Use of ACE-Inhibitors in Serbia in 2009 and 2010 A

Introduction Cardiovascular diseases (CVD) are the most frequent cause of morbidity and mortality in many countries as well as in our country. That explains why medications for the treatment of CVD are the most used group of drugs. The aim of this study was to analyze the consumption of ACE-inhibitors in Serbia and Norway during 2009 and 2010. Material and methods The data about the use of ACE-inhibitors in Serbia and Norway in 2009 and 2010 were taken from the Agency for Drugs and Medical Devices of the Republic of Serbia and from the site of Norwegian Institute of Public Health. Results Use of drugs of fi rst choice in the treatment of hypertension in Serbia was very uneven, where the consumption of ACE-inhibitors was dominant. Opposed to this condition, the consumption of the fi rst choice antihypertensive drugs was very balanced in Norway. During both analyzed years large part of consumption of ACE-inhibitors was taken by more expensive drugs in Serbia, as fosinopril, cilazapril and quinapril. In Norway in the observed period, dominated the consumption of cheaper drugs such as enalapril and ramipril. The situation is similar when it comes to fi xed combination of diuretics and ACE-inhibitors. In Norway dominated the fi xed combination of diuretics and cheaper ACE-inhibitors like enalapril and lisinopril. However, in Serbia, we have large consumption fi xed combinations of diuretics with expensive ACE-inhibitors, such as cilazapril and fosinopril. Conclusions In both countries, ACE-inhibitors and their fi xed combination with diuretics are most frequently used drugs within the group of drugs which is used for treatment of CVD in Serbia in 2009 and 2010. The amount and structure of the utilized ACE-inhibitors in Serbia is diff erent from the amount and structure of the utilized ACE inhibitors in Norway. From pharmacoeconomic point of view, high consumption of expensive ACE-inhibitors (plain and fi xed combination with diuretics) in 2009 and 2010 in Serbia resulted in the higher spending of funds.


INTRODUCTION
Cardiovascular disease (CVD) and kidney disease are the most common cause of morbidity and mortality in industrialized countries [1].In 2008, the rate of mortality from CVD in Serbia stood at 55.8% which ranks Serbia among the countries with the highest cardiovascular mortality [2].It is therefore understandable why drugs which are in use for the treatment of cardiovascular disease (group C according to ATC classifi cation) are the most frequently used group of drugs.Besides, consumption of drugs from the C group has steadily increased in Serbia.In 2004,the total consumption of drugs amounted to 30.54%, while in 2008 it amounted to 38.89% [2,3].In relation to all drugs of C group, in the world, and in our country angiotensin converting enzyme inhibitors (ACE-inhibitors), drugs used in treatment of hypertension and cardiac insuffi ciency, occupy an important place [4,5,6].
Hypertension is a major risk factor for the development of other cardiovascular diseases including coronary artery disease, stroke, heart failure and end stage of renal disease [4,7].According to the World Health Organization (WHO) and International Society of Hypertension (ISH) in 2003 was estimated that hypertension occurs in 4-5% of cases compared to the more global disease, and it is widespread in both developing and developed countries.Globally, complications associated with hypertension are the third in a row in terms of mortality.WHO estimates that the number of people diagnosed with hypertension will be increased by 60% over the next few years [5].Modern approach in treatment of hypertension is based on application of fi ve groups of drugs: diuretics, β-blockers, ACE-inhibitors, calcium channel blockers and angiotensin II receptor antagonists (ARBs).Also, in the treatment of hypertension is recommand use of fi xed combinations of ACE -inhibitors and angiotensin receptor blockers with diuretics and calcium channel blockers [4,5,8].
Th e mechanism of action of ACEinhibitors takes place through the renin-angiotensin-aldosterone system (RAAS).Hemodynamic eff ects of ACE-inhibitors are caused by reduction levels of angiotensin II and aldosterone, and by increasing levels of bradykinin.Bradykinin have vasodilator and hypotensive actions.Th ese drugs reduce tension at the level of the arteries and veins and relieve the heart by reducing aft erload and preload.As a result there is a decrease in systolic and diastolic blood pressure [9].Adverse eff ects of ACE-inhibitors include: hypotension, dry cough, hyperkalaemia, renal failure, fetal anomalies [9].Indications for the benefi t of ACE-inhibitors include: hypertension, congestive heart failure, myocardial infarction, ischemic heart disease, stroke [4].
Th e benefi ts of ACE-inhibitors over the other antihypertensives are refl ected in their increasing protective eff ect on the renal blood vessels in patients with diabetes mellitus.Th ey have multiple eff ects on kidneys, including reducing of renovascular resistance, and also slowdown deterioration of renal function that occurs in diabetic nephropathy and thus prevents the progression of microalbuminuria in proteinuria [10].ACE-inhibitors can be used in combination with a diuretic and with calcium channel blockers.Th ese drugs can be applied in fi xed combination with diuretics because, thiazide diuretics cause decrease of potassium and ACE-inhibitors potassiumsparing.In this way, it avoids the appearance of hypo or hyperkalaemia in the application of each of these drugs individually [4].On the other hand, in primary hypertension, ACEinhibitors do not show a signifi cant advantage because they both reduce blood pressure, like other antihypertensive drugs of fi rst choice.Th e advantage of ACE-inhibitors could be seen in terms of their kinetics, because most of these drugs are applied once a day [8].Seen from pharmacoeconomic aspect, the structure of ACE-inhibitors which are consumed in Serbia in recent years is not rational because the drugs of this group were much more in use than other drugs of fi rst choice in the treatment of arterial hypertension.We can also notice that the newer and more expensive preparations have priority, regardless they do not show signifi cant effi cacy compared to older and cheaper ACE-inhibitors [3,11,12,13].

THE AIM
Th e aim of this study was to analyze the consumption of ACE-inhibitors in Serbia during 2009 and 2010 from pharmacotherapeutic and pharmacoeconomic point of view, as well as comparing that with consumption in Norway, which has developed pharmacotherapeutic practice.

MATERIAL AND METHODS
Th e data about the use of ACE-inhibitors in Serbia in 2009 and 2010 were taken from the Agency for Drugs ans Medical Devices of the Republic of Serbia [14,15].Th e data of drug consumption in Norway were taken from the offi cial site of the Norwegian Institute of Public Health [16].Analysis of the consumption of drugs was done from the point of social perspective and there were no infl uence of any factors or any interest group.Th e amount of used drugs are expressed in the number of defi ned daily doses (DDD) per 1000 inhabitants per day (DDD/1000 inh/day).
Internationally recognized and widely accepted methodology in the study of drug use is based on the concept of anatomicaltherapeutic-chemical classifi cation of drugs (ATC) and defi ned daily doses.According to the ATC classifi cation the drugs that we use in treatment of cardiovascular diseases belong to the C group, whereas drugs that act on the renin angiotensin system are belonging to a group of C09.Further analyzed in C09A group, we have monocomponent products, and the combination of ACE-inhibitors with diuretics which belong to the C09B group.In order to facilitate comparison of the intensity of use of certain drugs in time and in diff erent geographical areas scientes created a separate statistical unit of measurement of use of drugs, labeled as defi ned daily doses (DDD).Th is unit is independent of price, size, packaging, protected names of individual manufacturers and even from the pharmaceutical dosage form.Th e concept of DDD off ered as a statistical unit of use the agreed amount of drug that is commonly used for the most common indication.DDD is defi ned, whenever its possible, in weight units (or units of activity, for example, insulin).When it is impractical or even impossible to express the weight of the DDD, like in case with combined preparations, for the monitoring unit is taken dosage form (tablets, capsules, ampoules) and then it is referred to as eff ective dose (ED) [17].

RESULTS
Consumption of drugs for the treatment of cardiovascular diseases in Serbia in 2009 and 2010 year was sizeable.Drugs of the C group in 2009 year accounted for 35.21% of total drugs consumed in Serbia, and 2010, share of these drugs in the total consumption was even higher and amounted to 39.82%.In Norway, consumption of drugs for the treatment of cardiovascular disease observed in this two years was lower than in Serbia, amounting to about 31%, without trend of increasing consumption.
Comparative review of drug of fi rst choice in the treatment of hypertension in Serbia and Norway in 2009 and 2010 are presented in Graphs 1 and 2. In the detailed analysis of the consumption of drugs from group C in the considered period in Serbia, it was found that the highest consumption in 2009 and 2010 was achieved in the group of drugs that act on the renin angiotensin aldosterone system (C09 group) and it was nearly half of all drugs that are used in the treatment of cardiovascular

DISCUSSION
Th e contemporary approach to pharmacotherapeutic treatment of high blood pressure is based on fi ve groups of drugs.Th ese includes: diuretics, β-blockers, ACE-inhibitors, calcium channel blockers and angiotensin receptor antagonists, and they are used like drugs of fi rst choice in the treatment of arterial hypertension.Th ere is no advantage in use from none of this fi ve groups.In some cases, comorbidity, lack of the eff ect of the products and prices can aff ect in choice of drug, but it certainly should not substantially aff ect the dominance of the consumption of some, of these fi ve groups of antihypertensive drugs [8].But, the situation in Serbia is differente.Consumption of these fi ve groups of drugs is uneven and consumption of ACE-inhibitors convincingly is on the fi rst place.In Serbia, the consumption of ACEinhibitors in 2010 was four times higher than in Norway (Graph 2).Opposed to this condition, the consumption of angiotensin receptor blockers in Norway was very large and the participation of drugs from this group was about 60%, while in Serbia it was only about 3% of total drugs consumed in Group C09.A similar In Serbia, in the group of plain ACEinhibitors during 2009, the most used preparation was enalapril, fosinopril then, and on the third place was ramipril.In 2010, the situation has not changed much.Enalapril was left in the fi rst place, and fosinopril, and ramipril have replaced their position.
Although the fosinopril, plain ACEinhibitor, has a high price, the consumption of this drug in Serbia is large.In 2009 this drug was on the second, in 2010 on the third place in overall consumption of plain ACE-inhibitors.In the same period, the consumption of fosinopril in Norway, as ACE-inhibitor with high price, was not detected, and the cheaper drugs such as enalapril and ramipril were dominant.Th e situation was similar when we looked at the consumption of fi xed combination of ACE-inhibitors with diuretics.During the observed period in Norway were dominant the fi xed combination of diuretics and cheaper ACE-inhibitors like enalapril and lisinopril.Other combinations in Norway haven not been present.In Serbia, the most frequently used fi xed combination was enalapril with diuretcs.However, in Serbia, we have large consumption fi xed combinations of diuretics with expensive ACE-inhibitors, such as cilazapril and fosinopril.
From pharmacoeconomic point of view on high consumption of expensive ACEinhibitors (plain and fi xed combination with diuretics) in 2009 and 2010 in Serbia have been allocated great fi nancial resources.
Th e savings would be large if the structure of consumed drugs from the group of ACE-inhibitors were as in Norway.We must stress that the saving funds would not be on the account of the quality of pharmacotherapy because it is well known that Norway is the country with a developed pharmacotherapeutical practice.
As we can see from the results of this study,the consumption of ACE-inhibitor in Serbia is very large.Th e question is whether such a high consumption of these drugs is justifi ed and do these drugs have an advantages in the treatment of hypertension when we compare them with other antihypertensives.Numerous comparative randomized studies have shown that a similar reduction in blood pressure can be achieved equally eff ectively in any of these fi ve groups of drugs: diuretics, β-blockers, ACE-inhibitors, calcium channel blockers or angiotensin receptor antagonists [8].According to the recommendations of the European Society of Hypertension, the treatment of isolated systolic hypertension should in most cases start with a diuretic, which is not very oft enly used in Serbia [8].Analysis of drug consumption in Serbia comparing with Norway, as the country with a developed pharmacotherapeutical practice, indicate that the structure of consumption of drugs from the pharmacotherapeutic point of view is not adequate and that ACE-inhibitors in the relation to the other four group of drugs have great advantage unjustifi ably.

CONCLUSIONS
In Serbia, ACE-inhibitors are the most used group of drugs from all drugs which are used in the treatment of cardiovascular diseases and their share in total consumption of drugs is higher than in Norway.
Th e structure of most frequently used drugs in the group of ACE-inhibitors and their fi xed combination with diuretics in Serbia is diff erent from the same drugs in Norway, the country with a developed pharmacotherapeutical practice.
From the pharmacoeconomic point of view on high consumption of expensive ACE-inhibitors (plain and fi xed combination with diuretics) in 2009 and 2010 in Serbia have been allocated great fi nancial resources.

Volume 1 •
In 2009 and 2010 in Serbia the most aplied were ACE-inhibitors.Consumption of ACEinhibitors in 2009 was 195.23 and in 2010 it was 190.39 DDD/1000 inh/day.On the sec-126 Number 3 • October 2014 • HOPH ond place were calcium channel blockers, whose consumption was three times lower in comparison to ACE-inhibitors.At the third position were beta blockers with four times lower consumption, while the fourth position occupy diuretics with nine times less applied consumption in relation to ACE-inhibitors.Used of ACE-inhibitors in Serbia in 2009 and 2010 was neglected.Using these fi ve groups of drugs in the observed period in Norway was balansed.In these two years the lower consumption had beta blockers and it ranged from approximately 40 DDD/1000 inh/day.Angiotensin receptor blockers were most applied and their consumption ranged about 78 DDD/1000 inh/day for (Graphs 1 and 2).
Th is research was supported by the Provincial Secretariat for Science and Technological Development, Autonomous Province of Vojvodina, Project No 114-451-3551/2013-01, and by the Ministry of Education, Science and Technological Development, Republic of Serbia, Project No 41012.

Table 3 .
Comparative During 2009 and 2010 in Serbia in the C09 group, the consumption of plain ACEinhibitors was dominant, and it was about 164 DDD/1000 inh/day or 82.50% of total drugs consumed in group C09.On the other hand, in Norway, in 2009 and 2010 year the consumption of plain ACE-inhibitors was approximately 45 DDD/1000 inh/day or 34% of total drugs consumed in C09 group.