VEGF inhibitor-induced hypertension: treat without stopping therapy

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A 70-year-old man with CKD stage G3b/A1 receiving therapy with sunitinib for metastatic renal cell carcinoma is referred to evaluate new-onset hypertension. He denies dyspnea, peripheral edema, or headache. BP is 158/90 mm Hg, increased from 132/76 mm Hg last month. Fundoscopic examination shows no papilledema. There is trace edema bilaterally. Neurologic examination is normal. Laboratory data: blood WBC count 10,400/µL (reference 4000–11,000); hemoglobin 11.4 g/dL (14–18); platelet count 310,000/µL (150,000–450,000); creatinine 1.6 mg/dL, stable (0.7–1.3). Urine studies: protein-to-creatinine ratio 0.3 mg/mg (<0.2). Urinalysis shows 1+ albumin and no blood, with negative microscopy. Peripheral blood smear shows no schistocytes. Which ONE of the following is the best NEXT STEP in management?

  1. A.Discontinue sunitinib
  2. B.Prescribe lisinoprilCorrect
  3. C.Perform renal artery duplex Doppler ultrasound
  4. D.Prescribe diltiazem

Explanation

Lisinopril should be prescribed in this patient with new-onset hypertension and no evidence of end-organ damage. Hypertension is a frequent complication of antiangiogenic therapy, but hypertension in the absence of end-organ damage does not mandate stopping therapy. The National Cancer Institute Angiogenesis Task Force recommends treatment to a target BP of <140/90 mm Hg or treatment to maintain the diastolic BP <20 mm Hg above baseline for patients with low-normal baseline BP. Some evidence suggests that hypertension is a biomarker for improved tumor response. The preferred classes of medications for treating hypertension in this scenario has yet to be established, but ACEIs or ARBs, especially in patients with proteinuria, or dihydropyridine calcium channel blockers are reasonable choices. A review of bevacizumab-induced hypertension in patients with ovarian cancer suggested amlodipine as first line followed by the addition of an ACEI or ARB if needed. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, are generally avoided because they inhibit cytochrome P450 3A4 and decrease sunitinib metabolism. Reasons to discontinue antiangiogenic therapy include posterior reversible encephalopathy syndrome, thrombotic microangiopathy, or nephrotic syndrome, none of which is present in this case. Arterial and venous thromboembolism have been reported with antiangiogenic therapy, most commonly with bevacizumab and aflibercept. Renal arterial or venous thrombosis could cause hypertension, but the absence of flank pain and hematuria make these diagnoses less likely. Thus, abdominal magnetic resonance venogram of the abdomen or renal artery duplex Doppler ultrasound would not be indicated. Proteinuria associated with antiangiogenic therapy may result from endothelial injury to glomerular capillaries and thrombotic microangiopathy. Collapsing focal segmental glomerulosclerosis has also been reported.

Why each option

A.
Sunitinib is stopped for PRES, thrombotic microangiopathy, or nephrotic syndrome, none present, and hypertension may even indicate tumor response.
B.
Correct. VEGF inhibitor hypertension without end-organ damage is treated while continuing therapy, and an ACE inhibitor suits his CKD with proteinuria.
C.
Renal artery thrombosis is rare with sunitinib, and without flank pain, hematuria, or creatinine change, duplex ultrasound is not indicated here.
D.
Diltiazem inhibits CYP3A4 and raises sunitinib levels, so non-dihydropyridine calcium channel blockers are avoided with tyrosine kinase inhibitors.

Reference: Maitland ML, J Natl Cancer Inst 2010 (NCI Angiogenesis Task Force recommendations for VEGF inhibitor hypertension); Lyon AR, Eur Heart J 2022 (ESC cardio-oncology guideline)

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