cardiovascular medicines prescribing in bulgaria

Доклади на Българската академия на науките Comptes rendus de l’Acad´emie bulgare des Sciences Tome 64, No 2, 2011

MEDECINE Pharmacologie et Toxicologie

CARDIOVASCULAR MEDICINES PRESCRIBING IN BULGARIA Guenka Petrova, Manoela Manova, Assena Stoimenova, Alexandra Savova, Plamen Peikov∗ (Submitted by Corresponding Member M. Vlaskovska on October 21, 2010)

Abstract This study aims to analyse the changes in prescribing, measured in defined daily dose (DDD) used by 1000 inhabitants per day (DID) of two groups of reimbursed cardiovascular medicines in Bulgaria (ACE inhibitors and inhibitors of AT receptors) during 2005–2007 regarding the introduction of new therapeutic molecules or generic versions, or new therapeutic molecules in the reimbursement practice. Prescribing data for the observed medicines were taken from the official database (INN) of ACE inhibitors and 5 inhibitors of AT receptors (sartans) were included. The database for the prescribed packages comprises of among 64 to 72 dosage forms of medicinal products sold under the observed 12 INN during the period. The prescribing data for various medicinal products were systematized by INN and were recalculated in mg active substances for all the packages under the same INN. Then the consumption in mg was converted in DID following the methodology of the World Health Organisation (WHO). Generic products were observed for enalapril, lisinopril and ramipril, as well as for 1 INN of sartans (losartan). For example, the consumption of different forms of enalapril was significantly higher in comparison with the other ACE-inhibitors and was increasing during the observed years (72.56–87.03– 98.88 DID). When the therapeutic competitors cilazapril and benazepril appeared in 2006, the overall prescribing of ACE inhibitors increased from 79 to 102 DID, and in 2007 it again increased up to 111 DID. The growth in the ACE inhibitors prescribing measured in DID is statistically significant. Similar trends are observed for the sartans pharmacology group but they are not so evident. 285

In general, our study confirms the results of other similar analyses on the influence of the generics entrance on the prescribing of medicines, but it adds some more evidence for the importance of the new therapeutic molecules, especially in the relatively new pharmacological groups as sartans. Key words: cardiovascular medicines, prescribing practice, ACE-inhibitors, sartans, DID

Introduction. The cardiovascular medicines prescribing is of particular interest because the cardiovascular diseases are the leading mortality and morbidity causes. Age-standardized mortality rate for cardiovascular diseases is 554.0 per 100 000 Bulgarian population [1 ] and hypertension is one of the leading causes for death and complications (108.1 per 100 000) [2, 3 ]. The progress in the discovery of new molecules and medicinal products acting on cardiovascular (CV) system resulted in increased prescribing all over the world in the last 20 years thus reaching approximately 10% of the worldwide medicines utilization [4–7 ]. In fact many studies show that when a new medicinal product (generic or new molecule) appears within the particular pharmacology group, it affects the prescribing patterns of the existing products [8–11 ]. CV medicines are among the most often prescribed therapeutic groups [12 ]. There are different studies, showing the increase in prescribing antihypertensive medicines, presented in mg after the introduction of new products [13, 14 ]. Other studies show a decrease in costs per defined daily dose (DDD) rapidly after patent expiry of the originator product and generics molecules appearance [9 ]. Some studies focus on the effects of generics and their possible influence on the utilization of original medicinal products [15, 16 ]. A variety of measures is also discussed aimed at introducing generic medicines national policy leading to cost saving for the health care system [17, 18 ]. The introduction of new generic medicinal products may also influence the consumption not only of the originator product in the pharmacology group but also of all other therapeutically interchangeable products [10 ]. Studies on the changes in CV medicines prescribing using the DDD methodology are not published for the Bulgarian practice. Our study aims to analyse the changes in prescribing, measured in DDD used by 1000 inhabitants per day (DID) of two groups of reimbursed cardiovascular medicines in Bulgaria (ACE inhibitors and inhibitors of AT-receptors) during 2005–2007 in respect to the introduction of new therapeutic molecules or generic versions in the reimbursement list. The analysis was made from the perspective of the reimbursement system and the main study question was: Did the introduction of new therapeutic molecules or generic versions within the groups lead to changes in prescribing measured in DID? Materials and methods. The prescribing of ACE inhibitors and sartans, included into the Positive Drug List and reimbursed by the NHIF in Bulgaria, 286

G. Petrova, M. Manova, A. Stoimenova

was analysed during 2005–2007. Prescribing data for the observed medicines were taken from the official database of the National Healthcare Insurance Fund (NHIF). Seven INN ACE inhibitors and five inhibitors of AT-receptors (sartans) were included. The database for the prescribed packages comprises of 64 to 72 dosage forms of medicinal products, sold under the observed 12 INN during the period. The prescribing data for different medicinal products were systematized by INN and recalculated in mg of active substances for all the packages under the same INN. The consumption in mg was then converted in DID for each INN and within the therapeutic group following the methodology of the World Health Organisation (WHO) [18 ] DID =

INN prescription (mg)/DDD × 1000. Number of inhabitants × 365

The health insured Bulgarian population was considered as 7 200 000 people according to the official national statistics [19 ]. The source for DDD for every included INN in 2009 was the official database of the NHIF due to the fact that this value was used by the institution. Then it was compared for consistency with the latest version of WHO DDD system [18 ]. No differences in the DDD were found. The fixed dose combinations were not included in the analysis because such were not reimbursed during the observed period. Z-test analysis was applied for the evaluation of the statistically significant differences among the prescribing in DID during 2005–2007. The confidence interval (CI) was set to 95%. The analysis investigated the changes in prescribing in DID among 2006 compared to 2005 and 2007 compared to 2006. Results. Of the observed medicinal products in the class of ACE inhibitors, only for 3 of the INN were observed generic competitors (enalapril, lisinopril and ramipril), as well as for 1 INN of sartans (losartan). The other INNs within the studied therapeutic groups were considered as therapeutic competitors without generic versions. New therapeutic competitors were included in the pharmacology group of ACE inhibitors in 2006 and these are cilazapril and benazepril. The irbesartan dropped out from the pharmacology group of sartans in 2007. As for the group of ACE-inhibitors the first product in terms of sales and generic entry was enalapril. In 2005, 2006 and 2007 there were estimated respectively 33, 42 and 39 dosage forms of enalapril. Consumption of different forms of enalapril was significantly higher than the other studied ACE-inhibitors and showed an increase during the observed years (72.56–87.03–98.88 DID). This was probably due to the fact that the medicines belonging to the group are well established on the market and have the lowest prices of the generic equivalents (Fig. 1). In 2006 when the number of prescribed dosage forms of enalapril increased from 33 to 42, its utilization in DID rose with 15 DID. Compt. rend. Acad. bulg. Sci., 64, No 2, 2011

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Fig. 1. ACE inhibitors prescribing in DID in 2005–2007

When the therapeutic competitors cilazapril and benazepril appeared in 2006 the overall prescribing of ACE inhibitors increased from 79 to 102 DID, and in 2007 it increased to 111 DID (Fig. 1). The overall growth of ACE inhibitors prescribing measured in DID is statistically significant (Table 1). Similar trends were observed for the sartans pharmacology group (Fig. 2) but they are not so significant. In 2005 the highest consumption in DID was of telmisartan, while in 2006 with the introduction of generic versions of losartan the consumption of the latter sharply increased (from 0.12 to 1.49 and to 3.70 DID). Two generic versions of losartan were introduced in 2006 and in 2007. Valsartan consumption was steady during the observed period while eprosartan and irbesartan prescribing had the smallest value in DID, probably due to the fact that these are the most contemporary therapeutic molecules in the sartans pharmacology group (Fig. 2). After the drop out of irbesartan the prescribing of the whole therapeutic group continued to grow up to 6.08 DID (Table 1). The changes in the drug consumption were not statistically significant for valsartan, while for irbesartan and eprosartan no difference was observed because of a lack of generic competition (Table 1). Discussion. The increased prescribing of the analysed medicines could be explained with the high prevalence of the cardiovascular diseases among the Bul288


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Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Cilazapril Benazepril Total sum Losartan Valsartan Telmisartan Irbesartan Eprosartan Total sum

INN

1

72.556 1.821 1.367 0.895 1.198 0.599 0.632

79.068 0.119 0.278 1.610 0.0006 0.0178 2.03

207798563 314300 730800 4231528 1540 46816 5324984

DID

2005 Prescribing in DDD 190679553 4786051 3594720 2352168 3150260 1574589 1661222

2006 Prescribing DID in DDD 228718528 87.031 9417385 3.583 4932360 1.877 11782162 4.483 6431420 2.447 3184122.7 1.212 3030644 1.1533 692160 0.03 553630 0.08 268742412 101.90 3927560 1.495 886704 0.3375 5631136 2.143 1680 0.0006 238588 0.0908 10685668 4.0669

2007 Prescribing DID in DDD 236211004 89.882 15490942 5.895 5944710 2.262 22046960 8.389 4545700 1.729 3770200 1.435 3722723 1.417 3899840 0.19 3979220 0.57 299611299 111.78 9717876 3.698 850640 0.324 5178040 1.970 0 0 219492 0.084 15966048 6.08 64.358 −0.014 57.138 n.a. n.a.

2006/ 2005 3612.818 188.165 55.946 260.355 124.472 61.847 62.849

Yes No Yes

213.401 −0.014 11.583 n.a. n.a.

z-test value Stat 2007/ sign 2006 Yes 1014.625 Yes 254.662 Yes 45.604 Yes 422.399 Yes 79.483 Yes 23.121 Yes 22.729

Results of the z-test analysis for statistical significance in consumption changes in DDD/1000 inh/day

Table

Yes No Yes

Stat sign Yes Yes Yes Yes Yes Yes Yes

Fig. 2. Sartans prescribing in DID in 2005–2007

garian population [21 ]. This growth was statistically significant, except for valsartan, and it was best evident for the INNs where the generic molecules had been introduced such as enalapril, ramipril, lisinopril and losartan. Thus we can conclude that the introduction or the availability of generic products leads to the increase in the consumption of the same INN. It seems that the introduction of generics benefits both the originator and the generic products. The prescribing of ACE inhibitors in DID was almost twice higher than the average figures, provided for the Nordic countries in 2002. More recent studies comparing the ACE inhibitors and sartans in Sweden, found that the ACE inhibitor prescribing was 62.3 DID, which is below our figures, while the sartans prescribing is extremely higher (38.8) [20, 21 ]. These figures should be commented carefully because other studies show that when the sartans utilization has been decreased by regulatory measures, the ACE inhibitors utilization has risen up. The sartans prescribing in Bulgaria is far below the international studies. Some differences could be explained by the existing reimbursement practice and marketing policy of the pharmaceutical companies. The latter is supported by the fact that during its first year on the market telmisartan, the leader in the group of sartans in Bulgaria was a relatively new molecule in the class. Our study confirmed that the introduction of new generic medicinal products changes the prescribing patterns and leads to increased consumption of well established molecules with more generic versions. 290


We also acknowledge the limits of the existing reimbursement medicines policy in the country, which does not apply most of the recommended measures for cost containment, oriented towards generics and supporting the generic competition as the introduction of the prescribing budgets, generic substitution and information campaigns. We do observe dynamic prescribing of cardiovascular medicines that correspond to the world trends and also that the new therapeutic molecules change significantly the prescribing of the new pharmacology groups. Conclusion. In general, our study confirms the results of similar analyses on the influence of generics entrance on the prescribing of medicines, but it adds some more evidence for the importance of the new therapeutic molecules, especially in the relatively new pharmacology groups such as sartans. This is the first analysis in Bulgaria employing DDD methodology for cardiovascular medicines prescribing in the reimbursement practice that reveals important differences among the country prescribing patterns and international practice. The low values of DID especially for sartans in comparison with Nordic countries suggest slower introduction of the new therapeutic molecules in the Bulgaria prescribing practice.

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∗

Department Pharmaceutical Chemistry Faculty of Pharmacy Medical University of Sofia 2, Dunav Str. 1000 Sofia, Bulgaria
