Pharmacoepidemiological Analysis of Statins Dispensing Patterns in Pharmacy Practice – Pro fi le and Side E ff ects A

Introduction: Modern way of life contributes to the ever increasing incidence of atherosclerosis and associated cardiovascular disease. Accordingly, prescribing of statins, drugs used for primary and secondary prevention of cardiovascular events, gains momentum worldwide. The aim of this study was to analyze profi le of drug dispensing, side eff ects frequency and correlation with treatment duration. Subjects and methods: The study included 44 randomly selected patients who used statins. The length of the follow-up was a one month, in the outpatient pharmacy situated in the city of Belgrade, where patients fi lled out the survey. Data were statistically analyzed and presented in tables and graph enclosed. Results: PResults showed that it is more frequent use of these drugs in secondary prevention of cardiovascular events, than in primary. Likewise, there is a signifi cant diff erence in distribution between diff erent therapy duration categories and indication (χ2 = 7.726; p = 0.021) and signifi cant diff erence in distribution between diff erent categories in weight gain (χ2=11.535; p=0.003). The average ages of respondents were 66.93±7.65 years, and average duration of therapy 31.68 months. Conclusion: Based on the results, it can be concluded that the use of statins is justifi ed in primary prevention up to 32 months of duration. After this period additional measures concerning its justifi cation are required. From the standpoint of pharmacovigilance, it is necessary to frequently conduct the evaluation of prescriptions and use of these drugs, in order to prevent side eff ects.


INTRODUCTION
Hyperlipidemia is the leading risk factor for the development of atherosclerosis and atherosclerotic cardiovascular disease, such is ischemic heart disease, cerebrovascular disease and peripheral vascular disease [1][2][3][4].Th ese diseases are a major cause of morbidity and mortality in middle-aged and elderly population.Th ese non-communicable "prosperity diseases" bear signifi cant work load and fi nancial burden for the health system particularly among the subpopulation of elderly [5][6][7].It is estimated that in 2008 in Serbia, even 49.8 % of persons older than 25 years had elevated cholesterol levels in the blood, with a higher incidence in males from 52 %, while the percentage of women were 47.4 % [8].
Searching for drugs, which, in comparison with the change of diet and lifestyle, will be more effi cient and faster, experienced golden age aft er 1994 when the Scandinavian study showed effi cacy of simvastatin for secondary prevention of coronary artery disease, and aft er 1995, when the study was published in Scotland wherein pravastatin signifi cantly reduced the mortality rate in patients with primary hypercholesterolemia [9,10].
Th e results of the Heart Protection Study, conducted on diabetic patients show that the use of simvastatin decreased cardiovascular mortality for more than 25%, independent of cholesterol levels, gender and age.Precisely this study, conducted on a large number of respondents, shows that there are a number of indications for statins uses.Th ey can be used in the primary or the secondary prevention of cardiovascular events, as well as in patients with type 2 Diabetes mellitus, and the age limit was moved to 80 years (28% of respondents had 80 years) [11].Huge budget impact of diabetic patients outsourcing from this exceptional consumer demand for medical services has been documented in local evidence [12].
According to data British heart foundation, in England has increased the number of prescribing statins from 290 000 to 52 million in the period from 1981 to 2008.Large number of patients these drugs purchased without a prescription.According to the analysis of 2008, carried out in Canada, most frequently used statin was rosuvastatin, in a dose of 10 mg, followed by atorvastatin in a dosage of 10 and 20 mg, and for them, simvastatin and pravastatin in a dosage of 20 and 40 mg [13].
Recent researches have shown that statins have a neuroprotective eff ect, thus creating the possibility of their use in new therapeutic areas, such as the therapy of Alzheimer's disease and other neurological disorders [14,15].Due to the aforementioned, as well as potential new indications, it is realistic to expect a further increase in the issuance and use of such drugs, and therefore are not negligible side eff ects of these drugs.Muscular disorders, ranging from asymptomatic increase in creatine kinase to rhabdomyolysis, have been most frequently discussed side eff ects of these drugs.Th e risk of rhabdomyolysis is less when it comes to statin monotherapy.Th e incidence of this undesirable eff ect, based on the studies done in the United States at 6 months of hospitalized patients, 0.44 in 10,000 patients, wherein the incidence increases in the combination therapy with a fi brate, to 5.98 in 10,000 patients [16].
Th e risk of these side eff ects is the dose-dependent, and increased with the simultaneous use of drugs that inhibit the metabolism of the statin in the liver, such as itraconazole, erythromycin and cyclosporine [17].As potential risk factors for the development of rhabdomyolysis are listed female gender, older age, hypothyroidism, Diabetes mellitus, kidney and liver decreased function, but this is not confi rmed by clinical trials or observational studies.
Th e aim of the study is to estimate statins consumption, drugs that were dispensed on prescription or bought without it, in consultation with a physician, in sample of the adult population of the city of Belgrade.Population profi le that uses these drugs was considered, an indication and the average duration of use, as well as the frequency of the most common side eff ects.Followed statins were atorvastatin, simvastatin, pravastatin and rosuvastatin.Th is research was largely driven by great upward trend in statins volume of sales and utilization in terms of defi ned daily doses (DDD) driven by transformation of regional pharmaceutical markets over the past decade [18,19,20].

Study design
Design of present study was conducted by type of survey research, for a time period from 15 th December 2013 to 15 th January 2014 in out-patient pharmacy situated in Belgrade.Questionnaire had two parts.Th e fi rst part had a general nature and provides information about years, gender, sex and drug indication (hyperlipidemia with, or without cardiovascular event).In this part, there were issues related to the drug itself, drug name, dose and the manner of issuing drug (with or without a prescription).Second part was related to the side eff ects of the medicine, through a threelevel scale, where patient was able to assess the prevalence of side eff ects from the questionnaire, and to add unusual adverse reaction, which appeared for the time of drug therapy.Adverse reactions whose presence the patient assessed are: loss of appetite, weight increase, ringing in the ears, nose bleeding, changes in the glucose level in the blood, dizziness, pain in joints and muscles, increase in liver enzymes levels, leg cramps, numbness of extremities and allergic reactions.

Study participants
In the study participated 44 randomly selected patients, that used statins, whether with prescription, or without it, with doctor's recommendation.All were residents of the City of

Statistical analysis
Numerical data were presented as mean ± standard deviation, while categorical variables were expressed as frequency.To determine correlation between therapy duration and side eff ects score, curve estimation was used.Cut point values for therapy duration were determined, in which signifi cant distribution changes of side eff ect scores.To estimate the diff erence between categorical variable groups, χ2 test was used.P values less than 0.05 were considered signifi cant.Statistical analyses were performed in SPSS, version 15 (Chicago, Illinois).

RESULTS
During the one-month survey, 44 patient were interviewed, 22 men and 22 women.Th e oldest patient had 85, and the youngest 54 years.Th ere was not signifi cant statistical diff erence in ages between sex (t=0.410,df=42, p=0.666).Hyperlipidemia with or without cardiovascu- lar event were present at 26 and 18 respondents, respectively.Th ere were no signifi cant diff erences in drug indication between sex (χ2=0.228,df=1).
Th e results showed that there was a non-linear relation of therapy duration and total score of side eff ects frequencies and intensity (Figure 1).
In fi gure 1, there was a uniform distribution of absence in cases of side eff ects (score=0) and occasional presence of one side eff ect (score=1), and occasional presence two or more side eff ects, or permanent present of one unwanted outcome (score>1) for the average therapy duration in this study (32 months).However, aft er 54 months of treatment period, there was absence of occasional presence two or more, or steadily presence one or more side eff ects (score>1).Th erefore, variable duration of therapy was transform in categorical variable with three modalities, as treatment duration: less or equal to 32 months (category 1), longer than 32 months and less or equal to 54 months (category 2), and longer than 54 months (category 3).Further, relationship between obtained categories and drug indication was tested.Th ere were no signifi cant diff erences in the distribution of various categories of duration of treatment by gender, as well as the manner of issuing of statins (Table 2.).
Results showed that there was significant diff erence in distribution between diff erent therapy duration categories and indication (χ2=7.726,p=0.021).Categories 2 and 3 had a higher proportion of patient with cardiovascular event, than category 1 (Table 2.).Th ere was a signifi cant diff in distribution between diff erent categories in weight gain (χ2=11.535;p=0.003).

DISCUSSION
In academic pharmacoepidemiology and pharmacovigilance questionnaries have long become standard tools for acquiring reliable data [21,22].Results of this study showed that people which use statins most commonly found in the seventh decade of life (66,93±7,65), as opposed to the indigenous populations of England, in which these drugs had been used most frequently in persons in the sixth decade [23].It is signifi cantly more frequent use of these drugs in patients with hyperlipidemia and CV events, than in patients who have only hyperlipidemia, without CV event.
According to the survey results, the most used statins were atorvastatin and rosuvastatin, respectively.Th ese results diff er from the results of studies carried out in Serbia in the period from 2004 to 2008, aft er which it is actually the most used statin simvastatin, in a percentage higher than 50% [24].Th e increasing use of atorvastatin relative to the simvastatin can be attributed to the higher effi ciency of this drug in cholesterol-lowering eff ect [25].Likewise, it can be expected increasing use of rosuvastatin, as has been demonstrated its higher effi ciency compared to equivalent doses of other drugs in this group, including atorvastatin [26].In the above-mentioned study in England, 70% of patients have used simvastatin, atorvastatin 22.3%, while rosuvastatin is used by only about 1.9% of patients [23].70% of respondents used these drugs on prescription, while the remaining 30% of patients purchased medications from this group of drugs.
In patients were not recorded cases of rhabdomyolysis, which is rare side eff ect (the incidence is less than 0, 01% [23].In the study there were no unusual side eff ects or the eff ects were provided outside the borders.Th is can be explained by the fact that the side eff ects are dose-dependent and doses used in Serbia are not high, compared to some countries, in which are used even dose of 80 mg of atorvastatin, where the risk of serious side eff ects, especially rhabdomyolysis, doubles [27]. It is known that the occasional interruption of statin therapy (once a year for a period of one to two months) is advisable, for the prevention of adverse outcomes of therapy.In this study was shown that such a practice is not enough, and that it should pay attention to the fact that the duration of statin therapy had a nonlinear eff ect on the frequency and intensity of adverse events commonly associated with their use.So, it is quite justifi ed in this way, to prevent adverse reactions to 32 months of therapy.However, aft er 32 months of treatment with statins, it is necessary to introduce additional precautions related to the prevention of weight gain, which teams up with a higher incidence of CV events.Conversely, aft er 32 months, as well as aft er 54 months of therapy, the frequency and intensity of the common side eff ects of statin therapy were almost clinically insignifi cant.Th erefore, aft er 32 months of treatment with statins, it is necessary for patients with hyperlipoproteinemia to take care of diet nutrition and intensify physical activity.

CONCLUSION
Modern life, which entails rising stress and less concern about adequate nutrition and physical activity, contributes to damaging health and the increasing number of patients suff ering from cardiovascular diseases.Th erefore, it is expected increase of statins use in the treatment or as a measure of primary prevention.Due to a number of adverse eff ects it is necessary to exert constant evaluation of adverse effects and prescribe these drugs when the benefi ts outweigh the risks.

Figure 1 .
Figure 1.Nonlinear eff ect of statin therapy duration on the total score of the frequency and intensity of adverse events.

Vuković MH et al:
Pharmacoepidemiological Analysis of Statins Dispensing Patterns in Pharmacy Practice -Profi le and Side Eff ects

Table 1 .
Quadratic function parameters of infl uence of the duration of statin therapy on the overall score frequency and intensity of adverse events