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Journal of Human Hypertension (2009) 23, 420–425 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh

ORIGINAL ARTICLE

Assessment of the use of angiotensin receptor blockers in major European markets among paediatric population for treating essential hypertension R Balkrishnan1, H Phatak2, G Gleim2 and S Karve1 1

Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus, OH, USA and 2Merck and Co. Inc., Whitehouse Station, NJ, USA

This study was conducted to assess the use of angiotensin receptor blockers (ARBs) in European paediatric patients experiencing essential hypertension. This was a retrospective analysis of the IMS MIDAS Prescribing Insight Medical Database. Five major important European markets, including France, Germany, Italy, Spain and the UK were studied for the usage of ARBs as either a monotherapy or fixed-dose combination (FDC) therapy . Paediatric patients with essential hypertension were identified using ICD-10 codes, and anatomical therapeutic chemical (ATC) classification was used to identify major classes of antihypertensives. Projected prescription data for paediatric patients (o18 years) in the time period of October 2005 to September 2006 were analysed. Special emphasis was placed on the category of 6–17 years of age, as many ARBs were recommended in children above 6 years of age. Out of 242 405 estimated paediatric patients with hypertension, 222 033 (91.6%) were diagnosed with essential hypertension. Out of 230 220 projected prescriptions dispensed

in these essential hypertensives, approximately 76.2% were for patients in the category of 6–17 years of. In the age group of 6–17 years, ARBs constituted 25.5% of the projected prescriptions, with 10.6% in the form of FDC of ARBs with hydrochlorothiazides (HCTz). Projected ARB prescription usage, either as a monotherapy or as an FDC with HCTz, was higher in Italy (35.7%), France (30.9%) and Spain (28.1%), but was lower in Germany (5.3%), and non-existent in the United Kingdom. Valsartan-based and losartan-based FDCs were commonly used in the age range of 6–17 years, and accounted for 39. and 13.9% of the projected prescription volume in the ARB–FDC category, respectively. In a majority of the important European markets, paediatric hypertensive patients in the age range of 6–17 years are often treated with ARB monotherapy or FDC therapy. Some ARBs lack necessary clinical studies to support its use in treating essential hypertension in paediatric patients. Journal of Human Hypertension (2009) 23, 420–425; doi:10.1038/jhh.2008.139; published online 4 December 2008

Keywords: paediatric hypertension; angiotensin receptor blockers

Introduction The prevalence of hypertension is estimated to be higher in European nations compared to the United States. A study by Wolf-Maier et al.1 estimated that the prevalence of hypertension was 44.2% in Europe compared to 27.6% in North America. As an initiative of the European commission, a survey evaluating the European health states identified hypertension as the most common cause for receiving long-term medical treatment by the respondents (36%).2 The high prevalence of hypertension among

Correspondence: Dr R Balkrishnan, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. E-mail: [email protected] Received 21 August 2008; revised 29 September 2008; accepted 23 October 2008; published online 4 December 2008

the European population is of great concern as hypertension is associated with the increased risk of related complications such as stroke and myocardial infraction.3–6 However, hypertension is not just limited to adult population. With lifestyle changes and changing food habits, an increase in prevalence of obesity and hypertension has also been observed in a paediatric population.7 It has been reported that paediatric hypertension progresses into adulthood, thus increasing the prevalence of adult hypertension significantly. The estimated prevalence of hypertension in children is 1 to 3%.7,8 Hypertension in children is classified as either primary hypertension or secondary hypertension. Primary or essential hypertension implies the absence of any underlying cause, whereas secondary hypertension is caused by some underlying disorder (for example, renal disease).9–11 Essential or primary hypertension has higher prevalence in older

Use of ARBs in paediatric hypertensives R Balkrishnan et al 421

children/adolescents compared to secondary hypertension, which is common in infants/preadolescent children.8–10,12 Several studies have shown an association between childhood obesity and elevated levels of blood pressure among children.13–15 Dietary modifications, weight reduction, and regular physical activity, in addition to pharmacologic treatment, are generally considered in achieving adequate blood pressure levels among children. Angiotensin-converting enzyme (ACE) inhibitors, diuretics and calcium channel blockers are the commonly prescribed antihypertensive medications in children.16,17 Angiotensin receptor blockers (ARBs), including losartan and valsartan (approved only in the United States by Food and Drug Administration (FDA) for paediatric indication), have been approved for use among children above the age of 6 years.18,19 ARBs provide safe and effective way of reducing blood pressure in paediatric hypertensives, but there is limited data available on their utilization pattern in Europe. With the knowledge that off label use of medication is common in the paediatric population,20–22 it will also be important to estimate the use of all ARBs within this population. The objective of our study was to assess the use of ARBs in European paediatric patients experiencing essential hypertension.

September 2006. Patients were categorized into two age groups (0–5 and 6–17 years). We determined the projected prescription volume of antihypertensive drugs among the patients identified. The six classes of antihypertensive medications considered for this study were (a) diuretics, (b) b-blockers, (c) calcium-channel blocker (CCB), (d) ACE inhibitors, (e) ARB and (f) centrally acting agents (direct vasodilators, centrally acting a-2 agonists and others). We emphasized on the 6–17 years of age category, as ARB losartan has been recommended in children above 6 years of age.19 For this study, we analysed the IMS MIDAS Prescribing Insight Medical Database. The IMS MIDAS Prescribing Insight is a comprehensive database providing details on prescription records, diagnosis and patient and physician demographics for 11 major countries. For the purpose of our study, we considered the data for five major European markets (France, Germany, Italy, Spain and the United Kingdom). The IMS MIDAS Prescribing Insight database has been used previously in a variety of studies evaluating prescription utilization trends,23–25 and thus is considered a valid source to achieve our study objective. The important features of the IMS MIDAS data set are described in Appendix 1.

Results

Materials and methods This was a retrospective analysis of IMS MIDAS Prescribing Insight Medical Database for the period 1 October 2005 through 30 September 2006. Paediatric patients (age o18 years) with essential hypertension were identified using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code, and the projected antihypertensive prescription use also was estimated. Population and data description

Paediatric patients with essential hypertension were identified using the following ICD-10-CM (I10) code during the period of 1 October 2005 through 30

The frequency distribution of paediatric patient visits for hypertension-related diagnosis across the selected European countries is presented in Table 1. During the study period, 242 405 patient visits were identified for hypertension, of which 222 033 (91.6%) were for essential hypertension. Over three quarters (n ¼ 168 433) of these visits were accounted to children between the age group of 6–17 years. The projected prescription volume for antihypertensive drugs for the same period was estimated to be 230 220. Over 76% of the estimated prescription volume was for the age group of 6–17 years. Thus, every patient visit related to hypertension may have resulted in an antihypertensive prescription. The ARB usage, either as a monotherapy or as fixed-dose combinations (FDCs) with hydrochlor-

Table 1 Number of paediatric patient visits for hypertension-related diagnosis across important European countries Countries

France Germany Italy Spain United Kingdom Europe

Number of patient visits for hypertension

106 753 38 451 41 267 49 958 5976 242 405

Number of patient visits for essential hypertension

Projected volume of prescriptions written for essential hypertension

All

6–17 years

All

6–17 years

97 195 35 378 37 593 48 121 3746 222 033

64 715 30 496 25 272 44 623 3327 168 433

100 024 35 964 38 579 49 954 5699 230 220

67 544 30 844 25 272 46 456 5280 175 396

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100% 90%

% of Rx Volume

80% 70% 60% 50% 40% 30% 20% 10% 0% Germany

France

ACE Inhibitors FDC ARB FDC CCBs

Italy

Spain

ACE Inhibitors Diuretics B-blockers Plain

The UK

EU

ARBs Centrally Active Agents B-blockers Comb

Figure 1 Use of various antihypertensive to treat paediatric hypertension in important European countries.

Table 2 Use of major antihypertensive classes across important European countries (summary) IMS MIDAS prescribing insight database in the moving annual total format (October 2005–September 2006) Drug class

ACE inhibitors (plain) ACE inhibitors FDC CCBs (plain) B-blockers (plain) B-blockers FDC Diuretics ARBs ARBs FDC Centrally acting agents (class C2*) Total

Projected Rx

%

Projected Rx (age group: 6-17 years)

%

56 312 17 757 28 883 33 324 326 24 952 35 002 25 458 8206 230 220

24.5 7.7 12.6 14.5 0.1 10.8 15.2 11.1 3.5 100.00

51 221 12 101 15 139 26 083 326 20 389 26 057 18 522 5 558 175 396

29.2 6.9 8.6 14.9 0.2 11.6 14.9 10.6 3.1 100.00

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; CCB, calcium-channel blocker; FDC, fixed-dose combination. *Centrally acting agents: direct vasodilators, centrally acting a-2 agonists and others.

othiazides (HCTz), was higher in Italy (35.7%), France (30.9%) and Spain (28.1%), but was lower in Germany (5.3%), and non-existent in the United Kingdom (Figure 1). Use of major antihypertensive classes across important European countries

Frequency distribution of the use of major antihypertensive classes across important European countries is shown in Table 2. In terms of projected prescription volume, ACE inhibitors and related FDCs (32.2%) were the most commonly prescribed antihypertensive drugs, followed by ARBs and related FDCs (26.3%) among the paediatric population. Among the age group of 0–5 years, ARBs (29%) were the frequently prescribed antihypertensive drug class (data not shown), whereas in the age group of 6–17 years, ACE inhibitors (32%) were the Journal of Human Hypertension

commonly used drug class. In summary, ARBs and related FDCs accounted for over 25% of the projected prescription volume across the European countries in terms of projected prescription volume, and were the second most commonly prescribed class of drugs in treating paediatric hypertension. The use of different ARBs and related FDC across the various age groups in the important European countries is presented in Table 3. Nearly 26% of overall prescriptions written for treating essential hypertension in paediatric population were for valsartan either in the form of monotherapy, nonFDCs or FDC therapy. For the monotherapy and nonFDC category, 26.9% of the prescriptions were written for candesartan. Valsartan lead the FDC category with a 34.6% of projected prescription volume for ARB-based FDC. In the age group of 6–17 years. Telmisartan lead the market with 21.8% of projected prescription volume in the monotherapy


Table 3 Use of different ARBs (FDC, monotherapy and non-FDC) in paediatric patients in important European countries (prescription volume) ARB type

FDC prescription volume 6–17 years (% of overall Rx for the drug)

Losartan-based Valsartan-based Telmisartan-based Candesartan-based Irbesartan-based Eprosartan-based Olmesartan-based Totala

2573 7240 2546 4104 1789 270 0 18 522

(13.9) (39.1) (13.7) (22.2) (9.7) (1.5) (0) (30.6)

Monotherapy and non-FDC prescription volume

Total (% of overall Rx for the drug) 2573 8816 5209 5052 1789 2019 0 25 458

(10.1) (34.6) (20.5) (19.8) (7.0) (8.0) (0) (42.1)

6–17 years (% of overall Rx for the drug) 2205 4911 5678 4863 5606 0 2794 26 057

(8.5) (18.8) (21.8) (18.7) (21.5) (0) (10.7) (43.1)

Total (% of overall RX written for treating essential hypertension in paediatric population)

Total (% of overall Rx for the drug)

4691 6600 5894 9417 5606 0 2794 35 002

(13.4) (18.9) (16.8) (26.9) (16.0) (0) (8.0) (57.9)

7264 15 416 11 103 14 469 7395 2019 2794 60 460

(12.0) (25.6) (18.4) (23.9) (12.2) (3.3) (4.6) (100)

Abbreviations: ARB, angiotensin receptor blockers; FDC, fixed-dose combinations. a Percentage compared to total.

and non-FDC therapy. Valsartan-based FDCs lead the market with 39.1% in terms of prescription volume in 6–17-year-old age group. Losartan had 12.0% of the overall projected prescription volume. In the age group of 6–17 years, losartan had 13.4% of the projected prescription volume in the monotherapy and non-FDC category. In the FDC category, losartan had 9.7% of the projected prescription volume in the age group of 6–17 years.

Discussion Our study identifies the important trends in prescribing patterns for treating paediatric hypertension in major European markets. This study focused on essential hypertension in paediatric patients in Europe, especially in the age group of 6–17 years. The off-label use of antihypertensive medication was found to be higher among the children of the age group of 6–17 years. These findings are consistent with other studies evaluating off-label antihypertensive drug use within a paediatric population.20,22 In this study, essential hypertension was present in all paediatric age groups, with 24.1 and 75.9% patient visits occurring in the age group of 0–5 years and 6–17 years, respectively. In a US-based study conducted in single paediatric nephrology practice, rates of essential hypertension were 14% in the age group of 2–6 years, 30% in the age group of 7–11 years and 35% in adolescents.26 That study was conducted using a case-series design, and hence results should be carefully evaluated. Hanna et al27 also indicated that 10% of all hypertension cases in children under 10 years of age were related to essential hypertension. Rates of essential hypertension from the above studies cannot be compared with rates from this study due to difference in the study design and nature of the data set. Higher rates

of essential hypertension in paediatric patients observed in the IMS MIDAS data set can be attributed to possible underestimation of secondary hypertension. This may be due to the data collection method, which has excellent coverage in primary care practitioners, but may have less than optimal coverage in paediatric cardiovascular specialists or paediatric nephrologists. It should also be noted that the other studies referred above are at least a decade old, and prevalence of essential hypertension has also increased during this period.28 Moreover, this data do not permit ascertainment of cause of hypertension. This increase in the prevalence of essential hypertension has been associated with increasing prevalence of obesity in children.7,29 It is possible that similar trends exist in the other western European countries. Nevertheless, essential hypertension remains a serious concern in paediatric hypertensives. Use of ARBs for the treatment of essential hypertension

Use of renin angiotensin aldesterone blockers for the treatment of paediatric hypertension has increased from 53% in 1995 to 83% in 2003.30 In this study, ARBs as either a monotherapy or as a non-FDC therapy constituted 15.2% of all estimated prescription volume for the treatment of paediatric hypertensives and 14.9% in the age group of 6–17 years. Also, in ARB monotherapy or non-FDC therapy category, candesartan accounted for 26.9% of projected prescription volume and telmisartan accounted for 21.8% of projected prescription volume in patients in the age group of 6–17 years. As mentioned before, only losartan was approved for treating paediatric hypertension during the study time period.19 Thus, the above findings strongly suggest the extensive use of ARBs’ in children, even though not all have been approved for treatment of paediatric hypertension. It may be possible that due Journal of Human Hypertension


to availability of data about efficacy and safety of losartan and valsartan among paediatric essential hypertensives, physicians may consider the use of other ARB’s to be safe and effective among the paediatric population. Thus, the observed off label ARB’s use might represent a class effect. Secondly, our study findings are consistent with prior study conducted by Yoon et al.22 in the United States, evaluating off label antihypertensive medications in children. The findings of this study suggest that among the age group, X12 years was 18 times more likely (95% confidance interval: 9.3– 34.9) to receive ARB’s compared with diuretics. The authors hypothesized that physicians were more likely to extrapolate adult doses for the age group X12 years, and thus, this group was more likely to receive off-label anti-hypertensive therapy. The aforementioned hypothesis may be extended for our study as well. Use of FDC of ARBs and hydrochlorothiazide diuretics

This study also found frequent use of FDCs of ARB with HCTz to treat paediatric essential hypertension. Overall, ARB FDCs constituted 11.1% of projected prescription volume for the treatment of essential hypertension in paediatric patients in Europe and 10.6% of children in the age group of 6–17 years. It is important to note that diuretics alone have been used in paediatric hypertension.19 In this study, diuretics comprised 10.8% of projected prescription volume for the treatment of essential hypertension among all paediatric hypertensives and 11.6% in the age range of 6–17 years. It is possible that some of this usage may have occurred in conjunction with ARBs. The fourth report by the National High Blood Pressure Education Programme, on diagnosis, evaluation and treatment of high blood pressure in children and adolescents recommends the use of diuretics, as their safety and efficacy has been well established among hypertensive children.19 Overall, over 25% of the prescription volume was for diuretics, thus our findings may reflect the recommendation of the fourth report. Several limitations of this study need a mention. IMS MIDAS prescribing data, despite employing scientifically rigorous data collection method, may not have adequate representation of paediatric specialists treating hypertension and other cardiovascular conditions. We were unable to differentiate between patients using ARBs as either a monotherapy or in combination with other agents. Prescription volume is projected, and hence does not reflect actual prescription usage. Owing to the lack of access to patient level data, we can present results only in patient visits and prescription volume format. Finally, this was an exploratory study, and thus, we limited our study to five major European markets. Future studies expanding to all European countries are necessary. Journal of Human Hypertension

What is known about topic K Losartan and valsartan are the only angiotensin receptor blockers (ARBs) that has been approved for paediatric hypertension. K Off-label use of medication is common in the paediatric population. K Limited data available on utilization pattern of ARB’s among paediatric population in Europe. What this study adds Projected IMS data indicated that many ARBs were commonly used to treat essential hypertension in paediatric patients in Europe, irrespective of paediatric indication. K Patterns of antihypertensive medication utilization to treat essential hypertension in paediatric patients were projected to vary across different countries. K Physicians in Europe were also projected to use fixed-dose combinations of ARB and hydrochlorothiazide to treat essential hypertension in paediatric patients. K

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Appendix 1 Important features of MAS MIDAS prescribing insight database across five major European countries Retail audits’ overview

Doctor sample size Doctor universe size Data collecting information Data sampling information Doctor specialties covered (yes/no) Non-drug-treated consultations included? Regions Refill information

Germany

France

Italy

Spain

The United Kingdom

2489 103 621 Pad books and electronic Random, stratified by region and specialty Yes

835 95 498 Pad books

1486 125 715 Case books

935 121 551 Case books

500 GPs 40 661 GPs Electronic

Random, stratified by region and specialty Yes

Stratified random

Random, stratified by region

Yes

Random, stratified by region and specialties Yes

No

Yes

Yes

Yes

Yes

All

All

All

All

No

Yes

No

All except Las palmas, tenerife, ceuta, melilla No

No

No

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