Journal of Cardiovascular Pharmacology and Therapeutics http://cpt.sagepub.com/
Efficacy and Safety of Alternate Day Therapy With Atorvastatin and Fenofibrate Combination in Mixed Dyslipidemia: A Randomized Controlled Trial Natarajan Harivenkatesh, Darling Chellathai David, Natarajan Haribalaji and Muthiah Kothandaramanujam Sudhakar J CARDIOVASC PHARMACOL THER 2014 19: 296 originally published online 10 February 2014 DOI: 10.1177/1074248413518968 The online version of this article can be found at: http://cpt.sagepub.com/content/19/3/296
Published by: http://www.sagepublications.com
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Clinical Study
Efficacy and Safety of Alternate Day Therapy With Atorvastatin and Fenofibrate Combination in Mixed Dyslipidemia: A Randomized Controlled Trial
Journal of Cardiovascular Pharmacology and Therapeutics 2014, Vol. 19(3) 296-303 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413518968 cpt.sagepub.com
Natarajan Harivenkatesh, MD, DNB, (DM)1, Darling Chellathai David, MD2, Natarajan Haribalaji, MBBS3, and Muthiah Kothandaramanujam Sudhakar, MD4
Abstract Introduction: The long half-life of atorvastatin and fenofibrate makes them suitable for alternate day therapy. Hence, we aimed to study the efficacy, safety, and cost-effectiveness of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia. Methods: Eligible patients with mixed dyslipidemia were randomly allotted into 2 equal parallel groups—alternate day therapy group (group 1) and daily therapy group (group 2). Patients in groups 1 and 2 received fixed dose combination of atorvastatin 10 mg and fenofibrate 160 mg on alternate days and daily, respectively, for 12 weeks. Mean percentage change from baseline in triglycerides (TGLs), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and TC–HDL ratio, incidence of adverse effects, and cost-effectiveness were compared in both the groups. Results: Among 110 patients randomized, 99 completed the study till 12 weeks treatment duration. The TGLs, non-HDL-C, TC, and LDL-C decreased by 56.4%, 49.7%, 36.5%, and 39.2%, respectively, in alternate day therapy group and by 57.5%, 51.2%, 37.5%, and 39.4%, respectively, in daily therapy group. The HDL-C levels increased by 20.1% in alternate day therapy group compared to 21.8% in daily therapy group. No statistically significant difference was seen between both the groups in mean percentage change in lipid parameters from baseline to end of 12 weeks. Incidence of adverse events was reasonably less in alternate day therapy group. Conclusion: Alternate day therapy with atorvastatin–fenofibrate combination is an effective and safe alternative to daily therapy in mixed dyslipidemia. Apart from significant cost savings, reasonable reduction in the incidence of adverse events is seen with alternate day regimen. However, larger studies are needed to more reliably confirm our interesting but preliminary results. Keywords alternate day therapy, atorvastatin, cost-effectiveness, fenofibrate, fixed dose combination, mixed dyslipidemia
Introduction Cardiovascular diseases are the leading cause of mortality worldwide.1 Atherosclerosis is a major contributor to cardiovascular diseases and the most important risk factor for the development of atherosclerosis is dyslipidemia. It has been reported that increased cholesterol level is the sixth leading global risk factor for death worldwide.2 According to World Health Organization, the estimated global prevalence of raised cholesterol levels among adults is 39% (37% for males and 40% for females).3 Recent estimates also depict that 53% of adults in the United States have dyslipidemia.4 Mixed dyslipidemia is characterized by increased triglycerides (TGLs) and low-density lipoprotein cholesterol (LDL-C) along with decreased high-density lipoprotein cholesterol (HDL-C). Presence of small-dense LDL particles increases the risk of atherogenesis in patients with mixed dyslipidemia.5 Mixed dyslipidemia is the commonest type of dyslipidemia
in patients with diabetes and metabolic syndrome and is strongly associated with the development of atherosclerosis and cardiovascular events. Due to increasing diabetic population, the prevalence of mixed dyslipidemia is also high.6,7
1
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India 2 Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India 3 Rathimed Speciality Hospital, Chennai, Tamil Nadu, India 4 Department of Internal Medicine, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India Manuscript submitted: November 1, 2013; accepted: December 3, 2013. Corresponding Author: Natarajan Harivenkatesh, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. Email: [email protected]
Downloaded from cpt.sagepub.com at UNIV FED DO RIO GRANDE DO NOR on April 22, 2014
Harivenkatesh et al
297
According to the recent estimates, mixed dyslipidemia is prevalent in 21% of the adults in the United States.4 Statins primarily reduce LDL-C but have only modest effects on HDL-C and TGL. On the other hand, fibrates primarily reduce TGL and increase HDL-C but have only modest effects on LDL-C. Hence, combination of statins and fibrates is frequently used for the treatment of mixed dyslipidemia.8-12 One of the major limitations of long-term pharmacological treatment of dyslipidemia is suboptimal adherence to drug therapy.13,14 Recent studies have shown that noncompliance with statins is around 30% to 50% thereby decreasing the therapeutic effects. Further around 50% of patients who begin treatment with hypolipidemic drugs discontinue the treatment at the end of first year.13-15 Common reasons for poor patient compliance with these drugs are the adverse effects produced by them like myopathy and high cost of drug therapy.14,16,17 One of the ways to minimize adverse effects, to reduce cost of drug therapy, and to improve patient compliance is to give these drugs on alternate days instead of daily therapy. Both atorvastatin and fenofibrate have long half-life (t½), which makes them suitable for alternate day therapy. Hence, this pilot study was designed to evaluate the efficacy and safety of alternate day therapy with fixed dose combination (FDC) of atorvastatin 10 mg and fenofibrate 160 mg in comparison with daily therapy in the treatment of mixed dyslipidemia.
Methods Study Design The present pilot study is a randomized, active-controlled, 2-group, parallel arm, open-labeled, single-center study. It was conducted in Sri Ramachandra Medical College Hospital, Chennai, a tertiary care teaching hospital in South India, from September 2010 to December 2011. The study was performed in accordance with declaration of Helsinki and ICH-GCP guidelines. The study protocol was reviewed and approved by Institutional Ethics Committee (CSP/10/AUG/11/26). The study was registered in Clinical Trials Registry—India before enrollment of the first study participant (CTRI/2010/091/ 001328). Written informed consent was obtained from all study participants before performing any study-related procedure.
Eligibility Criteria Patients of both gender aged >18 years who were diagnosed to have mixed dyslipidemia (TGLs 200 mg/dL and non-HDL-C 130mg/dL) and met the criteria for pharmacological treatment per updated National Cholesterol Education Program— Adult Treatment Panel III (NCEP-ATP III) guidelines were included in the study18 (Non-HDL-C ¼ Total cholesterol HDL-C). Patients already taking statins, fibrates, or other hypolipidemic drugs, patients with active hepatic disease and elevated liver enzymes (serum glutamic oxalo-acetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and
alkaline phosphatase >3 times the upper normal limit), uncontrolled diabetes mellitus in spite of drug therapy (hemoglobin A1c > 7%), serum creatinine >1.2 mg/dL, elevated creatine phosphokinase (CPK) levels, and muscular disorders, patients who had myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or cerebrovascular accident within 6 months preceding the study, patients receiving concomitant drugs that might interfere with metabolism of study drugs, postmenopausal women on hormone replacement therapy, pregnant and lactating women, women of child-bearing age not using acceptable methods of contraception, and patients unwilling to give informed consent were excluded from the study.
Study Procedure Patients who met the eligibility criteria were randomized to 2 parallel groups (alternate day therapy group and daily therapy group) in 1:1 ratio using computer-generated simple randomization in blocks of 10. Allocation concealment was maintained using serially numbered opaque-sealed envelopes. Study drug was the FDC of atorvastatin 10 mg and fenofibrate 160 mg. Patients on alternate day therapy group and daily therapy group received the study drug on alternate days and daily, respectively, for 12 weeks. There were 3 scheduled visits during the study; baseline visit, after 6 weeks, and after 12 weeks (end of study visit). Serum lipid profile (total cholesterol [TC], HDL-C, LDL-C, TGL, and TC–HDL ratio), creatinine, SGOT, and SGPT were analyzed in the baseline and after 12 weeks of therapy. Lipid profile estimations were done after overnight fasting using venous blood samples. Serum TC was measured using cholesterol oxidase method, TGLs using enzymatic assay, HDL-C using polymer–polyanion, and LDL-C using direct measure. Non-HDL-C was calculated using the formula (Non-HDL-C ¼ Total cholesterol HDL-C). The CPK levels were estimated only for patients with myalgia. The study drug was supplied as 6-week calendar pack to all study participants along with compliance card and patient diary. All the study participants were instructed to take the study drug orally with a glass of water after food at bedtime. All the study participants were advised to continue low-fat diet and physical exercise (as per NCEP-ATP III guidelines) throughout the treatment period.
Study End Points The primary efficacy end points were percentage change in TGL and non-HDL levels from baseline after 12 weeks of therapy. Secondary efficacy end points include percentage change in LDL-C, HDL-C, TC levels, and TC–HDL ratio from baseline after 12 weeks of therapy, cost-effectiveness, and patient compliance in both the groups. Safety end points were incidence of adverse events in both groups and percentage change in liver enzymes SGOT and SGPT from baseline after 12 weeks of therapy.
Downloaded from cpt.sagepub.com at UNIV FED DO RIO GRANDE DO NOR on April 22, 2014
298
Journal of Cardiovascular Pharmacology and Therapeutics 19(3)
Assessment of Patient Compliance Patient compliance was assessed by counting the number of empty blister packs and unused study medications, if any, returned by the study participants and by looking at the patient compliance card. Noncompliance was defined as less than 80% or more than 120% of the predicted number of empty blister packs being returned during the scheduled visits.
Cost-Effectiveness Analysis Since non-HDL-C represents the atherogenic form of lipoproteins,6 the drug treatment cost incurred for 1% reduction in non-HDL-C level during treatment period was compared in both the groups to analyze cost-effectiveness.
Adverse Event Reporting During the Study All the adverse events observed/complained by the study participants were reported in the case report form along with the information about severity (mild, moderate, or severe) and causal relationship to the study medication. Biochemical parameters assessed for safety profile were serum creatinine, SGOT, and SGPT.
Statistical Analysis Since this is a pilot study, no formal sample size calculation was done. A convenient sample of 110 patients was chosen for this study. All statistical analyses were performed using SPSS for windows version 16. Demographic data (age, sex, etc) and baseline patient characteristics were summarized by treatment groups using descriptive statistics to assess difference if any between them. Mean and standard deviation (SD) were provided for continuous data, while absolute frequencies and percentage were provided for categorical data. The TGL, LDL-C, TC, HDL-C, and non-HDL levels in each group before and after intervention were compared using paired ‘‘t’’ test. The mean percentage change in the above-mentioned lipid parameters from baseline to 12 weeks between both the groups was compared using student ‘‘t’’ test. Nonparametric tests were used for the data that did not follow normal distribution. P value
Efficacy and Safety of Alternate Day Therapy With Atorvastatin and Fenofibrate Combination in Mixed Dyslipidemia: A Randomized Controlled Trial Natarajan Harivenkatesh, Darling Chellathai David, Natarajan Haribalaji and Muthiah Kothandaramanujam Sudhakar J CARDIOVASC PHARMACOL THER 2014 19: 296 originally published online 10 February 2014 DOI: 10.1177/1074248413518968 The online version of this article can be found at: http://cpt.sagepub.com/content/19/3/296
Published by: http://www.sagepublications.com
Additional services and information for Journal of Cardiovascular Pharmacology and Therapeutics can be found at: Email Alerts: http://cpt.sagepub.com/cgi/alerts Subscriptions: http://cpt.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Apr 16, 2014 OnlineFirst Version of Record - Feb 10, 2014 What is This?
Downloaded from cpt.sagepub.com at UNIV FED DO RIO GRANDE DO NOR on April 22, 2014
Clinical Study
Efficacy and Safety of Alternate Day Therapy With Atorvastatin and Fenofibrate Combination in Mixed Dyslipidemia: A Randomized Controlled Trial
Journal of Cardiovascular Pharmacology and Therapeutics 2014, Vol. 19(3) 296-303 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413518968 cpt.sagepub.com
Natarajan Harivenkatesh, MD, DNB, (DM)1, Darling Chellathai David, MD2, Natarajan Haribalaji, MBBS3, and Muthiah Kothandaramanujam Sudhakar, MD4
Abstract Introduction: The long half-life of atorvastatin and fenofibrate makes them suitable for alternate day therapy. Hence, we aimed to study the efficacy, safety, and cost-effectiveness of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia. Methods: Eligible patients with mixed dyslipidemia were randomly allotted into 2 equal parallel groups—alternate day therapy group (group 1) and daily therapy group (group 2). Patients in groups 1 and 2 received fixed dose combination of atorvastatin 10 mg and fenofibrate 160 mg on alternate days and daily, respectively, for 12 weeks. Mean percentage change from baseline in triglycerides (TGLs), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and TC–HDL ratio, incidence of adverse effects, and cost-effectiveness were compared in both the groups. Results: Among 110 patients randomized, 99 completed the study till 12 weeks treatment duration. The TGLs, non-HDL-C, TC, and LDL-C decreased by 56.4%, 49.7%, 36.5%, and 39.2%, respectively, in alternate day therapy group and by 57.5%, 51.2%, 37.5%, and 39.4%, respectively, in daily therapy group. The HDL-C levels increased by 20.1% in alternate day therapy group compared to 21.8% in daily therapy group. No statistically significant difference was seen between both the groups in mean percentage change in lipid parameters from baseline to end of 12 weeks. Incidence of adverse events was reasonably less in alternate day therapy group. Conclusion: Alternate day therapy with atorvastatin–fenofibrate combination is an effective and safe alternative to daily therapy in mixed dyslipidemia. Apart from significant cost savings, reasonable reduction in the incidence of adverse events is seen with alternate day regimen. However, larger studies are needed to more reliably confirm our interesting but preliminary results. Keywords alternate day therapy, atorvastatin, cost-effectiveness, fenofibrate, fixed dose combination, mixed dyslipidemia
Introduction Cardiovascular diseases are the leading cause of mortality worldwide.1 Atherosclerosis is a major contributor to cardiovascular diseases and the most important risk factor for the development of atherosclerosis is dyslipidemia. It has been reported that increased cholesterol level is the sixth leading global risk factor for death worldwide.2 According to World Health Organization, the estimated global prevalence of raised cholesterol levels among adults is 39% (37% for males and 40% for females).3 Recent estimates also depict that 53% of adults in the United States have dyslipidemia.4 Mixed dyslipidemia is characterized by increased triglycerides (TGLs) and low-density lipoprotein cholesterol (LDL-C) along with decreased high-density lipoprotein cholesterol (HDL-C). Presence of small-dense LDL particles increases the risk of atherogenesis in patients with mixed dyslipidemia.5 Mixed dyslipidemia is the commonest type of dyslipidemia
in patients with diabetes and metabolic syndrome and is strongly associated with the development of atherosclerosis and cardiovascular events. Due to increasing diabetic population, the prevalence of mixed dyslipidemia is also high.6,7
1
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India 2 Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India 3 Rathimed Speciality Hospital, Chennai, Tamil Nadu, India 4 Department of Internal Medicine, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India Manuscript submitted: November 1, 2013; accepted: December 3, 2013. Corresponding Author: Natarajan Harivenkatesh, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. Email: [email protected]
Downloaded from cpt.sagepub.com at UNIV FED DO RIO GRANDE DO NOR on April 22, 2014
Harivenkatesh et al
297
According to the recent estimates, mixed dyslipidemia is prevalent in 21% of the adults in the United States.4 Statins primarily reduce LDL-C but have only modest effects on HDL-C and TGL. On the other hand, fibrates primarily reduce TGL and increase HDL-C but have only modest effects on LDL-C. Hence, combination of statins and fibrates is frequently used for the treatment of mixed dyslipidemia.8-12 One of the major limitations of long-term pharmacological treatment of dyslipidemia is suboptimal adherence to drug therapy.13,14 Recent studies have shown that noncompliance with statins is around 30% to 50% thereby decreasing the therapeutic effects. Further around 50% of patients who begin treatment with hypolipidemic drugs discontinue the treatment at the end of first year.13-15 Common reasons for poor patient compliance with these drugs are the adverse effects produced by them like myopathy and high cost of drug therapy.14,16,17 One of the ways to minimize adverse effects, to reduce cost of drug therapy, and to improve patient compliance is to give these drugs on alternate days instead of daily therapy. Both atorvastatin and fenofibrate have long half-life (t½), which makes them suitable for alternate day therapy. Hence, this pilot study was designed to evaluate the efficacy and safety of alternate day therapy with fixed dose combination (FDC) of atorvastatin 10 mg and fenofibrate 160 mg in comparison with daily therapy in the treatment of mixed dyslipidemia.
Methods Study Design The present pilot study is a randomized, active-controlled, 2-group, parallel arm, open-labeled, single-center study. It was conducted in Sri Ramachandra Medical College Hospital, Chennai, a tertiary care teaching hospital in South India, from September 2010 to December 2011. The study was performed in accordance with declaration of Helsinki and ICH-GCP guidelines. The study protocol was reviewed and approved by Institutional Ethics Committee (CSP/10/AUG/11/26). The study was registered in Clinical Trials Registry—India before enrollment of the first study participant (CTRI/2010/091/ 001328). Written informed consent was obtained from all study participants before performing any study-related procedure.
Eligibility Criteria Patients of both gender aged >18 years who were diagnosed to have mixed dyslipidemia (TGLs 200 mg/dL and non-HDL-C 130mg/dL) and met the criteria for pharmacological treatment per updated National Cholesterol Education Program— Adult Treatment Panel III (NCEP-ATP III) guidelines were included in the study18 (Non-HDL-C ¼ Total cholesterol HDL-C). Patients already taking statins, fibrates, or other hypolipidemic drugs, patients with active hepatic disease and elevated liver enzymes (serum glutamic oxalo-acetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and
alkaline phosphatase >3 times the upper normal limit), uncontrolled diabetes mellitus in spite of drug therapy (hemoglobin A1c > 7%), serum creatinine >1.2 mg/dL, elevated creatine phosphokinase (CPK) levels, and muscular disorders, patients who had myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or cerebrovascular accident within 6 months preceding the study, patients receiving concomitant drugs that might interfere with metabolism of study drugs, postmenopausal women on hormone replacement therapy, pregnant and lactating women, women of child-bearing age not using acceptable methods of contraception, and patients unwilling to give informed consent were excluded from the study.
Study Procedure Patients who met the eligibility criteria were randomized to 2 parallel groups (alternate day therapy group and daily therapy group) in 1:1 ratio using computer-generated simple randomization in blocks of 10. Allocation concealment was maintained using serially numbered opaque-sealed envelopes. Study drug was the FDC of atorvastatin 10 mg and fenofibrate 160 mg. Patients on alternate day therapy group and daily therapy group received the study drug on alternate days and daily, respectively, for 12 weeks. There were 3 scheduled visits during the study; baseline visit, after 6 weeks, and after 12 weeks (end of study visit). Serum lipid profile (total cholesterol [TC], HDL-C, LDL-C, TGL, and TC–HDL ratio), creatinine, SGOT, and SGPT were analyzed in the baseline and after 12 weeks of therapy. Lipid profile estimations were done after overnight fasting using venous blood samples. Serum TC was measured using cholesterol oxidase method, TGLs using enzymatic assay, HDL-C using polymer–polyanion, and LDL-C using direct measure. Non-HDL-C was calculated using the formula (Non-HDL-C ¼ Total cholesterol HDL-C). The CPK levels were estimated only for patients with myalgia. The study drug was supplied as 6-week calendar pack to all study participants along with compliance card and patient diary. All the study participants were instructed to take the study drug orally with a glass of water after food at bedtime. All the study participants were advised to continue low-fat diet and physical exercise (as per NCEP-ATP III guidelines) throughout the treatment period.
Study End Points The primary efficacy end points were percentage change in TGL and non-HDL levels from baseline after 12 weeks of therapy. Secondary efficacy end points include percentage change in LDL-C, HDL-C, TC levels, and TC–HDL ratio from baseline after 12 weeks of therapy, cost-effectiveness, and patient compliance in both the groups. Safety end points were incidence of adverse events in both groups and percentage change in liver enzymes SGOT and SGPT from baseline after 12 weeks of therapy.
Downloaded from cpt.sagepub.com at UNIV FED DO RIO GRANDE DO NOR on April 22, 2014
298
Journal of Cardiovascular Pharmacology and Therapeutics 19(3)
Assessment of Patient Compliance Patient compliance was assessed by counting the number of empty blister packs and unused study medications, if any, returned by the study participants and by looking at the patient compliance card. Noncompliance was defined as less than 80% or more than 120% of the predicted number of empty blister packs being returned during the scheduled visits.
Cost-Effectiveness Analysis Since non-HDL-C represents the atherogenic form of lipoproteins,6 the drug treatment cost incurred for 1% reduction in non-HDL-C level during treatment period was compared in both the groups to analyze cost-effectiveness.
Adverse Event Reporting During the Study All the adverse events observed/complained by the study participants were reported in the case report form along with the information about severity (mild, moderate, or severe) and causal relationship to the study medication. Biochemical parameters assessed for safety profile were serum creatinine, SGOT, and SGPT.
Statistical Analysis Since this is a pilot study, no formal sample size calculation was done. A convenient sample of 110 patients was chosen for this study. All statistical analyses were performed using SPSS for windows version 16. Demographic data (age, sex, etc) and baseline patient characteristics were summarized by treatment groups using descriptive statistics to assess difference if any between them. Mean and standard deviation (SD) were provided for continuous data, while absolute frequencies and percentage were provided for categorical data. The TGL, LDL-C, TC, HDL-C, and non-HDL levels in each group before and after intervention were compared using paired ‘‘t’’ test. The mean percentage change in the above-mentioned lipid parameters from baseline to 12 weeks between both the groups was compared using student ‘‘t’’ test. Nonparametric tests were used for the data that did not follow normal distribution. P value
