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4th Year Medical Student, San Diego School of Medicine, University of California
4th Year Medical Student, San Diego School of Medicine, University of California
Professor of Surgery, Head and Neck Surgery, Division of Otolaryngology/Head and Neck Surgery, San Diego School of Medicine and VA San Diego Healthcare System, University of California, 9500 Gilman Drive, San Diego, California 92093, fax 858/822-5908, tdavidson{at}ucsd.edu
Published Online, August 11, 2009. www.theannals.com, DOI 10.1345/aph.1M228
Case Report. The patient, who had been treated with simvastatin 20 mg/day for 9 years without any adverse effects, was started on ezetimibe/simvastatin 10/40 mg/day. At this time, his hemoglobin was 14.1 g/dL. He continued his only other medication, esomeprazole. After 2 months of ezetimibe/simvastatin therapy, he noticed epistaxis that increased from a few drops every other day to profuse bleeding for 20-30 minutes daily.
The increased epistaxis was attributed to the progression of HHT. Four months after starting ezetimibe/simvastatin, in an attempt to reduce the epistaxis, the patient underwent 2 consecutive laser cauterizations of his nasal mucosa, with no improvement. Two months later, his hemoglobin was 6.4 g/dL. He was transfused with 2 units of packed red blood cells (PRBCs), and a branch of the left facial artery was embolized. Yet, the epistaxis progressed. Due to significant drops in hemoglobin, 8 units of PRBCs were given over 6 months. Results of liver function tests were within normal limits while the patient was on ezetimibe/simvastatin.
The patient reported initiation of ezetimibe/simvastatin as the single change in his treatment regimen in the past year. When he stopped ezetimibe/simvastatin, his epistaxis decreased. After 6 weeks without ezetimibe/simvastatin, he had only one moderate nose bleed. Four months later, the patient's hemoglobin was stable at 13.1 g/dL. He then started simvastatin 40 mg monotherapy. The profound epistaxis returned and the patient discontinued the medication.
Discussion. The disappearance of symptoms after stopping ezetimibe/simvastatin suggests that either the combination therapy or the double dosage of simvastatin in the combination may have contributed to this patient's pathology. We have found no reports of combination therapy or statin-associated epistaxis in a search of PubMed with the terms epistaxis, nose bleed, bleed, or HHT combined with statins or ezetimibe. Ezetimibe plus simvastatin has been evaluated for safety in more than 3800 patients in clinical trials. None of the adverse effects found during clinical trials and postrelease of the drug included epistaxis or hemorrhagic symptoms. However, there is one case report describing ezetimibe-associated immune thrombocytopenia.2
In researching the pathologic process of epistaxis in HHT, we found a
possible overlap in pathways affecting angiogenesis. Our patient has HHT2,
which involves a missense mutation on the Activin-like protein 1
(ALK-1) gene on chromosome 12, leading to a nonfunctional
ALK-1 protein of the transforming growth factor-β (TGF-β)
receptor
superfamily.3
TGF-β is involved in vascular remodeling and angiogenesis through
vascular endothelial cell growth factor (VEGF). ALK-1 has been shown
to increase VEGF and angiopoietin-2, leading to increased blood vessel
permeability. The ALK-1 mutation manifests as cutaneous and/or mucous
telangiectases and arteriovenous
fistulas.4
Statins have been shown to inhibit the stimulatory effects of TGF-β
through a tumor necrosis factor-
pathway.4,5
We postulate that this may lead to an additive effect of abnormal VEGF
function from a nonfunctional ALK-1 in HHT and a statin's ability to
inhibit TGF-β.
There is no published literature on the safety of ezetimibe/simvastatin or statins in patients with HHT. The Naranjo probability scale demonstrates a possible likelihood that high-dose simvastatin was the cause of the severe epistaxis in our patient.6 The severity of the symptoms and clinical manifestations experienced by this patient are noteworthy and may warrant careful monitoring of HHT patients who are on cholesterol-lowering agents.
Footnotes
Financial disclosure: None reported
References
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