Updates in the ASCO 2019 Venous Thromboembolism Guidelines

Kelly M. Brunk, PharmD
PGY-2 Hematology/Oncology Pharmacy Resident
University of North Carolina Medical Center
Chapel Hill, NC

Bianka Patel, PharmD
PGY-2 Hematology/Oncology Pharmacy Resident
University of North Carolina Medical Center
Chapel Hill, NC

The first American Society of Clinical Oncology (ASCO) guideline on the management of venous thromboembolism (VTE) in patients with cancer was published in 2007.¹ This guideline was updated in 2013 and reaffirmed in 2015. Since 2015, advances have been made in the understanding of the relevance and impact of VTE in patients with cancer. Most notably, results from prospective randomized clinical trials have illustrated the potential use of direct oral anticoagulants (DOACs) in patients with cancer. To account for the expanded literature, ASCO published its most recent iteration of the VTE guideline on August 5, 2019.² In this article we summarize specific updates and review selected studies.

Risk Prediction of VTE in Cancer Patients

VTE risk among patients with cancer varies significantly. The guidelines recommend that patients with cancer be assessed for VTE risk both initially and periodically, particularly when they are starting systemic chemotherapy or at the time of hospitalization. The Khorana score is yielded by a validated scoring tool that includes patient-specific factors such as site of cancer, body mass index, and complete blood count values and may be used to predict VTE risk in patients with cancer. The Khorana score ranges from 0 to 7 points, where 0, 1–2, and 3 points or more represent low, intermediate, and high risk, respectively.^3,4 It is critical to educate patients on the signs and symptoms of VTE, especially during surgery and hospitalization and while they are receiving chemotherapy.

VTE Prophylaxis During Hospitalization or Systemic Chemotherapy

On the basis of a meta-analysis of three trials that failed to demonstrate a significant reduction in VTE risk among hospitalized patients with cancer, ASCO recommends that pharmacologic thromboprophylaxis be offered to patients with risk factors (e.g., infection, advanced age).⁵ Patients without additional risk factors may be offered prophylaxis in the absence of active bleeding or other contraindications. However, patients undergoing stem-cell transplantation, chemotherapy infusions, or minor procedures should not be offered routine pharmacologic thromboprophylaxis.

In the ambulatory setting, pharmacologic thromboprophylaxis is also discouraged. Thromboprophylaxis should be offered only to high-risk outpatients with a Khorana score of 2 or higher. ASCO’s recommendation of apixaban, rivaroxaban, or low-molecular-weight heparin (LMWH) is based on five meta-analyses and two randomized phase 3 trials. The first of these randomized controlled trials (RCTs), AVERT, compared apixaban 2.5 mg twice daily (n = 288) and placebo (n = 275) in patients initiating chemotherapy.⁶ The primary efficacy outcome was objectively documented VTE during a 180-day follow-up period. Approximately 50% of the patients had gynecologic cancer or lymphoma, and the 6-month all-cause mortality was 11%. AVERT demonstrated an absolute risk reduction (ARR) of 6% (number needed to treat [NNT] 17) with use of apixaban. Major bleeding, however, was higher in the apixaban arm (modified intent-to-treat hazard ratio [HR] 2; 95% confidence interval [CI] 1.01–3.95).

The second RCT, CASSINI, studied rivaroxaban 10 mg once daily (n = 420) and placebo (n = 421) in patients beginning systemic antineoplastic therapy. The primary efficacy outcome was a composite VTE endpoint during a 180-day follow-up period. Over 50% had pancreatic or gastric cancer, and the 6-month all-cause mortality was 22%, which demonstrates the differences in tumor groups between CASSINI and AVERT. CASSINI showed an ARR of 3.8% (NNT 27) with use of rivaroxaban. The difference in major bleeding in the two groups was not statistically significant.⁷

Perioperative VTE Prophylaxis in Cancer Patients

As recommended in previous VTE guideline iterations, patients undergoing major cancer surgery should continue pharmacologic thromboprophylaxis with LMWH for at least 7–10 days. The duration of prophylaxis should be extended, however, in patients undergoing abdominopelvic cancer surgery. The 2019 guideline update recommends LMWH prophylaxis for up to 4 weeks after either open or laparoscopic abdominal or pelvic surgery. Given the data provided by two meta-analyses and an RCT, extending postoperative administration of LMWH for 30 days reduces the risk of VTE without increasing bleeding complications.^8-10

Optimal Management of VTE in Cancer Patients

The 2019 ASCO VTE guidelines include LMWH, unfractionated heparin (UFH), fondaparinux, and rivaroxaban as options for the initial management of VTE in cancer patients. In the CLOT trial, LMWH was found to reduce the risk of recurrent thromboembolism (HR 0.48; p = .002) compared to vitamin K antagonists (VKAs) without increasing the risk of bleeding.¹¹ LMWH is preferred over UFH for the initial 5–10 days of parenteral anticoagulation in patients with newly diagnosed VTE and cancer. For long-term anticoagulation, LMWH, edoxaban, and rivaroxaban for at least 6 months are preferred over vitamin K antagonists. In a noninferiority trial, edoxaban (initiated after 5 days of parenteral anticoagulation) was noninferior to dalteparin for a composite outcome of recurrent VTE and major bleeding. When these outcomes were analyzed separately, edoxaban was associated with an increased risk of major bleeding, particularly in patients with gastrointestinal (GI) malignancies (HR 1.77; p = .04).¹² In the SELECT-D trial, patients treated with rivaroxaban had a lower risk of VTE recurrence at 6 months compared to LMWH (HR 0.43; 95% CI 0.19–0.99) but higher rates of nonmajor bleeding (HR 3.76; 95% CI 1.63–8.69).¹³ In addition to GI malignancies, caution with DOAC use is also warranted in genitourinary (GU) malignancies and in patients with mucosal tumors because of a higher risk of bleeding. Other key considerations for DOAC use include cost, drug interactions, GI absorption, and renal or hepatic impairment.

ASCO recommends that anticoagulation with LMWH, DOACs, or VKAs be continued beyond 6 months in selected patients with active cancer, such as those with metastatic disease or those receiving chemotherapy; the recommendation is based on studies showing that extended anticoagulation is associated with continued risk reduction and no increased risk of bleeding. However, the benefits of extended anticoagulation must be balanced against the risks.

Although no clear strategy exists for the management of patients with recurrent VTE while they are receiving anticoagulation, ASCO recommends treating with an alternative anticoagulant or increasing the dose of LMWH.¹⁴ Patients should also be assessed for compliance. The addition of a vena cava filter to LMWH may be considered as a last-line option. Currently no evidence supports the switching of DOACs in the setting of recurrent VTE.

Incidental pulmonary embolism (PE) and deep vein thrombosis have been shown to carry a similar risk of VTE recurrence, bleeding, and mortality in patients with cancer when compared to those with symptomatic VTE and should therefore be treated in the same manner as symptomatic VTE.¹⁵ There is also no clear strategy for the management of incidental VTE that includes splanchnic or visceral vein thrombosis and isolated subsegmental PE in cancer patients. The guidelines recommend that treatment for these be offered on a case-by-case basis with careful assessment of risks and benefits.

On the basis of inconclusive benefit and the long-term risk of VTE development, ASCO guidelines recommend against insertion of a vena cava filter for primary VTE prophylaxis or in patients with established VTE (a VTE diagnosis made earlier than within the past 4 weeks), but this course may be considered for patients with absolute contraindications to anticoagulation in the management of acute VTE (a VTE diagnosis made within the past 4 weeks).¹⁶

Patients with primary or metastatic central nervous system malignancies are at an increased risk for both thrombotic complications and intracranial hemorrhage.¹⁷ Although anticoagulation should be offered to those with established VTE, the preferred anticoagulant remains a question.

In the CLOT trial, 24% of patients had baseline renal impairment. Recurrent VTE occurred in 2.7% of patients treated with LMWH and in 17% of patients treated with VKA.¹¹ ASCO recommends anti-Xa measurement if LMWH is used in patients with moderate to severe renal impairment because of a higher risk of bleeding in this patient population. If anti-Xa measurement is unavailable, UFH and VKAs are considered safer options for initial and long-term treatment, respectively. The guidelines support the use of LMWH as the preferred option in obese patients. Caution should be used with DOACs in patients weighing more than 120 kg because of limited enrollment of these patients in clinical trials evaluating DOACs.¹⁸

Because of insufficient evidence, the guidelines recommend against anticoagulant use in order to improve survival in patients with cancer without VTE.¹⁹

Conclusions

The 2019 ASCO VTE guidelines provide updates in the comprehensive management of VTE in patients with cancer. For prevention, high-risk outpatients with cancer may be offered thromboprophylaxis with apixaban, rivaroxaban, or LMWH. For treatment, initial anticoagulation may include LMWH, UFH, fondaparinux, or rivaroxaban. Options for long-term anticoagulation include LMWH, edoxaban, or rivaroxaban. Notably, the risk of major bleeding is higher with long-term anticoagulation with DOACs, especially in GI and potentially GU malignancies. When deciding appropriate pharmacologic intervention, one must consider the indication as well as drug costs, drug-drug interactions, and patient-specific risk factors.²

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