Anticoagulant therapy for splanchnic vein thrombosis: a systematic review and meta-analysis.

Treatment of splanchnic vein thrombosis (SVT) is challenging, and evidence to guide therapeutic decisions remains scarce. The objective of this systematic review and meta-analysis was to determine the efficacy and safety of anticoagulant therapy for SVT. MEDLINE, EMBASE, and clinicaltrials.gov were searched from inception through December 2019, without language restrictions, to include observational studies and randomized controlled trials reporting radiological or clinical outcomes in patients with SVT. Pooled proportions and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. Of 4312 records identified by the search, 97 studies including 7969 patients were analyzed. In patients receiving anticoagulation, the rates of SVT recanalization, SVT progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were 58% (95% CI, 51-64), 5% (95% CI, 3-7), 11% (95% CI, 8-15), 9% (95% CI, 7-12), and 11% (95% CI, 9-14), respectively. The corresponding values in patients without anticoagulation were 22% (95% CI, 15-31), 15% (95% CI, 8-27), 14% (95% CI, 9-21), 16% (95% CI, 13-20), and 25% (95% CI, 20-31). Compared with no treatment, anticoagulant therapy obtained higher recanalization (RR, 2.39; 95% CI, 1.66-3.44) and lower thrombosis progression (RR, 0.24; 95% CI, 0.13-0.42), major bleeding (RR, 0.73; 95% CI, 0.58-0.92), and overall mortality (RR, 0.45; 95% CI, 0.33-0.60). These results demonstrate that anticoagulant therapy improves SVT recanalization and reduces the risk of thrombosis progression without increasing major bleeding. The incidence of recurrent VTE remained substantial in patients receiving anticoagulation, as well. Effects were consistent across the different subgroups of patients. This trial was registered on the PROPERO database at (https://www.crd.york.ac.uk/prospero//display_record.php?ID=CRD42019127870) as #CRD42019127870.

Direct oral anticoagulant plasma levels in hospitalized COVID-19 patients treated with dexamethasone.

Direct oral anticoagulants (DOACs) are not recommended in COVID-19 patients receiving dexamethasone because of potential drug-drug and drug-disease interactions affecting anticoagulant concentration and activity. To evaluate short- and long-term pharmacokinetic interactions, serial through and peak DOAC plasma levels were prospectively measured during and after dexamethasone therapy, as well as during the acute phase and after recovery from COVID-19 in hospitalized, non-critically ill patients undergoing treatment with DOACs. Thirty-three (18 males, mean age 79 years) consecutive patients received DOACs (17 apixaban, 12 rivaroxaban, 4 edoxaban) for atrial fibrillation (n = 22), venous thromboembolism (n = 10), and acute myocardial infarction (n = 1). Twenty-six patients also received dexamethasone at a dose of 6 mg once daily for a median of 14 days. Trough DOAC levels on dexamethasone were within and below expected reference ranges respectively in 87.5 and 8.3% of patients, with no statistically significant differences at 48-72 h and 14-21 days after dexamethasone discontinuation. Peak DOAC levels on dexamethasone were within expected reference ranges in 58.3% of patients, and below ranges in 33.3%, of whom over two thirds had low values also off dexamethasone. No significant differences in DOAC levels were found during hospitalization and after resolution of COVID-19. Overall, 28 patients were discharged alive, and none experienced thrombotic or bleeding events. In this study, dexamethasone administration or acute COVID-19 seemed not to affect DOAC levels in hospitalized, non-critically ill COVID-19 patients.

Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis.

BACKGROUND: The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on clinically relevant outcomes in hospitalized patients with COVID-19. METHODS: MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses. RESULTS: A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies). CONCLUSIONS: Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting. TRIAL REGISTRATION: PROSPERO registration ID for this study is CRD42020177243 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=177243 ).

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the third update of a review first published in February 2012. OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis, or an active control intervention. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references. SELECTION CRITERIA: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence. MAIN RESULTS: We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence). When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence). In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis, but did not report on VTE or major bleeding. When compared with placebo or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence). One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE: RR 0.84, 95% CI 0.41 to 1.73; major bleeding: RR 0.78, 95% CI 0.03 to 18.57; 1 study, 85 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.

Long-term performance of risk scores for venous thromboembolism in ambulatory cancer patients.

The long-term performance of prediction scores for venous thromboembolism (VTE) in cancer patients has been poorly investigated. We evaluated the discriminatory performance of the Khorana, PROTECHT, CONKO, and ONKOTEV scores for the first 3-6 months and for 12 months, and re-assessed scores after 3-6 months to determine the influence of variations in patients' risk classification on performance. Retrospective cohort of ambulatory patients with active cancer who were scheduled to receive first or new line of chemotherapy. The primary outcome was symptomatic or incidental VTE. A total of 776 patients were included of whom 540 (70%) had distant metastases. The time-dependent c-statistics of Khorana, PROTECHT, CONKO, and ONKOTEV scores at 6 months were 0.61 (95% CI 0.56 to 0.66), 0.61 (95% CI 0.55 to 0.66), 0.60 (95% CI 0.54 to 0.66), and 0.59 (0.52 to 0.66), respectively, with a tendency to decrease during follow-up. None of the scores discriminated between high and low risk patients at the conventional 3-point positivity threshold. The use of a 2-point positivity threshold improved performance of all scores and captured a higher proportion of VTE. The accuracy of risk scores re-assessed at 3-6 months was modest. The Khorana, PROTECHT, CONKO, and ONKOTEV scores are not sufficiently accurate when used at a conventional threshold of 3 points. Performance improves at positivity threshold of 2 points, as evaluated in recent randomized studies on VTE prophylaxis. Score accuracy tends to decrease over time suggesting the need of periodic re-evaluation to estimate possible variation of risk.

Iron status and oxidative stress in the aged rabbit heart.

Altered iron status may be relevant to the pathophysiology of aging. We have assessed redox-active catalytic low molecular weight iron (LMWI), non-heme iron (NHI), heme iron (HI), and total iron (TI) in the aerobically perfused hearts of aged rabbits (AR, about 4.5years old) and young adult control rabbits (YACR, 3-4months old); myocardial lipid and protein oxidations were also assessed as oxidative stress biomarkers. The levels of LMWI and NHI, as well as of lipid and protein oxidation, were higher, while HI content was lower, in the hearts of AR than in those of YACR; TI did not differ significantly between the two groups. Together with these findings, hemodynamic dysfunction, namely heightened end-diastolic pressure (EDP) and lowered coronary flow (CF), occurred in the AR hearts. Notably, such pattern of hemodynamic dysfunction associated with myocardial oxidant damage occurred in the hearts of other YACR perfused in the presence of a cell-permeable form of iron, i.e., the iron/hydroxyquinoline complex, pointing to the involvement of catalytic iron in the aged heart damage. Moreover, as shown in other AR, heart perfusion in the presence of the iron chelator deferoxamine (0.6mM or 3.6mM) reduced the myocardial levels of LMWI, without significantly affecting those of NHI, HI, and TI; concomitantly, in AR deferoxamine lowered myocardial lipid and protein oxidation, and reduced EDP with a tendency to augment CF. Instead, deferoxamine, even at high concentration of 3.6mM, had no significant effects in the YACR. In conclusion, altered iron status with catalytic LMWI burden occurs in the aged rabbit heart, eventually resulting in iron-dependent cardiac oxidative stress and hemodynamic dysfunction.

Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study.

In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13-34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95%CI: 2.8-12) for the Khorana score to 9.6% (95%CI: 6.6-13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95%CI: 1.0-3.1) or PROTECHT (subhazard ratio 2.1; 95%CI: 1.2-3.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low- and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012. OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS: For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016. SELECTION CRITERIA: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS: We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo. AUTHORS' CONCLUSIONS: In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

Treatment for superficial infusion thrombophlebitis of the upper extremity.

BACKGROUND: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Primary prophylaxis for venous thromboembolism in patients undergoing cardiac or thoracic surgery.

BACKGROUND: Cardiac and thoracic surgery are associated with an increased risk of venous thromboembolism (VTE). The safety and efficacy of primary thromboprophylaxis in patients undergoing these types of surgery is uncertain. OBJECTIVES: To assess the effects of primary thromboprophylaxis on the incidence of symptomatic VTE and major bleeding in patients undergoing cardiac or thoracic surgery. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). The authors searched the reference lists of relevant studies, conference proceedings, and clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS: We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). AUTHORS' CONCLUSIONS: The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.

Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study.

BACKGROUND: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN: Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS: 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS: The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS: This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION: The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE: None.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012. OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS: We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo. AUTHORS' CONCLUSIONS: In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Thromboembolic and bleeding risk in cardiac amyloidosis.

Cardiac amyloidosis represents a spectrum of conditions characterized by the accumulation of insoluble fibrils, resulting in progressive deposition and myocardial dysfunction. The exact mechanisms contributing to the heightened risk of thromboembolic events and bleeding tendencies in cardiac amyloidosis remain unclear. Proteins such as transthyretin in transthyretin amyloidosis and light chains in light-chain amyloidosis, along with acute phase proteins in amyloid A (AA) amyloidosis, play complex roles in the coagulation cascade, affecting both coagulation initiation and fibrinolysis regulation. The increased occurrence of atrial fibrillation, systolic and diastolic left ventricular dysfunction, and atrial myopathy in patients with cardiac amyloidosis may predispose them to thrombus formation. This predisposition can occur regardless of sinus rhythm status or even with proper anticoagulant management. Bleeding events are often linked to amyloid deposits around blood vessels, which may increase capillary fragility and cause coagulation disturbances, leading to unstable international normalized ratio levels during anticoagulant therapy. Thus, comprehensive risk assessment for both thrombotic and hemorrhagic complications, especially before commencing anticoagulant therapy, is imperative. This review will explore the essential pathophysiological, epidemiologic, and clinical aspects of thromboembolic and bleeding risk in cardiac amyloidosis, evaluating the existing evidence and uncertainties regarding thrombotic and bleeding risk assessment and antithrombotic treatment.

Unmet needs and barriers in venous thromboembolism education and awareness among people living with cancer: a global survey.

BACKGROUND: Venous thromboembolism (VTE) is a major preventable cause of morbidity, disability, and mortality in subjects with cancer. A global appraisal of cancer-associated VTE education and awareness is not available. OBJECTIVES: To evaluate VTE-related education, awareness, and unmet needs from the perspective of people living with cancer using a quantitative and qualitative approach. METHODS: This cross-sectional study used data from an online-based survey covering multidimensional domains of cancer-associated VTE. Data are presented descriptively. Potential differences across participant subgroups were explored. RESULTS: Among 2262 patients with cancer from 42 countries worldwide, 55.3% received no VTE education throughout their cancer journey, and an additional 8.2% received education at the time of VTE diagnosis only, leading to 63.5% receiving no or inappropriately delayed education. When education was delivered, only 67.8% received instructions to seek medical attention in case of VTE suspicion, and 36.9% reported scarce understanding. One-third of participants (32.4%) felt psychologically distressed when becoming aware of the potential risks and implications connected with cancer-associated VTE. Most responders (78.8%) deemed VTE awareness highly relevant, but almost half expressed concerns about the quality of education received. While overall consistent, findings in selected survey domains appeared to numerically differ across age group, ethnicity, continent of residence, educational level, metastatic status, and VTE history. CONCLUSION: This study involving a large and diverse population of individuals living with cancer identifies important unmet needs in VTE-related education, awareness, and support across healthcare systems globally. These findings unveil multilevel opportunities to expedite patient-centered care in cancer-associated VTE prevention and management.

Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. OBJECTIVES: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs). RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSION: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis.

Thrombophilia has been associated with pregnancy complications and recurrent miscarriage. The aim of this systematic review was to evaluate the controversial association between thrombophilia and failures of assisted reproduction technology (ART). A systematic search of the literature for studies reporting on thrombophilia in women undergoing ART up to April 2011 yielded 33 studies (23 evaluating anti-phospholipid antibodies, 5 inherited thrombophilia, and 5 both) involving 6092 patients. Overall, methodologic quality of the studies was poor. Combined results from case-control studies showed that factor V Leiden was significantly more prevalent among women with ART failure compared with fertile parous women or those achieving pregnancy after ART (odds ratio = 3.08; 95% confidence interval, 1.77-5.36). The prothrombin mutation, methylenetetrahydrofolate reductase mutation, deficiency of protein S, protein C, or anti-thrombin were all not associated with ART failure. Women with ART failure tested more frequently positive for anti-phospholipids antibodies (odds ratio = 3.33; 95% confidence interval, 1.77-6.26) with evidence of high degree of between-study heterogeneity (I(2) = 75%; P < .00001). Prospective cohort studies did not show significant associations between thrombophilia and ART outcomes. Although case-control studies suggest that women experiencing ART failures are more frequently positive for factor V Leiden and anti-phospholipid antibodies, the evidence is inconclusive and not supported by cohort studies.

Anamnestic frailty phenotype and adverse outcomes in patients treated with direct oral anticoagulants: Validation and comparative performance with frailty phenotype.

AIMS: The anamnestic frailty phenotype (AFP) is a quick, instrument-free tool derived from frailty phenotype (FP). We prospectively evaluated the discriminative capacity and prognostic value of AFP in ambulatory patients receiving DOACs for atrial fibrillation (AF) or venous thromboembolism (VTE), and compared AFP performance with that of FP. METHODS AND RESULTS: Sensitivity, specificity, positive and negative predictive value (PPV, NPV) with corresponding 95% confidence intervals (95%CI), were estimated for bleeding, thromboembolism, and all-cause mortality. Risk ratios (RRs) were calculated in frail versus non-frail patients. Of 236 patients (median age 78 years), 98 (42%) and 89 (38%) were classified as frail according to FP and AFP, respectively (Kappa= 0.76). Frailty, as assessed by AFP, was associated with higher risk of bleeding (RR 2.3; 95%CI, 1.2 to 4.6), and mortality (RR 4.4; 95%CI, 1.3 to 19.7). Similarly, to FP, AFP exhibited modest sensitivity and specificity, but high NPV that was 91% (95%CI, 85 to 95) for bleeding, 98% (95%CI, 94 to 100) for thromboembolism, and 98% (95%CI, 94 to 100) for mortality. CONCLUSION: Among patients receiving DOACs for AF or VTE, AFP was associated with an increased risk of adverse outcomes. AFP exhibited modest sensitivity and specificity, but excellent NPV. If confirmed, these findings suggest that AFP may represent a rapid, easy-to-use and unexpensive tool that may potentially help identify patients at lower risk for adverse outcomes and tailor anticoagulation management.