In 2001, the National Cholesterol Education Program

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1 At a Glance Practical Implications p 330 Author Information p 333 Full text and PDF Lipid Management When Converting Fluvastatin to Pravastatin: Medication Use Evaluation Original Research Rebecca A. Falter, PharmD; and Jennifer N. Clements, PharmD, BCPS, CDE In 2001, the National Cholesterol Education Program (NCEP) published guidelines regarding the detection, evaluation, and treatment of high blood cholesterol in adults. 1 The NCEP updated the Adult Treatment Panel (ATP) III guidelines in 2004 to provide more stringent low-density lipoprotein (LDL) cholesterol goals compared with the previous guidelines. Table 1 summarizes the 2004 update providing recommendations for LDL goals, therapeutic LDL options, and when medication therapy should be added to lifestyle modifications. 1 The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor class, also known as statins, have been shown to be the most effective in lowering LDL cholesterol. This class of medication has been shown to decrease morbidity and mortality in patients at risk for cardiovascular events. Each statin medication has a different effect on the amount of LDL reduction. The ATP III guidelines provide standard doses of the currently available statin medications to reduce LDL by 30% to 40%. An LDL reduction of 34% has been seen with pravastatin doses of 40 mg per day, while an LDL reduction of 35% has been seen with fluvastatin doses of 80 mg per day. 1 This information indicates a probable dosing ratio of 2:1 (fluvastatin to pravastatin) when converting patients lipid therapy. Veterans Affairs (VA) patients may be converted to a new therapy based on changes to the VA national formulary. This formulary may be updated due to changes in safety or efficacy as determined by new evidence from clinical studies or changes in cost. In August 2007, VA Medical Centers switched patients formerly on fluvastatin to pravastatin for cost avoidance. Table 2 summarizes the conversion of fluvastatin to pravastatin. 2 A study by Jacotot and colleagues followed 134 patients randomized to double-blind, double-placebo treatment beginning with either fluvastatin 40 mg or pravastatin 20 mg for 16 weeks. During the first 4 weeks of the study, patients received either medication dosed once daily. For the last 12 ABSTRACT Objectives: To determine whether conversion from fl uvastatin to pravastatin results in comparable low-density lipoprotein (LDL) cholesterol lowering effects. Study Design: Retrospective chart review of patients converted from fl uvastatin to pravastatin therapy. Methods: Patients of the Veterans Affairs Medical Center in the mid-atlantic region and associated Community-Based Outpatient Clinics with measured fasting lipid panel 24 weeks before and between 6 and 24 weeks after the conversion met the inclusion criteria. Primary and secondary end points were assessed using the paired t test to compare preconversion and postconversion mean LDL levels. Results: Among 70 patients meeting the inclusion criteria, there was no signifi cant difference between the mean LDL levels with fl uvastatin and pravastatin therapy. Following conversion, statistically signifi cant changes were found in total cholesterol (TC), triglycerides (TGs), and high-density lipoprotein (HDL) (P =.001,.045, and.008, respectively). The HDL improvement was considered clinically signifi cant because patients achieved their HDL goal with pravastatin therapy. Although there was a signifi cant difference in patients TC and TGs, patients generally remained at goal after the conversion. For patients with type 2 diabetes mellitus, conversion from fl uvastatin to pravastatin provided no statistically signifi cant difference regarding the lipid panel. There was a 2.44% incidence of total adverse drug reactions in the pravastatin group. Conclusions: Appropriate follow-up would be necessary to monitor variances in lipid parameters and provide appropriate dosage adjustments after the conversion. Patients requiring more stringent LDL control were well managed through this conversion. Pravastatin was well tolerated during the 24-week period following the conversion. (Am J Pharm Benefi ts. 2011;3(6): ) Vol. 3, No. 6 The American Journal of Pharmacy Benefi ts 329

2 n Falter Clements PRACTICAL IMPLICATIONS Retrospective chart review indicated that there were no significant differences in mean low-density lipoprotein cholesterol levels after patients were converted from fluvastatin to pravastatin therapy. n Although there was a significant difference in patients total cholesterol and triglycerides, patients generally remained at goal after the conversion. n Pravastatin was well tolerated, with a 2.44% incidence of total adverse drug reactions. n This research could help with development of formularies, implementation of strategies for cost savings, and evaluation of outcomes research. weeks of the study, fluvastatin patients were increased to 40 mg twice daily and pravastatin patients were increased to 40 mg daily. During the initial 4 weeks of treatment, fluvastatin 40 mg daily and pravastatin 20 mg daily were equally efficacious in lowering LDL levels. At the end of 16 weeks of treatment, a significant difference was found with fluvastatin 40 mg twice daily versus once daily, with LDL decreasing by 30.4% (P <.001). Among patients taking pravastatin 40 mg daily, LDL decreased by 26.6% but the decrease was not found to be statistically significant. Liver function tests (LFTs) and creatine phosphokinase (CPK) levels were monitored, and no abnormalities were observed throughout the study. 3 The primary objective for this retrospective study was to determine whether conversion of fluvastatin to pravastatin therapy results in comparable LDL-lowering effects. STUDY DESIGN This study was a retrospective chart review of VA patients converted from fluvastatin to pravastatin. The VA prescription database VISTA was used to evaluate prescription reviews followed by use of the Computerized Patient Record System to conduct medical chart reviews. The Administrative Officer used the FileMan program to extract the names of all patients who were converted from fluvastatin to pravastatin during the conversion. Patient data were collected and included diagnosis of diabetes per chart problem list, prescription number, LDL, total cholesterol (TC), triglycerides (TGs), highdensity lipoprotein (HDL) cholesterol, alanine aminotransferase, aspartate aminotransferase, and CPK levels, and incidence of possible adverse events. Adverse events were defined as a change in statin therapy after the conversion as documented in the patient s chart, an abnormal LFT result (defined as >3 times the upper limit of normal), an abnormal level of CPK (defined as >10 times the upper limit of normal), or a documented drug allergy to pravastatin. METHODS Patients meeting the defined inclusion and exclusion criteria were included. The number of patients was predefined by the conversion that had already taken place. Only patients of the VAMC and associated Community- Based Outpatient Clinics (CBOCs) with a measured fasting lipid panel 24 weeks prior to the conversion and a measured fasting lipid panel between 6 and 24 weeks after the conversion of fluvastatin to pravastatin met the inclusion criteria. Exclusion criteria included patients not from the VAMC or associated CBOCs, patients on multiple medications for dyslipidemia, patients not meeting their LDL goal previously on fluvastatin, lack of a fasting lipid panel 24 weeks prior to the conversion or between 6 and 24 weeks after the conversion, or patients not following the dosing conversion as provided. The LDL goals were determined by 2004 ATP III guidelines. There was no compensation for patients who participated in this study. Patient privacy was protected by assigning each patient a unique identification number consisting of the patient s pravastatin dose and an assigned sequential ending number (eg, 20prava-1). The patient identifiers Table 1. ATP III 2004 Update Summary a Risk Category LDL Goal Therapeutic Option Consideration of Medication Therapy in Addition to Lifestyle Modifications High risk <100 mg/dl <70 mg/dl LDL >100 mg/dl Moderately high risk <130 mg/dl <100 mg/dl LDL >130 mg/dl (Optionally: mg/dl) Moderate risk <130 mg/dl LDL >160 mg/dl Low risk <160 mg/dl LDL >190 mg/dl (Optionally: mg/dl) ATP indicates Adult Treatment Panel; LDL, low-density lipoprotein. a Adapted from reference The American Journal of Pharmacy Benefits November/December

3 Converting Fluvastatin to Pravastatin were promptly destroyed by placing in VAMC shred bins after the unique ID had been created for each patient. End Points The primary end point of this study was to compare mean LDL levels of fluvastatin and pravastatin therapy following a conversion. The secondary end points were to compare mean TC, TG, and HDL levels between fluvastatin and pravastatin therapy; to compare the percentages of type 2 diabetes mellitus (T2DM) patients who were at the desired LDL goal between the 2 statin groups; and to assess the incidence of adverse events following the conversion to pravastatin therapy. Statistics The primary end point was assessed using the paired t test to compare the preconversion and postconversion mean LDL levels ± the standard deviation. A significant difference from the null hypothesis was defined as a 2-sided α of.05. The secondary end points were assessed using the paired t test to compare the preconversion and postconversion mean levels of TC, TGs, and HDL ± the standard deviation and to assess the differences in T2DM patients who achieved their LDL goal with fluvastatin therapy versus pravastatin therapy. RESULTS The VAMC and associated CBOCs converted a total of 369 patients from fluvastatin to pravastatin. Of the Table 2. Dosing Conversion Before Conversion Fluvastatin 20 mg Fluvastatin 40 mg Fluvastatin 80 mg After Conversion Pravastatin 10 mg Pravastatin 20 mg Pravastatin 40 mg 369 patients, 70 patients met the inclusion criteria (Figure). All of the 70 included patients were male, with 17 patients having a diagnosis of T2DM. The remaining patients were excluded due to not following the dosing conversion, concomitant dyslipidemic therapy, lack of lipid panels 24 weeks before the conversion or 6 to 24 weeks after the conversion, or not meeting their LDL goal with fluvastatin therapy. Following the conversion, LDL levels did increase by an average of 4 mg/dl; however, these results were not statistically significant among all 70 patients (P =.093), as well as among the patients receiving maximized pravastatin therapy (P =.311). The conversion resulted in statistically significant differences in TC, TGs, and HDL with P =.001,.045, and.008, respectively (Table 3). TC and TG levels were less well controlled and HDL levels were more controlled with pravastatin therapy. Only the improvement of HDL was considered clinically significant, because patients achieved their HDL goal with pravastatin therapy. Although there was a significant difference in TC and TG values, patients generally remained at goal after Figure. Patient Population 369 Total patients converted to pravastatin 70 Included 299 Excluded 17 Subgroup of diabetic patients 190 Did not follow dosing conversion 27 Concomitant dyslipidemic therapy 51 No lipid panels ±24 weeks of conversion 31 Not at LDL goal with fluvastatin LDL indicates low-density lipoprotein. Vol. 3, No. 6 The American Journal of Pharmacy Benefits 331

4 n Falter Clements Table 3. Statistical Analysis End points No. Fluvastatin Group Mean a Pravastatin Group Mean a Mean ± SD Change in Mean P All patients LDL values TC values b TG values b HDL values b Patients on maximum therapy LDL values TC values b TG values HDL values b Patients with type II diabetes LDL values TC values TG values HDL values HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglyceride. a Values are given as milligrams per deciliter. b P <.05. the conversion. Most patients had no change with respect to remaining at their lipid panel goals after the conversion: 62.9% (LDL), 87.1% (TC), 80% (TGs), and 80% (HDL). For patients on maximum statin therapy, the conversion from fluvastatin to pravastatin resulted in statistically significant differences in TC and HDL. These changes may not be considered clinically significant, as patients remained at goal. The largest change in mean lipid panel values occurred with TGs ( mg/dl), though this change was not found to be significant. For T2DM patients, the conversion from fluvastatin to pravastatin resulted in no statistically significant differences in all lipid parameters. Most of the T2DM patients (88%) remained at their LDL goal after the conversion. The adverse drug reactions were documented when reviewing all pravastatin-converted patients (n = 369). Myalgias were reported per patient charts in 4 patients, gastrointestinal disturbances in 2 patients, rhabdomyolysis in 1 patient, dizziness in 1 patient, and increased LFTs in 1 patient. There was a 2.44% incidence of total adverse drug reactions in the pravastatin group. DISCUSSION The purpose of the study was to provide information regarding future formulary conversions from the standpoint of cost avoidance. As anticipated, the conversion to pravastatin did not provide significant improvements in the lipid panel. In addition, these results were not statistically significant either for the total population or for the maximum therapy and diabetic subgroups (P =.093,.311, and.387, respectively). Although LDL slightly increased, the increase was not considered to be clinically significant, as 80% of total patients and 88% of the T2DM patients remained at their LDL goal after the conversion. For patients who did not remain at their LDL goal, either an increase in dose or trial of a more potent statin could be considered. All results were comparable following the conversion of fluvastatin to pravastatin therapy, with a total cost savings of $ for the Martinsburg, West Virginia, VAMC. These results may be interpreted based on clinical significance, because a 1% reduction in LDL can result in a 1% decrease in coronary artery disease events. In addition, a 1 mg/dl reduction in HDL can result in a 2% to 3% increase in coronary artery disease events. 1 It was not the purpose of the study to evaluate cardiovascular events based on changes in lipid panels. As this study was a retrospective chart review, there are several limitations. First, the exact date that pravastatin therapy began might have varied by patient, and it was not assessed during this study, as there was no contact with the patients. Second, patients might have made lifestyle changes at any time during therapy that could positively or negatively affect the lipid panel results. Third, lack of a control group regarding lipid values might reflect the fact that the study was conducted during the Thanksgiving and winter holidays. More patients might have been included if the time frame to assess lipid panels had been set at 12 months; before 332 The American Journal of Pharmacy Benefits November/December

5 Converting Fluvastatin to Pravastatin the conversion, patients with well-controlled lipid panels could have a lipid panel drawn every 12 months versus 6 months per the inclusion criteria. Lastly, patient adherence was not assessed, as patients were not contacted during this study. It is unknown why 49% of the initially screened patients did not follow the recommended conversion. Therefore, it cannot be determined whether medication nonadherence might have played a role in the unmet lipid panel goals. Overall, it can be concluded that with this medication conversion, appropriate follow-up of 6 to 8 weeks as recommended by the current guidelines 1 should be considered to monitor variances in lipid parameters and provide appropriate dosage adjustments so that patients can continue to meet their lipid panel goals. Patients requiring more stringent LDL control were well managed through this conversion, as the majority of T2DM patients remained at goal. Pravastatin was well tolerated during the 24-week period following the conversion. Acknowledgments We acknowledge Michael Evanko, RPh, for his guidance and support in conducting this study, Florinda Vitanza, LPN, for assisting with data collection, and Wallace Marsh, MBA, PhD, for assisting with statistical analysis. Author Affiliations: Bernard J. Dunn School of Pharmacy, Shenandoah University (RAF, JNC), Winchester, VA. Author Disclosures: The authors (RAF, JNC) 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 (RAF, JNC); acquisition of data (RAF); analysis and interpretation of data (RAF, JNC); drafting of the manuscript (RAF, JNC); critical revision of the manuscript for important intellectual content (RAF, JNC); and supervision (JNC). Funding Source: This study was supported by the Department of Veterans Affairs and with resources and facilities at the Martinsburg, West Virginia, Veterans Affairs Medical Center. Address correspondence to: Jennifer N. Clements, PharmD, BCPS, CDE, Bernard J. Dunn School of Pharmacy, Shenandoah University, 1775 North Sector Court, Winchester, VA jcrist2@su.edu. REFERENCES 1. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763]. Circulation. 2004;110(2): Kelley C. Statin Criteria for Use (Pravastatin, Rosuvastatin, Atorvastatin, Fluvastatin, Fluvastatin XL). VHA Pharmacy Benefits Management (PBM) Services, Medical Advisory Panel (MAP) and VISN Pharmacist Executives (VPEs). Criteria%20for%20Use%20(Fluvastatin-Pravastatin-Atorvastatin-Rosuvastatin)- Final%20(9-11).doc. Updated September Accessed November 14, Jacotot B, Benghozi R, Pfister P, Holmes D; French Fluvastatin Study Group. Comparison of fluvastatin versus pravastatin treatment of primary hypercholesterolemia. Am J Cardiol. 1995;76(2):54A-56A. Vol. 3, No. 6 The American Journal of Pharmacy Benefits 333