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Original article

Comparative analysis of the use of fixed combinations of drugs acting on the renin-angiotensin system, in the Republic of Serbia and Nordic countries, in the period 2010-2015

Boris Milijašević1, Stefan Jovanović1, Danilo Medin2, Đurđa Cvjetković1, Dragana Milijašević3, Nataša Tomić4, Mladena Lalić-Popović5, Nemanja Todorović5

ABSTRACT

Introduction: Hypertension is one of the most significant risk factors for the development of cardiovascular disease (CVD) that can be mitigated. In a certain number of patients, the regulation of hypertension can be achieved by combining antihypertensive drugs – by using two medicines at the same time or by applying a fixed combination of two drugs in single dosage form.

Aim: The aim of this study was to analyze the consumption of fixed combinations of drugs from the subgroup of the anatomical-therapeutic-chemical (ATC) system of the C09 drug classification (agents acting on the renin-angiotensin system - RAS), in the Republic of Serbia, in the period from 2010 to 2015. Also, the aim was to compare the obtained results with the consumption of the same drugs in the Kingdom of Norway, the Republic of Finland, and the Kingdom of Denmark, for the same period. menski period.

Materials and methods: The concept of ATC classification and defined daily dose (DDD) was applied. Data on drug consumption were taken from annual reports of the Medicines and Medical Devices Agency of Serbia (ALIMS), the Norwegian Public Health Institute - Folkehelseinstituttet, the Finnish Drug Agency - Fimea and the Danish Data Protection Agency - Sundhedsdatastirelsen. The quantity of the drugs consumed was presented as the number of DDD per 1,000 inhabitants per day (DDD/1,000 inhabitants/day).

Results: The consumption of fixed combinations of angiotensin-converting enzyme (ACE) inhibitors and diuretics (C09BA) in Serbia, in 2010, amounted to about 14%, while in the last observed year it amounted to about 18% of the total consumption of drugs from the C09 subgroup. The consumption of the same group of drugs in Norway, in 2010, was about 5%, and in 2015, about 4%; in Finland it was slightly higher - in 2010, it was about 7%, and in 2015, about 5%; while in Denmark, in 2010, it amounted to about 12%, and in 2015, to about 10% of the total consumption of drugs from the C09 subgroup. The consumption of fixed combinations of angiotensin II receptor antagonists with diuretics is very small in Serbia and amounts to only about 1% of the total consumption of drugs acting on the RAS.

Conclusion: The consumption of fixed drug combinations of angiotensin II receptor antagonists with diuretics, in the observed four countries, in the analyzed six-year period, was the lowest in the Republic of Serbia. Also, the structure of the fixed combinations of drugs consumed differs greatly between the Republic of Serbia and the remaining three Nordic countries.


INTRODUCTION

Cardiovascular diseases (CVD) represent a large, heterogeneous group of illnesses. These diseases are the leading cause of death in most developed countries, as well as in many developing countries. The most important risk factors for CVD that can be mitigated are the following: hypertension, smoking, elevated levels of low-density-lipoproteins (LDL), decreased levels of high-density lipoproteins (HDL), diabetes mellitus, obesity, poor nutrition, physical inactivity, etc. The development of CVD is directly linked to the elevation in systolic and/or diastolic blood pressure, which is why controlling these parameters represents one of the main approaches in the prevention of cardiovascular diseases [1],[2]. It is estimated that, in 2010, the prevalence of hypertension in the world adult population was 31.1% [3]. It is also known that the prevalence of hypertension is on the rise, not only in the adult [3], but also in the pediatric population [4]. However, research has shown that, in some countries, the average value of blood pressure over time decreases, which is an indication of the pharmacotherapy practice development in these countries. Such data have been recorded in countries like Norway [5], Finland [6], and Denmark [7]. The research carried out in Serbia has demonstrated that the prevalence of hypertension is significantly higher than the world average, and it is estimated at around 47% [8], while mortality rates for diseases caused by hypertension have risen by 113.6%, in the period between 2009 and 2018 [9].

The main goal of pharmacotherapy for hypertension is to avoid its risks while maintaining a normal quality of life. The European Society of Hypertension (ESH) and The European Society of Cardiology (ESC) recommend, as drugs of first choice when starting medicamentous therapy in treating hypertension [10],[11], the following groups of medicaments: diuretics, beta-adrenergic blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor blockers. However, according to the experience up to date, it has been established that in at least 75% of patients with a hypertension diagnosis there is a need for combining antihypertensive drugs, since monotherapy does not achieve satisfactory results [12]. In a certain number of patients, the regulation of hypertension can be achieved by combining antihypertensive drugs – by using two medicines at the same time or by applying a fixed combination of two drugs in single dosage form.

According to the current ESH/ESC guidelines, the primary combinations of antihypertensive drugs are [10],[11]:

  • Diuretic + ACE inhibitor
  • Diuretic + angiotensin receptor blocker
  • Diuretic + calcium antagonist
  • ACE inhibitor + calcium antagonist
  • Angiotensin receptor blocker + calcium antagonist

The result of this approach to hypertension treatment is a reduced number of adverse reactions to drugs, which is the consequence of a lower drug dosage in the fixed combination as compared to the situation when full doses of drugs are given in monotherapy. Thus, it can be expected that the application of fixed antihypertensive drug combinations will bring about a more significant lowering of blood pressure and its better control, as compared to the application of separate antihypertensive drugs. The advantage of fixed drug combinations lies in simpler drug dosing, a better compliance, and in a theoretically lower price, when compared to the sum of the costs of the individual drugs that make up the combination [10],[11].

Research into the consumption of ACE inhibitors in Serbia and Norway, during 2009 and 2010, has shown a difference, between the analyzed countries, in the quantity and structure of the drugs applied from this group. As opposed to Norway, where the application of drugs of first choice for hypertension treatment was balanced, in Serbia, the consumption of ACE inhibitors was dominant. The differences in the structure of applied ACE inhibitors related to the application of more expensive drugs in Serbia than in Norway, both monocomponent drugs, and their combinations with diuretics [13]. A study analyzing the prescribing of antihypertensive drugs in Novi Sad, during a six-month period in 2011 and 2012, also demonstrated an uneven proportion of drugs of first choice, as well as differences to the practices that are in place in Nordic countries (Finland and Norway) [14]. The noted differences indicate the need for further analysis of the consumption of this group of drugs in Serbia, as well as the need for further comparison with countries which have a well-developed pharmacotherapy practice, especially when the prevalence and the risks that hypertension carries are taken into account.

The aim of this study was to analyze the consumption of fixed combinations of drugs from the subgroup of the anatomical-therapeutic-chemical (ATC) system of the C09 drug classification (agents acting on the renin-angiotensin system - RAS), in the Republic of Serbia, in the period from 2010 to 2015.

Also, the aim was to compare the obtained results with the consumption of the same drugs in the Kingdom of Norway, the Republic of Finland, and the Kingdom of Denmark (countries with well-developed pharmacotherapy practices), in the same period.

MATERIALS AND METHODS

The data on drug consumption in the Republic of Serbia, in the period between the years 2010 and 2015, were taken from printed annual reports published by the Medicines and Medical Devices Agency of Serbia (ALIMS) [15],[16],[17],[18],[19],[20].

The data on drug consumption in the Kingdom of Norway were taken from the official website of the Norwegian Institute of Public Health - Folkehelseinstituttet [21].

The data on drug consumption in the Republic of Finland were taken from the official website of the Finnish Drug Agency – Fimea [22].

The data on drug consumption in the Kingdom of Denmark were taken from the official website of the Danish Data Protection Agency - Sundhedsdatastirelsen [23].

The quantity of drugs consumed is calculated by means of the defined daily dose (DDD) methodology, according to the ATC classification, and in keeping with the World Health Organization (WHO) guidelines for drug utilization research [24]. DDD represents the quantity of the active ingredient (average dose) which is used in the adult population, in one day, to treat the main indication [25]. The DDD is a statistical unit of drug usage and does not depend on the cost, the dosage form, or size of the drug packaging. The number of DDD per 1,000 inhabitants per day (DDD/1,000 inhabitants/day) provides insight into the number of individuals in the population (per 1,000) who had used a certain drug and who had been exposed to its influence during the day.

The results on the consumption of fixed drug combinations from the C09 subgroup are shown in the tables as the quantity of drugs consumed, expressed as the number of DDD/1,000 inhabitants/day, and as the percentage of the entire consumption of this subgroup.

RESULTS

Table 1 shows that the consumption of fixed combinations of drugs from the ATC subgroup C09 (C09B and C09D) in Serbia was on the rise during the observation period, except in the years 2013 and 2015, when a mild decrease in fixed combinations of ACE inhibitors (C09B) was registered, as compared to the preceding years. In the first place is the consumption of the combination of ACE inhibitors and diuretics (C09BA), which in 2010 amounted to 27.30 DDD/1,000 inhabitants/day, or 13.87%, and in 2015 it was 61.70 DDD/1,000 inhabitants/day, or 17.57% of the total consumption of drugs in the C09 subgroup. The most used fixed combination of drugs in 2010 was fosinopril with hydrochlorothiazide (C09BA09). Its consumption in that observed year amounted to 8.70 DDD/1,000 inhabitants/day, or 4.42% of the total consumption of drugs in the C09 subgroup, while its consumption in year 2015 was 8.35 DDD/1,000 inhabitants/day, or 2.38% of the total consumption of drugs in the C09 subgroup. As noted, the consumption of fixed combinations of ACE inhibitors and calcium channel blockers (C09BB) in Serbia is negligible.

Table 1. Overview of the consumption of angiotensin-converting enzyme inhibitors, combinations (subgroup C09B); and the consumption of angiotensin II receptor antagonists, combinations (subgroup C09D), in Serbia, in the period 2010 – 2015, presented as the number DDD/1,000 inhabitants/day and as the percentage (%) of total consumption in the C09 group

Table 2 shows that the consumption of fixed combinations of ACE inhibitors (C09B) in Norway is constantly decreasing. In the first place is the consumption of the combination of ACE inhibitors and diuretics (C09BA), which, in 2010, amounted to 6.51 DDD/1,000 inhabitants/day, or 4.89%, and in 2015, it was 5.19 DDD/1,000 inhabitants/day, or 3.61% of the total consumption of drugs in the C09 subgroup. The fixed combination of enalapril with hydrochlorothiazide (C09BA02) was dominantly consumed, and, in 2010, it amounted to 3.79 DDD/1,000 inhabitants/day, or 2.85% of the total consumption of drugs in the C09 subgroup. Its consumption in 2015 was 3.17 DDD/1,000 inhabitants/day, or 2.21% of the total consumption of drugs in the C09 subgroup. As observed, the consumption of fixed combinations of ACE inhibitors with calcium channel blockers (C09BB) in Norway is negligible.

The consumption of fixed combinations of angiotensin II receptor antagonists with diuretics (C09DA) in Norway is quite high; however, it registered a constant mild decrease during the observation period. The most used fixed combination of drugs is losartan with hydrochlorothiazide (C09DA01), while the second most used fixed combination is candesartan with hydrochlorothiazide (C09DA06). The application of the combination of angiotensin II receptor antagonists with calcium channel blockers (C09DB) in Norway, during the observation period, registered a rise, and was 2.69 DDD/1,000 inhabitants/day, or 2.02% in 2010, while in 2015 it amounted to 4.37 DDD/1,000 inhabitants/day, or 3.04% of the total consumption of drugs in the C09 subgroup. The most applied fixed combination from this subgroup of drugs is valsartan with amlodipine (C09DB01).

Table 2. Overview of the consumption of angiotensin-converting enzyme inhibitors, combinations (subgroup C09B); and the consumption of angiotensin II receptor antagonists, combinations (subgroup C09D), in Norway, in the period 2010 – 2015, presented as the number DDD/1,000 inhabitants/day and as the percentage (%) of total consumption in the C09 group

The consumption of fixed combinations of ACE inhibitors in Finland is constantly decreasing (Table 3). In the first place is the consumption of the combination of ACE inhibitors and diuretics (C09BA), which, in 2010, amounted to 15.24 DDD/1,000 inhabitants/day, or 7.45%, and in 2015 it was 11.90 DDD/1,000 inhabitants/day, or 5.18% of the total consumption of drugs in the C09 subgroup; with the dominant consumption being that of the fixed combination of enalapril with hydrochlorothiazide (C09BA02). The consumption of fixed combinations of ACE inhibitors with calcium channel blockers (C09BB) was quite low, but constant, during the six-year observation period.

The consumption of fixed combinations of angiotensin II receptor antagonists with diuretics (C09DA) in Finland is quite high and relatively constant. In 2010, the consumption of fixed combinations of angiotensin II receptor antagonists with diuretics (C09DA), in Finland, amounted to 26.18 DDD/1,000 inhabitants/day, or 12.80% of the total consumption of drugs in the C09 subgroup; while in 2015 it was 27.56 DDD/1,000 inhabitants/day, or 11.99% of the total consumption of drugs in the C09 subgroup. Similarly to Norway, the fixed combination of losartan with hydrochlorothiazide (C09DA01) was the most consumed one in Finland, while the second most consumed fixed combination of drugs was candesartan with hydrochlorothiazide (C09DA06).

Of all the fixed combinations of ACE inhibitors, during the observation period, in Denmark, consumption was registered for the fixed combinations of ACE inhibitors with diuretics (C09BA). In 2010, the consumption of drugs from this subgroup amounted to 19.20 DDD/1,000 inhabitants/day, or 11.96%, and in 2015 it was 17.60 DDD/1,000 inhabitants/day, or 9.92% of the total consumption of drugs in the C09 subgroup. The trend of a decrease in the consumption of this drug combination was registered in each of the observed years. The consumption of the fixed combination of enalapril with hydrochlorothiazide (C09BA02) was dominant, and in 2010 it amounted to 12.9 DDD/1,000 inhabitants/day, or 8.04% of the total consumption of drugs in the C09 subgroup. The consumption of this fixed drug combination in 2015 was 12.3 DDD/1,000 inhabitants/day, or 6.93% of the total consumption of drugs in the C09 subgroup. The consumption of fixed combinations of ACE inhibitors with calcium channel blockers (C09BB) in Denmark was not registered in the six-year observation period.

The consumption of fixed combinations of angiotensin II receptor antagonists with diuretics (C09DA) in Denmark showed a constant increase throughout the observation period. In 2010 it amounted to 16.40 DDD/1,000 inhabitants/day, or 10.22%, while in 2015 it was 23.20 DDD/1,000 inhabitants/day, or 13.07% of the total consumption of drugs in the C09 subgroup. The consumption of the fixed combination of losartan with hydrochlorothiazide (C09DA01) was dominant, while all other fixed combinations of drugs from this subgroup were used in a very small quantity.

Table 3. Overview of the consumption of angiotensin-converting enzyme inhibitors, combinations (subgroup C09B); and the consumption of angiotensin II receptor antagonists, combinations (subgroup C09D), in Finland, in the period 2010 – 2015, presented as the number DDD/1,000 inhabitants/day and as the percentage (%) of total consumption in the C09 group

Table 4. Overview of the consumption of angiotensin-converting enzyme inhibitors, combinations (subgroup C09B); and the consumption of angiotensin II receptor antagonists, combinations (subgroup C09D), in Denmark, in the period 2010 – 2015, presented as the number DDD/1,000 inhabitants/day and as the percentage (%) of total consumption in the C09 group

DISCUSSION

Based on the results obtained, it is evident that, during the observation period, in Serbia, the consumption of the fixed combinations of ACE inhibitors and diuretics (C09BA) showed an increase from around 14%, in 2010, to around 18% of the total consumption of drugs in the C09 subgroup, in year 2015. In Nordic countries, the consumption of fixed combinations of ACE inhibitors and diuretics is lesser than in Serbia, and is decreasing with time. In 2010, their consumption in Norway was around 5%, while in 2015 it was less than 4%; in Finland it was somewhat higher, and in 2010 it amounted to 7%, while in 2015 it was around 5%; in Denmark, it was around 12% in 2010, and in 2015, it was around 10% of the total consumption of drugs in the C09 subgroup. In all four countries, the first place, as to consumption, belongs to the combination of enalapril with hydrochlorothiazide. In Serbia, the combination of ramipril with hydrochlorothiazide makes up a significant portion of consumption, while it shows no consumption in Norway, and in Finland and Denmark, consumption is registered, but it is significantly lower than the fixed combination of enalapril with hydrochlorothiazide.

Fixed combinations of drugs are very important in arterial hypertension treatment. Most studies show that a combination of two or more medications is necessary in order to achieve blood pressure regulation [11],[12],[26]. Combinations of two drugs in a single dosage form are widely available today, especially combinations of angiotensin receptor antagonists with thiazide diuretics; combinations of ACE inhibitors with thiazide diuretics or calcium channel antagonists; as well as combinations of beta blockers with diuretics, and thiazides with potassium-sparing diuretics [26]. The availability of individual fixed drug combinations in the observed countries is shown in Tables 1-4.

By combining ACE inhibitors with diuretics (usually thiazides) a better control of hypertension is achieved, in cases where the ACE inhibitor itself is not sufficiently effective, or in cases of chronic heart failure, when furosemide is usually added. The combination of ACE inhibitors with diuretics is also interesting in relation to potassium, since, although the diuretic (usually it is hydrochlorothiazide) lowers the potassium level in the blood, ACE inhibitors elevate the potassium level, so an imbalance in potassium does not occur [27]. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study speaks in favor of the effectiveness of fixed combinations of drugs in patients with type 2 diabetes, where the fixed combination of the ACE inhibitor perindopril with the diuretic indapamide has brought about a statistically significant decrease in the number of cardiovascular and renal diseases [28]. The combination of ACE inhibitors and calcium channel antagonists (C09BB) is present on the Serbian market, though its consumption in all the observed countries is small. ACE inhibitors and calcium channel antagonists provide a long-term and beneficial effect on cardiovascular complications connected to arterial hypertension. The mechanism of their action on the heart, blood vessels, and the kidneys is synergistic in the lowering of blood pressure, with a good tolerance and a low percentage of adverse drug reactions. It has been demonstrated that this combination of drugs improves the survival outlook in cardiac insufficiency [29].

Angiotensin II receptor antagonists also act on the RAS but through a different mechanism than ACE inhibitors. They cause a lesser number of adverse drug reactions as they do not cause an increase in bradykinin, which is why they are used as ACE inhibitor replacements [27].

According to our results, in comparison to the analyzed Nordic countries, Serbia consumes the smallest quantity of angiotensin II receptor antagonist combinations. The consumption of fixed combinations of angiotensin II receptor antagonists with diuretics in Serbia is very small and amounts to only 1% of the total consumption of drugs acting on the RAS. The consumption of this drug combination in Norway registered a mild decrease and was over 25 times higher in 2010, i.e. over 22 times higher in 2015, than in Serbia. In Finland, the consumption of this fixed drug combination is constant, and, during the observation period, it was 14 times higher than in Serbia. The consumption of this fixed drug combination in Denmark registered a mild increase, and was more than 10 times higher in 2010, i.e. more than 13 times higher in 2015, than in Serbia.

Angiotensin receptor blockers are also used as a fixed combination with calcium channel blockers, and more recent research has shown that the combination of amlodipine with valsartan leads to a more significant decrease in blood pressure than individual components in monotherapy. Also, when compared to monotherapy, a better tolerance of this combination has been proven [29]. The consumption of this fixed drug combination, in the period between 2010 and 2015, was very small in all four countries observed. In Serbia and Denmark, the consumption of this fixed drug combination was almost impossible to measure, while in Norway and Finland, it was between 1% and 3% of the total consumption of drugs in the C09 subgroup.

A study examining drug consumption among the hypertensive adult population in the United States of America (USA), in the period between 2001 and 2010, involved 9,320 patients. The study showed that, in the observed decade, the proportion of people with hypertension using drugs for regulating blood pressure had increased, and that the greatest increase had been in the use of combined antihypertensive therapy. Combined antihypertensive therapy was more efficient than monotherapy, and it entailed the application of several antihypertensive drugs in a single or multi dosage form. Just like in the Nordic countries, the application of certain drugs of first choice for hypertension treatment, in USA, was also balanced [30]. A more recent study, on a sample of similar size, again showed a higher consumption of combined therapy for regulating hypertension in USA, as compared to monotherapy, but also a higher cost for the patients using this therapy [31].

A study carried out in neighboring Croatia shows that a change occurred in the prescribing of antihypertensive drugs, in the period between 2000 and 2016. The most prescribed group of antihypertensive drugs in all the observed years was the group of drugs acting on the RAS (C09), with an increase in the share of fixed combinations of ACE inhibitors with diuretics in the total consumption. The greatest increase in drug consumption during the observation period did, in fact, relate to these fixed combinations and was as much as +856.58%. In Croatia, just like in Serbia, the consumption of drugs from the C09 ATC group is dominant, in comparison with other drugs of first choice for hypertension treatment. This was especially evident at the end of the observation period [32].

This study analyzes only the data available in Serbian and English. Analysis of potential differences in national hypertension clinical practice guidelines, in the countries observed, was not performed.

CONCLUSION

The results of this paper indicate the increase in the consumption of the drugs from the analyzed group (the C09 ATC group – drugs acting on RAS), while the demonstrated differences in the type of drugs consumed, between Serbia and the Nordic countries, indicate the need for aligning Serbian national practice with practices implemented in countries with developed pharmacotherapy. Future research should investigate the economic justification and the effects on health of such a consumption of the analyzed drugs, for the purpose of implementing the obtained results into clinical practice guidelines.

  • Conflict of interest:
    None declared.

Informations

Volume 1 No 1

September 2020

Pages 35-48
  • Keywords:
    defined daily dose, cardiovascular diseases, hypertension, renin-angiotensin system
  • Received:
    25 April 2020
  • Revised:
    22 June 2020
  • Accepted:
    29 June 2020
  • Online first:
    30 August 2020
  • DOI:
Corresponding author

Boris Milijašević
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty
of Medicine, University of Novi Sad
3 Hajduk Veljkova Street, 21000 Novi Sad, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.



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