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Secondary Prevention Of Stroke

11. Cancer- Associated Ischemic Stroke

 

7th Edition – 2020 UPDATED


11.1 Cancer Associated Ischemic Stroke
  1. Patients with active malignancy who experience an arterial ischemic stroke or transient ischemic attack should undergo a standard etiological work-up for their stroke, including vascular imaging and cardiac rhythm monitoring [Evidence Level C]. Refer to Section 1 on Stroke Investigations for additional information.  

  2. Stroke mechanisms associated with malignancy may be considered when determining etiological investigations, including non-bacterial (marantic) endocarditis, hypercoagulability, paradoxical embolism due to venous thrombosis, tumor-related vascular compression, and stroke related to anti-cancer treatments [Evidence Level C].

  3. In patients with active malignancy and arterial ischemic stroke or transient ischemic attack in whom a cancer-associated hypercoagulable state may have contributed to the stroke, anticoagulation could be considered over antiplatelet therapy [Evidence Level C]. 

    1. When anticoagulation is used, low-molecular weight heparin therapy is preferred [Evidence Level C]. The role of direct oral anticoagulants is unknown but under study and may be reasonable after consideration of patient preference. 

Section 11 Clinical considerations
  1. Management decisions for these patients should be made in collaboration with a health professional with expertise in Hematology, Oncology or Thrombosis, and should take into account the type of underlying cancer, the risk of bleeding, the extent of neoplastic disease, the patient’s overall prognosis and expressed goals of care.

  2. In patients with active malignancy and arterial ischemic stroke or transient ischemic attack with a concurrent venous thromboembolism (deep vein thrombosis or pulmonary embolism) in whom the stroke is presumed to be due to a paradoxical embolus, anticoagulation for secondary prevention should follow guidelines for the management of DVT and PE in cancer patients which includes low molecular weight heparin (LMWH) and selected DOACs (Refer to www.thrombosiscanada.ca). 

Rationale +-

A diagnosis of cancer can increase the risk of stroke.  This has been found to occur across time following a diagnosis of cancer, and has occurred more frequently in persons with brain, lung or gastrointestinal tract cancer, or with more advanced cancers.  Stroke may be a result of traditional cardiovascular risk factors, as well as cancer-mediated factors including hypercoagulability, non-bacterial thrombotic endocarditis (NBTE), direct tumor compression of blood vessels, or treatment-related effects which potentiate stroke.  With increasing survival rates from cancer, there is a greater need to assess stroke risk and to optimize stroke prevention strategies. The risk of stroke among cancer patients is two times that of the general population and rises with longer follow-up time (Zaorsky et al, Nature Communications, 2019).

System Implications +-
  1. Integrated systems of care for people with cancer and stroke to efficiently manage appointments and ensure coordination of care and safety with respect to medication and treatment options.
  2. Support for ongoing research into the relationship between cancer and stroke
  3. Awareness and education efforts for health professionals and the public
Performance Measures +-
  1. Proportion of people who experience an acute stroke who also have a diagnosis of cancer.  
  2. Median time from diagnosis of cancer to stroke event.  
  3. Proportion of people with stroke and cancer with elevated serum biomarkers such as high D-Dimer levels and fibrin degradation products.
  4. Proportion of people with acute ischemic stroke and previous cancer diagnosis who receive intravenous thrombolysis and or endovascular treatment.
  5. Proportion of people with acute ischemic stroke and previous cancer diagnosis who are treated with antiplatelet agents (or anticoagulants (and specific type of anticoagulant – LMWH, warfarin or DOAC).
  6. Mortality rates for people with pre-existing cancer who experience an acute stroke (stratified by ischemic or hemorrhage).
  7. Proportion of people with pre-existing cancer who experience an acute stroke (stratified by ischemic or hemorrhage) who have a recurrent stroke within 90 days, 6 months or one year of index stroke.

Reference: Dardiotis et al, Int J Oncol. 2019 Mar; 54(3): 779–796. Published online 2019Jan02 Jan2.  doi: 10.3892/ijo.2019.4669

Measurement Notes:

  • Performance measures should be stratified by the type of cancer and treatment approaches (e.g., recent chemotherapy,  radiation or surgery).
Summary of the Evidence +-

Cancer-Associated Ischemic Stroke 
Evidence Table and Reference List 

Increased Risk of Stroke Associated with Cancer

A diagnosis of cancer can increase the risk of stroke in the months or years following the diagnosis, particularly among persons with lung cancer or with more advanced cancers (Navi et al. 2017). In a case-control study including 327,389 persons >66 years, with newly diagnosed breast, colorectal, lung, pancreatic, or prostate cancer shorter term, the cumulative 3-month incidence of ischemic stroke was significantly higher in all types of cancer patients, except for prostate cancer (Navi et al. 2015). For lung cancer, the risk of any stroke was significantly higher at all follow-up points (<1 month, 1-3 months, 3-6 months, 6-9 months, and 9-12 months). Hazard ratios ranged from 1.63 at 6-9 months to 7.43 at < 1 month after cancer diagnosis. The risk of any stroke was significantly higher at one or more follow-up points for all other cancers, as well. Stroke risk may also be increased long-term following a cancer diagnosis, as well.  Jang et al. (2019) studied 20,707 persons sampled from a population database with cancer and 675,594 without cancer. The incidence of stroke in both groups was examined up to 7 years after cancer diagnosis using both the entire sample and propensity-score matching. The mean follow-up duration of cancer group was 69.7 months and 82.7 months in the non-cancer group. The cumulative incidence of any stroke using the entire cohort, was significantly higher in the cancer group (3.43% vs.1.07%), as were the cumulative incidences of ischemic stroke (3.10% vs. 0.91%), hemorrhagic stroke (0.46% vs. 0.21%) and death (22% vs. 2.03%). The risk of incident stroke was significantly higher in the cancer group (HR=1.09, 95% CI 1.00-1.18) using data from the entire cohort and was higher when the propensity-matched data were used (HR=1.13, 95% CI 1.02- 1.26).  Additionally, the risk of any and ischemic stroke was significantly higher in persons who received chemotherapy (adj HR= 1.21, 95% CI 1.03–1.41 and adj HR= 1.19, 95% CI 1.01–1.40, respectively). Zöller et al. (2012) reported the standardized incidence ratios (SIR) for ischemic stroke following a cancer diagnosis < 6 months previously was 1.6%, which decreased to 1.1% at ≥10 years.  The SIRs for hemorrhagic stroke were higher (2.2% at <6 months, 1.2% at ≥10 years and 1.2% overall). Not only is the risk of incident stroke increased following a cancer diagnosis, the risk of recurrent stroke is also increased. Navi et al. (2014) reported the cumulative prevalence of recurrent ischemic stroke were 7%, 13% and 16% at one, 3 and 6 months among 263 patients with active systemic cancer, with a hospital admission for stroke.

Cancer-related Hypercoagulopathy

Thrombosis is a common complication of malignancy and represents a frequent cause of death in cancer patients with a history of stroke. In the OASIS Cancer study (Lee et al. 2017) included 268 patients admitted to a single hospital with an acute ischemic stroke and active systemic cancer. Routine anticoagulation studies (D-dimer, PT, aPTT, fibrinogen and platelet counts) were conducted to assess possible hypercoagulopathy. During hospitalization, plasma D-dimer level was serially monitored after the start of the anticoagulation treatment. The pre-treatment and post treatment plasma D-dimer levels were divided into quartiles and their independent relationship with overall and 1-year survival was examined. Baseline D-dimer levels in the 4 quartiles (Q) were: Q1: <2.08 µg/mL; (25.1%), Q2: 2.08–9.06 µg/mL (24.7%), Q3: 9.06–23.26 µg/mL (25.5%) and Q4: >23.26 µg/mL (24.7%). When Q3 and Q4 groups were combined, the risks of overall and one-year mortality were increased significantly compared with group 1 (reference), HR=2.19, 95% CI, 1.46–3.31 and 2.70, 95% CI 1.68–4.35, respectively after adjustment for stroke mechanism, age, NIHSS score, primary cancer type, cancer histology (adenocarcinoma vs others), and atrial fibrillation. Among a subgroup of 113 patients in D-dimer groups 3 and 4 who were treated with anticoagulants, D-dimer levels were reduced (median of 8.17 µg/mL). Post-treatment D-dimer level was independently associated with poor 1-year survival (adjusted HR=1.03; 95% CI, 1.01–1.05 per 1 µg/mL increase, p= 0.015) but not with overall survival. After discharge from hospital, a D-dimer level of 3.17 µg/mL was identified as the cut-point, above which the risk of death within one month was increased significantly (OR=1.07, 95% CI, 1.04–1.10 per 1 µg/mL increase, p<0.001). Schwarzbach et al. (2012) also reported mean D-dimer levels were significantly higher in patients with active malignant cancer admitted to a hospital following ischemic stroke compared with persons in an age and sex-matched control group (7.64 vs. 5.36 μg/mL, p<0.05). The prevalence of DVT and PE was significantly higher in patients with cancer (8% vs. 1%, p<0.01) and in patients with cancer with an unidentified and/ or cancer-associated stroke etiology compared with patients with cancer with a definite/ probable stroke etiology (15% vs. 1%, p<0.01).

Treatment with Antithrombotics

Ravi al. (2018) published one of the only RCTs examining the use of antithrombotics in patients with active cancer who had sustained an ischemic stroke within the previous month. Twenty patients were randomized to receive either subcutaneous enoxaparin (1 mg/kg twice daily) or oral aspirin (81-325 mg/d) for 6 months; however, 6 patients in the enoxaparin group crossed over to use aspirin after a median of 6 days. Treatment groups were too small to conduct inferential statistics. One year after enrollment, three patients in the aspirin group had nonfatal gastrointestinal bleeding and one patient had a nonfatal myocardial infarction. In the enoxaparin group, one patient had a nonfatal pulmonary hemorrhage, and one had a fatal recurrent acute ischemic stroke.

Sex and Gender Considerations

No studies were found that address sex differences on this topic.

 

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