The clinico-economic analysis of pharmacotherapy in patients with non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) have become the most common liver diseases in the world. Aim. To conduct the clinico-economic analysis of pharmacotherapy in patients with NASH, who underwent treatment in one of the healthcare institutions of Kharkiv in 2013. Materials and methods. The study materials were case histories of patients and such regulatory documents of the Ministry of Health of Ukraine as the State Formulary (SF) of Medicines of Ukraine (2013), methodological recommendations on the diagnosis and pharmacotherapy of the digestive system diseases (2007), the Unified Clinical Protocol (UCP) “Non-alcoholic steatohepatitis” (Order No. 826 dated November 6, 2014). The pharmacoeconomic methods used were АВС, VEN and frequency analyses. Results. The results of the study demonstrated that the pharmacotherapy of patients with NASH complied with the main requirements specified in the Ukrainian Methodological Recommendations (2007), but did not meet the require ments of the NASH UCP by the approaches of the pathogenetic therapy prescribed. The results of “formal” VEN analysis showed that most drugs prescribed (76 %) were classified as group V – vital drugs since they were present in the SF of Ukraine. A predominant portion (83.2 %) of costs associated with the pharmacotherapy in patients with NASH was spent on these drugs. However, 16.8 % of the costs spent on 24 % of drugs, which are absent in the SF, indicates the need for further correction of the NASH pharmacotherapy in the healthcare institution under study. Conclusions. The pharmacotherapy of patients with NASH in the healthcare institution of Kharkiv is rational from clini- cal and economic point of view, but requires further correction in accordance with the SF and the new UCP for NASH.

The pharmacoeconomic analysis of the NASH therapy has become a subject of the research conducted by foreign scientists [1,[8][9][10]. These works present the results of the studies performed using the "cost-effectiveness" and "cost-utility" methods, as well as data on costs for the treatment of NASH. The treatment of patients suffering from NASH and NAFLD is associated with significant costs. For example, in the healthcare system of Iran the total costs for NAFLD pharmacotherapy in adult population exceed 1 billion dollars a year [10]; in the US, according to the five-year studies, healthcare costs have increased by 26 % due to the increase in the number of the overweight population and the incidence of NAFLD [1].
Until 2014 to make a diagnosis and perform the rational treatment of NASH physicians in Ukraine used the methodological recommendations by O. Ya. Babak and N. V. Kharchenko "The rational diagnosis and pharmacotherapy of diseases of the digestive system: methodological recommendations" (2007) [11]. In 2014 the Unified Clinical Protocol (UCP) of the Primary, Secondary (Specialized) Medical Care "Nonalcoholic steatohepatitis" was approved by the Order of the Ministry of Health of Ukraine No. 826 dated November 6, 2014. It is based on the principles of evidence-based medicine taking into account the results of studies of the best world practices. In accordance with this medico-technological document (MTD) the basic method for treating NASH and preventing serious complications is modification of the diet and life style, as well as the pharmacotherapy targeted at stopping and reducing the impact of such risk factors as insulin resistance, dyslipidemia, obesity and the metabolic syndrome [12].
The search for recent scientific publications and pharmacoeconomic studies conducted in Ukraine has shown that there are no current statistical data on the NASH prevalence, as well as no publications concerning analysis of quality of the NASH therapy in accordance with MTD recommended by the Ministry of Health of Ukraine (MOH), such as the State Formulary (SF) of Medicines of Ukraine and the UCP of the Primary, Secondary (Specialized) Medical Care of Patients with NASH. The abovementioned facts demonstrate the necessity for assessment of drug prescribing to patients with NASH, and it will promote optimization of both the pharmacotherapy itself and its costs.
The aim of this work is to give the comprehensive assessment of the drug consumption and the rationality of the pharmacotherapy in patients with NASH, who underwent treatment in one of the healthcare institutions of Kharkiv in 2013, by analyzing the therapy compliance with the current MTD based on the results of clinico-economic analysis of the SF of Ukraine (the 5th edition, 2013) [13], the Ukrainian methodological recommendations on the diagnosis and pharmacotherapy of the digestive system diseases (2007) [11] and the UCP of the Primary, Secondary (Specialized) Medical Care of patients with NASH (2014) [14].

Materials and Methods
For this purpose the following objectives should be performed: to carry out the retrospective analy-sis of medication administration records of patients with NASH; to determine the frequency of prescribing drugs to patients with NASH; according to the results of "formal" VEN analysis in order to assess the therapeutic quality based on the presence of prescribed drugs in the annually revised medical regulatory document -the State Formulary of (SF) Medicines of Ukraine (the 5th edition, 2013) [13]; to assess compliance of the NASH therapy approaches with the requirements of the Ukrainian Methodological Recommendations (2007) [11] and with the NASH UCP (2014) [14]; to determine the structure and rationality of costs for the NASH therapy according to the ABC analysis results [15]. When determining the cost of the treatment course with drugs prescribed to patients with NASH the average retail price for these drugs was used as of May 2015 [16].

Results and Discussion
According to the Ukrainian Methodological Recommendations (2007) [11] been in effect before introduction of the UCP for NASH treatment the following basic principles can be identified (Fig.).
With introduction of the UCP the recommendations for the life style modification have remained valid, but with updated data regarding the physical activity and the body weight loss (BMI < 25 kg/m 2 ), while approaches to the NASH pharmacotherapy have changed due to the clinical studies performed with the results based on the data of evidence-based medicine [9].
To date, the following drugs should be prescribed for the NASH pharmacotherapy in accordance with the UCP: 1. Tocopherol (Vitamin Е) in a daily dose of 200-400 mL (only in patients with biopsy-proven NASH, without diabetes mellitus).
2. Omega-3 fatty acids, metformin and pioglitazone that should be used only for correction of concomitant metabolic disorders.
The UCP for the NASH treatment that came into effect after its approval by the MOH of Ukraine from November 6, 2014 [14] contains no information regarding prescription of hepatoprotectors and drugs with ursodeoxycholic acid. It indicates their unproved efficacy for this pathology.
The results of the retrospective analysis of case histories showed that 54 patients (30 males (56 %) and 24 females (44 %) aged from 20 to 85 years) diagnosed with non-alcoholic steatohepatitis underwent treatment in the Kharkiv healthcare institution during 2013. The average duration of staying of one patient in the hospital was 14 days. In addition to the main diagnosis of NASH, the majority of patients had concomitant diseases; chronic pancreatitis (33 %) and cholecystitis (43 %) were the most common.
To treat 54 patients 74 drugs were prescribed, including 51 drugs for the treatment of concomitant diseases and 23 drugs for the NASH treatment. The total costs for pharmacotherapy of 54 patients with NASH were 100,376.44 UAH. On average 1,859 UAH were spent on the treatment course per a patient. Over the period examined 355 prescriptions of drugs to patients with NASH were recorded in the healthcare institution studied. It is on average 6.6 drugs per a patient, and indicates the presence of polypragmasy and the need to reduce the number of prescriptions to 4-5.
The first stage of our work included frequency analysis, on its basis top-10 leaders were determined by the number of prescriptions. A half of these top-10 leaders (Thiotriazolin, Ursochol, Berlithion, Phosphogliv, Espa-lipon) was prescribed to patients with NASH within combined therapy regimens, and other drugs were used for the therapy of concomitant diseases.
In 2013 during the NASH treatment the prescription of hepatotropic agents Thiotriazolin (Galychfarm) and Ursochol (Darnytsia) met the Methodological Recommendations applicable at that time (2007). However, at present this approach to the pharmacotherapy of patients with NASH does not meet the current UCP (2014). It should be also noted that among the metabolic drugs prescribed for the NASH pharmacotherapy the leading positions were occupied by Berlithion and Espa-lipon corresponding to the pharmacotherapy approaches that were applicable at the time of the study. Such metabolic drugs recommended by the UCP for the NASH treatment as L-carnitine, lecithin, choline and B vitamins (except for prescription of a combined drug Neurobion to one patient) were prescribed to none of the patients. Thus, predominant approaches to the NASH pharmacotherapy met the requirements applicable at the time of the study, but were not consistent with the new UCP.
The next stage of our work included the assessment of the rationality of costs based on the results of ABC analysis, which comprised distribution of drugs into three groups by their cost. According to Drugs of group A are the most cost-intensive and of primary interest when analyzing the results obtained. Table presents distribution of costs for drugs of group A by trade names (TN). Five leaders of group A by costs included drugs for pathogenetic and symptomatic therapy of NASH -hepatoprotectors Heptral and Phosphogliv, antioxidant Thiotriazolin, as well as drugs affecting metabolic processes (Berlithion and Espa-lipon); 55.68 % of the total amount of costs was spent on them. Therefore, most costs from group A were spent on drugs for the NASH treatment. The first leader in the ABC ranking by TN was the metabolic drug Berlithion containing alpha lipoic acid (Berlin-Chemie/Menarini Group, Germany) -19.35 % of the total amount of costs (79.84 %). It was prescribed to 18 patients and had the highest price per a pack and per a treatment course. This drug was prescribed to NASH patients suffering from concomitant diabetic polyneuropathy.
To determine how rational money was spent on the NASH treatment VEN analysis performed in accordance with the SF (the 5th edition, 2013) Comparison of the results of frequency and "formal" VEN analyses showed that 9 out of 10 leaders by the number of prescriptions are classified as vital drugs (Thiotriazolin, Spasmobru, Duspatalin, Sodium Chloride, Berlithion and Ursochol, Espa-lipon, Dalargin, Creon 10,000) since they are included in the SF (the 5th edition). Only the hepatotropic drug Phosphogliv manufactured by Pharmstandard is a non-essential drug as it has the insufficient evidence base and is not included in the SF (the 5th edition).
According to the results of АВС/VEN analysis 87.5 % of drugs in group A (14 out of 16 drugs) were referred to the index "V" (vital drugs) (Tab.). The SF did not contain the abovementioned hepatotropic drug Phosphogliv and the homeopathic medicinal product Traumeel S manufactured by Heel (Germany). It is associated with the low evidence base of their efficacy. The results of АВС/frequency analysis demonstrated that the major costs were spent on frequently prescribed drugs: drugs of group A were prescribed 234 times, and it was more than a half (65.9 %) of all prescriptions.
Thus, comparison of the results of АBC, VEN and frequency analyses indicated that the main approaches to the therapy of patients with NASH complied with the clinical recommendations (2007) applicable at the time of the study, but did not meet the requirements of the NASH UCP (2014). A small number of prescriptions and an insignificant part of costs were associated with non-essential drugs that were not included in the SF (2013). Therefore, in general, the actual pharmacotherapy of patients with NASH in the Kharkiv healthcare institution is rational from clinical and economic point of view, but requires further correction in accordance with the SF of Ukraine and the new UCP. CONCLUSIONS 1. The pharmacotherapy of patients with NASH has complied with the main requirements specified in the Ukrainian Methodological Recommendations on the diagnosis and treatment of the digestive system diseases (2007), but it has not met the current requirements of the NASH UCP (2014) by the approaches of the pathogenetic therapy prescribed. It requires further correction of drug prescription in the healthcare institution studied taking into account the new medico-technological document of the MOH of Ukraine.
2. According to the results of АВС/VEN analysis a predominant portion (82 %) of the total costs for the pharmacotherapy was spent on drugs included in the SF of the 5th edition (76 %). However, 16.8 % of the costs spent on 24 % of drugs, which are absent in the SF, indicates the need for further correction of the NASH pharmacotherapy in the given healthcare institution.
Conflicts of Interest: authors have no conflict of interest to declare.