Association Between Aortic Dissection and Systemic Exposure of Vascular Endothelial Growth Factor Pathway Inhibitors in the Japanese Adverse Drug Event Report Database

Ôshima, Yasuo; Tanimoto, Tetsuya; Kikuchi, Yuji; Tojo, Arinobu

doi:10.1161/circulationaha.116.025144

Cited by 40 publications

(56 citation statements)

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“…Hypertension is a major cause of aortic dissection, and half of aortic dissection cases have been reported to have hypertension at baseline. 3) However, in the current case, BP elevation was well controlled by angiotensin II type 1 receptor blockers and Ca antagonists. This finding indicates that additional mechanisms and/or multiple hits may contribute to aortic dissection.…”

Section: Discussionmentioning

confidence: 46%

“…The Japanese Adverse Drug Event Report database showed that the occurrence rate of aortic dissection in the VEGF pathway inhibitors of patients with cancer was 0.3%. 3) The median time to onset was 105 days (range: 4-1363 days) after the administration of VEGF inhibitors; therefore, the present case could be the latest onset case of VEGF inhibitor-induced aortic dissection. Niwa, et al reported the first case of axitinib-associated acute aortic dissection (Stanford type A) in a patient with metastatic renal cell carcinoma.…”

Section: Discussionmentioning

confidence: 69%

“…The common adverse cardiovascular side effects of these angiogenesis inhibitors are hypertension, proteinuria, and cardiac dysfunction. Sunitinib-or sorafenib-induced aortic dissection associated with hypertension has been reported, 3) but axitinib-induced aortic dissection rarely occurs. Mechanistically, VEGF has acute vasodilating effects on the peripheral vessels stimulating the syntheses of nitric oxide and prostaglandin I2 via VEGFR2.…”

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confidence: 99%

“…VEGF inhibition causes capillary rarefaction, 8) which may contribute to the development of hypertension. 9,10) VEGFR inhibitor-induced hypertension has been thought to induce aortic dissection 3) ; however, the precise role of VEGFR inhibitors in the initiation of aortic dissection remain unclear. In the present study, we reported the first case of aortic dissection and cardiac dysfunction coincidence in a patient with metastatic renal cell carcinoma after the serial treatment of sorafenib and axitinib for six years.…”

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confidence: 99%

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Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma

et al. 2018

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Angiogenesis inhibitors, such as sorafenib and axitinib, which target vascular endothelial growth factor (VEGF) signaling, are widely used for renal cell carcinoma, including metastasis. In this study, we report a case of cardiovascular adverse events of aortic dissection and cardiac dysfunction during treatment with sorafenib and axitinib for metastatic renal cell carcinoma. A 66-year-old man had been administered sorafenib for 2 years after nephrectomy due to renal cell carcinoma. To control the progression of metastatic lung tumor, axitinib was started after sorafenib for four years. During the treatment, angiotensin II type 1 receptor blockers and Ca antagonists were used to strictly control the axitinib-induced hypertension and proteinuria. Aortic dissection and cardiac dysfunction occurred coincidentally. Considering the critical role of VEGF signaling in the homeostasis of the cardiovascular system, we speculated that the long-term use of axitinib and sorafenib directly influenced the initiation of aortic dissection and cardiac dysfunction. Although the precise mechanisms underlying the aortic dissection and cardiac dysfunction induced by angiogenesis inhibition are still elusive, onco-cardiologists and oncologists should pay careful attention to cardiovascular toxicity and complications in patients with cancer, particularly patients undergoing long-term cancer treatment.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 69%

mentioning

confidence: 99%

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confidence: 99%

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Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma

et al. 2018

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“…Using a Japanese Adverse Drug Event Report database, Oshima et al reported that 49 of 16 441 patients (0.3%) treated with systemic vascular endothelial growth factor pathway inhibitors (VPIs) developed aortic dissection (30 times higher than in subjects not exposed to VPIs). This includes 11 of 4975 (0.22%) patients treated with sorafenib . While aortic dissection is rare, it is likely caused by an increase in blood pressure and delayed healing of damaged endothelium.…”

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Successful treatment of aortic dissection during sorafenib therapy for hepatocellular carcinoma

Tsuchiya

Ogawa

Watanabe

et al. 2018

Clinical Case Reports

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Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer

Kang,

Yeon,

Kim

et al. 2023

JAMA Netw Open

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ImportanceThe association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases.ObjectiveTo investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator.Design, Setting, and ParticipantsThis national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023.ExposureOral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator.Main Outcomes and MeasuresHazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes.ResultsAmong 127 710 patients with cancer eligible for the study (80 386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37 308 patients received VEGFR-TKIs and 90 402 patients received capecitabine. Among 27 535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged ≥65 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24).Conclusions and RelevanceIn this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.

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Association Between Aortic Dissection and Systemic Exposure of Vascular Endothelial Growth Factor Pathway Inhibitors in the Japanese Adverse Drug Event Report Database

Cited by 40 publications

References 5 publications

Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma

Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma

Successful treatment of aortic dissection during sorafenib therapy for hepatocellular carcinoma

Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer

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