Authors
Tony Wan, MD, FRCPC, DRCPSC (biography and disclosures)
Disclosures: Received honoraria from AstraZeneca for work on the regional clinical protocol for the reversal of direct oral anticoagulants in patients with major bleeding. Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with published ASH and ASCO guidelines on thromboprophylaxis. Recommendations are consistent with current practice patterns. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.
Domnick Manhas, MD, FRCPC (biography, no disclosures)
What I did before
Patients with active cancer have an increased risk of venous thromboembolism (VTE) because of the hypercoagulable status secondary to the malignancy and cancer therapy.1 It is estimated that 15% of all cancer patients will develop VTE, resulting in significant morbidity and mortality.2 The cost of cancer-associated thrombosis is substantial to the healthcare system.3 Currently, routine thromboprophylaxis is not recommended given the fear of increased risk of bleeding, modest absolute risk reduction in VTE, and inconvenience.2 However, a selected group of cancer patients with very high VTE risk will benefit from thromboprophylaxis.
The American Society of Clinical Oncology (ASCO) guideline recommends that pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7 to 10 days. Extended prophylaxis with low molecular weight heparin (LMWH) for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis.4 The American Society of Hematology (ASH) guideline suggests that for patients with cancer who had undergone a major abdominal pelvic surgical procedure, continuing pharmacological thromboprophylaxis post-discharge rather than discontinuing at the time of hospital discharge.5
Both ASCO and ASH guidelines recommend consideration of thromboprophylaxis in high-risk ambulatory cancer patients with a low bleeding risk during systemic chemotherapy, a period that is associated with a particularly high risk of VTE (Table 1).4, 5 The Khorana score (Table 2) has been prospectively validated to identify patients with active cancer at a high risk of VTE.6 A score ≥ 2 indicates an intermediate-to-high risk of VTE (≥ 1.8% in 2.5 months) and a score ≥ 3 indicates a high risk of VTE (≥ 6.7% in 2.5 months). Therefore, it has been used to determine which patients would benefit the most from thromboprophylaxis (Table 1).
Table 1. Summary of guideline recommendations on thromboprophylaxis in ambulatory cancer patients
| American Society of Hematology | American Society of Clinical Oncology |
| For ambulatory patients with cancer receiving systemic therapy, the ASH guideline panel recommends no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists (VKAs) (strong recommendation, very low certainty in the evidence of benefits, but high certainty about the harms).
For ambulatory patients with cancer at low risk for thrombosis receiving systemic therapy, the ASH guideline panel suggests no thromboprophylaxis over oral thromboprophylaxis with a DOAC (direct oral anticoagulants) (apixaban or rivaroxaban) (conditional recommendation, moderate certainty in the evidence of effects). For ambulatory patients with cancer at intermediate risk for thrombosis receiving systemic therapy, the ASH guideline panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) or no thromboprophylaxis (conditional recommendation, moderate certainty in the evidence of effects). For ambulatory patients with cancer at high risk for thrombosis receiving systemic therapy, the ASH guideline panel suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) over no thromboprophylaxis (conditional recommendation, moderate certainty in the evidence of effects). Remarks: Classification of patients as being at low, intermediate, or high risk for VTE should be based on a validated risk assessment tool (i.e., Khorana score) complemented by clinical judgment and experience. The panel noted that, even for patients at high risk for thrombosis, thromboprophylaxis should be used with caution for those at high risk for bleeding. The direct factor Xa inhibitors apixaban and rivaroxaban are the only DOACs that were evaluated for the primary prophylaxis for ambulatory patients with cancer receiving chemotherapy. |
Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer (type: evidence-based; evidence quality: intermediate to high; strength of recommendation: strong).
High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or low-molecular-weight heparin (LMWH) provided there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting (Type: evidence-based; evidence quality: intermediate to high for apixaban and rivaroxaban, intermediate for LMWH; strength of recommendation: moderate). |
Table 2. Khorana score to predict risk of VTE for cancer patients depending on type of cancer and other factors
| Cancer type |
|
| Pre-chemotherapy platelet count ≥350×10⁹/L |
|
| Hemoglobin < 100 g/l |
|
| Pre-chemotherapy leukocyte count > 11×106/L |
|
| BMI ≥ 35 kg/m² |
|
Before the recent clinical guideline updates, we did not routinely assess VTE risk or offer thromboprophylaxis to ambulatory cancer patients with no recent major surgeries. This practice is likely the same for most physicians providing care to cancer patients. Physicians are potentially missing a great opportunity to prevent one of the most common and morbid complications in cancer patients.
What changed my practice
Recent clinic trials have looked at cancer patients with higher Khorana scores to see if they would benefit from thromboprophylaxis. The CASSINI trial randomized cancer patients with Khorana score ≥ 2 to either Rivaroxaban 10 mg daily or placebo. The primary efficacy endpoint was objectively confirmed VTE and the safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). The Rivaroxaban group had a non-statistically significant 2.8% absolute risk reduction in VTE compared with the placebo group. There was no statistical difference in the rate of major bleeding. Given the high rate of premature discontinuation and non-statistically significant reduction in VTE, this trial was primarily hypothesis-generating.7
In the AVERT trial, ambulatory cancer patients on chemotherapy with a Khorana score ≥ 2, were randomized to apixaban 2.5 mg PO twice daily or placebo. Similar to the CASSINI trial, the primary efficacy endpoint was objectively confirmed VTE and the safety endpoint was major bleeding as defined by the ISTH. The trial showed a statistically significant reduction in the incidence of VTE (4.2% vs. 10.2%). However, this came at the expense of an increased risk of major bleeding (3.5% vs. 1.8%). Major bleeding occurred mainly in patients with gynecological and gastrointestinal malignancies.8
A systematic review and meta-analysis pooled the data from the AVERT and CASSINI trials and brought up an important point. The trials enrolled two very different patient populations in terms of VTE risk and bleeding risk. In the CASSINI trial, the number of patients with a high bleeding risk and a high VTE risk, such as patients with pancreatic and gastrointestinal cancer, made up over half of the study population. However, more than half the study population had gynecologic and hematologic malignancies and less than one-fifth had gastrointestinal cancer in the AVERT trial. Overall, the meta-analysis did not observe an increased risk of major bleeding or clinically non-relevant non-major bleeding in the treatment group. The authors hypothesized based on limited analysis of patient subgroups that patients with a Khorana score > 3 would benefit from a greater absolute risk reduction in VTE in comparison with patients with a Khorana score > 2.9
A cost analysis published in the Canadian Medical Association Journal (CMAJ) looked at the systematic cost of using apixaban for thromboprophylaxis in ambulatory cancer patients during chemotherapy. The model included cancer patients with a Khorana score > 2 and apixaban 2.5 mg twice daily as the thromboprophylaxis regimen. The authors found that over a lifetime, the healthcare cost per patient was $7902.98 in the apixaban model and $14,875 in the usual care model (no thromboprophylaxis). It was shown there was an improvement in quality-adjusted life years in the apixaban model. However, the authors admit that, given the limited data, there is significant uncertainty in their results.10
There are no ongoing studies on the use of thromboprophylaxis in ambulatory cancer patients reported on https://www.clinicaltrials.gov at the time we wrote this article.
What I do now
Thromboprophylaxis in high-risk ambulatory cancer patients is a promising strategy to reduce one of the most common complications in cancer patients. Further research is needed to improve patient selection. Direct oral anticoagulants (DOAC) including apixaban and rivaroxaban can provide effective thromboprophylaxis in a selected group of ambulatory patients with active cancer. The most recent clinical guidelines recommend the consideration of thromboprophylaxis in ambulatory cancer patients with a high risk of VTE and a low risk of bleeding during systemic chemotherapy. We believe all physicians who treat cancer have the responsibility to educate patients about VTE risk and assess the need for thromboprophylaxis. Patients with Khorana scores ≥ 2 and low bleeding risk should be considered for low-dose Rivaroxaban or Apixaban for the duration of their chemotherapy. At this time, generic Apixaban is available while Rivaroxaban is not yet generic and the BC Special Authority does not cover its use for thromboprophylaxis in cancer patients. Given that this is an evolving area of clinical research, physicians can refer patients to the Thrombosis Clinic for expert assessment.
Resources
- Mdcalc Khorana Score to use with general cancer patients (i.e., solid tumours and lymphomas), not patients with brain tumours or myelomas: Khorana risk score for venous thromboembolism in cancer patients. MDCalc. Accessed August 10, 2023. (View on mdcalc.com)
- Patient resource: Should I take anticoagulants to prevent blood clots while I am receiving chemotherapy? CLOT PLUS (Premium LiteratUre Service), McMaster University. Accessed August 10, 2023. (View on plus.mcmaster.ca)
- Thrombosis Canada. Accessed August 10, 2023. https://thrombosiscanada.ca
References
- Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: burden, mechanisms, and management. Thromb Haemost. 2017;117(2):219-230. doi:10.1160/TH16-08-0615 (Request with CPSBC or view with UBC)
- Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8(1):11. doi:10.1038/s41572-022-00336-y (Request with CPSBC or view with UBC)
- Heit JA. Epidemiology of venous thromboembolism. Nature reviews cardiology. 2015;12(8):464-474. doi.org/10.1038/nrcardio.2015.83 (View)
- Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020;38(5):496-520. doi:10.1200/JCO.19.01461 (View)
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer [published correction appears in Blood Adv. 2021 Apr 13;5(7):1953]. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442 (View)
- Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. doi:10.1182/blood-2007-10-116327 (View)
- Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019;380(8):720-728. doi:10.1056/NEJMoa1814630 (Request with CPSBC or view with UBC)
- Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711-719. doi:10.1056/NEJMoa1814468 (Request with CPSBC or view with UBC)
- Li A, Kuderer NM, Garcia DA, et al. Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: A systematic review and meta-analysis. J Thromb Haemost. 2019;17(12):2141-2151. doi:10.1111/jth.14613 (View)
- Kimpton M, Kumar S, Wells PS, Coyle D, Carrier M, Thavorn K. Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer. CMAJ. 2021;193(40):E1551-E1560. doi:10.1503/cmaj.210523 (View)
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Do most chemo regimens have the same VTE risk or does it vary by tumour site/regimen? What bleeding risk tool was used in these studies?
To my knowledge there has not been large trial looking at the risk of different chemotherapy regimens and VTE risk. Likely due to cancer and chemo being very heterogeneous. The major VTE risk scores have looked at cancer types I suspect as it is easier to model and validate the scoring system. AVERT in their supplementary appendix have a table showing what chemotherapy the patients were on. Both the placebo and treatment arm have similar amount of patients in each type of chemotherapy regimen.
For bleeding risk tools both trials did not use a tool to risk stratify patients. However, both trials attempted to exclude patients at higher risk of bleeding. For AVERT they excluded: hepatic disease with coagulopathy, acute leukemia, or myeloproliferative neoplasm; a planned stem-cell transplantation, a life expectancy of less than 6 months, renal insufficiency with a glomerular filtration rate of less than 30, or a platelet count of less than 50.
For the CASSINI trial they excluded patients with a diagnosis of brain tumour, hematologic malignancy excluding lymphoma, bleeding diathesis/active bleeding, life expectancy less the 6 months and high risk for bleeding. Looking at both the trial design paper and NEJM publication what constituted high risk of bleeding is unclear.
Overall, when starting a patient on anticoagulation there are many scores that exist to help guide the decision making but ultimately it comes down to clinical judgment
I hope that helps!