The American Journal of Geriatric Pharmacotherapy 2] Pearson et al.

Effectiveness of the Addition of Ezetimibe to Ongoing Statin Therapy in Modifying Lipid Profiles and Attaining Low-Density Lipoprotein Cholesterol Goals in Older and Elderly Patients: Subanalyses of Data from a Randomized, Double-Blind, Placebo-Controlled Trial

Thomas Pearson, MD, MPH, PhDI; Margo Denke, MD2; Patrick McBride, MD, MPH3; Wendy P. Battisti, PhD4;William E. Brady, MS4; and Joanne Palmisano, MD 4

I University of Rochester School of Medicine and Dentistry;, Rochester, New Yorg' 2University of Texas Health Science Center in San Antonio, Kerrviffe, Texas; 3University of Wisconsin Medical School, Madison, Wisconsin; and 4Merck & Co., Inc., West Point, Pennsylvania

ABSTRACT Background: The Ezetimibe Add on to Statin for Effectiveness (EASE) trial examined the effectiveness and safety

profile of ezetimibe (EZE) added to ongoing statin therapy in 3030 patients with low-density lipoprotein choles- terol (LDL C) levels exceeding National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) goals.

Objective: Because people aged >65 years are at increased risk for development o f coronary heart disease (CHD), these subgroup analyses of data from the EASE trial were conducted to determine the extent of change in LDL C levels and attainment o f N C E P ATP III LDL C goals with the addition o f EZE to ongoing statin therapy in patients aged 65 to 74 years (the older group) and ~75 years (the elderly group).

Methods: In the multicenter (299 sites), community based, double blind, placebo controlled EASE trial, patients were randomly assigned in a 2:1 ratio to receive EZE 10 m g / d or placebo in addition to their ongoing statin ther apy for 6 weeks. The primary efficacy end point was the percent reduction in LDL-C levels, and the principal sec- ondary end point was the proportion of patients achieving NCEP ATP III target LDL C levels. The effects o f the addition o f EZE on additional lipid and lipoprotein measures and high sensitivity C reactive protein were also exam ined, as was tolerability. Study analyses were performed in the modified intent-to-treat population.

Results: This subgroup analysis included data from 841 patients in the older age group (579 EZE + statin, 262 placebo + statin), which constituted 27.8% of the overall EASE population, and 466 in the elderly group (307 EZE + statin, 159 placebo + statin), which constituted 15.4% of the overall EASE population. The former group included 436 (51.8%) men and 405 (48.2%) women, with a mean (SD) age of 69.2 (3.0) years; the latter group included 227 (48.7%) men and 239 (51.3 %) women, with a mean age o f 78.5 (3.2) years. The characteristics of the 2 groups were comparable at baseline. In the older group, 7 1 7 (85.3%) had CH D or a CH D risk equivalent, as did 421 (90.3%) of those in the elderly group. Thirty two patients in the older group and 17 in the elderly group dis continued the study. The reasons for discontinuation included clinical adverse events (n - 23), withdrawal of con sent (n - 15), loss to follow-up (n - 4), protocol deviation (n - 2), and other reasons (n - 5). EZE + statin signifi- cantly reduced LDL C compared with placebo + statin (older group: mean [SE] treatment difference, 25.1% [1.4]; P < 0.001; elderly group: treatment difference, 22.0% [ 1.8]; P < 0.001). The LDL C-lowering effects of treatment were consistent in the 2 groups. EZE + statin therapy significantly improved other lipid parameters (triglycerides,

Some of the data herein were presented in oral form at the 2004 Annual Scientific Session of the American College of Cardiology March 7-10, 2004, New Orleans, Louisiana, and in poster form at the 17th World Conference of Family Doctors, October 13-17, 2_004, Orlando, Florida.

Accepted for publication September 30, 2005. doi: I0. I016Ij.amjopharm 2005 12.009 Printed in the USA. Reproduction in whole or part is not permitted 1543-5946/05/$1900

218 December2005 Volume ] • Number 4 Copyright © 2005 Excerpta Nedica Inc

T Pearson et al. The American Journal of Geriatric Pharmacotherapy

n o , h i g h density lipoprotein cholesterol, and total cho lesterol, P < 0.001 in both age groups; high density lipo protein cholesterol, P < 0.03 in the older group only) and high sensitivity C reactive protein levels compared with EZE + placebo (P < 0.03). The attainment o f LDL-C goals also was significantly increased with EZE + statin compared with placebo + statin (older group: 72.3% vs 18.9%, respectively; odds ratio [OR] - 14.59; 95% CI, 9.55 to 22.28; P < 0.001; elderly group: 73.3% vs 18.9%; OR - 13.44; 95% CI, 7.72 to 23.41; P < 0.001). EZE + statin therapy was well tol erated by patients in both age groups, with a safety pro- Ne comparable to that of placebo + statin.

Conclusions: In these older and elderly patients, many o f them at high risk for CHD, EZE added to ongoing statin therapy was well tolerated and was an effective treatment option for improving lipid profiles and attainment of LDL-C goals. Adding EZE im- proved rates of attainment of NCEP ATP III LDL C goals without increases in the dose or potency ofstat in therapy. Further studies are necessary to determine whether these results can be generalized to other older and elderly populations. (A m ] Geriatr Pharmaco ther. 2005 ;3 :218 -228 ) Copyright © 2005 Excerpta Medica, Inc.

Key words: statin, combination therapy, elderly, sim vastatin, ezetimibe.

I N T R O D U C T I O N Advancing age is a known risk factor for coronary heart disease (CHD). Approximately 85% of patients who die of C HD are aged a65 years. <2 Numerous studies have indicated that treating hypercholesterolemia with a statin decreases cardiovascular morbidity and mortality, 34 indud ing in the older population (those aged a65 years).<~m However, these patients remain undertreated, ll Older patients with hypercholesterolemia are more likely to have CHD, a C HD risk equivalent, or other multiple risk factors, and may require more aggressive treatment. However, physicians are often hesitant to use higher or more potent doses of statins in this population./; Older patients are at increased risk for adverse drug effects due to changes in metabolism, age related declines in hepatic and renal function, comorbidities, and polypharmacy, with the accompanying risk for drug interactions. These factors increase the challenge of achieving low density lipoprotein cholesterol (LDL-C) goals in older patients using statin therapy alone.

Although statins are well tolerated, 13,14 increasing age and cardiovascular risk appear to be inversely cor-

related with the aggressiveness ofstatin therapy, as illus trated by the results o f a retrospective cohort study including 396,077 patients aged ~66 years who had a history of cardiovascular disease or diabetes. 12 Only 75,617 (19.1%) patients were prescribed statins. The probability of the prescription of statins was 6.4% lower for each 1 year increase in age and each 1% increase in predicted 3 year mortality risk. Clinicians may have concerns about titration to higher statin doses to achieve aggressive LDL C targets in high risk older patients due to the increased potential for adverse events, 1<16 particularly given the number of concomi- tant medications prescribed for comorbid conditions. Therapies that address these concerns and enhance lipid management are needed to improve clinical out- comes in older patients. There is a limited amount of information regarding the efficacy of lipid lowering therapies in older patients, particularly those aged ~75 years. Thus, it is important to establish the efficacy and tolerability of lipid modifying therapies that can be used in combination with statins in older patients.

The Ezetimibe Add on to Statin for Effectiveness 17 (EASE) trial was a multicenter, community practice based, placebo-controlled study that enrolled 3030 hypercholesterolemic patients who were using a statin but had not achieved their National Cholesterol Education Program Adult Treatment Panel I l l (NCEP ATP III) LDL C goal. 18 The present subgroup analy ses of data from the EASE trial were conducted to determine the extent of change in LDL-C levels and attainment of NCEP ATP III LDL C goals with the addition of ezetimibe (EZE) to ongoing statin therapy in patients aged 65 to 74 years (the older group) and a75 years (the elderly group). The tolerability of the addition of EZE was also examined.

P A T I E N T S A N D M E T H O D S T h e EASE Trial

The design and primary results o f the multicenter, randomized, double blind, placebo controlled, parallel group EASE trial have been described elsewhereJ 7 In brief, patients were recruited from 299 community- based practices across the United States from January 2003 to August 2003. Eligible patients were aged >18 years, were following a cholesterol-lowering diet and had been using a stable approved close of any statin for at least 6 weeks before study entry, and met all key inclusion criteria. At screening, plasma LDL-C levels on statin therapy were required to exceed the LDL C goal, as determined based on patients' NCEP ATP III risk category (Table I). 18 Screening fasting triglyceride

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The American Journal of Geriatric Pharmacoth~rapy T Pearson et al.

Table I. National Cholesterol Education Program Adult Treatment Panel III goals for low-density l ipopro- tein cholesterol (LDL-C). Is

Risk Category LDL C Goal

CHD or CHD risk equivalent (10 year risk >20%) < 100 mg/dL ~_2 CHD risk factors (10~ear risk ~20~) < 130 mg/dL 0 I CHD risk factor (l O-year risk < 10%) < 160 mg/dL

CHD - coronary heart disease

(TG) levels had to be ~350 m g / d L to allow calculation of LDL C. Patients were excluded from the study if they had alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine kinase (CK) levels >1.5 times the upper limit of normal (ULN) or had impaired renal function (creatinine ~2.0 mg /dL) .

The study included a screening phase 1 week before the baseline visit and a 6 week treatment phase. At visit 2 (week 0), patients were allocated via a computer- generated randomization schedule (employing an interac tive voice response system) in a 2:1 ratio to receive either EZE 10 m g / d or placebo in addition to their current statin therapy. EZE or placebo was taken at the same time of day as the continued statin therapy. The statin type and dose were to be maintained throughout the study.

Blood specimens were collected at visit 1 (eligibility), visit 2 (blinded baseline lipid measures), and visit 3 (blinded final lipid measures). Investigators were not blinded to laboratory safety results. Safety evaluations included physical examinations, measurement of vital signs, monitoring for adverse experiences, and routine laboratory evaluations, including serum ALT, AST, and CIC Patients could be withdrawn from the study for persistent elevations (at 2 consecutive measurements) in ALT or AST >3 times the ULN, a single CK level a l 0 times the ULN with muscle symptoms or persistent unexplained CK elevations a20 times the ULN without muscle symptoms, or any other serious adverse event.

Medical Research Laboratories (Highland Heights, Kentucky), which is certified by the National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention, performed the clinical labora tory analyses. Plasma total cholesterol (TC) and TG lev- els were determined using enzymatic methods. High density lipoprotein cholesterol (HDL C) was measured after precipitation of apolipoprotein B-containing lipoproteins (low density lipoprotein and very low den sity lipoprotein) in whole plasma by heparin manganese chloride. LDL-C was calculated using the Friedewald

equation: LDL C - TC ( H D L C + T G / 5 ) . High sensitivity C reactive protein (hs CRP) was measured by the immunonephelometric method.

Patients' compliance with double blind study medi cation was assessed using data collected on the study therapy case report form. Compliance was calculated by dividing the number o f tablets taken (determined by pill count) by the number of tablets that should have been taken and multiplying by 100.

Study Design The present subgroup analyses were based on efficacy

and tolerability data from older (age 65 74 years) and elderly (age :-75 years) patients in the EASE trial. The primary objective was to assess the effectiveness in low- ering LDL C levels of adding EZE 10 m g / d to current statin therapy compared with adding placebo. The main secondary objective was to assess changes in LDL-C goal attainment. The effects of the addition o f EZE 10 m g / d on additional lipid and lipoprotein measures and hs-CRP were also examined, as was tolerability.

Statistical Analysis Based on previous data, 19 it was determined that a

sample size o f 235 patients in each age group was nec essay to detect a 9% difference between treatment groups with 99% power at an c~ of 0.05 (2-sided).

Analyses were performed in the modified intent to treat population. For the effectiveness analyses, this included all randomized patients with a baseline assess- ment of the variables of interest and at least 1 valid postbaseline assessment. The safety analyses included all randomized patients who received at least i dose of double blind study medication. Laboratory safety analyses included all treated patients with at least 1 postbaseline laboratory assessment.

The percentage changes from baseline after 6 weeks of treatment were analyzed for LDL C (prespecified) and other lipid measures, including HDL-C, TG, TC, and non H D L C, using an analysis o f variance (ANOVA) model with terms for treatment, NCEP ATP III risk category, and percentage above the LDL-C goal at screening (<8%, ~8% to <18%, ~18% to <30%, or >30%), age subgroup, and interaction between treat ment and subgroup. The results are presented as means, with the exception o f the results for TG, which are presented as medians and for which the ANOVA model was analyzed using normal-scores rank transfor- mations of the percent change from baseline.

The proportions of patients reaching their NCEP ATP III LDL-C goal after 6 weeks of treatment were

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2] Pearson et al. The American ]ou~aal of Geriatric Pharmacotherapy

analyzed using a logistic regression mode l with terms similar to those described for the A N O V A model . Because L D L - C levels were calculated at screening for de te rmina t ion o f eligibility and baseline L D L C levels were calculated at r andomiza t ion 1 week later, it was possible for a pat ient to be at goal at baseline. The pres- ent analyses were restricted to patients who were no t at goal at baseline.

A pos t hoc analysis o f hs -CRP was p e r f o r m e d on archived se rum samples f rom 2479 patients for w h o m both a valid baseline value and 1 postbasel ine value were available. Because the distr ibution o f hs -CRP measurements was skewed, the previously described A N O V A model was analyzed using rank t ransformed values (with Tukey normal scores). The results are pre- sented as medians and 95% CIs.

RESULTS A total o f 5802 patients were screened for the EASE study; 2 7 7 2 were excluded, the majori ty (73%) because

they were found to be at their N C E P ATP I I I target L D L C level. The remain ing 3030 eligible patients were r andomized to receive E Z E 10 m g / d (n - 2020) or placebo (n - 1010) in addit ion to their current statin t rea tment . This popula t ion included the 841 older patients (579 E Z E + statin, 262 placebo + statin) and 466 elderly patients (307 E Z E + statin, 159 placebo + statin) included in the present repor t . Thi r ty two pa tients in the older g roup discont inued the study, as did 17 in the elderly group. T h e reasons for discontin nat ion included clinical adverse events (n - 23) , with drawal o f consent (n - 15), loss to fol low-up (n - 4) , p ro tocol deviat ion (n - 2), and other reasons (n - 5).

Pat ient Character ist ics T h e older age g roup included 436 (51.8%) men and

405 (48.2%) women , with a mean (SD) age o f 6 9 . 2

(3.0) years; the elderly group included 2 2 7 (48.7%) men and 239 (51.3%) women , with a mean age o f 78.5 (3.2) years (Table I I ) . The characteristics o f the treat

Table II. Baseline characteristics of older (age 65-74 years) and elderly (age >75 years) patients in the Ezetimibe Add-on to Statin for Effectiveness trial.

Age 6~74 Years Age :-75 Years

EZE + Statin Pbo + St~tin EZE + Statin Pbo + St~tin (n 579) (n 262) (n 307) (n 159)

Sex, no. (%) Hale 303 (52.3) 133 (50.8) 147 (47.9) 80 @03) Female 276 (47i~) 129 (~ 9 i~) 160 (5)iI) 79 (497)

White 492 (8510) ] ] 5 (8519) 261 (85.0) 137 (862) Black 46 ~ i9) ~0 (~i6) 16 (52) 6 (38) Hispanic 22 (3.8) 12 (4.6) 12 (39) 9 (57) Other 19 (313) 5 (I I9) 18 (59) 7 (44)

Characteristics of metabolic syndromel t noi (~) Waist circumference >102 cm men, >88 cm women 353 (61.0) 160 (6 I. I) 172 (56.0) 96 (604) TG >150 mgldL 313 (54.1) 142 (54.2) 143 (46.6) 81 (509) HDL C <40 rn2/dL men, <50 mg/dL women 189 (32.6) 85 (32.4) 97 (31.6) 38 (239) Hypertension (SBP >160 mm Hg or DBP >100 mm Hg) 535 (92.4) 249 (95.0) 295 (96. I) 153 (962) Diabetes/FG >110 rag/alL 273 (47.2) 121 (46.2) 134 (43.6) 70 (440) >3 of above characteristics 343 (59.2) 164 (62.6) 179 (58.3) 90 (566)

Waist circumference, mean (SD) blale I 0511 (1217) 13018 (I IiI) IOIi7 (I I/6) I023 (115) Female 97.4 (14.6) 98ii (16.1) 9316 (12.8) 963 (139)

EZE - ezetimibe; Pbo - placebo; TG - triglycerides; HDL-C - high-dens~ lipoprotein cholesterol; SBP sure; FG - fasting glucose *Percentages may exceed 100 due to rounding tAccording to N~ional Eduction Program Adult Treatment Panel III guidelines 18

- systolic blood pressure; DBP - diastolic blood pres-

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The American Journal of Geriatric Pharmacoth~rapy T Pearson et al.

ment groups within each age category were compara ble at baseline. Hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg) was prevalent in both age groups (older group, 73.1%; elderly group, 79.6%). Other diagnoses secondary to hypercholesterolemia were present in 98.8% (n - 833) of the older group and 99.8% (n - 464) of the elderly group. Key secondary diagnoses included vascular dis orders, primarily hypertension (older group, 77.8%; elderly group, 85.2%); musculoskeletal disorders (55.3% and 64.2%, respectively); cardiac disorders (43.9% and 50.4%); gastrointestinal disorders (45.8% and 44.0%); metabolic disorders (29.3% and 27.9%); endocrine dis orders (15.7% and 18.2%); and renal and urinary tract disorders (15.0% and 20.0%). Three or more character- istics of the metabolic syndrome were present in -59% of these patients. Previous and concomitant drug use (other than statins) was comparable between treatment groups within each age group (data not shown).

The percentage of patients at high risk for CHD increased with increasing age ( f igure 1). Among older patients, 7 1 7 (85.3%) had a diagnosis of CHD or an NCEP ATP III risk equivalent for CHD, compared with 421 (90.3%) elderly patients. None of the elderly patients were in the lowest risk category (<2 risk fac tors). Of patients with CHD or a CHD risk equivalent, 230 (32.1%) in the older group and 120 (28.5%) in the

elderly group exceeded their NCEP ATP III LDL C goal by :-30% at baseline.

Patients' lipid-lowering medications induded all mar- keted types and doses ofstatins available at the time of the EASE trial (Table III). (Rosuvastatin was not yet mar keted.) The distribution of statins and doses was similar between the 2 treatment groups. Usage was 37.6% ator vastatin, 29.4% simvastatin, 20.4% pravastafin, 6.9% lova statin, and 5.3% fluvastafin.

Median baseline hs CRP levels were 2.4 m g / L in older patients and 1.9 m g / L in elderly patients. Median baseline hs-CRP levels >3 m g / L occurred in 290 of 688 (42.2%) older patients and 125 of 377

(33 .2%) elderly patients. Overall, compliance was >95% in 92.9% of patients

receiving EZE and 91.6% in patients receiving placebo.

Effectiveness The addition of EZE to ongoing statin treatment

significantly reduced LDL C from baseline by >26% in both age groups (P < 0.001) (Table IV), resulting in a 22% to 25% reduction in LDL C compared with the ad dition of placebo to ongoing statin therapy. Treatment effects were consistent in the 2 age groups (Figure 2). EZE + statin therapy also significantly improved other lipid parameters (TG, n o ~ H D L C, and TC, P < 0.001 in both age groups; HDL-C, P < 0.03 in the elderly

~6 a~

[ ] CHD or CHD risk equivalent • :-2 CHD risk factors • <2 CHD risk factors

40

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60. I

45-54

65.2

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75.0

21.2

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55-64

90.3 85.3

13.1

I I . 7 8.8 I 0 . 9

I 65-74 ~75

Age Group (y)

Distr ibut ion of National Cholesterol Education Program Adu l t Treatment Panel III coronary heart disease risk categories, by age. (Groups aged <65 years are presented for comparison only.) CHD = coronary heart disease.

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2: Pearson et al. The American Journal of Geriatric Pharmacotherapy

Table III. Particular statins and doses used at baseline, by no. (%) of older (age 65-74 years) and elderly (age >75 years) patients.

Age 65-74 Years Age ~75 Years

Statin and EZE + Statin Pbo + Statin EZE + Statin Pbo + Statin Dose, mg (n 575*) (n 262) (n 305") (n 159)

Ato rvastatJ n i0 73 (,27) 32 (,~2) 42 (,38) 25 (,57) 20 61 (106) 30(115) 34 (11 I) 16 (101) 40 46 (80) 27 (103) 28 (9.2) 14 (8.8) 80 34 (59) 15 (5.7) II (3.6) 3 (I.9)

F luvastati nl- 20 4 (07} 2 (0.8) 2 (0.7) 0 (0) 40 7 (I 2) 5 (I .9) 2 (0.7) 3 (I .9) 80 20 (35) 6 (2.3) 16 (5.2) 2 (I.3)

Lovastati n I0 6 (I O) 2 (0.8) 6 (2.0) I (0.6) 20 12 (21) 7 (2.7) 8 (2.6) 4 (2.5) 40 15 (26) 4 (I.5) I0 (3.3) 8 (5.0) 80 s (09) i (0.4) 0 (0) i (0.6)

P ravastati n i o 3 (o5) 2 (0.8) i (0.3) o (o) 20 38 (66) 12 (4.6) 32 (105) I0 (6.3) 40 63 (I 10) 33 (126) 23 (7.5) 16 (10 I) 80 17 (30) 8 (3.1) 6 (2.0) 3 (I.9)

S imvastatin 10 I B (23) 5 (I.9) 10 (B.B) 3 (I.9) 20 52 (90) 33 (126) 28 (9.2) 16 (10 I) 40 84 (,46) 25 (9.5) 28 (9.2) 2B (,45) 80 22 (38) 13 (5.0) 18 (5.9) II (6.9)

EZE - ezetimibe; Pbo - placebo *Four patients in the older group and 2 in the elderly group did not take statins during the study -'No patients were using fluvastatin I 0 or 160 mg.

group only) and hs CRP levels compared with EZE + placebo (P < 0.03) (Table IV).

In those patients not at their NCEP ATP III LDL C goal at baseline, EZE + statin therapy significantly increased attainment of LDL-C goals compared with placebo + statin (older group: 72.3% vs 18.9%, respec tively; odds ratio [OR] - 14.59; 95% CI, 9.55 to 22.28; P < 0.001; elderly group: 73.3% vs 18.9%; Oil, - 13.44; 95% CI, 7.72 to 23.41; P< 0.001) (Figure 3).

Safety and Tolerability The addition of EZE to ongoing statin therapy was

generally well tolerated, with an overall safety profile similar to that o f placebo added to statin therapy. There

were no serious drug related adverse events. Discon tinuations due to drug-related adverse events occurred in 1% of EZE recipients in both the older and elderly groups, compared with 2% and 1%, respectively, in those who received placebo. The blinded investigators consid- ered few adverse events to be drug related, and the inci dence of drug related adverse events was comparable for EZE + statin and placebo + statin redpients within each age group (-5% for each group and treatment). No spe dfic clinical adverse event, regardless of its relationship to study drug, was detected in >2% of older or elderly EZE + statin recipients.

The most frequently occurring gastrointestinal dlsor ders reported as drug related in the older group were

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The American Journal of Geriatric Pharmacoth~rapy 27 Pearson et al.

Table IV. Changes from baseline and percent changes from baseline in lipid measures and high-sensitivity C-reactive protein (hs-CRP) levels in older (age 65-74 years) and elderly (age >75 years) patients.

Age 65 74Years Age >75Years

EZE + Statin Pbo + Statin EZE + Statin Pbo + Statin

Lipid measures No. of patients 561 252 297 152

LDL-C, mg/dL Baseline 1243 1234 1219 122. I At 6 wk 920 1215 903 I 16.6 % Change -262 - I I -265 -4.5 Difference between treatments, mean (SE) 25. I (14)* 220 (I .8)*

Triglycerides, mg/dL Baseline 152.0 1560 144.0 144.0 At 6 wk 132.0 1500 124.0 151.0 % Change -12.6 - 4 4 -13.2 -1.4 Difference between treatments, median (95% CI) ~ 6 @114 to ~ . 8 ) * 122 @17.6 to ~ . 0 ) *

HDL C, rng/dL Baseline 49.2 499 49.6 50.9 At 6 wk 49.8 496 50. I 50.2 % Change 1.3 02 1.5 -1.5 Difference between treatments, mean (SE) I I (09) 29 (I.2)t

Non-HDL C, mg/dL Baseline 157.5 1579 154.2 153.3 At 6 wk 121.1 1542 118.1 148.2 % Change -23.7 -23 -24.2 -3.7 Difference between treatments, mean (SE) -21.4 (12_)* -205 (I .6)*

Total cholesterol, mg/dL Base li ne 206.7 207 9 203.8 204. I At 6 wk 170.9 2038 168.2 198.4 % Change -18.2 - 2 4 -18.6 -3.7 Difference between treatments, mean (SE) -15.8 (10)* -149 (I .3)*

hs-CRP, mg/Lt No. of patients 476 212 251 126 Baseline 25 23 24 2. I A t 6 w k 21 24 I 8 2.4 % Change 129 0 105 21.0 Difference between treatments, median (95% CI) - I 13 (-20.4 to -1.8)t - I 82 ( -332 to -3.8)t

EZE - ezetimibe; Pbo - placebo; LDL C - low density lipoprotein cholesterol; HDL C - High dens~y lipoprotein cholesterol *P < 0001 between treatments within age subgroup tp < 0.03 between treatments within age subgroup $~1 his was a post hoc analysis of a subset of patients

diarrhea (2% EZE + statin, 1% placebo + statin) and nausea (2% and 1%, respectively); rates o f diarrhea in el- derly patients were <1% with EZE + statin and placebo + statin. N o clinical hepatobiliary adverse events were reported as drug related. There were no cases o f rhab-

domyolysis, and no patients had CK devations >10 times the U L N during the 6 weeks o f active t reatment or the 2 weeks o f additional safety monitor ing.

Laboratory adverse events also were int?eqnent with EZE + statin therapy (Table V). N o older patients and

224

T Pearson et al. The American Journal of Geriatric Pharmacotherapy

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|

r ~

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t23

c t~

5

0-

- 5 -

-I0

15

20

25-

30

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[ ] Ezedmibe 10 mg/d • Placebo

- ~ - Between-trea~nent difference

<45 45~54 55~4 65 74 a75 (n = 178) (n = 563) (n = 905) (n = 813) (n = 449)

Age Group (y)

Figure 2. Percent change in low-density lipoprotein cholesterol (LDL-C) in patients reaching the LDL-C goal. (Groups aged <65 years are presented for comparison only.) *P < 0.001 between treatments.

8o

o 70

u, C3 60

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I

65 74 e75

Age Group (y)

• Ezetimibe

[] Placebo

Proportions of older (age 65-74 years) and elderly (age 075 years) patients reaching the low-density lipoprotein cholesterol (LDL-C) goal.*P < 0.001 between treatments.

1 elderly patient had consecutive ALT elevations 03 times the ULN. One older patient and no elderly patients had consecutive AST elevations ~3 times the ULN.

D I S C U S S I O N

Hypercholesterolemia is prevalent in individuals aged 065 years, and the incidence of CHD is significantly in creased in this growing populationJ 8 Several major pre vention trials have demonstrated the significant benefits of lipid lowering in patients at risk for cardiovascular events, including those aged >65 years. 3,6,a lo,1<2o Achieving tar get cholesterol levels in this population can be difficult, however, and these patients are often undertreated, ll,~l,~2

Enrollment of large numbers o f older and elderly patients in the EASE trial 17 permitted analysis of the tol- erability and effectiveness of adding EZE to statin ther apy in these age groups in terms o f further reductions in LDL-C and improvements in attainment of NCEP ATP III LDL C goals compared with the addition of placebo. Compared with adding placebo, the addition of EZE 10 m g / d to the current type and dose of statin therapy resulted in a further 22% to 25% reduction in LDL C in these patients• In a previous study in patients using statin therapy, 19 the addition of EZE resulted in a

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The American Journal of Geriatric Pharmacoth~rapy T Pearson er al.

TableV. Laborator T adverse events (no. [%]) in older (age 65-74 years) and elderly (age >75 years) patients.

Age 65-7"~ Years Age ~75Years

Laboratory Adverse Event EZE + Statin Pbo + Statin EZE + Statin Pbo + Statin

(n = 5@) (n = 259) (n = 300) (n = 156)

ALT :-3 x ULN on 2 consecutive occasions AST ~3 x ULN on 2 consecutive occasions

C K > I 0 x U L N

o (o) o (o) I (<1) o (o) I (<1) o (o) o (o) o (o) o (o) o (o) o (o) o (o)

F7E- ezetimibe; Pbo - placebo;ALT- alanine aminotransferase; ULN - upper lima of normal; A S T - aspactate aminotra~sferase; C K - creatine kinase.

similar 25% decrease in LDL C levels from baseline, compared with 4% with the addition of placebo.

Limited information is available on the efficacy of lipid lowering therapies in older patients, particularly those aged a75 years. Importantly, this analysis found that the LDL C~lowering effects of the addition o f EZE to ongoing statin therapy were consistent across the older and elderly age groups. These results are consistent with those of a pooled analysis that examined the efficacy of combination therapy with EZE + statin compared with statin or placebo in older (a65 years) and elderly (>75 years) patients who were not using statin therapy at baseline. ;3 That analysis reported that the addition of EZE to statin therapy produced a significantly greater decrease in LDL C levels, regardless of age group.

The addition of EZE to statin therapy also signifi cantly improved other aspects of the lipid profile, includ- ing TG, n o > H D L C, and TC, in the 2 age groups (P < 0.001); H D L C was significantly improved in the elderly group only (P < 0.03). Furthermore, adding EZE pro- vided significant additional improvements in hs CRP lev els (P < 0.03). This substance appears to play an impor tant role in the pathogenesis of atherosclerosis 44 and is an independent predictor of cardiac disease, regardless of lipoprotein levels. ;~ Evidence is emerging to suggest that achieving target hs-CRP levels improves clinical out- comes, at least for secondary prevention. 26 Additional prospective studies are needed, however, to understand the long-term effects on cardiovascular risk of redudng hs CRP levels27; it is not known whether the additional reductions in hs CRP seen with EZE + statin will lead to reductions in cardiovascular risk.

The majority of patients aged >65 years in the EASE trial 17 were at high risk based on NCEP ATP III crite ria (CHD or CHD risk equivalent)J a This is consistent with data suggesting that older patients should be con sidered for aggressive lipid lowering therapy. 2a Recent recommendations from the NCEP Coordinating Corn-

mittee include use of more aggressive LDL C goals for high- and moderate-risk patients 49 than in previous rec- ommendations. 18 An optional goal of <70 m g / d L is recommended for those patients considered to be at extremely high risk. 29 Importantly, in this study, 72 .3%

of patients aged >65 years who were not at the LDL C goal o f<100 m g / d L at baseline while taking their cur rent type and dose of statin reached the goal when EZE was added to ongoing statin therapy, compared with 18.9% of patients in whom placebo was added to ongo ing statin therapy. Thus, the addition o f EZE may offer a strategy for helping older patients achieve their LDL C goal, improve their lipid profile, and further reduce their hs-CRP level without an increase in the statin dose or a switch to a more potent statin.

In general, the results for these older and elderly patients were similar to those in the overall study popu- lation. 17 Goal attainment in the older and elderly popu lations were comparable to those in the overall high risk population from the EASE trial, in which 70% of EZE + statin recipients and 17% of placebo + statin re cipients reached their goal. There were no marked differences in the distribution of statin types and doses or in the distribution o f secondary diagnoses and co morbidities in older and elderly patients compared with the overall study population.

Adverse events were few and similar in the EZE + statin and placebo + statin groups, with no indication that any gastrointestinal, musculoskeletal, or hepatic adverse events occurred more frequently in either the older or elderly group. Although study treatment was limited to a 6-week period, previous 3-month studies have indicated that EZE added to a statin had a favor able safety profile in older and elderly patients. 23

C O N C L U S I O N S In these older and elderly patients with hypercholes terolemia, many o f them at high risk for CHD, the

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addition of EZE to ongoing statin therapy was well tolerated and was an effective treatment option for improving lipid profiles and attainment of LDL-C goals. Adding EZE improved rates of attainment o f NCEP ATP II I LDL C goals without increases in the dose or potency of statin therapy. Further studies are necessary to determine whether these results can be generalized to other older and elderly populations.

A C K N O W L E D G M E N T S This study was sponsored by Merck/Schering Plough Pharmaceuticals, Nor th Wales, Pennsylvania.

The authors thank the 299 community based prac tices that enrolled patients for this study. They also acknowledge the contributions of Lisa Gazdick, BS, Betsy Desrosiers, MS, Christine Durkan, RN, BSN, Joann Hunsberger, MS, and Wendy Roska, BS, all employees of Merck & Co., Inc.

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Address cor respondence to: Thomas A. Pearson, MD, MPH, PhD, University o f Rochester, Communi ty and Preventive Medicine, 601 Elmwood Avenue, Box 644, Rochester, NY 14642. E-mail: ThomasPearson@urmcxochester .edu

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