Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

BACKGROUND: There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment. METHODS: We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. RESULTS: During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. CONCLUSION: Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Predictors of long-term post-thrombotic syndrome following high proximal deep vein thrombosis: a cross-sectional study.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of proximal deep vein thrombosis (DVT) of the lower limb, but predictors of PTS are not well established. We aimed to examine predictors of PTS in patients with long-term PTS following proximal DVT. METHODS: During 2006-09, 209 patients with a first time acute upper femoral or iliofemoral DVT were randomized to receive either additional catheter-directed thrombolysis or conventional therapy alone. In 2017, the 170 still-living participants were invited to participate in a cross-sectional follow-up study. In the absence of a gold standard diagnostic test, PTS was defined in line with clinical practice by four mandatory, predefined clinical criteria: 1. An objectively verified DVT; 2. Chronic complaints (> 1 month) in the DVT leg; 3. Complaints appeared after the DVT; and 4. An alternative diagnosis was unlikely. Possible predictors of PTS were identified with multivariate logistic regression. RESULTS: Eighty-eight patients (52%) were included 8-10 years following the index DVT, and 44 patients (50%) were diagnosed with PTS by the predefined clinical criteria. Younger age and higher baseline Villalta score were found to be independent predictors of PTS, i.e., OR 0.96 (95% CI, 0.93-0.99), and 1.23 (95% CI, 1.02-1.49), respectively. Lack of iliofemoral patency at six months follow-up was significant in the bivariate analysis, but did not prove to be significant after the multivariate adjustments. CONCLUSIONS: In long-term follow up after high proximal DVT, younger age and higher Villalta score at DVT diagnosis were independent predictors of PTS.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Limitations of the Villalta scale in diagnosing post-thrombotic syndrome.

INTRODUCTION: The Villalta scale is currently the recommended tool for diagnosing post-thrombotic syndrome (PTS) in clinical studies, but there is concern that the sensitivity and specificity of the scale might be low. We aimed to evaluate the diagnostic accuracy of the Villata scale using criteria in line with clinical practice as a reference. MATERIAL AND METHODS: We invited patients with a history of proximal DVT during 2006-09 to participate in a cross-sectional follow-up study of long-term complications after DVT. PTS was diagnosed by the Villalta scale, and by the following four mandatory and predefined clinical criteria used as a reference for PTS: 1. Objectively verified DVT; 2. chronic complaints (>1 month) in the DVT leg; 3. complaints appeared after the DVT; and 4. an alternative diagnosis was unlikely. RESULTS: We included 88 of 170 eligible patients (52%). With our clinical criteria as a reference the sensitivity and specificity of the Villalta scale for diagnosing PTS were 75% (95% CI 60-87%) and 66% (95% CI 50-80%), respectively. Fifteen patients were diagnosed with PTS by the Villalta scale only. These patients more often experienced pain or had comorbidity that could explain their leg symptoms and signs. Eleven patients diagnosed with PTS by the clinical criteria only, had more fluctuating heaviness and edema. CONCLUSIONS: Our findings indicate that the diagnostic accuracy of the Villalta scale has limitations. Incorporating chronicity, whether the leg problems appeared following the DVT, fluctuations of heaviness and edema, and comorbidity in PTS assessment may improve the diagnostic accuracy.

Does the Villalta scale capture the essence of postthrombotic syndrome? A qualitative study of patient experience and expert opinion.

BACKGROUND: The Villalta scale is recommended for diagnosing and grading of postthrombotic syndrome (PTS) in clinical studies, but with limitations in specificity and sensitivity. OBJECTIVES: To explore the typical complaints of PTS through patients experience and expert opinion and relate this to the items of the Villalta scale. PATIENTS/METHODS: A qualitative study design with focus group interviews including patients with PTS and health care workers experienced in PTS patient care. RESULTS: Typical PTS complaints were reflected within four main domains: (a) agonizing discomforts; patients without venous ulcers often described other discomforts than pain; (b) skin changes; these were common and sometimes present before deep vein thrombosis (DVT). Except for venous ulcers, skin changes were considered of less importance; (c) fluctuating heaviness and swelling during the day and with activity; (d) post-DVT concerns; fear of DVT recurrence, health services failing to meet the patients' expectations, and psychological and social restrictions. These findings are not necessarily captured or well reflected in the Villalta scale. CONCLUSION: Our findings indicate that the Villalta scale does not capture typical PTS complaints or their importance to the patients. A revision of the diagnosis and grading should be considered.

Infrainguinal inflow assessment and endovenous stent placement in iliofemoral post-thrombotic obstructions.

PURPOSE: To assess the technical success, patency, and clinical outcome, following assessment of inflow and infrainguinal endovenous stent placement in patients with iliofemoral post-thrombotic obstruction with infrainguinal involvement. METHODS: A retrospective analysis of 39 patients with iliofemoral post-thrombotic venous obstruction accepted for infrainguinal stent placement in the period November 2009-December 2016. The clinical status was categorized according to the Clinical Etiological Anatomical Pathophysiological (CEAP) classification and symptom severity was assessed using Venous Clinical Severity Score (VCSS). The inflow was categorized as "good", "fair", or "poor" depending on vein caliber and extent of post-thrombotic changes in the inflow vessel(s). Stent patency was assessed by duplex ultrasound. Median follow-up was 44 months (range 2-90 months). RESULTS: Stent placement was successful in all 39 patients. Primary patency after 24 months was 78%. Thirty of 39 patients (77%) had open stents at final follow-up. Re-interventions were performed in four patients and included catheter-directed thrombolysis (CDT) in all and adjunctive stenting in two. Twenty-eight of 39 patients (72%) reported a sustained clinical improvement. Patients with "good" inflow had better patency compared to those with "fair"/"poor" (p = 0.01). One patient experienced acute contralateral iliofemoral thrombosis; this segment was successfully treated with CDT and stenting. No other complications required intervention. CONCLUSION: Infrainguinal endovenous stent placement was a feasible and safe treatment with good patency and clinical results, and should be considered in patients with substantial symptoms from post-thrombotic obstructions with infrainguinal involvement. Stents with good inflow have better patency and inflow assessment is essential in deciding the optimal stent landing zone.

Late consequences of venous thromboembolism: Measuring quality of life after deep vein thrombosis and pulmonary embolism.

The identification of specific post-thrombotic complications as well as an increased appreciation of the importance of patient-reported outcome measures have triggered an interest in studying health-related quality of life (HRQoL) in patients with a history of venous thromboembolism (VTE). In order to enable a comprehensive assessment of HRQoL in clinical trials it is recommended that both generic and disease-specific questionnaires be used. SF-36 and EQ-5D are the most widely used generic questionnaires in VTE studies, whereas several disease-specific questionnaires have been developed to evaluate HRQoL following deep vein thrombosis (DVT) and in chronic venous disease (CVD). The most widely used of these is the VEINES-QOL/Sym, which was developed for CVD. VT-QOL and DVTQOL are both questionnaires developed to evaluate HRQoL after DVT, while PEmb-QoL is currently the only available disease-specific questionnaire developed specifically for pulmonary embolism (PE). Although studies show inconsistent results, patients who sustain DVT seem in general to report similar HRQoL compared to the general population. However, patients who develop PTS after DVT report poorer HRQoL using both generic and disease-specific questionnaires. HRQoL appears to be impaired in patients who sustain PE compared to the general population. In these patients, persistent dyspnea after PE has been shown to be a predictor of reduced HRQoL. Further work is needed to develop practical, patient-derived, valid, reliable and responsive disease-specific HRQoL instruments covering the specific aspects of these diseases.

Diagnostic scales for the post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is the most common long-term complication after deep vein thrombosis (DVT) developing in up to 70% of the patients. PTS is diagnosed on the basis of typical symptoms and signs of the lower limb with a previous DVT, but no objective diagnostic test exists. A number of diagnostic scales have been developed primarily for research purposes. An optimal diagnostic test for PTS should be reliable and easy to use, sensitive and specific, able to grade PTS severity, and to identify changes over time. We have identified reports on seven diagnostic scales that have been used for the diagnosis of PTS; the Widmer classification, the Clinical-Etiological-Anatomical-Pathological (CEAP) classification, the Venous Clinical Severity Score (VCSS), the Brandjes scale, the Ginsberg measure, the Villalta scale, and the Patient-reported Villalta scale. The aim of this paper was to review and present the existing diagnostic scales for PTS in adults and their utility in clinical studies.

Radiology response in the emergency department during a mass casualty incident: a retrospective study of the two terrorist attacks on 22 July 2011 in Norway.

OBJECTIVES: To describe the use of radiology in the emergency department (ED) in a trauma centre during a mass casualty incident, using a minimum acceptable care (MAC) strategy in which CT was restricted to potentially severe head injuries. METHODS: We retrospectively studied the initial use of imaging on patients triaged to the trauma centre following the twin terrorist attacks in Norway on 22 July 2011. RESULTS: Nine patients from the explosion and 15 from the shooting were included. Fourteen patients had an Injury Severity Score >15. During the first 15 h, 22/24 patients underwent imaging in the ED. All 15 gunshot patients had plain films taken in the ED, compared to three from the explosion. A CT was performed in 18/24 patients; ten of these were completed in the ED and included five non-head CTs, the latter representing deviations from the MAC strategy. No CT referrals were delayed or declined. Mobilisation of radiology personnel resulted in a tripling of the staff. CONCLUSIONS: Plain film and CT capacity was never exceeded despite deviations from the MAC strategy. An updated disaster management plan will require the radiologist to cancel non-head CTs performed in the ED until no additional MCI patients are expected. KEY POINTS: • Minimum acceptable care (MAC) should replace normal routines in mass casualty incidents. • MAC implied reduced use of imaging in the emergency department (ED). • CT in ED was restricted to suspected severe head injuries during MAC. • The radiologist should cancel all non-head CTs in the ED during MAC.

Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.

BACKGROUND: Post-thrombotic syndrome is a common complication after acute proximal deep vein thrombosis (DVT) and is associated with reduced quality of life and a substantial cost burden. In the 2-year results of the CaVenT study, additional catheter-directed thrombolysis reduced the risk of post-thrombotic syndrome by 14% compared with conventional therapy, but did not affect quality of life. In this study we report results at the 5-year follow-up, aiming to assess whether findings for post-thrombotic syndrome and quality of life have persisted. METHODS: Between Jan 3, 2006, and Dec 22, 2009, we recruited patients aged 18-75 years with a first-time high proximal leg DVT from 20 hospitals in the Norwegian southeastern health region. With sealed envelopes, participants were randomly assigned (1:1) to standard treatment with compression stockings and anticoagulants (control group) or to standard treatment plus catheter-directed thrombolysis with alteplase within 21 days from symptom onset. Pre-specified outcomes in this analysis were post-thrombotic syndrome at 5 years as assessed with the Villalta score and scores for quality of life at 5 years with EQ-5D and the disease-specific VEINES-QOL/Sym. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00251771. FINDINGS: At 5 year follow-up (last date Oct 14, 2014), data were available for 176 patients (84% of the 209 patients originally randomised)--87 originally assigned to catheter-directed thrombolysis and 89 originally assigned to the control group. 37 patients (43%; 95% CI 33-53) allocated to catheter-directed thrombolysis developed post-thrombotic syndrome, compared with 63 (71%; 95% CI 61-79) allocated to the control group (p<0·0001), corresponding to an absolute risk reduction of 28% (95% CI 14-42) and a number needed to treat of 4 (95% CI 2-7). Four (5%) patients assigned to catheter-directed thrombolysis and one (1%) to standard treatment had severe post-thrombotic syndrome (Villalta score ≥ 15 or presence of an ulcer). Quality-of-life scores with either assessment scale did not differ between the treatment groups. INTERPRETATION: Additional catheter-directed thrombolysis resulted in a persistent and increased clinical benefit during follow-up for up to 5 years, supporting the use of additional catheter-directed thrombolysis in patients with extensive proximal DVT. However, allocation to this therapy did not lead to better quality of life. The optimal endovascular thrombolytic approach needs further investigation. FUNDING: Southeastern Norway Regional Health Authority, the Research Council of Norway, University of Oslo, Oslo University Hospital.