This retrospective study strongly suggests that splitting a 10-mg ezetimibe tablet yields a 5-mg dose that is clinically equivalent to the 10-mg dose.
Objective: To compare the clinical efficacy of ezetimibe 5 mg (prescribed as a 10-mg tablet split in half) with a whole 10-mg tablet.
Study Design: From January 2003 through July 2005, all Bronx Veterans Administration ezetimibe prescriptions were for 10 mg. In August 2005, it was mandated that all new ezetimibe prescriptions be 5 mg, prescribed as a 10-mg tablet split in half.
Methods: The impact of the 2 ezetimibe dosing strategies on percent lowering of low-density lipoprotein cholesterol (LDL-C) and achievement of National Cholesterol Education Program Adult Treatment Panel III (ATP III) goals was assessed in all patients prescribed ezetimibe 5 or 10 mg.
Results: A total of 272 patients were prescribed ezetimibe; 86 received 5 mg and 186 received 10 mg. Of those 272 patients, 197 had evaluable baseline and posttreatment LDL-C (55 taking the 5-mg dose and 142 taking the 10-mg dose). The effects of ezetimibe 5 and 10 mg on all lipid parameters were similar. Ezetimibe 10 mg reduced LDL-C by 26.1%, whereas 5 mg reduced LDL-C by 25.8%. The percentages of patients achieving goal LDL-C were similar: 61.8% (5 mg) and 60.5% (10 mg).
Conclusion: These data strongly suggest that ezetimibe 5 mg and ezetimibe 10 mg are clinically equivalent with respect to LDL-C reduction and achievement of ATP III LDL-C goals. Widespread adoption of this low-dose strategy could result in a potential cost savings of more than a billion dollars annually, with a potential reduction in hepatotoxicity.
(Am J Manag Care. 2008;14(10):637-641)
Splitting a 10-mg ezetimibe tablet yields a 5-mg dose that appears to be clinically equivalent to the 10-mg dose.
The relationship between elevated low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease is well established.1 Clinical trials, mostly with statins2-4 but also with other drugs and even ileal bypass surgery,5,6 have clearly shown that LDL-C–lowering therapy reduces the risk for coronary heart disease. Clinical guidelines such as the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) identify elevated LDL-C as the primary target of cholesterol-lowering therapy.1
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.
METHODSOur 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.
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).
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.
Author Affiliations: From the James J. Peters VA Medical Center (LB, BG, SSL-B, SA, CE), Bronx, NY; and the Mount Sinai School of Medicine (LB, BG, SA, CE), New York, NY.
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: firstname.lastname@example.org.
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