Blood Thinners Do Not Reduce Arterial Clot Risk in Patients with Cancer

Blood clots are one of the challenges patients face during cancer treatment. They can reduce quality of life and complicate treatment. Various approaches have been developed to reduce this risk, including drugs that prevent clotting, known as anticoagulants. A new study, however, shows that anticoagulants do not reduce the risk of clots forming in arteries, the vessels carrying blood from the heart to the body, among patients receiving outpatient cancer treatment. Their use is also associated with increased bleeding risk. These findings were reported in JACC: CardioOncology.

A Review of Anticoagulant Effectiveness and Safety

Researchers conducted a systematic review of 14 randomized trials to examine the effectiveness and safety of anticoagulants for preventing arterial thromboembolism (ATE) in patients receiving outpatient cancer treatment. The trials compared oral or parenteral (injected) anticoagulation with no anticoagulation in patients receiving systemic anticancer therapy.

The trials included low-molecular-weight heparins, direct oral anticoagulants and warfarin. Arterial clotting events included heart attack, ischemic stroke, intra-abdominal arterial embolism and peripheral arterial occlusion.

Anticoagulant Use and ATE Risk

Compared with standard care or placebo, anticoagulant use was not associated with a reduction in clotting risk (relative risk [RR],0.73; 95% CI, 0.50 to 1.04). Similarly, anticoagulants did not reduce all-cause mortality risk (RR, 0.99; 95% CI, 0.95 to 1.02).

However, anticoagulant use was associated with increased risks of major bleeding (RR, 1.56; 95% CI, 1.12 to 2.17) and minor bleeding (RR, 2.25; 95% CI, 1.45 to 3.48).

The researchers said, "Our data do not support routine anticoagulant use to prevent blood clots in ambulatory patients with cancer who do not require hospitalization."

Conclusion

These findings indicate that anticoagulants are not an effective strategy for reducing clotting risk in patients with cancer. Their use is also associated with increased bleeding risk. Alternative strategies are therefore needed to reduce clot formation. Future research in this area is important for making cancer treatment safer and more effective.

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Further Reading: Editorial Commentary on the Study

Anticoagulants to Prevent Arterial Thrombosis in Patients with Cancer: To Use or Not to Use?

Cancer increases the risk of thromboembolic ischemic stroke in patients with venous thromboembolism (VTE), arterial thromboembolism (ATE) and atrial fibrillation (AF). Traditionally, attention to the relationship between thrombosis and cancer has focused on VTE, the second leading cause of death in cancer, affecting approximately 5% of patients. ATE in patients with cancer has received much less attention.

ATE has long been recognized in patients with cancer. Cancer increases the risk of ATE, including myocardial infarction (MI) and stroke, by a factor of 2 (see our article What Is the Relationship Between Cancer and Heart Disease? ).

ATE risk is higher in older men and in patients with lung or kidney cancer. Cancer-related ATE mechanisms include embolization by tumor cells or nonbacterial thrombotic endocarditis, peripheral microcirculatory thromboembolism associated with disseminated intravascular coagulation, and paradoxical cerebral embolism.

Preventing ATE in patients with cancer requires several important considerations. These patients often have both increased thrombotic risk and increased bleeding risk. Certain cancers, such as gastrointestinal or intracranial tumors, coagulation abnormalities, comorbidities such as kidney or liver disease, and interactions between anticancer drugs and anticoagulants make anticoagulation for ATE prevention particularly challenging.

Anticoagulant therapy has proved effective for VTE prevention in cancer. Anticoagulation is strongly recommended for stroke prevention in patients with AF who do not have a high bleeding risk and whose CHA2DS2-VASc scores (congestive heart failure, hypertension, age≥75, diabetes, prior stroke, vascular disease, age 65 to 74 and female sex) are≥2 for men or≥3 for women. In this context, a study supports anticoagulation in patients with AF and newly diagnosed cancer: those with CHA2DS2-VASc scores≤2 who were not receiving anticoagulation at cancer diagnosis had a higher ATE risk than patients with AF but without cancer.

However, the effect of anticoagulation on preventing ATE and MI in patients with cancer who do not have AF is unknown. The study by Xu and colleagues on anticoagulant effectiveness and safety for preventing ATE in ambulatory patients with cancer is therefore important. They conducted the first systematic review and meta-analysis of 14 randomized controlled trials involving more than 10,000 participants. These trials compared oral or parenteral anticoagulation with no anticoagulation in patients receiving systemic anticancer therapy who had no other indication for anticoagulation. Anticoagulant use was not associated with fewer MIs, ischemic strokes, intra-abdominal arterial emboli or peripheral arterial occlusions compared with placebo or standard care (relative risk: 0.73; 95% CI, 0.50-1.04; P=0.08, I2=0%). However, major and minor bleeding risks increased with anticoagulant use, and all-cause mortality was not reduced.

Using a meta-analysis, the study assessed the effect of anticoagulants on ATE prevention in ambulatory patients receiving systemic anticancer treatment. Its findings support earlier results from a single randomized trial showing no benefit from routine low-molecular-weight heparin. However, important limitations apply when using pooled meta-analysis data to derive treatment indications for individual patients with cancer.

First, cancer is a complex disease with different phenotypes associated with different cancer types, patients and treatments, all of which can greatly affect the risk-benefit balance of anticoagulation. Different cancer therapies may also influence ATE in different ways. For example, accelerated atherosclerosis and plaque rupture have been associated with androgen deprivation therapy (gonadotropin-releasing hormone agonists), immune checkpoint inhibitor therapy, nilotinib, ponatinib, radiotherapy and vascular endothelial growth factor inhibitors. Coronary thrombosis, in contrast, has been associated with alkylating agents (cisplatin and cyclophosphamide), erlotinib, immune checkpoint inhibitor therapy, immunomodulatory imide drugs (lenalidomide and thalidomide), monoclonal antibodies (vascular endothelial growth factor inhibitors and anti-CD20), nilotinib and platinum agents.

Cancer type and clinical stage, together with comorbidities such as diabetes, previous or recurrent MI, prior coronary revascularization, dyslipidemia, smoking, peripheral arterial disease and chronic kidney failure, also require ATE risk stratification followed by individualized treatment.

In many cases, progression from stable atherosclerotic disease to acute coronary syndrome involves rupture or erosion of vulnerable plaques, exposing the lipid core to blood. This triggers platelet aggregation and subsequent intra-arterial thrombus, causing partial occlusion (unstable angina or non-ST-elevation MI) or complete occlusion (ST-elevation MI). In these situations, antiplatelet therapy has a greater therapeutic effect than anticoagulation. Xu and colleagues did not report the frequency of antiplatelet use at enrollment, limiting definitive recommendations. For example, in the RIETE (Computerized Registry of Patients with Venous Thromboembolism) cohort of patients with cancer who had experienced VTE, 86% of subsequent ATE events occurred during heparin treatment, versus only 6.3% during antiplatelet therapy. Antiplatelet therapy combined with low-dose oral anticoagulation effectively reduces adverse limb events and overall cardiovascular disease risk in patients with lower-extremity arterial disease. European Society of Cardiology guidelines recommend low-dose rivaroxaban plus aspirin for long-term secondary prevention in patients at high ischemic risk without a high bleeding risk (Class 2, Level of Evidence: A).

The improvement in cardiovascular outcomes with combination therapy versus anticoagulation alone comes at the cost of more major bleeding events, which may be more frequent during active cancer treatment. The multicenter COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial, published in 2017, compared rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, and aspirin 100 mg daily alone in patients without cancer who had stable coronary or peripheral arterial disease. The study showed reductions in all-cause mortality (3.4% versus 4.1%; P=0.01) and cardiovascular mortality (1.7% versus 2.2%; P=0.02). Unfortunately, rivaroxaban 2.5 mg twice daily plus aspirin increased major bleeding risk in COMPASS (3.1% versus 1.9%; P<0.001), although fatal bleeding and symptomatic bleeding into critical organs did not differ. The hypothesis that the COMPASS approach benefits patients with cancer requires further randomized trials accounting for their increased baseline bleeding risk.

Current guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population include low-dose aspirin (75-100 mg daily) for selected adults aged 40 to 70 with higher ASCVD risk but no increased bleeding risk (Class IIb), and recommend it for secondary prevention in all patients (Class I-A). Antiplatelet therapy is not recommended for people at low or intermediate cardiovascular risk because of increased major bleeding risk (Class III). AF occurs in 2% to 16% of patients with cancer. For stroke prevention in patients with AF who do not have a high bleeding risk, anticoagulation is recommended when CHA2DS2-VASc scores are≥2 for men or≥3 for women, and should be considered for scores≥1 in men or≥2 in women.

In conclusion, patients with cancer have higher risks of ASCVD, coronary heart disease and ATE because of shared risk factors, cardiovascular toxicity from cancer treatments, and cancer-induced proinflammatory and prothrombotic states. However, it remains necessary to determine whether anticoagulation, alone or combined with antiplatelet agents (possibly clopidogrel, which has fewer gastrointestinal adverse effects than aspirin), provides a net clinical benefit for ATE prevention. Which patients benefit, at what cancer stage and with which comorbid risk factors requires further clinical investigation.