ASH 2021 Guidelines for Management of VTE in Patients with Cancer

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

American Society of Hematology (ASH) formed a multidisciplinary guideline panel and the guidelines summarized below are based on updated and original systematic reviews of evidence, conducted under the direction of the McMaster University GRADE Center with international collaborators. The main objective is to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

RECOMMENDATIONS
Primary prophylaxis for hospitalized medical patients with cancer.
♦ For patients without VTE, the panel suggests using thromboprophylaxis over no thromboprophylaxis and in whom pharmacologic thromboprophylaxis is used, the panel suggests using Low Molecular Weight Heparin (LMWH) over UnFractionated Heparin (UFH).
♦ For patients without VTE, the panel suggests using pharmacologic thromboprophylaxis over mechanical thromboprophylaxis or a combination of pharmacologic and mechanical thromboprophylaxis.
♦ For hospitalized medical patients with cancer, the ASH guideline panel suggests discontinuing thromboprophylaxis at the time of hospital discharge rather than continuing thromboprophylaxis beyond the discharge date.
Primary prophylaxis for patients with cancer undergoing surgery.
♦ For patients without VTE undergoing a surgical procedure at lower bleeding risk, the panel suggests using pharmacologic rather than mechanical thromboprophylaxis and for those undergoing a surgical procedure at high bleeding risk, the panel suggests using mechanical rather than pharmacologic thromboprophylaxis.
♦ For patients without VTE undergoing a surgical procedure at high risk for thrombosis, except in those at high risk of bleeding, the panel suggests using a combination of mechanical and pharmacologic thromboprophylaxis rather than mechanical prophylaxis alone or pharmacologic thromboprophylaxis alone.
♦ For all patients, the panel suggests using LMWH or Fondaparinux for thromboprophylaxis rather than UFH.
♦ The panel makes no recommendation on the use of Vitamin K Antagonists (VKAs) or Direct Oral AntiCoagulants (DOACs) for thromboprophylaxis, as there are no data.
♦ The panel suggests using postoperative thromboprophylaxis over preoperative thromboprophylaxis.
♦ For patients who have undergone a major abdominal/pelvic surgical procedure, the panel suggests continuing pharmacologic thromboprophylaxis, postdischarge rather than discontinuing at the time of hospital discharge.
Primary prophylaxis in ambulatory patients with cancer receiving systemic therapy.
♦ For patients at low and intermediate risk for thrombosis receiving systemic therapy, the panel recommends/suggests no thromboprophylaxis over parenteral thromboprophylaxis respectively. For patients at high risk, the panel suggests parenteral thromboprophylaxis (LMWH) over no thromboprophylaxis.
♦ The panel recommends no thromboprophylaxis over oral thromboprophylaxis with VKAs.
♦ For patients at low risk for thrombosis, the panel suggests no thromboprophylaxis over oral thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban). For patients at intermediate risk, the panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) or no thromboprophylaxis. For patients at high risk, the panel suggests thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban) over no thromboprophylaxis.
♦ For patients with multiple myeloma receiving Lenalidomide, Thalidomide, or Pomalidomide-based regimens, the panel suggests using low-dose Aspirin or fixed low-dose VKAs or LMWH.
Primary prophylaxis for patients with cancer with Central Venous Catheter (CVC).
♦ The panel suggests not using parenteral or oral thromboprophylaxis.
Initial treatment (first week) for patients with active cancer and VTE.
♦ The panel suggests DOAC (Apixaban or Rivaroxaban) or LMWH be used for initial treatment of VTE.
♦ The panel recommends/suggests LMWH over UFH and Fondaparinux respectively, for initial treatment of VTE.
Short-term treatment for patients with active cancer (initial 3-6 months).
♦ The panel suggests DOACs (Apixaban, Edoxaban, or Rivaroxaban) over LMWH and VKAs, and LMWH over VKAs.
♦ For patients with incidental (unsuspected) Pulmonary Embolism (PE), or SubSegmental PE (SSPE), the panel suggests short-term anticoagulation treatment rather than observation.
♦ For patients with visceral/splanchnic vein thrombosis, the panel suggests treatment with short-term anticoagulation or observation.
♦ For patients with CVC-related VTE receiving anticoagulant treatment, the panel suggests keeping the CVC over removing the CVC.
♦ For patients with recurrent VTE despite receiving therapeutic LMWH, the panel suggests increasing the LMWH dose to a supratherapeutic level or continuing with a therapeutic dose.
♦ For patients with recurrent VTE despite anticoagulation treatment, the panel suggests not using an Inferior Vena Cava filter over using a filter.
Long-term treatment (>6 months) for patients with active cancer and VTE.
♦ The panel suggests long-term anticoagulation for secondary prophylaxis (> 6 months) rather than short-term treatment alone (3-6 months), and the panel suggests continuing indefinite anticoagulation over stopping after completion of a definitive period of anticoagulation.
♦ For patients requiring long-term anticoagulation (> 6 months), the panel suggests using DOACs or LMWH.

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Lyman GH, Carrier M, Ay C, et al. Blood Adv 2021;5: 927–974.

Immune Checkpoint Inhibitor Therapy and Risk of Venous Thromboembolism

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.
Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer management. They bind to either PD-1 receptor or its ligand PD-L1 and block their interaction, thereby reversing the PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. This can however be accompanied by various off-target manifestations of autoimmunity induced by immune checkpoint inhibitors with resulting systemic inflammation on the hemostatic system. The risk of Venous ThromboEmbolism (VTE) and Arterial ThromboEmbolism (ATE) associated with ICIs is currently unclear. The goal of this study was to quantify the risk of VTE/ATE in patients with cancer, treated with ICIs, explore clinical impact, and investigate potential clinical risk factors.

The authors conducted a single-center, retrospective cohort study at the Medical University of Vienna, Austria, and included 672 patients with histologically confirmed cancer, who were treated with one or more doses of an Immune Checkpoint Inhibitor (Nivolumab, Pembrolizumab, Ipilimumab, Atezolizumab, or Avelumab), between 2015 and 2018. Patients received a median of 7 cycles of therapy. About a third of patients (30.4%) had Malignant Melanoma, whereas 24% had Non Small Cell Lung Cancer, 11% had Renal Cell Carcinoma, 10.4% had Head and Neck Squamous Cell Carcinoma and 5% had Urothelial cancer. Majority of patients (86%) had advanced disease at the time of ICI initiation. The median patient age was 64 years, 39% were female and most patients had an ECOG Performance Status of 0 or 1. Approximately 13% of patients had a history of VTE prior to the initiation of ICI therapy. Approximately 9% of patients had a history of ATE, and was associated with the current cancer diagnosis in 2.2% of the total cohort. At the time of ICI therapy initiation, 16.5% received continuous anticoagulation and 20% received antiplatelet therapy. The Primary outcomes of the study were cumulative incidence rates of VTE and ATE. Secondary outcomes included the association of VTE/ATE with Overall Survival (OS), Progression Free Survival (PFS), and radiological Disease Control Rate (DCR). The median follow up was 8.5 months.

It was noted that the cumulative incidences of VTE and ATE during ICI therapy were 12.9% and 1.8% respectively. The occurrence of VTE was associated with increased mortality with shorter OS. The median OS after the occurrence of VTE was 11.6 months compared with 25.5 months in those without VTE (P<0.001). The researchers noted that the number of fatal Pulmonary Embolisms were not high (N=2) in this study, suggesting that the impact of VTE goes beyond direct VTE-related mortality. The diagnosis of VTE was further associated with shorter PFS. Median PFS after VTE was 1.7 months compared with 6.7 months in those without VTE (P<0.001). The occurrence of ATE was not associated with risk of mortality or early progression of disease. However, this could have been due to relatively low number of ATE events and potential lack of statistical power. Therefore, definite conclusions cannot be drawn. Prior history of VTE predicted VTE occurrence. Distant metastasis was associated with VTE risk, although this was not statistically significant. The researchers did not find association of VTE with ECOG Performance Status or Khorana score, and the rates of VTE were comparable between tumor types and different immune Checkpoint Inhibitors. No association with VTE risk was observed for patients undergoing continuous anticoagulation or anti-platelet therapy at baseline.

It was concluded that despite the limitations of this study, patients with cancer undergoing treatment with Immune Checkpoint inhibitors are at a high risk of developing thromboembolic complications, especially VTE, and VTE occurrence was associated with increased mortality. The authors added that further studies are needed to better understand the risk of VTE and ATE associated with ICIs, and thus improve patient care by preventing thromboembolic complications.

Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Moik F, Chan WE, Wiedemann S, et al. Blood.2021;137:1669-1678.

Somatic Tumor Mutations and Risk for Thrombosis

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.

The researchers conducted this study to assess potential associations between tumor molecular signatures and Cancer Associated Thrombosis, including tumor-specific mutations, and the presence of Clonal Hematopoiesis. The authors analyzed deep-coverage targeted DNA-sequencing data of more than 14,000 solid tumor samples from 11,695 patients, using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform, to identify somatic alterations associated with Venous ThromboEmbolism (VTE). Among the patients included, more than 15 different solid tumor types were represented and 72% had metastatic disease at time of analysis.
Among these patients, there were 693 episodes of Cancer Associated Thrombosis, and the authors in addition to looking for associations with standard clinical variables such as diagnosis, stage and therapy, also assessed potential linkage of Cancer Associated Thrombosis with oncogenic mutations. The Primary endpoint was defined as the first instance of cancer-associated Pulmonary Embolism and/or proximal/distal lower extremity Deep Vein Thrombosis.

It was noted that several genes were found to be significantly associated with the VTE risk, regardless of tumor type. Independent of tumor type, the following mutations were associated with increased risk of Cancer Associated Thrombosis: KRAS (HR=1.34 suggesting 1.34 times higher risk), STK11 (HR=2.12), KEAP1 (HR=1.84), CTNNB1 (HR=1.73), CDKN2B (HR=1.45) and MET (HR=1.83). Mutations in SETD2 were associated with a decreased risk of Cancer Associated Thrombosis (HR=0.35). Clonal Hematopoiesis (CH) is an aging associated biologic state, with genetic mutations occurring in the background of active malignancies. The presence of Clonal Hematopoiesis was not associated with an increased risk of Cancer Associated Thrombosis.

The authors from this study concluded that this is the first large-scale study to explore the link between cancer genomics and thrombosis. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. It remains unclear whether drugs targeting these genetic alterations would alter the course of Cancer Associated Thrombosis.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors. Dunbar A, Bolton KL, Devlin SM, et al. Blood 2021;137:2103-2113.

ASH 2021 Guidelines for Management of VTE in Patients with Cancer

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

American Society of Hematology (ASH) formed a multidisciplinary guideline panel and the guidelines summarized below are based on updated and original systematic reviews of evidence, conducted under the direction of the McMaster University GRADE Center with international collaborators. The main objective is to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

RECOMMENDATIONS
Primary prophylaxis for hospitalized medical patients with cancer.
♦ For patients without VTE, the panel suggests using thromboprophylaxis over no thromboprophylaxis and in whom pharmacologic thromboprophylaxis is used, the panel suggests using Low Molecular Weight Heparin (LMWH) over UnFractionated Heparin (UFH).
♦ For patients without VTE, the panel suggests using pharmacologic thromboprophylaxis over mechanical thromboprophylaxis or a combination of pharmacologic and mechanical thromboprophylaxis.
♦ For hospitalized medical patients with cancer, the ASH guideline panel suggests discontinuing thromboprophylaxis at the time of hospital discharge rather than continuing thromboprophylaxis beyond the discharge date.
Primary prophylaxis for patients with cancer undergoing surgery.
♦ For patients without VTE undergoing a surgical procedure at lower bleeding risk, the panel suggests using pharmacologic rather than mechanical thromboprophylaxis and for those undergoing a surgical procedure at high bleeding risk, the panel suggests using mechanical rather than pharmacologic thromboprophylaxis.
♦ For patients without VTE undergoing a surgical procedure at high risk for thrombosis, except in those at high risk of bleeding, the panel suggests using a combination of mechanical and pharmacologic thromboprophylaxis rather than mechanical prophylaxis alone or pharmacologic thromboprophylaxis alone.
♦ For all patients, the panel suggests using LMWH or Fondaparinux for thromboprophylaxis rather than UFH.
♦ The panel makes no recommendation on the use of Vitamin K Antagonists (VKAs) or Direct Oral AntiCoagulants (DOACs) for thromboprophylaxis, as there are no data.
♦ The panel suggests using postoperative thromboprophylaxis over preoperative thromboprophylaxis.
♦ For patients who have undergone a major abdominal/pelvic surgical procedure, the panel suggests continuing pharmacologic thromboprophylaxis, postdischarge rather than discontinuing at the time of hospital discharge.
Primary prophylaxis in ambulatory patients with cancer receiving systemic therapy.
♦ For patients at low and intermediate risk for thrombosis receiving systemic therapy, the panel recommends/suggests no thromboprophylaxis over parenteral thromboprophylaxis respectively. For patients at high risk, the panel suggests parenteral thromboprophylaxis (LMWH) over no thromboprophylaxis.
♦ The panel recommends no thromboprophylaxis over oral thromboprophylaxis with VKAs.
♦ For patients at low risk for thrombosis, the panel suggests no thromboprophylaxis over oral thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban). For patients at intermediate risk, the panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) or no thromboprophylaxis. For patients at high risk, the panel suggests thromboprophylaxis with a DOAC (Apixaban or Rivaroxaban) over no thromboprophylaxis.
♦ For patients with multiple myeloma receiving Lenalidomide, Thalidomide, or Pomalidomide-based regimens, the panel suggests using low-dose Aspirin or fixed low-dose VKAs or LMWH.
Primary prophylaxis for patients with cancer with Central Venous Catheter (CVC).
♦ The panel suggests not using parenteral or oral thromboprophylaxis.
Initial treatment (first week) for patients with active cancer and VTE.
♦ The panel suggests DOAC (Apixaban or Rivaroxaban) or LMWH be used for initial treatment of VTE.
♦ The panel recommends/suggests LMWH over UFH and Fondaparinux respectively, for initial treatment of VTE.
Short-term treatment for patients with active cancer (initial 3-6 months).
♦ The panel suggests DOACs (Apixaban, Edoxaban, or Rivaroxaban) over LMWH and VKAs, and LMWH over VKAs.
♦ For patients with incidental (unsuspected) Pulmonary Embolism (PE), or SubSegmental PE (SSPE), the panel suggests short-term anticoagulation treatment rather than observation.
♦ For patients with visceral/splanchnic vein thrombosis, the panel suggests treatment with short-term anticoagulation or observation.
♦ For patients with CVC-related VTE receiving anticoagulant treatment, the panel suggests keeping the CVC over removing the CVC.
♦ For patients with recurrent VTE despite receiving therapeutic LMWH, the panel suggests increasing the LMWH dose to a supratherapeutic level or continuing with a therapeutic dose.
♦ For patients with recurrent VTE despite anticoagulation treatment, the panel suggests not using an Inferior Vena Cava filter over using a filter.
Long-term treatment (>6 months) for patients with active cancer and VTE.
♦ The panel suggests long-term anticoagulation for secondary prophylaxis (> 6 months) rather than short-term treatment alone (3-6 months), and the panel suggests continuing indefinite anticoagulation over stopping after completion of a definitive period of anticoagulation.
♦ For patients requiring long-term anticoagulation (> 6 months), the panel suggests using DOACs or LMWH.

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Lyman GH, Carrier M, Ay C, et al. Blood Adv 2021;5: 927–974.

COVID-19 Associated Coagulopathy: Diagnosis and Management

SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the number of infected cases continue to exponentially increase worldwide. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

One of the most important and significant poor prognostic features in patients with COVID-19 is the development of coagulopathy, which is associated with an increased risk of death. The coagulation changes seen suggest the presence of a hypercoagulable state that can potentially increase the risk of thromboembolic complications. The coagulation abnormalities mimic other systemic coagulopathies associated with severe infections, such as Disseminated Intravascular Coagulation (DIC) or Thrombotic MicroAngiopathy (TMA), but the features are distinct in that, with DIC associated with sepsis, thrombocytopenia is usually more profound, and D-dimer concentrations do not reach the high values as seen among patients with COVID-19. COVID-19 infection related coagulopathy can also be associated with increased Lactate DeHydrogenase (LDH), and in some patients strikingly high ferritin levels, reminiscent of findings in TMA.

Severe COVID-19 infection is characterized by high concentrations of proinflammatory cytokines and chemokines such as Tumor Necrosis Factor-α (TNF-α) and interleukins including IL-1 and IL-6. IL-6 can induce tissue factor expression on mononuclear cells, initiating coagulation activation and thrombin generation, whereas TNF-α and IL-1 suppress endogenous anticoagulant pathways.
Management-of-Coagulopathy-in-COVID-19-Patients
The International Society of Thrombosis and Haemostasis (ISTH) in this publication provided an interim guidance, with the aim to help Health Care Specialists risk stratify patients admitted with COVID -19, and manage coagulopathy, which may develop in some of these patients, utilizing easily available laboratory parameters. Based on the currently available literature, majority of the patients with COVID-19, present with severe pneumonia and respiratory failure. Lymphopenia is a common hematological abnormality. The interim guidance statement by the ISTH on the management of coagulopathy is based on evolving clinical knowledge and better understanding of the pathogenesis of COVID-19.

1) Initial evaluation of COVID-19 patients should include measurement of D-dimers, Prothrombin Time, Platelet count and Fibrinogen levels.
2) Higher D-dimer levels on admission, has been reported in patients with severe COVID-19 illness, and is one of the most important predictors of mortality.
3) Modest prolongation of Prothrombin Time (15.5 seconds) has been reported at admission, in the non-survivors. Subtle changes in the PT will not be picked up if the PT is reported as International Normalized Ratio (INR). It should be noted that INR is not the same as PT ratio.
4) Thrombocytopenia at the time of admission may be, but is not a consistent prognosticator and platelet count of less than 100 × 109/L may only be seen in 5% of patients
5) Fibrinogen should be regularly monitored in COVID-19 patients, as non-survivors with severe illness usually develop Disseminated Intravascular Coagulation around day 4, with significant worsening noted at days 10 and 14.
6) In the absence of any contraindications such as active bleeding and platelet count less than 25 × 109/L, prophylactic dose Low Molecular Weight Heparin (LMWH) should be considered in all patients who require hospital admission for COVID‐19 infection, including those who are non‐critically ill, to protect patients against septic-like coagulopathy and Venous ThromboEmbolism (VTE). The anti‐inflammatory properties of LMWH may be an added benefit in COVID infection where pro‐inflammatory cytokines are markedly raised.
7) Abnormal PT or aPTT is not a contraindication for pharmacological thromboprophylaxis as Lupus-like inhibitors have been reported in some patients with COVID-19, and may be the reason for aPTT prolongation.
8) In COVID-19 patients already on anticoagulation for VTE or Atrial Fibrillation, therapeutic doses of anticoagulant therapy should be continued, but may need to be held if the platelet count is less than 30-50 x 109/L or if the fibrinogen is less than 1.0 g/L.
9) Bleeding is rare in the setting of COVID‐19 and if present should be managed by maintaining platelet counts >50×109/L (>20×109/L goal in non-bleeding patients), maintaining fibrinogen levels at >2.0 g/L, and the Prothrombin ratio at <1.5.

ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. Thachil J, Tang N, Gando S, et al. J Thromb Haemost 2020 Mar 25; [e-pub]. (https://doi.org/10.1111/JTH.14810)

ELIQUIS® May Be Safer for the Treatment of Venous Thromboembolism Associated with Cancer

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging. Treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations is often recommended for this patient group, based on efficacy data. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Parenteral LMWH however can be inconvenient and expensive, leading to premature discontinuation of treatment.Anticoagulants

Direct Oral Anticoagulant agents have been proven to be as effective as COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of VTE, and are associated with less frequent and less severe bleeding, and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban), which are Factor Xa inhibitors. Compared to COUMADIN®, the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), require no laboratory monitoring and have a fixed dosing schedule.

Three open-label, randomized, controlled trials have compared direct Factor Xa inhibitors with subcutaneous LMWH FRAGMIN® (Dalteparin). In the Hokusai VTE Cancer noninferiority trial, SAVAYSA® (Edoxaban)‎ when compared with FRAGMIN® was associated with a lower rate of recurrent VTE, but this was offset by a similar increase in the risk of major bleeding. In the SELECT-D trial, XARELTO® was associated with relatively low VTE recurrence in patients with cancer, but with higher clinically relevant non-major bleeding, compared with FRAGMIN®. In the ADAM VTE Trial, oral ELIQUIS® therapy was associated with very low rates of bleeding and significantly lower VTE recurrence compared to parenteral FRAGMIN®. The inconsistent results from these studies have been attributed to patient selection (cancer type, types of cancer therapies and prognosis), duration of treatment, and primary efficacy outcomes of these studies. SAVAYSA® and XARELTO® are often recommended as alternatives to LMWH in patients with cancer, although higher risk of clinically important bleeding has been reported with both these agents, particularly in patients with GI malignancies, including pancreatic cancer.

The Caravaggio trial is a multinational, randomized, open-label, noninferiority trial which was conducted to assess whether oral ELIQUIS® would be noninferior to subcutaneous FRAGMIN® (Dalteparin), a LMWH, for the prevention of recurrent VTE in patients with cancer, without increasing the risk of major bleeding. In this study, 1155 patients with cancer who had symptomatic or incidental acute proximal DVT or PE were randomly assigned to receive ELIQUIS® 10 mg orally twice daily for the first 7 days, followed by 5 mg orally twice daily (N=576) or FRAGMIN® 200 IU/kg administered subcutaneously once daily for the first month, followed by 150 IU/kg subcutaneous once daily (N=579). The demographic and clinical characteristics of the patients in both treatment groups were well balanced and advanced active cancers associated with high thromboembolic risk such as lung and colorectal cancers were well represented. This study included patients receiving a variety of cytotoxic and biologic therapies. Anticoagulant treatments were administered for 6 months. The Primary endpoint was objectively confirmed recurrent VTE during the trial period. The principal safety outcome was major bleeding.

The Primary endpoint of recurrent VTE occurred in 5.6% of patients in the ELIQUIS® group and in 7.9% of patients in the FRAGMIN® group (HR=0.63; P<0.001 for noninferiority). Major bleeding occurred in 3.8% of patients in the ELIQUIS® group and 4.0% of patients in the FRAGMIN® group (HR=0.82; P=0.60). Major GI bleeding occurred in 1.9% of patients in the ELIQUIS® group and in 1.7% of patients in the FRAGMIN® group and major non-gastrointestinal bleeding occurred in 1.9% and 2.2% of patients respectively. There were no fatal bleeding episodes noted in the ELIQUIS® group, whereas 2 patients had a fatal bleed in the FRAGMIN® group. These findings with regards to bleeding are in contrast to the results of previously published studies, which showed a higher incidence of bleeding with other Direct Oral AntiCoagulants, compared with FRAGMIN®, in a similar patient population.

It was concluded that in this study which included patients with predominantly advanced active cancer and acute symptomatic VTE, oral ELIQUIS® was noninferior to subcutaneous FRAGMIN® for the treatment of cancer-associated VTE, without an increased risk of major bleeding. The authors added that these findings may expand the proportion of patients with both cancer and VTE who would be eligible for treatment with ELIQUIS®, including patients with active gastrointestinal malignancies. It should be noted however that LMWH should still be preferred for patients who have undergone surgery involving the upper GI tract, as Direct Oral AntiCoagulants are absorbed in the stomach or proximal small bowel, as well as for those patients with bleeding or thrombocytopenia, recurrent VTE, CNS cancers, or those with severe renal impairment, and in the perioperative setting.
Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. Agnelli G, Becattini C, Meyer G, et al. for the Caravaggio Investigators. N Engl J Med 2020; 382:1599-1607

Periprocedural Bridging Increases Bleeding Risk without Reduction in VTE Rates for Patients on Long Term Anticoagulants

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. It is estimated that in the US, more than 6 million patients are on chronic anticoagulation and approximately 250,000 patients need to temporarily interrupt their anticoagulant therapy annually, prior to an invasive procedure, to decrease the risk of excess periprocedural bleeding.

Despite a significant and rapid increase in the use of Direct Oral AntiCoagulants (DOACs) in the recent decade, Vitamin K Antagonists (VKAs) such as COUMADIN® (Warfarin) remain the most frequently prescribed anticoagulants in the US and worldwide. VKAs must be interrupted several days prior to a planned procedure to allow for regeneration of vitamin K-dependent coagulation factors (Factors II, X, VII and IX as well as protein C and S) and subsequent normalization of coagulation. Bridging with short-acting parenteral anticoagulants during the periprocedural period is often recommended for individuals at high thromboembolic risk. Previously published studies have shown a significantly higher incidence of major bleeding with bridging, with no difference in thromboembolic outcomes and further, current guidelines fail to identify patients with high-enough thromboembolic risk to justify periprocedural bridging. There is presently no randomized study that shows a clear benefit of periprocedural bridging for patients on long-term anticoagulants, whereas there are abundant data suggesting an increased bleeding risk with bridging.

In this publication, the authors performed a systematic review comparing recurrent VTE and bleeding outcomes, with and without periprocedural bridging, in order to better define risks and benefits of bridging in patients with previous VTE, requiring VKA interruption to undergo an elective invasive procedure. This systematic review involved searching the PubMed and Embase databases from inception to December 7, 2017 for randomized and nonrandomized studies and included adults with previous VTE requiring VKA interruption to undergo an elective procedure, and those that reported VTE or bleeding outcome. This analysis included 28 cohort studies, with 6915 procedures.

It was noted that the pooled incidence of recurrent VTE with bridging was 0.7% and 0.5% without bridging. The pooled incidence of any bleeding was 3.9% with bridging and 0.4% without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for VTE was 0.8% for any bleeding.

The authors noted that this is the first study to systematically assess the risks and benefits of periprocedural bridging in the specific population of patients with previous VTE and they concluded that patients at low and moderate thromboembolic risk do not benefit from periprocedural bridging, and on the contrary, periprocedural bridging increases the risk of bleeding, compared with VKA interruption without bridging, without a significant difference in periprocedural VTE rates. Periprocedural Bridging in Patients with Venous Thromboembolism: A Systematic Review. Baumgartner C, Kouchkovsky I, Whitaker E, et al. The American Journal of Medicine 2019;132:722-732

ELIQUIS® for Thromboprophylaxis in Ambulatory Patients with Cancer

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life. Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The benefit of thromboprophylaxis in this patient population however is uncertain. This is because previously published randomized trials included cancer patients both at both low and high risk for VTE.Predicting-VTE-in-cancer-patients-using-a-Risk-Score

Khorana score is a validated risk tool which helps to identify patients at increased risk for VTE. Several studies have suggested benefit from thromboprophylaxis in patients with a score of 3 or higher, whereas the benefit of thromboprophylaxis in patients with a score of 2 is unclear, although there is a substantial risk of VTE in this group as well. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule.

The AVERT (Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients ) trial is a randomized, placebo-controlled, double-blind clinical trial which evaluated the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score 2 or more). Eligible patients (N=574) were randomized in a 1:1 ratio to receive apixaban or placebo and 563 patients were included in the modified intention-to-treat analysis. The first dose of apixaban or placebo was administered within 24 hours after the initiation of chemotherapy. The mean patient age was 61 years, and the common types of primary malignancies were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Eligible patients included those who had a newly diagnosed cancer or progression of known cancer after complete or partial remission and who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months. Inclusion required a Khorana score of 2 or higher. Exclusion criteria included hepatic disease associated with coagulopathy, platelet count of less than 50,000 per cubic millimeter, acute leukemia, myeloproliferative neoplasm, planned stem-cell transplantation and GFR of less than 30 ml/min. The Primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main Safety outcome was a major bleeding episode.

Venous thromboembolism occurred in 4.2% in the apixaban group and 10.2% in the placebo group (HR=0.41; P<0.001). This benefit and was predominantly driven by a lower rate of pulmonary embolism in the apixaban group than in the placebo group. The rate of major bleeding was significantly higher with apixaban than with placebo in the modified intention-to-treat analysis (3.5% versus 1.8%, respectively; HR=2.00), but the rate however was not significantly higher with apixaban than with placebo in the analysis of outcomes during the treatment period (2.1% versus 1.1%, respectively; HR=1.89). There was no significant difference in the Overall Survival between the treatment groups and the authors attributed this to trial design and the fact that most of the patients had advanced cancer, which was the most common cause of death.

It was concluded that thromboprophylaxis with apixaban at a dose of 2.5 mg twice daily resulted in a significantly lower risk of venous thromboembolism when compared to placebo, among ambulatory cancer patients who were initiating chemotherapy, and had an intermediate to high risk of venous thromboembolism. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. Carrier M, Abou-Nassar K, Mallick R, et al. for the AVERT Investigators. N Engl J Med 2019;380:711-719

Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents Associated with Lower Risk of Major Bleeding Compared with Concomitant Warfarin and Antiplatelet Agents

SUMMARY: It is estimated that up to 30% of patients with nonvalvular atrial fibrillation may receive antiplatelet agents along with oral anticoagulants, due to comorbid cardiovascular conditions. The concomitant use of Vitamin K Antagonist (VKA) such as Warfarin along with antiplatelet agents, has in previously published studies, shown to increase the risk of bleeding, compared with VKAs alone.

Direct Oral AntiCoagulants (DOACs) are often prescribed for thromboembolic events. This class of anticoagulants, have a rapid onset and offset of action, short half-life, predictable anticoagulant effects, no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and DOACs are ineffective in patients with mechanical heart valves. Direct Oral AntiCoagulants have a favorable efficacy and safety profile, compared with Vitamin K Antagonists (VKAs) and are increasingly being used for ischemic stroke prevention among patients with nonvalvular atrial fibrillation. In several clinical studies, DOACs have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to Vitamin K Antagonist (VKA) such as Warfarin. Meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of DOACs along with AcetylSalicylic Acid (ASA), in nonvalvular atrial fibrillation has shown similar risk of major bleeding but a decreased risk of intracranial hemorrhage, when compared with VKAs plus ASA. Some of the studies included in this meta-analysis however had methodological limitations.MOA-of-New-Oral-Anticoagulants

In order to address this clinically important safety issue, the authors conducted this population-based study to compare the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC/antiplatelet use and concomitant VKA/antiplatelet use, in patients with nonvalvular atrial fibrillation. This study was conducted among a cohort of patients with newly diagnosed nonvalvular atrial fibrillation, between January 2011 and March 2014, using computerized health care databases from Quebec. Of the 14, 407 patients included in this study, 5301 patients initiated concomitant DOAC/antiplatelet use, while 9106 patients initiated concomitant VKA/antiplatelet use. DOACs included PRADAXA® (Dabigatran), XARELTO® (Rivaroxaban), or ELIQUIS® (Apixaban) and antiplatelet agents included ASA (Aspirin), Dipyridamole, PLAVIX® (Clopidogrel), EFFIENT® (Prasugrel), or BRILINTA® (Ticagrelor). Three separate analyses were conducted for intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding. The median follow up was 1.6 months which was primarily driven by discontinuation of antiplatelet therapy.

It was noted that concomitant DOAC/antiplatelet therapy was associated with a similar risk of gastrointestinal bleeding (HR 1.08) but with a decreased risk of intracranial hemorrhage (HR 0.46) and other major bleeding (HR 0.68), compared with concomitant VKA/antiplatelet therapy.

The authors concluded that based on the results of this population-based study, compared with concomitant Vitamin K Antagonist /antiplatelet use, concomitant Direct Oral AntiCoagulants/antiplatelet use was associated with a similar risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage and other major bleeding. These findings could provide guidance to physicians and help in decision making, for patients requiring concomitant treatment with oral anticoagulants and antiplatelets. Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents and the Risk of Major Bleeding in Patients with Nonvalvular Atrial Fibrillation. Douros A, Renoux C, Yin H, et al. The American Journal of Medicine 2019; 132:191-199