Because of their safety and efficacy, statins are the cornerstone of LDL-C–lowering therapy. However, some patients -- particularly those categorized as very high risk in the update to ATP III, who have an optional LDL-C goal of <70 mg/dL⁷ -- do not achieve their target LDL-C levels despite statin therapy.^8-10 Thus, the need arises for the use of other agents to lower LDL-C. These include niacin, bile acid sequestrants, and ezetimibe.

Ezetimibe is the first member of a class of lipid-lowering compounds called the cholesterol absorption inhibitors, which inhibit the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall.¹¹ Ezetimibe is available only in a 10-mg dose, as either monotherapy or in combination with simvastatin as Vytorin.^12-15 Ezetimibe has been shown to be well tolerated, although recently concerns have been raised about potential dose-related hepatotoxicity.^16,17

During its clinical development, a wide range of doses of ezetimibe were evaluated, from 0.625 mg to 40 mg; 5 mg lowered LDL-C significantly, albeit to a slightly lesser degree than 10 mg in some trials.^18-20 The majority of these trials were done in patients not receiving a statin and looked at LDL-C lowering, as opposed to achievement of NCEP goals. In fact, in the peer-reviewed medical literature evaluating the effect of 5 mg of ezetimibe in combination with statins, the sample size was 8 patients who received low-dose lovastatin.²¹

Approximately 2 years ago, aware of the fact that the 5-mg ezetimibe dose was effective at lowering LDL-C, our institution adopted a policy that all new prescriptions of ezetimibe be for a 10-mg tablet split in half using a pill-splitter provided to the patients, yielding essentially a 5-mg daily dosage. This policy was instituted to reduce pharmacy costs. Of note, our institution did not require that the patients receiving ezetimibe 10 mg be converted to a split-tablet 5-mg regimen. This afforded us the opportunity to evaluate the clinical efficacy of the 2 different dosing strategies on LDL-C lowering and achievement of NCEP goals in a real-world setting, particularly one where patients were largely treated with high-dose statins. Ezetimibe, as a stand-alone tablet or in Vytorin, is the third most commonly prescribed lipid-lowering agent, with worldwide annual sales of more than $5 billion.^22,23 If the split tablet were clinically equivalent to a whole tablet, widespread implementation of this alternative dosing strategy could result in significant cost savings combined with potential improved safety.

METHODS
Our population consisted of all patients at the Bronx Veterans Administration (VA) Medical Center who received at least one 30-day prescription of ezetimibe from January 2003 (when ezetimibe became available at the VA) to July 2006. Patients were identified from computerized pharmacy records. The only exclusion criterion was the absence of an evaluable LDL-C result either before or after ezetimibe was prescribed. Reasons for not having an evaluable LDL-C result included multiple medication changes surrounding the “treatment” period (eg, statin dose was changed after the pre-ezetimibe LDL-C level was obtained) or the absence of a recorded LDL-C assessment either before or after initiation of ezetimibe (eg, patient was followed by a physician outside the VA).

Based on a review of each subject’s electronic medical record, an LDL-C goal was determined in accordance with ATP III. If the medical record clearly documented an LDL-C goal of <70 mg/dL for a particular patient in accordance with the 2004 update to ATP III, this was adopted as the LDL-C goal.

Statistical Analyses
The baseline value used for comparisons for each of the lipid values was the most recent value obtained before initiation of ezetimibe. The lipid values used for the posttreatment assessment were the first lipid values recorded after a minimum of 4 weeks of ezetimibe therapy.

The primary variables for analysis were the percentage of patients achieving their ATP III treatment goal and the percent change from baseline in LDL-C. Secondary analyses included achievement of LDL-C goal and the change in LDL-C in the following subgroups: (1) patients receiving ezetimibe in addition to statins and (2) patients who were receiving high-dose statins, defined as simvastatin 80 mg, atorvastatin ≥40 mg, or rosuvastatin ≥20 mg.

Within-group differences for the change in lipid values were evaluated by paired t test. Between-group differences for the percent change in lipid values and continuous variables were evaluated by unpaired t test. Baseline characteristics for categorical data were compared using Pearson’s chi-square test with Yates correction. Significance of .05 was assumed for all analyses.

RESULTS
A total of 272 patients were prescribed ezetimibe; 86 took the 5-mg split tablet and 186 took the 10-mg tablet. Of those 272 patients, 197 had evaluable baseline and posttreatment LDL-C results (55 [74%] taking the 5-mg dose and 142 [76%] taking the 10-mg dose). The most common reasons for not having an evaluable LDL-C result were the absence of an LDL-C assessment after initiation of ezetimibe (n = 21) and multiple medication changes during the “treatment” period (n = 17). LDL-C assessment was performed on average 30.7 and 36.7 days before initiation of ezetimibe and 133.2 and 126.1 days after the initiation of ezetimibe in the 5-mg and 10-mg groups, respectively.

Baseline characteristics are shown in the Table. There were no significant between-group differences in age, weight, prior coronary revascularization, or LDL-C (Table). Overall statin usage (83.6% vs 67.6%), as well as high-dose statin usage (74.5% vs 53.5%), was significantly greater in the ezetimibe 5-mg cohort, whereas more patients in the 10-mg group received atorvastatin (Table). A non–statistically significant increase in nonstatin lipid-lowering therapies was seen in the 10-mg cohort.



The effects of 5 mg and 10 mg of ezetimibe on LDL-C and total cholesterol were similar; significant reductions in LDL-C of 25.8% (P <.001) and 26.1% (P <.001) and total cholesterol of 16.0% (P <.001) and 18.9% (P <.001) were demonstrated in the 5-mg and 10-mg groups, respectively (Figures 1A and 1B). The majority of patients achieved their LDL-C goal in the 5-mg and 10-mg groups (61.8% and 60.5%, respectively). No change in high-density lipoprotein cholesterol was seen with either dose of ezetimibe. A nonsignificant (P = .97) reduction in triglycerides was seen with ezetimibe 5 mg (6.1%) and 10 mg (5.7%).

LDL-C lowering was similar in patients receiving ezetimibe 10 mg in combination with simvastatin (29.0%) or atorvastatin (30.3%), as well as in patients receiving ezetimibe 5 mg in combination with simvastatin (28.8%). Nine patients in the 5-mg group were receiving background atorvastatin, and 9 others were not receiving any statin; thus, the lipid-lowering effect of ezetimibe 5 mg could not be evaluated in these subgroups. In those patients receiving high-dose statins, LDL-C was reduced to a similar degree in those prescribed 5 mg and those prescribed 10 mg (27.1% vs 29.9%; P = .52).

DISCUSSION
Pill-splitting strategies have been implemented in various healthcare settings to reduce costs.^24,25 The clinical outcomes of splitting tablets in the statin class of drugs have been the most extensively studied and implemented. Patients who received equal doses of simvastatin either as whole or split tablets had similar decreases in LDL-C. Pill splitting of statins is standard practice in the VA healthcare system; this resulted in a 1-year cost savings of more than $46 million in 2003.²⁴ Pill splitting is a particularly effective strategy in clinical situations where the therapeutic goal is numeric, such as systolic blood pressure or LDL-C.

Clinical trials during the development of ezetimibe demonstrated efficacy of the 5-mg dose with respect to LDL-C lowering.^18-20 The majority of these trials were done in patients not receiving a statin and looked at LDL-C lowering, as opposed to achievement of NCEP goals. Furthermore, clinical trials use select populations who may not be representative of the general population. Thus, data are needed to evaluate whether this cost-saving tablet-splitting strategy is effective at achieving ATP III goals and lowering LDL-C in a statin-treated population in a real-world setting.

This retrospective study strongly suggests that in a statin-treated population a 5-mg split tablet is clinically equivalent to a whole 10-mg tablet. Although some of the early clinical trials did show differences between the ezetimibe regimens, whether these differences are clinically meaningful is unknown. A large clinical trial would be required to address this question.

Clinically meaningful differences are relevant to realworld medical decisions. Scientific evidence as to what works best and what’s good value in terms of improving health outcomes is needed. Patients and payers should expect to receive the best value for every healthcare dollar spent. In this particular instance, use of a whole 10-mg ezetimibe tablet seemingly represents poor utilization of healthcare resources.

Furthermore, efficacy and safety concerns recently were raised regarding ezetimibe.^16,26 The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study failed to show any difference between simvastatin plus ezetimibe compared with simvastatin alone on the progression of carotid atherosclerosis; consequently, the benefits of ezetimibe with respect to atherosclerotic outcomes are in question.^26,27 Potential liver toxicity may be secondary to either an idiosyncratic drug reaction or a conjugation defect resulting in impaired hepatic excretion of ezetimibe and accumulation of toxic levels of intrahepatic ezetimibe.¹⁷ Thus, potential added benefits of the tablet-splitting strategy are (1) to significantly lower the costs to the healthcare system for an agent whose clinical benefit has come into question and (2) to reduce ezetimibe-related hepatotoxicity.

This study also demonstrates that in the clinical setting the ezetimibe tablet is capable of being split by patients to yield clinically significant LDL-C reduction. As our population was elderly, this suggests that pill splitting could be implemented broadly.

Our study has several limitations. The retrospective and nonrandomized design resulted in cohorts of patients who were not treated concurrently. That introduced the risk of a time-dependent effect apart from the independent variables examined. In addition, baseline and follow-up lipid values were not determined at prespecified time points, as would be done in a prospective clinical trial. The absence of an evaluable LDL-C result in all patients may have introduced additional bias.

Our analysis included a number of variables that provide reasonable assurance that these limitations did not affect our results. These included similarities with respect to baseline lipid parameters, timing of LDL-C assessment before and after initiation of ezetimibe, and demographics. In addition, the real-world nature of our study may make our results more generalizable with respect to LDL-C lowering in the clinical setting than a randomized clinical trial.

CONCLUSION
These data strongly suggest that ezetimibe as a 5-mg split tablet is comparable to a whole 10-mg tablet with respect to achievement of ATP III LDL-C goals and lowering of LDL-C. This clinical equivalency is achieved at half the cost and potentially reduced toxicity. In a post-ENHANCE world, the most effective strategy for using ezetimibe (an agent without proven outcome benefits) from a healthcare value perspective would be to initiate therapy with the 5-mg dose.

This finding has implications for therapeutic decision making regarding patients who are not at their LDL-C goal. If additional LDL-C lowering is deemed necessary in a patient receiving the split tablet, increasing the dose of a statin or switching to a more potent statin would likely yield greater LDL-C lowering than increasing the dose of ezetimibe. If a patient is receiving the maximum dose of the most potent statin, consideration can be given to titration of ezetimibe or the initiation of therapy with an agent from a different class of LDL-C–lowering medications. Furthermore, in those situations where ezetimibe has been up-titrated without incremental LDL-C reduction, downtitration should be strongly considered.

Implementing this ezetimibe dosing strategy in our own institution, a process we have begun, could result in significant annual savings of more than $40,000, while VA-wide implementation could result in annual savings of more than $70 million. Worldwide adoption of this strategy could result in annual cost savings of more than $1 billion, with a potentially improved safety profile.

Funding Source: None reported.

Author Disclosure: The authors (LB, BG, SSL-B, SA, CE) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (LB, BG, SSL-B, SA, CE); acquisition of data (LB, BG, SSL-B, SA); analysis and interpretation of data (LB, BG, SA, CE); drafting of the manuscript (LB, SSL-B, SA); critical revision of the manuscript for important intellectual content (LB, SA); statistical analysis (BG, SA, CE); administrative, technical, or logistic support (BG, SA); and supervision (LB).

Address correspondence to: Lawrence Baruch, MD, James J. Peters VA Medical Center, 130 W Kingsbridge Rd, Bronx, NY 10468. E-mail: lawrence.baruch@va.gov.

REFERENCES
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.
2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288(23):2998-3007.
4. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
5. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323(14):946-955.
6. Buchwald H, Varco RL, Boen JR, et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med. 1998;158(11):1253-1261.
7. Grundy SM, Cleeman JI, Merz CN, et al; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol. 2004;44(3):720-732.
8. Foley KA, Simpson RJ, Crouse JR, Weiss TW, Markson LE, Alexander CM. Effectiveness of statin titration on low-density lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events. Am J Cardiol. 2003;92(1):79-81.
9. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160(4):459-467.
10. Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000. Circulation. 2003;107(17):2185-2189.
11. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106(15):1943-1948.
12. Pearson T, Denke M, McBride P, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL-C in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc. 2005;80(5):587-595.
13. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J. 2005;149(3):464-473.
14. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1092-1097.
15. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003;24(8):729-741.
16. Berenson A. Data about Zetia risks was not fully revealed. New York Times. December 21, 2007. http://www.nytimes.com/2007/12/21/business/21drug.html?_r=1&scp=1&sq=zetia&st=cse&oref=slogin. Accessed September 12, 2008.
17. Stolk MF, Becx MC, Kuypers KC, Seldenrijk CA. Severe hepatic side effects of ezetimibe. Clin Gastroenterol Hepatol. 2006;4(7):908-911.
18. Stein E. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl. 2001;3(suppl E):E11-E16.
19. Bays HE, Moore PB, Drehobl MA, et al. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther. 2001;23(8):1209-1230.
20. Dujovne CA, Bays H, Davidson MH, et al. Reduction of LDL-C in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study. J Clin Pharmacol. 2001;41(1):70-78.
21. Kosoglou T, Statkevich P, Meyer I, et al. Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin. Curr Med Res Opin. 2004;20(6):955-965.
22. Herper H, Langreth R. Merck and Schering’s problem study. Forbes. December 21, 2007. http://www.forbes.com/healthcare/2007/12/21/vytorin-cholesterol-schering-biz-health-cx_mh_1221enhance.html. Accessed September 12, 2008.
23. Vuppalanchi R, Chalasani N. Statins for hyperlipidemia in patients with chronic liver disease: are they safe? Clin Gastroenterol Hepatol. 2006;4(7):838-839.
24. Parra D, Beckey NP, Raval HS, et al. Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol. 2005;95(12):1481-1483.
25. Gee M, Hasson NK, Hahn T, Ryono R. Effects of a tablet-splitting program in patients taking HMG-CoA reductase inhibitors: analysis of clinical effects, patient satisfaction, compliance, and cost avoidance. J Manag Care Pharm. 2002;8(6):453-458.
26. Berenson A. Drug has no benefit in trial, makers say. New York Times. January 14, 2008. http://www.nytimes.com/2008/01/14/business/14cnd-drug.html?scp=1&sq=”drug%20has%20no%20benefit”&st=cse. Accessed September 12, 2008.
27. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431-1443.