The cases this week were designed to consider the complexities of VTE management in cancer patients.
VTE is four to seven times as common in the cancer population compared to the general population.
Cancer associated thrombosis is the second commonest cause of death in cancer patients after disease progression.
It is the source of a huge amount of morbidity for patients with associated anxiety regarding treatment delays, bleeding issues or further thrombosis. It is often a challenging situation to manage as patients may well have bleeding and thrombosis risk factors and may even have this present simultaneously (as seen in short case 2).
Importantly a good haematologist will consider patient choice, prognosis of the disease and practical considerations such as drug interactions, abnormalities in blood tests, surgery and biopsies.
Role of thromboprophylaxis in cancer patients: (Case 1)
There is no benefit in unselected thromboprophylaxis in ambulatory cancer patients. The number needed to treat for the population as a whole is which is felt to be too high to warrant unselected intervention (NNT 60) from Cochraine review of 3538 patients. The review found no difference in mortality at 12 and 24 months despite reductions in symptomatic VTE rates but it did show possible increased bleeding rates while on prophylaxis.
In 2008 Khorana et al. Devised a validated score to evaluate the risk of thrombosis in a cancer patients. This score suggested if patients scored 3 or more had a high risk of VTE (7.8% over 2.5 months, compared to 0.8% for low risk individuals). The use of this tool is recommended by ASCO, ESMO and BSH guidelines.
It should be stressed that NICE guidance suggests that all patients with active cancer therapy should be considered for thromboprophylaxis on admission to hospital unless there are contraindications.
NICE also suggest that consideration is given to thromboprophylaxis for ambulatory cancer patients with other thrombotic risk factors. It also advocates consideration of prophylaxis in pancreatic cancer patients while on chemotherapy and myeloma patients on Thalidomide, Lenolidamide or Pomalidamide.
In our short case one the patients Khorana score is 1 (score for bladder cancer 1-8 -2% risk over 2.5 months of VTE). He had some bleeding risk factors to consider such as his history of active haematuria and iron deficiency at present. He was also planned to start chemotherapy which cause thrombocytopenia. It was decided no thromboprophylaxis was indicated.
Management of Cancer associated thrombosis: (Case 1)
It is important to have a sound understanding of the literature with regards to anticoagulation to be able to apply the principles to practice.
Here is a quick summary of the important trials in this area:
CLOT trial 2003: Dalteparin Vs VKA – Recurrent thrombosis reduced in Dalteparin group (9% Vs 17%) and similar bleeding risk (4% Dalteparin Vs 6% VKA). Minor criticism of this trial is in VKA arm 50% of recruited patients in VKA arm had poor time in INR range.
CATCH trial 2015: Tinzaparin Vs VKA – Reduced recurrence rates in Tinzaparin group with major bleeding rates the same (2%) but lower clinically relevant non major bleeds in Tinzaparin group.
This established LMWH is superior to VKA in management of cancer associated thrombosis.
HOKUSAI VTE 2018: Edoxaban 60mg OD (After 5 days LMWH) Vs LMWH. No difference VTE recurrence rates (12.8% Edoxaban Vs 13.5% LMWH). Increased major bleeding rates in trial (6.9% Edoxaban Vs 4% LMWH) when analysed these were particularly GI bleeds and convincingly on subgroup analysis were linked to urothelial and GI malignancy patients. ICH rates in both groups were the same.
SELECT-D 2018: Rivaroxaban (15mg BD for 21 days then 20mg OD) Vs LMWH. Reduced VTE recurrence rates (4% Rivaroxaban Vs 11% LMWH). Increased major bleeding on Rivaroxaban (6% Rivaroxaban vs 4% LMWH) and clinically relevant non major bleeding. This finding lead to stopping recruitment for upper GI malignancy cancer patients early. In this trial again ICH rates were not increased with Rivaroxaban.
ADAM VTE 2019: Apixaban (10mg BD 7 days to 5mg BD) Vs LMWH. Primary outcome in this trial was Major bleeds with 0% in Apixaban group compared to 1.4% in LMWH group. These rates were low compared to other DOAC Vs LMWH trials and this may be due to selection of patients and small study population of 287 patients. This trial also confirmed statistically significant lower VTE recurrence rates of (0.7% Apixiban Vs 6.3%).
CARVAGGIO 2020: Apixiban (10mg BD for 7 days to 5mg BD) Vs LMWH. Recurrent VTE rates 5.6% Apixaban Vs 7.9% LMWH) statistically significant for non inferiority of Apixaban in this setting. Major bleeding rates same (3.8% Apixaban Vs 4% LMWH) this included Major GI bleeds. It did find an increase in clinically significant non major bleeding rates in Apixiban group and these were mainly in genitourinary and upper airway bleeds. Older patients >75 years appeared to have more major bleeding on Apixiban on subgroup analysis.
These trials have established DOACs are non inferior to LMWH in terms of recurrent VTE. DOACs may be associated with increased clinically relevant minor bleeding and it seems that patients with GI malignancy are at increased risk of major bleeding on these drugs.
Recent ESMO guidelines sensibly suggest particular patient groups where care should be taken with DOACS:
Frail patients – None of the DOAC trials included patients with ECOG <2.
Luminal GI cancers, Genitourinary cancers, nephrostomy tubes or those with known Gastritis, Oesophagitis or Colitis – Increased bleeding risk on DOACs.
Thrombocytopenia – Patients will require interruption of DOAC if plt <50.
Pharmacokinetic considerations – CYP3A4 pathway used for metabolism of DOACS. Many anti cancer drugs can interact with this pathway including Biclutamide, TKI, Paclitaxel plus supportive medications such as Azol anti fungals.
Poorly controlled vomiting and patients with GI resection – May affect absorption of DOACs
The patients choices and values may also need to be considered and often a patient has a clear idea of which anticoagulant they would prefer and the decision making and the risk/ benefit need to be shared with the patient.
IVC Filters in cancer associated thrombosis: (Case 2)
BSH guidelines suggest these can be considered as an option for patients with an acute VTE and an absolute contraindication to anticoagulation. These are not a permanent substitute to anticoagulation and need to be inserted with clear plan for removal.
IVC filters that are left in situ can lead to serious complications due to stent migration, perforation of IVC and occlusion can occur in up to 20% of patients who have stents left in for 5 years.
In short case 2 the patient had a PE and DVT in the context of haemorrhagic cerebral metastasis with neurological deficit. It was unlikely that she would ever be considered suitable for anticoagulation and hence an IVC filter was unlikely ever to be able to be removed. The patient also had a poor prognosis from her metatstatic malignancy and hence this intervention was felt to be inappropriate in her case.
BSH guidelines also support the use of IVC filters when need for urgent surgery and VTE within last 4 weeks due to high recurrence rates during interruption of anticoagulation. This would clearly be important to consider for any cancer surgery in patients with recent thrombosis.
Many thanks for your help this week I hope it was interesting and that you feel more confident in the recent literature surrounding this area of practice.
Akl EA, Kahale LA, Hakoum MB, Matar CF, Sperati F, Barba M, Yosuico VED, Terrenato I, Synnot A, Schünemann H. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database of Systematic Reviews 2017, Issue 9. Art. No.: CD006652.
Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE guideline [NG89] Published date: 21 March 2018.
Khorana AA et Al. Development and validation of a predictive model for chemotherapy associated thrombosis. Blood, 111, 4902-4907.
Watson, H.G., Keeling, D.M., Laffan, M., Tait, R.C., Makris, M. and (2015), Guideline on aspects of cancer‐related venous thrombosis. Br J Haematol, 170: 640-648.
Moik F, Pabinger I, Ay C. How I treat cancer-associated thrombosis. ESMO Open 2020;4:e000610. doi:10.1136/ esmoopen-2019-000610
Key N et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update Journal of Clinical Oncology 38, no. 5 (February 10, 2020) 496-520.
Guidelines on use of Vena cava filters. Br J Haematol, 136 :90-595.