Socio-Economic Status and the Therapeutic Effectiveness of Antihypertensive Treatment – the Design of the LEO Study

By Schmidt, A C Bramlage, P; Lichtenthal, A; Eckert, M; Scholze, J

Key words: Compliance – Effectiveness – Hypertension – Persistence – Socio-economic class – Study design ABSTRACT

Objective:The risk of arterial hypertension and subsequent cardiovascular disease morbidity and mortality increases with low socio-economic status (SES). Even small differences in blood pressure, whether untreated or despite treatment, account for this substantial difference. Most of the increased risk in the low socio- economic group is due to traditional cardiovascular risk factors such as overweight and obesity, alcohol consumption and a sedentary life style. Intense treatment of arterial hypertension has been shown to overcome these prognostic inequalities. Therefore, drugs with high efficacy, optimal treatment adherence and a low potential for drug-related side effects are needed in order to reduce the cardiovascular risk burden of patients with a low SES. The angiotensin receptor blocker (ARB) olmesartan will be used to investigate the effectiveness of this drug in different socio- economic classes.

Research design and mefftotfs: The LEO (Long-term Effectiveness of Olmesartan in different Socioeconomic groups) study is a large observational long-term study which has been set up to test the effectiveness of olmesartan within this context. The study has a matched-pairs design (1403 patients in both the low and the high socio-economic classes).

Main outcome measures: The LEO study will test whether this regimen can reduce the SES-related difference in long-term blood pressure control and compliance in the low SES population.

Conclusions: The study may generate valuable information about the antihypertensive effectiveness of olmesartan alone or in combination with hydrochlorothiazide in different socio-economic classes. It will further test whether the drug helps to reduce the inherent inequalities in cardiovascular prognosis between different socio-economic groups.

Current status: The study commenced in July 2007. Results are anticipated in December 2008.

Introduction

Arterial hypertension is highly prevalent in Germany1 2 and worldwide3. It contributes substantially to morbidity and mortality in the population. To lower blood pressure (BP), many effective treatment regimens are available” and a lowered BP has been shown to be associated with a decrease in cardiovascular risk5. However, BP control rates are low in primary care2 – and particularly low in Germany67.

In Finland, a study was conducted in the 1990s which compared patients with good BP control to those without8. Men with severe hypertension lost 2.6 work years and women 2.2 work years compared with patients with adequate BP control. Life expectancy in patients with inadequate BP control was reduced by 2.7 years for males and 2.0 years for females. A cost estimate performed using this study showed that patients with a well-controlled BP were less expensive for the health-care system than patients with uncontrolled BP. The differences amounted to between US $15000 and US $90000. Indirect costs were also taken into consideration in this calculation.

Arterial hypertension and its consequences cost the German health- care system approximately euro35 billion, and because the majority of costs are indirect costs, this figure accounts for only roughly 1 6% of the total costs. Considering only work as a factor for the loss of economically active years of life due to arterial hypertension and its concomitant diseases, this amounts to 398 000 lost years.

Olmesartan was introduced in 2002 for the treatment of arterial hypertension. Its long half-life and strong BP lowering effect together with a placebo-like tolerability makes olmesartan a candidate drug for high therapeutic adherence9. Furthermore, it has a particularly rapid onset of action as compared to other ARBs’0. This is important in the light of the VALUE study” in which an early onset of a BP lowering effect translated into a reduction of cardiovascular events as compared to a slower onset.

Contributing factors

Socio-economic status (SES) is usually inversely related to mortality from coronary heart disease (CHD), hypertensive heart disease, stroke and renal failure12-14. This inverse gradient is both stronger and found more consistently in women than in men. In England and Wales for example, the standardised mortality ratio for stroke in men aged 20-64 years was 62 in Social Class I (high SES) compared with 179 in Social Class V (low SES) for the years 1979- 1983. A similar social class pattern exists for stroke mortality in women. Furthermore, the decline in mortality from cardiovascular diseases in recent decades has been greatest among higher SES groups15,16. In Germany the prevalence of hypertension in the low SES group is higher than in the higher SES groups (30.4 vs. 19.1%)17. No data on a differential prescription pattern in patients with a high SES compared with a low SES have been published, but it can be assumed that patients with private health insurance usually get more new drug classes than those with the statutory health insurance.

Multiple barriers to optimal hypertension care exist, and include patient-related factors leading to noncompliance such as frequent dosing, health beliefs, drugdrug interactions, associated medical conditions, drugrelated side effects and others1821. Furthermore, recent data suggest that physicians’ attitudes and treatment strategies such as a lack of effective screening strategies, inadequate treatment goals and drug prescribing also hamper the potential effectiveness of current therapy22-24. Knowledge of these factors, therefore, could contribute to better BP goal achievement and attainment. Today, the American Heart Association (AHA) recognises a lack of adherence as the number 1 problem in the treatment of various cardiovascular diseases. Poor adherence to treatment is considered responsible for 10% of all hospitalisations and 23% of admissions to secondary care centres. Adherence is crucial for therapeutic success since the benefits of treating hypertension are not fully attained until a patient has been treated for 4-5 years25. Adherence is achieved when patients, being prescribed a certain antihypertensive drug regimen, stay on this therapy for months and years and BP goals are met (usually 140/90 mmHg as set forth by a variety of guidelines4,25). Little or no medical benefit can be expected in patients who discontinue their antihypertensive therapy. Adherence is achieved if several independent criteria are met. These include acceptance, persistence and compliance (see Figure 1). Adherence to a treatment can be improved, for example, by selecting treatments with lower levels of side effects or concerns for longterm use, or by prescribing the minimum number of different medications, e.g. prescribing a fixed combination for someone with high BP instead of two separate tablets with the same ingredients. Another key issue in improving adherence is simplifying the dosage regimen, by selecting preparations that need less frequent dosing during the day.

The Seventh Report of the US Joint National Committee on Prevention, Detection, Evaluation and Treatment of High BP (JNC VII) states that therapy can attain its goal only if the patient is sufficiently motivated to follow prescriptions, and this can be achieved through a positive relationship with the clinician25. An efficient ‘therapeutic alliance,26 is a potent motivator for patients25,27. Non-compliance leads to a poorer BP goal achievement and, therefore, to the faster development of concomitant disease.

Different studies within recent years were able to demonstrate that compliance is highest with the newer antihypertensive drug classes than with the older ones. An analysis of American health insurance data (Pennsylvania Medicaid Management Information System, 1997) demonstrated that non-compliance is the main reason for not achieving BP goals in patients with arterial hypertension28. The lowest compliance was found in patients who received diuretics. During one year, 95% of patients discontinued treatment on this drug class. ACE inhibitors (ACEI; ARBs were not available for the time span analysed) had a compliance that was 20% higher than that of diuretics. In this study the cost of treatment was also determined, based on per patient and year. The treatment cost for a compliant patient was US$340 per year. Non-compliant patients were almost twice as expensive.

Figure 1. Nomenchture within the context of adherence (modified from42)

Figure 2. Adherence to antihypertensive therapy (modified from29) . Percentage of patients staying on initial antihypertensive therapy at 12 and 48 months. AIIAs = angiotensin II receptor antagonists; ACEI = angiotensin converting enzyme inhibitors; *p < 0.01 versus AIlA; [dagger]p = 0.095 versus AIIA; [double dagger]p < 0.03 versus AIIA

More recent studies found comparable results for the difference in compliance between antihypertensive drug classes29-31. Generally, the newer ARBs had the highest compliance compared with all other antihypertensive drug classes, diuretics being the worst. Conlin et al. investigated a group of 15 175 patients with arterial hypertension treated with various drug classes as monotherapy over a 4-year follow-up period29. While a slow and continuous decline in persistence was observed in all drug classes, persistence was highest in patients treated with angiotensin receptor blockers (see Figure 2). Conlin’s results have been essentially confirmed in the two subsequent analyses by Hasford and Erkens30,31. In these analyses only the relative persistence of ACEIs, CCBs and BBs changed, ARBs and diuretics were unchanged. Socio-economic aspects of hypertension treatment

Measure of SES

SES is typically measured by means of education, income and occupation32. Cardiovascular disease is inversely associated with SES, irrespective of which of these measures is used33. Education has a considerable advantage as a measure of SES because it is reliably recalled and quantifiable by the number of years of education. In addition, reverse causation cannot confuse interpretation because diseases in adulthood cannot result in lower levels of education. However, a given amount of education may differ between different cultures and birth cohorts. Income is also often used as a measure for SES, but it may fall as a result of poor health. Nevertheless, it is a better measure than education for a patient’s purchasing capacity (goods and healthcare). Occupational categories are also often used, reflecting power, income and education, as a measure of SES. Limitations include reverse causation effects and the difficulties of classifying new occupations, women and children.

Relationship between SES and hypertension

In the former West Germany, inverse SES-BP (lower SES, higher BP) associations were found in women only34, whereas a later survey found an inverse association among both men and women in West and East Germany35. A recent study by Schneider et al.17 documented a significantly higher prevalence of cardiovascular disease, including hypertension, in patients with a low socio-economic status in Germany. They analysed the dataset of the German federal health survey and found a hypertension prevalence of 19.1% in patients with a high socio-economic status as compared to 30.4% in patients with a low socioeconomic status with an Odds Ratio of 0.647 [95% CI 0.535- 0.802]. A study by Maratta et al.36 demonstrated in an elderly Italian population that the metabolic syndrome was more frequent in patients with a low education (no school-leaving qualification) or in patients with no current employment. Publication bias notwithstanding, lower SES is associated with higher BPs in most studies from developed countries (Figure 3)37. The differences between SES groups are small, the age-adjusted difference between the highest and lowest SES group being about 2-3 mmHg for systolic BP in most studies. However, this small difference in BP is important at the population level. In contrast, among adults in undeveloped and developing countries a direct association between an increasing SES and a higher BP has often been observed.

Figure 3. Potential pathways by which socio-economic status may be associated with blood pressure (modified from Colhoun37)

A substantial part of the SES gradient is accounted for by the SES gradient in BMI (people with a low SES are more likely to be obese)37. Alcohol consumption also appears to account for part of the association in men though few studies have reported its specific effect. Overall, there is little evidence to suggest that SES itself increases BP other than through conventional risk factors for hypertension. However, stronger relationships may exist between BP and more specific stressful aspects of low SES such as unemployment or job insecurity.

To describe economic aspects of BP treatment it is worthwhile looking at Poland (Figure 4). In this country, many patients with hypertension are elderly and almost half of the patients do not purchase the prescribed drugs, or purchase only some of them. This is because health insurance only partly covers the costs and the patients cannot afford to pay the rest38. Also for Poland, deterioration in BP awareness was documented for 2002 as compared to 1997 and 1994, a transition period from a budget-financed to an insurance-based system. This had mostly occurred in small towns and among those less educated and worse off financially. In the three surveys (1994, 1997, 2002), BP awareness levels among men were 65, 60 and 54%, respectively (p < 0.001); among women, the figures were 77, 71 and 64%, respectively (p < 0.0001).

The need for a large and simple non-interventional study

SES-related differences in BP levels or the detection and treatment of hypertension in this patient population might explain the mortality gradient in hypertensionrelated disorders such as coronary heart disease (CHD), hypertensive heart disease, stroke and renal failure. Even a small difference in BP between socio-economic groups could, therefore, have a substantial impact on cardiovascular disease mortality4. What can be done to improve the situation?

Already, back in 1977, the HDFP (Hypertension Detection and Follow-up Program) study39 demonstrated that intensive management of hypertension can abolish the SES differences in hypertension associated mortality. The prerequisite of intensive management of hypertension is optimal adherence to treatment, drugs or drug-drug combinations with a high efficacy but a low potential for side effects, a rapid onset of action and good effectiveness. Angiotensin II receptor blockers (in this case olmesartan) alone and in combination with hydrochlorothiazide (HCTZ) appear to be suitable candidate drugs for testing whether this regimen may reduce the SES- related mortality increase in the low SES population, thus helping to overcome inherent inequalities in hypertension care and cardiovascular prognosis between patients of different socio- economic background. This paper will describe the design of the LEO (Longterm Effectiveness of Olmesartan in different Socioeconomic groups) study.

Figure 4. Awareness of arterial hypertension according to income, education, gender, age and place of residence43

Study design

Based on what has been stated above, the aim of the LEO study is to investigate the role of socio-economic factors on the therapeutic effectiveness BP goal achievement of 130/80 mmHg for patients with type 2 diabetes mellitus and 140/90 mmHg for all other patients, as well as compliance with treatment of the angiotensin receptor blocker olmesartan alone or in combination with HCTZ.

Design

This is a 12-month, multi-centre, open-label, prospective, observational post-authorization survey, which is being conducted by 4700 general physicians, practitioners and internists (GPs) throughout Germany. This specific study type is regulated by the German Drug Law (AMG) No 67(6) and is primarily intended to gather knowledge about the safety and effectiveness of marketed drugs in daily practice. The Associations of Statutory Health Insurance Fund Accredited Physicians, as well as the higher authorities, have been duly notified about this investigation. Due to the non- interventional nature of the study, no ethics committee approval or patient informed consent has to be obtained in accordance with the German local laws and regulations. The participating GPs will receive a small remuneration for the documentation of each patient in accordance with the ‘Gebuhrenordnung fur Arzte’ (GOA), which is common practice for this type of post authorization survey (PAS).

Patients and study conduct

The participating physicians will collect data on the background characteristics of the patients and on key efficacy variables and adverse events (AEs) and document them in case report forms (CRFs). Patients with an indication for treatment with olmesartan with or without HCTZ will be selected by the GPs. Only adult patients can be included (>/= 18 years), and there are no additional exclusion criteria regarding concomitant medication or concomitant diseases except those specified in the Summary of Product Characteristics (SmPC). The GPs will select patients with uncontrolled arterial hypertension for once-daily treatment with olmesartan 10, 20 or 40 mg as monotherapy or a combination of 20 mg olmesartan with 12.5 mg and 25 mg HCTZ, respectively. The prescription of additional antihypertensive agents is allowed, as is the discontinuation of other medications, if necessary.

Matched pairs approach

Using computerised control- and data validation routines, the intention-to-treat population will be cleaned from all implausible and/or incomplete datasets (case-wise deletion). In the next step, two patient cohorts will be built, which only differ with respect to their socio-economic score (high/low SES). With a pair-building procedure (‘matched pairs’), which reduces inter-individual variance and thus increases discriminatory power of the respective test methods, pairs with corresponding parameters of selected patient criteria will be formed. The following patient criteria are used for pair-building (hierarchically): baseline BP 150-1 90 mmHg/1 10-1 40 mmHg, duration of hypertension (+-1 year), age (+-2 years), gender, body weight (+-5 kg), no cardiovascular risk factors and no overweight. Should this result in fewer than 1 400 patients per cohort (lower limit for conduction of the statistical comparative tests), the respective criteria will be dropped in reverse hierarchical order until the minimum number of patients per cohort is achieved.

Statistical assumptions

Although the LEO study is designed as a longitudinal non- interventional trial, matched patient subgroups will be identified which will only differ in their socioeconomic status. In comparative biometrical tests, differences in therapeutic effectiveness of up to d = 5% will be detected (reference 70%). The null hypothesis is the following: ‘There is no difference in therapeutic effectiveness of olmesartan/olmesartan plus HCTZ between patients of different socio- economic groups’. Referring to interference statistics of clinical studies, a one-sided a of 5% and for the risk ss a risk level of 10%is assumed. Calculating the necessary size of the study according to Schneiderman40: ‘The proper size of a clinical trial: Grandma’s Strudel Method’ 1403 patients per group are needed, corrected for continuity (Figure 5). Differences in effectiveness (endpoint variables) between different socio-economic classes will be evaluated with distribution-free statistical methods. For continuous variables the ‘matched pairs signed rank test’ (Wilcoxon) and for discontinuous variables the U-Test (Mann and Whitney) will be used. Documentation at baseline and at 3 and 12 months

A number of patient variables will be collected, including diagnosis, cardiac risk factors, nutritional habits, occupation, place of residence, financial situation, insurance status, previous treatment, concomitant disease, concurrent medication/changes in medication, laboratory values (if acquired), body weight, various vital parameters, clinical global impression (CGI), reasons for switching to olmesartan, drug-related adverse events, reasons for premature discontinuation, acceptance of therapeutic approach, validation of medication, compliance (pill-counting), continuation of therapy, overall effectiveness and overall compliance. For details on timing see Table 1 .

Monitoring concept

The collected data, SAE forms and CRFs will not be consistently verified in comparison with the source data in the patient files, but the forms will be systematically screened for plausibility and completeness. To further improve the quality of data, telephone interview monitoring in a randomised sub-sample of physicians (irrespective of the actual data quality of the questionnaires) will be conducted in which the CRFs will be compared with the original data. This will be done by the Contract Research Organization SIMW, Wegberg, Germany. An informed consent is not necessary for this approach because anonymity of patients is preserved throughout.

Figure 5. Sample size estimate for the LEO study. CRFs = case report forms; ITT = intention to treat; pts. = patients; SES = socio- economic status

Table 1. Patient documentation for the LEO study

Patients will be asked by their treating physicians to bring their packs of Votum/Votum plus with them at the 3- and 12-month visits. The physician is requested to remove the clip of the outer package and to attach it to the CRF. This ensures that only patients who actually receive the medication under investigation are documented.

Adverse events (AEs)

The following features of AEs will be recorded if these occur: description, first occurrence, grade of severity, outcome of events (recovered, recovered with sequelae, unresolved), likelihood of causal relationship (possible, probable, improbable, no relationship). If any serious adverse events (SAEs) occur, the GPs are obliged to report them by completing a form within 24 h and transmitting it to the manufacturer, who then forwards the report in a standardized format to the relevant authority (Bundesinstitut fur Arzneimittel und Medizinprodukte, Bonn, Germany).

With regard to the safety of olmesartan alone or in combination with HCTZ, the trial, with 14 000 patients (returned CRFs 85%), is adequately sized to identify rare drug-related AEs, i.e. those that may not have been detected in previous clinical studies. AEs with an incidence of 1: 12 526 will be detected with a probability of 95% and very rare events with an incidence of 1 : 20000 with a probability of – 60%.

Discussion

Literature on socio-economic aspects of hypertension is rare; the most recent comprehensive review of epidemiological studies in this field is almost 1 0 years old37 (for a detailed Table on the studies available readers are referred to this article). Even rarer are studies on the impact of different antihypertensive drug classes and treatment regimens on SES-related inequalities in BP control and cardiovascular prognosis; we did not find any at all.

These kinds of studies ideally have to be performed in primary care to allow the inclusion of a mostly unselected population of patients from all socio- economie classes and with all stages of hypertension and associated end organ disease. The topic under investigation is of particular importance since hypertension treatment is, despite the availability of a large variety of effective drugs, largely deficient in reaching guideline- recommended BP goals in a broad patient population. Even in the US, being at the forefront of BP control, roughly 50% of treated patients are uncontrolled on current antihypertensive therapy3.

The LEO study was, therefore, set up to overcome this apparent problem and to study the impact of an efficacious and well tolerated angiotensin receptor blocker with the aim of closing the gap in treatment success between patients of different socio-economic classes. The study will be able to provide information on the effectiveness of a BP-lowering treatment with the ARB olmesartan in daily practice in different socioeconomic groups. This drug has been shown to lead to a substantial BP reduction in randomised controlled trials’”, has a good tolerability profile41 and belongs to a drug class which is known for its high compliance29. Therefore, this study, given that it shows that patients with a low socio-economic status can be treated as effectively as patients with a high socio- economic status in terms of BP control and compliance, will provide evidence to support its use across all socio-economic borders.

The study is, however, limited by the fact that it is not randomised and that the results may be influenced by unknown confounding variables. It would further benefit from a control group of patients with a low SES who are controlled with conventional drugs such as diuretics, beta-blockers and ACE inhibitors in order to document the relative improvement of ARB treatment over older approaches. However, this is not possible within the present setting, due to the expected substantial increase in patient numbers needed.

Although limitations exist, the study will be the first approach to clarify whether ARBs are able to interfere with poor hypertension prognosis in patients with a low SES. Given that we were not able to identify any studies on the impact of different antihypertensive classes on SES-related BP goal achievement, it may lead to further prospective studies or retrospective analyses from other randomised trials or treatment registries with the ultimate aim of improving treatment success in an indication that is presently characterized by overall low success rates.

Conclusions

The LEO study may generate valuable information about the antihypertensive effectiveness of olmesartan alone or in combination with HCTZ in different socio-economic classes. It will further test whether the drug helps to reduce the inherent inequalities in cardiovascular prognosis between different socioeconomic groups. This is of particular importance in the light of a low control rate of arterial hypertension in Germany and worldwide.

Acknowledgements

The study is supported by Berlin Chemie AG, Berlin, Germany. We wish to acknowledge the support of all participating physicians. AS is also an employee of Berlin Chemie AG.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4075_2, Accepted for publication: 03 July 2007

Published Online: 13 July 2007

doi: 1 0. 1 1 85/030079907X226078

A.C. Schmidt(a), P. Bramlage(b), A. Lichtenthal(c), M. Eckert (d), J. Scholze(a)

a Charite-Universitaetsmedizin, Department of Internal Medicine, Outpatient Clinic, Berlin, Germany

b Institute for Clinical Pharmacology, Medical Faculty Carl- Gustav Carus, Technical University Dresden, Dresden, Germany

c Berlin-Chemie AG, Medicine & Research, Cardiovascular Dept, Berlin, Germany

d SIMW GmbH, Wegberg, Germany

Address for correspondence: Dr. med. Andre C. Schmidt, Charite Universitatsmedizin Berlin, Department of Internal Medicine, Outpatient Clinic, Chariteplatz 1, 10098 Berlin, Germany. Tel.: +49 30 450 514012; Fax: +49 30 450 514903; e-mail: andre.schmidt@charite.de

Copyright Librapharm Aug 2007

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