Outcomes of Patients Receiving Direct Oral Anticoagulants for Myeloproliferative Neoplasm Associated Venous Thromboembolism

Introduction Myeloproliferative neoplasms (MPN) are associated with an increased rate of venous thromboembolism (VTE), which can be a major cause of morbidity and mortality especially in the more indolent diseases of polycythaemia rubra vera (PV) and essential thrombocythaemia (ET). Splanchnic vein thromboses are common in MPN and may have high recurrence rates between 15-20% over 10 years1. Traditionally, vitamin K antagonists (VKA) have been the mainstay of anticoagulation for MPN-associated VTE and recent data suggests a high rate of recurrent VTE on their discontinuation in MPN patients2. In the last 5 years, there has been a significant change to the use of direct oral anticoagulants (DOAC) in non-MPN associated VTE and limited data is available in the MPN setting due to the exclusion of malignancies from initial Phase III studies. Methods A retrospective review of patients treated at a single tertiary centre for MPN was performed. Clinical details were obtained from electronic clinical notes, imaging and prescriptions. Results A total of 102 patients were identified as having a MPN-associated VTE with 24 of these receiving DOACs. The median age at VTE was 48 years (range 27.4-92.2 years) with 10 males (41.7%), primary diagnosis: 10 PV, 5 ET, 7 myelofibrosis (MF) and 2 MPN/myelodysplasia overlap. 18 patients were JAK2 V617F positive, 1 pt had MPL mutation and 5 pts were triple negative. In total 29 thrombotic events were recorded - 10 splanchnic (34.4%), 10 pulmonary embolism (34.4%), 5 deep vein thrombosis (17.2%), 2 cerebral venous sinus thrombosis (6.9%), 1 superficial thrombophlebitis (3.4%). The median follow-up period was 2.2 years (range 0.7-7.5 years) with 16 patients initiated on DOAC (12 rivaroxaban and 4 apixaban) and 8 patients changed from VKA or heparin (3 rivaroxaban, 3 apixaban and 1 edoxaban). Two patients used more than one DOAC in this period. 21 patients were receiving long-term anticoagulation and 3 had defined courses of anticoagulation due to provocation. 21 patients were receiving cytoreductive agents or regular venesection along with anticoagulation. During the total follow-up period of patients receiving DOACs, amounting to 66 pt years, there were no VTE recurrences in 23 patients and indeterminate imaging for 1. There were no episodes of major bleeding but 2 patients (8.3%) had clinically relevant non-major bleeding both of which were taking aspirin in addition to DOAC. Conclusions These results suggest that there were very low/no recurrence rates of VTE and no major bleeding in patients with MPN-associated VTE who are receiving DOACs. These include heterogeneous sites of VTE including splanchnic vein thromboses and cerebral venous sinus thrombosis. Of note, cytoreductive measures were also used in a majority of these patients. We suggest that DOACs could be safely used in this group in appropriately selected patients with MPN. References: 1. Finazzi G, De Stefano V, Barbui T. Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm. Blood Cancer J. 2018; 8(7): 64. 2. De Stefano V, Ruggeri M, Cervantes F et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia. 2016; 30(10): 2032-38. Table Disclosures McLornan: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. Harrison:AOP: Honoraria; Promedior: Honoraria; Gilead: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; CTI: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Incyte: Speakers Bureau.

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Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials

Blood ◽

10.1182/blood-2014-04-571232 ◽

2014 ◽

Vol 124 (12) ◽

pp. 1968-1975 ◽

Cited By ~ 387

Author(s):

Nick van Es ◽

Michiel Coppens ◽

Sam Schulman ◽

Saskia Middeldorp ◽

Harry R. Büller

Keyword(s):

Venous Thromboembolism ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Similar Efficacy ◽

Efficacy And Safety ◽

Phase 3 ◽

Key Points ◽

Acute Venous Thromboembolism

Key Points DOACs have similar efficacy as VKAs in the treatment of acute symptomatic VTE, but significantly reduce the risk of major bleeding. The efficacy and safety of DOACs in the treatment of acute VTE are consistent in clinically important subgroups.

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Impact of Age, Sex, and Renal Function on the Efficacy and Safety of Direct Oral Anticoagulants vs. Vitamin K Antagonists for the Treatment of Acute Venous Thromboembolism: A Meta-Analysis of 22,040 Patients

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.700740 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bo Zhou ◽

Haoyu Wu ◽

Chen Wang ◽

Bowen Lou ◽

Jianqing She

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Creatinine Clearance ◽

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Efficacy And Safety ◽

Acute Venous Thromboembolism

Objective: In this study, we conducted a meta-analysis to assess the impact of age, sex, and renal function on the efficacy and safety of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) for the treatment of acute venous thromboembolism (VTE).Methods: Electronic databases (accessed till June 2021) were systematically searched to investigate randomized clinical trials evaluating apixaban, dabigatran, edoxaban, and rivaroxaban vs. VKAs for the treatment of acute VTE. Results were presented as odds ratio (OR) and 95% CIs.Results: Direct oral anticoagulants were associated with a borderline higher efficacy in women (OR: 0.79, 95% CI: 0.62–1.02), a significantly higher efficacy in patients with age more than 75 years (OR: 0.51, 95% CI: 0.32–0.80), and creatinine clearance <50 ml/min (OR: 0.57, 95% CI: 0.32–0.99). The primary safety endpoint of major or clinically relevant non-major bleeding was significantly reduced in DOACs as compared to VKAs in both patients with age <75 years (OR: 0.79, 95% CI: 0.70–0.89) and patients with age more than 75 years (OR: 0.75, 95% CI: 0.59–0.96). DOACs also show an advantage in terms of major or clinically relevant non-major bleeding in men (OR: 0.72, 95% CI: 0.60–0.86) and patients with creatinine clearance of more than 50 ml/min (OR: 0.75, 95% CI: 0.67–0.84).Conclusions: Direct oral anticoagulants have exhibited clinical preference among patients with acute VTE with decreased thrombosis and bleeding events, especially in patients with age more than 75 years and creatinine clearance <50 ml/min.

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Effectiveness and Safety of Apixaban for Treatment of Venous Thromboembolism in Daily Practice

TH Open ◽

10.1055/s-0040-1713683 ◽

2020 ◽

Vol 04 (02) ◽

pp. e119-e126 ◽

Cited By ~ 1

Author(s):

Stephan V. Hendriks ◽

Frederikus A. Klok ◽

Wilhelmina J.E. Stenger ◽

Albert T.A. Mairuhu ◽

Jeroen Eikenboom ◽

...

Keyword(s):

Venous Thromboembolism ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Daily Practice ◽

Phase Iii ◽

Comparable Efficacy ◽

Phase 3 ◽

Recurrent Vte

Abstract Introduction Phase 3 trials have shown comparable efficacy of direct oral anticoagulants (DOACs) and vitamin K antagonists in patients with acute venous thromboembolism (VTE), with less major bleeding events in patients randomized to DOAC treatment. With DOACs being increasingly used in clinical practice, evaluation of the DOACs in daily practice-based conditions is needed to confirm their safety and effectiveness. The aim of this study is to evaluate the effectiveness and safety of apixaban in VTE patients in daily practice. Methods In this retrospective cohort study, consecutive patients diagnosed with VTE in two Dutch hospitals (Leiden University Medical Center, Leiden and Haga Teaching Hospital, The Hague) were identified based on administrative codes. We assessed recurrent VTE, major bleeding and mortality during a 3-month follow-up period in those treated with apixaban. Results Of 671 consecutive VTE patients treated with apixaban, 371 presented with acute pulmonary embolism (PE) and 300 patients with deep-vein thrombosis. During 3 months treatment, 2 patients had a recurrent VTE (0.3%; 95% confidence interval [CI]: 0.08–1.1), 12 patients had major bleeding (1.8%; 95% CI: 1.0–3.2), and 11 patients died (1.6%; 95% CI: 0.9–2.9), of which one patient with recurrent PE and one because of a intracerebral bleeding. Conclusion In this daily practice-based cohort, apixaban yielded a low incidence of recurrent VTE, comparable to the phase 3 AMPLIFY study patients. The incidence of major bleeding was higher than in the AMPLIFY-study patients, reflecting the importance of daily practice evaluation and the fact that results from phase III clinical studies cannot be directly extrapolated toward daily practice.

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Venous Thromboembolism and Renal Impairment: Insights from the SWIss Venous ThromboEmbolism Registry (SWIVTER)

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0039-1698770 ◽

2019 ◽

Vol 45 (08) ◽

pp. 851-858 ◽

Cited By ~ 3

Author(s):

David Spirk ◽

Tim Sebastian ◽

Martin Banyai ◽

Jürg H. Beer ◽

Lucia Mazzolai ◽

...

Keyword(s):

Venous Thromboembolism ◽

Renal Impairment ◽

Clinical Outcomes ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Real Life ◽

Similar Rate ◽

Increased Risk

AbstractRenal impairment (RI) has increased substantially over the last decades. In the absence of data from confirmatory research, real-life data on anticoagulation treatment and clinical outcomes of venous thromboembolism (VTE) in patients with RI are needed. In the SWIss Venous ThromboEmbolism Registry (SWIVTER), 2,062 consecutive patients with objectively confirmed VTE were enrolled. In the present analysis, we compared characteristics, initial and maintenance anticoagulation, and adjusted 90-day clinical outcomes of those with (defined as estimated creatinine clearance < 30 mL/min) and without severe RI. Overall, 240 (12%) patients had severe RI; they were older, and more frequently had chronic and acute comorbidities. VTE severity was similar between patients with and without severe RI. Initial anticoagulation in patients with severe RI was more often performed with unfractionated heparin (44 vs. 24%), and less often with low-molecular-weight heparin (LMWH) (52 vs. 61%) and direct oral anticoagulants (DOACs; 4 vs. 12%). Maintenance anticoagulation in patients with severe RI was more frequently managed with vitamin K antagonists (70 vs. 60%) and less frequently with DOAC (12 vs. 21%). Severe RI was associated with increased risk of 90-day mortality (9.2 vs. 4.2%, hazard ratio [HR]: 2.27, 95% confidence interval [CI]: 1.41–3.65), but with similar risk of recurrent VTE (3.3 vs. 2.8%, HR: 1.19, 95% CI: 0.57–2.52) and major bleeding (2.1 vs. 2.0%, HR: 1.05, 95% CI: 0.41–2.68). In patients with severe RI, the use of LMWH versus any other treatment was associated with reduced mortality (HR: 0.37; 95% CI: 0.14–0.94; p = 0.036) and similar rate of major bleeding (HR: 0.59, 95% CI: 0.17–2.00; p = 0.39). Acute or chronic comorbidities rather than VTE severity or recurrence may explain increased early mortality in patients with severe RI. The higher rate of VTE recurrence, specifically fatal events, than major bleeding reinforces the need for effective anticoagulation in VTE patients with severe RI.

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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

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.199 ◽

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

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Safety and timing of resuming dabigatran after major gastrointestinal bleeding reversed by idarucizumab

SAGE Open Medical Case Reports ◽

10.1177/2050313x17753336 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1775333 ◽

Cited By ~ 1

Author(s):

Gian Galeazzo Riario Sforza ◽

Francesco Gentile ◽

Fabio Stock ◽

Francesco Caggiano ◽

Enrica Chiocca ◽

...

Keyword(s):

Atrial Fibrillation ◽

Case Report ◽

Major Bleeding ◽

Acute Treatment ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Oral Vitamin ◽

Bleeding Events ◽

Massive Rectal Bleeding

The recent introduction of direct oral anticoagulants, including rivaroxaban, dabigatran, apixaban, and edoxaban, for the acute treatment and secondary prevention of venous thromboembolism and in atrial fibrillation has been shown to provide greater clinical benefit than oral vitamin K antagonists. However, direct oral anticoagulants are associated with adverse events, the most common being major bleeding; such events require the reversal of the anticoagulant effects by specific agents. In this case report, we describe an 87-year-old female with atrial fibrillation treated with dabigatran who had massive rectal bleeding. Idarucizumab 5 g (2 × 2.5 g/50 mL) was successfully used to reverse dabigatran effect; subsequent to this, treatment with dabigatran was resumed, and there were no further bleeding events. This suggests that dabigatran can be safely restarted after major bleeding, but this outcome needs to be confirmed in studies involving larger groups of patients.

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Anticoagulation in Acute Neurological Disease

Seminars in Neurology ◽

10.1055/s-0041-1733793 ◽

2021 ◽

Vol 41 (05) ◽

pp. 530-540

Author(s):

Cina Sasannejad ◽

Kevin N. Sheth

Keyword(s):

Intracerebral Hemorrhage ◽

Neurological Disease ◽

Sinus Thrombosis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Cerebral Venous Sinus Thrombosis ◽

Metabolic Complications ◽

Reversal Agents ◽

Clinical Scenarios ◽

Patients At Risk

AbstractWhile anticoagulation and its reversal have been of clinical relevance for decades, recent academic and technological advances have expanded the repertoire of its application in neurological disease. The advent of direct oral anticoagulants provides effective, mechanistically elegant, and relatively safer therapeutic options than warfarin for eligible patients at risk for neurological sequelae of prothrombotic states, particularly given the recent availability of corresponding reversal agents. In this review, we examine the provenance, indications, safety, and reversal tools for anticoagulant medications in the context of neurological disease, with specific attention to acute ischemic stroke, cerebral venous sinus thrombosis, and intracerebral hemorrhage. We will use specific clinical scenarios to illustrate the complex factors that must be considered in the use of anticoagulation, including intracranial pathology such as intracerebral hemorrhage, traumatic brain injury, or malignancy; metabolic complications such as chronic kidney disease; pregnancy; and advanced age.

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Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-020-02304-3 ◽

2020 ◽

Cited By ~ 2

Author(s):

Marco Valerio Mariani ◽

Michele Magnocavallo ◽

Martina Straito ◽

Agostino Piro ◽

Paolo Severino ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Risk ◽

Bleeding Complications ◽

Efficacy And Safety

Abstract Background Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

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

Journal of Pharmacy Practice ◽

10.1177/0897190018775580 ◽

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.

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P690Incidence of events between vitamin K antagonists and direct oral anticoagulants in patients with cancer

European Heart Journal ◽

10.1093/eurheartj/ehz747.0295 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Pardo Sanz ◽

L M Rincon ◽

G De Lara ◽

A Tamayo ◽

L C Belarte ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Risk ◽

Systemic Embolism ◽

Bleeding Events ◽

Patients With Cancer

Abstract Background Balance between embolic and bleeding risk is challenging in patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF). We aimed to evaluate the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with breast cancer. We also compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer. Methods It is an ambispective observational multicentric study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain in the period 2011–2018. A total of 1237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. The incidence of thromboembolic and major bleeding events according to the antithrombotic strategy with VKAs or DOACs was evaluated in the cohort of 637 patients with cancer. Analysis were conducted using SPSS software V.22.0 and R V.3.5.1, with a two-tailed significance value of 0.05. Results Mean follow-up was 3.1 years. Both groups were similar in age, CHA2DS2-VASc and HASB-LED scores. There was no evidence that the incidence of ischemic stroke/systemic embolism differed between patients with cancer treated with AVK and DOAC after CHA2DS2-VASc adjustment: HR 0.91 (95% CI, 0.42–1.99). In addition, no significant differences in the incidence of major bleeding events were found between DOACs and VKA after adjustment for HAS-BLED score: HR 1.53 (95% CI, 0.93–2.53) (Figure 3). Gastrointestinal bleeding was the main source of haemorrhages in both groups (45% of bleedings among patients treated with DOACs and, 37% in VKAs group). Metastatic disease or active chemotherapy were studied as potential covariates but none of them posed any relevant change in the result. Kaplan-Meier analysis Conclusions Cancer patients treated with DOACs did not differ versus those treated with VKAs with regards to stroke or systemic embolism in a model adjusted for CHA2DS2-VASc. Neither significant differences were found for bleeding events in a model adjusted for baseline HASBLED.

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