Tag: Venous Thrombo Embolism

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.

Clinically, VTE is classified as provoked, occurring after transient risk factors such as surgery, trauma, or immobility, or unprovoked, when no clear trigger is identified. Standard management involves 3 months of anticoagulation for provoked events and extended therapy for unprovoked events because of their higher recurrence risk (6–10% per year after discontinuation). However, many patients present with provoked VTE in the context of enduring risk factors such as obesity, chronic inflammatory disease, atherosclerotic cardiovascular disease or chronic pulmonary conditions, factors that may sustain a prothrombotic milieu even after the transient trigger has resolved. Current guidelines offer limited direction for this increasingly common patient subset.

Venous thromboembolism (VTE) is a frequent and clinically significant complication in patients with cancer, contributing substantially to morbidity, disruptions in systemic cancer therapy, and mortality. Direct oral anticoagulants (DOACs) have reshaped management strategies, offering efficacy comparable to vitamin K antagonists with improved convenience and safety.

Among DOACs, Apixaban (ELIQUIS®) and Rivaroxaban (XARELTO®) are widely used. However, until recently, the absence of direct comparative randomized data has limited evidence-based selection between agents, particularly in patients with elevated bleeding risk, such as those with malignancy.

Study Design and Methods

The COBRRA (Comparison of Bleeding Risk between Rivaroxaban and Apixaban) trial was an international, prospective, randomized, open-label study and represents the first randomized, head-to-head comparison of Apixaban and Rivaroxaban in patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis.

A total of 2,760 patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis were randomized 1:1 to:

• Apixaban: 10 mg twice daily for 7 days, followed by 5 mg twice daily
• Rivaroxaban: 15 mg twice daily for 21 days, followed by 20 mg once daily

The Primary endpoint was clinically relevant bleeding (major or clinically relevant nonmajor bleeding) over 3 months. Secondary outcomes included all-cause mortality and recurrent VTE.

Notably, patients with cancer-associated thrombosis were excluded, reflecting historical standards at the time of trial design.

Key Results: Significant Reduction in Bleeding with Apixaban

At 3 months, Apixaban demonstrated a significant reduction in clinically relevant bleeding:

• 3.3% (Apixaban) vs 7.1% (Rivaroxaban)
• Relative Risk (RR): 0.46 (95% CI, 0.33–0.65; P<0.001)

This represents a 54% reduction in bleeding risk with Apixaban.

• Clinically relevant nonmajor bleeding:
  • 2.9% (Apixaban) vs 4.9% (Rivaroxaban)
• Major bleeding was also lower with Apixaban (notably rare overall)

Common bleeding events included vaginal and gastrointestinal bleeding, with consistently lower rates observed in the Apixaban arm.

Comparable Efficacy

• Recurrent VTE rates were similar between groups (~1%)
• The improved safety profile of Apixaban did not compromise antithrombotic efficacy

Safety

• No deaths due to bleeding were reported
• Non-bleeding serious adverse events were comparable between groups

Relevance to Oncology Practice

Although cancer patients were not included, the findings have important indirect implications for oncology:

1. Bleeding Risk Is Paramount in Cancer

Patients with malignancy often have:

• Tumor-related mucosal bleeding (e.g., GI, GU cancers)
• Treatment-related thrombocytopenia
• Drug–drug interactions with systemic therapies

In this context, the lower bleeding risk observed with Apixaban is highly clinically meaningful, particularly for patients at elevated hemorrhagic risk.

2. Alignment with Emerging Oncology Data

Subsequent cancer-specific trials (e.g., CARAVAGGIO) have already demonstrated that Apixaban is effective and relatively safe in cancer-associated thrombosis, with a favorable bleeding profile compared with other DOACs in certain settings.

The COBRRA findings reinforce a growing body of evidence suggesting that Apixaban may be the preferred DOAC when bleeding risk is a major concern.

3. Practical Treatment Considerations

• Dosing strategy matters: The extended 21-day high-dose phase with Rivaroxaban may contribute to early bleeding risk
• Pharmacokinetics: Higher peak drug levels with once-daily Rivaroxaban may increase mucosal bleeding, relevant in GI or GU malignancies
• Adherence: Despite slightly lower adherence with Apixaban in the trial, efficacy remained preserved

Limitations and Applicability to Oncology

• Exclusion of cancer-associated thrombosis limits direct generalizability
• Short follow-up (3 months) does not address extended anticoagulation
• Underrepresentation of diverse populations
• Not powered for efficacy differences

Despite these limitations, the biologic and pharmacologic insights are highly translatable to oncology populations

Clinical Takeaways

• Apixaban significantly reduces clinically relevant bleeding compared with Rivaroxaban in acute VTE
• Efficacy remains equivalent, supporting its use as a first-line agent
• For oncology patients, particularly those with high bleeding risk, Apixaban may represent a more favorable therapeutic option
• These findings may help inform DOAC selection in cancer-associated thrombosis, alongside existing oncology-specific trial data and guidelines

Conclusion

The COBRRA trial provides the first randomized evidence demonstrating a clear safety advantage of Apixaban over Rivaroxaban in acute VTE. For oncology clinicians, where balancing thrombosis prevention with bleeding risk is critical, these data support prioritizing Apixaban in appropriate patients, while awaiting further dedicated studies in cancer-associated thrombosis populations.

Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism. Castellucci LA, Chen VM,  Kovacs MJ, et al.for the COBRRA Trial Investigators. N Engl J Med 2026;394:1051-1060

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.

Clinically, VTE is classified as provoked, occurring after transient risk factors such as surgery, trauma, or immobility, or unprovoked, when no clear trigger is identified. Standard management involves 3 months of anticoagulation for provoked events and extended therapy for unprovoked events because of their higher recurrence risk (6–10% per year after discontinuation). However, many patients present with provoked VTE in the context of enduring risk factors such as obesity, chronic inflammatory disease, atherosclerotic cardiovascular disease or chronic pulmonary conditions, factors that may sustain a prothrombotic milieu even after the transient trigger has resolved. Current guidelines offer limited direction for this increasingly common patient subset.

Study Rationale and Design

The Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism (HI-PRO) trial sought to clarify whether continued low-intensity anticoagulation could safely reduce recurrence risk in such patients. This single-center, double-blind, randomized study enrolled 600 adults who had completed at least 3 months of standard anticoagulation for a provoked VTE and who also had at least one enduring risk factor for recurrence. Participants were randomized 1:1 to receive Apixaban (ELIQUIS®) 2.5 mg twice daily or placebo for 12 months.

Enduring risk factors included obesity (BMI ≥30), chronic lung disease, autoimmune or inflammatory disorders, and atherosclerotic cardiovascular disease (limited to ≤35% of patients per arm to control for aspirin use). Eligible VTE events included deep vein thrombosis, pulmonary embolism (including isolated subsegmental PE), or both.

The Primary efficacy endpoint was symptomatic recurrent VTE by day 365. The Primary safety endpoint was major bleeding per International Society on Thrombosis and Haemostasis (ISTH) criteria.

Results

The study population had a mean age of 59.5 years, 57% were women, and 19% were non-White.

By 12 months, symptomatic recurrent VTE occurred in 1.3% of patients receiving Apixaban versus 10.0% of those receiving placebo (Hazard Ratio [HR] 0.13; 95% CI, 0.04–0.36; P<0.001), representing an 87% relative risk reduction. The composite cardiovascular outcome, including cardiovascular death, nonfatal myocardial infarction, stroke, or limb ischemic events, was infrequent and comparable between groups (0.7% vs. 1.0%).

Major bleeding was rare, occurring in one patient (0.3%) in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding occurred more often with Apixaban (4.8% vs. 1.7%; HR 2.68; 95% CI, 0.96–7.43; P=0.06), with vaginal, hematuric, and rectal bleeding being the most common types. Nonfatal adverse events were balanced between arms.

Medication adherence was high throughout the study, and no deaths were attributed to bleeding or cardiovascular causes.

Interpretation

Extended-duration, low-intensity Apixaban provided robust protection against recurrent VTE in patients with provoked events and ongoing risk factors, an underrepresented and clinically relevant population. The recurrence rate in the placebo group (10% at 1 year) underscores that the conventional dichotomy of provoked versus unprovoked VTE may oversimplify recurrence risk. Patients with enduring prothrombotic conditions appear to have recurrence risks comparable to those with unprovoked events.

The low incidence of major bleeding supports the safety of this approach, though the modest increase in nonmajor bleeding emphasizes the need for individualized risk–benefit assessment, especially in those also receiving antiplatelet therapy.

Clinical Implications

The HI-PRO findings challenge the traditional framework that limits extended anticoagulation to unprovoked VTE and cancer-associated thrombosis. Instead, they highlight that patients with provoked VTE but persistent risk factors, such as chronic inflammatory states, cardiometabolic disease, or obesity, may benefit from continued low-intensity anticoagulation beyond the initial 3-month course.

Incorporating enduring risk factors into recurrence-risk models and treatment algorithms could help refine long-term management. Emerging approaches such as VTE-PREDICT scoring, polygenic risk assessment, and AI-driven modeling may further individualize these decisions.

Takeaway

Among patients with provoked VTE and ongoing risk factors, 12 months of low-dose Apixaban therapy significantly reduced recurrent VTE with a favorable safety profile. The HI-PRO trial supports a more nuanced, risk-adapted approach to secondary prevention, where the duration and intensity of anticoagulation are guided not solely by the event’s provoked or unprovoked status, but by the persistence of underlying prothrombotic conditions.

Apixaban for Extended Treatment of Provoked Venous Thromboembolism. Piazza G, Bikdeli B, Pandey AK, et al. for the HI-PRO Trial Investigators. N Engl J Med 2025;393:1166-1176.

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. Traditionally, a six-month course of either Direct Oral AntiCoagulants (DOACs) or Low-Molecular-Weight Heparin (LMWH) has served as the standard initial treatment duration.

However, cancer is a chronic and often progressive condition, and the thrombotic risk doesn’t dissipate once the initial treatment window concludes. Clinical guidelines generally recommend the continuation of anticoagulation for as long as the malignancy remains active or systemic therapy is ongoing. Yet, this approach necessitates a careful balancing act – prolonged anticoagulation mitigates thrombotic recurrence but heightens the risk of bleeding, a risk that persists over time.

A major challenge in this domain has been the lack of robust evidence from randomized clinical trials to guide extended anticoagulation beyond six months, particularly regarding the optimal dose that maintains efficacy while minimizing harm. While reduced-dose anticoagulation has emerged as a promising strategy in non-cancer populations, its application to cancer-associated thrombosis had not been thoroughly evaluated until recently.

The Apixaban Cancer Associated Thrombosis (API-CAT) trial is a large, randomized, double-blind, noninferiority study aimed to determine whether a reduced dose of Apixaban (2.5 mg twice daily) could effectively prevent recurrent VTE in patients with active cancer, while also offering a safer bleeding profile, compared to the standard full dose (5 mg twice daily). All participants had previously completed a minimum of six months of anticoagulation for either proximal deep-vein thrombosis or pulmonary embolism. The trial enrolled 1,766 patients, randomly assigned to either the reduced-dose (N=866) or full-dose (N=900) Apixaban group. The baseline characteristics of the patients in this trial were similar to those in observational studies and randomized trials. The median age of the patients was 69 years, and 43% were men. Among patients with active cancer, the most frequent sites of the primary cancer were the breast (22.7%), colon or rectum (15.2%), gynecologic system (12.1%), and lung (11.3%). The Primary efficacy outcome was centrally adjudicated fatal or nonfatal recurrent VTE over the 12-month follow-up period and key Secondary outcome was clinically relevant bleeding, which was defined as a composite of adjudicated major or clinically relevant nonmajor bleeding during the 12-month follow-up period.

The results were compelling: the reduced-dose regimen demonstrated noninferiority to the full dose in preventing VTE recurrence. Specifically, recurrent events occurred in 2.1% of patients in the reduced-dose group compared to 2.8% in the full-dose group (adjusted subhazard ratio=0.76; P=0.001 for noninferiority). More importantly, the incidence of clinically relevant bleeding – a composite measure that included both major and non-major events with real-world impact – was significantly lower in the reduced-dose group (12.1% vs. 15.6%; adjusted subhazard ratio=0.75; P=0.03). The incidence of death was similar in the two groups (19.6% in the full-dose group and 17.7% in the reduced-dose group), and most deaths were related to cancer.

Notably, the study defined clinically relevant bleeding more broadly than previous trials—capturing both major and non-major events that impact patient well-being and quality of life. This approach reflects the reality that even so-called “minor” bleeds can significantly affect daily functioning and emotional health, particularly in patients with incurable malignancies.

In conclusion, reduced-dose Apixaban offers a clinically effective and safer alternative for extended anticoagulation in patients with active cancer, successfully preventing recurrent venous thromboembolism while minimizing bleeding risks. With cancer patients living longer due to advances in immunotherapy and targeted treatments, clinicians are increasingly tasked with navigating long-term thrombosis prevention strategies. The API-CAT trial helps address a key evidence gap and marks a significant advancement in the long-term management of cancer-associated thrombosis and reinforces the importance of personalized care in oncology.

Cancer-Associated Venous Thromboembolism- Beyond 6 Months. Mahe I, Carrier M, Mayeur D, et al. for the API-CAT Investigators. N Engl J Med 2025;392:1439-1440

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. Treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations is often recommended for this patient group, based on efficacy data. LMWH activates antithrombin, which in turn accelerates the inactivation of coagulation enzymes thrombin (Factor IIa), Factor Xa and Factor IXa. Parenteral LMWH however can be inconvenient and expensive, leading to premature discontinuation of treatment.

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.

Patients with cancer are often found to have distal DVTs. In patients with isolated distal DVT, the best treatment strategy remains unclear and evidence is lacking for the optimal duration of anticoagulation therapy. Further, prolonged anticoagulation therapy, beneficial as it may be, could increase the risk of bleeding.

The ONCO DVT study is a multicenter, open-label, adjudicator-blinded, randomized, clinical trial, conducted at 60 institutions in Japan. This study included 601 cancer patients with isolated distal DVT, who were randomly assigned in a 1:1 ratio, to receive either Edoxaban (SAVAYSA®) for 12 months (N=296) or 3 months (N=305). Edoxaban was given at a dose of 60 mg orally once daily but it was dose-reduced to 30 mg in 75% of patients due to either creatinine clearance of 30-50 mL/min or a body weight of 60 kg or less, or due to concomitant treatment with potent P-glycoprotein inhibitors. The researchers hypothesized that 12-month Edoxaban treatment was superior to a 3-month Edoxaban treatment for reducing thrombotic events, in cancer patients with isolated distal DVT. Eligible patients had active cancer and newly diagnosed isolated distal DVT confirmed by ultrasonography. The mean age was 71 years and 72% of the patients were women. The most common type of cancer was gynecologic cancer (27%), followed by lung cancer (11%), colon cancer (10%) and pancreatic cancer (8%). The most common reason for conducting ultrasonography was due to a high-risk status with elevated D-dimer levels (38%), followed by elevated D-dimer levels before surgery (24%) and suspected DVT based on the symptoms (20%). Patients were excluded from this study if they were on anticoagulation therapy at the time of the diagnosis, if they had pulmonary embolism, or if they were expected to have a life prognosis of 3 months or less by the treating physicians. The Primary endpoint was symptomatic recurrent Venous ThromboEmbolism (VTE) or VTE-related death at 12 months. The Secondary endpoint was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Hemostasis.

The Primary endpoint of a symptomatic recurrent VTE event or VTE-related death occurred in 1% of patients in the 12-month Edoxaban group and in 7.2% of patients in the 3-month Edoxaban group (odds ratio, 0.13). The Secondary endpoint of major bleeding occurred in 9.5% of patients in the 12-month edoxaban group and in 7.2%of patients in the 3-month edoxaban group (Odds Ratio=1.34), and this was not statistically significant. There were no differences noted in prespecified subgroup analyses, stratified by age, body weight and renal function.

It was concluded that in cancer patients with symptomatic or asymptomatic isolated distal DVT, anticoagulation with Edoxaban for 12 months was superior to 3 months with respect to symptomatic recurrent VTE or VTE-related death, without increasing the risk of bleeding. The authors added that this is the first and only randomized clinical trial to show the superiority of longer duration, over shorter duration anticoagulation therapy, for reducing thrombotic events in cancer patients with isolated distal DVT. Since this study only included Japanese, it is unclear if this data would be applicable to people of other races and ethnicities.

Edoxaban for 12 Months Versus 3 Months in Cancer Patients with Isolated Distal Deep Vein Thrombosis (ONCO DVT study): An Open-label, Multicenter, Randomized Clinical Trial. Yamashita Y, Morimoto T, Muraoka N, et al., on behalf of the ONCO DVT Study Investigators. Originally published 28 Aug 2023. https://doi.org/10.1161/CIRCULATIONAHA.123.066360 Circulation. 2023;0

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 numbers of infected cases continue to increase worldwide. As of May 1, 2022, over 81.4 million total cases have been reported in the US and 993,000 individuals have died from COVID-19. 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 patient’s 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. COVID-19 infection also has a direct effect on endothelial cells, resulting in an exaggerated inflammatory response, down regulation of Angiotensin Converting Enzyme 2 receptors, and activation of the coagulation system. The relative incidence of pulmonary embolism is higher with COVID-19 infection and has been attributed to immunothrombosis (thrombosis in the pulmonary vessels from local inflammation). The increased risk of bleeding has been attributed to endothelial dysfunction, coagulopathy, or DIC. Previously published studies on the risk of venous thromboembolism after COVID-19 infection have shown conflicting results.

The researchers conducted this analysis using self-controlled case series and matched cohort study methods, and the objective of this study was to quantify the risk of deep vein thrombosis and pulmonary embolism, as well as bleeding after covid-19. Using Swedish national health databases, the researchers identified 1,057,174 individuals who tested positive for SARS-CoV-2 between February 2020 and May 2021. The incidence of first deep venous thrombosis (DVT), pulmonary embolism (PE), and bleeding during the subsequent 180 days was recorded, regardless of disease severity. A cohort of 4,076,342 individuals who did not have COVID-19 served as matched controls. The mean age was 40.2 years, 49% were males and 51% were females.

After statistical adjustments, the risks for DVT, PE, and bleeding were significantly higher in the 30 days following diagnosis of COVID-19 compared to the matched control group (risk ratios 5, 33 and 2; meaning 5 times, 33 times, 2 times more respectively). These risks remained significantly elevated for three, six, and two months after COVID-19, respectively. Further, there was a higher risk of events in patients with comorbidities, patients with more severe covid-19, and during the first pandemic wave, compared with the second and third waves.

It was concluded that the finding from this study support thromboprophylaxis to avoid thrombotic events, especially for high risk patients, and strengthens the importance of vaccination against covid-19. The authors added that it remains unclear whether the period of thromboprophylaxis after covid-19 should be extended, and additional clinical research would be beneficial.

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. Katsoularis I, Fonseca-Rodríguez, Farrington P, et al. BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-069590 (Published 06 April 2022)

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.

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.

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.

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.