Vascular endothelial growth factor tyrosine kinase inhibitor targeted therapy: a potential cause of an acute aortic dissection lesser known to the emergency physician
- 1 Emergency Medicine, Tan Tock Seng Hospital, Singapore
- 2 Vascular Surgery, Woodlands Health, Singapore
- 3 Clinician-Scientist Fellow, Lee Kong Chian School of Medicine, Singapore
- Correspondence to Dr Jocelyn Ting; jocelyn.ting@mohh.com.sg
Abstract
A 59-year-old Chinese male presented to the emergency department with acute onset epigastric pain. He had no cardiovascular risk factors and was only on targeted therapy, pazopanib, for newly diagnosed metastatic renal clear cell carcinoma. He was found to have a Stanford type B acute aortic dissection with moderately elevated systolic blood pressure of 150 mm Hg. Although not a listed side effect, various case reports have shown a potential association between the use of vascular endothelial growth factor tyrosine kinase inhibitor targeted therapy and an acute aortic dissection. It would be prudent to consider the possibility of an aortic dissection in patients on such drugs with suspicious clinical presentation, even in the absence of other risk factors.
Background
Pazopanib is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) targeted therapy used for advanced renal cell carcinoma or soft tissue sarcomas. Its most commonly recognised side effect is hepatotoxicity. It is usually started at a dose of 800 mg once a day. Known adverse reactions include that of hypertension, hypothyroidism, interstitial lung disease, and arterial or venous thrombotic events.1 Aortic dissection is not a listed side effect or adverse reaction related to this medication. There are few case reports of VEGF TKI-associated aortic dissections. Existing case reports contain patients with known baseline hypertension, which could have been a confounding factor contributing to their development of an aortic dissection. Other reports include patients who received a longer duration of VEGF inhibitors (2–4 years) before developing an aortic dissection.
Case presentation
A 59-year-old Chinese male of good premorbid status was newly diagnosed with metastatic renal clear cell carcinoma. He was not a smoker. He had no chronic medical conditions apart from a history of peptic ulcer disease.
He was started on pazopanib 800 mg once a day in January 2021 by his oncologist. He received counselling on side effects including hypertension, hepatotoxicity and thyroid function abnormalities. During the course of treatment, pazopanib was held off for 6 weeks due to derangements in his liver function tests. It was restarted at 400 mg once a day when his blood tests normalised. A staging CT scan of the thorax, abdomen and pelvis done on 20 April 2021 showed a reduction in size of his right kidney mass as well as liver, pulmonary and peritoneal metastases. No dissection flap or vascular aneurysm was visualised on this scan. The dose of pazopanib was then increased to 600 mg daily on 22 April 2021. His outpatient ambulatory blood pressure readings during the course of treatment ranged from 112/75 mm Hg to 141/94mm Hg.
He subsequently presented to the emergency department on 26 April 2021 (6 days after his staging CT scan) with 1 day of sudden onset epigastric pain. There were no associated symptoms of chest pain, breathlessness or vomiting.
His vital signs were as follows: afebrile, blood pressure of 153/71 mm Hg, pulse rate of 60 and oxygen saturation of 100% on room air. He had epigastric tenderness on examination. There were no radial-radial or radial-femoral delays. A bedside ultrasound showed a dissection flap in the abdominal aorta (figure 1). Bilateral femoral, dorsalis pedis and posterior tibial pulses were otherwise well felt. While in the emergency department, his blood pressure ranged from 133/69 mm Hg to 168/106 mm Hg and heart rate ranged from 45 to 82 beats per minute.
Ultrasound image (A) in long-axis view and (b) in short-axis view showing a dissection flap.
Investigations
An urgent CT aortogram performed showed an aortic dissection (figure 2). This extended from distal to the origin of the left subclavian artery to the left common iliac artery bifurcation (figure 3). All visceral vessels and the right external iliac artery were supplied by the true lumen. Although the left external iliac artery was supplied by the false lumen on the CT aortogram, there was good contrast flow. There was otherwise no aortic aneurysmal change, thrombosis or end-organ malperfusion. He had no clinical evidence of acute limb ischaemia.
CT image in axial view showing a dissection flap.
CT image in coronal view showing a dissection flap extending through the (A) thoracic and (B) abdominal aorta.
Treatment
He was admitted for further investigations and monitoring. Intravenous labetalol was administered to maintain systolic blood pressure at <120 mm Hg and heart rate at <60 beats per minute, in accordance with the American College of Cardiology guidelines.2 Formal transthoracic echocardiogram showed a normal aortic root with preserved ejection fraction. Blood pressure was managed with oral hypertensives titrated against intravenous labetalol. During the course of stay, there were no clinical signs and symptoms of end-organ malperfusion. There was no derangement in his liver and renal function tests. A repeat CT aortogram on day 5 of admission showed a stable Stanford type B aortic dissection. There was improved perfusion in the left common iliac and external iliac arteries. There continued to be no aortic aneurysmal change, thrombosis or end-organ malperfusion.
Outcome and follow-up
He was managed medically with hypertensive control and discharged on carvedilol 12.5 mg two times a day and nifedipine 30 mg once a day. After a discussion with his oncologist, pazopanib was stopped and switched to an immunotherapy agent, nivolumab. Surveillance CT aortogram after 2 months showed a stable Stanford type B aortic dissection with no worsening dissection, aneurysmal change or end-organ perfusion.
Discussion
An aortic dissection results from a tear in the intimal layer. A dissection plane is created as blood tracks along the medial layer. Risk factors for aortic dissections include connective tissue disorders, hypertension, hyperlipidaemia, diabetes mellitus or a history of smoking.3 Medical therapy remains the mainstay of management. However, some evidence suggests that thoracic endovascular aortic repair has positive effects on long-term aortic remodelling.4 VEGF TKI medications have been associated with hypertension.5 It has been postulated that the effect of hypertension and inhibition of endothelial proliferation6 could be the cause of an acute aortic dissection. Various case reports have illustrated this phenomenon. A 48-year-old male with well-controlled hypertension developed a fatal Stanford A aortic dissection after a period of treatment with pazopanib, lapatinib and sunitinib.7 Another case report includes a 68-year-old male with a 58-pack-year smoking history. He presented with chest pain and high blood pressure of 210/120 mm Hg 20 days into his second cycle of sunitinib. He was found to have a Stanford B aortic dissection requiring an endoprosthesis.8 A Japanese pharmacostudy has found an association between systemic treatment with VEGF inhibitors and an increased risk of aortic dissection.9 A Canadian safety review published in 2018 similarly showed a possible link between VEGF TKI use and arterial dissections and aneurysms.10
In the above case, the patient had no pre-existing modifiable risk factors, no family history of aortic dissections and was normotensive prior to commencement of pazopanib. He only developed hypertension and an aortic dissection after the use of a VEGF TKI targeted therapy. Therefore, it is possible that there is a link between these three events. For example, his use of pazopanib could have directly led to an aortic dissection. Alternatively, it could have led to the development of hypertension and in turn an aortic dissection.
In the emergency setting, a focused bedside ultrasound is often performed to evaluate the abdominal aorta in patients who present with abdominal pain, back pain or syncope. Emergency physicians are taught to recognise ultrasound features of abdominal aortic aneurysms and in some institutions, aortic dissections. A high index of suspicion and the visualisation of an intimal flap on ultrasound would allow the emergency physician to identify an aortic dissection. For this potentially fatal condition to be managed expeditiously, emergency physicians should recognise the possible link between it and the use of VEGF TKI inhibitors.
Learning points
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Physicians should consider an acute aortic dissection in patients on vascular endothelial growth factor (VEGF) inhibitors presenting with abdominal pain or chest pain. A bedside focused ultrasound could potentially aid in diagnosis if a dissection flap is seen.
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The proposed mechanism of VEGF inhibitors causing an aortic dissection includes that of hypertension and suppressed healing of damaged endothelium, although the exact pathophysiology is not entirely known.
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Prior to starting VEGF therapy, modifiable risk factors like hypertension and smoking should be addressed. Blood pressure monitoring should be carried out regularly after initiation of therapy.
Ethics statements
Patient consent for publication
Footnotes
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Contributors JT and ZJL managed the patient. JT wrote the manuscript, reviewed the records, edited and approved the final version. ZJL contributed to writing the manuscript and approved the final version. All authors have approved the version of the manuscript submitted for publication.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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