjusted ORs for VTE were observed among neutrophils_high/MetS(+) (OR, 3.58; P<0.0001) and CD34(+)_low/MetS(+) (OR, 3.98; P<0.0001) subjects as compared with the neutrophils_low/MetS(-) and CD34(+)_high/MetS(-) groups respectively. In conclusion, low CD34(+) blood cell count and high circulating neutrophils interplay with MetS in raising the risk for venous thromboembolic events.

Thromboembolic Complications in COVID-19 Patients Hospitalized in Italian Ordinary Wards: Data from the Multicenter Observational START-COVID Register.

Background Coronavirus disease 2019 (COVID-19) infection causes acute respiratory insufficiency with severe interstitial pneumonia and extrapulmonary complications; in particular, it may predispose to thromboembolic disease. The reported incidence of thromboembolic complications varies from 5 to 30% of cases. Aim We conducted a multicenter, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe the clinical characteristics of patients at admission and bleeding and thrombotic events occurring during the hospital stay. Results The number of hospitalized patients included in the START-COVID-19 Register was 1,135, and the number of hospitalized patients in ordinary wards included in the study was 1,091, with 653 (59.9%) being males and 71 years (interquartile range 59-82 years) being the median age. During the observation, two (0.2%) patients had acute coronary syndrome episodes and one patient (0.1%) had an ischemic stroke; no other arterial thrombotic events were recorded. Fifty-nine patients had symptomatic venous thromboembolism (VTE) (5.4%) events, 18 (30.5%) deep vein thrombosis (DVT), 39 (66.1%) pulmonary embolism (PE), and 2 (3.4%) DVT+PE. Among patients with DVT, eight (44.4%) were isolated distal DVT and two cases were jugular thrombosis. Among patients with PE, seven (17.9%) events were limited to subsegmental arteries. No fatal PE was recorded. Major bleeding events occurred in nine (1.2%) patients and clinically relevant nonmajor bleeding events in nine (1.2%) patients. All bleeding events occurred among patients receiving thromboprophylaxis, more frequently when treated with subtherapeutic or therapeutic dosages. Conclusion Our findings confirm that patients admitted to ordinary wards for COVID-19 infection are at high risk for thromboembolic events. VTE recorded among these patients is mainly isolated PE, suggesting a peculiar characteristic of VTE in these patients.

Serum uric acid levels and the risk of recurrent venous thromboembolism.

Essentials Increase in serum uric acid (SUA) levels has been widely associated with higher risk of cardiovascular disease. We investigated the link between SUA levels and the risk of venous thromboembolism (VTE) recurrence. Patients with SUA levels ≥ 4.38 mg/dL showed a three-fold increase in the risk of VTE recurrence. Elevated SUA levels are associated with increased risk of recurrent VTE independently from traditional risk factors. ABSTRACT: Background The link between serum uric acid (SUA) and the risk of cardiovascular disease is well established. However, the impact of SUA levels on the risk of venous thromboembolism (VTE) recurrence is unknown. Objectives To investigate the association between SUA and the risk of VTE recurrence. Patients and Methods We performed a monocenter, prospective study on 280 patients with a previous episode of VTE that completed the oral anticoagulant period. SUA levels at enrollment were correlated with the risk of VTE recurrence (mean follow-up 71.1 ± 29.2 months). Results Patients were stratified according to SUA tertiles distribution at baseline (tertiles cut-off: I ≤ 4.37 mg/dL, II 4.38--5.54 mg/dL, III ≥ 5.55 mg/dL). Fifty episodes of VTE recurrence occurred during the follow-up and Kaplan-Meier survival analysis showed that subjects in the lower tertile of SUA distribution had significantly lower risk of future VTE recurrence (P = .003). No differences were seen among patients belonging to the second and the third tertile of SUA distribution. A multivariate Cox regression analysis showed that higher tertiles of SUA distribution had about three-fold increase in the risk of VTE recurrence as compared to subjects with SUA ≤ 4.37, independently from potential confounders (hazard ratio [HR] 3.04, 95% confidence interval [CI] 1.15--8.05 P = .025). Moreover, we observed that the adjusted hazard of VTE recurrence increased by 30% for each additional unit of SUA (mg/dL; HR 1.30, 95% CI 1.01--1.22, P = .040). Conclusion Elevated SUA levels are associated with increased risk of future VTE recurrence independently from traditional risk factors.

MAC Project-Monitoring Anticoagulant Therapy Observational Study: Rationale and Protocol.

Real-life studies complement data from registrative trials. Because of the delayed registration of direct oral anticoagulants in Italy, scarce real-life data on such treatments is available for the Italian population. The aim of the MAC project is to collect real-life clinical information in unselected patients given oral anticoagulants for venous thromboembolism, during a 5-year follow-up period. This is a prospective-cohort, multi-center, observational study performed in four Italian centers. The estimated samples size is 4,000 patients. The efficacy outcomes are: incidence of symptomatic recurrent venous thromboembolism and of post-thrombotic syndrome. The safety outcomes are: incidence of major bleeding, clinically relevant non-major bleeding, minor bleeding, serious adverse events, and mortality. The MAC project has the potential to improve our understanding of the epidemiology and of the therapeutic strategies adopted in Italian patients with venous thromboembolism. Clinical Trial Registration: WWW.ClinicalTrials.Gov, identifier: NCT0432939.

Individually shortened duration versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome: a cost-effectiveness analysis.

BACKGROUND: The IDEAL DVT study showed that it was safe to shorten the duration of elastic compression therapy on an individualised basis after deep vein thrombosis for prevention of post-thrombotic syndrome. In this study, we assessed the cost-effectiveness of this strategy. METHODS: IDEAL DVT was a multicentre, randomised, non-inferiority trial that included patients with acute proximal deep vein thrombosis of the leg. After 6 months of elastic compression therapy, patients were randomly assigned (1:1) to the standard 2 years of elastic stocking compression therapy or shortened duration of compression therapy based on the patient's Villalta score. For our cost-effectiveness analysis, we assessed quality-adjusted life-years (QALYs), measured with the three-level version of EQ-5D (EQ-5D-3L; Dutch and UK tariff) and the 36-item Short Form Health Survey (SF-36), and costs in € (health-care and societal perspective) according to the intention-to-treat approach. Data were collected at 3, 6, 12, and 24 months after diagnosis of thrombosis. We calculated incremental net monetary benefit using a QALY threshold of €30 000, and obtained bootstrapped means and 95% CIs. IDEAL DVT is registered with ClinicalTrials.gov, number NCT01429714. FINDINGS: Between March 22, 2011, and July 1, 2015, 865 patients were enrolled in IDEAL DVT. 437 were assigned to individualised duration of elastic compression therapy and 428 to standard duration of elastic compression therapy. Nine patients were eventually excluded because of recurrent venous thromboembolism within 6 months after the first event. From a societal perspective, for every QALY lost measured with the EQ-5D Dutch tariff, cost savings were €305·992 (incremental net monetary benefit €3205, 95% CI 502-5741), and for every QALY lost based on the Short-Form Six-Dimension (SF-6D) utility score (derived from SF-36), cost savings were €6030·941 (€3540, 95% CI 1174-5953). Using the UK tariff for EQ-5D, the individualised strategy was more effective and less costly (€4071, 1452-6647). The probability that the individualised strategy was cost-effective was 99% at a threshold of €30 000 per QALY (EQ-5D Dutch tariff). INTERPRETATION: Individually shortened duration of elastic compression therapy was cost-effective compared with standard duration elastic compression therapy. Use of an individualised approach to elastic stocking compression therapy for the prevention of post-thrombotic syndrome after deep vein thrombosis could lead to substantial costs savings without loss in health-related quality of life. FUNDING: Netherlands Organisation for Health Research and Development.

Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial.

BACKGROUND: Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. METHODS: We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score

Chronic kidney disease is associated with increased risk of venous thromboembolism recurrence.

INTRODUCTION: It is currently unclear whether chronic kidney disease (CKD) and the decrease in renal function can influence the risk of venous thromboembolism (VTE) recurrence. MATERIALS AND METHODS: We performed an ambispective observational study on 409 patients with a previous episode of VTE. All the patients were included in the retrospective analysis whereas a subgroup of 260 individuals, without history of recurrence and that stopped oral anticoagulation, were then followed-up for a mean of 52.3±20.7months. RESULTS: At the enrollment, subjects with history of recurrent VTE were prevalently male with higher blood pressure and lower eGFR. Prevalence of CKD (defined as eGFR<60ml/min/1.73m2) was higher in patients with previous VTE recurrence with an adjusted OR of 5.69 (IC95% 2.17-14.90, p<0.001) compared to patients with normal eGFR. Similar findings were obtained from the prospective study where an adjusted 5.32 HR for VTE recurrence was seen in patients with CKD compared to subjects with normal renal function (IC95% 1.49-18.95, p=0.010). An increase in the risk of recurrent VTE was also observed in patients with mild decrease in renal function (eGFR 60-90 vs ≥90ml/min/1.73m2 adjusted HR 2.84, IC95% 1.13-7.11, p=0.025). Moreover, a multivariate Cox regression analysis including eGFR as continuous variable showed that renal function decrease was independently associated with the risk of VTE recurrence (p=0.001). CONCLUSIONS: CKD and mild decrease in renal function are associated with a significant increase in the risk of recurrent VTE.

Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis.

BACKGROUND: The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain. METHODS: In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity. RESULTS: During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4). CONCLUSIONS: Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention. (ClinicalTrials.gov number, NCT01285661).

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis. A post-hoc analysis.

Post-thrombotic syndrome (PTS) is a common complication of deep-vein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48-64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51-1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.

The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis.

Diagnosis of recurrent deep-vein thrombosis (DVT) is difficult because of limitations in distinguishing acute from old thrombi. In the past, an ultrasound method for diagnosis of recurrent ipsilateral DVT was developed, which relies on repeated measurements of the diameters of the common femoral and popliteal veins. To assess the safety of withholding anticoagulation from patients with improved or stable compression vein diameters, 205 consecutive patients presenting with suspected recurrent ipsilateral DVT were evaluated. The vein diameter was measured under compression with the transducer and compared with earlier ultrasound results. Patients with stable or improved ultrasound findings had repeat ultrasound assessments after 2 (+/- 1) and 7 (+/- 1) days. Patients with repeatedly normal ultrasound results were followed-up for six months to determine the incidence of symptomatic recurrent venous thromboembolism. Of the 205 patients, 153 had stable or improved ultrasound findings. Repeat ultrasound assessment became abnormal in 3, and recurrence was confirmed by venography in all. A six months follow-up was done in the remaining 150 patients with repeatedly normal ultrasound tests and showed 2 (1.3%; 95% CI, 0.02 to 4.7%) confirmed non-fatal venous thromboembolic complications. The positive predictive value of a stable or improved ultrasound was 90% (95% CI, 77 to 97%). In conclusion, it is safe to withhold anticoagulant treatment from patients with suspected recurrent ipsilateral DVT in whom compression ultrasonography showed improved or stable vein diameters.

Lower Limb Ischemia: Aortoiliac Thrombosis Related to Antiphospholipid Syndrome (APS)-Case Report and Review of the Literature.

Antiphospholipid syndrome (APS) is recognized as one of the main determinants of hypercoagulable conditions. The literature reports the incidence of this syndrome in a third of patients who underwent surgery for peripheral revascularization. Antiphospholipid antibodies are divided into two categories in relation to specific diagnostic tests. The first group is called lupus anticoagulant and consists of immunoglobulins that inhibit the phospholipid dependent coagulation tests in vitro. The second group is defined by their ability to conduct the phospholipid in an ELISA test. The occurrence of thrombotic events in patients with systemic erythematosus lupus (SEL) and anticoagulant antibodies was described for the first time in 1963 by Bowie. The discovery of anti-cardiolipin antibodies in antiphospholipid syndrome is due to Harris et al. who described the syndrome. Primitive APS was consequently defined in the absence of further underlying illnesses. In this disease, arterial thrombosis occurs mainly in the brain. Peripheral arteries are affected less frequently. Thrombosis of the great vessels is reported as anecdotal.