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Abdulaziz Dahham N. Alshalan et al, 2019;3(9):751–754. International Journal of Medicine in Developing Countries https://doi.org/10.24911/IJMDC.51-1549965220

ORIGINAL ARTICLE The impact of changing branded into generic at the National Guard Hospital in Riyadh, Saudi Arabia Abdulaziz Dahham N. Alshalan1, Mohammed Fawzan A. Almuhraj1*, Faris Awadh G. Alotaibi1, Mohammed Aldegiri2, Hind Almodaimegh2

ABSTRACT Background: Health care expenditure remains one of the major issues to tackle for all the countries around the globe. To overcome this, some hospitals involve in the process of changing from the brand named drugs to their generic counterparts. However, the question that remains among the physicians and the patient group is whether these generic drugs could compromise the effectiveness and safety. Thus, the objective of the present study is to explore the impact of changing statins from their brand to generic counterparts on the level of low-density lipoprotein (LDL) in patients with hyperlipidemia. Methodology: A retrospective chart review was conducted at King Abdulaziz Cardiac Centre, National Guard Hospital in Riyadh, Saudi Arabia during the period of January 2018–May 2018. A total of 876 patients were made to switch from brand to generic . The lipid profile [total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides] analyzed during the year 2016 (the switching period) was compared with the lipid profile results recorded in 2017. Other labs tests were also investigated to check for variations. Results: A total of 500 patients were analyzed during the study. Significance difference was found on compari- son of the mean values for: LDL (2.5 vs. 2.2 mmol/l; p = 0.000), HDL (1.0 vs. 0.90 mmol/l; p = 0.006), cholesterol (4.2 vs. 3.8 mmol/l; p = 0.000), and triglycerides (1.7 vs. 2.0 mmol/l; p = 0.425). Conclusion: The patients who switched from brand named drugs to generic named drugs had better outcome according to the lab results. Our findings support the hospital’s efforts in switching statin from brand (Lipitor®) to generic statin and maintaining the efficacy of the drug. Keywords: Statins, generic drugs, LDL.

Introduction

Dyslipidemia is defined as an abnormal amount of lowering the risk of CVD by controlling the serum lipid lipids [triglycerides, low-density lipoprotein (LDL), levels [3]. The Generic drug should contain the same high-density lipoprotein (HDL) cholesterol, and/or fat basic content as the brand named product, in terms of phospholipids] in the blood. This imbalance in cholesterol pharmacological properties. Generic manufacturers, in levels is reported to be one of the most dangerous risk this case, do not require repeating the pre-clinical and factors that lead to atherosclerosis and cardiovascular clinical testing. There should be no difference observed diseases (CVD) [1]. The outcome of the vascular diseases in the absorption coefficient between the generic drug could be improved by lowering LDL cholesterol levels. Patients with cardiovascular diseases are advised to keep their LDL level below 100 mg/dl. Patients with two or Correspondence to: Mohammed Fawzan A. Almuhraj more risk factors of cardiovascular diseases are further *Al-Maarefa University, Ad Diriyah, Saudi Arabia. advised to maintain their LDL levels less than 130 mg/dl Email: [email protected] and patient with one or fewer risk factors with the level Full list of author information is available at the end of of LDL less than 160 mg/dl [2]. Statins, also known as the article. β-Hydroxy β-methylglutaryl-CoA reductase, are used in Received: 20 February 2019 | Accepted: 13 May 2019

© IJMDC. https://www.ijmdc.com 751 The impact of changing branded statins into generic drugs

and the brand name drug to be bioequivalent [4]. The weight, nationality, marital status, and occupation), effect of the recommended dose of will co-morbidities (diabetes mellitus, hypertension, liver reduce the LDL level from 18% to 41%. The effect of diseases, heart failure, and atherosclerosis), lab tests newly available statin known as at dose range results [aspartate aminotransferase (AST), alanine between 10 and 80 mg is found to reduce the LDL level transaminase (ALT), creatine kinase (CK), serum from 35% to 61% [2]. The and European creatinine (SCR), hemoglobin a1c (HbA1c), LDL, Authorities do not recommend specific statins for CVD HDL, triglyceride, and serum cholesterol], and the type management guidelines. Some nation do recommend of statin used. The collected lab results obtained during specific statins, for example, the recommended guideline the years 2016 and 2017 were compared to assess the for management of cardiovascular risk in Dutch is changes. All the study subjects aged above 18 years, simvastatin 40 mg and pravastatin 40 mg and the United having complete lab profile for the year 2016 and 2017 Kingdom (UK) National Institute for Therapeutics and and followed using atorvastatin or brand Clinical Excellence recommends the starting therapy with name and then shifted to a generic drug, was included 40 mg daily simvastatin and the recommended Guideline in the study. The individuals using simvastatin were of the Netherlands require the patients to be at very high excluded. The study primarily aimed at exploring the risk of CVD or the preferred statins should not achieve impact of changing statins from brand to generic products the recommended goal to use more potent statins, such as on the level of LDL in patients with hyperlipidemia in atorvastatin or rosuvastatin [3]. A study that carried out in National Guard Hospital in Riyadh, Saudi Arabia. Data New Zealand with 126 adult patients with atherosclerotic management and analysis were achieved using Statistical disease established that the switching from simvastatin Package for the Social Sciences (SPSS 21.0). Descriptive to less potent fluvastatin due to economic issues resulted statistical analyses were performed for the study sample. in a significant increase in cholesterol levels among 94% Continuous variables were represented as mean and of the population and the thrombotic vascular event standard deviations (SDs), median and interquartile increased three-fold in the comparison between the range. Proportions and percentages were used for 6-month pre- and post-switching period. A secondary categorical variables. Interferential statistics were carried case study conducted in the UK among audited patients out using a Chi-square test to compare frequencies with with acute coronary syndromes leads to cardiovascular a 95% confidence interval. Statistical significance was consequences. The study had a group of 100 subjects considered at p < 0.05. administered with atorvastatin (40–80 mg) for the treatment of myocardial infarction or unstable angina Results and the second group of 121 patients was treated with simvastatin (40-mg dose). A follow-up from 3 to 6 months A total of 876 patients switched from the brand to the period revealed a significant increase in the mortality generic drug. Among the total, 376 patients were excluded from analysis for various reasons (patient who did not use (17% vs. 5%) and the cardiac re-admissions (53 vs. 33) in the group treated with simvastatin compared with the atorvastatin or rosuvastatin brand name, patient below group treated by atorvastatin [5,6]. In the present study, 18 years of age, patients with missed or uncompleted we aim to investigate the effect of rosuvastatin usage on lab results for the period 2016 and 2017, and patients on controlling LDL levels in comparison with atorvastatin. simvastatin). The mean age of the study population was found to be 63.4 years with SD of 11.8 years. The mean Subjects and Methods of sample weights was calculated as 80.7 kg with SD of 15.2 kg and semi-normal distribution with mild outliers. A retrospective chart review was conducted at King Distribution of samples according to the height showed Abdulaziz Cardiac Centre, National Guard Hospital in normal distribution, the mean and SD heights were 164.0 Riyadh, Saudi Arabia during the period of January 2018– ± 9.4. The majority of the sample was males, Saudi, and May 2018. The Pharmacy Department in the Cardiac married. Less than half of the patients were unemployed Center started to change the statin from brand name to as shown in Table 1. Around two-thirds of patients had generic name to minimize the cost of drugs in April 2016. diabetes mellitus (DM) and hypertension (HTN), and 11 A total of 876 patients were made to switch from brand patients had liver disease. Patients with heart failure (HF) to generic statin. The lipid profile (total cholesterol, and atherosclerosis were 126 and 121, respectively, as LDL-cholesterol, HDL-cholesterol, and triglycerides) shown in Table 2. Among the total, 146 patients were on analyzed during the year 2016 (the drug switching rosuvastatin and 354 patients were on atorvastatin. period) was compared lipid profile results recorded in The mean AST value in 2016 was 37.7 with SD ± 65.5 2017. Previously, all the patients who used the brand and in 2017, it was 22.9 with SD ± 20.3 and p = 0.000. name of atorvastatin and the brand name of rosuvastatin The mean ALT value in 2016 was 29.2 with SD ± 33.2 and shifted to generic name of statin were classified by the in 2017, it was 23.8 with SD ± 13.5 and p = 0.001. The hospital electronic system. We also investigated other mean CK value in 2016 was 308.4 with SD ± 835.9 and labs tests to check for variations. The ethical approval in 2017, it was 149.7 with SD ± 238.4 and p = 0.000. The was obtained from the King Abdullah International mean SCR value in 2016 was 111.7 with SD ± 128.5 and Medical Research Center. The data collected for this in 2017, it was 112.4 with SD ± 104.5 and = 0.733. The study included patient demographics (age, gender, height, p

752 The impact of changing branded statins into generic drugs

mean HbA1c value in 2016 was 8.5 with SD ± 6.1 and in 2.5 ± 0.6 and in 2017, it was 1.8 ± 1.0. LDL mean with 2017, it was 8.3 with SD ± 5.8 and p = 0.444. The mean rosuvastatin 20 mg in 2016 was 2.7 ± 1.1 and in 2017, LDL value in 2016 was 2.5 with SD ± 1.07 and in 2017, it was 2.3 ± 1.1. LDL mean with rosuvastatin 40 mg in it was 2.2 and SD ± 0.9 and p = 0.000. The mean HDL 2016 was 2.7 ± 1.3 and in 2017, it was 2.3 ± 0.7 (Table 4). value in 2016 was 1.0 with SD ± 0.7 and in 2017, it was 0.90 with SD ± 0.2 and p = 0.006. The mean triglycerides Discussion value in 2016 was 1.7 with SD ± 1.2 and in 2017, it was This is a retrospective chart review study aimed at exploring 2.0 with SD ± 6.9 and p = 0.425. The mean cholesterol value in 2016 was 4.2 with SD ± 1.2 and in 2017, it was the impact of changing statins from brand to generic products. Our findings were in agreement with other major 3.8 with SD ± 1.1 p = 0.000 (Figure 1; Table 3). studies that compared the switching of drugs from brand to LDL mean with atorvastatin 10 mg in 2016 was 1.9 ± 0.8 generic statin. Our result was found to be counteracting a and in 2017, it was 1.5 ± 0.6. LDL mean with atorvastatin few studies that compared switching from brand to generic 20 mg in 2016 was 2.3 ± 0.8 and in 2017, it was 2.1 ± 1.0. atorvastatin. A retrospective study by Rahalkar et al. [7] LDL mean with atorvastatin 40 mg in 2016 was 2.4 ± 1.0 had reported switching brand to generic statin leading and in 2017, it was 2.2 ± 0.9. LDL mean with atorvastatin to no change in LDL and triglycerides but resulting in 80 mg in 2016 was 2.5 ± 1.0 and in 2017, it was 2.3 a significant change in HDL levels. Kim et al. [8] study ± 0.8. LDL mean with rosuvastatin 10 mg in 2016 was showed equal efficacy of atorvastatin in comparing to the brand. Furthermore, another study from Loch et al. [4] study showed no difference in the efficacy of generic statins and support the idea of switching to generic statins. Table 1. Demographic details of the study population. Also, Jackevicius et al. [6] study showed no significant Variable N = 500 % differences with those who taking generic atorvastatin compared with individuals on branded statin. Recently, Gender millions of people around the world who still cannot afford Male 384 76.8 the costly branded drugs are switching to generic drugs. Female 116 23.2 Although few negative results regarding the drugs dosage Nationality and other impaired clinical data do exits and provide a Saudi 463 92.6 bad impression about generic drugs, a lot of studies had successfully compared the level of effectiveness and Non-Saudi 37 7.4 safety for various generic drugs. Regardless of growing Marital status Married 495 99.0 Single 5 1.0 Occupation Employed 210 42.0 Non employed 290 58.0

Table 2. Co morbidities.

Co morbidity N = 500 % DM Yes 326 65.2 Figure 1. The lipid profile in 2016 and 2017. No 174 34.8 HTN Table 3. Lab Indicators comparison in 2016 and 2017. Yes 330 66.0 2016 2017 Indicator p-value No 170 34.0 Mean ± SD Mean ± SD Liver D AST 37.7 ± 65.5 22.9 ± 20.3 0.000 Yes 11 2.2 ALT 29.2 ± 33.2 23.8 ± 13.5 0.001 No 489 97.8 CK 308.4 ± 835.9 149.7 ± 238.4 0.000 HF Scr 111.7 ± 128.5 112.4 ± 104.5 0.733 Yes 126 25.2 HbA1c 8.5 ± 6.1 8.3 ± 5.8 0.444 No 374 74.8 LDL 2.5 ± 1.07 2.2 ± 0.9 0.000 Atherosclerosis HDL 1.0 ± 0.7 0.90 ± 0.2 0.006 Yes 121 24.2 TG 1.7 ± 1.2 2.0 ± 6.9 0.425 No 379 75.8 Cholesterol 4.2 ± 1.2 3.8 ± 1.1 0.000

753 The impact of changing branded statins into generic drugs

Table 4. LDL comparison on statin usage. Consent for publication Informed consent was obtained from all the participants. Statin 2016 2017 Atorvastatin 10 mg 1.9 ± 0.8 1.5 ± 0.6 Ethical approval Atorvastatin 20 mg 2.3 ± 0.8 2.1 ± 1.0 The ethical approval was obtained from King Abdullah International Medical Research Center's (KAIMRC) Atorvastatin 40 mg 2.4 ± 1.0 2.2 ± 0.9 (RC18/002/R). Atorvastatin 80 mg 2.5 ± 1.0 2.3 ± 0.8 Rosuvastatin 10 mg 2.5 ± 0.6 1.8 ± 1.0 Author details 1 Rosuvastatin 20 mg 2.7 ± 1.1 2.3 ± 1.1 Abdulaziz Dahham N. Alshalan , Mohammed Fawzan A. Almuhraj1, Faris Awadh G. Alotaibi1, Mohammed Aldegiri2, Rosuvastatin 40 mg 2.7 ± 1.3 2.3 ± 0.7 Hind Almodaimegh2 1. Al-Maarefa University, Ad Diriyah, Saudi Arabia 2. King Abdulaziz Medical City, Riyadh, Saudi Arabia supporting evidence, the general perception about generic References drugs among some patients and physicians still remains questionable. Patient those who use branded drugs are 1. Hussien ZM, Ahmed LT, Hussain QG. Effect of atorvastatin usually worried about switching to generic counterparts. and garlic on lipid profile in hyperlipidemic patients. Physicians and pharmacists usually discourage the use of Diyala J Med. 2013;5(1):63–8. generic statins, even a recent study reported that every third 2. Pasupathia P, Saravanan G, Raoc Y, Farookc J, pharmacist believes that generic drugs are less effective Bakthavathsalamc G. Effective analysis of atorvastatin and not equal to branded counterparts [4]. versus in simvastatin patients with hyperlipidemia. J Pharm Sci Res. 2009;1:16–21. Conclusion 3. Liew D, Webb K, Meerding WJ. PCV126 the cardiovascular consequences of switching from atorvastatin to Switching the patient to generic statin does not affect generic simvastatin in The Netherlands. Value Health. the outcome of management for the patient with 2010;13(3):A173–4. https://doi.org/10.1016/S1098- hyperlipidemia. Furthermore, the study found that the 3015(10)72844-8 patient on generic statins had better control of LDL 4. Loch A, Bewersdorf JP, Kofink D, Ismail D, Abidin IZ, Veriah compared to patients on the branded stain. This study RS. Generic atorvastatin is as effective as the brand-name supports the procedure of changing from brand statin drug (LIPITOR®) in lowering cholesterol levels: a cross- to generic statins at National Guard Hospital in Riyadh, sectional retrospective cohort study. BMC Res Notes. Saudi Arabia without comprising health care. Generic 2017;10(1):291. https://doi.org/10.1186/s13104-017- needs more studies to ensure their safety 2617-6 and efficacy to encourage physicians and pharmacist to 5. Phillips B, Roberts C, Rudolph AE, Morant S, Aziz F, further encourage the prescription of this medication. O’Regan CP. Switching statins: the impact on patient outcomes. Br J Cardiol. 2007;14(5):280–5.

List of Abbreviations 6. Jackevicius CA, Tu JV, Krumholz HM, Austin PC, Ross JS, ALT Alanine transaminase Stukel TA, et al. Comparative effectiveness of generic AST Aspartate aminotransferase atorvastatin and Lipitor® in patients hospitalized CK Creatine kinase with an acute coronary syndrome. J Am Heart CVD Cardiovascular diseases Assoc. 2016;5(4):e003350. https://doi.org/10.1161/ DM Diabetes mellitus JAHA.116.003350 HbA1c Haemoglobin A1c 7. Rahalkar AR, Ban MR, Hegele RA. Clinical equivalence HDL High-density lipoprotein of proprietary and generic atorvastatin in lipid clinic HF Heart failure patients. Can J Cardiol. 2013;29(4):418–22. https://doi. HTN Hypertension org/10.1016/j.cjca.2012.05.010 LDL Low-density lipoprotein 8. Kim SH, Park K, Hong SJ, Cho YS, Sung JD, Moon GW, SCR Serum creatinine Yoon MH, Lee MY, Hyon MS, Kim DW, Kim HS. Efficacy SD Standard deviation and tolerability of a generic and a branded formulation SPSS Statistical Package for the Social Sciences of atorvastatin 20 mg/d in hypercholesterolemic Korean UK United Kingdom adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy Conflict of interest . Clin Therap. 2010;32(11):1896–905. https:// The authors declare that there is no conflict of interest doi.org/10.1016/j.clinthera.2010.10.004 regarding the publication of this article. Funding None.

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