Vascular Complications in Patients with Hepatocellular Carcinoma Treated with Sorafenib

Abstract

VEGF(R)-targeted therapies are associated with an increased risk of thromboembolism and bleeding, which might be pronounced in patients with increased cardiovascular risk. Nevertheless, sorafenib represents an important treatment option in patients with hepatocellular carcinoma (HCC). We retrospectively investigated the risk of arterial/venous thromboembolic and bleeding events in 252 patients treated with sorafenib for HCC between 05/2006 and 03/2020 at the Medical University of Vienna. Cardiovascular risk was assessed using Framingham score. Eight patients (3.2%) experienced 11 arterial/venous thromboembolic events. Only two patients (0.8%) developed arterial thromboembolism even though cardiovascular risk was low, intermediate, and high in 15 (8.7%), 104 (60%), and 54 (31.2%) of 173 assessable patients. Median overall survival (OS) was shorter in the high risk vs. low/intermediate risk group 7.4 (95% CI: 3.4–11.3) vs. 10.0 (95% CI: 6.8–13.2 months) and independently associated with OS in multivariable analysis HR: 1.53 (95% CI: 1.07–2.19; p = 0.019). Forty-eight (19%) patients experienced a bleeding, most commonly gastrointestinal bleeding (14%) followed by epistaxis (4.7%). Advanced liver dysfunction was not associated with an increased incidence of bleeding/venous thromboembolism. Sorafenib represents a safe treatment option even in patients with increased cardiovascular risk. Bleeding complications were comparable with previous reports, even though patients with more advanced liver disease were included.

Safety of direct oral anticoagulants in patients with advanced liver disease

“…While bleeding episodes in this population may be related to a DOAC-associated haemostatic failure, it cannot be excluded that these bleedings were triggered by other risk factors such as portal hypertension 19 or tyrosine kinase inhibitor therapy. 35 While no baseline or laboratory parameter was predictive of spontaneous bleeding in the US study, 18 we did observe an association of spontaneous bleeding with liver function. However, it is unclear whether the observed increased bleeding risk simply reflects the more fragile haemostatic balance in patients with more pronounced liver dysfunction or is caused by DOAC treatment.…”

“…Importantly, we observed that CPS‐B/C patients receiving DOAC had a significantly higher risk for spontaneous bleeding when compared with patients with CPS‐A cirrhosis. While bleeding episodes in this population may be related to a DOAC‐associated haemostatic failure, it cannot be excluded that these bleedings were triggered by other risk factors such as portal hypertension 19 or tyrosine kinase inhibitor therapy 35 …”

“…While bleeding episodes in this population may be related to a DOAC‐associated haemostatic failure, it cannot be excluded that these bleedings were triggered by other risk factors such as portal hypertension 19 or tyrosine kinase inhibitor therapy. 35 …”

Evaluation of cardiovascular events in patients with hepatocellular carcinoma treated with sorafenib in the clinical practice. The CARDIO‐SOR study

“…3,4 Nonetheless, other important cardiovascular toxicities (including myocardial ischemia, QT prolongation, cerebrovascular accidents (CVA) or vascular peripheral ischemia) do not seem to have been highlighted during drug development or the pivotal randomised controlled trials for regulatory approval, due to its apparently low incidence. 2,5,6 To date, only a few clinical studies have focused on the cardiovascular complications in actual clinical practise. Moreover, most clinical information available comes from renal studies, 7 with a different clinical profile of patients than those affected by HCC.…”

“…Sorafenib (SOR) is a multitarget TKI, 2 mainly used for the treatment of advanced hepatocellular carcinoma (HCC) and renal cell carcinoma. Although SOR significantly prolongs patients' overall survival (OS), its use is associated with different adverse events (AEs), mainly dermatological and gastrointestinal but also cardiovascular, especially high blood pressure (BP) 3,4 .…”