Publication
Article
Successful Conversion of Patients With Hypercholesterolemia From a Brand Name to a Generic Cholesterol-Lowering Drug
Objective: To evaluate the safety and effectiveness of a simvastatin-to-lovastatin therapeutic conversion program.
Study Design: Observational database study of a therapeuticconversion in members of the Northern and Southern Californiaregions of Kaiser Permanente, using a pretest/posttest design.
Methods: All patients actively converted from simvastatin tolovastatin between April 1, 2002, and March 31, 2003, were identifiedfor inclusion in the analysis. The conversion from simvastatinto lovastatin was based on an equipotent dose ratio of 1 mg of simvastatinto 2 mg of lovastatin. Electronic prescription record andlaboratory data were collected for converted patients beginning365 days before changing therapy through June 30, 2003. The primaryeffectiveness end point was a comparison of the preconversionand postconversion low-density lipoprotein cholesterol(LDL-C) levels. Safety end points included an analysis of preconversionand postconversion alanine aminotransferase (ALT) testsand creatine kinase values.
P
Results: A total of 33 318 converted patients met criteria forinclusion in the analysis. The mean LDL-C was lowered from 110.9to 108.4 mg/dL (< .001) following the conversion to lovastatin.The percentage of patients with serum ALT levels greater than 3times the upper limit of normal (ULN) was similar before (0.7%)and after (0.6%) conversion from simvastatin to lovastatin.Creatine kinase elevations greater then 10 times the ULN occurredat similar rates before and after the conversion.
Conclusions: Overall, patients had an improvement in theirlipid profile without evidence of hepatic or muscle enzyme elevations.Appropriately selected patients can be safely and effectivelyconverted from simvastatin to lovastatin.
(Am J Manag Care. 2005;11:546-552)
It is well established that the 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors(statins) reduce the risks of cardiovasculardisease. Results from large, randomized clinical trialshave established the safety and efficacy of statins withdemonstrated reductions in total and coronary heartdisease (CHD) mortality, acute coronary syndromes,revascularization procedures, and stroke.1-8 Currently,the National Cholesterol Education Program's AdultTreatment Panel III (ATP III) recommends statins asfirst-line agents when drugs that lower low-densitylipoprotein cholesterol (LDL-C) are indicated to achievetreatment goals.9,10
Selection of a statin(s) for inclusion on a formulary isreasonably made on the basis of comparative efficacy,clinical benefit, safety, and relative cost. In December2001, generic versions of lovastatin were approved bythe Food and Drug Administration. With the availabilityof a generic formulation, lovastatin became the mostcost-effective statin for patients requiring mild to moderateLDL-C reductions within Kaiser Permanente (KP).
As the first statin approved for clinical use, lovastatinhas undergone extensive study evaluating safety andefficacy. Dose-ranging studies with lovastatin demonstratedLDL-C reductions of up to 41% with lovastatin80 mg daily, along with favorable effects on high-densitylipoprotein cholesterol (HDL-C) and triglyceride(TG) levels.11-13 Lovastatin has been shown to reducecardiovascular events in a large primary preventionstudy.4 In this study lovastatin was shown to reduce therisk of a first coronary event in men and women withaverage or mildly elevated LDL-C and TG levels andbelow-average HDL-C.4 Angiographic studies havedemonstrated beneficial effects of lovastatin with areduction in the progression of coronary athersclerosis.14-17 In 2 of these studies, lovastatin also demonstratedclinical benefit in a secondary-prevention population.16,17At the time generic lovastatin was approved, brandedsimvastatin (Zocor) was commonly prescribed withinKP. Compared with simvastatin, the LDL-C-loweringpotency of lovastatin is approximately half on a milligram-to-milligram basis (10-40 mg of simvastatinbeing approximately equipotent to 20-80 mg of lovastatin).11-13,18-21 Relative safety appears to be similarwhen equipotent doses of simvastatin and lovastatin arecompared.22,23
Based on the evidence of comparable efficacy andsafety, a conversion program to switch eligible patientsfrom simvastatin to lovastatin was undertaken in theNorthern and Southern California Regions of KP. In thispaper, we report our experience in converting a largepopulation of patients from branded simvastatin togeneric lovastatin.
METHODS
KP is a large, national, not-for-profit, group-modelHMO providing integrated healthcare services to itsmembers. Between April 2002 and March 2003, a campaignwas undertaken within KP California to convertpatients taking simvastatin to an equipotent dose oflovastatin. The conversion from the formulary brandedsimvastatin product to generic lovastatin in selectedpatients (see criteria under "Patients") was deemedappropriate by medical staff committees involved withformulary decisions (regional pharmacy & therapeuticscommittees), cholesterol management, and specialistcommittees. Primary care providers were informed whentheir patients were potential candidates for the conversion.Providers either approved or disapproved the conversionfor each patient.
Patients approved for conversion were informed by aletter from the prescribing physician/provider that theconversion was going to occur. Conversion occurred atthe pharmacy when the patients came in to pick up theirprescription. Patients were counseled by the pharmacistabout the conversion and given written materials withtheir lovastatin prescription. Converted patients alsowere provided with instructions and a lab slip for a follow-up fasting LDL-C and serum alanine aminotransferase(ALT) test to be performed 6 to 8 weeks afterstarting lovastatin. This study (evaluating the conversion)was approved by the regional KP institutionalreview boards in both Northern and Southern California.
Design
The study was designed as a pre-post observationalanalysis of patients converted from simvastatin tolovastatin. The conversion from simvastatin to lovastatinwas based on an equipotent dose ratio of 1 mg ofsimvastatin to 2 mg of lovastatin (eg, patients receivingsimvastatin 10 mg/day were converted to lovastatin 20mg/day). The patient's healthcare provider had discretionover the conversion dose of lovastatin, includingreducing the amount a patient received based on clinicalcircumstances.
Electronic data were collected on all patients activelyconverted between April 1, 2002, and March 31,2003. Patient prescription records for the year beforeconversion (simvastatin therapy) and the months afterconversion (while on lovastatin therapy) were recorded.The daily doses of simvastatin and lovastatin weredetermined based on the tablet strength and the directionsfor use. Laboratory data were collected beginning365 days before the conversion through June 30, 2003,for each patient. This allowed for a minimum of 3months of follow-up for all patients. Laboratory monitoringconsisted of baseline and postconversion lipidresults (LDL-C, HDL-C, and TG) and all serum transaminasetests (ALT and aspartate aminotransferase[AST]). Creatine kinase (CK) tests were not required bythe conversion protocol, but were captured if orderedby the patient's provider as part of usual care.
If a patient's baseline LDL-C was more than 10%above the identified goals for primary and secondaryprevention, <130 mg/dL and <100 mg/dL, respectively,then a dosage adjustment was suggested as part of theconversion. A threshold of 10% above goal was basedupon the prevailing opinion within the medical groupsin early 2001 that slight elevations in LDL-C (eg, anLDL-C of 103 mg/dL for secondary prevention) did notnecessarily warrant a dosage adjustment. Therefore, thethresholds for dose escalation recommendations were143 mg/dL or greater for primary prevention and 110mg/dL or greater for secondary prevention. For example,if a primary prevention patient had a baseline LDL-Cof 150 mg/dL while taking simvastatin 10 mg/day, therecommended lovastatin conversion dose would be 40mg/day instead of an equipotent lovastatin dose of 20mg/day. The maximum lovastatin dose allowed on anyconversion was 80 mg/day. If a patient was not at goalon simvastatin 40 mg daily, the recommendation was toadjust the dose to simvastatin 80 mg daily. In responseto the postconversion LDL-C values, the decision toadjust a patient's lovastatin dosage was left up to the primarycare provider. For purposes of this study we comparedthe final lovastatin dosage with the preconversionsimvastatin dosage.
Patients
All patients age ≥18 years receiving simvastatin atdoses up to 40 mg daily were potential candidates forthe conversion. To be eligible for the analysis, patientswere required to have a baseline and a postconversionLDL-C lab test.
Exclusions from the conversion were based on safetyconsiderations and the presence of potentially interactingdrugs. Therefore, patients at increased risk of muscletoxicity were not converted. These included patientswith decreased renal function (women with a serumcreatinine [SCr] concentration of ≥2.0 mg/dL and menwith a SCr concentration of ≥2.5 mg/dL), patients takingdrugs known to interfere with lovastatin metabolism(cyclosporine, macrolide antibiotics, azole antifungals,verapamil, amiodarone, protease inhibitors, and nefazodone),patients currently taking niacin or fibrates,patients with known HIV infection, and patients receivingmore than 40 mg of simvastatin per day.
International
Classification of Diseases, Ninth Revision
ICD-9
ICD-9
Patients were divided into primary-prevention andsecondary-prevention categories. Estimating a patient's10-year CHD risk was not possible because family historyof heart disease, tobacco use, and blood pressuremeasurements were not available in our electronicdatabases. Therefore, secondary-prevention patientswere defined as those meeting criteria for inclusioninto 1 of 2 KP disease management registries at thetime of conversion (Diabetes Registry and/or CoronaryArtery Disease [CAD] Registry). Inclusion in theDiabetes Registry is based on diagnosis coding ([] code 250 -diabetes) and prescription records(oral antidiabetic agents and/or insulin). Inclusion inthe CAD Registry is based on diagnosis coding (codes 410, 411, 412 and 414—ischemic heart disease,440—atherosclerosis, 443.9—peripheral vascular disease),procedure codes (Current Procedural Terminology36.0x—percutaneous transluminal coronaryangioplasty, 36.1x—coronary artery bypass graft), andprescription records (oral and topical nitrates).Patients not meeting inclusion criteria for 1 of theseregistries were categorized in the primary-preventiongroup.
End Points
Conversion effectiveness was determined by comparingbaseline and postconversion LDL-C results.Baseline LDL-C tests had to be done within 365 days ofthe conversion date while the patient was on simvastatin.If a patient had multiple LDL-C tests within the365-day window, then the lab value closest to the conversiondate was used for the analysis. PostconversionLDL-C lab tests needed to be done at a minimum of 4weeks after the conversion date. For patients with multipleLDL-C tests performed postconversion, the lastLDL-C test result on lovastatin therapy was the primaryend point used in the analysis. This result reflected anydosage titrations done subsequent to the initial conversion.We also analyzed the first postconversion LDL-Ctest results.
Although HDL-C and TG laboratory tests were recommendedfor all converted patients, this was not arequirement for inclusion in the analysis. Baseline andpostconversion HDL-C and TG laboratory tests used thesame timing criteria established for LDL-C testing.
The primary safety end points were a comparison ofALT and CK elevations postconversion versus preconversion.All ALT and CK tests done within 365 daysbefore the conversion date (baseline) were collected.Postconversion ALT and CK tests were those done atany point after the conversion date through the end oftherapy or June 30, 2003. If a patient had multiple ALTor CK tests, then the highest (maximum) test result wasused for comparison. Therefore, the maximum resultwas not necessarily the test done immediately beforeconversion. CK increases associated with a myocardialinfarction were excluded from the safety analysis. Forpurposes of this analysis, a myocardial infarction wasdefined as a Troponin I result of ≥0.3 ng/mL, or a combinationof a CK-MB percentage of ≥3 plus a total CKMBof ≥8.1 mg/dL.
Statistical Analysis
t
P
Patients served as their own controls with the prepostdesign. A chi-square test and McNemar's test wereused for categorical outcome variables and frequencyresults. A paired test and the Wilcoxon signed ranktest were used for continuous variables, with a decisionbased on the distribution of the results (normal vs nonnormaldistribution). Multivariate logistic regressionwas used to evaluate patient risk factors associated withelevated CK laboratory results after conversion. Giventhe large population of patients converted from simvastatinto lovastatin, a 2-sided < .01 was defined as thelevel necessary to achieve statistical significance.
RESULTS
A total of 33 318 patients met criteria for inclusion inthe analysis. Patient demographics are listed in Table 1.Patients converted to lovastatin were elderly and predominantlymale. Within our population, more womenwere being treated for primary prevention than for secondaryprevention, while the split was more even withmale patients. The average duration of lovastatin followupwas 11 months, and the mean time between conversionand the last LDL-C laboratory test was more than6 months. On initial conversion, the majority ofpatients (82.7%) received an equipotent dose of lovastatin,with a small percentage (5.6%) receiving a doseincrease. We observed further dosage titration duringthe follow-up period, and an additional 5.1% of patientshad their lovastatin dose increased.
P
P
The frequency of follow-up LDL-C testing varied, with47.9% of patients having only a single test performed and6.9% having 4 or more tests done. Based on eachpatient's last or only test result during follow-up (primary end point), LDL-C decreased by an average of 2.5mg/dL, HDL-C increased by 2.2 mg/dL, and TG decreasedby 1.6 mg/dL following the conversion (< .001,Table 2). Results were slightly different when the firstpostconversion lab tests were analyzed: average LDL-Cdecreased by 1.8 mg/dL, HDL-C decreased by 1.0 mg/dL,and TG increased by 1.0 mg/dL. Improvements in lipidtest results were seen in both primary-prevention andsecondary-prevention patients. All lipid changes werehighly significant (< .001), except for TG changes insecondary-prevention patients. This level of statisticalsignificance is likely due to the large size of the studypopulation.
P
When grouped by postconversion dosage adjustment,all 3 groups of patients (dose increase, dose decrease,and equipotent dose) had lower LDL-C values after conversion,although differences were not always statisticallysignificant. In patients who received an equipotentdose of lovastatin, the change in LDL-C was not statisticallysignificant (= .78).
P
P
The percentage of patients at target LDL-C values forsecondary prevention (<100 mg/dL) changed from55.7% preconversion to 56.4% postconversion (= .12,not significant). For primary-preventionpatients, the percentage ofpatients at goal postconversion wassignificantly higher than the percentageat goal preconversion (< .001).
Only 72.6% of the patients whomet inclusion criteria had both abaseline and a postconversion ALTmeasurement done (Table 3). Anequal number of patients experiencedmild elevations in ALT beforeand after converting to lovastatin.Marked elevations in ALT, greaterthan 3 times the upper limit of normal(ULN), occurred in 0.7% of thepatients before and 0.6% of patientsafter the conversion. Compared withpatients who had normal ALT valuesat baseline, patients with marked elevationsin ALT before converting weremore likely to have marked elevationsafter conversion (Table 4).
As CK tests were ordered at thediscretion of the primary careproviders, the total number ofpatients with CK tests at baseline andpostconversion was different. Ofthose tested, marked CK increases(>10 ULN) occurred at the same ratebefore and after the conversion(Table 3). No patient with a marked elevation in CKbefore conversion experienced a similar increase onlovastatin. Male patients (odds ratio [OR] = 1.8, 95%confidence interval [CI] = 1.1, 3.0) and those with elevatedCK results (>500 U/L) before conversion (OR =16.1, 95% CI = 9.7, 26.3) were more likely to have elevatedCK tests (>500 U/L) postconversion. Lovastatindosage and age were not associated with increased oddsof elevated CK test results postconversion.
DISCUSSION
Our results in 33 318 patients support the effectivenessand safety of converting patients from simvastatinto lovastatin. Postconversion lipid, ALT, and CK levelswere similar to the preconversion levels. In a comparisonof preconversion and postconversion average lipidtest results, LDL-C decreased, HDL-C increased, andTG decreased. Rates of ALT and CK elevations werenot significantly different before and after the conversion.These data confirm our a priori hypothesisthat lovastatin is an effective and safe alternative formanaging hypercholesterolemia.
Our results are consistent with previous statin conversionstudies.24-27 Three of these studies included relativelysmall numbers of patients (approximately 100) intheir analysis.24-26 The investigators in these studiesfound no difference in the preconversionand postconversion lipid levelsand concluded that the conversionwas safe and effective. Safety andeffectiveness, however, are difficult toassess with sample sizes of only 100patients. Ito et al conducted a largestudy involving 1032 VeteransAdministration patients who completeda conversion from pravastatinto simvastatin.27 Individual simvastatindoses were titrated to achievepredefined LDL-C results. In thisstudy, LDL-C improved from 116mg/dL to 99 mg/dL, and the percentageof patients at goal improved from44% to 69% postconversion. Liverfunction tests and CK results weresimilar at baseline and postconversion.The authors concluded thatconversion was effective and costsaving.
One strength of our study is thelarge population of patients we wereable to observe. This is importantwhen evaluating both the effectivenessand the safety of a therapeuticconversion. In particular, our largesample provided the power necessary to evaluaterates of hepatic and muscle enzyme elevationsassociated with these 2 statins. Increasesin ALT greater than 3 times the ULN andincreases of CK greater than 10 times the ULNoccurred at similar rates with simvastatin andlovastatin.
Our rate of marked hepatic enzyme elevationwas comparatively low (0.6-0.7%).28 A possibleexplanation for the low rate observed inour population was that patients were beingsuccessfully treated with simvastatin and weretherefore self-selected. Patients intolerant tosimvastatin and not taking the drug were notinvolved in the conversion. We also specificallyexcluded certain populations who werepotentially at higher risk for toxicity based oncoexisting conditions and potentially interactingdrugs.
There was no difference in the rate of increasedCK values between simvastatin (preconversion)and lovastatin (postconversion). However, the rate ofmarked CK elevations was higher in our population than isusually reported in the literature.29 An explanation forthe higher rates in our study is that our rates reflect onlythose patients who had CKtests ordered; most of thepublished incidence ratesreport CK elevations as apercentage of the total numberof patients on statinprescriptions.
The slightly improvedlipid results we observed atequipotent doses mayreflect external patient factorsassociated with theconversion. Patients mayhave become more compliantwith their new regimendue to increased contactwith providers. Patients alsoknew that laboratory followupwas a necessary part ofthe conversion, and the factthat outreach efforts weremade to those patients whofailed to get laboratory tests done could also have affectedthe results.
A limitation of this study is that it relied on electronicdata capture and did not include direct patient contactor chart reviews by the investigators. This can leadto misclassification errors, especially when separatingpatients into primary-prevention and secondary-preventioncategories based on registry data, or when evaluatingpostconversion dose-adjustment groupings. Oneanomalous finding was that patients with effective postconversiondosage reductions also achieved lower postconversionLDL-C values. Information not capturedelectronically but available to the provider may explainthese results. For example, providers may have decidedto reduce the dose based on clinical circumstances outsideof LDL-C results and CK or ALT values.
Another limitation to this study is that clinical outcomeswere not measured; lipid laboratory results wereused as surrogate effectiveness markers and the primaryend point for this analysis. The follow-up period also wasshort and variable, ranging from 3 to 15 months.Therefore, we were unable to assess patients' persistence(long-term adherence) with their new lovastatin regimen.
The relative cost of statins within managed careorganizations is highly dependent on contracting, suchthat a cost analysis would have limited generalizability.Although generic lovastatin is the most cost-effectivestatin for mild to moderate LDL-C reductions within KP,this may not be the case in other organizations or outsideof the managed care environment. From thepatient's perspective, the availability of a generic statinmay still be an advantage, especially for patients withtiered or generic-only drug coverage plans.
The results of our study revealed that just 56.4% and72.2% of patients had reached the identified LDL-Cgoals of <100 and <130 mg/dL in the secondary-preventionand primary-prevention groups, respectively.Although this did represent an increase from preconversionvalues, significant opportunity for improvementremains. Although the original conversionprogram actively recommended consideration ofdosage adjustment in patients with baseline LDL-C valuesat 10% above goal, it was not designed with anaggressive titration feature. Ongoing conversion programsnow recommend a dosage or medication adjustmentin patients whenever the baseline LDL-C value isgreater than goal.
CONCLUSION
This study of more than 33 000 patients demonstratesthat appropriately selected patients can be safelyand effectively converted from branded simvastatin(Zocor) to generic lovastatin.
From the Pharmacy Analytic Service, Kaiser Permanente Southern California, Downey,Calif (TCC); the Pharmacy Outcomes Research Group, Oakland, Calif (JC); the SouthernCalifornia Permanente Medical Group, Harbor City, Calif (VB); the Drug Information Service,Oakland, Calif (CR); and the Permanente Medical Group, Santa Clara, Calif (EL, DC).
This research was presented at the 2004 American Heart Association ScientificMeeting, New Orleans, La, November 9, 2004.
Address correspondence to: Craig Cheetham, PharmD, MS, Pharmacy Analytic Service,Kaiser Permanente, 9521 Dalen Street, Downey, CA 90242. E-mail:craig.t.cheetham@kp.org.
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