Management updates for cancer-associated and COVID-19–related thromboses

Prof. Pantep Angchaisuksiri
Ramathibodi Hospital, Mahidol University
Thailand
09 Jul 2021

Management of cancer-associated thrombosis (CAT) and coronavirus disease 2019 (COVID-19)–related thrombosis presents several challenges in terms of thromboprophylaxis and treatment strategies. These topics were discussed by Professor Pantep Angchaisuksiri of Ramathibodi Hospital, Mahidol University in Bangkok, Thailand, at the Advances in Medicine (AIM) 2021 virtual meeting organized by the Chinese University of Hong Kong.

 

NOACs as VTE standard of care

“Non–vitamin K antagonist oral anticoagulants [NOACs] are the standard of care in treatment of venous thromboembolism [VTE] in patients without cancer,” said Angchaisuksiri. [Chest 2012;141(Suppl 2):e419S-e496S; Blood 2014;124:1968-1975]

A meta-analysis of six landmark phase III randomized controlled trials compared the NOACs apixaban, dabigatran, edoxaban and rivaroxaban vs vitamin K antagonists (VKAs) for treatment of acute symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), or both. Pooled results showed that recurrent VTE occurred in 2.0 percent of NOAC recipients vs 2.2 percent of VKA recipients (relative risk [RR], 0.90; 95 percent confidence interval [CI], 0.77 to 1.06). Compared with VKAs, NOACs also significantly reduced the risk of major bleeding, intracranial bleeding, fatal bleeding, and clinically relevant non-major bleeding. [Blood 2014;124:1968-1975]

“These results show that NOACs are as effective as VKAs at reducing the risk of recurrent VTE and are associated with a lower risk of major bleeding,” noted Angchaisuksiri.

Management of CAT

“Cancer is an important risk factor for VTE. Patients with cancer have a 4.1-fold increased risk of thrombosis vs patients without cancer,” Angchaisuksiri explained. [Circulation 2003;107:I17-I21]

“Importantly, there is a high rate of VTE recurrence in patients with active cancer and a high mortality risk in patients who develop CAT,” he added. [Throm Haemost 2017;117:57-65]

Both fatal PE and fatal bleeding are more common in patients with cancer and VTE vs those without cancer. [J Thromb Haemost 2006;4:1950-1956] The risks of recurrent VTE and major bleeding during anticoagulation therapy (ie, intravenous standard heparin or low-molecular-weight heparin [LMWH]) are also higher in patients with cancer. [Blood 2002;100:3484-3488]

NOACs as an option in CAT

“LMWH has traditionally been the standard treatment of choice for VTE in cancer patients,” said Angchaisuksiri. This is supported by results of a meta-analysis of randomized clinical trials, which demonstrated that LMWH reduced the risk of VTE by approximately 40 percent vs VKAs (RR, 0.60; 95 percent CI, 0.45 to 0.79), with comparable safety in terms of major bleeding (RR, 1.07; 95 percent CI, 0.66 to 1.73). [Thromb Res 2015;136:582-589]

“Recently, international guidelines have added the NOACs apixaban, edoxaban and rivaroxaban as therapeutic options for CAT based on results of randomized clinical trials comparing NOACs with LMWH,” he noted. (Table)

HK-DAI-140md_01

One of these trials was Hokusai VTE Cancer, a phase III, multicentre, prospective, open-label, blinded endpoint evaluation study that included 1,046 patients with cancer and acute symptomatic or incidental VTE. Patients were randomly assigned to receive daily oral edoxaban (after LMWH for ≥5 days) or daily subcutaneous dalteparin for ≥6 months and ≤12 months. [N Engl J Med 2018;378:615-624]

The primary endpoint, a composite of recurrent VTE or major bleeding during the 12 months after randomization, occurred in 12.8 percent vs 13.5 percent of patients in the edoxaban vs dalteparin group (hazard ratio [HR], 0.97; 95 percent CI, 0.70 to 1.36; p=0.006 for noninferiority). Recurrent VTE occurred in 7.9 percent vs 11.3 percent of patients in the edoxaban vs dalteparin group (HR, 0.71; 95 percent CI, 0.48 to 1.06; p=0.09), while major bleeding occurred in 6.9 percent vs 4.0 percent of the patients (HR, 1.77; 95 percent CI, 1.03 to 3.04; p=0.04). [N Engl J Med 2018;378:615-624]

“These results demonstrate noninferiority of oral edoxaban vs dalteparin with respect to the composite outcome of recurrent VTE or major bleeding, supporting the use of edoxaban as an alternative to LMWH in patients with CAT,” said  Angchaisuksiri.

Similar results were shown for rivaroxaban vs dalteparin in the SELECT-D study, and for apixaban vs dalteparin in the ADAM VTE and Caravaggio studies. [J Clin Oncol 2018;36:2017-2023; J Thromb Haemost 2020;18:411-421; N Engl J Med 2020;382:1599-1607]

These results have led several guidelines to include NOACs along with LMWH as preferred anticoagulants for management of CAT. (Table) 

“Opting for NOACs as initial therapy will depend on patients’ oral absorption, risk of bleeding, tumour type and preference, as well as potential for drug-drug interactions,” noted Angchaisuksiri. [Blood Adv 2021;5:927-974; J Clin Oncol 2020;38:496-520; Lancet Oncol 2019;20:e566-e581; J Thromb Haemost 2018;16:1891-1894; Eur Heart J 2020;41:543-603]

Management of COVID-19–related thrombosis

In a systematic review, Angchaisuksiri and colleagues reported a higher incidence  of VTE among patients with COVID-19  treated in the intensive care unit (ICU) vs those treated in non-ICU settings (28 percent vs 10 percent). “We also found a significantly higher incidence of DVT in the compression ultrasound [CUS] screening vs non-CUS screening subgroup [32 percent vs 6 percent],” he said. [Thromb J 2020;18:34]

“Since approximately 25 percent of patients admitted to the ICU developed VTE, careful monitoring for VTE and its complications in the ICU setting is recommended. We also suggest thromboprophylaxis for all hospitalized patients with COVID-19 in the absence of contraindications,” he added. [Thromb J 2020;18:34]

Similarly, the 2021 American Society of Hematology (ASH) conditionally recommends using prophylactic-intensity over intermediateor therapeutic-intensity anticoagulation in patients with COVID-19–related critical illness who do not have suspected or confirmed VTE. [Blood Adv 2021;5:872-888]

COVID-19 Vaccines and VITT

Several reports have suggested that vaccination with the ChAdOx1 nCoV-19 adenoviral vector vaccine may result in the rare development of immune thrombotic thrombocytopenia, similar to autoimmune heparin-induced thrombocytopaenia. [N Engl J Med 2021;NEJMoa2105385; N Engl J Med 2021;384:2124-2130; N Engl J Med 2021;384:2092-2101]

“However, these vaccine-induced immune thrombotic thrombocytopaenia [VITT] events are rare and can be managed, especially if detected early,” stressed Angchaisuksiri. “The benefits of COVID-19 vaccination far outweigh the risks of developing VITT.” [J Thromb Haemost 2021;19:1585-1588]

Summary

The NOACs apixaban, edoxaban and rivaroxaban have emerged as valid therapies in appropriate patients with CAT. For COVID-19–related thrombosis, ASH currently suggests prophylactic-intensity anticoagulation in pa-tients with critical illness who do not have suspected or confirmed VTE. Meanwhile, COVID-19 VITT is rare and can be managed with prompt detection and treatment.

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