Am J Cardiovasc Drugs DOI 10.1007/s40256-014-0096-x

ORIGINAL RESEARCH ARTICLE

Simvastatin Prescribing Patterns Before and After FDA Dosing Restrictions: A Retrospective Analysis of a Large Healthcare Claims Database Rhianna M. Tuchscherer • Kavita Nair • Vahram Ghushchyan • Joseph J. Saseen

Ó Springer International Publishing Switzerland 2014

Abstract Background Muscle-related events, or myopathies, are a commonly reported adverse event associated with statin use. In June 2011, the US FDA released a Drug Safety Communication that provided updated product labeling with dosing restrictions for simvastatin to minimize the risk of myopathies. Objective Our objective was to describe prescribing patterns of simvastatin in combination with medications known to increase the risk of myopathies following updated product labeling dosing restrictions in June 2011. Methods A retrospective observational analysis was carried out, in which administrative claims data were utilized to identify prescribing patterns of simvastatin in combination with calcium channel blockers (CCBs) and other pre-specified drug therapies. Prescribing patterns were analyzed on a monthly basis 24 months prior to and 9 months following product label changes. Incidence of muscle-related events was also analyzed.

Results In June 2011, a total of 60 % of patients with overlapping simvastatin–CCB claims and 94 % of patients with overlapping simvastatin–non-CCB claims were prescribed an against-label combination. As of March 2012, a total of 41 % and 93 % of patients continued to be prescribed against-label simvastatin–CCB and simvastatin– non-CCB combinations, respectively. The most commonly prescribed dose of simvastatin was 20 mg (39 %). Againstlabel combinations were most commonly prescribed at a simvastatin dose of 40 mg (56 %). Amlodipine was the most commonly prescribed CCB in combination with simvastatin (70 %) and the most common CCB prescribed against-label (67 %). Conclusions Despite improvements in prescribing practices, many patients are still exposed to potentially harmful simvastatin combinations. Aggressive changes in simvastatin prescribing systems and processes are needed to improve compliance with FDA labeling to improve medication and patient safety.

During the time of project completion, Dr. Tuchscherer was a PGY2 resident at the University of Colorado. R. M. Tuchscherer Department of Family Medicine and Community Health, University of Minnesota School of Medicine, Minneapolis, MN, USA K. Nair  V. Ghushchyan  J. J. Saseen (&) Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd. (C238 V20-2126), Aurora, CO 80045, USA e-mail: [email protected] V. Ghushchyan American University of Armenia, Yerevan, Armenia J. J. Saseen School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Key Points The US FDA released a Drug Safety Communication in June 2011 highlighting updated product labeling for simvastatin. These changes included new dose restrictions, contraindications, and stricter maximum dose limitations to promote safer use and minimize risk of muscle-related events. Our observational analysis revealed that use of against-label prescribing of simvastatin in combination with other medications continues despite the known risk of muscle injury.

R. M. Tuchscherer et al.

1 Introduction HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) are established as first-line therapy for the treatment of dyslipidemia [1, 2]. Their beneficial effects in reducing cardiovascular morbidity and mortality are well documented, and evidence from controlled trials reveals that statins are generally well tolerated, with favorable safety profiles [3–7]. However, of the associated adverse effects, muscle-related events are commonly reported and may range in severity from mild myalgias to life-threatening cases of rhabdomyolysis. These have collectively been referred to as myopathies [8]. A joint Clinical Advisory published by the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute (ACC/ AHA/NHLBI) in 2002 acknowledged the potential risk of muscle-related disease with the use of statin medications. It further provided clinical practice recommendations for their appropriate use, including cautions, contraindications, and safety monitoring. This report identified several risk factors that may increase a patient’s risk of developing statin-associated myopathies. These risk factors included advanced age (especially [80 years), small body frame and frailty, multi-system disease, use of multiple medications, and perioperative periods. Of note, several specific medications were also identified as increasing the risk of statin-associated myopathy, with a broad recommendation for clinicians to check statin product labeling for drugspecific warnings prior to prescribing these agents concomitantly. Medications listed in the report included the following: fibrates, nicotinic acid, cyclosporine, azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone, verapamil, and amiodarone [9]. In June 2011, the US FDA released a Drug Safety Communication that introduced new labeling with additional dosing restrictions for simvastatin. These changes were implemented to promote safer use of simvastatin, including minimizing the risk of muscle-related adverse events. These changes were based on evidence from the SEARCH trial and other data collected during the FDA’s ongoing safety review. Revised simvastatin labeling provided restrictions on the highest dose of simvastatin (80 mg per day), new contraindications in terms of concomitant use with various other medications, and stricter maximum dose limitations with simvastatin when used concomitantly with other specific medications [10]. Of note, some label changes, including the calcium channel blocker (CCB) dosing restrictions, reflected evidence from pharmacokinetic analyses that indicated increased simvastatin levels when administered concomitantly [11–15]. As such, the new product label included a maximum FDA-

approved simvastatin dose of 10 mg when used concomitantly with diltiazem and verapamil, which was decreased from the previous maximum doses of 40 mg and 20 mg daily, respectively. Moreover, this new product label also included a maximum FDA-approved simvastatin dose of 20 mg when used concomitantly with amlodipine [10, 16]. Previous FDA-approved labeling did not have a maximum dose restriction for simvastatin when given concomitantly with amlodipine. Clinical experience reveals that individual patients often have many concurrent cardiovascular risk factors. As such, CCBs are frequently prescribed in patients who also require statin therapy [17, 18]. Therefore, for patient safety, it is important for clinicians to comply with FDA-approved dosing when interacting combinations of simvastatin with CCBs are utilized. This study looked to describe prescribing patterns of simvastatin in combination with three common CCBs (amlodipine, diltiazem, and verapamil) as well as other medications known to increase the risk of myopathy before and after revised FDA dosing restrictions were included in the simvastatin product labeling in June 2011.

2 Methods 2.1 Study Design and Setting We conducted a retrospective observational analysis of simvastatin prescribing patterns using data from the PharMetricsÒ Integrated Database (IMS Health, Inc.). This database contains de-identified inpatient and outpatient claims, diagnosis, and procedure information based on International Classification of Diseases, ninth revision (ICD-9) codes, Current Procedural Terminology, fourth edition (CPT-4) codes, retail pharmacy claims, and mail order pharmacy claims from a 10 % sample of over 70 million members from more than 45 health plans across the USA. In order to identify a pattern, we observed the prescribing patterns of simvastatin in combination with CCBs or other pre-specified therapies on a monthly basis for 24 months prior to the simvastatin product labeling changes in June 2011 and for 9 months following these labeling changes. Therefore, the study timeframe was 1 June 2009 to 31 March 2012. Study investigators did not have access to claims data beyond March 2012, thus prescribing patterns were not analyzed beyond this date. For the purposes of this study, prescribing patterns were observed and analyzed utilizing a prescription-based approach on a month-by-month basis. As such, pharmacy claims were used to identify concurrent prescribing. A

Simvastatin Prescribing Before and After FDA Dosing Restrictions

prescription claim for simvastatin along with a prescription claim for one of the other medications of interest within the same month was used to define concurrent prescribing. Once concurrent prescribing was identified using this definition, the doses of the medications were analyzed to classify their use in combination as ‘against-label’ or ‘clinically acceptable’ according to FDA-approved dosing for simvastatin per product labeling. 2.2 Study Participants To effectively identify prescribing patterns, only study participants with continuous enrollment in their health plans throughout the entire study timeframe were identified for inclusion. Patients were then included if they met the following criteria: aged 18–86 years as of 1 June 2009 and one or more prescription claim(s) for simvastatin within the study timeframe. Exclusion criteria included concurrent claim(s) for any other medication of which use with simvastatin was recommended to be avoided prior to June 2011, or documented stage 4 or 5 chronic kidney disease (CKD). Excluded medications included itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, nefazodone, boceprevir, and telaprevir. Of note, these exclusion criteria were only utilized for the additional analysis of musclerelated adverse events because they could directly influence assessment of the secondary objective. 2.3 Study Outcomes For the primary study analysis, the primary outcome was the use of against-label and clinically acceptable simvastatin–CCB dosing combinations before and after June 2011. CCBs with dosing restrictions following June 2011 included amlodipine, diltiazem, and verapamil. For the secondary study analysis, the outcome was the use of against-label and clinically acceptable simvastatin–nonCCB combinations before and after June 2011. Only those medications with new contraindications or dose restrictions following the June 2011 label changes were analyzed. Newly contraindicated medications with simvastatin as of June 2011 included cyclosporine, danazol, gemfibrozil, and posaconazole, while dosing restrictions with amiodarone and ranolazine were updated to not exceed 10 mg and 20 mg of simvastatin, respectively. FDA product labeling for simvastatin from June 2011 was used to define againstlabel prescribing and clinically acceptable prescribing of specific other drugs cited in product labeling in combination with simvastatin (Table 1). The incidence of muscle-related adverse events before and after the June 2011 product labeling changes was also evaluated in additional analyses.

Table 1 Against-label and clinically acceptable dosing combinations [16] Against-label simvastatin doses (mg)

Clinically acceptable simvastatin doses (mg)

Amlodipine

40, 80

5, 10, 20

Diltiazem

20, 40, 80

5, 10

Verapamil

20, 40, 80

5, 10

Primary analysis

Secondary analysis Amiodarone

20, 40, 80

5, 10

Cyclosporine

5, 10, 20, 40, 80

NAa

Danazol

5, 10, 20, 40, 80

NAa

Gemfibrozil

5, 10, 20, 40, 80

NAa

Posaconazole

5, 10, 20, 40, 80

NAa

Ranolazine

40, 80

5, 10, 20

a

Concomitant use with simvastatin was contraindicated following June 2011 product labeling changes NA not applicable

2.4 Data Collection and Statistical Analysis Administrative claims data provided information on patient demographics, including age, sex, and insurance coverage. Medications of interest were identified through the use of generic product identifier and therapeutic classification system (GPI/TCS) codes from the Wolters Kluwer Master Drug Database (version 2.5). Pharmacy claims data were then utilized to identify prescribing of simvastatin and the other medications of interest through the use of National Drug Codes (NDCs). ICD-9-Clinical Modification (ICD-9CM) codes available within the administrative claims data were utilized to classify muscle-related adverse effects including myopathy (359.4, 359.81, 359.9), myalgia/myositis (729.1), rhabdomyolysis (728.88), and other indications of muscle-related adverse events (791.3, E942.2), as well as CKD (585.4, 585.5, 589.9). All administrative claims data were provided to investigators de-identified, with no possibility for patient identification. Due to the observational design of this study, descriptive statistics were utilized for the primary and secondary analyses. A Chi-squared test was utilized to compare incidence of muscle-related adverse events. This study was reviewed and approved by the Colorado Institutional Multiple Review Board at the University of Colorado.

3 Results Overall, 14,206 patients were identified with continuous enrollment throughout the study timeframe (1 June 2009 to 31 March 2012). Patient demographics for this population

R. M. Tuchscherer et al. Table 2 Patient demographics Demographics

Total patients (N = 14,206)

Gender, N (%) Female

6,982 (49)

Male

7,224 (51)

Mean age in 2009 (years)

56.9

Insurance, N (%) Commercial

8,628 (61)

Medicaid

356 (3)

Medicare risk

769 (5)

SCHIP

2,878 (20)

Medicare cost

1,126 (8)

Missing/unknown

449 (3)

SCHIP State Children’s Health Insurance Program

are included in Table 2. Gender was fairly even, with men representing 51 % of identified patients. The average age was 57 years, and the majority of patients were enrolled in some form of a commercial insurance plan. Observed simvastatin and CCB prescribing patterns are presented in Fig. 1. On average, 468 patients (range 391–549) were identified each month with overlapping prescriptions for simvastatin and one of the CCBs (amlodipine, diltiazem, or verapamil). At the time of the product labeling changes in June 2011, a total of 60 % of patients with overlapping simvastatin–CCB claims were prescribed a combination considered to be against-label, and this decreased to 41 % by March 2012, a drop of 19 %. Results for simvastatin and the non-CCB prescribing patterns are presented in Fig. 2. Use of simvastatin concurrently with one of the non-CCB medications (cyclosporine, danazol, gemfibrozil, posaconazole, amiodarone, or ranolazine) was much less frequent, with an average of 53 patients (range 35–70) with overlapping claims each month. At the time of the product labeling changes in June 2011, a total of 94 % of patients with overlapping simvastatin–non-CCB claims were prescribed a combination considered to be against-label. This prescribing pattern remained relatively unchanged, as 93 % of patients continued to be prescribed against-label combinations in March 2012. The most commonly prescribed dose of simvastatin was 20 mg (39 %), followed by 40 mg (36 %), 80 mg (15 %), 10 mg (9 %), and lastly, 5 mg (1 %). Patients prescribed against-label combinations were most commonly prescribed a dose of 40 mg (56 %) or 80 mg (25 %). The remaining patients with against-label claims were prescribed simvastatin at a dose of 20 mg or less (17 % prescribed 20 mg, 2 % prescribed 10 mg, and \1 % prescribed 5 mg). Amlodipine was the most commonly prescribed CCB in combination with simvastatin, representing 79 % of

patients with a claim for this simvastatin–CCB combination, followed by diltiazem (14 %) and verapamil (7 %). Gemfibrozil was the most commonly prescribed non-CCB in combination with simvastatin (79 %). An additional 12 % of patients were prescribed amiodarone in combination with simvastatin, 6 % had overlapping claims of ranolazine and simvastatin, and the remaining 3 % of patients were prescribed a combination of cyclosporine and simvastatin. No patients were identified as having overlapping claims for posaconazole or danazol with simvastatin. The distribution of against-label and clinically acceptable prescribing of these medications concurrently with simvastatin is listed in Table 3. Amlodipine was the most common CCB prescribed against-label in combination with simvastatin (67 %). Additionally, gemfibrozil represented the most common non-CCB prescribed against-label (79 % of patients). A total of 127 muscle-related adverse events were documented out of a total of 22,030 incidents of againstlabel simvastatin–CCB overlapping claims. Only 89 muscle-related adverse events were identified out of 13,949 incidents of clinically acceptable simvastatin–CCB overlapping claims over the 34-month study timeframe. However, there was no difference in the rate of muscle-related adverse events between these groups (0.006 vs. 0.006 % for against-label vs. clinically acceptable, respectively; P = 0.5).

4 Discussion Statins are first-line therapy for the treatment of dyslipidemia based on proven clinical benefits, but their use, especially in combination with various other medications, does not come without potential risk [2, 19]. Frequency of muscle-related adverse events reported from patients in clinical trials tends to vary, with some of the highest rates (11–29 %) reported in observational studies [19–21]. However, the spectrum of muscle-related adverse effects is multifaceted. Patients may complain of myalgia (muscle aches, soreness, stiffness, tenderness, or cramps), defined as unexplained muscle complaints with normal creatine kinase (CK) level, or myopathy (muscle weakness), which may or may not be associated with elevated CK levels. Rather, patients may also demonstrate myositis (muscle inflammation), myonecrosis (muscle enzyme elevations or hyper-CK-emia), or myonecrosis with myoglobinuria or acute renal failure. This last item is also referred to as clinical rhabdomyolysis [19]. While many risk factors for the development of muscle-related adverse events are nonmodifiable (e.g. age [80 years, female gender, renal or liver disease), avoidance of medications alone or in combinations known to increase the risk of muscle-related

Simvastatin Prescribing Before and After FDA Dosing Restrictions 100% 90%

Patients with Overlapping Claims

Fig. 1 Bar graph of simvastatin and calcium channel blocker prescribing patterns from June 2009 through March 2012. Each individual bar represents the total number of patients with an overlapping claim for simvastatin and one of the calcium channel blockers (amlodipine, diltiazem, or verapamil) during each month within the study timeframe. Bars above the trend line denote clinically acceptable combinations and bars below the trend line represent againstlabel combinations

Acceptable

80%

Against-Label

70% 60% 50% 40% 30% 20% 10% 0%

Month 100% 90% Acceptable

Patients with Overlapping Claims

Fig. 2 Bar graph of simvastatin and non-calcium channel blocker prescribing patterns from June 2009 through March 2012. Each individual bar represents the total number of patients with an overlapping claim for simvastatin and one of the pre-specified non-calcium channel blocker study medications during each month within the study timeframe. Bars above the trend line denote clinically acceptable combinations and bars below the trend line represent againstlabel combinations

80% Against-Label

70% 60% 50% 40% 30% 20% 10% 0%

Month

adverse events is possible. Safe prescribing patterns with the use of simvastatin must be facilitated and improved to increase patient safety [22, 23]. Our study set out to observe prescribing patterns of simvastatin in relation to the US FDA’s announcement in June 2011 of updated dosing restrictions to minimize the risk of muscle-related adverse events. Our observational

analyses demonstrate an impact, albeit limited, of these product labeling changes. Against-label prescribing of simvastatin–CCB dosing combinations decreased by approximately 20 % within the first 9 months following these updated dosing restrictions. Previous literature suggests that negative outcome data, such as the potential for muscle-related adverse events associated with

R. M. Tuchscherer et al. Table 3 Against-label and clinically acceptable use Againstlabel, N (%)

Clinicallyacceptable, N (%)

Amlodipine

6,423 (67)

6,156 (95)

Diltiazem

1,933 (20)

247 (4)

Verapamil

1,182 (13)

75 (1)

Total

9,538 (100)

6,478 (100)

Amiodarone Cyclosporine

207 (12) 50 (3)

9 (16) NAa

Danazol

0 (0)

NAa

Gemfibrozil

1,426 (81)

NAa

Posaconazole

0 (0)

NAa

Ranolazine

73 (4)

49 (84)

Total

1,756 (100)

58 (100)

Patients with CCB claims

Patients with non-CCB claims

a

Concomitant use with simvastatin was contraindicated following June 2011 product labeling changes CCB calcium channel blocker, NA not applicable

inappropriate simvastatin prescribing, tend to have a more immediate and significant impact on prescribing patterns than is seen with positive outcome data [24]. While the decrease in against-label prescribing as shown in our results is encouraging, our results further demonstrate that inappropriate prescribing of potentially harmful combinations including simvastatin still persist despite the increased risk with use. This was especially true for the non-CCB against-label combinations. However, even with CCBs, a decrease in prescribing of against-label simvastatin–CCB combination therapy to 40 % is still unacceptable and exposes patients to potential harm. Prescribing of simvastatin in combination with one of the three CCBs was much more common than prescribing of simvastatin with one of the non-CCBs of interest. However, the overall rate of against-label prescribing was higher with the non-CCB medications, most likely because 4 of the 6 non-CCB medications (cyclosporine, danazol, gemfibrozil, and posaconazole) were absolutely contraindicated with concurrent use of any dose of simvastatin. The remaining two non-CCBs (amiodarone and ranolazine) as well as the CCBs (amlodipine, diltiazem, and verapamil) are still considered safe for use concurrently with simvastatin at the appropriately recommended doses. The analysis of incidence of muscle-related adverse events was an additional endpoint of this study. Although no difference was observed in rates of muscle-related adverse events in patients receiving against-label versus clinically acceptable combination therapies, we do not believe the results of this analysis reflect the true risk that exists with the use of the against-label combinations reviewed in this study. Previous studies have demonstrated

an increase in the incidence of rhabdomyolysis when statin medications are used concurrently with various other therapies similar to those analyzed in these analyses. Additionally, this study was also not powered to detect such a difference [25]. The estimation of muscle-related adverse events in this study relied on ICD event coding for various incidents. Although this methodology has been used in other publications, clinical experience suggests that various diagnoses such as those looked at in our analysis (i.e. muscle-related adverse events) are frequently undercoded within medical claims [25–28]. Avoidance of drug interactions known to increase patients’ risk of muscle-related adverse events is one of the few modifiable risk factors associated with the use of statin therapies. Drug interactions with statin medications involve complex interferences with various transporters and enzymes involved in the metabolism process. Different medications have the potential to interfere with different components of the metabolism pathways, thus making the true comprehension of these interactions challenging [29]. Regardless of which pathway is affected, the end result involves increased concentrations of statin medication. It is these increased concentrations that then contribute to increased occurrences of muscle-related adverse events [19, 29]. Dosing restrictions such as those analyzed with simvastatin in this study are therefore mandated to minimize the known risk from these combinations. There may be several reasons for continued use of against-label prescribing with simvastatin. First, it is possible that many practitioners remain unaware of some of the contraindications and dosing restrictions included in the June 2011 simvastatin product labeling. Moreover, mechanisms for potentiation of muscle-related adverse events differ between the various statin medications. Precautions, warnings, and restrictions are inconsistent between each of the individual medications within the statin drug class [19, 22, 23]. For example, while simvastatin use is restricted to a maximum dose of 20 mg when used concomitantly with amlodipine since the product labeling changes in June 2011, none of the remaining statin therapies have any restrictions for use with concurrent amlodipine therapy [19]. Such variations in restrictions have the potential for significant confusion and frustration when prescribing. Use of electronic health records and electronic prescribing technology has demonstrated a significant reduction in prescribing and medication errors [30]. While this technology has contributed greatly to an increase in medication safety, the likelihood for delays in updating this technology with new and continually changing information still exists. Additionally, a study published in the Archives of Internal Medicine in 2009 revealed that providers have a tendency to over-ride a majority of medication-related alerts generated by electronic prescribing systems. Alert

Simvastatin Prescribing Before and After FDA Dosing Restrictions

fatigue—the act of over-riding important warnings—minimizes the potential benefits that electronic prescribing may provide with respect to patient safety [31]. As such, prescribers cannot solely rely on electronic prescribing systems to reduce the incidence of adverse events [32]. Finally, prescribers may consider the risk of development of muscle-related adverse events to be insignificant due to the lack of strong, supportive evidence for some of the current prescribing restrictions. We recognize that this study includes specific limitations beyond those associated with any retrospective study design. First, the administrative claims data utilized within this study only allowed for the analysis of an insured patient population, thus these results may not be representative of the entire US population. Second, our definition of concurrent prescribing used a prescription-based approach. While this has many advantages over alternative approaches (e.g., using days’ supply), our approach may overestimate the proportion of patients in our study with overlapping claims. Additionally, the study investigators only had access to data through 31 March 2012 (9 months following the changes in the simvastatin product labeling). It is possible that prescribing patterns have continued to improve, with less against-label prescribing at present. Finally, the accuracy and reliability of our data rely on the completeness with which the information is provided in the administrative claims.

5 Conclusions The results of this study indicate that prescribing of against-label simvastatin–CCB combinations has steadily declined since 2011. However, unsafe and against-label prescribing of simvastatin with CCBs persisted at a rate of approximately 40 % at 9 months after changes in the simvastatin FDA labeling. Although prescribing of simvastatin in combination with certain non-CCB medications known to increase risk of myopathy was less common, use of these against-label simvastatin–non-CCB combinations was exceptionally high and remained unchanged at the same 9-month time point after changes in the simvastatin FDA labeling. Despite improvements in prescribing practices of simvastatin, this analysis indicates that a large number of patients are still exposed to potentially harmful simvastatin medication combinations. Aggressive changes in simvastatin prescribing systems and processes are needed to improve compliance with FDA labeling to improve medication and patient safety. Acknowledgments Richard R. Allen M.S, Peak Statistical Services, conducted statistical analyses. Conflict of interest Joseph J. Saseen served as a consultant for Astra Zeneca in March of 2014. He also serves as a board member for

the National Lipid Association and is the editor of the American College of Clinical Pharmacology (ACCP) publication Pharmacist’s Guide to Lipid Management. Rhianna M. Tuchscherer, Kavita Nair, and Vahram Ghushchyan have no conflicts of interest directly related to the content of this study.

References 1. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39. doi:10. 1161/01.CIR.0000133317.49796.0E. 2. Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, et al. ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013. doi:10.1161/01.cir.0000437738.63853.7a. 3. Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA. 2013;310(22):2451–2. doi:10.1001/jama.2013.281348. 4. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81. doi:10. 1016/S0140-6736(10)61350-5. 5. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20(4):641–57. doi:10.1177/ 2047487313480435. 6. Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104(2):109–24. doi:10.1093/qjmed/hcq165. 7. Jacobson TA. NLA task force on statin safety–2014 update. J Clin Lipidol. 2014;8(3 Suppl):S1–4. doi:10.1016/j.jacl.2014.03. 003. 8. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33(3):171–87. doi:10.2165/11319380-000000000-00000. 9. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation. 2002;106(8):1024–8. 10. U.S. Food and Drug Administration. FDA Drug Safety Communication: new restrictions, contraindications, and dose limitations, for Zocor (simvastatin) to reduce the risk of muscle injury. Published June 8, 2011. http://www.fda.gov/Drugs/DrugSafety/ ucm256581.htm. Accessed 29 Aug 2013. 11. Son H, Lee D, Lim LA, Jang SB, Roh H, Park K. Development of a pharmacokinetic interaction model for co-administration of simvastatin and amlodipine. Drug Metab Pharmacokinet. 2014;29(2):120–8. 12. Park CG, Lee H, Choi JW, Lee SJ, Kim SH, Lim HE. Nonconcurrent dosing attenuates the pharmacokinetic interaction between amlodipine and simvastatin. Int J Clin Pharmacol Ther. 2010;48(8):497–503. 13. Nishio S, Watanabe H, Kosuge K, Uchida S, Hayashi H, Ohashi K. Interaction between amlodipine and simvastatin in patients

R. M. Tuchscherer et al.

14.

15.

16. 17.

18.

19.

20.

21. 22.

23.

with hypercholesterolemia and hypertension. Hypertens Res. 2005;28(3):223–7. doi:10.1291/hypres.28.223. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67(3):267–74. doi:10.1067/mcp.2000.104609. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64(2):177–82. doi:10.1016/S0009-9236(98)90151-5. Zocor package insert. Merck. 2011. http://www.accessdata.fda. gov/scripts/cder/drugsatfda/index/cfm. Accessed 29 Aug 2013. Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. J Am Coll Surg. 2008;207(6):928–34. doi:10.1016/j.jamcollsurg.2008.08. 022. Delgado-Montero A, Zamorano JL. Atorvastatin calcium plus amlodipine for the treatment of hypertension. Expert Opin Pharmacother. 2012;13(18):2673–85. doi:10.1517/14656566. 2012.742064. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S58–71. doi:10.1016/j. jacl.2014.03.004. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403–14. doi:10.1007/s10557-005-5686-z. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781–90. doi:10.1016/S0140-6736(07)60716-8. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012;11(6):933–46. doi:10. 1517/14740338.2012.712959. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373–87. doi:10.1517/ 14740338.2011.540568.

24. Bestul MB, McCollum M, Hansen LB, Saseen JJ. Impact of the women’s health initiative trial results on hormone replacement therapy. Pharmacotherapy. 2004;24(4):495–9. 25. Amend KL, Landon J, Thyagarajan V, Niemcryk S, McAfee A. Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population. Ann Pharmacother. 2011;45(10):1230–9. doi:10.1345/aph.1Q110. 26. Saseen JJ, Agashivala N, Allen RR, Ghushchyan V, Yadao AM, Nair KV. Comparison of patient characteristics and gout-related health-care resource utilization and costs in patients with frequent versus infrequent gouty arthritis attacks. Rheumatology (Oxford). 2012;51(11):2004–12. doi:10.1093/rheumatology/kes183. 27. Fife D, Zhu V, Voss E, Levy-Clarke G, Ryan P. Exposure to oral fluoroquinolones and the risk of retinal detachment: retrospective analyses of two large healthcare databases. Drug Saf. 2014;37(3):171–82. doi:10.1007/s40264-014-0138-y. 28. Alford JC, Saseen JJ, Allen RR, Nair KV. Persistent use of against-label statin-fibrate combinations from 2003–2009 despite United States Food and Drug Administration dose restrictions. Pharmacotherapy. 2012;32(7):623–30. doi:10.1002/j.1875-9114. 2011.01090.x. 29. Kellick KA, Bottorff M, Toth PP. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol. 2014;8(3 Suppl):S30–46. doi:10.1016/j.jacl.2014.02.010. 30. Porterfield A, Engelbert K, Coustasse A. Electronic prescribing: improving the efficiency and accuracy of prescribing in the ambulatory care setting. Perspect Health Inf Manag. 2014;11:1g. 31. Isaac T, Weissman JS, Davis RB, Massagli M, Cyrulik A, Sands DZ, et al. Overrides of medication alerts in ambulatory care. Arch Intern Med. 2009;169(3):305–11. doi:10.1001/archinternmed. 2008.551. 32. Ranji SR, Rennke S, Wachter RM. Computerised provider order entry combined with clinical decision support systems to improve medication safety: a narrative review. BMJ Qual Saf. 2014. doi:10.1136/bmjqs-2013-002165.

Simvastatin prescribing patterns before and after FDA dosing restrictions: a retrospective analysis of a large healthcare claims database.

Muscle-related events, or myopathies, are a commonly reported adverse event associated with statin use. In June 2011, the US FDA released a Drug Safet...
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