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INTRODUCTION

Venous thromboembolism (VTE) is a significant cause of morbidity, mortality, and long-term disability worldwide, especially in patients hospitalized with an acute medical illness. One of the two major types of VTE, deep-vein thrombosis (DVT) is a venous blood clot that completely or partially occludes a vein, typically in the lower extremities such as the thigh or pelvis and leading to ischemia and pain. More importantly, DVT is a significant cause of pulmonary embolism (PE) — venous blood clots in the lungs that can result in occlusion of pulmonary blood flow.

Key signs and symptoms of PE are shortness of breath and hypoxia; the condition carries a high risk of sudden death.¹ More than 40% of proximal DVTs create emboli that lodge in the lungs; in 70% of patients experiencing a PE, a DVT is also found.² Because of this interconnectedness of the two conditions and the severity of outcomes, it is important to prevent and treat DVTs even when asymptomatic.

EPIDEMIOLOGY, MORTALITY, AND COSTS OF VTE CARE

Each year, more than 10 million cases of VTE are reported worldwide.³ In the United States, the incidence of VTE is estimated at 1.1 to 2.2 per 1,000 person–years.⁴ VTE is responsible for more than 500,000 hospitalizations annually in the United States.⁵ While unknown , the number of VTE-associated deaths in the United States is estimated to be between 100,000 and 300,000 per year.^5,6 Thirty-day mortality following VTE is 18% (5.5% following DVT alone and 44.4% following PE with or without DVT).⁴ Of DVT-, PE-, and VTE-associated deaths, only 8% are diagnosed antemortem, while 34% occur suddenly following a diagnosis of PE; in 59% of patients, the diagnosis of PE is found postmortem.⁴

Patients who are hospitalized or were recently hospitalized are particularly prone to developing VTE. Approximately 60% of all VTE cases are associated with a recent hospital stay, making its prevention a leading concern.³ Hospital-associated VTE is the leading cause of hospital-associated death and disability worldwide regardless of economic status of the country; it is responsible for more deaths and greater disability in hospitalized patients than adverse drug events, nosocomial pneumonia, and catheter-associated blood stream infections.^3,7 The annual costs of VTE are substantial, estimated to be as high as $69.3 billion; preventable hospital-associated VTE costs $14.2 billion.⁸

COMPLICATIONS OF VTE

The risk of a patient experiencing a recurrent VTE event is approximately 30% over 10 years and is highest within the first 6 to 12 months following a first event.⁹ Recurrent VTE events are more common in patients with PE than in patients with DVT and higher in those with idiopathic or unprovoked VTE, in whom no identified risk factors or cause are found, such as thrombophilia, surgery, vein trauma, or immobilization. Following cessation of anticoagulation, recurrence rates of DVT or PE are as follows¹⁰:

• For patients experiencing VTE following surgery — 1% after 1 year and 3% after 5 years
• For patients with a nonsurgical reversible risk factor — 5% after 1 year and 15% after 5 years
• For patients with unprovoked VTE — 10% after 1 year and 30% after 5 years

Following DVT, between 30% and 50% of patients develop postthrombotic syndrome (PTS).^11,12 Also called chronic venous insufficiency, PTS occurs when a blood clot damages or destroys one or more venous valves whose function is to promote blood flow back to the heart while an individual is sitting or standing. Symptoms of PTS include leg heaviness (especially at the end of the day or after prolonged standing), cramps, pruritus, and paresthesias, often accompanied by leg edema. Leg ulcers can develop in up to 10% of patients with PTS. Graduated elastic compression stockings (30–40 mm Hg pressure) are often recommended for prevention of PTS, although the efficacy of stockings has been questioned in results of recent trials.¹¹ PTS adversely affects patients' quality of life and is a significant economic burden in the United States; treatment costs exceed $200 million annually.¹³

Chronic thromboembolic pulmonary hypertension (CTEPH), a type of pulmonary hypertension that occurs secondary to unresolved or repeated thromboembolic events in the lungs, is a late complication of PE that develops in 0.1% to 9.1% of those surviving PE. The most common risk factor for this complication, a history of PE, is reported by about 80% of patients with CTEPH.¹⁴ Early symptoms of CTEPH may be absent. Diagnosis is often difficult as symptoms of CTEPH include dyspnea and hemoptysis, which are similar to those of PE. Patients often develop right-sided heart failure from increased pressures and workload. Three-year survival rates in patients diagnosed with CETPH are between 11% and 30% depending on risk factors and treatments.¹⁵

REVIEW OF GUIDELINES FOR PREVENTING VTE IN PATIENTS HOSPITALIZED WITH ACUTE MEDICAL ILLNESS

Two-thirds of all cases of VTE are associated with at least one identifiable risk factor; remaining cases are idiopathic.¹⁶ As mentioned previously, hospitalization for acute medical illness is the most common single risk factor for developing VTE. Patients hospitalized for acute medical illness have a 10-fold increased risk of developing VTE compared with other community dwellers.¹⁷

In the absence of appropriate VTE prophylaxis measures, 10% to 40% of patients hospitalized with acute medical illness develop VTE.¹⁸ Acute medical illnesses associated with an increased VTE risk in hospitalized patients are listed in Table 1.^18,19 Additional risk factors for VTE in nonsurgical patients hospitalized with acute medical illness are shown in Table 2.¹⁸ Most hospitalized medical patients have multiple medical conditions and/or risk factors.¹⁸

Patient Case 1 Patient 1, JS, is a 71-year-old, 75-kg male (BMI, 25 kg/m2) with a history of asthma who is admitted to the medical unit with a diagnosis of influenza and pneumonia. His admission VS are BP 133/88 mm Hg, HR 95 bpm, RR 25, T 103.3. His admission laboratories are WNL except an increased WBC with a left shift. He requires 2 L oxygen by nasal cannula to maintain an oxygen saturation of 97%. Blood culture results are pending. There is an order for complete bedrest in the medical record. The patient is receiving a nebulized beta agonist and intravenous antibiotics. His anticipated length of hospitalization is 4 days. What are Patient 1/JS's risk factors for VTE? Answer: JS's risk factors for VTE are that he is hospitalized with acute medical illness (infection), age >70 years, and immobility.

Patient Case 2 Patient 2, LL, is a 68-year-old black female (weight, 100 kg) with a history of hypertension, type 2 diabetes, and chronic kidney disease who was admitted to the coronary intensive care unit (CCU) with hypertension and acute heart failure. Her "dry" weight at her last clinic visit was 90 kg. Her physical exam is notable for leg edema and rales on respiratory exam. Her current medications include furosemide (intravenous), aspirin, atorvastatin, lisinopril, carvedilol, and insulin (metformin to be restarted at hospital discharge). Her VS are BP 170/100 mm Hg, HR 95 bpm, RR 18, T 97.8. Her laboratories are WNL except serum creatinine of 1.32 mg/dL (estimated GFR 51.5, estimated CrCl 64.4 mL/min) and blood glucose of 280 mg/dL. There is an order for complete bedrest in the medical record. Her anticipated length of hospitalization is 7 days. What are Patient 2 LL's risk factors for VTE? Answer: Patient 2 LL's risk factors for VTE are that she is hospitalized with acute medical illness (heart failure) and immobility.

Table 1. Acute Medical Illnesses Associated with Venous Thromboembolism Stroke Heart failure Cancer Chronic obstructive pulmonary disease exacerbation Infection Myocardial infarction Sepsis

Table 2. Selected Additional Risk Factors for Venous Thromboembolism in Hospitalized Nonsurgical Patients with Acute Medical Illness18,19,20 Immobility Prior VTE Age >70 years Leg edema Hemiplegia Inflammatory bowel disease Obesity Inherited or acquired thrombophilia Presence of a central venous catheter Platelet count >350 x 109/L Elevated D-dimer Abbreviation used: VTE, venous thromboembolism.

VTE Risk Assessment Models for Patients Hospitalized with Acute Medical Illness

In the most current consensus guidelines from the American College of Chest Physicians, anticoagulant thromboprophylaxis is recommended for all patients hospitalized for acute medical illness unless they are identified as low risk.²¹ Risk assessment has been shown to reduce VTE-associated mortality and 30-day hospital readmission. The International Society of Thrombosis and Haemostasis (ISTH) recommends VTE risk assessment in all hospitalized patients.²²

Several risk assessment models (RAM) have been studied for stratifying hospitalized patients with acute medical illness as low (<1%) or high risk for VTE.²³ Four of the most common validated tools used in practice are the PADUA risk score, GENEVA and Simplified GENEVA risk scores, and the IMPROVE-RAM (Table 3).^24-30 In the trials used in developing these RAMs, risk was assessed at 3 months (90 days) after admission.^24-30 High-risk patients have a 3-to 4-fold higher rate of VTE occurrence at 90 days after hospital admission, compared with those at low risk.²⁰

Gibson et al. recently advocated the addition of a baseline D-dimer laboratory test (increased risk at ≥2 times the upper limit of the normal) into the IMPROVE-RAM tool to improve VTE risk discrimination and classification of low-and high-risk patients.¹⁹ This biomarker has not yet been incorporated by professional associations into clinical practice guidelines.

In VTE RAMs, the definitions of immobility vary widely qualitatively and quantitatively. Most use terms such as "immobile," "bedrest," or "chairbound."³¹ Table 3 lists common RAM definitions.

Calculate Patient 1/JS's PADUA risk score. Is this patient at low or high risk for VTE? Answer: JS's PADUA risk score is 6 points (reduced mobility, 3 points; age ≥70, 1 point; respiratory failure, 1 point; infection, 1 point). Because the score is >3, this patient is at high risk of VTE. Other risk scores may give different assessments.

Calculate Patient 2/LL's IMPROVE risk score. Is this patient at low or high risk for VTE? Answer: LL's IMPROVE risk score is 3 points (CCU admission, 1 point; age >60, 1 point; length of hospitalization, 1 point). Because the score is ≥3, this patient is at high risk for VTE. Other risk scores may give different assessments.

Table 3. Clinical Venous Thromboembolism Risk Prediction Tools for Patients Hospitalized with Acute Medical Illness
Risk Assessment Model	Risk Factors	Weighting of Risk Factors	Risk Classification	Web Address of Risk Calculator
GENEVA Risk Score24	Active malignancy Previous VTE Known hypercoagulable state Cardiac failure Respiratory failure Recent stroke (<30 months) Recent myocardial infarction (<1 month) Acute infection (including sepsis) Acute rheumatic disease Nephrotic syndrome	2 points each	Low risk: 1–2 points High risk: ≥3 points	Not available
	Immobilization (complete bedrest or inability to walk for >30 min/d for >3 days) Age >60 years BMI >30 kg/m2 Recent travel >6 hours Chronic venous insufficiency Pregnancy Hormonal therapy Dehydration (assessed subjectively by the treating physician)	1 point each
Simplified GENEVA Risk Score25	Previous VTE	3 points	Low risk: 1–2 points High risk: ≥3 points	Not available
	Hypercoagulable state Cancer or myeloproliferative syndrome Cardiac or respiratory failure Acute infection or rheumatic disease Immobilization (complete bedrest or inability to walk for more than 30 min for at least 3 days)	2 points each
	Age >60 years BMI >30 kg/m2 Recent stroke or myocardial infarction	1 point each
PADUA Risk Score26	Active cancer (metastases or treatment <6 months ago) Previous VTE (with exclusion of superficial vein thrombosis) Thrombophilia Reduced mobility (bedrest with bathroom privileges either due to the patient's limitations or physician's order for ≥3 days)	3 points each	Low risk: 0–3 points High risk: ≥4 points	https://www.mdcalc.com/padua-prediction-score-risk-vte
	Recent (≤1 month) trauma and/or surgery	2 points
	Age ≥70 years Heart and/or respiratory failure Acute myocardial infarction or ischemic stroke Acute infection and/or rheumatologic disorder Obesity (BMI ≥30 kg/m2) Ongoing hormonal treatment	1 point each
IMPROVE-RAM27-29	Previous VTE	3 points	Low risk: 0–2 points High risk: ≥3 points	http://www.outcomes-umassmed.org/improve/risk_score/index.html
	Cancer Thrombophilia Lower limb paralysis	2 points each
	Immobilization >7 days Age >60 years Stay in intensive-or cardiac-care unit	1 point each
Intermountain RAM30	Prior VTE An order for bedrest Peripherally inserted central venous catheter Cancer diagnosis	1 point each	Low risk: 0 points High risk: ≥1 points	Not available
Abbreviations used: BMI, body mass index; VTE, venous thromboembolism.

The IMPROVE RAM was conceptually developed to be used in conjunction with a bleeding risk assessment tool, the IMPROVE bleeding risk score (BRS). The IMPROVE BRS is used to assess the benefit versus risk of using anticoagulant VTE prophylaxis.^32,33

The IMPROVE BRS consists of 13 weighted risk factors for major bleeding in patients with acute medical illness (Table 4).³² In a validation study, the odds ratio of major bleeding in patients with an IMPROVE BRS score of ≥7 versus those with a score of <7 (adjusted for the administration of anticoagulant prophylaxis) was 2.6 (95% CI: 1.1–5.9).³³ Rosenberg et al. found that an IMPROVE BRS score of ≥7 was associated with a 2.3-fold increased risk of any bleeding (4.68% vs. 2.12%, P <0.0001) and a 2.2-fold increased risk of major bleeding (3.2% vs 1.5%, P <0.0001) compared with patients with a score of <7.³⁴

While the IMPROVE BRS has been validated, it has not been commonly incorporated into U.S. practice guidelines at this time. Patients who are actively bleeding or are estimated to be at high risk of bleeding should receive nonpharmacologic VTE prophylaxis using graduated compression stockings (GCS) or intermittent pneumatic compression (IPC).

What are Patient 2/LL's risk factors for bleeding with anticoagulant VTE prophylaxis according to the IMPROVE Bleeding Risk Assessment score? Answer: LL's IMPROVE Bleeding Risk Assessment score is 4.5 points: GFR 30–60, 1 point; age 40– 84 years, 1 point; ICU admission, 2.5 points. Because the score is less than 7, this patient would not be classified as high risk for bleeding with anticoagulation for VTE prophylaxis.

Table 4. IMPROVE Bleeding Risk Assessment Score in Patients with Acute Medical Illness32
Risk Factor for Major Bleeding	Point(s)
GFR 30–59 vs ≥60 mL/min/m2 Male vs female Age 40–84 years vs <40 years Current cancer Rheumatic disease Presence of central venous catheter     ICU/CCU admission GFR <30 vs ≥60 mL/min/m2    Hepatic failure (INR >1.5)       Age 85 years vs 40 years Platelet count <50 x 109 cells/L   Bleeding in 3 months before admission  Active gastroduodenal ulcer	1 1 1.5 2 2 2 2.5 2.5 2.5 3.5 4 4 4.5
Abbreviations used: GFR = glomerular filtration rate, ICU = intensive care unit, CCU = coronary care unit, INR = international normalized ratio.

U.S. Clinical Practice Guidelines for VTE Prophylaxis in Acutely Ill Medical Patients

The 2012 American College of Chest Physicians (ACCP) guidelines for VTE prophylaxis for nonsurgical patients with acute medical illness recommend VTE risk assessment in all patients.²¹ For acutely ill patients with medical illness, not at low risk and including patients who are critically ill, thromboprophylaxis with either low-molecular weight heparin (LMWH), low-dose subcutaneous (subcut) unfractionated heparin (UFH) twice daily, low-dose UFH subcut three times daily, or fondaparinux is recommended (Table 5).²¹

While apixaban, dabigatran, and rivaroxaban are approved for VTE prophylaxis following hip replacement surgery and apixaban and rivaroxaban are approved for VTE prophylaxis following knee replacement surgery, they are not approved by FDA for VTE prophylaxis for patients with acute medical illness. While fondaparinux has been studied for VTE prophylaxis in medical patients, it is not approved by FDA for that use and has been typically reserved for patients needing VTE prophylaxis who have a recent history of heparin-induced thrombocytopenia.³⁵ For patients who are actively bleeding or considered high risk for bleeding, nonpharmacologic prophylaxis with GCS or IPC are recommended.²¹

While not the focus of this review, the American Heart Association (AHA) and American Stroke Association (ASA) recently updated the recommendations for acute stroke management and gave a class I recommendation to IPC and a grade IIb recommendation to UFH and LMWH added to usual care of aspirin and hydration for VTE prevention. There was concern noted for an increased risk of intracranial and extracranial bleeding with heparins compared with IPC. The AHA/ASA 2018 guidelines specifically recommend against use of GCS alone.³⁶

Table 5. 2012 ACCP Recommendations for Venous Thromboembolism in Nonsurgical Patients with Acute Medical Illness21

Low-dose UFH 5000 units subcut every 12 hours Low-dose UFH 5000 units subcut every 8 hours Enoxaparin 40 mg subcut once daily for patients with CrCl ≥30 mL/min Enoxaparin 30 mg subcut once daily for patients with CrCl <30 mL/min Dalteparin 5000 units once daily

Abbreviations used: CrCl, creatinine clearance estimated using actual body weight; subcut, subcutaneously; UFH, unfractionated heparin.

A meta-analysis of more than 34,000 patients reported the efficacy and safety of UFH and LMWHs for prophylaxis in hospitalized medical patients for VTE prophylaxis, excluding patients with stroke and myocardial infarction. In 10 randomized controlled trials of either LMWH or UFH compared with placebo or no treatment, use of "heparins" reduced the odds of DVT, but not PE, and increased the frequency of major bleeding. Heparins had no effect on mortality. LMWHs significantly reduced the risk of DVT compared with UFH in a meta-analysis of six trials (OR 0.77; 95% CI 0.62–0.96) with no difference in PE or mortality. Major bleeding was also significantly reduced with LMWHs (OR 0.43; 95% CI 0.22–0.83).³⁷

A second meta-analysis of 8 randomized controlled trials of more than 8,000 patients evaluating LMWHs and fondaparinux found that the rate of symptomatic plus asymptomatic DVT (assessed using ultrasound) was reduced by almost 50% compared with controls (2.70% vs 5.01%, OR 0.520; 95% CI 0.41–0.67) as was the frequency of all-cause VTE (symptomatic and asymptomatic DVT plus PE) (3.1% vs 5.8%, OR 0.512; 95% CI 0.41–0.64).³⁸ Symptomatic DVT and PE were infrequent and not statistically reduced with anticoagulants (DVT, 0.5% vs 1.0%, and PE, 0.43% vs 0.87%, in treated vs controls).³⁸

Over the past 10 years, the price of UFH has increased and the prices of LMWHs have decreased. A recent cost-effectiveness analysis suggests that use of LMWHs are cost-saving (estimated at Can$9.27) and result in a small incremental quality-adjusted life–year (QALY) gained of 0.0000108 over a 3-month time horizon. The primary driver of the cost savings is reduced rate of VTE. In this analysis cost-effectiveness of long-term models also demonstrated that LMWH was dominant.³⁹

VTE Prophylaxis in Acutely Ill Medical Patients

Recent data from the National Inpatient Sample of 20.8 million evaluable inpatients discharged from U.S. acute care hospitals in 2014 indicated that 35% (7.3 million) met 2012 ACCP criteria for VTE prophylaxis.⁴⁰ In a single-center, observational trial of patients admitted to Mayo Clinic Hospital in Olmstead County, MN, a VTE prophylaxis rate of more than 90% (median hospital stay of 3 days and prophylaxis duration of 70 hours) was reported, suggesting that low-risk patients may be receiving prophylaxis.⁴¹

More recently, this finding was confirmed in a preliminary report from the Michigan Hospital Safety Collaborative, which included data from 51 hospitals and reported that 4 of 5 patients at either low risk for VTE or high risk for bleeding (defined by PADUA or IMPROVE RAMs) were receiving prophylaxis. Therefore, more attention is needed to identify the most appropriate patients to receive anticoagulant VTE prophylaxis.⁴²

Duration of VTE Risk in Patients Hospitalized with Acute Medical Illness

In a clinical trial of 236 patients screened with ultrasound at the time of hospital admission, DVT was found in 6% of asymptomatic patients, suggesting that individual risk factors and not just hospitalization are important predictors of thrombosis.⁴³ During hospitalization, fewer than 1% of patients with acute medical illness are diagnosed with symptomatic VTE.³⁰ Most of the studies described above evaluated thromboprophylaxis given for the acute hospitalization period of approximately 6 to 14 days.⁴⁴ The 2012 ACCP guidelines for VTE prophylaxis for nonsurgical patients specifically recommend against extended prophylaxis outside of the hospitalization period.²¹

More recent information from the IMPROVE Registry of more than 15,000 patients with acute medical illness suggests that much of the elevated VTE risk occurs after the hospital stay, with a reported medium time to symptomatic VTE event of 17 days (IQR 6–43 days) and medium time to postdischarge symptomatic event of 44 days (IQR 25–68 days).²⁶ The rate of symptomatic VTE events doubled in the first 21 days after discharge, and the rate of fatal PE was 5 times higher in the first 30 days postdischarge than during hospitalization.²⁶ An observational trial of 989 high-risk medical patients hospitalized in the Canadian province of Calgary indicated that 80% of symptomatic VTE events occurred within 57 days of hospital discharge.⁴⁵ In the Michigan Hospital Safety Collaborative study, 75% of reported cases of VTE occurred following hospital discharge (median 19.5 days).⁴² These data suggest that a longer duration of VTE prophylaxis should be considered.

A study of Market Scan Medicare and commercial insurance data from more than 17,000 patients hospitalized with acute medical illness reported a median duration of hospitalization of 5 days and median duration of VTE prophylaxis of 5.6 days.⁴⁶ Only 7.1% of patients received both inpatient and outpatient prophylaxis. These data suggest an unmet medical need for VTE prophylaxis.⁴⁶

Four large randomized controlled trials have evaluated a strategy of shorter-versus extended-duration prophylaxis (Table 6).^47-51 In the EXCLAIM, ADOPT, MAGELLAN, and APEX trials, in-hospital, short-duration prophylaxis for 6–14 days was compared with extended-duration prophylaxis (up to 30 days after hospital discharge) in more than 36,000 hospitalized patients with acute medical illness. In EXCLAIM and MAGELLAN, extended-duration enoxaparin and rivaroxaban reduced the frequency of VTE events but increased the risk of major bleeding.^47,49 In ADOPT, an extended course of treatment with apixaban was not superior to a short-course treatment with enoxaparin and bleeding was increased.⁴⁸ In the APEX trial, betrixaban, a new direct oral anticoagulant (DOAC) that inhibits factor Xa, reduced VTE events but did not increase major bleeding. The composite safety outcome of major or clinically relevant nonmajor bleeding was increased with betrixaban compared with placebo.^50,51

Three meta-analyses have reported outcomes of a strategy of shorter-versus extended-duration prophylaxis.^52-54 The analysis by Liew et al. found a 48% reduction in symptomatic proximal or distal DVT [0.34% vs 0.66%; RR 0.52, 95% CI 0.35–0.77); NNT 313], a 39% reduction in symptomatic nonfatal PE [0.24% vs 0.4%, RR 0.6, 95% CI 0.38–0.99, NNT 625] with an increased risk of major bleeding (0.78% vs 0.37%; RR 2.8, 95% CI 1.50–2.90, NNH 244]. However, they did note trial heterogeneity with betrixaban in the APEX trial.⁵² Similar results were reported by both Cohen et al. and Dentali et al.^53,54 No differences were found in either VTE mortality or overall mortality.^52-54

With the exception of results from the APEX trial, these aggregate data support a limited role for either enoxaparin or DOACs in extended VTE prophylaxis in acutely ill medical patients. The 2012 ACCP guidelines recommend against extended prophylaxis.²¹ At that time, the results of EXCLAIM were available and did not support a role for extended prophylaxis. Betrixaban is the only agent that has been approved by the FDA for this indication.⁵¹

According to the 2012 ACCP Guidelines for VTE Prophylaxis in Nonsurgical Patients and FDA drug approvals, what anticoagulant regimens may be used for Patient 1/JS during hospitalization? Answer: Any one of the following regimens would be appropriate for JS: 1) Enoxaparin 40 mg subcut once daily for the duration of hospitalization OR 2) Dalteparin 5000 subcut units once daily for the duration of hospitalization OR 3) UFH 5000 units subcut every 12 hours (twice daily) for the duration of hospitalization OR 4) UFH 5000 units subcut every 8 hours (three times daily) for the duration of hospitalization OR 5) Betrixaban 160 mg loading dose orally day 1 followed by 80 mg orally once daily for 35–42 days

According to the 2012 ACCP Guidelines for VTE Prophylaxis in Nonsurgical Patients and FDA drug approvals, what anticoagulant regimens may be used for Patient 2/LL during hospitalization? Answer: Any one of the following regimens would be appropriate for LL: 1) Enoxaparin 40 mg subcut once daily for the duration of hospitalization OR 2) Dalteparin 5000 subcut units once daily for the duration of hospitalization OR 3) UFH 5000 units subcut every 12 hours (twice daily) for the duration of hospitalization OR 4) UFH 5000 units subcut every 8 hours (three times daily) for the duration of hospitalization OR 5) Betrixaban 80 mg loading dose orally day 1 followed by 40 mg orally once daily for 35–42days (The dose is reduced because carvedilol is a P-glycoprotein inhibitor.) A list of P-gp inhibitors is available on the FDA website. It includes amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil. (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter actionsLabeling/ucm093664.htm Accessed 2/14/18)

Betrixaban

Betrixaban is an oral factor Xa inhibitor that binds to and inhibits the active site on factor Xa, inhibiting free factor Xa activity and prothrombinase activity and thus reducing thrombin generation.⁵¹ The VTE prophylaxis dose of betrixaban in patients with normal renal function who are not receiving P-glycoprotein (P-gp) inhibitors is a loading dose of 160 mg followed by 80 mg once daily for 35 to 42 days.⁵¹

The bioavailability of betrixaban is 34%. The time-to-peak betrixaban concentration is 3–4 hours. Its effective half-life is 19–27 hours in patients with normal renal function, which is longer than other DOACs. Unlike other DOACs, betrixaban is metabolized primarily by CYP450-independent plasma hydrolysis to two inactive metabolites and is eliminated unchanged in the feces (85%) and urine (11%).⁵¹

Anti-Xa activity of betrixaban is 0.09–0.44 U/mL at betrixaban concentrations of 5–25 ng/mL.⁵⁵

The mean area under the serum concentration–time curve (AUC) of betrixaban is increased 2.63-fold in patients with severe renal impairment (defined as eGFR_MDRD ≥15 to <30 mL/min), 2.27-fold in patients with moderate renal impairment (defined as eGFR_MDRD ≥30 to <60 mL/min), and 1.89-fold in patients with mild renal impairment (defined as eGFR_MDRD ≥60 to <90 mL/min).⁵⁵ Product labeling states that for patients with a CrCl ≥15 mL/min to 30 mL/min (calculated using the Cockgroft–Gault equation using actual body weight), the loading and maintenance doses of betrixaban should be reduced by 50%. Betrixaban has not been studied in patients receiving hemodialysis. It is not known whether betrixaban is removed by hemodialysis.⁵¹

Betrixaban is a substrate for P-gp. Concomitant use of betrixaban with the P-gp inhibitors amiodarone, azithromycin, verapamil, ketoconazole, or clarithromycin can result in a 2-to 3-fold increase in betrixaban AUC and C_max.^51,56 The dose of betrixaban should be reduced by 50% in patients receiving any P-gp inhibitor.⁵¹ Additional drug interaction studies with other P-gp inhibitors are needed.

To avoid high concentrations, betrixaban should be taken at the same time of the day with food. Both low-fat and high-fat meals reduce the AUC and C_max of betrixaban for up to 6 hours following food.⁵¹

No specific antidote is available to reverse betrixaban. However, a current clinical decision pathway on bleeding management with DOACs from the ACC recommends supportive care and prothrombin complex concentrates for treatment of clinically significant bleeding.⁵⁷

As shown in Table 6, results of the main APEX trial were analyzed using a modified intention-to-treat (mITT) analysis including patients who took at least 1 dose of study medication and had an adequate assessment of VTE (by ultrasound). Extended-duration betrixaban was superior in efficacy to enoxaparin/placebo in acutely ill medical patients at high risk for VTE and in the subgroups of patients with elevated baseline D-dimer (≥2 times the upper limit of the normal range) and in those 75 years of age or older.^50,51,55 Extended duration of betrixaban is noninferior to enoxaparin/placebo for major bleeding but does increase clinically relevant nonmajor bleeding.^50,51

Table 6. Randomized Controlled Trials Evaluating a Shorter versus Extended Duration of VTE Thromboprophylaxis
Study	N	Key Inclusion Criteria	Acute Medical Illnesses Studied	Mean (± S.D.) age (years)	Length of Hospitalization or Treatment	Treatments: Active / Control	Key Efficacy Results	Key Safety Results
EXCLAIM47	5,963	Age ≥40 years with reduced mobility for up to 3 days   Anticipated decreased level of mobility (total bedrest or sedentary) of 5 ± 2 days and likely to continue at a lower-than-premorbid activity level after the initial 5 ± 2 day period	Infection, 32.8%   NYHA Class III or IV heart failure, 18.4%   Respiratory illness, 30.4%   Active cancer, 13.3%   Acute ischemic stroke, 9.7%   History of prior VTE, 6.7%   Inflammatory or rheumatic disease, 2.9%	67.9 ± 12.1	Median duration of open-label enoxaparin, 8 days   Median duration of randomized treatment — enoxaparin, 27 days; placebo, 28 days	Open-label enoxaparin 40 mg subcut once daily for 10 ± 4 days (some received outpatient prophylaxis with enoxaparin or placebo subcut for an additional 28 ± 4 days)   Enoxaparin 40 mg subcut once daily for 10 ± 4 days (and additional enoxaparin 40 mg subcut for 28 ± 4 days)   Median treatment duration, 28 days	Composite of symptomatic or asymptomatic proximal DVT, symptomatic PE, or fatal PE at 28 ± 4 days: Enoxaparin, 2.5% Placebo, 4.0% Absolute risk difference, –1.53% (95.8% CI, –2.54% to –0.52%)	Major bleeding (up to 2 days after treatment): Enoxaparin, 0.8% Placebo, 0.2% Absolute risk difference, 0.51% (95% CI, 0.12% to 0.89%)
ADOPT48	6,528	Age ≥40 years   Moderately or severely reduced / restricted mobility for up to 3 days	Infection, 22%   NYHA Class III or IV heart failure, 38%   Respiratory illness, 37%   Active cancer, 4%   History of prior VTE, 4.3%   Inflammatory or rheumatic disease, 2%	66.8 ± 12.0	Mean (± SD) duration of apixaban, 24.9 ± 10.0 days; mean duration of enoxaparin, 7.3 ± 4.0 days	Apixaban 2.5 mg twice daily for 30 days (with enoxaparin placebo subcut for ≥6 days)   Enoxaparin 40 mg subcut for ≥ 6 days (with apixaban oral placebo twice daily for 30 days)	Composite of asymptomatic proximal DVT, symptomatic DVT, fatal or nonfatal PE and VTE-related death 30 days: Apixaban, 2.71% Enoxaparin/placebo: 3.06% RR 0.87 (95% CI 0.62–1.23)	Major bleeding: Apixaban, 0.47% Enoxaparin/placebo, 0.19% RR 2.58 (95% CI 1.02–7.24)   Major plus clinically relevant nonmajor bleeding: Apixaban, 2.67% Enoxaparin/placebo, 2.08% RR 1.28 (95% CI 0.93–1.76)
MAGELLAN49	8,101	Age ≥40 years   Anticipated complete immobilization for ≥1 day during the hospitalization and anticipated decreased level of mobility for ≥4 days and additional anticipated ongoing decreased mobility thereafter	Infection, 46%   NYHA Class III or IV heart failure, 32%   Respiratory illness, 28%   Active cancer, 7%   Acute ischemic stroke, 17%   History of prior VTE, 5.0%   Inflammatory or rheumatic disease, 4%	71.0	Median hospitalization, 11 days	Rivaroxaban 10 mg orally once daily 35 ± 4 days (with enoxaparin placebo subcut daily 10 ± 4 days)   Enoxaparin 40 mg subcut daily for 10 ± 4 days (and rivaroxaban placebo orally daily for 35 ± 4 days)	Composite of symptomatic proximal DVT, symptomatic DVT, symptomatic nonfatal PE and VTE-related death at day 10 ± 4 days (noninferiority): Rivaroxaban, 2.7% Enoxaparin/placebo, 2.7% RR 0.97 (95% CI 0.71–1.31)   Composite of symptomatic proximal DVT, symptomatic DVT, symptomatic nonfatal PE and VTE-related death at day 35 ± 4 days (superiority): Rivaroxaban: 4.4% Enoxaparin/placebo: 5.7% RR 0.77 (95% CI 0.62–0.96)	Composite of treatment-emergent major and clinically relevant nonmajor bleeding (up to 2 days after last treatment) at day 10 ± 4 days: Rivaroxaban, 2.8% Enoxaparin/placebo, 1.2% RR 2.3 (95% CI 1.63–3.17)   Composite of treatment-emergent major and clinically relevant nonmajor bleeding (up to 2 days after last treatment) at day 10 ± 4 days: Rivaroxaban, 4.1% Enoxaparin/placebo, 1.7% RR 2.5 (95% CI 1.85–3.25)
APEX50,51	7,513	Age ≥40 years (with risk factors for VTE)   Severe immobilization for at least 24 hours and moderate immobilization for ≥3 days	Infection, 29.6%   NYHA Class III or IV heart failure, 44.6%   Respiratory illness, 11.9%   Active cancer, 12.4%   Acute ischemic stroke, 11.2%   History of prior VTE, 8.3%   Inflammatory or rheumatic disease, 3.0%	76.6 ± 8.46	Median hospitalization, 10 days   Median treatment with enoxaparin, 9 days   Median treatment with betrixaban, 36 days	Betrixaban 160 mg oral loading dose followed by 80 mg once daily orally for 35–42 days (and placebo subcutaneous injections for 10 ± 4 days)   Enoxaparin 40 mg subcut once daily for 10 ± 4 days (and oral placebo for 35–42 days)   For patients with CrCl 15-29 mL/min: Enoxaparin 20 mg subcut once daily   Betrixaban 80 mg oral loading dose followed by 40 mg once daily orally   Patients taking selected P-gp inhibitors: 80 mg oral loading dose followed by 40 mg once daily orally	Composite of asymptomatic proximal DVT between 32–47 days, symptomatic proximal or distal DVT, symptomatic nonfatal PE or VTE-related death between day 1–42: Betrixaban, 4.4% Enoxaparin/placebo, 6.0% (RR 0.75, 95% CI 0.61–0.91)   Composite of symptomatic VTE through day 42: Betrixaban, 0.9% Enoxaparin/placebo: 1.5% (RR 0.64, 95% CI 0.42–0.98)	Major bleeding (up to 7 days after treatment): Betrixaban, 0.67% Enoxaparin/placebo, 0.57% RR 1.19 (0.67–2.12)   Clinically relevant nonmajor bleeding: Betrixaban, 2.45% Enoxaparin/placebo, 1.02% RR 2.39 (95% CI 1.64–3.49)
Abbreviations used: CrCl, creatinine clearance; DVT, deep-vein thrombosis; NYHA, New York Heart Association; P-glycoprotein, P-gp; PE, pulmonary embolism; subcut, subcutaneously; VTE, venous thromboembolism.

A post-hoc analysis of the APEX trial (mITT population) suggested a reduction in the risk of all-cause stroke and ischemic stroke in patients admitted with acute medical illness with extended-duration betrixaban compared with enoxaparin/placebo.⁵⁸

A recent analysis of the APEX data demonstrated a significant reduction in the risk of VTE-related rehospitalization at 42 days (0.25% versus 0.75%) and at 77 days (0.45% versus 1.04%; HR 0.44, 95% CI 0.25–0.80, absolute risk reduction 0.59%; NNT 170) in the overall population with extended-duration betrixaban compared with enoxaparin/placebo.⁵⁹

No pharmacoeconomic analyses of betrixaban and the APEX trial are currently available. The wholesale acquisition cost for a 35–42-day course of betrixaban is approximately $540, which is higher than the cost of short-duration enoxaparin ($122.10).⁶⁰ However, discounted pricing for betrixaban is available to hospitals. The anticipated cost to the patient with commercial insurance is $50, according to information on the product patient support website.

VTE Prophylaxis in Patients at Low and High Extremes of Body Weight

Because obesity is a risk factor for VTE and patients at low body weight may be more prone to bleeding, clinicians must consider data on whether anticoagulant dosing for VTE prophylaxis should be altered in these patient groups.

The definition of obesity varies by trial but has included patients who weigh more than 100 kg, as well as those with BMIs in the obese and morbidly obese categories (≥30 kg/m², ≥35 kg/m², or ≥40 kg/m²). To date, there is insufficient evidence to suggest that enoxaparin dosing should be altered in patients with obesity. Various dosing regimens have been studied, including weight-based enoxaparin (dosed at 0.5 mg/kg once daily) as well as fixed dosing of 60 mg once daily and 40 mg twice daily. A recent analysis of 11 trials suggests weight-based enoxaparin dosing or higher than usual or more frequent fixed dosing achieves anti-factor Xa levels within a target prophylaxis range more effectively, compared with fixed dosing of 40 mg. However, the poor quality of the trials, especially their small sample sizes and lack of long-term clinical outcomes such as VTE occurrence, makes interpretation difficult.^61–63

Data on dalteparin and UFH in medically ill patients with obesity are scarce, but doses as high as 7500 IU daily with dalteparin and 7500 units three times daily with UFH have been studied.^64,65 Obesity was not associated with an increased VTE or bleeding risk in the PREVENT trial of medically ill patients randomized to dalteparin or placebo.⁶⁶ In the recent APEX trial, very few enrolled patients had a BMI of ≥30 kg/m² (betrixaban, n = 40; enoxaparin, n = 19).⁶⁷ While recent guidelines have suggested that usual dosing may result in lower-than-anticipated anti-factor Xa levels and anti-factor Xa level monitoring may be considered for patients who are very obese (>145 kg), no specific dosing recommendations are suggested.⁶³

Patients at low body weight may be at increased bleeding risk. Enoxaparin and dalteparin labeling do not give specific guidance on avoiding use or adjusting the dose for patients with low body weight. Those weighing less than 45 kg were excluded from the APEX trial; because of this, betrixaban should be avoided in adult patients weighing less than 45 kg.⁶⁸

CONCLUSION

In acutely ill medical patients, VTE is a common cause of morbidity and mortality. The risk of VTE may be assessed as low or high through assessment using validated models. Use of RAMs improves identification of patients most appropriate for VTE prophylaxis and identifies low-risk patients for whom prophylaxis is not recommended. Common risk factors used to identify patients at high risk for VTE in clinical trials include acute infection, heart failure, respiratory failure, active cancer, inflammatory or rheumatic disease, and prior history of VTE.

While in-hospital prophylaxis rates have improved as a result of recent research, the risk of VTE continues to increase following hospitalization, peaking at approximately 30 to 45 days. Clinical trials with enoxaparin and rivaroxaban demonstrated a reduction in VTE events but at a cost of increased major bleeding. Recently, extended-duration betrixaban has demonstrated superiority to short-course enoxaparin with similar major bleeding and increased clinically relevant nonmajor bleeding. Betrixaban is the only DOAC that is approved by FDA for VTE prophylaxis in acute medically ill patients. This agent offers the advantage of being administered orally rather than subcutaneously.

Betrixaban requires dose adjustment in patients with severe renal insufficiency and those using P-gp inhibitors concomitantly. While the acquisition cost of betrixaban is higher than enoxaparin, betrixaban has also demonstrated a reduction in rehospitalization. Further examination of betrixaban's cost-effectiveness and drug interactions is needed. It is anticipated that updated clinical practice guidelines will include a summary and recommendations regarding the use of betrixaban.

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