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Patient Case: R.D. is a 76-year-old female (BMI 32 kg/m²) who presents to the hospital with increasing shortness of breath, wet cough, and swelling in her legs. She says she gets short of breath while doing minimal activities and has been not been moving around a lot at home. She is admitted for the exacerbation of her heart failure. Her other medical conditions include hypertension, type 2 diabetes mellitus, moderate renal insufficiency (creatine clearance 55 mL/min), hypothyroidism, and dyslipidemia. Her home medications include furosemide 40 mg once daily, metformin 1000 mg twice daily, lisinopril 20 mg once daily, metoprolol succinate 100 mg once daily, empagliflozin 10 mg once daily, levothyroxine 100 mcg once daily, and atorvastatin 80 mg once daily. Her vital signs are stable, and her labs are within normal limits with a creatine clearance of 48 mL/min.

Is R.D. at risk of developing a venous thromboembolism during her hospitalization?

Introduction

Patients with venous trauma, venous stasis, or hypercoagulability are predisposed to the formation of venous thromboembolism (VTE).¹ These factors are represented in the commonly recognized risk factors for development of VTE (Table 1).² When the natural anticoagulation and fibrinolytic systems are overcome by a procoagulant setting, VTE can develop. Trauma or damage to the vascular endothelium can lead to the release of tissue factor (TF), which initiates the extrinsic clotting cascade by activation of factor VII.³ This TF-VIIa complex, with Ca⁺², leads to the activation factor X and the common pathway of the clotting cascade. Factor Xa then converts prothrombin (factor II) into the very potent procoagulant thrombin (IIa), which in turn converts fibrinogen into fibrin, which stabilizes the clot.⁴ During this process, areas of vascular injury expose proteins such as collagen and Von Willebrand factor, which are responsible for platelet adhesion.⁵ Once platelets adhere to the area of injury, they are then activated, leading to expression of glycoprotein IIb/IIIa receptors. Fibrinogen links platelets by binding glycoprotein IIb/IIIa receptors on different platelets resulting in platelet aggregation.⁶ Unlike arterial thrombus, which is heavily composed of platelets, venous thrombus incorporates mainly fibrin and red blood cells, with platelets playing a smaller role.⁷

Hospitalized patients are often immobile for several days. Immobility is a known risk factor for development of VTE since it promotes venous stasis and impairs venous return from the lower extremities.² Venous stasis also causes endothelial hypoxia at the site of stasis, which damages the endothelium and activates the intrinsic and extrinsic clotting cascades.⁸ Decreased venous return from the lower extremities also leads to local accumulation of clotting factors that may trigger thrombogenesis.

VTE is composed of deep vein thrombosis (DVT) and pulmonary embolism (PE) and represents one of the most preventable sources of in-hospital morbidity and mortality.⁹ The most current United States (US) statistics found there are more than 1.2 million VTE events annual, with about 857,000 DVTs and 370,000 PEs.¹⁰ Venous thrombosis usually occurs in the cusp of venous valves. As a thrombus forms around the valve, the valve is irreversibly damaged, potentially leading to chronic venous insufficiency or post-phlebetic syndrome in one-third of patients.^11,12 The damaged valve is an attractive environment for future thrombosis, with about one-third of patients developing a recurrent VTE in the subsequent 5 years.¹² The most feared consequence of DVT is PE. Once a thrombus has formed in the deep veins of the legs, portions of the thrombus may embolize and flow upstream into the central circulation. The embolus will travel through the right side of the heart and lodge in the pulmonary vasculature causing PE. Twenty percent of untreated DVTs progress to clinically significant PE.¹⁰ The consequences of PE can be catastrophic. The 30-day mortality is 5.1% and 9.1% for patients with a DVT or PE, respectively, and the 1-year mortality is approximately 20% and 40%, respectively.^13,14 Due to these serious consequences, prevention of the initial VTE is critical.

The acute medically ill comprise a heterogeneous group of patients. While the definition of “medically ill” may vary, the largest groups are typically composed of hospitalized patients aged 40 years or older with a heart failure exacerbation, respiratory disease (such as chronic obstructive pulmonary disease [COPD]) or with an infectious process. Other medical conditions included as medically ill, but occurring less frequently, are patients with inflammatory bowel disease, rheumatic diseases, ischemic stroke, or sometimes cancer.¹⁵

In the absence of prophylaxis, 60% to 70% of all VTE events in the United States occur in acute medically ill patients and contribute to a significant increase in healthcare cost.^16-18 The role of anticoagulant-based thromboprophylaxis with unfractionated heparin (UFH), low-molecular weight heparin (LMWH), or fondaparinux during the inpatient setting is well-established, with numerous trials having evaluated the ability to reduce the risk of VTE compared to no prophylaxis.^19-22 One meta-analysis of 9 trials and 19,958 patients suggests that anticoagulation-based prophylaxis is associated with 57%, 62% ,and 53% significant relative reductions in rates of any PE, fatal PE, and symptomatic DVT, respectively, and no significant increase in risk of major bleeding compared to no prophylaxis.²³ An additional meta-analysis of 36 trials suggest that both UFH and LMWH provide significant reductions in DVT and PE compared to no prophylaxis.²⁴ Data from these trials have influenced guideline recommendations from national organizations, as well as quality measures from regulatory agencies such as The Joint Commission, on the importance of providing VTE prophylaxis in hospitalized medically ill patients.^25-27 The duration of VTE prophylaxis in these initial trials lasted 6 to 14 days.¹⁵ However, prophylaxis is usually provided for the duration of hospitalization, which is typically 3-5 days, and not administered after hospital discharge.^28,29

Patient Case: R.D. has multiple risk factors for development of VTE during her hospitalization. They include age > 40 years, immobility, hospitalization for medical illness (heart failure), and obesity. Although she is clearly a candidate for injectable anticoagulant prophylaxis during her hospital stay, does she have a risk of VTE after she leaves the hospital?

Extended VTE Risk in Medically Ill Patients

Once patients are discharged from the hospital the perception is that the risk of VTE has diminished. Unfortunately, several observational trials have revealed that the risk of VTE continues after discharge. In fact, 50% to 75% of all VTE events that occur in acute medically ill patients occur within the first 30 days after discharge.^10-12 This seems logical since patients do not resume their prehospital level of mobilization immediately upon discharge, and immobility may extend for some time after leaving the hospitalized setting. This represents a problem for the medical community that has generally been ignored without acceptable pharmacological options.

One study that followed more than 11,000 medically ill patient after discharge demonstrated that over 50% of the accumulative 6-month VTE risk occurs in the first 30 days.³⁰ This risk varied based on the medical illness, with about 45% within the first 30 days in patients with cancer, to about 50% in patients with COPD, 65% in patients with heart failure, and about 75% in patients hospitalized with an infectious disease. An additional study reviewed VTE events in medically ill patients in a retrospective cohort in Massachusetts and found a higher rate of events after discharge than during admission.³¹ In this analysis, the majority of VTE events (67%) occurred within 30 days of discharge. Although there were VTE events between 1 and 2 months (20%) and between months 2 and 3 (13%), the first 30 days after discharge clearly represented the highest risk window for development of a VTE. A similar type of review among Olmsted County residents in Minnesota demonstrated that 75% of VTE events occurred after discharge, with a median time to VTE from discharge of 19.5 days.³²

Patient Case: Upon admission, R.D.’s furosemide is increased to 40 mg IV once daily, metoprolol succinate is decreased to 50 mg once daily, and spironolactone 25 mg once daily is added to her regimen. Since the risk of VTE in medically ill patients continues after discharge, especially during the next 30 days, the team would like to know if there are data to support extended VTE prophylaxis in this patient.

Data Evaluating Extended Prophylaxis in Medically Ill Patients

The concept of extended VTE prophylaxis in medically ill patients is not new. Several anticoagulants have been investigated over the past decade with mixed results. In general, all trials evaluated medically ill patients (eg, heart failure, respiratory disease, infections process) with immobility for several days. Since each trial had a moderately different definition of immobility, Table 2 includes the definitions used in each trial.^33-36 The primary efficacy and safety results of these trials are summarized in Table 3.^33-37

Enoxaparin

The first trial to evaluate the efficacy and safety of extended VTE prophylaxis in medically ill patients was the EXCLAIM trial (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients with Prolonged Immobilization).³³ All patients received subcutaneous (SC) enoxaparin 40 mg once daily for 6 to 14 days. Upon completion of the open-label prophylaxis, patients were then randomized in a double-blinded fashion to continue SC enoxaparin or placebo for an additional 24 to 32 days. The primary endpoint of the trial was the combination of proximal DVT (symptomatic or asymptomatic), symptomatic PE, and fatal PE at the end of the extended prophylaxis period. Major bleeding was the primary safety outcome. The definition of major bleeding was similar to that used by the International Society of Thrombosis and Haemostasis (ISTH), except that a hemoglobin drop of at least 3 g/dL was used instead of a hemoglobin drop of at least 2 g/dL.³⁸ The investigators evaluated major bleeding using both definitions.

During the final interim analysis of the trial, the data and safety monitoring board (DSMB) determined that the VTE event rate was lower than expected and it would be unlikely that the 40% relative reduction in VTE would be statistically different between the extended prophylaxis and placebo groups (2.5% vs 4.2%; p = 0.16), although there would be an increase in major bleeding (0.9% vs 0.5%; p = 0.05).³³ Therefore, the DSMB recommended terminating the trial as originally designed. It was noted by the DSMB that patients with level 1 immobility did demonstrate a reduction in VTE with extended prophylaxis consistent with the trial expectations (2.4% with extended therapy vs 6.1% with placebo) and, therefore, suggested the trial protocol be amended and continued in that subgroup of patients. After addition analysis of patients with level 2 immobility, patients with a history of VTE, previous or active cancer, or age greater than 75 year of age were identified to be at increased risk of VTE (3.5% with extended therapy vs 5.5% with placebo). Therefore, these patients continued to be enrolled in the trial as well.

Patients received open-label enoxaparin for a median of 8 days and randomized therapy for a median of 27 days.³³ At the end of the trial, patients randomized to extended enoxaparin VTE prophylaxis demonstrated a significant 37% relative reduction in the primary endpoint compared to placebo (Table 3). The difference was driven by an 80% relative reduction in symptomatic VTE with the use of extended prophylaxis compared to placebo (0.2% vs 1.0%; p < 0.001). The benefit of extended prophylaxis remained at 90 days (2.6% vs 4.2%; p = 0.003). The significant reduction in VTE with extended enoxaparin prophylaxis came with a significant increase in major bleeding. The increase in major bleeding was evident regardless if the original definition of major bleeding by the EXCLAIM trial investigators was used (0.7% vs 0.2%; p = 0.02), or if the more stringent criteria of the ISTH definition was used (Table 3).³³

The data from the EXCLAIM trial did not change clinical practice. Patients demonstrating benefit of extended prophylaxis were more restrictive than those needing initial inpatient prophylaxis, with only those with level 1 immobility and those with level 2 immobility and high-risk features being potential candidates. Furthermore, while there was a significant benefit that was driven by a reduction in symptomatic events, the absolute reduction in symptomatic events was only 0.8%. This benefit was considered to be offset by an increase in major bleeding of 0.5%.³³

Apixaban

The first direct oral anticoagulant (DOAC) to be evaluated for extended VTE prophylaxis in medically ill patients was apixaban in the ADOPT trial (Apixaban Dosing to Optimize Protection from Thrombosis).³⁴ Patients with acute medical illness besides heart failure or respiratory failure had to have at least one additional risk factor. Patients were randomized in a double-blind, double-dummy fashion SC enoxaparin 40 mg once daily for the duration of the hospital stay (minimum of 6 days) or apixaban 2.5 mg twice daily for 30 days. The primary endpoint of the trial was the combination of symptomatic DVT, asymptomatic proximal DVT, symptomatic PE, and death related to VTE. The ADOPT trial used the ISTH definition of major or clinically relevant nonmajor (CRNM) bleeding.³⁸

During the time period when patients in both groups received VTE prophylaxis, the rate of the primary outcome was similar in patients receiving apixaban compared to enoxaparin (1.7% vs 1.6%; p = 0.82).³⁴ Although more patients in the placebo group developed a VTE during the extended prophylaxis time period compared to the apixaban group (0.8% vs 1.3%), the difference was not significant. Patients receiving apixaban demonstrated only a 13% relative reduction in total VTE at the end of the study that was not significant compared to enoxaparin/placebo (Table 3). Major bleeding was significantly higher in patients receiving extended duration apixaban by more than 2-fold compared to short course enoxaparin (Table 3). Major plus CRNM bleeding was also higher in patients receiving apixaban, but this was not significantly different (2.7% vs 2.1%; p = 0.12). Based on the lack of efficacy and increase in major bleeding, extended VTE prophylaxis with apixaban would only be expected to produce patient harm and should not be recommended. The failure of apixaban in the ADOPT trial may be multifactorial. Some possible explanations may be adherence issues with the twice-daily dosing, the lower than expected rate of VTE, or the inclusion of lower risk patients. Only 26% of patients in the ADOPT trial had severely restricted mobility, as well as the lower amounts of patients aged 75 years or older, or with a history of cancer or previous VTE compared to any of the other extended prophylaxis trials.^33-36

Betrixaban

The APEX trial (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) evaluated the use of betrixaban for extended VTE prophylaxis in medically ill patients.³⁶ In addition to the criteria used for other extended prophylaxis trials, patients were also required to have at least 1 additional baseline factor associated with increased risk of VTE, which included a D-dimer concentration at least 2 times the upper limit of normal, age of at least 75 years, or at least 2 additional clinical risk factors for VTE. Patients were randomized in a double-blind, double-dummy fashion to receive SC enoxaparin 40 mg daily for 6 to 14 days, followed by oral placebo at discharge for a total duration of 35 to 42 days, or an oral betrixaban loading dose of 160 mg, followed by oral betrixaban 80 mg once daily for a total of 35 to 42 days. Patients with a creatinine clearance of at least 15 mL/min to less than 30 mL/min received half-dose enoxaparin (20 mg once daily) or half-dose betrixaban (80 mg loading dose, followed by 40 mg daily). The same dose adjustment was used for patients randomized to betrixaban who were also receiving concomitant strong P-glycoprotein (P-gp) inhibitors. The primary endpoint was the same as in the ADOPT trial and was evaluated at the end of betrixaban therapy (days 35 to 42).^34.35 Symptomatic VTE was also evaluated at the end of the standard prophylaxis period (betrixaban vs enoxaparin) and at least 30 days post betrixaban to evaluate for a potential rebound effect (day 77).³⁵ The primary safety endpoint was ISTH defined major bleeding.³⁸

At the completion of betrixaban therapy, extended prophylaxis provided a significant 24% relative reduction in the primary endpoint compared to enoxaparin/placebo (Table 3).³⁵ While most of the events prevented were asymptomatic DVT, there was a significant 40% relative reduction in symptomatic VTE with the use of betrixaban at the end of therapy (0.9% vs 1.5%; p = 0.04). During the time in which both groups received VTE prophylaxis, the rates of symptomatic events were not significantly different between betrixaban and enoxaparin (0.27% vs 0.34%; p = 0.44). Symptomatic events occurring only during the extended betrixaban period were significantly lower in patients receiving betrixaban compared to placebo (0.88% vs 1.31%; p = 0.041). In the 30-day follow up period after discontinuation of betrixaban, patients who had received betrixaban continued to have a suppression of symptomatic events (0.06%), while patients who had received enoxaparin followed by placebo demonstrated a continued increase in symptomatic events (0.42%; p = 0.007).³⁹ These findings 30 days after discontinuation of betrixaban demonstrated a lack of a rebound of VTE events. Furthermore, these findings suggest this duration of VTE prophylaxis may truly cover the “at-risk period” for the medically ill patient and longer periods of prophylaxis would be unnecessary.

In an attempt to assess the impact of extended prophylaxis on “harder” endpoints, a post-hoc analysis of the APEX trial was conducted to evaluate fatal and irreversible events.⁴⁰ Irreversible efficacy events included cardiopulmonary death, myocardial infarction, PE, and ischemic stroke. Irreversible safety events included fatal bleeding or intracranial hemorrhage. Extended prophylaxis with betrixaban provided a significant reduction in these fatal and irreversible events at days 35 to 42 (2.9% vs 4.1%; p = 0.006), as well as at the day 77 follow-up period (3.6% vs 5.2%; p = 0.002). Patients receiving full-dose betrixaban also demonstrated significant reductions in VTE-related rehospitalization at day 42 (0.24% vs 0.93%; p = 0.002) and at day 77 (0.46% vs 1.25%; p = 0.002) compared to patients receiving enoxaparin/placebo.⁴¹ While not significant at day 42 (0.31% vs 0.59%), there was a greater than 50% reduction in VTE-related mortality with the use of betrixaban at day 77 (0.34% vs 0.79%; p = 0.035) compared to use of enoxaparin/placebo.⁴²

Unlike the prior extended-duration trials, treatment with extended prophylaxis with betrixaban was not associated with an increase in ISTH defined major bleeding compared to standard duration enoxaparin (Table 3).³⁵ Major bleeding was not significantly different during the active standard prophylaxis period (0.24% for both groups; p = 0.88), or during the extended prophylaxis period (0.44% betrixaban vs 0.33% placebo; p = 0.42).³⁹ Overall, there was an approximate 2-fold increase in the secondary safety outcome of major or CRNM bleeding with the use of betrixaban compared to enoxaparin/placebo (4.1% vs 1.7; p = <0.001).³⁵ Nevertheless, the results of the APEX trial are the first to demonstrate the ability to significantly reduce VTE with extended prophylaxis without significantly increasing major bleeding. These data led to betrixaban becoming the first Food and Drug Administration (FDA) approved agent for oral administration during hospitalization and extended VTE prophylaxis after discharge in medically ill patients.

Rivaroxaban

The MAGELLAN trial (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin) evaluated to impact of extended rivaroxaban VTE prophylaxis in medically ill patients.³⁶ Like the APEX trial, in addition to the criteria use for other extended prophylaxis trials, patients were also required to have at least one additional baseline factor associated with increased risk of VTE, which included age of 75 years or more, prolonged immobilization, history of cancer, history of VTE, history of heart failure, a thrombophilia, an acute infectious process contributing to hospitalization, or a body mass index greater than 35 kg/m². Patients were randomized in a double-blind, double-dummy fashion SC enoxaparin 40 mg once daily for 6 to 14 days or rivaroxaban 10 mg daily for 31 to 39 days. The primary endpoint of the trial was the same as that in the ADOPT and APEX trial.^34-36 The primary endpoint was designed to be evaluated at 2 time points, day 10 for noninferiority, and day 35 for superiority. The primary safety outcome was ISTH major and CRNM bleeding.³⁶

At the day 10 analysis, the primary endpoint occurred in 2.7% of both groups, meeting the trials definition of noninferiority (p = 0.003).³⁶ At the 35-day analysis, extended VTE prophylaxis with rivaroxaban provided a significant 23% relative reduction in the primary endpoint compared to enoxaparin/placebo (Table 3). This benefit of reduced VTE with rivaroxaban came with a cost of significantly more major bleeding compared to enoxaparin/placebo at day 10 (0.6% vs 0.3%; p = 0.03), as well as at day 35 (Table 3).

As with the EXCLAIM trial, the initial results of the MAGELLAN trial did not change clinical practice regarding extended VTE prophylaxis in medically ill patients. Subsequently, the MAGELLAN investigators took the initiative to re-examine their data do determine if any patient groups within the trial contributed more the increase in major bleeding than others. Upon this analysis, 5 patient groups were found to be associated with the highest rates for major bleeding.³⁷ These 5 groups included patients with a history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, patients being hospitalized for treatment of active cancer, patients with a gastroduodenal ulcer in the past 3 months, patients with bleeding in the last 3 months, and patients receiving dual antiplatelet therapy. These patient groups accounted for slightly under 20% (n = 1551) of the total study population. An evaluation of the efficacy and safety data from the MAGELLAN subgroup, with these 5 groups excluded from both randomized arms, was then conducted.

Similar to the initial analysis, the MAGELLAN subgroup 10-day analysis found no significant difference in the primary efficacy endpoint between patients receiving rivaroxaban and enoxaparin (2.4% vs 3.0%; p = 0.26).³⁷ Unlike the initial analysis, major bleeding was not significantly increase with the use of rivaroxaban compared to enoxaparin in the MAGELLAN subgroup (0.4% vs 0.3%). At the 35-day analysis, the benefit of rivaroxaban in reducing VTE grew from 23% in the initial analysis to 32% in the MAGELLAN subgroup compared to enoxaparin/placebo (Table 3). Although major bleeding was almost 3-fold higher with the use of rivaroxaban extended prophylaxis in the initial analysis, the difference was not significantly different in the MAGELLAN subgroup (Table 3).

Rivaroxaban is now the second agent to receive FDA approval for use during the hospitalization and extended VTE prophylaxis in medically ill patients. Although the MAGELLAN subgroup did demonstrate a significant reduction in VTE without increasing major bleeding, the FDA did not provide approval based only on a post-hoc subgroup analysis of this trial. The MARINER trial (Medically Ill Patient Assessment of Rivaroxaban versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) prospectively excluded the five high-risk bleeding groups in their study design.⁴³ In this trial, extended VTE prophylaxis with rivaroxaban provided a similarly low rate of major bleeding compared to placebo (0.28% vs 0.15%; p = 0.12). Therefore, the exclusion of the 5 high-risk bleeding groups from MAGELLAN was prospectively confirmed. These safety data combined with the 32% relative reduction in VTE with extended prophylaxis were the data used for FDA approval of rivaroxaban 10 mg once daily for this indication.

Patient Case: After this discussion of these data with the team, they still have a couple questions. First, they want to know if all medically ill patients require extended prophylaxis. Since the members of the team have not used extended VTE prophylaxis in medically ill patients before, they would like to know if is supported by any national organizations.

Patient Selection and Clinical Impact

The number of patients in whom extended VTE prophylaxis would be appropriate is less than those who receive inpatient prophylaxis. Criteria in the extended prophylaxis studies, especially APEX and MAGELLAN, were more restrictive than the original inpatient acute medically ill trials.^33-36 The inpatient VTE prophylaxis trials simply required patients aged 40 years or more and hospitalization for an acute medical illness.^19-22 In the extended prophylaxis trials, inclusion criteria were similar to those for the inpatient VTE prophylaxis trials, but also required a specific evaluation of patient immobility (Table 2) and additional specific risk factors.^33-36 A recent analysis estimated approximately 7.2 million patients per year in the United States would be candidates for inpatient VTE prophylaxis following the American College of Chest Physicians (ACCP) 2012 guidelines.^25,44 The investigators found that approximately 50% of medically ill patients (3.5 million) would be eligible for extended prophylaxis.⁴⁴ Moving forward, it will be important for institutions to develop adequate patient risk assessment tools to appropriately identify patients who would benefit from extended prophylaxis, as well as those in whom extended prophylaxis would not be beneficial. Applying the trial inclusion and exclusion criteria from the APEX and MAGELLAN subgroup trials (Table 4) would be the optimal starting point for defining the appropriate patients.^35-37

The clinical impact these data are impactful for multiple reasons. One important change to current practice is that inpatient VTE prophylaxis can now be provided with an oral agent instead of the injectable options of low molecular weight heparin, unfractionated heparin, or fondaparinux that have been used for decades. While it is appreciated that patients prefer oral to injectable medications, there is also an ability to improve the utilization of a course of VTE prophylaxis with these oral agents.⁴⁵ Multiple studies have demonstrated that many patients refuse doses of injectable VTE prophylaxis while hospitalized. One study found that patients were nearly 4-fold more likely not to receive an ordered dose of injectable VTE prophylaxis medication compared to other oral medications on their regimen.⁴⁶ Another study found that 41% of hospitalized patients did not receive all ordered doses of injectable VTE prophylaxis.⁴⁷ Interestingly, this grew to 67% in patients on medicine floors, which was significantly higher than patients on all other study floors (p < 0.001). Therefore, the availability of an oral VTE prophylaxis option for inpatient care is an important advancement.

A common mechanism for clinicians to use when evaluating the clinical impact of a new approach to therapy is consideration and comparisons of number needed to treat (NNT) and number needed to harm (NNH). Results of the APEX and MAGELAN subgroup trials produced a NNT of 59 and 56 to prevent one VTE with betrixaban and rivaroxaban, respectively.^35,37 These findings are lower, but comparable to the NNT of 67 with enoxaparin in the EXCLAIM trial (demonstrated efficacy) and much lower than the NNT of 250 with apixaban in the ADOPT trial (did not demonstrate efficacy).^33,34 A NNT in the 50s is clinically important, especially when considering this is achieved with only 30 days of outpatient therapy and not a year or more as with many therapies. Although one criticism of these data is that several of the VTE events prevented are asymptomatic proximal DVT events, and not all symptomatic events. This is a misunderstanding of the importance of preventing asymptomatic proximal DVT. Multiple studies have demonstrated that medically ill patients with asymptomatic proximal DVT diagnosed with compression ultrasound have a significant increase in mortality at 90 days by at least 3-fold.^48-50 Therefore, prevention of asymptomatic proximal DVT is a clinically important outcome. From the safety perspective. The NNH to cause 1 major bleed in the APEX and MAGELAN subgroup trials was 1000 and 500 with betrixaban and rivaroxaban, respectively.^35,37 These are much lower that demonstrated in the EXCLAIM (NNH 200) and ADOPT (NNH 333) trials.^33,34 When these NNT and NNH are evaluated in balance, the benefit-to -risk ration is about 9-fold in favor of providing extended VTE prophylaxis with the FDA approved agents.

National Organizations

Despite publication of groundbreaking data in reputable peer-reviewed journals, it is not uncommon for clinicians to wait to see if new therapies of approaches to care are endorsed by national organizations before adopting them into their clinical practice. Although both ACCP and the American Society of Hematology (ASH) do not recommend extended VTE prophylaxis in medically ill patients, it is important to put these into the context in which they were written.^25,26 The latest guidelines on VTE prevention from ACCP were published in 2012.²⁵ At the time ACCP made this recommendation, only data from the EXCLAIM and ADOPT trials were available. Based on the data from these trials, it would be logical for ACCP to not recommend extended VTE prophylaxis in medically ill patients. The guidelines on VTE prevention from ASH were published in 2018.²⁶ At the time when the ASH guidelines were being written, data from EXCLAIM, ADOPT, and the initial analysis of MAGELLAN were available. Although the positive data from APEX had been published, betrixaban had yet to receive FDA approval. The data from the MAGELLAN subgroup and MARINER were not yet available.

A number of national organizations have published recommendations on extended VTE prophylaxis in medically ill patients with all of the currently available data. The Anticoagulation (AC) Forum now recommends up to 42 days of VTE prophylaxis in selective medically ill patients with the use of betrixaban or rivaroxaban.⁵¹ The NAFT also recommends extended VTE prophylaxis with betrixaban or rivaroxaban for medically ill patients who would have meet the APEX or MAGELLAN study criteria (Table 4).⁵²

For about 10 years, the use of VTE prophylaxis in medically ill patients has been part of the Center for Medicaid & Medicare Services (CMS) core measures (VTE-1 and VTE-2) evaluated by Joint Commission. Historically, prophylaxis with a LMWH, UFH, or fondaparinux was needed to fulfil this core measure. With the FDA approval of betrixaban and rivaroxaban for VTE prophylaxis in medically ill patients, CMS has added these two specific agents as options in meeting the VTE-1 and VTE-2 core measures.⁵³ This acknowledgment of CMS of the importance to these agents in the prevention of VTE in medically ill patients can provide clinicians with confidence in using them in their clinical practice. Unfortunately, betrixaban is no longer commercially available. Betrixaban was marked by Portola Pharmaceuticals. In early 2020, Alexion Pharmaceuticals began acquisition of Portola Pharmaceuticals (completed June 2, 2020).⁵⁴ Since betrixaban did not fit into Alexion Pharmaceuticals strategy, and Portola could not find another buyer, the agent was officially discontinued in April 2020.⁵⁵ Subsequently, rivaroxaban 10 mg once daily is the only currently available agent for extended prophylaxis in medically ill patients.

The Role of the Pharmacist

Pharmacists are in a unique position to ensure appropriate use of extended VTE prophylaxis in medically ill patients. Although some may consider the decision for extended prophylaxis to take place at discharge, it actually should take place upon admission. As in the clinical trials, the criteria for assessing appropriate risk and safety are based on information obtained on presentation to the hospital (Table 4).^35-37 The pharmacist has access to the patients’ medical information to ensure that patients meeting the appropriate risk criteria are started on rivaroxaban, assuming they do not have a contraindication such as being in one of the 5 high-risk bleeding groups.³⁷

Patients who should receive extended VTE prophylaxis, but do not, are at considerable risk of developing VTE in first 30 days after discharge.^30,31 Thirty-day readmission rates are costly to the US healthcare system and have come under significant scrutiny from CMS. Hospitals and systems with unacceptable 30-day readmission rates received reduced payment from CMS. In fiscal year 2015, eligible hospitals were penalized a combined $420 million due to avoidable hospital readmission.⁵⁶ The Hospital Readmission Reduction Program is part of Section 3025 of the Affordable Care Act, and states that hospitals may receive reduced reimbursement when an unplanned readmission occurs within 30 days for any of the following hospitalizations: acute myocardial infarction, COPD, heart failure, pneumonia, CABG surgery, or total knee or hip replacement.⁵⁷ It important to note that the 30-day readmission does not have to be for the same diagnosis, but any readmission counts against the hospital’s readmission rate. Of the listed conditions, COPD, heart failure, and pneumonia are all considered in medically ill patients that have increased risk of VTE within 30 days of discharge. Providing appropriate extended VTE prophylaxis provides an opportunity to reduce readmission rates in these patients.

Good transition-of-care programs have demonstrated the ability to significantly reduce hospital readmissions and save institutions millions of dollars.⁵⁸ The transition of care from the inpatient setting to the outpatient setting is a critical time when medication errors are known to occur.⁵⁹ Pharmacists have significantly increased their role in the transition-of-care process over the last several years. While transition of care is usually considered when a patient enters and leaves the hospital, it actually involves any change in patient care. In all of these transition-of-care scenarios, pharmacists are the key components to ensure that medications are initiated or discontinued when appropriate.⁶⁰

There are several potential transition-of-care programs that have been developed with a variety of different components.⁵⁸ One of the most successful and reproduced programs is Project RED (Re-Engineered Discharge).⁶¹ The 12 components of Project RED are listed in Table 5. A number of these should be driven by a pharmacist, such as being sure the discharge medications and plan are consistent with current guidelines, patient education, assessing patient understanding, education if problems arise, and telephone reinforcement of the discharge plan. The telephone follow-up in Project RED was specifically completed by a pharmacist and occurred within 2 to 4 days after discharge. The thought was that patients may be overwhelmed with information at the time of discharge and following up with them shortly after discharge would improve patient education and adherence. This follow-up was not simply a call to see if they had any questions, but instead to completely go over their discharge medications again to confirm understanding. Implementing the multidisciplinary approach to transitions of care in Project RED was able to reduce 30-day readmission rates by 30% (p = 0.009).

In the area of extended VTE prophylaxis in medically ill patients, pharmacists need to play a significant role in the transition of care. Patients need support to ensure successful transitions. Pharmacists need to provide simple, easy-to-understand instructions written specifically for a patient and/or caregiver. They need to work to ensure that patients fill prescriptions, check that medications are covered by a patient’s insurance, and teach patients the importance of adherence. Pharmacists should provide patients their 30 days of rivaroxaban before discharge through a meds-to-beds program, which helps ensure patients get their medications and contributes to reduced hospital readmissions.⁶² Patient education on the severity of VTE and the importance of prevention will help empower patients to be involved their care. The pharmacist should also provide patient education and monitoring for potential adverse effects. With the use of rivaroxaban, patients need to be educated on signs of bleeding such as the appearance in the urine or stool, more frequent or harder-to-stop nosebleeds, increased bruising, and increased bleeding when brushing and flossing teeth. This education should also include how to self-manage minor bleeding events, as well as when to seek medical care. Pharmacists should not assume that other healthcare providers have already provided this education or provided it as in-depth as the pharmacist is capable of doing.

Conclusion

Despite utilization of inpatient prophylaxis, many VTE events still occur soon after hospital discharge. While some attempts to reduce this risk with extended prophylaxis demonstrated a reduction of thrombotic events, they were limited by significant increases in major bleeding. The use of betrixaban in the APEX trial and rivaroxaban in the MAGELLAN subgroup trial with rivaroxaban seems to have changed this paradigm by providing a significant reduction in VTE events without a significant increase in major bleeding. Identification of appropriate patients for extended prophylaxis will be critical to optimize the efficacy and safety of this therapy and to attempt to appropriately balance resource allocation. The pharmacist has a key responsibility in assuring a successful transition of care to the outpatient setting through several roles that include, but are not limited to, identifying appropriate patients on admission, assuring medication acquisition through a meds-to-beds or similar program, and patient education on VTE and appropriate use of rivaroxaban.

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