Heart and Blood Diseases

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Thrombosis

Pulmonary Embolism

Embolism

Thromboembolism

Venous Thromboembolism

Venous Thrombosis

Embolism and Thrombosis

Vascular Diseases

Lung Diseases

Respiratory Tract Diseases

Samuel Z Goldhaber, MD

Evaluation of physician responses to BICS-Clinical Information 3-screen alerts that informs the clinician that his/her patient may be eligible for thromboprophylaxis.

Background and Significance:

Scope of the Problem: VTE is the third most common cardiovascular disease (heart attack and stroke are more common) but is the most preventable medical problem among patients hospitalized with other illnesses. DVT often causes chronic venous insufficiency, a potentially disabling and painful condition that lowers the quality of life. Acute PE may cause death or disabling chronic thromboembolic pulmonary hypertension. After discharge from a short-term hospital stay, one study reported that the incidence of DVT was 48 per 100,000 and the incidence of PE (with or without DVT) was 23 per 100,000.9 In addition, the incidence of VTE increases dramatically with age.10-11 Clinical manifestations of DVT often include swelling, pain, and extremity discoloration and may lead to PE. Manifestations of PE may include dyspnea, pleuritic pain, cough, and hemoptysis or may be asymptomatic.12-13 The 28-day mortality rate for a first VTE event is alarmingly high, approximately 11%.14 In addition, 3-month mortality rates for PE have been reported as high as 17%.15 However, appropriate prophylaxis-using anticoagulants, mechanical measures, or both anticoagulants plus mechanical measures-can prevent most episodes of VTE16. For example, mechanical measures as simple as "low tech" and inexpensive graduated compression stockings can reduce VTE rates.16a, 16b, 16c

Burden to Patients: VTE is associated with complications including recurrence of DVT or PE, chronic thromboembolic pulmonary hypertension, death, or the subsequent development of post-thrombotic syndrome. The risk of VTE recurrence is greatest within 6-12 months after the first event and continues for at least 10 years,17 and is a risk factor for death after PE.18 The post-thrombotic syndrome can have devastating effects on the patients' quality of life and is associated with venous hypertension that may cause pain, edema, skin changes, varicose veins, and skin ulcers. Valve dysfunction, which can lead to venous hypertension, is most often caused by a previous DVT.19 The cumulative incidence of the development of postthrombotic syndrome after a VTE event is high: 17% at one year, 23% at 2 years, and 29% at 8 years, with 30% of these cases classified as severe.20

Burden to Society: Direct medical costs to the United States health care system related to VTE events and complications approximate at least $600 million annually. Bullano and colleagues21 estimate that managed care plans pay a median of $3,131 per incident DVT, $6,424 per incident PE, and $12,200 for a DVT plus PE combination event. A 2004 registry of 5,451 patients with ultrasound-confirmed DVT at 183 institutions in the United States revealed that DVT led to hospitalization in 80% of those diagnosed as outpatients. Those initially diagnosed with DVT as inpatients remained hospitalized for a median of 12 days.7

Role of computerized healthcare delivery systems:

The use of computerized physician order entry (CPOE) is growing and is currently utilized in about 10% of U.S. Hospitals.22 When linked with clinical decision support, it provides a unique and important tool to improve ordering decisions, thereby reducing medication errors, transcribing errors, decreasing the frequency of adverse drug events, and increasing compliance with evidence-based clinical guidelines.23 This leads to overall improved patient care. There is growing recognition of the importance and utility of CPOE technology, and currently, there is a concerted effort nation-wide to implement it in all hospitals and private practices. CPOE programs provide an excellent platform to increase the implementation of clinical practice guidelines, thereby changing physician behavior.

At Brigham and Women's Hospital, we have developed an electronic alert system, which is integrated with the CPOE system but functions independently. We have created risk score criteria by which the system determines the risk of DVT or PE for a particular patient. All the information needed to accomplish this risk assessment is stored in the computer system, allowing the process to run in an automated fashion. The system according to present criteria determines whether to generate an alert. To do this, the system checks for the existence of current orders for prophylaxis, using the Brigham and Women's Hospital CPOE system. The presence of medication class orders for anticoagulants or general care orders for mechanical prophylaxis prevents the computer from issuing an alert. We will enhance this computerized system to produce a series of alerts that provide more information related to prescription or omission of thromboprophylaxis. We aim to test this new system in our proposed study.

At Brigham and Women's Hospital, we also leverage the use of the multiple outpatient electronic medical records and inpatient CPOE systems to facilitate the process of medication reconciliation before, during, and after the hospital stay. This system aggregates medication data from electronic medical records (EMR) and CPOE systems so that clinicians can efficiently generate an accurate pre-admission medication list. Information collected with the use of this application subsequently supports the writing of admission and discharge orders by physicians, performance of admission assessment by nurses, and reconciliation of inpatient orders by pharmacists. Medication histories are thus seamlessly transferred during transition of care from inpatient admission to discharge to home, rehabilitation, or skilled nursing facilities. This efficient system will allow us to carefully document the use or omission of thromboprophylaxis orders. Furthermore, for 90 day follow-up, we will be able to track thromboprophylaxis prescriptions after hospital discharge by using a combination of the Brigham and Women's Hospital's pharmacy's electronic outpatient prescription reconciliation program and Partners' internally developed EMR, the Longitudinal Medical Record.

The Longitudinal Medical Record is used by our outpatient clinics to record clinical visit information such as history, notes, problems, medications, and allergies, and provides inpatient and outpatient test results, including imaging tests and laboratory blood tests, from 7 Partners-affiliated institutions: Brigham and Women's Hospital, Massachusetts General Hospital, Dana Farber Cancer Institute, Newton Wellesley Hospital, North Shore Medical Center, Faulkner Hospital, and Spaulding Rehabilitation Hospital. The Longitudinal Medical Record is especially useful for following patients who might undergo evaluation for a new problem, such as sudden onset of shortness of breath, at a suburban hospital such as Newton Wellesley Hospital, after a prior hospitalization at Brigham and Women's Hospital for treatment of a complicated medical illness with a high risk of VTE. In our 2005 randomized trial of electronic alerts for VTE prophylaxis,8 we relied upon the Longitudinal Medical Record to achieve 94% follow-up at 90 days of all patients enrolled at Brigham and Women's Hospital.

Between 2000 and 2004, we developed a computer generated alert system for VTE prophylaxis and tested it in a large randomized controlled trial at Brigham and Women's Hospital. The system was linked to the patient database, identifying patients at high risk for VTE (defined as ≥ 4 score points and shown in Table 1) who were not receiving prophylaxis. High-risk patients not receiving VTE prophylaxis were randomized to an intervention group in which their physicians received an electronic alert or a control group in which physicians were not alerted. Patients in the intervention group experienced a 41% reduction in the incidence of symptomatic VTE events within 90 days, without an increase in the risk of major or minor bleeding. However, prophylactic measures were prescribed for only 33.5% of the patients in the intervention group. For the remaining patients (66.5%), we were surprised that physicians declined to implement the suggested intervention, initiation of VTE prophylaxis.

There is still considerable scope for electronic methodology and technology to increase prophylaxis rates and reduce the rates of VTE. Therefore, we will focus these new study initiatives on improving our current methods and strategies to further reduce the incidence of VTE.

Significance of our proposed studies:

Our projects will address several gaps in our understanding of the issues related to implementation of VTE prophylaxis in hospitalized patients. We aim to identify subgroups in the hospitalized population that are at especially high risk for VTE. An improved and novel automated electronic alerting system will facilitate this identification. Our new alert system will be much more rigorous than our prior protocol. The new alert will have three sequential screens rather than the single alert screen that we had in the prior version.

This computerized system will identify hospitalized patients at high risk for VTE and will analyze their records to determine whether they have received thromboprophylaxis orders. If the system identifies any high-risk patient who does not have orders for thromboprophylaxis, then a series of prompts will be issued to the ordering physician. The physician whose patient is at risk for VTE will be requested to institute prophylaxis. If the automated request is not followed, a series of alerts will query reasons for withholding preventive measures. Further prompts will lead to centralized computer-generated ordering of graduated compression stockings, unless the physician opts out and unselects this order. Important elements in the alerts include an up-to-date selection of pharmacological agents, doses based on renal clearance, and the documentation of reasons for withholding prophylaxis by the ordering physician.

We will follow all high-risk patients whose physicians received an alert. We will determine whether within 90 days, the patient has developed symptomatic DVT or PE. The Longitudinal Medical Record will facilitate follow-up after hospital discharge.

Through the use of this novel alert system, we will identify patients at high risk for VTE, maximize the implementation of VTE prophylaxis, learn the rationale for physicians' withholding anticoagulant or mechanical prophylaxis in some high-risk patients, and test whether this novel electronic intervention reduces clinically important episodes of PE and DVT. The success of this program will provide a useful model for dissemination of VTE preventive strategies nationwide and worldwide.

3 Screen Electronic Alert

Multi-Screen Electronic Alert for Venous Thromboembolism Prevention

Eisai Inc.

Brigham and Women's Hospital

Director, VTE Research Group

Diseases and Abnormalities at or Before Birth

Neoplasms

Nervous System Diseases

Aneurysm

Arteriovenous Malformations

Congenital Abnormalities

Hemangioma

Intracranial Aneurysm

Vascular Malformations

Cardiovascular Abnormalities

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Intracranial Arterial Diseases

Cerebrovascular Disorders

Brain Diseases

Central Nervous System Diseases

Fibrinolytic Agents

Anticoagulants

All Drugs and Chemicals

Bone Density Conservation Agents

Heparin

Calcium heparin

Calcium

Calcium, Dietary

First infused with 5000 IU of Heparin Sodium, then continuous infusion at a rate of 18 IU / kg.h during the hybrid operation.

infusion Heparin Sodium at a rate of 18 IU / kg.h during the hybrid operation.

Heparin Sodium

Infusion Heparin Sodium at a rate of 18 IU / kg.h

Yong Cao, Doctor

Yong Cao, M.D.

In the stage of randomized controlled study, our purpose is to obtain the Intraoperative anticoagulation program supported by evidence-based medicine.

This study is divided into anticoagulation program in cerebral aneurysm with hybrid operation and anticoagulation program in cerebral arteriovenous malformations with hybrid operation two parts, and each part divide into two stage, on the stage of registration study. This study is a multi-center, single-blind, prospective cohort study. Record the patient's intraoperative activated coagulation time Changes in detail, to observe the effect of activated coagulation time maintenance level on hemorrhage event rate of Intraoperative and postoperative 48 hours, purpose to find out the safety range of activated coagulation time level in cerebral aneurysm and arteriovenous malformations with hybrid operation. On the stage of randomized controlled study. This study is a multicenter, single-blind, prospective, randomized controlled study. Patients is divided into intraoperative standard dose group of Heparin Sodium and low dose group of Heparin Sodium randomly. To observe the effect of different anticoagulation regimens on activated coagulation time safety coverage rate during surgery, and finally develop a scientific and effective intraoperative anticoagulant therapy program.

Exploration of Anticoagulation Program in Cerebral Aneurysm and Arteriovenous Malformations With Hybrid Operation 2

Multi-center，Single Blind，Prospective Randomized Controlled Trial of Exploration of Anticoagulation Program in Cerebral Aneurysm and Arteriovenous Malformations With Hybrid Operation

Activated coagulation time average value falls in the safety coverage rate from the beginning of surgery to 48 hours after surgery.

Hemorrhage event include intracranial hemorrhage caused by non-surgical reasons, as well as other organs or parts of the massive bleeding or small bleeding, Including subperitoneal hemorrhage, intraocular hemorrhage, gross hematuria, epistaxis time prolonged or repeated, gastrointestinal bleeding, hemoptysis, subconjunctival hemorrhage, hematoma greater than 5cm, bleeding difficult to control the and so on.

Ischemia event include Cerebral infarction and transient ischemic attack.

All the blood lost during the surgery should be collected and measured.

Tang-Du Hospital

Kunming Medical University

First Affiliated Hospital of Fujian Medical University

Nanjing PLA General Hospital

Fujian Medical University Union Hospital

Beijing Tiantan Hospital

principal

Central Nervous System Stimulants

Other Dietary Supplements

Caffeine

Physicians alerted about their high risk patients who are not receiving any VTE prophylaxis.

Physicians not alerted about their high risk patients who are not receiving any VTE prophylaxis.

An alert from study staff informing a physician that his/her patient is at high risk for DVT and/or PE, but is not receiving any prophylaxis.

Human Alert

Samuel Z. Goldhaber, MD

To evaluate physician response to human alerts that inform the clinician that his/her patient may be eligible for thromboprophylaxis. Medical records are reviewed to evaluate prescribing decision and to evaluate rates of venous thromboembolism.

Background Information and Rationale for the Study:

Venous thromboembolism (VTE) is often avoidable in hospitalized patients because proven prevention strategies have been established for patients at risk. North American and European prophylaxis guidelines have been widely disseminated. However, despite intensive educational efforts, VTE prevention remains underutilized.

At Brigham and Women's Hospital, we undertook a comprehensive program aimed at increasing the frequency of VTE prophylaxis in high risk patients. This novel strategy required: 1) devising a risk score that reliably and quickly identified patients at high risk of VTE, and 2) conducting a randomized controlled trial in which high risk patients without prophylaxis were randomized into an intervention or control group. The intervention group's physicians received a single alert explaining that the patient was at high risk, was not receiving prophylaxis, and urged that prophylaxis be selected from a template of available pharmacological and mechanical options. In contrast, the control group's physicians received no alert.

Each of 8 common risk factors was weighted according to a point scale. At least 4 score points were required to be deemed at "high risk" for VTE.

3 of the 8 risk factors were considered major and were assigned a score of 3 points each:

1. Cancer
2. Prior VTE
3. Hypercoagulability

One of the 8 risk factors, surgery, was considered intermediate and was assigned a score of 2.

4 of the 8 risk factors were considered minor and were assigned a score of 1 point each:

1. Advanced age (\> 70 years of age)
2. Obesity (Body Mass Index \> 29)
3. Bed rest
4. Hormone replacement therapy or oral contraceptives

There were 2,506 patients in the randomized controlled trial of a computer alert: 1255 in the intervention group and 1251 in the control group. The incidence of symptomatic VTE at 90 days was high: 8.2% in the control group. This high incidence validates the 8 risk factor and point score methodology.

The intervention group had an overall 41% reduction in VTE, without any increase in major bleeding. There was a 60% reduction in the incidence of symptomatic pulmonary embolism.

Identification of Patients at Risk for Venous Thromboembolism (VTE):

A VTE risk profile will be computed for each hospitalized patient using 8 common risk factors. Each risk factor is weighted according to a point score. To be included in this trial, the point score must equal or exceed 4 points.

Minor (Low) Risk Factors (1 POINT each):

* Advanced Age (\>70 years of age)
* Obesity (BMI \>29, or the presence of the word "obesity" in admission exam notes)
* Bed rest / Immobility (not related to surgery)
* Female Hormone Replacement Therapy or Oral Contraceptives

Intermediate Risk Factor (2 POINTS each):

· Major Surgery (\> 60 minutes)

Major (High) Risk Factors (3 POINTS each):

* Cancer (active)
* Prior VTE
* Hypercoagulability

Increased VTE risk is defined as a cumulative VTE risk score 4, so that patients with at least 1 major risk factor (cancer, prior VTE, or hypercoagulability) plus at least 1 additional intermediate risk factor (major surgery or bed rest) or minor risk factor (advanced age, obesity, or hormone replacement therapy/oral contraceptives) become eligible. In the absence of a major risk factor, patients with 1 intermediate risk factor plus at least 2 minor risk factors become eligible.

Screening for Venous Thromboembolism Prophylaxis:

If the cumulative VTE risk score is ³4, orders are reviewed to detect ongoing mechanical or pharmacological prophylactic measures. Mechanical prophylactic measures include graduated compression stockings and intermittent pneumatic compression devices. Pharmacological prophylactic measures include unfractionated heparin, enoxaparin, dalteparin, fondaparinux, tinzaparin, and warfarin.

Randomization:

Randomization Envelopes containing the statement "ALERT" (Intervention) or "NO ALERT" (Control) will be provided by Harvard Clinical Research Institute (HCRI), to randomize patients who meet all inclusion criteria.

The intervention is informing the responsible physician that: 1) his or her patient is at high risk for VTE, 2) is not receiving prophylaxis, and 3) VTE prophylaxis is recommended. For control patients, VTE prevention guidelines are available, but no specific prompt is provided to use them.

Follow Up:

Ninety-day follow-up is performed in all study patients by medical record review and through contact with the subject's Primary Care Physician.

Data Collection and Study Endpoints:

The primary endpoint is clinically diagnosed DVT or PE at 90 days. Safety endpoints include total mortality and hemorrhagic events at 30 and 90 days, respectively. We define major bleeding as intracranial, intraocular, retroperitoneal, pericardial, or bleeding that requires surgical intervention or that resulted in a hemoglobin loss greater than 3 g/l.

DVT is diagnosed if there is loss of vein compressibility by ultrasound or a filling defect by CT scan or by conventional contrast venography. PE is diagnosed by a positive contrast chest CT scan, a high-probability ventilation perfusion scan, or conventional pulmonary angiogram.

Multi-Center Human Alert Trial to Prevent DVT and PE

Physician Alerts to Prevent DVT and Pulmonary Embolism in Hospitalized Patients

Sanofi

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Infective Agents

Amino Acids

Apixaban

Factor Xa Inhibitors

Antithrombins

Antithrombin III

Protease Inhibitors

Serine Proteinase Inhibitors

HIV Protease Inhibitors

Enzyme Inhibitors

Serine

apixaban 2.5 mg orally twice daily for primary prevention of VTE for a duration of 6 months

Patients living with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE) due to the disease itself and the use of targeted therapies, including immunomodulatory drugs (IMiDs). Prevention of VTE has become a major management challenge during MM treatment. There is a paucity of data with respect to the non-vitamin K oral anticoagulants (NOACs) in the cancer population. However, the NOACs offer comparable efficacy but improved safety compared with warfarin. Apixaban has shown excellent safety and efficacy for treatment and prevention of recurrent VTE (1,2). The safety and efficacy of apixaban for primary prevention of VTE in MM patients has not been established.

Aim #1: To quantify the 6-month rate of major and clinically relevant non-major bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE.

Hypothesis #1: The 6-month rate of major and clinically relevant non-major bleeding in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE will be ≤3% (2). Although the MM population, in general, has a higher medical acuity than that of the previous large randomized controlled trials of apixaban, we will be selecting a stable population of MM patients who are appropriate for immunomodulatory therapy.

Aim #2: To quantify 6-month rate of symptomatic VTE in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE.

Hypothesis #2: The 6-month rate of symptomatic VTE in MM patients receiving IMiDs who are prescribed apixaban 2.5 mg orally twice daily for primary prevention of VTE will be \<7% (3). Although additional therapies for MM such as dexamethasone and erythropoietin-stimulating agents may further increase the risk of VTE, the rate of incident VTE should be reduced to \<7% with apixaban.

MM is associated with an increased risk of venous thromboembolism (VTE). The use of targeted therapies, including immunomodulatory drugs (IMiDs), has improved outcomes for patients with MM but also increases the risk of VTE. Prevention of VTE has become a major management dilemma during MM treatment. There is a paucity of data with respect to the non-vitamin K oral anticoagulants (NOACs) in the cancer population, including patients with MM. However, the NOACs have been shown to offer comparable efficacy but improved safety compared with warfarin. Apixaban has shown excellent safety and efficacy for treatment and prevention of recurrent VTE (1,2). Compared with injectable thromboprophylactic regimens such as enoxaparin, apixaban offers the advantages of being orally administered and less reliant on renal clearance. The safety and efficacy of apixaban for primary prevention of VTE in MM patients has not been established. The current study will evaluate apixaban (2.5 mg twice daily) in a patient population without a history of prior VTE. Although the current study population is high risk for VTE, it is likely to be lower risk for VTE than those of the prior randomized controlled trials of apixaban for secondary prevention. Furthermore, current practice is to provide MM patients receiving IMiDs with prophylactic doses (not treatment doses) of low-molecular weight heparin (such as enoxaparin 40 mg injected daily). Accordingly, the rationale to test apixaban (2.5 mg twice daily) is consistent with the standard practice of prophylactic anticoagulation.

The current study will provide event rates that will inform the design of a larger randomized controlled trial. If safe and effective, apixaban will satisfy a critical unmet need and will represent a substantial advance and "game changer" in the prevention of VTE in this high risk patient population.

Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma

Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma Receiving Immunomodulatory Therapy

Symptomatic deep vein thrombosis or pulmonary embolism

Major and clinically relevant non-major bleeding. Using the ISTH classification, bleeding is defined as major if it is overt and associated with a decrease in the hemoglobin level of 2 g/dL or more, requires the transfusion of 2 or more units of blood, occurs into a critical site, or contributes to death (12).

Using the ISTH classification, clinically relevant nonmajor bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, surgical intervention, or interruption of the study drug.

All-cause mortality at 6 months will be recorded. Cause of death will be classified as related to cancer, myocardial infarction, PE, other cardiovascular or other disease state. Death will be attributed to PE if there is evidence to support an association with PE.

6-month rates of myocardial infarction and stroke will be calculated.

Bristol-Myers Squibb

Gregory Piazza

Sponsor Investigator

apixaban 2.5 mg orally twice daily for primary prevention of VTE for a duration of 6 months

Apixaban: apixaban 2.5 mg orally twice daily for primary prevention of VTE for a duration of 6 months

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

The study is limited by small sample size. The study included 10 patients receiving IMiD monotherapy for maintenance which are patients at lowest risk for VTE due to the absence of dexamethasone and low disease burden.

Frequency of Symptomatic Venous Thromboembolism

Frequency of Major and Clinically Relevant Non-major Bleeding

Frequency of All-cause Mortality

Frequency of Atherothrombotic Events

Overall Study

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Lymphatic Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Acute Graft Versus Host Disease

Pharmaceutical Solutions

Antineoplastic Agents

Asparaginase

Children aged 1 to \<18 years weighing 6 to \<35 kg randomized to apixaban will receive a fixed dose apixaban based on body weight tier twice a day for approximately 28 days.

Children aged 1 to \<18 years weighing ≥ 35 kg will receive 2.5 mg of apixaban twice a day for approximately 28 days. Subjects ≥ 5 years may be administered either 2.5-mg, 0.5-mg tablets or oral solution apixaban. Subjects \< 5years and \< 35 kg may be administered 0.5-mg tablets only

No systemic anticoagulant prophylaxis

The purpose of this study is to compare the effect of a blood thinning drug called Apixaban versus no administration of a blood thinning drug, in preventing blood clots in children with leukemia or lymphoma. Patients must be receiving chemotherapy, including asparaginase, and have a central line (a catheter inserted for administration of medications and blood sampling)

A Study of the Safety and Effectiveness of Apixaban in Preventing Blood Clots in Children With Leukemia Who Have a Central Venous Catheter and Are Treated With Asparaginase

A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of Apixaban for Thromboembolism Prevention Versus No Systemic Anticoagulant Prophylaxis During Induction Chemotherapy in Children With Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoma (T or B Cell) Treated With Asparaginase

The number of participants with non-fatal deep vein thromboses (DVT) (including asymptomatic and symptomatic), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST); and venous thromboembolism (VTE) related-death objectively confirmed by a blinded, independent adjudication committee.

Symptomatic events are included during the intended treatment period. Asymptomatic events are included from scans up to Day 40.

The number of participants with major bleeding adjudicated by a blinded, independent adjudication committee. Adjudicated major bleeding is defined as bleeding that satisfies one or more of the following criteria:

1. fatal bleeding
2. clinically overt bleeding associated with a decrease in hemoglobin of at least 20g/L (ie, 2g/dL) in a 24-hour period
3. bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; and/or
4. bleeding that requires surgical intervention in an operating suite, including interventional radiology.

The number of participants with non-fatal asymptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee

The number of participants with non-fatal symptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee

The number of participants with non-fatal pulmonary embolism (PE) adjudicated by a blinded, independent adjudication committee

The number of participants with cerebral venous sinus thrombosis (CVST) adjudicated by a blinded, independent adjudication committee

The number of participants with venous thromboembolism (VTE)-related-death adjudicated by a blinded, independent adjudication committee

The number of participants with major and clinically relevant non-major bleeding (CRNMB) adjudicated by a blinded, independent adjudication committee

CRNM bleeding is defined as bleeding that satisfies one or both of the following:

1. overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition and
2. bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room

The number of participant deaths adjudicated by a blinded, independent adjudication committee

The number of participants with an arterial thromboembolic event including paradoxical embolism and stroke adjudicated by a blinded, independent adjudication committee

The number of participants with a central venous access device (CVAD)-related infection adjudicated by a blinded, independent adjudication committee

The number of participants needing catheter replacements during the study

The number of participants with central venous access device (CVAD) patency restoration events after thrombolytic therapy use

The number participants experiencing superficial vein thrombosis events.

Clots that occur in a superficial vein ie, cephalic vein, basilic vein (upper extremity) or saphenous vein (lower extremity) confirmed by radiographic imaging.

The number of participants with clinically relevant non-major bleeding events (CRNMB) adjudicated by a blinded, independent adjudication committee.

CRNM bleeding is defined as bleeding that satisfies one or both of the following:

1. overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition and
2. bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room

The number of participants with minor bleeding events adjudicated by a blinded, independent adjudication committee.

Minor bleeding defined as any overt or macroscopic evidence of bleeding that does not fulfill the criteria for either major bleeding or CRNMB

The number of platelet transfusions needed during the study.

The events are not adjudicated. A subject could have more than one platelet transfusion.

The maximum observed concentration (Cmax) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.

The trough observed concentration (Cmin) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.

The area under the concentration-time curve \[AUC(TAU)\] was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.

Anti-FXa Activity was measured to characterize the relationship between apixaban plasma concentration and anti-FXa activity in pediatric subjects receiving induction chemotherapy

Pfizer

Participants will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase

No systemic anticoagulant prophylaxis during induction chemotherapy

Standard of Care

Participants will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase.

Weight range - Dose

\>/=35 kg - 2.5 mg twice daily \<35 to 25 kg - 2 mg twice daily \<25 to 18 kg - 1.5 mg twice daily \<18 to 10.5 kg - 1 mg twice daily \<10.5 to 6 kg - 0.5 mg twice daily

Total

Ethnicity (NIH/OMB)

Bristol-Myers Squibb Study Director

The Number of Participants With Non-Fatal DVT, PE, and CVST, and VTE-Related-Death

The Number of Participants With Adjudicated Major Bleeding

The Number of Participants With Non-fatal Asymptomatic Deep Vein Thromboses (DVT)

The Number of Participants With Non-fatal Symptomatic Deep Vein Thromboses (DVT)

The Number of Participants With Non-fatal Pulmonary Embolism (PE)

The Number of Participants With Cerebral Venous Sinus Thrombosis (CVST)

The Number of Participants With Venous Thromboembolism (VTE)-Related-death

The Number of Participants With Major and Clinically Relevant Non-Major Bleeding (CRNMB)

The Number of Participant Deaths

The Number of Participants With an Arterial Thromboembolic Event

The Number of Participants With a CVAD-Related Infection

The Number of Participants Needing Catheter Replacements During the Study

The Number of Participants With CVAD Patency Restoration Events After Thrombolytic Therapy Use

The Number Participants Experiencing Superficial Vein Thrombosis Events

The Number of Participants With Clinically Relevant Non-Major Bleeding Events (CRNMB)

The Number of Participants With Minor Bleeding Events

The Number of Platelet Transfusions Needed During the Study

Participants will be administered 2.5mg apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase

Participants Weight Range ≥ 35 kg

Participants will be administered 2mg apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase

Participants Weight Range 25 to < 35 kg

Participants will be administered 1.5mg apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase

Participants Weight Range 18 to < 25 kg

Participants will be administered 1mg apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase

Participants Weight Range 10.5 to < 18 kg

All randomized participants in the apixaban arm with available pharmacokinetic data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
3 Screen Electronic Alert	NCT00550082	Deep Vein Throm... Pulmonary Embol... Cancer		18 Years -	Brigham and Women's Hospital
Exploration of Anticoagulation Program in Cerebral Aneurysm and Arteriovenous Malformations With Hybrid Operation 2	NCT03306836	Cerebral Aneury... Arteriovenous M...	Heparin Sodium Heparin Sodium	- 70 Years	Beijing Tiantan Hospital
Multi-Center Human Alert Trial to Prevent DVT and PE	NCT00409136	Pulmonary Embol... Deep Vein Throm... Cancer Surgery	Human Alert	18 Years -	Brigham and Women's Hospital
Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma	NCT02958969	Venous Thromboe... Multiple Myelom...	Apixaban	18 Years -	Dana-Farber Cancer Institute
Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma	NCT02958969	Venous Thromboe... Multiple Myelom...	Apixaban	18 Years -	Dana-Farber Cancer Institute
A Study of the Safety and Effectiveness of Apixaban in Preventing Blood Clots in Children With Leukemia Who Have a Central Venous Catheter and Are Treated With Asparaginase	NCT02369653	Lymphoma Acute Lymphobla...	Apixaban No systemic ant...	1 Year - 17 Years	Bristol-Myers Squibb
Exploration of Anticoagulation Program in Cerebral Aneurysm and Arteriovenous Malformations With Hybrid Operation 1	NCT03306823	Cerebral Aneury... Arteriovenous M...		- 70 Years	Beijing Tiantan Hospital
Multi-Center Human Alert Trial to Prevent DVT and PE	NCT00409136	Pulmonary Embol... Deep Vein Throm... Cancer Surgery	Human Alert	18 Years -	Brigham and Women's Hospital
Study on Thrombosis Therapy in German Cancer Patients	NCT01559883	Cancer Deep Vein Throm... Pulmonary Embol...	no intervention...	18 Years -	LEO Pharma

Spots Global Cancer Trial Database for anticoagulation