KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY

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KAUNAS UNIVERSITY OF MEDICINE

FACULTY OF PHARMACY

DEPARTMENT OF BASIC AND CLINICAL PHARMACOLOGY

UTILIZATION AND COSTS OF DRUGS FOR ASTHMA AND CHRONIC

OBSTRUCTIVE PULMONARY DISEASE TREATMENT IN LITHUANIA

ON 2006-2009 YEAR

MASTER WORK

Supervised by:

Edmundas Kaduševičius, MD., PharmD., PhD., Assoc. professor of clinical pharmacology Performed by:

Asta Petraityt÷, Faculty of Pharmacy, 5/3 gr

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ABBREVIATIONS

AA Arachidonic Acid

ATC Anatomical Therapeutic Chemical Classification ATS American Thoracic Society

BMD Bone Mineral Density CEA Cost-Effectiveness Analysis

CHIF Compulsory Health Insurance Fund COPD Chronic Obstructive Pulmonary Disease CRP C- reactive protein

CysLT Cysteinyl Leukotriene

DALY Disability-Adjusted Life Year DDD Defined Daily Dose

DPI Dry Powder Inhaler

ERS European Respiratory Society

FEV1 Forced Expiratory Volume in one second FVC Forced Vital Capacity

GINA Global Initiative for Asthma

GOLD Global Initiative for Obstructive Lung Disease HPA Hypothalamic–Pituitary–Adrenal

ICER Incremental Cost-Effectiveness Ratio ICS Inhaled Corticosteroid

IgE Immunoglobulin E LABA Long-Acting β2-Agonist 5-LO 5-Lipoxygenase

LTD4 Leukotriene D4 (and similar) LTRA Leukotriene Receptor Antagonist MDI Metered-Dose Inhaler

NICE National Institute for Health and Clinical Excellence NO Nitric oxide

PEF Peak Expiratory Flow SABA Short-Acting β2-Agonist

SR Slow-release

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1. INTRODUCTION

Chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases and diabetes, are by far the leading cause of mortality in the world, representing 60% of all deaths. This invisible epidemic is an under-appreciated cause of poverty and hinders the economic development of many countries [1].

Respiratory conditions impose an enormous burden on society. Hundreds of millions of people suffer every day from chronic respiratory diseases. According to the latest World Health Organization (WHO) estimates (2007), currently 300 million people have asthma, 210 million people have chronic obstructive pulmonary disease (COPD) while millions have allergic rhinitis and other often under-diagnosed chronic respiratory diseases. Furthermore, asthma is considered to be the most common chronic disease among children [2].

Chronic respiratory diseases are a group of chronic diseases affecting the airways and the other structures of the lungs. Common chronic respiratory diseases include asthma, bronchiectasis, COPD, chronic rhinosinusitis, lung cancer and neoplasms of respiratory and intrathoracic organs, lung fibrosis, chronic pleural diseases, pneumoconiosis, rhinitis and series of other chronic respiratory diseases.

Concerning wide amount of the information on chronic respiratory conditions, this study focuses on the following chronic obstructive airway diseases: asthma and COPD.

Asthma is an inflammatory disorder of the lungs that affects people of all ages and is a significant source of morbidity and mortality [3, 4]. Asthma is one of the most common chronic diseases in the world. Asthma prevalence increases globally by 50% every decade. If the current trends continue, it is estimated that the number of people with asthma could grow to as many as 400-450 million people worldwide by 2025 – there may be an additional 100 million more asthmatics [5].

COPD is also an increasing public health problem. In 1990 it was ranked as the twelfth leading cause of disability-adjusted life-years (DALYs) lost and, according to projections, it will become the fifth such cause in 2020 [6]. In 2002 COPD was the fifth leading cause of death, 3 million people died of COPD in 2005, which corresponds to 5% of all deaths globally. WHO predicts that it will become the third leading cause of death worldwide by 2030 [7].

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COPD and asthma are costly diseases, generating considerable health-care costs as well as indirect costs. In the European Union, the total direct costs of respiratory diseases are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (€38.6 billion) of this cost of respiratory disease [9].

Asthma is also costly disease – the economic costs associated with asthma are estimated to rank as one of the highest among chronic diseases due to the significant healthcare utilization associated with this condition [10]. Globally, the economic costs associated with asthma exceed those of tuberculosis and HIV/AIDS combined [11]. Developed economies can expect to spend 1 to 2% of their health-care budget on asthma [5].

In Europe, the total cost of asthma currently hovers at approximately €17.7 billion per year. Outpatient costs account for the highest proportion at approximately €3.8 billion, followed by expenses for anti-asthma drugs (€3.6 billion). Inpatient care accounts for a relatively minor cost of just €0.5 billion [12].

In the study of COPD-related illness costs, Sullivan and colleagues had indicated that the largest proportion of total expenditures was for inpatient hospitalization and emergency department care (72.8%). Outpatient clinic and office visits accounted for 15.0% of expenditures, and prescription drug costs were responsible for 12.2% [13].

The overall costs of asthma, including individual direct costs (Annex 1), indirect costs, and intangible quality of life costs, are all related to asthma severity [14]. Patients with severe asthma are responsible for approximately 50% of all direct and indirect costs, even though this patient population represents just 10 to 20% of all asthma sufferers. By contrast, the 70% of asthma patients with mild disease account for only 20 % of total asthma costs [15, 16].

Not surprisingly, there is a striking direct relationship between the severity of COPD and the cost of care and the distribution of costs changes as the disease progresses as well [9].

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Relevance and novelty of this work

Asthma and COPD are the diseases of considerable importance due to its high consumption of health care resources they generate. According to the statistical statements, prevalence of both asthma and COPD is increasing. Considering to limited government budgets, rising prices and an aging population, it is necessary to dispose the healthcare resources rationally.

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2. ASTHMA: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT

Correctly defining asthma is necessary for proper diagnosis and management of the condition. Asthma is defined as a chronic inflammatory disease characterized by airway inflammation, airflow obstruction or bronchoconstriction and bronchial hyper-reactivity [19].

Clinically, asthma is characterised by episodic exacerbations of symptoms such as coughing, wheezing, chest tightness and breathing difficulties in response to various triggers such as tobacco smoke, dust, pollens and exercise. These episodes are typically associated with extensive but variable airflow obstruction that may be reversible either spontaneously or with treatment [20, 21].

2.1. Epidemiology

Global Initiative for Asthma (GINA) defines asthma as one of the most common chronic diseases in the world. It is estimated that around 300 million people in the world currently have asthma. Asthma has become more common in both children and adults around the world in recent decades. Estimates suggest that asthma prevalence increases globally by 50% every decade. The rate of asthma increases as communities adopt western lifestyles and become urbanized. With the projected increase in the proportion of the world's population that is urban from 45 to 59% in 2025, there is likely to be a marked increase in the number of asthmatics worldwide over the next 15 years. It is estimated that there may be an additional 100 million persons with asthma by 2025.

The global prevalence of asthma ranges from 1 to 18% of the population in different countries [22]. The highest asthma prevalence between developed countries are found in the United Kingdom (>15%), New Zealand (15.1%), Australia (14.7%), the Republic of Ireland (14.6%), Canada (14.1%) and the United States (10.9%). There have also been sharp increases in South Africa and the countries of the former Eastern Europe, including the Baltic States [11].

United States

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Australia

In Australia over 2.2 million Australians have currently diagnosed asthma. The prevalence of asthma in Australia is relatively high, by international standards: 14-16% of children (one in six); 10-12% of adults (one in nine). In 2004, 311 people died from asthma – the latest figures [25]. Europe

In Europe around 30 million people have asthma. The United Kingdom has amongst the highest prevalence of asthma in the world, with asthma occurring in 16% of the population. It is estimated that there are 5.2 million people with asthma in the UK [26].

In Scandinavia and Baltic States (Denmark, Estonia, Finland, Iceland, Latvia, Lithuania, Norway, Poland, Sweden) the mean prevalence of clinical asthma is 4.9% of the total population (70.2 million) [22].

According to the Lithuanian Health Information Centre statistics, the morbidity of asthma is increasing in Lithuania. Between 2001 and 2005 the prevalence of asthma has increased almost 50%: from 24209 till 35785.

The prevalence rates of the disease were estimated per 1000 inhabitants for two groups – 0-17 years children and adults in 2004-2008. The morbidity of asthma is sharply upper in children (Figure 2) [27]. If the current trends continue, in the future there will be more asthmatics among adults, the costs of asthma will be increasing as well.

10 17,6 20,1 23,1 25,9 8,5 8,9 9,5 0 5 10 15 20 25 30 2005 2006 2007 2008 P re v a le n ce r a te p er 1 0 0 0 i n h a b it a n ts

Children (0-17 years) Adults

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2.2. Burden of asthma

Asthma requires significant healthcare utilization. As already mentioned in the introduction, developed economies can expect to spend 1 to 2% of their health-care budget on asthma. In Europe, the total cost of asthma currently hovers at approximately €17.7 billion ($21.65 billion) per year [11] and in the US – $18 billion annually [28]. Despite the availability of effective preventive therapy, costs associated with asthma are increasing. Table 1 provides the costs of asthma in some countries. The studies describing the costs are difficult to compare because of differences in study designs, definitions of costs and different time periods [10].

Table 1 Direct and indirect costs for asthma treatment in different countries

Country Total direct costs/person (million of dollars)*

Total indirect costs (million of dollars)*

Total cost (million of dollars)* United States [29] 7,301 955 8,256 Canada [30] 397 257 654 Switzerland [31] 860 553 1,413 Australia [32] 273 81 354 Denmark [33] 402,668 822,067 1,224

United Kingdom [34] Data not available Data not available 773

*All costs are converted and adjusted into 2008 US dollars. Studies’ duration – 1 year

The costs associated with asthma management can be classified as direct, indirect and intangible [35]. Direct costs include inpatient care, emergency visits, physician visits, nursing services, ambulance use, drugs and devices, blood and diagnostic tests, research, and education. Indirect costs or morbidity costs include school days lost, travelling, waiting time, and lost productivity for the caretaker of asthmatic children. Intangible costs of asthma include grief, fear, pain, unhappiness. These costs apply not only to the patient but also to his/her friends and family and are associated with the quality of life.

Medications and hospitalization have been found to be the most important cost driver of direct costs, while work/school absenteeism accounted for the greatest percentage of indirect costs.

Series of studies reported medications as forming the largest proportion of the direct costs related to asthma, accounting for 38-89% of the total cost [10]. As the drugs are found to be one of the main contributors to the cost of asthma and the fact that the costs of drugs are increasing worldwide there is a necessity to organize the treatment as more rational as it could be and should be and use the limited resources effectively.

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consider three main characteristics. First of them is the cost-minimization analysis, which is appropriate when alternative therapies have identical outcomes, but differ in costs [36]. The second, a cost-effectiveness analysis (CEA) is a formal method for comparing the benefits and costs of a medical intervention to its next best alternative in order to determine whether it is of sufficient value to adopt or reimburse [37]. The main output from a effectiveness study is the incremental cost-effectiveness ratio (ICER) which compares two alternative interventions’ average costs (C1 and C2) and effects (E1 and E2) in the form of the following ratio:

The third, cost-consequence analysis is an alternative to cost-effectiveness whereby the analyst presents the disaggregated resource uses, unit costs, and consequences for all of the alternatives. Cost-consequence analysis leaves the weighting of the costs and consequences up to the given decision-maker. Armed with the results of an incremental economic analysis such as a CEA or a cost-consequence analysis, decision makers are better equipped to address an intervention’s value [38].

Examining the cost-effectiveness of different treatments, in addition to their clinical efficacy, allows us to choose the optimal strategy in managing patients (Annex 2).

Pharmacoeconomic cost-effectiveness analyses have shown that salmeterol/fluticasone is a cost-effective treatment option for moderate persistent asthma management, when compared with fluticasone with or without the addition of leukotriene modifiers. Leukotriene modifiers are less-cost-effective than inhaled corticosteroids or combined inhaled corticosteroids and long-acting β2-agonists for mild or moderate persistent asthma. Anti-IgE antibody has been shown inconsistently, to be cost-effective in patients with moderate to severe allergic asthma. Although the acquisition cost of levalbuterol is higher, one study showed that it may be more cost-effective than albuterol after taking into account reduction in hospitalizations. Cost-effectiveness analyses and clinical efficacy of medications, together with other patient-specific factors, are important information to be considered when selecting treatment regimens for asthma [28].

2.3. Classification of asthma

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Asthma control may be defined in a variety of ways. In general, the term control may indicate disease prevention, or even cure. However, in asthma, where neither of these are realistic options at present, it refers to control of the manifestations of disease. Ideally this should apply not only to clinical manifestations, but to laboratory markers of inflammation and pathophysiological features of the disease as well. There is evidence that reducing inflammation with controller therapy achieves clinical control, but because of the cost and/or general unavailability of tests such as endobronchial biopsy and measurement of sputum eosinophils and exhaled nitric oxide, it is recommended that treatment be aimed at controlling the clinical features of disease, including lung function abnormalities [52-56]. Table 3 provides the characteristics of controlled, partly controlled and uncontrolled asthma [50].

Table 3 Levels of asthma control

Characteristic Controlled

(All of the following)

Partly Controlled (Any measure present in any

week)

Uncontrolled

Daytime symptoms None (twice or

less/week)

More than twice/week

Limitations of activities None Any

Nocturnal

symptoms/awakening

None Any

Need for reliever/rescue treatment

None (twice or less/week)

More than twice/week Lung function (PEF or

FEV1)*

Normal <80% predicted or

personal best (if known)

Three or more features of partly controlled asthma present in any week

Exacerbations None One or more/year§ One in any week†

* Lung function is not a reliable test for children 5 years and younger

§ Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate † By definition, an exacerbation in any week makes that an uncontrolled asthma week

Complete control of asthma is commonly achieved with treatment, the aim of which should be to achieve and maintain control for prolonged periods with due regard to the safety of treatment, potential for adverse effects and the cost of treatment required to achieve this goal [57].

2.4. Aetiology, pathogenesis and pathophysiology of asthma

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Host factors

Genetic. Asthma has a heritable component. Multiple genes may be involved in the pathogenesis of asthma. Family studies and case-control association analyses have identified a number of chromosomal regions associated with asthma susceptibility.

Obesity. Obesity has also been shown to be a risk factor for asthma. Certain mediators such as leptins may affect airway function and increase the likelihood of asthma development.

Sex. Male sex is a risk factor for asthma in children. Prior to the age of 14, the prevalence of asthma is nearly twice as great in boys as in girls. As children get older the difference between the sex’s narrows, and by adulthood the prevalence of asthma is greater in women than in men. The reasons for this difference are not clear. However, lung size is smaller in males than in females at birth, but larger in adulthood [50].

Environmental factors

Allergens. Although much childhood and adult asthma is associated with atopy, the classic notion that the majority of exacerbations in atopic patients with asthma are related to allergen exposure with resultant inflammation [59].

Infections. Approximately 80% of exacerbations are associated with respiratory tract viral infections, with rhinoviral infection responsible for about two thirds of cases [60].

Occupational sensitizers. Over 300 substances have been associated with occupational asthma, which is defined as asthma caused by exposure to an agent encountered in the work environment. These substances include highly reactive small molecules such as isocyanates, irritants that may cause an alteration in airway responsiveness, known immunogens such as platinum salts, and complex plant and animal biological products that stimulate the production of IgE.

Tobacco smoke, air pollution and diet have also been associated with an increased risk for the onset of asthma, although the association has not been as clearly established as with allergens and respiratory infections [50].

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Airway inflammation

Airway inflammation is a major factor in the pathogenesis and pathophysiology of asthma. Understanding the complex mechanisms of asthma’s inflammatory processes can help to delineate therapeutic implications [63].As noted in the definition of asthma, airway inflammation involves an interaction of many cell types and multiple mediators with the airways that eventually results in the characteristic pathophysiological features of the disease: bronchial inflammation and airflow limitation that result in recurrent episodes of cough, wheeze, and shortness of breath. The processes by which these interactive events occur and lead to clinical asthma are still under investigation. The phases of asthma

Asthma occurs in phases because the inflammatory response is composed of a multitude of mediated interactions, each with its own time frame. The corresponding response in terms of inflammation consists of interactions between an allergen and a mast-cell-bound IgE molecule. This activates the mast cell, which then releases histamine and other mediators of inflammation resulting in smooth muscle contraction, increased vascular permeability, and vasodilation. This early response is rapid, occurring within minutes, and attracts other inflammatory cells that join in the response. Glandular activity is also stimulated by this inflammatory cascade, resulting in the secretion of mucus into the airways. The mucus causes coughing and may result in dyspnea if the obstruction is significant. Wheezing results from the contraction of airway smooth muscle in bronchospasm.

The longer-term result of this inflammation is a cellular infiltrate consisting of eosinophils, neutrophils, and basophils, all of which release additional mediators of inflammation. The number of lymphocytes and monocytes within the lung increase within 12 hours. These cells may be particularly important in bringing about the chronic form of inflammatory response in asthma through the release of cytokines and arachidonic acid-derived mediators. This activity takes place in a time frame of from 2 hours to several days and longer following activation of the mast cells by antigen. This is called the late-phase response.

Long-term inflammation is also associated with another detrimental response – that of fiber deposition. Fibrosis, together with smooth muscle hypertrophy, thickens the airway walls and causes further obstruction [64].

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Bronchoconstriction

In asthma, the dominant physiological event leading to clinical symptoms is airway narrowing and a subsequent interference with airflow. In acute exacerbations of asthma, bronchial smooth muscle contraction occurs quickly to narrow the airways in response to exposure to a variety of stimuli including allergens or irritants. The development of airway narrowing is also associated with airway oedema due to increased microvascular leakage in response to inflammatory mediators, and mucus hypersecretion [66].

Airway hyper responsiveness

Airway hyper responsiveness – an exaggerated bronchoconstrictor response to a wide variety of stimuli – is a major, but not necessarily unique, feature of asthma. The mechanisms influencing airway hyper responsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyper responsiveness. Treatment directed toward reducing inflammation can reduce airway hyper responsiveness and improve asthma control [19].

Airway remodelling

In some persons who have asthma, airflow limitation may be only partially reversible. Permanent structural changes can occur in the airway; these are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy. Airway remodelling involves an activation of many of the structural cells, with consequent permanent changes in the airway that increase airflow obstruction and airway responsiveness and render the patient less responsive to therapy [67]. These structural changes can include thickening of the sub-basement membrane, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation, and mucous gland hyperplasia and hypersecretion [19].

2.5. Pharmacological management of asthma

According to the GINA, the goals for successful management of asthma are to: • Achieve and maintain control of symptoms;

• Maintain normal activity levels, including exercise;

• Maintain pulmonary function as close to normal as possible; • Prevent asthma exacerbations;

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International GINA guidelines assign the highest level of evidence to randomized controlled trials. Advances in science have led to an increased understanding of asthma and its mechanisms as well as improved treatment approaches [68].

Both national and international asthma guidelines are now used in virtually every country and have had important benefits in improving the management of asthma. The principles of modern asthma therapy and overall goal of every asthma management programme is to achieve control of the disease [69].

This paper reviews and compares both international GINA and national (British, American and Australian) guidelines and its recommendations to pharmacological treatment of asthma. Lithuanian guidelines of asthma are based on the international GINA recommendations.

2.5.1. Reliever medications

Medications to treat asthma can be classified as relievers and controllers. Relievers are medications used on an as-needed basis that acts quickly to reverse bronchoconstriction and relieve its symptoms such as cough, chest tightness and wheezing. These medications include inhaled acting β2-agonists (SABAs), inhaled anticholinergics, acting theophylline and oral short-acting β2-agonists.

Short-acting β2-agonists

All reviewed guidelines recommend that inhaled SABAs are the medications of choice for relief of bronchospasm during acute exacerbations of asthma and for the pre-treatment of exercise-induced bronchoconstriction. Inhaled SABAs work more quickly and/or with fewer side effects than the alternatives.

SABAs include salbutamol (albuterol), terbutaline, fenoterol, levalbuterol HFA (hydrofluoralkane), reproterol and pirbuterol. Formoterol, a long-acting β2-agonist, is approved for symptom relief because of its rapid onset of action, but it should only be used for this purpose on regular controller therapy with inhaled glucocorticosteroids.

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The adverse effects of SABAs include tachycardia, skeletal muscle tremor, hypokalemia, increased lactic acid, headache, hyperglycemia. Inhaled route, in general, causes few systemic adverse effects. Patients with pre-existing cardiovascular disease, especially the elderly, may have adverse cardiovascular reactions with inhaled therapy. Systemic administration as tablets or syrup increases the risk of the side effects [19].

GINA recommends that inhaled SABAs should be used only on an as-needed basis at the lowest dose and frequency required. Good asthma control is associated with little or no need for short-acting β2-agonist. The frequency of SABA use can be clinically useful as a barometer of disease activity, because increasing use of SABA has been associated with increased risk for death or near death in patients who have asthma [19].

Inhaled SABAs, when used regularly, cause subtle but significant worsening of asthma control. Overuse of inhaled β2-agonists is associated with increased risk of death from asthma in a dose–response fashion. β2-agonists enhance airway responses to allergens, including induced airway hyper responsiveness and induced airway inflammation.

Inhaled β2-agonists are effective relievers and preventers of bronchoconstriction and asthma symptoms. SABAs should be used exclusively as needed for relief of symptoms and their requirement should be infrequent: the need for excessive doses of β2-agonists provides a useful marker of asthma (lack of) control [70].

Anticholinergics

Anticholinergic bronchodilators used in asthma include ipratropium bromide and oxitropium bromide. Inhaled ipratropium bromide is a less effective reliever medication in asthma than SABAs. It has a slower onset of action (30–60 minutes) than other relievers.

The bronchodilation is achieved by competitive inhibition of muscarinic cholinergic receptors. Because of the inhibition of these receptors, inhalation of ipratropium or oxitropium can cause a dryness of the mouth and a bitter taste, increased wheezing in some individuals, blurred vision if sprayed in eyes [50].

The clinical implication of anticholinergics in asthma therapy is that these agents may be alternative for patients who do not tolerate SABAs for relief of acute bronchospasm.

Theophylline

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loading dose over 20 min followed by 0.4 mg/kg/hr continuous infusion) and monitoring (serum levels should be maintained between 10-15 µg/mL).

The adverse effects include nausea, vomiting, headache. At higher serum concentrations: seizures, tachycardia and arrhythmias. Short-acting theophylline should not be administered to patients already on a long-term treatment with sustained-release theophylline unless the serum concentration of theophylline is known to be low and/or can be monitored [50].

Systemic glucocorticosteroids

A typical short course of oral glucocorticosteroids for an exacerbation is 40-50 mg prednisolone given daily for 5 to 10 days depending on the severity of the exacerbation [50].

Adverse effects of short-term high-dose systemic therapy are uncommon but include reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, rounding of the face, mood alteration, hypertension, peptic ulcer and aseptic necrosis of the femur. Consideration should be given to coexisting conditions that could be worsened by systemic corticosteroids, such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, diabetes mellitus, osteoporosis and Strongyloides [19].

Magnesium sulphate

The British guideline on the management of asthma recommends that there is some evidence that, in adults, magnesium sulphate has bronchodilator effects.

Giving a single dose of intravenous magnesium sulphate could be considered for patients with: acute severe asthma who have not had a good initial response to inhaled bronchodilator therapy; life threatening or near fatal asthma.

Intravenous magnesium sulphate (1.2-2 g intravenous infusion over 20 minutes) should only be used following consultation with senior medical staff. More studies are needed to determine the optimal route, frequency and dose of magnesium sulphate therapy [71].

2.5.2. Long-term asthma management

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and other systemic steroid-sparing therapies. Inhaled glucocorticosteroids are the most effective controller medications currently available [50].

Glucocorticosteroids

Today, in all national and international guidelines for asthma management, inhaled corticosteroids (ICSs) are the recommended first-line therapy for persistent asthma of all severities and patients of all ages and are the most effective asthma medications currently available [72].

National Institute for Health and Clinical Excellence (NICE) recommends that the introduction of regular preventer therapy with ICSs should be considered when a person has had exacerbations of asthma in the previous 2 years, is using inhaled SABAs three times a week or more, is symptomatic three times a week or more, or is waking at night once a week because of asthma [73].

The corticosteroids available for the treatment of asthma are: beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, flunisolide and triamcinolone acetonide. ICSs differ in potency and bioavailability. Budesonide and beclomethasone dipropionate are considered equivalent on a microgram for microgram basis (1:1 dose ratio). Half the dose of fluticasone propionate, mometasone furoate or ciclesonide in micrograms is equivalent to a given dose of budesonide/beclomethasone dipropionate (2:1 dose ratio). Equivalent doses of ICSs are provided in Annex 3 [50, 73].

Mechanism of treatment

The mechanism of action of corticosteroids in asthma has not been fully elucidated. However, corticosteroids are known to exert their effects by binding to a glucocorticosteroid receptor located in the cytoplasm of target cells [74].

Acting via the glucocorticosteroid receptor, ICS repress the expression of inflammatory cytokines, their receptors, adhesion molecules and other disease-inducing mediators. These effects of ICS and their ability to promote apoptosis of many cell types including the eosinophil act to reduce the attraction and activation of inflammatory cells in the lungs, thereby attenuating

inflammation [75].

Furthermore, ICS suppress the pro-inflammatory activity of airway epithelial and smooth muscle cells, resident cells with an important pro-inflammatory capacity. Since these cells produce chemokines, cytokines and pro-fibrotic mediators, they are no longer innocent bystanders in the inflammatory process and have become important additional targets for the anti-inflammatory

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Starting dose of inhaled steroids

The review guidelines recommend start patients at a dose of ICS appropriate to the severity of disease. In adults, a reasonable starting dose will usually be 400 µg per day and in children 200 µg per day. In children under five years, higher doses may be required if there are problems in obtaining consistent drug delivery. The dose of ICS must be titrate to the lowest dose at which effective control of asthma is maintained [71].

Pharmacokinetics and pharmacodynamics of ICSs

Characteristics of ICS that can enhance anti-inflammatory effects include small particle size, prolonged pulmonary residence time, high glucocorticosteroid receptor binding affinity, lipophilicity and lipid conjugation. All of these properties must be balanced to maximize efficacy, safety and tolerability [77].

Clinical effectiveness

All types of ICS monotherapy achieve successful control of persistent asthma in a

significant proportion of patients [78].

According to the NICE, all the ICSs are associated with favourable changes from baseline to endpoint across efficacy outcomes. In pairwise comparisons, there are few statistically significant differences between the ICSs. However, it is concluded that it is reasonable to assume that there are no differences in clinical effectiveness between the different ICSs at both low and high doses [73]. Adverse effects

Adverse events associated with ICS use can be categorized into local or systemic events (Table 5). Local adverse effects from ICSs include oropharyngeal candidiasis, dysphonia, occasionally coughing from upper airway irritation, bronchospasm and pharyngitis. For pressurized metered-dose inhalers the prevalence of these effects may be reduced by using certain spacer devices. Mouth washing after inhalation may reduce oral candidiasis. The use of prodrugs that are activated in the lungs but not in the pharynx (e.g., ciclesonide) and new formulations and devices that reduce oropharyngeal deposition may minimize such effects without the need for a spacer or mouth washing [50].

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Table 5 Potential local and systemic side effects of inhaled corticosteroids.

Local adverse effects Systemic adverse effects

Oropharyngeal candidiasis Pharyngitis

Dysphonia Reflex cough Bronchospasm

Suppressed HPA-axis function Adrenal crisis

Suppressed growth velocity in children Decreased lower-leg length in children Reduced bone mineral density

Bone fractures Osteoporosis

Skin thinning, skin bruising Cataracts

Glaucoma

Oral systemic corticosteroids

Long-term oral glucocorticosteroid therapy may be required for severely uncontrolled asthma, but its use is limited by the risk of significant adverse effects. Systemic glucocorticosteroids should be used at lowest effective dose. Patients with asthma who are on long-term systemic glucocorticosteroids should receive preventive treatment for osteoporosis. Caution and close medical supervision are recommended when considering the use of systemic glucocorticosteroids in patients with asthma who also have tuberculosis, parasitic infections, osteoporosis, glaucoma, diabetes, severe depression or peptic ulcers. Fatal herpes virus infections have been reported among patients who are exposed to these viruses while taking systemic glucocorticosteroids, even short bursts. Because of the side effects of prolonged use, oral glucocorticosteroids in children with asthma should be restricted to the treatment of acute severe exacerbations [50].

Long-acting β2-agonists

ICS therapy is the first line of treatment for asthma of all severities. For patients whose asthma is not sufficiently controlled by a low dose of ICS, an alternative option to increasing the ICS dose is the add-on therapy. According to the reviewed guidelines, the first choice as add-on therapy to inhaled steroids in adults and children (5-12 years) is an inhaled long-acting β2-agonist (LABA), which improves lung function and symptoms and decreases exacerbations.

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given alone. Daily use of LABA generally should not exceed 100 µg salmeterol or 24 µg formoterol.

The most important action of LABAs is stimulating the β2-adrenoreceptors located in

airway smooth muscle resulting in smooth muscle relaxation [80].

The two currently available LABAs are highly selective β2-adrenoceptor agonists which produce a bronchodilator effect lasting for at least 12 hours after a single inhalation. Both agents are highly potent. Onset of bronchodilation with formoterol fumarate is within 2–3 minutes whereas the onset of bronchodilation with salmeterol takes approximately 10 minutes and the maximal effect may not be apparent for several hours. Formoterol fumarate is more lipophilic than salmeterol and has a much higher degree of intrinsic agonist activity. Both drugs are relatively well tolerated at recommended doses but their therapeutic window is fairly narrow [74].

Combination medications

The greater efficacy of combination treatment has led to the development of fixed combination inhalers that deliver both ICS and LABA simultaneously (fluticasone propionate plus salmeterol, budesonide plus formoterol). Controlled studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately. Fixed combination inhalers are more convenient for patients, may increase compliance and ensure that LABA is always accompanied by a glucocorticosteroid. In addition, combinations inhalers containing formoterol and budesonide may be used for both rescue and maintenance. Both components of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance and provide improvements in asthma control at relatively low doses of treatment [50].

The combination of LABA and ICS should be considered when: • Symptoms or sub-optimal lung function persist on ICS alone.

• It is desirable to reduce the current dose of ICS while maintaining optimal asthma control. • Initiating asthma treatment in a patient with moderate to severe asthma in whom rapid symptom

improvement is needed. Adverse effects

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Leukotriene modifiers

Currently available leukotriene modifiers include leukotriene receptor antagonists (LTRAs) (montelukast, pranlukast and zafirlukast) and a 5-lipoxygenase (5-LO) inhibitor zileuton, that blocks leukotriene synthesis [81].

Clinical studies have demonstrated that leukotriene modifiers have a small and variable bronchodilation effect, reduce symptoms including cough, improve lung function and reduce airway inflammation and asthma exacerbations. They may be used as an alternative, not preferred, treatment for adult patients with mild persistent asthma. Leukotriene modifiers used as add-on therapy may reduce the dose of ICSs required by patients with moderate to severe asthma and may improve asthma control in patients whose asthma is not controlled with low or high doses of ICS. Several studies have demonstrated that leukotriene modifiers are less effective than inhaled LABAs as add-on therapy [50].

Several types of observations support an important role for LTRAs in asthma control. The early-phase response (most likely caused by acute airway smooth muscle contraction) and the late-phase response (thought to involve oedema and inflammatory cell recruitment and activation) of asthma can be blocked by these agents [65]. Due to the limited efficacy data and the need for liver function monitoring, zileuton is a less desirable alternative than LTRAs, although provides similar efficacy to montelukast [19].

Sustained-release theophylline

It is available in sustained-release formulations that are suitable for once or twice daily dosing. Data on the relative efficacy of theophylline as a long-term controller is lacking. However, available evidence suggests that sustained-release theophylline has little effect as a first-line controller. It may provide benefit as add-on therapy in patients who do not achieve control on ICSs alone. Additionally in such patients the withdrawal of sustained-release theophylline has been associated with deterioration of control. As add-on therapy, theophylline is less effective than inhaled LABAs.

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Cromones

Sodium cromoglycate and nedocromil sodium are alternative, not preferred, medications for the treatment of mild persistent asthma. They can also be used as preventive treatment before exercise or unavoidable exposure to known allergens.

The mechanism of cromones appears to involve the blockade of chloride channels and modulate mast cell mediator release and eosinophil recruitment. Adverse effects are infrequent and include headache, nausea, minor throat irritation and cough. Some patients may complain about the distinctive taste of nedocromil [25].

Anti-IgE

Anti-IgE therapy (omalizumab) is recommended, within its licensed indication, as an option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy, only in adults and adolescents (12 years and older) who have been identified as having severe unstable disease [82].

In the pathogenesis of allergic disease, IgE plays a central role [63]. IgE is the immunoglobulin that mediates the acute allergic response in mast cells and basophils through cross-linking of high-affinity IgE receptors, and may increase allergen uptake by dendritic cells [83]. Omalizumab, an IgE-specific humanized monoclonal antibody, binds to the IgE molecule, prevents IgE from interacting with high or low affinity IgE receptors and results in rapid decreasing levels of circulating free IgE [84]. The decreased binding of IgE on the surface of mast cells leads to a decrease in the release of mediators in response to allergen exposure [19].

According to the NICE, omalizumab add-on therapy should only be initiated if the patient fulfils the following criteria of severe unstable allergic asthma:

• Confirmation of IgE mediated allergy to a perennial allergen by clinical history and allergy skin testing.

• Either two or more severe exacerbations of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of asthma within the previous year, at least one of which required admission to hospital, and a further two which required treatment or monitoring in excess of the patient’s usual regimen, in an accident and emergency unit.

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2.5.3. Treatment steps

All current asthma guidelines recommend a stepwise approach to therapy based on asthma control and severity. The GINA guidelines recommend a five-step therapeutic approach (Annex 4).

Intermittent asthma

Step 1: As-needed reliever medication

Step 1 treatment with an as-needed reliever medication is reserved for untreated patients with occasional daytime symptoms (cough, wheeze, dyspnea occurring twice or less per week, or less frequently if nocturnal) of short duration (lasting only a few hours) comparable with controlled asthma. Between episodes, the patient is asymptomatic with normal lung function and there is no nocturnal awakening. When symptoms are more frequent, and/or worsen periodically, patients require regular controller treatment (see Steps 2 or higher) in addition to as-needed reliever medication.

For the majority of patients of all ages in Step 1, a short-acting inhaled β2-agonist is the recommended reliever treatment. An inhaled anticholinergic, short-acting oral β2-agonist or short-acting theophylline may be considered as alternatives, although they have a slower onset of action and higher risk of side effects. Short course of oral systemic corticosteroids may be needed.

Persistent asthma

Step 2: Reliever medication plus a single controller

Treatment Steps 2 through 5, combine an as-needed reliever treatment with regular controller treatment. NICE recommends that the introduction of regular preventer therapy should be considered when a person has had exacerbations of asthma in the previous 2 years, is using inhaled SABAs three times a week or more, is symptomatic three times a week or more, or is waking at night once a week because of asthma.

At Step 2, a low-dose inhaled glucocorticosteroid is recommended as the initial controller treatment for asthma patients of all ages. Equivalent doses of ICSs, some of which may be given as a single daily dose, are provided in Annex 3.

Alternative controller medications include leukotriene modifiers, appropriate particularly for patients who are unable or unwilling to use ICSs or who experience intolerable side effects from ICS treatment and those with concomitant allergic rhinitis.

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intolerable. Cromones (nedocromil sodium and sodium cromoglycate) have comparatively low efficacy, though a favourable safety profile.

Step 3: Reliever medication plus one or two controllers

A proportion of patients with asthma may not be adequately controlled at Step 2. At Step 3, the recommended option for adolescents and adults is to combine a low-dose of inhaled glucocorticosteroid with an inhaled long-acting β2-agonist, either in a combination inhaler device or as separate components. Because of the additive effect of this combination, the low-dose of glucocorticosteroid is usually sufficient and need only be increased if control is not achieved within 3 or 4 months with this regimen. The long-acting β2-agonist formoterol, which has a rapid onset of action whether given alone or in combination inhaler with budesonide, has been shown to be as effective as short-acting β2-agonist in acute asthma exacerbation.

If a combination inhaler containing formoterol and budesonide is selected, it may be used for both rescue and maintenance.

Another option for both adults and children, but the one recommended for children, is to increase to a medium-dose of ICSs. For all patients of all ages on medium or high dose of ICS delivered by a pressurized MDI, use of a spacer device is recommended to improve delivery to the airways, reduce oropharyngeal side effects and reduce systemic absorption.

Another option at Step 3 is to combine a low-dose ICS with leukotriene modifiers. Alternatively, the use of sustained-release theophylline given at low-dose may be considered. These options have not been fully studied in children 5 years and younger. In addition, theNICE and the British guidelines recommend that slow-release β2-agonist tablets may also improve lung function and symptoms, but side effects occur more commonly.

Step 4: Reliever medication plus two or more controllers

The selection of treatment at Step 4 depends on prior selections at Steps 2 and 3. However, the order in which additional medications should be added is based, as far as possible, upon evidence of their relative efficacy in clinical trials. Where possible, patients who are not controlled on Step 3 treatments should be referred to a health professional with experience in the management of asthma for investigation of alternative diagnoses and/or causes of difficult-to-treat asthma.

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high-dose inhaled glucocorticosteroid is also associated with increased potential for adverse effects. At medium- and high-doses, twice-daily dosing is necessary for most but not all inhaled glucocorticosteroids. With budesonide, efficacy may be improved with more frequent dosing (four times daily).

Leukotriene modifiers as add-on treatment to medium- to high-dose ICSs have been shown to provide benefit, but usually less than that achieved with the addition of a LABA. The addition of a low-dose sustained-release theophylline to medium- or high-dose ICS and LABA may also provide benefit. In addition, the British guidelines also recommend slow release β2-agonist tablets as the alternative option, though caution needs to be used in patients already on long-acting β2-agonist β2-agonists.

Step 5: Reliever medication plus additional controller options

Addition of oral glucocorticosteroids to other controller medications may be effective, but is associated with severe side effects and should only be considered if the patient’s asthma remains severely uncontrolled on Step 4 medications with daily limitation activities and frequent exacerbations. Patients should be counselled about potential side effects and all other alternative treatments must be considered.

Addition of anti-IgE treatment to other controller medications has been shown to improve control of allergic asthma when control has not been achieved on combinations of other controllers including high-doses of inhaled or oral glucocorticosteroids.

When asthma control has been achieved, ongoing monitoring is essential to maintain control and to establish the lowest step and dose of treatment necessary, which minimizes the cost and maximizes the safety of treatment.

Asthma management in children 5 years and younger

According to the GINA guidelines, all young children with asthma should be prescribed a reliever medication to use as needed for quick relief of symptoms. Parents and caregivers should be aware of how much reliever medication the child is using-regular or increased use indicates that asthma is not well controlled. A short-acting inhaled β2-agonist is the recommended choice of reliever medication for most patients in this age group.

If the child’s asthma is not controlled with as-needed use of reliever medication, a low-dose inhaled glucocorticosteroid is the recommended initial controller treatment (Annex 5).

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medication regimen and avoidance of risk factors. If control is maintained for at least 3 months, decrease treatment to the least medication necessary to maintain control. Monitoring is still necessary even after control is achieved, as asthma is a variable disease [85].

2.5.4. Inappropriate use of inhaled short acting β2-agonists and its association with patient health status

There is considerable controversy about the regular use of short-acting β2-agonists for the treatment of asthma. Patients who are on inhaled short-acting bronchodilators are one of the most vulnerable populations. Although case–control studies have suggested that excessive use of these drugs may worsen asthma control and increase the risk of fatal or near-fatal asthma, the controversy remains unresolved because of the confounding that exists among disease control, disease severity and the use of short-acting β2-agonists. Whatever the cause-and-effect relation between the use of short-acting β2-agonists and disease severity, their excessive use, in conjunction with under use of inhaled corticosteroids, may be a marker for poorly controlled asthma and excessive use of health care resources [86].

Use of short-acting β2-agonists is considered as one of the four dimensions of asthma control [87]. Observable indicators of asthma control include the frequency and severity of day-time and night-time symptoms, the extent of activity limitation due to asthma, the level of lung function and the frequency with which short-acting bronchodilator medication is required [88].

Use of acting β2-agonists was defined as inappropriate when high doses of short-acting β2-agonists were taken in conjunction with low doses of inhaled corticosteroids. High doses of SABAs were defined as nine or more canisters per year, with each canister giving 200 inhalations of albuterol 100 µg or equivalent. Low doses of inhaled corticosteroids were defined as less than beclomethasone 100 µg or equivalent per day. In terms of numbers DDD, a high dose of short-acting β2-agonists was defined as equal or more than 225 DDDs per year and a low dose of corticosteroids as less than 45.625 DDDs per year [87]. Appropriate medication use was defined as 4 or fewer canisters of albuterol and at least 400 µg/day of beclomethasone [86].

In a cross-sectional study a total of 23 986 patients were identified as having filled a prescription for a short-acting β2-agonists (for inhalation) in 1995. Of these, 3069 (12.8%) filled prescriptions for 9 or more canisters of β2-agonists, and of this group of high-dose β2-agonists users, 763 (24.9%) used no more than 100 µg/day of inhaled beclomethasone.

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admission (adjusted RR 1.93, 95% CI 1.35–2.77). It is also found that inappropriately treated asthmatic patients were more likely than appropriately treated patients to receive more prescriptions, more likely to visit more prescribing physicians. Thus, inappropriately treated patients appear to have poorer outcomes, independent of disease severity or control.

It is impossible to determine from this analysis whether the high use of health care resources by those with inappropriate use of asthma medication is related specifically to excessive β2-agonists use. An alternative reason might be that excessive β2-agonists use is a marker of poor asthma management and that under use of inhaled corticosteroids is responsible for the poorer outcomes. It can be concluded, however, that these patients experienced greater asthma related morbidity and generated higher health care costs. Furthermore, because urgent admission is defined as “a need for immediate assessment due to life-threatening conditions”, mortality rate may also be higher in this group.

Despite the inability to say why some patients have high use of β2-agonists, the results do show that patients who receive excessive doses of short-acting β2-agonists with suboptimal doses of inhaled corticosteroid use more health care services. Although it is not surprising that patients with inappropriate use received more prescriptions per prescribing physician, the finding that they received prescriptions from a greater number of unique physicians was unexpected. This may indicate deliberate solicitation of prescriptions from multiple physicians, or it may reflect a lack of continuity of care, which may partially explain the poorer outcomes in this group.

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3. COPD: BASIC FACTS AND PHARMACOLOGICAL MANAGEMENT

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD as „a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases”[89]. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributors of which vary from person to person.

The characteristic symptoms of COPD are chronic and progressive dyspnea, cough and sputum production. Chronic cough and sputum production may precede the development of airway limitation by many years [9].

3.1. Epidemiology

COPD is one of the leading causes of morbidity and mortality worldwide. According to the latest WHO estimates (2007), currently 210 million people have COPD and 3 million people died of COPD in 2005. The WHO estimates that COPD as a single cause of death shares 4th and 5th places with HIV/AIDS (after coronary heart disease, cerebrovascular disease and acute respiratory infection). WHO predicts that COPD will become the third leading cause of death worldwide by 2030 [7].

United States

Despite advances in care, the COPD epidemic persists, causing more than 120,000 deaths per year in the United States alone. Population-based surveys show that as many as 24 million people in the United States have airflow limitation consistent with COPD [90].

Australia

More than 600,000 Australians are estimated to have COPD and, as the population ages, the burden of COPD is likely to increase.. COPD ranks fourth among the common causes of death in Australian men and sixth in women [91].

Europe

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COPD is the fifth leading cause of death in the United Kingdom after ischemic heart disease, stroke, lung cancer, and pneumonia. In England, in 2002/2003, COPD was recorded as the reason for hospital admission in 109,243 cases and accounted for 1,094,922 bed-days, with a median duration of stay of 6 days (2001/2002 data) [93].

According to the Lithuanian Health Information Centre, in Lithuania, the highest prevalence of COPD is between 55-64 years old men. 118640 Lithuanians had COPD in 2003. During 2007 asthma and COPD together were responsible for 2.3 % deaths [27].

COPD is expected to increase globally in the coming decades. The main reasons are the changing age distribution in all countries, with increased life expectancy and an ever-increasing proportion of the population living to > 60 years, and the increased uptake of smoking, especially in developing countries. In the western world, age-specific rates of mortality, as well as morbidity, have started to decrease for males and will presumably stabilise for females in the near future. The time trends in developing countries will depend on tobacco control and control of other particulate exposures [94].

3.2. Burden of COPD

COPD is a costly disease with both direct costs (value of health care resources devoted to diagnosis and medical management) and indirect costs (monetary consequences of disability, missed work, premature mortality, and caregiver or family costs resulting from the illness). In developed countries, exacerbations of COPD account for the greatest burden on the health care system. In the European Union, the total direct costs of respiratory disease are estimated to be about 6% of the total health care budget, with COPD accounting for 56% (€38.6 billion) of this cost of respiratory disease [9].

The major drivers of the direct cost of COPD are hospital care and medication. The cost of COPD management also varies according to the severity of disease and whether patients are managed in hospital or at home. In a study in Spain of 1,510 patients with COPD monitored over 1 year, the hospital costs represented 43% of the mean annual cost per patient, drugs – 40% [93].

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Table 8 Direct and indirect costs associated with COPD in different countries Country

(Year of publication)

Costs Cost per patient per

year

Global costs per year (in millions)

Spain (1992) Direct and indirect € 959 Direct: € 319

Indirect € 451

USA (2000) Direct Stage I: $ 1681

Stage II: $ 5037 Stage III: $ 10 812

Sweden (2000) Direct and indirect Direct: € 109

Indirect € 541

Italy (2002) Direct Stage I: € 151

Stage II: € 3001

Stage III: € 3912

Spain (2003) Direct Stage I: € 1185

Stage II: € 1640

Stage III: € 2333

€ 427

Spain (2004) Direct € 909 € 239

USA (2005) Direct and indirect $ 32 000

Cost-effectiveness of pharmacological treatments

There is very little literature documenting the cost-effectiveness of most medical interventions for COPD.

Rutten-van Molken and associates investigated the costs and effects of adding inhaled anti-inflammatory therapy to inhaled β2-agonist therapy by analyzing data from a randomized trial of 274 adult participants aged 18 to 60 years. Patients were selected for inclusion if they met the age criteria and had been diagnosed as having moderately severe obstructive airway disease, as defined by pulmonary function criteria. Patients were eligible if they had either asthma or COPD. Each patient was randomized to receive either fixed-dose inhaled terbutaline plus inhaled placebo, inhaled terbutaline plus 800 mg inhaled beclomethasone per day, or inhaled terbutaline plus inhaled ipratropium bromide, 160 mg/d. Patients were followed up for up to 2.5 years or until premature withdrawal.

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It was performed a retrospective, chart-based cost- minimization analysis of theophylline

vs ipratropium bromide for patients with COPD. They found that patients treated with ipratropium

had lower costs and a greater number of complication-free months compared with those taking theophylline.

A post hoc pharmacoeconomic evaluation of two multicenter, randomized trials comparing salbutamol plus ipratropium with salbutamol alone and ipratropium alone in a total of 1,067 patients with COPD was conducted by Friedman et al. Data on outcomes and the total cost of treatment were compared. The authors concluded that the inclusion of ipratropium in a pharmacologic treatment regimen was associated with a lower rate of exacerbations, lower overall treatment costs, and improved cost-effectiveness. There were, however, no differences in total costs between the ipratropium-alone and salbutamol-plus-ipratropium treatment arms.

Because COPD is highly prevalent and can be severely disabling, medical expenditures for treating COPD can represent a substantial economic burden for societies and for public and private health insurers worldwide [96]. Pharmacoeconomical analysis is needed for establishing the values of the treatments and allocating the scarce resources of health care system effectively.

3.3. Classification of COPD

Classification of COPD symptoms, severity, or stages is important as a basis for guidelines for treatment, prognostic indicators regarding various aspects of the disease including progression, exacerbation, hospitalization, and mortality [97]. Stages of COPD that were identified include:

Stage I: Mild COPD – Characterized by mild airflow limitation (FEV1/FVC < 0.70; FEV1 ≥ 80% predicted). Symptoms of chronic cough and sputum production may be presented, but not always. At this stage, the individual is usually unaware that his or her lung function is abnormal.

Stage II: Moderate COPD – Characterized by worsening airflow limitation (FEV1/FVC < 0.70; 50% ≤ FEV1 < 80% predicted), with shortness of breath typically developing on exertion and cough and sputum production sometimes also present. This is the stage at which patients typically seek medical attention because of chronic respiratory symptoms or an exacerbation of their disease. Stage III: Severe COPD – Characterized by further worsening of airflow limitation (FEV1/FVC < 0.70; 30% ≤ FEV1 < 50% predicted), greater shortness of breath, reduced exercise capacity, fatigue and repeated exacerbations that almost always have an impact on patients’ quality of life.

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without arterial partial pressure of CO2 (PaCO2) greater than 50 mm Hg while breathing air at sea level. At this stage, quality of life is very appreciably impaired and exacerbations may be life threatening [9].

3.4. Aetiology, pathogenesis and pathophysiology of COPD

The identification of risk factors is an important step toward developing strategies for prevention and treatment of any disease. The risk factors for COPD are separated into host factors and exposures.

Host factors

COPD is a polygenic disease and a classic example of gene-environmental interaction. The genetic risk factor that is best documented is a severe hereditary deficiency of α1-antitrypsin, a major circulating inhibitor of serum proteases. Although α1-antitrypsin deficiency is relevant to only a small part of the world’s population, it illustrates the importance of gene-environment interactions in the pathogenesis of COPD. All patients with airflow limitation and family history of respiratory illnesses, and patients presenting with airflow limitation at relatively early age (4th or 5th decade) should be evaluated for α1-antitrypsin deficiency.

Exploratory studies have revealed a number of candidate genes that influence a person’s risk of COPD. However, when several studies of a given trait are available, the results are often inconsistent. Several of these genes are thought to be involved in inflammation and, therefore, are related to potential pathogenic mechanisms of COPD [9, 94].

Airway hyperresponsiveness has also been demonstrated to be a risk factor for COPD. The mechanism for this, however, is not clear. Some asthma patients also develop fixed airflow limitation and thus fulfil the requirements for COPD diagnosis.

Worldwide, COPD is more prevalent in males than in females. However, this is a consequence of the marked difference in smoking (and other) exposures between males and females. Recent data from several large studies suggest that females may in fact be more susceptible to the effects of tobacco than males [94].

Exposures

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A subject’s socioeconomic background plays an important role that is not only the result of exposure to tobacco and occupational hazards. Whether the effect is due to impaired growth of lungs and airways or an increased rate of infection is not clear [94].

Pathological changes characteristic of COPD are found in the proximal airways, peripheral airways, lung parenchyma and pulmonary vasculature. The pathological changes include chronic inflammation with increased numbers of specific inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair. In general, the inflammatory and structural changes in the airways increase with disease severity and persist on smoking cessation [9].

Inflammation

The inflammation in the respiratory tract of COPD patients appears to be an amplification of the normal inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this amplification are not yet understood but may be genetically determined. Some patients develop COPD without smoking, but the nature of the inflammatory response in these patients is unknown [98]. Lung inflammation is further amplified by oxidative stress and an excess of proteinases in the lung. Together, these mechanisms lead to the characteristic pathological changes in COPD.

Oxidative stress

Oxidative stress may be an important amplifying mechanism in COPD. Biomakers of oxidative stress are increased in the exhaled breath condensate, sputum and systemic circulation of COPD patients. Oxidative stress is further increased in exacerbations. Oxidants are generated by cigarette smoke and other inhaled particulates and released from activated inflammatory cells such as macrophages and neutrophils. There may also be a reduction in endogenous antioxidants in COPD patients. Oxidative stress has several adverse consequences in the lungs, including activation of inflammatory genes, inactivation of antiproteases, stimulation of mucus secretion and stimulation of increased plasma exudation. Many of these adverse effects are mediated by peroxynitrite, which is formed via an interaction between superoxide anions and nitric oxide. In turn, the nitric oxide is generated by inducible nitric oxide synthase, which is expressed in the peripheral airways and lug parenchyma of COPD patients [99, 100].

Protease-antiprotease imbalance

KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY