scholarly journals Treatment and secondary prophylaxis of venous thromboembolism with direct oral anticoagulants in patients with severe hereditary thrombophilia

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Pasquale Madonna ◽  
Anna Guida ◽  
Maria Gabriella Coppola ◽  
Paolo Tirelli ◽  
Ernesto Grasso
Keyword(s):  
Venous Thromboembolism ◽  
Early Onset ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor V Leiden ◽  
Secondary Prophylaxis ◽  
Factor V ◽  
Efficacy And Safety ◽  
Hereditary Thrombophilia ◽  
At Iii

Deficiency of protein C (PC), protein S (PS), antithrombin III (AT III), and homozygosity or combined heterozygosity for Factor V Leiden (FVL) and Factor II (FII) 20210A mutation represent severe hereditary thrombophilia (SHT) and are associated with a higher risk of early-onset venous thromboembolism (VTE). In literature, few papers have described the efficacy and safety of therapy with direct oral anticoagulants (DOACs) in VTE occurring in patients with SHT. In our setting, we identified 8 patients who have suffered from early-onset VTE and underwent therapy with DOACs (6 rivaroxaban, 2 apixaban). Among them, 2 AT III deficiency, 2 PC deficiency, 3 PS deficiency, 1 combined heterozygosity for FVL, and FII 20210A were detected. During the follow-up, neither recurrences of VTE nor hemorrhagic episodes were observed. This report describes the efficacy and safety of therapy with anti-Xa in the treatment and secondary prophylaxis of VTE in patients with SHT.

Evaluation of Efficacy and Safety of Direct Oral Anticoagulants (DOACS) in the Treatment of Venous Thromboembolism in Cancer Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5016-5016
Author(s):  
Ali McBride ◽  
Reem Diri ◽  
Chris Campen ◽  
Ivo Abraham
Keyword(s):  
Pancreatic Cancer ◽  
Pulmonary Embolism ◽  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Secondary Prophylaxis ◽  
Efficacy And Safety ◽  
Bleeding Episodes ◽  
Current Guidelines

Abstract Background: Nearly twenty percent of all patients with deep venous thrombosis (DVT) or pulmonary embolism (PE) have an underlying malignancy. Current guidelines recommend low molecular weight heparin (LMWH)-based therapy for venous thromboembolism (VTE) treatment in cancer patients; however, patient considerations including access for treatment and monitoring, co-pay costs and self-administration can be a limitation for its use. Alternative treatments such as direct oral anticoagulants (DOACs) are an attractive alternative to patients and clinicians because of limited monitoring, fixed dosing and limited drug and food interaction. Current guidelines, including those of the American Society of Clinical Oncology and National Comprehensive Cancer Network, do not recommend the use of DOACs for VTE treatment at this time in cancer patients as there is limited data for VTE treatment and secondary prophylaxis with DOAC's. Methods :We performed a retrospective evaluation of cancer patients at our institution with an active VTE diagnosis who were administered DOACs (rivaroxaban, apixaban and dabigatran) between November 2013 and April 2016. Data collected included patient demographics, diagnosis, and chemotherapy regimen, previous history of VTE, and efficacy and safety during anticoagulation with DOAC's. Results : One hundred and thirty-seven patients were included in the study (Table 1), with 112 patients on rivaroxaban, 20 patients on apixaban, and 5 patients on dabigatran. DOACs were administered to treat deep venous thrombosis (DVT) in 86 patients, pulmonary embolism (PE) in 31 patients, and both DVT and PE diagnosis in 20 patients. Only four patients had a secondary clot on therapy during treatment: one patient with pancreatic cancer on apixaban developed recurrent portal vein thrombosis, and three patients with pancreatic cancer, adenocarcinoma of the lung, and Factor V Leiden deficiency on rivaroxaban; 2 patients developed recurrent DVT, and 1 patient developed recurrent PE. Overall, 34/137 (25%) patients experienced a total of 37 bleeding episodes, of which 33/37 were classified as clinically relevant non-major bleeding and 4/37 as minor bleeding. Thirty eight patients had their doses held ,discontinued, discontinued or switched to different anticoagulation therapy; in 11 patients secondary to bleeding, four failed therapy, three experienced intolerance to DOAC, two patients were changed secondary to drug interactions and two patients could not continue therapy secondary to co-pay costs, and two were held prior to surgery. Ten patients had recurrent (>2) bleeding episodes including epistaxis, hematochezia, hematuria, and hematemesis. Conclusion :In our analysis, DOACs did yield efficacy in cancer patients treated for secondary prophylaxis of VTE with few noted side effects. In our study, DOAC's did not cause fatal or major bleeding. Future prospective studies are warranted for secondary prophylaxis in this setting. Table 1. Baseline characteristics and outcomes of patients on DOAC's for Secondary DVT prophylaxis Evaluation of Efficacy and Safety of DOACsin the Treatment of Venous Thromboembolism in Cancer Patients Evaluation of Efficacy and Safety of DOACsin the Treatment of Venous Thromboembolism in Cancer Patients Disclosures McBride: Sanofi: Research Funding.

Direct Oral Anticoagulants in Select Patients With Hypercoagulable Disorders

2020 ◽  
pp. 106002802096855
Author(s):  
Sara M. Valanejad ◽  
Kyle A. Davis
Keyword(s):  
Antiphospholipid Syndrome ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor V Leiden ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Protein C Deficiency ◽  
Antithrombin Deficiency ◽  
Safety And Efficacy ◽  
Hereditary Thrombophilia

Objective: To summarize the literature assessing the safety and efficacy of direct oral anticoagulants (DOACs) for the acute treatment and secondary prevention of venous thromboembolism (VTE) in select patients with hypercoagulable disorders. Data Sources: An electronic PubMed literature search was conducted from January 2010 to July 2020 using the following keywords: DOAC, rivaroxaban, apixaban, dabigatran, edoxaban, thrombophilia, cancer, antiphospholipid syndrome, protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden, prothrombin G20210A gene mutation, congenital thrombophilia, hypercoagulable, hereditary thrombophilia, acquired thrombophilia. Study Selection and Data Extraction: Articles were included if they reported clinical outcomes associated with cancer-associated VTE, antiphospholipid syndrome (APS), and other hereditary thrombophilias. Data Synthesis: The safety and efficacy of using a DOAC is highly dependent on the type of hypercoagulable disease state. Current trials support the use of edoxaban, rivaroxaban, and apixaban for the treatment of cancer-associated thrombosis (CAT), with apixaban being preferred because of lower bleeding rates compared with standard of care. The use of DOACs, especially rivaroxaban, have been associated with worse outcomes in patients with APS, whereas data on DOAC use in hereditary thrombophilia remains scarce and limited to low-risk patients. Relevance to Patient Care and Clinical Practice: This review evaluates the literature assessing the safety and efficacy of DOACs in patients with various hypercoagulable disorders. Conclusions: The current body of evidence supports the use of select DOACs for the treatment of CAT. In contrast, DOAC use in patients with APS and hereditary thrombophilia should be avoided at this time.

scholarly journals Safety and efficacy of direct oral anticoagulants (DOACs) vs low molecular weight heparin (LMWH) in malignancy induced venous thromboembolism-a systematic review and meta analysis

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
A Abdul Razzack ◽  
N Hussain ◽  
S Adeel Hassan ◽  
S Mandava ◽  
F Yasmin ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Low Molecular Weight Heparin ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Low Molecular Weight ◽  
Efficacy And Safety ◽  
Dichotomous Data ◽  
Significant Difference

Abstract Funding Acknowledgements Type of funding sources: None. Background- Low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) have been proven to be more effective in the management of venous thromboembolism (MVTE). The efficacy and safety of LMWH or DOACs in treatment of recurrent or malignancy induced VTE is not studied in literature. Objective To compare the efficacy and safety of LMWH and  DOACs in the management of malignancy induced  VTE Methods- Electronic databases ( PubMed, Embase, Scopus, Cochrane) were searched from inception to November  28th, 2020. Dichotomous data was extracted for prevention of VTE and risk of major bleeding in patients taking either LMWH or DOACs. Unadjusted odds ratios (OR) were calculated from dichotomous data using Mantel Haenszel (M-H) random-effects with statistical significance to be considered if the confidence interval excludes 1 and p < 0.05.  Results- Three studies with 2607 patients (DOACs n = 1301 ; LMWH n = 1306) were included in analysis. All the study population had active cancer of any kind diagnosed within the past 6 months. Average follow-up period for each trial was 6 months. Patients receiving DOACs have a lower odds of recurrence of MVTE as compared to LMWH( OR 1.56; 95% CI 1.17-2.09; P = 0.003, I2 = 0). There was no significant difference in major bleeding among patients receiving LMWH or DOACs  (OR-0.71, 95%CI 0.46-1.10, P = 0.13, I2 = 22%) (Figure 1). We had no publication bias in our results (Egger’s regression p > 0.05). Conclusion- DOACs are superior to LMWH in prevention of MVTE and have similar major bleeding risk as that of LMWH. Abstract Figure. A)VTE Recurrence B)Major Bleeding events

First-Line Therapies for VTE Treatment and Secondary Prophylaxis in Patients With Cancer: A New Direction

2018 ◽  
Vol 33 (3) ◽  
pp. 356-363
Author(s):  
Samantha M. Vogel ◽  
Leticia V. Smith ◽  
Evan J. Peterson
Keyword(s):  
Venous Thromboembolism ◽  
English Language ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Secondary Prophylaxis ◽  
Careful Consideration ◽  
Patients With Cancer ◽  
Study Selection ◽  
Meta Analyses

Objective: To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs). Data Sources: PubMed was searched using terms “venous thromboembolism,” “cancer,” and “anticoagulation.” This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations. Study Selection: English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer. Data Analysis: Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered. Conclusion: DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

scholarly journals Does aspirin prevent venous thromboembolism?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 634-641
Author(s):  
Robert Diep ◽  
David Garcia
Keyword(s):  
Venous Thromboembolism ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Secondary Prophylaxis ◽  
Treatment Modalities ◽  
Surgical Patient ◽  
Vein Thrombosis ◽  
Disease Therapy ◽  
Deep Vein ◽  
Arterial Vascular Disease

Abstract Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation.

Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism

2016 ◽  
Vol 116 (10) ◽  
pp. 747-753 ◽  
Author(s):  
Philip S. Wells ◽  
Annelise Segers ◽  
Walter Ageno ◽  
Marjolein P. A. Brekelmans ◽  
Alexander T. Cohen ◽  
...  
Keyword(s):  
Body Weight ◽  
Venous Thromboembolism ◽  
Dose Reduction ◽  
Drug Exposure ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Efficacy And Safety ◽  
P Glycoprotein ◽  
Recurrent Vte ◽  
Glycoprotein Inhibitors

SummaryDirect oral anticoagulants simplify venous thromboembolism (VTE) treatment by obviating the need for coagulation monitoring. Nonetheless, renal function, body weight and P-glycoprotein inhibitors influence drug levels. The objective of this analysis was to determine whether reduction in edoxaban dose based on clinical criteria avoids excess drug exposure and preserves efficacy and safety in the Hokusai-VTE study. After initial heparin, patients received edoxaban or warfarin for 3-12 months. Edoxaban was given once daily at a dose of 60 mg, which was reduced to 30 mg in patients with a creatinine clearance of 30–50 ml/minute, body weight ≤60 kg or receiving certain P-glycoprotein inhibitors. The primary efficacy outcome was recurrent VTE and the principal safety outcome was major or clinically relevant non-major bleeding. A total of 8292 patients with acute VTE were randomised, 733 and 719 patients in the edoxaban and warfarin groups met the criteria for dose reduction. These patients were older, more often female or Asian and had more extensive VTE. Edoxaban levels were lower in the 30 mg edoxaban group. Rates of recurrent VTE and bleeding with the 30 mg and 60 mg edoxaban dose were comparable: VTE rates were 3.0 % and 3.2 % and clinically relevant bleeding rates were 7.9 % and 8.6 %, respectively. Rates of recurrent VTE and bleeding in the warfarin-treated patients meeting the criteria for dose reduction were 4.2 % and 12.8 %, respectively. The reduced dose edoxaban regimen maintained efficacy and safety compared with the 60 mg dose but was safer than warfarin in patients meeting the criteria for dose reduction.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Outpatient Management in Patients with Venous Thromboembolism with Edoxaban: A Post Hoc Analysis of the Hokusai-VTE Study

2017 ◽  
Vol 117 (12) ◽  
pp. 2406-2414 ◽  
Author(s):  
Andria Medina ◽  
Gary Raskob ◽  
Walter Ageno ◽  
Alexander Cohen ◽  
Marjolein Brekelmans ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Similar Efficacy ◽  
Initial Therapy ◽  
Risk Difference ◽  
Efficacy And Safety ◽  
Open Label ◽  
Safety Outcome ◽  
Recurrent Vte

AbstractDirect oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

Direct oral factor Xa inhibitors for the treatment of acute cancer-associated venous thromboembolism: A systematic review and network meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e23156-e23156
Author(s):  
Harry E Fuentes ◽  
Robert McBane ◽  
Waldemar Wysokinski ◽  
Alfonso Javier Tafur ◽  
Charles L. Loprinzi ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Indirect Comparison ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Efficacy And Safety ◽  
Patients With Cancer

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.

scholarly journals One- Week Prophylaxis with Enoxaparin after Hospital Discharge Is Effective in Preventing Venous Thromboembolism in Living Liver Donors- Single Institution Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2442-2442
Author(s):  
Leila Khaddour ◽  
Zaid Al Saheli ◽  
Yaser Alkhatib ◽  
Marwan Abouljoud ◽  
Philip Kuriakose
Keyword(s):  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Antiphospholipid Antibody ◽  
Factor V ◽  
Right Hepatectomy ◽  
At Iii ◽  
Thrombophilia Screening ◽  
Liver Donation ◽  
Living Liver Donors ◽  
Liver Donors

Background: Living donor liver transplant (LDLT) has expanded organ availability to patients with advanced liver failure. While this procedure decreased morbidity and mortality in recipients, it could pose a risk to the donors. Deep vein thrombosis and pulmonary embolism are known postoperative complications associated with morbidity and mortality in living liver donors. At our institution thrombophilia screening starts during donor selection process with antiphospholipid antibody panel and screening coagulation tests for all candidates. This is followed by hematology evaluation to determine the need for inherited thrombophilia screening and accordingly, hypercoagulability risk. Additionally, the institution strategy for venous thromboembolism (VTE) prevention in liver donors involves prophylactic subcutaneous heparin within 24 hours of the surgery and maintained until discharge followed by enoxaparin for 7 days after discharge. We conducted this retrospective analysis to evaluate the efficacy of these measures in reducing the rate of VTE in this population. Methods: Retrospective electronic medical chart review to analyze data on living liver donors in our institution between January 2000 and February 2019. Inclusion criteria: all adult living liver donors who underwent partial right hepatectomy and followed for at least 6 weeks after surgery. The primary endpoint is the rate of VTE within 6 weeks of liver donation in patients who received post-discharge enoxaparin for one week in comparison to donors who did not receive enoxaparin. Secondary endpoints: re-admission rate and bleeding events. All continuous data was presented using means, medians and standard deviation, while categorical data were presented using counts and percentages. Results: At our institution 112 liver donors underwent right hepatectomy. Baseline characteristics (Table-1): The average age was 34 years, 58% were females and 86% were white. 10% of donors reported family history of DVT/PE. 90% of donors were screened for antiphospholipid antibody syndrome, with one case with positive titers. 34% of donors were screened for protein C (PC), Protein S (PS) and Antithrombin deficiency (AT-III). There were no cases of PC or AT-III deficiency, but one case of mild PS deficiency was identified. 38% cases were screened for factor V Leiden and prothrombin mutations, with 3 donors carrying heterozygous factor V Leiden mutation and one with heterozygous prothrombin mutation. All donors received prophylactic heparin during their stay in the hospital. A total of 15 donors had coagulation factors checked before and after the surgery. Post operatively, there was significant transient deficiency in PC, PS and AT-III, as well as significant increase in factor VIII level. This imbalance peaked within one week of surgery, with PC mean activity of 48%, PS mean activity of 48%, AT-III mean activity of 53% and FVIII of 290%. Factor activities started to recover by third week of surgery and returned to baseline within 8 weeks (figure 1). A total of 100 patients received one week of prophylaxis with Enoxaparin after being discharged from the hospital (Table-2). There was no VTE incidents in this group. 14/100 were readmitted to the hospital within 6 weeks of initial hospital admission; none due to bleeding. A total of 12 patients did not receive any pharmacological preventive measures upon discharge; due to in-hospital bleeding in 3 cases, prior to starting this strategy in 4 cases, unknown reason in 5 cases. VTE events and subsequent readmissions occurred in 2/12 (16.7%) (figure 2). Odds ratio could not be performed due to the very small number of patients in the comparison group (Table-2). Conclusion: Partial hepatectomy for liver donation is associated with significant remote hypercoagulable state due to the sudden loss in liver volume and concomitant transient deficiency of PC, PS and AT-III as well as increasing Factor VIII activity. This thrombophilia peaks within one week after the surgery and starts to recover by the third week. Clinicians should consider performing baseline thrombophilia screening and subsequently exclude potential donors with preexisting hypercoagulable state. Extending pharmacological VTE prevention with enoxaparin for 7 days after hospital discharge has been successful in reducing the VTE risk without increasing risk of bleeding or readmission rate in our patient population. Disclosures Kuriakose: Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy.

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