Although the death rates from coronary heart disease

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1 Effectiveness of Ezetimibe Monotherapy in Patients With Hypercholesterolemia Howard S. Friedman, PhD, MMS; Srinivasan Rajagopalan, PhD; Jaime P. Barnes, SM; and Robert D. Prentice, MB, ChB, FRCGP At a Glance Practical Implications p 268 Author Information p 273 Full text and PDF Disease Management Although the death rates from coronary heart disease (CHD) have declined over the years, CHD is still the leading cause of mortality in the United States. 1,2 In 24, CHD accounted for 869,724 deaths in the United States alone. 1 In addition, the economic burden of CHD is increasing, with total direct and indirect costs in the United States estimated at $448.5 billion for Hyperlipidemia is recognized as a major modifiable risk factor for CHD, particularly when it occurs in association with other risk factors such as hypertension, smoking, and diabetes. 3,4 A strong correlation between elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of CHD has been well established. 4 Clinical trials have shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) can significantly lower LDL-C levels and reduce CHD-related morbidity and mortality. 5-9 These findings have led to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines and the American Heart Association/American College of Cardiology (AHA/ACC) guideline update (26) for aggressive cardiovascular risk management. 4,1 The NCEP ATP III guidelines placed patients with CHD into 5 risk categories, each with specific LDL-C treatment goals. The AHA/ACC 26 guideline update states that the target LDL- C goals for all patients with CHD and other clinical forms of atherosclerotic disease should be less than 1 mg/dl and that it is reasonable to treat such patients to a goal of less than 7 mg/dl (Table 1). 4,1 Patients with established CHD and other clinical forms of atherosclerotic disease are in the very high risk category and those without atherosclerotic disease but with CHD risk equivalents are in the high-risk group. Patients without CHD risk equivalents are at moderate risk, and patients with zero to one (-1) risk factor are in the lowest-risk group. CHD risk equivalents include diabetes and multiple risk factors that confer a 1-year risk ABSTRACT Objective: To evaluate the effectiveness of ezetimibe monotherapy for patients with moderate- to very high risk hypercholesterolemia in a managed care setting. Study Design: Retrospective analysis using administrative claims data from a large, employer-sponsored, insurancebased medical, pharmacy, and laboratory database. Methods: Patients with newly fi lled prescriptions for ezetimibe were identifi ed from July 1, 24, through December 31, 27. Patients were insured health plan members 18 years old or older with pharmacy benefi ts who were continuously enrolled for 6 months before and 3 months after initiating ezetimibe. The Wilcoxon signed rank test was used to evaluate changes in lowdensity lipoprotein cholesterol (LDL-C) measurements. The proportion of patients reaching their target American Heart Association/American College of Cardiology guideline (26) LDL-C goal was calculated. Adherence to ezetimibe was estimated from prescription refi lls. Results: The average percent LDL-C decline within 1 to 3 months of initiating ezetimibe was 18.5% ± 18.2% in the total population (P <.1 comparing baseline with postindex measurements); results for the diabetic subcohort were similar (17.4% ± 19.4%, P <.1 comparing baseline to postindex measurements). Approximately 35% of the total population and 3% of the diabetics reached their target LDL-C goal within 1 to 3 months of initiating ezetimibe. Patients with adherence (percent days covered) 75% or greater had higher percentage reductions in LDL-C than patients with adherence less than 5% (P <.1). Conclusions: Ezetimibe is an effective LDL-C lowering agent in patients with moderate- to very high risk hypercholesterolemia, including diabetics, in a managed care setting. It may offer an alternative for statin-intolerant patients. (Am J Pharm Benefi ts. 21;2(4): ) Vol. 2, No. 4 The American Journal of Pharmacy Benefi ts 267

2 n Friedman Rajagopalan Barnes Prentice PRACTICAL IMPLICATIONS This retrospective study compared the effectiveness of ezetimibe monotherapy for lowering low-density lipoprotein cholesterol (LDL-C) in a managed care population with results obtained in clinical trials. n Ezetimibe monotherapy appeared to have similar efficacy in clinical practice and clinical trials. n Results from this study reconfirmed that better adherence to therapy improved patients ability to reach their target LDL-C goals. n Managed care intervention programs may benefit by offering initiatives that improve medication adherence in patients with hypercholesterolemia. for CHD that is greater than 2%. In addition to reducing LDL-C levels to less than 1 mg/dl, an LDL-C level less than 7 mg/dl is a reasonable therapeutic goal for all patients at very high risk of myocardial infarction or death. 4,1 Several studies have reported poor goal attainment in CHD populations treated in clinical practice 11,12 ; these patients are far less likely to achieve LDL-C targets than those treated in clinical trials. 13 Frolkis et al compared expected LDL-C lowering based on the package inserts of atorvastatin, simvastatin, and pravastatin with the actual reductions achieved by hyperlipidemic patients in a preventive cardiology practice. 14 The mean observed reduction in LDL-C of 26% (±2%) was significantly lower than the expected reduction of 34% (±7%). 14 Treatment in clinical practice is rarely delivered as effectively or uniformly as in controlled efficacy trials. Factors such as population heterogeneity, patient adherence, and actual costs of treatment to the patient all contribute to the discrepancy seen between efficacy and effectiveness studies. 15 Table 1. LDL-C Goals as a Function of Risk Category a Risk Category Very high risk LDL-C Goal, mg/dl <7 b High risk <1 Moderately high risk <1 c Moderate risk <13 Low risk <16 AHA/ACC indicates American Heart Association/American College of Cardiology; LDL-C, low-density lipoprotein cholesterol. a According to the 26 AHA/ACC guidelines. b Optional goal; standard goal is 1 mg/dl. c Optional goal; standard goal is 13 mg/dl. Studies with statins have shown there is a lack of adherence to treatment by patients with CHD, and patient adherence worsens over time A significant portion of these patients are reluctant to take statins because of associated musculoskeletal symptoms, or as a result of reports in the media regarding myopathy. 19 Myopathy and rhabdomyolysis have been rarely reported for all statins, 2,21 and fatal rhabdomyolysis has been reported for all statins except fluvastatin. 22 Polypharmacy also can contribute to poor patient adherence, particularly in the elderly population, because of the higher number of drugs prescribed to elderly patients compared with the rest of the population. 23,24 Drug drug interactions have limited the use of statins in a number of patients, including patients taking select fibrates, protease inhibitors, and anticoagulants such as warfarin. 21 One specific example is the voluntary removal of cerivastatin from the market due to reports of fatal rhabdomyolysis particularly in association with gemfibrozil. 25 Current alternatives for patients with hypercholesterolemia who are intolerant to statins include bile acid sequestrants, niacin, and esters from plant sterols. Although these medications provide some reduction in LDL-C levels, the major barrier to their use is lack of patient compliance due to a range of associated side effects. 3 These data suggest the need for new interventions that are effective, safe, and well tolerated to increase the percentage of patients attaining LDL-C goals and, ultimately, to reduce the risk and burden of CHD. Ezetimibe has a mechanism of action different from that of other currently available lipid-lowering medications in that it aims to block cholesterol absorption at the intestinal brush border to reduce LDL-C levels without affecting absorption of triglycerides, lipid-soluble vitamins, or most concurrently administered medications. 26,27 The efficacy of ezetimibe monotherapy was demonstrated in a pooled analysis of 2 phase III clinical trials with a total of 1179 patients with primary hypercholesterolemia. Ezetimibe monotherapy significantly reduced mean LDL-C by 18.2% (P <.1) and resulted in a statistically significant small increase in high-density lipoprotein cholesterol (HDL-C) (1%; P <.1) and a statistically significant reduction in triglycerides ( 8.%; P <.1). Ezetimibe was well tolerated, with a safety profile similar to that of placebo. 28 As outlined above, several studies have found that patients receiving various lipid-lowering therapies do not achieve levels of LDL-C reduction in clinical practice similar to those obtained in clinical trials. In this study, we examined LDL-C lowering by ezetimibe monotherapy 268 The American Journal of Pharmacy Benefits August 21

3 Effectiveness of Ezetimibe Monotherapy in a managed care population to assess its effectiveness compared with the results obtained in clinical trials. METHODS A retrospective cohort study was conducted using administrative claims data from the 24 to 27 Ingenix Claims Database (i3 Innovus, Eden Prairie, MN). This database contains pharmacy and medical claims information for more than 2 million employed, commercially insured patients and their dependents, and laboratory results for approximately 15% of the population. Study Population Patients with newly filled prescriptions for ezetimibe were identified from July 1, 24, through December 31, 27. The period of study was from 6 months prior to the index date (the index date was the date of the first claim for ezetimibe) to 3 months following the index date. The length of time a patient was treated was variable between the index and postindex dates. A subcohort of patients with diabetes also was investigated. The study sample was selected from the population of insured health plan members age 18 years or older who had pharmacy benefits and were continuously enrolled throughout the study period. All patients included in the study had no previous claim for lipid-lowering therapy for at least 6 months prior to the index date, at least 1 LDL-C measurement within 6 months prior to the index date, and at least 1 LDL-C measurement between 1 and 3 months after the index date, and they had no change in their treatment regimen between the index date and the first posttreatment LDL-C measurement (months 1-3). Patients were categorized by risk level according to the updated AHA/ACC 26 guidelines, and only those in moderate-risk and high-risk categories were included. Patients identified as low risk for CHD (no CHD or CHD risk equivalents and -1 major CHD risk factors such as age, smoking, and family history of premature CHD) were excluded because of the potential misclassification of this risk category. As risk levels were assigned based on data provided by administration claims, a patient without CHD or CHD risk equivalents may be inadvertently classified as low risk because of the underreporting of certain risk factors such as smoking or family history of premature CHD. Patients who took medications that impact lipid levels or interact with ezetimibe at any time during the study period also were excluded. Patients could not have filled a prescription for any lipidlowering therapy including statins, ezetimibe, bile acid sequestrants, fibrates, and prescription-strength niacin Figure 1. Patient Selection Criteria and Resulting Sample Sizes First prescription of interest, July 1, 24, through December 31, 27 N = 163,244 Enrolled 6 months before, 3 months after index date and age 18 years or older on index date n = 91,463 No lipid-lowering therapies within 6 months before the index date n = 32,712 No liver disease n = 31,98 Only one strength on index date n = 31,968 LDL-C laboratory test within 6 months before the index date n = 7913 LDL-C laboratory test within 1-3 months after the index date n = 1895 No change in regimen, brand, or strength before the first post-treatment LDL-C measurement n = 167 No interacting drugs during the preindex and postindex periods n = 1138 No low-risk patients n = 663 No patients below goal at baseline n = 562 Diabetic subset of patients evaluated in the current study n = 227 LDL-C indicates low-density lipoprotein cholesterol. during the 6 months prior to the index date. Patients could not have filled a prescription for any lipid-lowering therapy besides ezetimibe during the time period from the index date to the first laboratory date. Patients with liver disease identified using the International Classification of Diseases, Ninth Revision, Clinical Vol. 2, No. 4 The American Journal of Pharmacy Benefits 269

4 n Friedman Rajagopalan Barnes Prentice Table 2. Patient Characteristics a Variable Total Population (N = 562) Diabetic Subcohort (n = 227) Demographics Female Age at baseline, mean ± SD, y 56.6 ± ± 1.4 Select comorbidities (during 18-day preindex period) Benign neoplasm Arthritis Cancer Depression or other affective and anxiety disorders Osteoporosis Renal failure Risk factors (used in determining revised 24 NCEP ATP III risk categorization) Age risk (male >45 years and female >55 years at baseline) Hypertension Diabetes Low HDL-C at baseline (<4 mg/dl) Chronic ischemic heart disease Stroke Angina Atherosclerosis Revascularization 2..4 Myocardial infarction Other acute and subacute ischemic heart disease NCEP ATP III indicates National Cholesterol Education Program Adult Treatment Panel III; HDL-C, high-density lipoprotein cholesterol. a Values represent number (percentage) unless indicated otherwise. Modification (ICD-9-CM) diagnostic codes, and patients at or below target LDL-C at baseline also were excluded (Figure 1). Optional goals were used for very high risk and moderately high risk patients (Table 1). Data Collection Data on variables related to ezetimibe therapy, adherence, and goal attainment were obtained from the medical claims database; these included demographics, cardiovascular history, and serum lipid levels. Information on demographic variables including sex and age was obtained from enrollment files. Drug use and prescription fill dates were obtained from the pharmacy claims database using National Drug Codes. Information regarding patients risk for CHD or CHD equivalents were obtained from the medical and pharmacy claims database prior to the index date using the AHA/ACC guidelines, ICD-9-CM codes, Current Procedural Terminology codes, and prescription records. Comorbidities were identified using the ICD-9-CM diagnostic codes during the 18-day time frame before the index date. Serum lipid level data for total cholesterol, LDL-C, HDL-C, and triglycerides were collected for 2 time periods: (1) baseline measurement taken within 6 months before the index date, and (2) postindex measurement taken 1 to 3 months after the index date. Attainment of the LDL-C goal was based on the 26 AHA/ACC guidelines (Table 1). Adherence was based on prescription refill activity, measured as the proportion of days covered by filled prescriptions for ezetimibe between the index date and the first postindex measurement. 29 For patients with multiple LDL-C laboratory values available within 1 to 3 months after the index date, the value from the first test following the index date was used for the adherence calculation. RESULTS Descriptive Analyses A total of 562 patients were identified as new ezetimibe users who were at moderate to high risk for CHD and met all the study inclusion criteria; lowrisk patients were excluded. From this population, a 27 The American Journal of Pharmacy Benefits August 21

5 Effectiveness of Ezetimibe Monotherapy Table 3. Outcome Measurements in the Total Population (N = 562) a,b Variable Baseline Lipid Measurements, mg/dl c Postindex Lipid Measurements, mg/dl d Change (Postindex Level Minus Baseline Level), mg/dl Total cholesterol ± ± ± ± 12.7 LDL-C ± ± ± ± 18.2 HDL-C 5. ± ± ± ± 12.1 Triglycerides ± ± ± ± 33. Other Outcome Measures 35.1 Percentage of patients reaching goal in 1-3 months Adherence e 85 ± 2 Days between index date and postindex 6.5 ± 17.5 lab measurement Percentage Change ([Postindex Level Minus Baseline Level]/ Baseline Level) HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. a Values represent mean ± SD unless otherwise indicated. b Total population refers to the total sample meeting all of the inclusion criteria ( 2% of patients were missing total cholesterol, HDL-C, or triglyceride measurements). c Within 6 months before the index date (mean ± SD). d 1-3 months after the index date (mean ± SD). e The percentage of days covered between the index date and the first postindex measurement (based on prescription refill activity). Table 4. Outcome Measurements in the Diabetes Subcohort (N = 227) a Variable Baseline Lipid Measurements, mg/dl b Postindex Lipid Measurements, mg/dl c Change (Postindex Level Minus Baseline Level), mg/dl Total cholesterol ± ± ± ± 13.3 LDL-C ± ± ± ± 19.4 HDL-C 48.6 ± ± ± ± 12.9 Triglycerides 176. ± ± ± ± 32.4 Other Outcome Measures 29.5 Percentage of patients reaching goal in 1-3 months Adherence d 83 ± 2 Days between index date and postindex 62. ± 17.7 lab measurement HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. a Values represent mean ± SD unless otherwise indicated. b Within 6 months before the index date (mean ± SD). c 1-3 months after the index date (mean ± SD). d The percentage of days covered between the index date and the first postindex measurement (based on prescription refill activity). Percentage Change ([Postindex Level Minus Baseline Level]/ Baseline Level) subcohort of 227 patients with diabetes also was identified (Figure 1). In the overall population, the most common comorbidities included hypertension, diabetes, low HDL-C (<4 mg/dl), chronic ischemic heart disease, and benign neoplasm. Similar trends were also seen within the diabetic subcohort (Table 2). Lipid Measurements The Wilcoxon signed rank test was used to evaluate changes in LDL-C measurements. Results showed a significant decrease in LDL-C values (P <.1) from baseline to postindex measurements. This finding was similar in both the total population and the diabetic subcohort (Table 3 and Table 4). The average percent LDL-C decline within 1 to 3 months of initiating ezetimibe monotherapy treatment was 18.5% ± 18.2% in the total population (Table 3). Measurements for the diabetic subcohort were similar, with an LDL-C decline of 17.4% ± 19.4% (Table 4). Analyses of the baseline and postindex LDL-C distributions show the decrease in LDL-C measurements for Vol. 2, No. 4 The American Journal of Pharmacy Benefits 271

6 n Friedman Rajagopalan Barnes Prentice Figure 2. Postindex LDL-C Distributions Show a Decrease in LDL-C Compared With Baseline for the Total Population (Panels A and B) and the Diabetic Subcohort (Panels C and D) A Patients B Patients C Patients D Patients <1 135 <1 1 <1 69 < Total Population Baseline LDL-C Measurement, mg/dl Total Population Postindex LDL-C Measurement, mg/dl Diabetic Subcohort Baseline Diabetic Subcohort Postindex both the total population and the diabetic subcohort (Figure 2). Based on the 26 AHA/ACC guidelines, approximately 35% of the total population treated with ezetimibe 55 LDL-C Measurement, mg/dl LDL-C Measurement, mg/dl LDL-C indicates low-density lipoprotein cholesterol >2 8 >2 11 >2 3 >2 monotherapy reached their target LDL-C goal within 1 to 3 months of initiating therapy. Approximately 3% of the diabetic subcohort also reached their target LDL-C goal within 1 to 3 months on ezetimibe monotherapy (Table 4). Adherence As seen in Figure 3, patients in the total population whose adherence rate (percent of days covered) was 75% or greater had statistically significant LDL-C reductions (P <.1), with an average of 2.% ± 16.3% decline from the baseline LDL-C measurement. Patients whose adherence was 75% or greater had higher percentage reductions in LDL-C than patients whose adherence was less than 5% (P <.1). DISCUSSION AND CONCLUSIONS This study demonstrates that ezetimibe is an effective LDL-C lowering agent in patients with moderate- to very high risk hypercholesterolemia, including diabetic patients in a managed care setting. Ezetimibe was associated with a mean LDL-C percent decrease from baseline to endpoint of 18.5% ± 18.2% in the overall population and 17.4% ± 19.4% in the diabetic subcohort. This decline in LDL-C is similar to rates previously reported in clinical trials ( 18%). 28 In addition, within 1 to 3 months of initiation of ezetimibe therapy, a reduction in triglycerides and a slight increase in HDL-C were observed in both the total population and diabetic subcohort (Tables 3 and 4). Increased levels of HDL-C and decreased levels of triglycerides have been reported to lower the risk of CHD. 3 The effectiveness of ezetimibe, as with other CHD medications, depends on patient adherence. 31 In the present study, overall patient adherence (based on prescription fill activity) was 85% in the total population and 83% in the diabetic subcohort (Tables 3 and 4). Patients with poor adherence rates had more limited LDL-C percent declines (Figure 3). Parris et al observed a similar relationship between adherence and LDL-C reductions in a study examining the relationship of adherence to statins and LDL-C goal attainment. 32 Of the 44% of patients in the Parris et al study who achieved their LDL-C goal, the mean adherence rate was 82% compared with a mean of 61% for the patients who did not attain their goal during the 9-month study. 32 Because this study was a retrospective analysis of an administrative claims database, several limitations should be taken into consideration. First, risk categories were assigned based on data provided by administrative claims. As such, patients without CHD or CHD risk 272 The American Journal of Pharmacy Benefits August 21

7 Effectiveness of Ezetimibe Monotherapy equivalents may have been inadvertently assigned to a risk level lower than their true medical condition due to underreporting of certain risk factors such as smoking or family history of premature CHD. That would have had no impact on the observed LDL-C change and percent LDL-C change, but would have resulted in a lower assigned LDL-C goal and a higher percentage of patients achieving that goal. To avoid this potential skewing of the analysis and confounding of the interpretation of the results, the analysis was limited to patients in the very high risk, high-risk, and moderate-risk categories. Additional limitations inherent to the current study include the following: (1) data regarding medication samples used by patients were not available in retrospective claims; (2) adherence was measured based on prescription fill activity rather than patient reporting; and (3) the sample size was limited, partially due to availability of LDL-C laboratory data. Despite these limitations, this study is able to offer insights into the effectiveness of ezetimibe monotherapy in reducing LDL-C levels in a managed care setting, and further emphasizes the importance of patient adherence for improved health-related outcomes. Although lowering LDL-C has a well-established relationship with reducing the risk of cardiovascular events, studies demonstrating the efficacy of ezetimibe with respect to clinical outcomes have not been completed, and the analysis of clinical outcomes was beyond the scope of the current study. The clinical benefit of ezetimibe is currently being evaluated in the IMPROVE-IT trial, where cardiovascular outcomes with simvastatin or simvastatin plus ezetimibe are being evaluated in patients with acute coronary syndrome. 33 IMPROVE-IT is expected to include approximately 18, patients and has an estimated completion date of June In conclusion, ezetimibe monotherapy may offer an important alternative for patients with hypercholesterolemia, including those with diabetes. It may be particularly useful for those who are intolerant to statins and those in whom statins are contraindicated. Author Affiliations: From Analytic Solutions, LLC (HSF), New York, NY; Med Data Analytics, Inc (SR), Williamsville, NY; Schering-Plough Pharmaceuticals (JPB), Kenilworth, NJ; and formerly of Blue Cross Blue Shield of North Carolina (RDP), Raleigh, NC. Funding Source: This study was funded by Merck and Company/ Schering-Plough Pharmaceuticals. Author Disclosures: Dr Friedman reports serving as a consultant for Schering-Plough Pharmaceuticals; Dr Rajagopalan reports serving as a consultant for Merck and Company; Dr Barnes reports being employed by and owning stock in Schering-Plough Pharmaceuticals; and Dr Prentice reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Figure 3. Relationship Between Adherence and Percent LDL-C Decline LDL-C Decline, % <5 (n = 56) 7.2 >5 <75 (n = 85) 18.4 Adherence, % LDL-C indicates low-density lipoprotein cholesterol. >75 (n = 421) 2. Authorship Information: Concept and design (HSF, SR, JPB, RDP); acquisition of data (SR); analysis and interpretation of data (HSF, SR, JPB); drafting of the manuscript (HSF, JPB, RDP); critical revision of the manuscript for important intellectual content (HSF, SR, JPB, RDP); statistical analysis (HSF, SR); obtaining funding (HSF, SR, JPB); and supervision (JPB). Address correspondence to: Howard S. Friedman, PhD, MMS, Analytic Solutions LLC, 26 Prince Street, Suite 2B, New York, NY howard@analytic-consulting.com. REFERENCES 1. Rosamond W, Flegal K, Furie K, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 28 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published correction appears in Circulation. 21;122(1):e1. Kissela, Bret corrected to Kissela, Brett]. Circulation. 28;117(4):e25-e Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 27;26(1): Stein EA. Managing dyslipidemia in the high-risk patient. Am J Cardiol. 22;89(5A):5C-57C. 4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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