Hypercholesterolemia in the Elderly Patient: A Cautionary Tale Regarding Drug Therapy

Introduction

As the US population ages, primary care physicians will be faced with difficult challenges when treating medical conditions in the very elderly. In clinical practice, wherever possible, treatment decisions are based on evidence found in clinical trials; however, in many of these trials, the age range of the study population is often lower than the population treated in the community. This is often seen in clinical trials of hyperlipidemia, which are targeted toward a younger population. One drug that is available for cholesterol management is the combination of ezetimibe and simvastatin, which was approved by the US Food and Drug Administration (FDA) in July 2004 for the treatment of hypercholesterolemia. We examine several important clinical situations faced by physicians treating the elderly by describing a case of fulminant liver failure induced by ezetimibe/simvastatin in an 86-year-old female patient.

Case Presentation

An 86-year-old woman with a medical history of hypertension, coronary artery disease treated with coronary artery bypass graft (CABG) surgery, permanent pacemaker placement, and repair of an ascending aortic aneurysm presented to an outside hospital in September 2009 with reports of fatigue, dark-colored urine, jaundice, and light-colored stools. Her symptoms started 2 to 3 weeks prior to admission. Oral daily medications on admission included clopidogrel 75 mg, ezetimibe/simvastatin 10/20 mg, nebivolol 10 mg, aspirin 81 mg, and ferrous sulfate 325 mg. Physical examination was significant for jaundice and bilateral lower-extremity swelling. Laboratory testing showed significantly elevated liver enzymes, with an aspartate aminotransferase (AST) of 3080 U/L, alanine aminotransferase (ALT) of 1201 U/L, total bilirubin of 18.1 mg/dL, and albumin of 3.4 g/dL. The international normalized ratio (INR) was elevated to 1.8 (Table). A computed tomography scan of the abdomen was done, which showed multiple 2 to 3-mm low-density areas in the liver, large ascites, and no biliary duct dilatation. All medications were discontinued and she was started on vitamin K 10 mg subcutaneously once a day. The patient’s liver enzymes continued to remain elevated, so she was transferred to a tertiary care center for further management and evaluation for possible liver transplantation 10 days after her presentation to the outside hospital.

Upon transfer to the tertiary care center, laboratory testing showed an AST of 714 U/L, ALT of 472 U/L, total bilirubin of 19.7 mg/dL, and INR of 3.19 (Table). A diagnosis of fulminant liver failure was made, with the most likely cause being drug-induced versus autoimmune hepatitis. She was started on intravenous methylprednisolone 48 mg once daily, and a liver biopsy was performed on day 2 of admission. The liver biopsy showed patchy, predominantly midzonal hepatocyte degeneration and necrosis with portal fibrosis, consistent with drug-induced liver injury. The patient was then tapered off of steroids, and she showed gradual improvement in her liver function tests and INR. She was discharged on hospital day 10 and has continued to follow-up as an outpatient, with significant improvement in liver function 5 months after discharge.

Discussion

The case patient was first seen in an outpatient clinic 4 years before her current admission to the outside hospital in September 2009, and was well known to the medical attending. At that time, she was 82 years old, had hypertension, and had been a chronic alcoholic for many years, drinking 2 to 3 beers per night. Her medications at that time included verapamil and hydrochlorothiazide. Hypertension in the elderly is a common problem seen by many internists, but at that time there were no definite guidelines for treating it in the very elderly. Clinical trials have clearly shown benefit in cardiovascular mortality and morbidity from treatment of patients younger than 60 years of age.¹ A meta-analysis published in 1999 by Gueyffier et al² showed a significant reduction in stroke, heart failure, and major cardiovascular events by treating hypertension in the very elderly (age >80 years), but also showed an increase in all-cause mortality. In 2008, data from the Hypertension in the Very Elderly Trial (HYVET) resolved these conflicting results and showed a clear benefit of treating hypertension in the very elderly³; however, there was no mention of alcohol intake, liver disease, or other life-threatening diseases in the population studied in HYVET. Because it was presumed that treating the alcoholism in the case patient would lead to an improved outcome and reduced blood pressure, her physicians chose to treat her.

The case patient also had an ascending aortic aneurysm that was diagnosed 3 years prior to her September 2009 presentation. The size of the aneurysm at diagnosis was 5.3 cm, and it was incidentally found on a routine echocardiogram. Based on a consultation with a cardiothoracic surgeon, the decision was made to observe the size of the aneurysm every 6 months and to delay surgical intervention as long as possible given her advanced age. However, after 1 year, the patient was lost to follow-up and then was found in January 2009 to have an aortic aneurysm the size of 6 cm when she presented to an outside cardiologist as an outpatient. At that time, a cardiac catheterization was performed, which showed left main coronary artery disease, and she underwent aortic aneurysm repair and CABG surgery. After surgery, she had an episode of syncope and was found to have complete heart block. She subsequently underwent placement of a permanent pacemaker. Surgery for ascending aortic aneurysm is usually indicated for those that are greater than 5.5 cm; however, in patients with increased comorbidities (including old age), it is usually deferred until the size becomes greater than 6 cm.^4,5 Medical management for ascending aortic aneurysm includes control of systolic blood pressure. The goal should be to bring blood pressure down to a low-normal range (ie, a systolic pressure of 105-120 mm Hg).⁴ Patients should also be advised against strenuous isometric exercise such as heavy lifting or straining to avoid abrupt increase in intrathoracic pressure and blood pressure.⁴

At initial presentation to the medicine attending at the outpatient clinic in December 2005, the case patient’s lipid panel was normal, except for elevated high-density lipoprotein (HDL) cholesterol levels (Table). After counseling, she gradually stopped drinking alcohol, which was associated with a decrease in HDL cholesterol and increase in low-density lipoprotein (LDL) cholesterol levels. The patient was never started on treatment for her high LDL because of her age and high alcohol intake in the past. Several studies have shown that intensive statin therapy in older patients with coronary artery disease is beneficial^6-8; however, the safety of statins in chronic alcoholics is not clear. Onofrei et al⁹ suggested that statins show benefit in patients with chronic liver disease, including those with hepatitis C, cirrhosis, and liver transplants; however, there have been no randomized clinical trials to address this. After her CABG surgery, the case patient was started on ezetimibe/simvastatin by her cardiologist. Ezetimibe/simvastatin was approved by the FDA in 2004 after clinical trials showed it to be more efficacious than statin monotherapy in lowering lipid levels^10-13; however, there are several limitations to these trials. The maximum length of follow-up was 24 weeks, which might not have been long enough to show significant side effects. Also, the age range of the study populations was 18 to 79 years and did not differentiate patients based on preexisting liver disease. Since the approval of ezetimibe/simvastatin, there has been one published case report of fulminant liver failure from ezetimibe/simvastatin necessitating liver transplantation.¹⁴

The patient was a 70-year-old woman with a history of hypertension, hyperlipidemia, and myocardial infarction. She was started on ezetimibe/simvastatin 10 weeks prior to experiencing liver failure. Before switching to ezetimibe/simvastatin, she had been on a stable dose of simvastatin for 18 months. It was postulated that her age put her at an increased risk of liver failure.¹⁴ The case patient’s physicians thoroughly investigated all possible causes for her fulminant liver failure. Her viral hepatitis panel was negative and autoimmune causes of liver failure were ruled out. Liver biopsy was consistent with drug-induced liver failure. She was started on ezetimibe/simvastatin prior to liver failure, and there were no other new medications started. After stopping ezetimibe/simvastatin, she had complete recovery of her liver function, and remained asymptomatic 5 months after this episode. The case patient was 86 years old with recently documented coronary artery disease when she was started on ezetimibe/simvastatin. She also had a history of extensive alcohol intake, which likely contributed to her risk of liver injury. As patients age, the risks of liver injury must continue to be taken into account when selecting the best treatment for both hyperlipidemia and documented coronary artery disease. In this particular patient, an argument could be made for using a statin with close monitoring given her history of alcohol use. We suggest that further studies need to be undertaken in the very elderly to determine the most efficacious treatments of common chronic medical conditions while preserving function and preventing harm.

Acknowledgment

The authors would like to thank William H. Frishman, MD, for his guidance in this article. The authors report no relevant financial relationships. Dr. Shah is Internal Medicine Resident, and Dr. Eskridge is Assistant Professor of Medicine, Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla.

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