An Observational Study of Ezetimibe in Cardiac Transplant Recipients Receiving Calcineurin Inhibitors

Abstract

Background: Cardiac transplant patients are at risk for developing cardiac allograft vasculopathy, and dyslipidemia in this patient population has been associated with increased risk. Data evaluating the efficacy and safety of ezetimibe in this population are minimal. Objectives: The purpose of this study was to assess the effects of ezetimibe, alone or in combination with other lipid-lowering agents, in cardiac transplant recipients receiving calcineurin inhibitors (CNIs). Methods: This study was a single-center retrospective chart review. Data on demographics, medications prescribed for dyslipidemia and prevention of transplant rejection, results of lipid panels, CNI blood concentrations, and adverse effects were extracted from medical records of cardiac transplant recipients who were prescribed ezetimibe, either alone or in combination with other lipid-lowering agents, and seen at least once in a 12-month period at a cardiac transplantation clinic of an 800-bed teaching hospital. Results: There were 71 patients prescribed ezetimibe in whom a safety analysis was performed. Approximately 49% (n = 35) were included in the analysis for lipid lowering. Ezetimibe significantly decreased low-density lipoprotein cholesterol (LDL-C; 129 mg/dL vs 94 mg/dL, P < .0001), non–high-density lipoprotein cholesterol (non-HDL-C; 170 mg/dL vs 127.5 mg/dL, P = .0058), and total cholesterol (236 mg/dL vs 200 mg/dL, P < .0001). There was no significant change in HDL-C and triglycerides as compared with baseline. The proportion of patients achieving goal LDL-C < 100 mg/dL significantly increased from 11.5% at baseline to 60.5% after the addition of ezetimibe (P < .0001). Ezetimibe had no measurable effect on blood CNI concentrations or doses. Adverse effects were reported by 15.5% of patients (n = 11), with 4% (n = 3) of patients discontinuing therapy. The most common complaints were gastrointestinal intolerance and myalgia. Conclusions: Ezetimibe was associated with lower LDL-C in cardiac transplant recipients either as combination therapy in patients with elevated LDL-C or as monotherapy, with a low frequency of adverse effects.

Keywords

ezetimibe cardiac transplant statin safety dyslipidemia hyperlipidemia

Cardiac transplant patients are at risk for developing cardiac allograft vasculopathy (CAV), and dyslipidemia in this patient population has been associated with increased risk.^1-3 Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are recommended by the International Society for Heart and Lung Transplantation in all cardiac transplant recipients, regardless of cholesterol concentrations, to delay the onset of CAV.¹ The European Society of Cardiology (ESC) recommends statins as the first-line lipid-lowering therapy in all solid organ transplant patients.² Although a specific goal for low-density lipoprotein cholesterol (LDL-C) is not specified by either organization, both guidelines recommend conservative initial dosing of statins secondary to the increased risk of myopathy when coadministered with calcineurin inhibitors (CNIs).^1,2 Because many cardiac transplant centers target LDL-C concentrations of less than 100 mg/dL, as recommended by the Canadian Cardiovascular Society transplantation guidelines,³ the combination of ezetimibe, which reduces LDL-C by an additional 15% to 18% is a therapeutic option.⁴ Ezetimibe is recommended by the ESC as second-line lipid-lowering therapy in cardiac transplant patients with either statin intolerance or with elevated LDL-C while receiving maximally tolerated statin doses.²

Many statins are metabolized by CYP3A isoenzymes, as are CNIs, and coadministration may lead to increased statin concentrations and risk of myopathy (fluvastatin, pravastatin, rosuvastatin, and pitavastatin have less potential for interaction).^6,7 Both cyclosporine and tacrolimus, and many statins (and their metabolites) are also inhibitors of the hepatic organic anion transport protein 1B1 (OATPIBI), which may also account for observed increases in statin plasma concentrations.⁵ Coadministration of ezetimibe with cyclosporine has been reported to increase ezetimibe area under the curve up to 3-fold and cyclosporine exposure by 15%.^4,8 Ezetimibe product labeling cautions on an increased risk of myopathy when ezetimibe is coadministered with a statin.⁴ Currently, there are only 3 published clinical trials evaluating the effects ezetimibe in cardiac transplant recipients in a total of 117 patients: 1 retrospective observational study,⁹ 1 prospective observational study,¹⁰ and 1 randomized, placebo-controlled trial.¹¹ The purpose of our retrospective observational study was to assess the impact of ezetimibe on lipid levels and the frequency of adverse effects, alone or in combination with other lipid-lowering agents (statins, niacin, gemfibrozil, fenofibrate, bile acid resins, and fish oil), in cardiac transplant recipients receiving CNIs. Our study is the largest published report to date of ezetimibe safety in a cardiac transplant population.

Methods

Study Design

This study was a retrospective chart review, and the clinical research was determined to be exempt by our center’s Committee on Studies Involving Human Beings. Medical records of cardiac transplant patients were included in the study if they were prescribed ezetimibe, either alone or in combination with other lipid-lowering agents (statins, niacin, gemfibrozil, fenofibrate, bile acid resins, and fish oils) and evaluated at least once in a 12-month period at the cardiac transplantation clinic of an 800-bed teaching hospital and regional transplant referral center that performs more than 50 cardiac transplants per year. Patients may have been concurrently treated with nucleotide blocking agents, corticosteroids, and sirolimus during the study period. For patients taking sirolimus, doses remained unchanged during the study period. Data were included in the analysis for all included patients from the start of their clinic medical record and for at least 8 months following study inclusion.

Patient data were included in the efficacy analysis if they had baseline LDL-C blood concentrations recorded within 1 year prior to the start of ezetimibe and at least 1 additional LDL-C recorded between 4 weeks and 1 year following the start of ezetimibe with no change in lipid-lowering therapy between the 2 determinations. Patients were included in the safety analysis if they had received at least 1 dose of ezetimibe. The primary outcome of the study was the mean change in fasting LDL-C. Secondary outcomes included mean change in total cholesterol (TChol), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and percentage of patients achieving LDL-C <100 mg/dL following ezetimibe treatment. Secondary outcomes related to safety included the incidence of gastrointestinal complaints (defined as abdominal pain, nausea, vomiting, and diarrhea) requiring discontinuation of ezetimibe, myalgia (defined as muscle pain, weakness, or cramping with or without CK elevations of <10 times the upper limit of the normal range), myopathy (defined as symptoms of myalgia in combination with increased creatine kinase blood concentrations >10 times the upper limit of the normal range), liver toxicity (defined as transaminases greater than or equal to 3 times the upper limit of the normal range), and mean changes in blood trough concentrations or doses of CNI following ezetimibe treatment.

Statistical Analysis

Summary statistics are reported as number (percentage), range, mean ± standard deviation, or median (interquartile range) as appropriate. Mean change in LDL-C, TChol, TG, HDL-C, liver transaminases, and blood concentration and doses of CNIs were analyzed using the Student t test for paired data or the Wilcoxon rank sum test for nonparametric variables. The percentage of patients achieving LDL-C <100 mg/dL was analyzed using McNemar’s test. A P value of ≤.05 was considered statistically significant. Statistical analyses were performed using SPSS version 15.0 (SPSS Inc, Chicago, IL).

Results

Out of 541 patients in the transplant program, 71 (13% of the transplant population at our center) were prescribed ezetimibe and were assessed for adverse events, whereas 35 (6.5% of the transplant population at our center and 49.3% of patients prescribed ezetimibe) were included in the assessment of LDL-C lowering (Figure 1). Baseline patient characteristics are described in Table 1. The average age of the overall population was 61 years. Most patients were Caucasian, and two-thirds were male. The average time since transplant was 7.7 ± 5.1 years, and the mean duration of follow-up while receiving ezetimibe was 19.7 ± 13.1 months. The average daily dose of ezetimibe was 10.1 mg ± 2.6 (range = 5-30 mg/d). Of the patients assessed for LDL-C lowering, 25 were prescribed ezetimibe plus a statin with or without other lipid-lowering therapy, 8 patients were prescribed ezetimibe alone, and 2 patients were prescribed ezetimibe plus nonstatin lipid-lowering therapy. Average doses of statins prescribed during the study are shown in Table 2, with most patients receiving low- to medium-LDL-lowering doses. At the time of this study, the majority of patients were receiving cyclosporine as the CNI. Patients who were excluded from LDL-C assessment had similar baseline characteristics compared with those included in the assessment for adverse effects, with the exception of slightly higher baseline hepatic transaminases (Table 1).

Figure 1.

Study profile.

Table 1.

Patient Characteristics.

Variable	Overall Population (Safety Analysis Population), n = 71	Efficacy Analysis Population, n = 35	Patients Excluded From Efficacy Analysis, n = 36	P Value^a
Age (years)^b	61 ± 10 (31-79)	60.4 ± 10 (31-79)	61 ± 10 (41-77)	.66
Male, n (%)	47 (66)	23 (66)	24 (67)	.57
Caucasian, n (%)	62 (87)	32 (91)	30 (83)	.36
Years posttransplant^b	7.7 ± 5.1 (0-19)	7.1 ± 4.9 (1.1-18)	8.1 ± 5.2 (0-19)	.39
Weight (kg)^b	90 ± 20 (60.5-135)	87.3 ± 20 (61.8-135)	91.1 ± 21 (60.5-135)	.32
SCr (mg/dL)^b	1.73 ± 1 (0.6-7.1)	1.76 ± 1.02 (0.8-5.7)	1.69 ± 1.03 (0.6-7.1)	.76
ALT (U/L)^b	28 ± 13 (4-160)	27 ± 10 (10-57)	39 ± 29 (4-160)	.03
AST (U/L)^b	33 ± 23 (15-102)	25 ± 7 (15-46)	31 ± 16 (15-102)	.03
Cyclosporine, n (%)	43 (61)	19 (54)	24 (67)	.53
Tacrolimus, n (%)	25 (35)	14 (40)	11 (31)	.53
Cyclosporine level (ng/mL)^b	99 ± 52 (2.2-332)	107 ± 64 (55-332)	93 ± 40.8 (2.2-212)	.44
Tacrolimus level (ng/mL)^b	9.02 ± 3.1 (5-18.1)	9.1 ± 2.6 (5-13.9)	8.9 ± 3.8 (5.8-18.1)	.85
Sirolimus level (ng/mL)^b	9.1 ± 4.4 (4.8-13.6)	6.85 ± 2.9 (4.8-8.9)	13.6 (13.6)	.31
Cardiac allograft vasculopathy,^c n (%)	13 (18)	5 (14)	8 (22)	.29
Hypertension, n (%)	63 (89)	30 (86)	33 (92)	.34
Diabetes mellitus, n (%)	25 (35)	12 (34)	13 (36)	.54
Chronic renal insufficiency, n (%)	11 (15)	7 (10)	4 (11)	.24
Posttransplant heart failure, n (%)	11 (15)	4 (11)	7 (19)	.27
Ezetimibe dose (mg)^b	10.1 ± 2.6 (5-30)	9.7 ± 1.18 (5-10)	10.4 ± 3.46 (5-30)	.25
Follow-up (months)^b	19.7 ± 13.1 (0.7-44.7)	18.3 ± 11.6 (1-44.7)	20.1 ± 14.5 (0.7-44)	.40

P Values pertain to the comparison between the overall population and efficacy analysis population.

Values are mean ± SD (range).

As described in the patient medical record from either dobutamine stress testing or coronary angiography.

Table 2.

Prescribed Statins and Dosing.^a

Statin	Dose (mg): Overall Population; Safety Analysis Population (n = 50)	Dose (mg): Efficacy Analysis Population (n = 25)	Dose (mg): Population Excluded From Efficacy Analysis (n = 25)
Atorvastatin (n = 14)	32.9 ± 18.2	31 ± 22.1	36 ± 8.9
Fluvastatin (n = 1)	80	80	–
Pravastatin (n = 26)	35.8 ± 15.3	36.2 ± 12.6	35.5 ± 18.6
Rosuvastatin (n = 3)	13.3 ± 5.8	10^b	15 ± 7.1
Simvastatin (n = 6)	17.1 ± 11.1	10^b	18.3 ± 11.7

All values are mean ± SD (range).

Only one patient in this group

Ezetimibe was associated with significantly reduced LDL-C (129 mg/dL vs 94mg/dL, P < .0001), non-HDL-C (170 mg/dL vs 127.5 mg/dL, P = .0058), and TChol (236 mg/dL vs 200 mg/dL, P < .0001; Table 3). There was no significant difference in HDL-C compared with baseline. There was also no significant difference in TG. (There were 2 patients with very high TG of ≥600 mg/dL at baseline who were excluded from the analysis). The proportion of patients achieving a goal LDL of <100 mg/dL significantly increased from 11.5% at baseline to 60.5% following the addition of ezetimibe (P < .0001).

Table 3.

Effect of Ezetimibe on the Lipid Panel.

	n	Baseline	Follow-up	P Value
LDL-C	35	129 ± 42	94 ± 31	<.0001
TChol (mg/dL)^a	35	236 ± 72	200 ± 66	<.0001
Non-HDL-C (mg/dL)^b	35	170 ± 47	128 ± 35	.0058
HDL-C (mg/dL)^b	35	50 ± 12	54 ± 14	.22
TG (mg/dL)^a	35	242 ± 105	207 ± 105	.03
TG (mg/dL)^c	33	216 ± 92	208 ± 105	.07

Values are mean ± SD.

Values are median ± SD.

Analysis performed excluding 2 patients with TG ≥600 mg/dL.

Abbreviations: LDL-C, low-density lipoprotein cholesterol; TChol, total cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Ezetimibe had no measureable effect on blood CNI concentrations or doses (Table 4).

Table 4.

Effect of Ezetimibe on Calcineurin Inhibitor Dose and Blood Concentrations.^a

	n	Baseline	Follow-up	P Value
Tacrolimus concentration (ng/mL)	10	9.1 ± 3	7 ± 2.5	.11
Tacrolimus dose (mg/d)	10	4 ± 1.5	3.8 ± 1.9	.34
Cyclosporine concentration (ng/mL)	8	101 ± 34	106 ± 53	.73
Cyclosporine dose (mg/d)	8	206 ± 58	213 ± 64	.48

All values are mean ± SD.

Of the 71 patients assessed for adverse effects, 11 patients (15.5%) reported that they were present; 3 of these patients discontinued ezetimibe because of adverse effects (Table 5). The most common complaints were gastrointestinal intolerance and myalgia (occurring in 5.8% and 4.2% of patients, respectively). There was 1 report of myopathy with concurrent statin use where ezetimibe and the statin were temporarily stopped but eventually restarted.

Table 5.

Adverse Events Reported During Ezetimibe Treatment (N = 71).

Event	Percentage of Patients (n)	Comments
Gastrointestinal
Diarrhea	2.8 (2)	Both patients had reported prior diarrhea associated with mycophenolate
Abdominal pain/cramping	2.8 (2)	One patient discontinued ezetimibe, the other patient was receiving 30 mg (exceeds maximum recommended dose of 10 mg)—dose reduced
Elevated liver transaminases >3× ULN (normal = 35 IU/L)	2.8 (2)	Both patients were also receiving statins
Myalgia	5.6 (4)	For 3 patients ezetimibe was held back and then restarted after pain persisted despite its discontinuation; 1 patient (CK = 324) was receiving ezetimibe monotherapy; ezetimibe was permanently discontinued
Myopathy	1.4 (1)	One patient (CK = 1254) was also receiving a statin; ezetimibe was discontinued and then restarted when symptoms persisted despite its discontinuation

Abbreviations: ULN, upper limit of the normal range; CK, creatinine kinase.

Discussion

Our study has shown that ezetimibe is associated with lower LDL-C and a low frequency of side effects in cardiac transplant recipients. Our results demonstrated a 27% reduction in LDL-C compared with baseline. Our institutional goal LDL-C reflects that established by the Canadian Cardiovascular Society guidelines for the treatment of dyslipidemia in cardiac transplant patients (LDL-C < 100 mg/dL).³ Ezetimibe use in our population was associated with a 6-fold increase in the number of patients achieving this goal. The results of our study are similar to those seen in a study by Shaw et al,¹¹ the only randomized, controlled trial published to date, of 59 cardiac transplant recipients receiving cyclosporine. In their 6-month study, ezetimibe reduced LDL-C by approximately 26%, as compared with placebo. Tolerability was the same between both groups, and no patient receiving ezetimibe withdrew from the study because of myalgias. As in our study, ezetimibe had no effect on blood concentrations of cyclosporine or dose.¹¹ Our results also resemble those seen in 2 previously published observational studies, 3 months and 12 months in duration, showing improvements in patient lipid profiles, with minimal occurrence of adverse effects when used as monotherapy for the management of dyslipidemia or in combination with other lipid-lowering agents in cardiac transplant recipients.^9,10 In comparison, our study extends safety follow-up to more than 18 months. Data on the use of ezetimibe in other types of transplant recipients, mainly renal transplant patients, also suggest that the combination of ezetimibe and statins is safe.^12-18

Our study also evaluates the effects of ezetimibe on tacrolimus blood concentrations. In the 10 patients with stable tacrolimus dose information noted for consecutive blood concentrations, we did not observe any changes following the addition of ezetimibe. Although this information is reassuring, further pharmacokinetic studies are necessary to confirm this finding. Although sirolimus can increase LDL-C, TC, and TGs, we included 3 patients who were receiving sirolimus throughout the study period because they were receiving stable sirolimus doses.¹⁹

The impact of statins on CAV is most likely mediated by a variety of factors, including lipids, inflammation, and immune-mediated effects. Although statins have been shown to affect each of these pathways, it is unknown whether lipid lowering alone with ezetimibe will have the same beneficial effects as statins in preventing CAV. Nonetheless, these patients should receive added measures for lipid-lowering because of a high incidence of dyslipidemia in this patient population and the propensity for CNIs to worsen this common comorbidity.

Limitations of this study are that it is an observational study, and patients were not randomized to ezetimibe or placebo. In addition, it was a retrospective chart review, which may underestimate safety because we relied on clinicians to document adverse drug events in the patient’s medical record. We did not have access to baseline lipid panels prior to any lipid-lowering medications being started and immediately prior to ezetimibe initiation for all patients. Long-term outcomes, including CAV and malignancy, were not assessed.

Ezetimibe was associated with lower LDL-C in cardiac transplant recipients either as combination therapy or as monotherapy in patients who are intolerant of a statin. Future work should evaluate the addition of ezetimibe to a statin or ezetimibe monotherapy in patients with CAV and rejection.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Costanzo

Dipchand

Starling

. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29:914-956.

European Association for Cardiovascular Prevention and Rehabilitation; Reiner

Catapano

De Backer

. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818.

Ross

Hendry

Dipchand

. 2001 Canadian Cardiovascular Society consensus conference on cardiac transplantation. Can J Cardiol. 2003;19:620-654.

Zetia (ezetimibe) [product information]. Whitehouse Station, NJ: Merck & Co, Inc; 2012.

Kallioski

Niemi

. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693-705.

Staatz

Goodman

Tett

. Effect of CYP3A and ABCB1 single nucleoside polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet. 2010;49:141-175.

Page

Miller

Lindenfeld

. Drug therapy in the heart transplant recipient part IV: drug–drug interactions. Circulation. 2005;111:230-239.

Bergman

Burke

Larson

. Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects. J Clin Pharmacol. 2006;46:321-327.

V-V

Racine

Pelletier

Carrier

Cossette

White

. Impact of ezetimibe on cholesterol subfractions in dyslipidemia cardiac transplant recipients receiving statin therapy. Clin Transplant. 2009;23:249-255.

10.

Crespo-Leiro

Paniagua

Marzoa

. The efficacy and safety of ezetimibe for treatment of dyslipidemia after heart transplantation. Transplant Proc. 2008;40:3060-3062.

11.

Shaw

Chaggar

Ritchie

. The efficacy and tolerability of ezetimibe in cardiac transplant recipients taking cyclosporine. Transplantation. 2009;87:771-775.

12.

Puthenparumpil

Keough-Ryan

Kiberd

Lawen

Kiberd

. Treatment of hypercholesterolemia with ezetimibe in the kidney transplant population. Transplant Proc. 2005;37:1033-1035.

13.

Langone

Chuang

. Ezetimibe in renal transplant patients with hyperlipidemia resistant to HMG-CoA reductase inhibitors. Transplantation. 2006;81:804-807.

14.

Panichi

Manca-Rizza

Paoletti

. Safety and effects on the lipid and C-reactive protein plasma concentration of the association of ezetimibe plus atorvastatin in renal transplant patients treated by cyclosporine-A: a pilot study. Biomed Pharmacother. 2006;60:249-252.

15.

Buchanan

Smith

Corbett

Nelson

Shihab

. A retrospective analysis of ezetimibe treatment in renal transplant recipients. Am J Transplant. 2006;6:770-774.

16.

Kohnle

Pietruck

Kribben

Philipp

Heemann

Witzke

. Ezetimibe for the treatment of uncontrolled hypercholesterolemia in patients with high-dose statin therapy after renal transplantation. Am J Transplant. 2006;6:205-208.

17.

Almutairi

Peterson

Molinari

Walsh

Alwayn

Peltekian

. Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia. Liver Transpl. 2009;15:504-508.

18.

Kastelein

Akdim

Stroes

. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.

19.

Morrisett

Abdel-Fattah

Hoogeveen

. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. 2002;43:1170-1180.