KAUNAS UNIVERSITY of MEDICINE Department of Basic & Clinical Pharmacology

KAUNAS UNIVERSITY OF MEDICINE Department of Basic & Clinical Pharmacology

Trends in the use of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists in Lithuania on 2005 – 2007 years

The author: Asta Dičkutė a student of Pharmacy faculty of Kaunas University of Medicine

Work supervisor: Lekt. Edmundas Kaduševičius

Kaunas 2008

1 TABLE OF CONTENTS Abbreviations...... 3 1. Introduction and novelty of the master work...... 4 2. Objective and tasks...... 8 3. The renin-angiotensin aldosterone system: physiological role and pharmacologic inhibition .. ...9 3.1 Components of the renin-angiotensin aldosterone system...... 9 3.2.Description and clasification of AT1 and AT2 receptors...... 11 3.3 Classical Endocrine Pathway of Angiotensin Biosynthesis………………………..…………...12 3.4 Tissue renin-angiotensin aldosterone system and Alternative Pathways of Angiotensin Biosynthesis………………………………………………………………………………………...13 3.5 Dysregulation of the renin-angiotensin aldosterone system in Cardiovascular Disorders…..…16 3.6 Renin-angiotensin aldosterone system inhibition. Early Preclinical Findings…………………17 3.7. Pharmacologic Intervention in the Renin-Angiotensin System Cascade…………………..….17 4. Angiotensin – converting enzyme inhibitors. History. Chemical structure. Pharmacokinetics....19 4.1 History…….....…………………………………………………………………………………19 4.2 Chemical structure…………….………………………………………………………………..20 4.3 Pharmacokinetics of the ACE inhibitors…………………..………………………………...... 23 5. Angiotensin II antagonists. History. Chemical structure. Pharmacokinetics…………..………..25 5.1 History……………………………………………………………………….…………………25 5.2 Chemical structure………………………………………….………………………………….25 5.3 Pharmacokinetics of angiotensin II antagonists………………………………………………..27 6. Head-to-head efficacy comparisons………………………………………………………….….29 7. Results …………………………………………………...... …………………………...37 8. Discussion ……………………………………………………….……………………………..65 9. Acknowledgments……………………………………………………………………………….67 10. Conclusions. ………………………………………………………………….…..…………….68 11. Summary……………………………………………………………………………………….69 13 Santrauka…………………………………………………………………………………….….71 14. Literatures……………………………………………………………………………….……..73 15. Annexes…………………………………………………………………………..……………75

2 ABBREVIATIONS ACE-I - angiotensin-converting enzyme inhibitors ARA - angiotensin receptor antagonists BP – blood pressure BKR-2 - the bradykinin receptor type 2 CAGE - chymostatin-sensitive angiotensin generating enzyme CVD – cardiovascular diseases EU - Europe Union GFR - glomerular filtration rate HgbA1c - glycated hemoglobin IHD – isheamic heart diseases JG - juxtaglomerular cells LV – left ventricular mRNA - messenger ribonucleic acid PGE-2 - prostaglandin E2 PGI-2 - prostaglandin I2 PRA - plasma renin activity RAAS – the renin-angiotensin aldosterone system RAS – the renin–angiotensin system RCT - randomized controlled trial UK - United Kingdom USA - United States of America WHO – World Health Organisation

1. INTRODUCTION AND NOVELTY OF THE MASTER WORK Cardiovascular disease is one of the main causes of death in the world in 2005. Among the 58 million deaths in the world in 2005, noncommunicable diseases were estimated to account for 35 million. Sixteen million of the 35 million deaths occur in people aged under 70 years. The majority of deaths (80%) from noncommunicable diseases occur in low and middle income countries, where most of the world‘s population lives, and the rates are higher than in high income countries. Deaths from noncommunicable diseases occur at earlier ages in low and middle income countries than in high income countries.[1]. Among the noncommunicable diseases, cardiovascular diseases are the leading cause of death, responsible for 30% of all deaths – or about 17.5 million people – in 2005[1]. In addition to the high death toll, noncommunicable diseases cause disability. The most widely used summary measure of the burden of disease is disability-adjusted life years (DALYs), which combines years of healthy life lost to premature death with time spent in less than full health. Almost half of the global burden of disease is caused by noncommunicable diseases, compared with 13% by injuries and 39% by communicable diseases, maternal and perinatal conditions, and nutritional deficiencies combined. While the share of cardiovascular diseases, chronic respiratory diseases and cancer decreases, other noncommunicable diseases increase from 9% to 28%, primarily due to a larger share for mental disorders, and to a lesser extent due to impairments of the sense organs (sense and hearing) and musculoskeletal system (mainly arthritis). [1] Cardiovascular diseases remain the major cause of death across Europe, and a major cause of morbidity and loss of quality of life. [2] Every year more than 4 million Europeans die from diseases of the heart and blood vessels. The prevalence of many cardiovascular diseases increases exponentially with ageing, especially coronary heart disease, heart failure, atria fibrillation, hypertension and aortic stenosis. This is a challenge for modern cardiology since all surveys show that management of elderly patients often differs from management in younger patients. Specific attention is needed for guideline development and adherence with respect to elderly. [2] The population in Europe is ageing rapidly. At present (latest available data ≈ 2004), 13.7% of the European population is aged 65 years or older which is twice the world level. [2]

Figure 1. Population of Europe in 2004. [2]

There is an apparent west-east gradient with more elderly people in the Western countries. [2] This reflects the longer life-expectancy in Western countries, which is partly a result of the lower age-specific mortality from cardiovascular diseases. Cardiovascular disease is the main cause of death in most countries in Europe. At present (latest available data ≈ 2004), the average age standardised cardiovascular mortality ratio is 5.1 per 1,000 inhabitants for men, and 3.4 for women. [2] CVD is the main cause of death before the age of 65 for men in 28 of the 49 countries of Europe for which we have mortality data and for women in 17 countries. In women, the countries where CVD is the main cause of death before the age of 65 are all Central and Eastern European countries. [3] CVD is the main cause of death before the age of 65 for men in ten countries in the EU (Estonia, Finland, Greece, Ireland, Latvia, Lithuania, Poland, Slovakia, Sweden and the UK). [3] Lithuania is ascribed to the states of high risk cardiovascular diseases by World Health Organisation and Europen Society of Cardiology. [4] About 55 percent of all deaths and 25-50 percent of disablement and 15-20 percent of all medical consultations are because of cardiovascular diseases. Cardiovascular diseases are one of the main causes of death and disablement among middle aged and elder men and women in Lithuania. Mortality from cardiovascular diseases increased 16.6 percent since 2000 till 2005. [4] Cardiovascular diseases are the leading cause of death, responsible for more than a half of all deaths (or 23,8 thousand of 43,8 thousand people) in Lithuania in 2005. Among the cardiovascular diseases, an ischemic heart disease is the leading cause of death (15 thousand deaths in 2005). [4]

5 Almost 89 percent of all deaths from cardiovascular diseases occur in people aged 60 years old and more. The biggest rate of mortality from cardiovascular diseases is in Alytus, Utena, Taurage districts in Lithuania in 2005. [4] Almost 52 percent of all deaths (or 562 people of 1090.86 total deaths) are from cardiovascular diseases in Lithuania in 2006. [4] Age adjusted death rates by cause of death, 2006 Deaths per 100 000 European standard population Causes of death Total 1090,86 Malignant neoplasms 195,45 Diseases of the circulatory system 562,05 External causes of death 149,77 Intentional self-harm 28,94

Table.1. Age adjusted death rates by cause of deaths in Lithuania in 2006 [4]

Among the cardiovascular diseases ischaemic heart diseases are the leading cause of death, responsible for 56 percent of all deaths – or about 13.7 thousand people – in 2006 in Lithuania. Almost 82 percent of all deaths from cardiovascular diseases occur in people aged 65 years and more. [4] The morbidity of cardiovascular diseases increases between young and able-bodied population. [4] The decrease of risk factors is one of the main components of the IHD medical treatment strategy. It is important to decrease risk factors for healthy people and patients with IHD symptoms (primary and secondary prevention of the disease). The other not less important component of secondary prevention is the treatment with medicine. It is set that people sick with IHD and using every of the main medicines (aspirin, BAB, AKF inhibitor or statin) have ¼ less isheamic heart attacks, people who use drugs combinations decrease heart attacks till ¾ ones. [5] Drugs that inhibit the renin–angiotensin system (RAS), namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARA) are gaining increasing popularity as initial medications for the management of hypertensive patients. In the year 2002, ACE-I were the most commonly prescribed drugs for the treatment of hypertension in USA. [3] ACE inhibitors and angiotensin II receptor antagonists use in Europe countries increased from 31.0% in the first survey to 74.6% in EUROASPIRE III. [5]

6 Although their antihypertensive efficacy as monotherapy is similar to other antihypertensive agents, they have the advantage of better tolerability, limited side effects and a favourable metabolic profile. When compared to other antihypertensive agents (diuretics, beta-adrenergic blockers and calcium antagonists) in large clinical trials, ACE-I and ARA provided no additional advantages regarding improvement in cardiovascular and total mortality. With the exception of the superiority of ARA in prevention of stroke, RAS inhibitors have no advantage over other agents in prevention of other cardiovascular morbid events, namely, heart failure (though ACE-I are superior to calcium antagonists), coronary heart disease and total cardiovascular events. However, there is the possibility that these agents have other benefits beyond blood pressure lowering. At equal degrees of blood pressure reduction, RAS inhibitors prevent or delay the development of diabetes mellitus and provide better end-organ protection, kidneys, blood vessels and the heart when compared with other antihypertensive agents. The combined use of ACE-I and ARA is particularly useful in organ protection. RAS inhibitors are specifically indicated in the treatment of hypertension in patients with impaired left ventricular systolic function, diabetes, proteinuria, impaired kidney function, myocardial infarction, multiple cardiovascular risk factors and possibly elderly patients. The main limitation of the ACE-I is cough and rarely angioedema. Elderly patients or those who are volume depleted or receiving large doses of diuretics or in heart failure are liable to develop hypotensive reaction and/or deterioration in kidney function. [13] New methods for prevention and treatment of cardiovascular diseases have delayed the onset of clinical manifestations, have improved the immediate disease outcome, and have improved life expectancy. This has resulted in an increasing number of patients who survive a cardiovascular event, and who require subsequent medical or interventional therapy. The burden of cardiovascular disease has shifted from the middle aged to the elderly, and remains high. [2] In Lithuania like in other EU countries expenses for drugs increase very fast compare with other sectors in health system. Lithuania predicted to spend 587.8 million on drugs and medical goods in 2007. In 2006 Medical expenses amounted to 507 mill. compared to 447 mill. in previous year. [11] Compensation expenses on cardiovascular drugs were 24.6% of all compensation expenses on drugs in 2005. [4] Because of increased expenses on drugs various methods of regulation must be applied. A rational distribution of funds helps to decrease expenses on drugs. [10] This work is a new look at two antihypertensive drug classes: Angiotensin converting enzyme inhibitors and Angiotensin II antagonists. The point of work is to perform head-to-head efficiency comparison between. Angiotensin converting enzyme inhibitors and Angiotensin II antagonists and to make pharmacoeconomic decisions reasonably using cost minimisation and reference prices methods.

7 2. OBJECTIVE AND TASKS

2.1. OBJECTIVE To evaluate the tendencies of utilization of angiotensin converting enzyme inhibitors and angiotensin II receptors antagonists in Lithuania during 2005-2007 years.

2.2. TASKS The main tasks are as follows: 1. To introduce importance of Renin-angiotensin-aldosterone system for human blood pressure regulation – literature review. 2. To evaluate differences and similarities between angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists and the same within pharmaceutical group (to perform head-to- head comparison). 3. To evaluate utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists by ATC/DDD methodology in Lithuania during 2005-2007 years. 4. To compare utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in Lithuania with other EU countries. 5. To perform pharmacoeconomic analysis of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists by cost minimisation and reference price analysis.

8 3. THE RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS): PATH PHYSIOLOGICAL ROLE AND PHARMACOLOGIC INHIBITION The renin-angiotensin aldosterone system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extra cellular volume. Dysregulation of the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders. [9]

3.1 Components of the RAAS As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. [8] The renin-angiotensin aldosterone hormonal cascade begins with the biosynthesis of renin by the juxtaglomerular cells (JG) that line the afferent (and occasionally efferent) arteriole of the renal glomerulus. Active renin secretion is regulated principally by 4 interdependent factors: (1) a renal baroreceptor mechanism in the afferent arteriole that senses changes in renal perfusion pressure, (2) changes in delivery of NaCl (sensed as changes in Cl- concentration) to the macula densa cells of the distal tubule (which lie close to the JG cells and, together, form the ―JG apparatus‖), (3) sympathetic nerve stimulation via beta-1 adrenergic receptors, and (4) negative feedback by a direct action of Ang II on the JG cells. Renin secretion is stimulated by a fall in perfusion pressure or in NaCl delivery and by an increase in sympathetic activity. Control of renin secretion is a key determinant of the activity of the RAAS. Renin regulates the initial, rate-limiting step of the RAAS by cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang I [9], which is changed through angiotensin-converting enzymes (ACE) to an octapeptide angiotensin II, a biologically active, potent vasoconstrictor. [9] Angiotensin II is associated with a variety of morphologic and functional changes in the cardiovascular system, and all are associated with hypertension and can affect multiple organs. This affects the blood vessel integrity, the kidneys, the heart, and the brain. [6]

RAAS = renin-angiotensin-aldosterone system; ACE = angiotensin converting enzyme; LVH = left ventricular hypertrophy; LV = left ventricular. Figure 2. Deleterious effects of the RAAS [6]

There are multiple pathways of angiotensin II production—2 of them are described here. On the left-hand side is the classical pathway where ACE is the enzyme responsible for the conversion of angiotensin-1 to angiotensin II. On the right-hand side there is depicted an alternate pathway, which is mainly tissue loss pathway and will involve different enzymes such as CAGE, cathepsin G, or chymase. [6]

NO = nitric oxide; AT = angiotensin II receptor; t-PA = tissue plasminogen factor; CAGE = chymostatin- sensitive angiotensin generating enzyme; ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blocker. Figure 3. Multiple pathways of angiotensin II production and sites of action of ACEI and ARA. [6]

10 ACE is a membrane-bound exopeptidase and is localized on the plasma membranes of various cell types, including vascular endothelial cells, microvillar brush border epithelial cells (e.g., renal proximal tubule cells), and neuroepithelial cells. It is this membrane-bound ACE that is thought to be physiologically important. ACE also exists in a soluble form in plasma, but this form may simply reflect turnover and clearance of membrane-bound ACE. ACE (also known as kininase II) metabolizes a number of other peptides, including the vasodilator peptides bradykinin and kallidin, to inactive metabolites. [7] Thus, functionally, the enzymatic actions of ACE potentially result in increased vasoconstriction and decreased vasodilatation. Although Ang II is the primary active product of the RAAS, there is evidence that other metabolites of Ang I and II may have significant biological activity, particularly in tissues. [9] As already noted, Ang II is the primary effector of a variety of RAAS-induced physiological and path physiological actions. [9]

3.2. Description and classification of AT1 and AT2 receptors Angiotensin-2 has multiple receptors, but 2 receptors are predominating or are better known. The AT1 receptor is responsible for hypertrophy/proliferation, vasoconstriction, aldosterone release, and also antidiuretic hormone. The second well-known receptor is the AT2 receptor. This AT2 receptor is responsible for antiproliferation or apoptosis, nitric oxide release, differentiation, and vasodilatation. [6] Both receptors have high binding affinities for the AngII peptide. AT1 receptors are expressed in various parts of the body and are associated with their respective functions, such as blood vessels, adrenal cortex, liver, kidney and brain, while AT2 receptors are highest in fetal mesenchymal tissue, adrenal medulla, uterus and ovarian follicles. [7] We know that the AT1 receptor is always expressed [6], The type 1 (AT1) receptor mediates most of the established physiological and pathophysiological effects of Ang II. These include actions on the cardiovascular system (vasoconstriction, [9] , and this is preferential to the coronary, the renal, and the cerebral paths, [6] increased blood pressure, increased cardiac contractility, vascular and cardiac hypertrophy, kidney (renal tubular sodium reabsorption, inhibition of renin release), sympathetic nervous system, and adrenal cortex (stimulation of aldosterone synthesis). [7] The AT1 receptor also mediates effects of Ang II on cell growth and proliferation, inflammatory responses, and oxidative stress. [9] The AT2 receptor counteracts almost all this action of the AT1 receptor. It is a receptor which can be expressed during stress or injury; it causes vasodilatation, apoptosis, inhibition of cell growth, tissue repair, and antiproliferation; it decreases growth of vascular and smooth muscle cells, and it is mainly seen in embryogenesis in the fetus state. The AT2 receptor is particularly dense in the brain and the kidney. The 2 receptor subtypes have different signaling cascades and different biological activities. [6]

Figure 4. Angiotensin II receptor stimulation [6]

As already noted, Ang II, via the AT1 receptor, also stimulates the production of aldosterone by the zona glomerulosa, the outermost zone of the adrenal cortex. Aldosterone is a major regulator of sodium and potassium balance and thus plays a major role in regulating extracellular volume. It enhances the reabsorption of sodium and water in the distal tubules and collecting ducts (as well as in the colon and salivary and sweat glands) and thereby promotes potassium (and hydrogen ion) excretion.12 Ang II, together with extracellular potassium levels, are the major regulators of aldosterone, but Ang II synthesis may also be stimulated by adrenocorticotrophic hormone (ACTH; corticotrophin), norepinephrine, endothelin, and serotonin and inhibited by atrial natriuretic peptide and nitric oxide (NO). It is also important to note that Ang II is a major trophic factor for the zone glomerulosa, which can atrophy (reversibly) in its absence. [9]

3.3 Classical Endocrine Pathway of Angiotensin Biosynthesis Juxtaglomerular (JG) cells associated with the afferent arteriole entering the renal glomerulus are the primary site of renin storage and release in the body. A reduction in afferent arteriole pressure causes the release of renin from the JG cells, whereas increased pressure inhibits renin release. Beta1- adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells (macula densa) of distal tubules lie adjacent to the JG cells of the afferent arteriole. The macula densa senses the amount of sodium and chloride ion in the tubular fluid. When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. There is evidence that prostaglandins (PGE2 and PGI2) stimulate renin release in response to reduced NaCl transport across the macula densa. When afferent

12 arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule. This serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension. When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII. [8] The concept of a circulating endocrine cascade has been frequently misinterpreted to imply that Ang II is a circulating ―hormone,‖ but this is in fact unlikely. Instead, both Ang I and Ang II, which have very short half-lives, are probably synthesized very close to their site of action, with renin serving as the circulating hormonal signal that initiates the pathway at local sites. The diverse actions of Ang II mediated by the AT1 receptor play a key role in restoring or maintaining circulatory homeostasis. In addition to stimulating the production (and release) of aldosterone from the adrenal cortex, Ang II promotes the constriction of renal and systemic arterioles and the reabsorption of sodium in proximal segments of the nephron. The increase in blood pressure and volume, resulting from the effects of Ang II and aldosterone on their target organs, serves to restore renal perfusion and thereby inhibits further release of renin. Although the RAAS thus plays an important role in normal circulatory homeostasis, continued or inappropriate activation of the system is thought to contribute to the pathophysiology of diseases such as hypertension and heart failure. [9]

3.4 Tissue RAAS and Alternative Pathways of Angiotensin Biosynthesis The evidence that angiotensin synthesis can occur in several tissues as well as the circulation, together with the characterization of several subtypes of angiotensin receptors and signal transduction pathways, the identification of truncated angiotensin peptides with possible unique actions, and most recently, the identification of putative cell surface receptors for renin and prorenin, has resulted in expansion of the traditional circulating RAAS paradigm to include the so-called ―tissue RAAS.‖ The prevailing concept is that the RAAS functions both as a circulating system and as a tissue paracrine/autocrine system. [9] There is evidence that local or ―tissue‖ Ang II biosynthesis may be initiated by renin and/or angiotensinogen taken up from the circulation. In addition, independent Ang II generating systems have been postulated to exist in the heart, peripheral blood vessels, kidney, brain, adrenal glands, pituitary, adipose tissue, testes, ovaries, and skin.7,13 Serine proteases, including several kallikrein- like enzymes (tonins), cathepsin G, and chymase are thought to contribute to Ang II formation in the tissue RAAS. [9]

13 Studies have suggested that non-ACE pathways are, by inference, responsible for about 40% of Ang II generation in the intact human kidney and that chymase is the dominant Ang II-generating pathway in the human heart, coronary arteries, and atherosclerotic aorta in vitro. It has thus been proposed that abnormal activation of the tissue RAAS may contribute to the pathogenesis of cardiovascular disease even in the absence of derangements in the circulating system. It must be considered, however, that the bulk of the evidence favoring alternate enzymatic pathways in the synthesis of angiotensin peptides comes from in vitro or indirect observations, so that such concepts remain speculative at present. [9] Under physiological conditions, the apparent function of the cardiac RAAS is to maintain cellular balance of inhibiting and inducing cell growth, and proliferation and mediation of adaptive responses to myocardial stretch. The majority of Ang II in cardiac tissue appears to be produced by local synthesis of Ang I and subsequent local conversion to Ang II, rather than from uptake of peptides from the systemic circulation. Although it has been suggested that locally synthesized renin and/or additional proteolytic enzymes may be involved in this synthetic process, current evidence favors the concept that circulating renin and angiotensinogen, which are able to pass through the endothelial barrier, are taken up by cardiac tissue where they act locally. Ang II exerts an inotropic effect (at least in atrial preparations), mediates myocyte hypertrophy via the AT1 receptor, and is involved in cardiac remodeling. Pathologic activation of cardiac RAAS, perhaps through local upregulation of ACE levels, has been proposed to contribute to the development and maintenance of left ventricular hypertrophy. [9] Vascular smooth muscle, endothelial, and endocardial cells generate Ang I and Ang II, again apparently via the uptake of circulating renin. It has been suggested that the vascular RAAS contributes to the maintenance of cardiovascular homeostasis through its effects on both AT1 and AT2 receptors and mediates long-term effects on vascular remodeling by stimulating proliferation of vascular smooth muscle cells and fibroblasts. Endothelial dysfunction is associated with upregulation of local tissue ACE, which might contribute to disrupting the balance of vasodilation and vasoconstriction. Activation of vascular ACE may also alter other functions, including vascular smooth muscle cell growth and the inflammatory and oxidative state of the vessel wall. In addition, the production of reactive oxidative species (superoxide and hydrogen peroxide), which is enhanced by Ang II, has been associated with inflammation, atherosclerosis, hypertrophy, remodeling, and angiogenesis. [9] The intrarenal RAAS may explain the primary role of Ang II as a paracrine substance in the control of renal function. The direct intrarenal actions of Ang II include renal vasoconstriction, tubular sodium reabsorption, sensitivity of tubuloglomerular feedback, modulation of pressure- natriuresis, and promotion of renal tissue growth. Under normal conditions, Ang II constricts both the

14 afferent and efferent arterioles and stimulates mesangial cell contraction, which results in reduced renal blood flow, glomerular filtration rate (GFR), and filtered sodium load. On the one hand, overactivation of the intrarenal RAAS may thus contribute to the pathophysiology of sodium- retaining states, such as hypertension and congestive heart failure (CHF). On the other hand, in conditions characterized by severe impairment of renal perfusion, such as renal artery stenosis, the afferent circulation, which is dilated as a result of autoregulation, is relatively refractory to the constrictive actions of Ang II, and the predominant constriction of efferent arterioles by Ang II plays a major role in maintaining glomerular perfusion pressure and, thus, GFR. Although systemic Ang II may affect CNS function at selected sites, the brain is largely isolated from the circulating RAAS by the blood-brain barrier. Therefore, local Ang II synthesis by a brain RAAS has been proposed to play a role in central blood pressure regulation. Increases in brain renin activity, renin and angiotensinogen mRNA, and detectable numbers of AT1- and AT2-receptor subtypes have been reported in hypertensive rats. Selective inhibition of brain AT1- and AT2-receptors has been shown to lower blood pressure in hypertensive rats. Furthermore, direct administration of Ang II into the brain has been shown to increase blood pressure as a result of the combined effects of vasopressin release, sympathetic nervous system activation, and inhibition of baroreflexes. Studies in transgenic rats with permanent inhibition of brain angiotensinogen synthesis have demonstrated significantly lower systolic blood pressure compared with controls. [9] All components of the RAAS are present in adrenal cortex and comprise the adrenal RAAS. Renin and angiotensinogen mRNA have been identified in the adrenal gland, and Ang II formation has been demonstrated in zona glomerulosa cells. Most (90%) adrenal renin activity has been localized to the zona glomerulosa, and more than 90% of adrenal Ang II originates at local tissue sites. In transgenic animal models it has been shown that sodium restriction can increase adrenal renin and aldosterone independently of plasma or kidney renin concentrations. Additionally, bilateral nephrectomy, which decreases cardiac and vascular renin, does not decrease adrenal renin in experimental animals. These findings support the concept of kidney-independent renin (and thus, Ang II) production in the adrenal glands. It is not known if the adrenal RAAS functions as a paracrine or autocrine system or if it has a pathophysiologic role, and the relative importance of systemic versus locally synthesized Ang II in the control of adrenal function is uncertain. [9] Generally speaking, it is thought that the physiologic role of tissue RAAS is complementary to the classical circulating RAAS and serves as a mechanism for longer-term maintenance of balance or homeostasis at the tissue level between opposing effects mediated by the system (e.g., growth promotion and inhibition in the heart and vasculature). Pathophysiologic processes might hypothetically occur when components of the RAAS are overexpressed or inhibited, thus disturbing the intricate balance of this regulatory system. [9]

15 3.5 Dysregulation of the RAAS in Cardiovascular Disorders Dysregulation of the RAAS is involved in the pathogenesis of several hypertensive disorders. It should be noted that RAAS dysregulation in clinical hypertensive disorders has been conceptualized at the level of the classical circulating RAAS, and the potential contributions of tissue RAAS dysregulation remain poorly defined. In addition to RAAS involvement in secondary forms of hypertension, there is evidence that perturbations of the RAAS are involved in essential hypertension as well as in the responses of cardiovascular and renal tissue to hypertensive and nonhypertensive injury. It is established that plasma renin levels vary widely in patients with ―essential‖ hypertension. Approximately 15% of patients with essential hypertension have mild to moderate increases in plasma renin activity (PRA), with several postulated mechanisms, including increased sympathetic activity and mild volume depletion. Such high- renin essential hypertension is particularly prevalent among younger males. The majority (50% to 60%) of essential hypertensive patients have PRA within the ―normal‖ range, although it has been argued that a normal renin level in the face of hypertension (which ought to suppress renin secretion) may be inappropriate. Therapeutic responses to RAAS blocking agents indicate that maintenance of normal renin levels may indeed contribute to blood pressure elevation, suggesting that renin-dependent mechanisms may be involved in more than 70% of patients with essential hypertension. On the other hand, about 25% to 30% have evidence of low or suppressed renin levels, a finding that may be an expected response or that may, in some cases, reflect, by analogy to primary aldosteronism, sodium or volume excess (so- called ―volume-dependent‖ hypertension). Low-renin hypertension is more common among older people with hypertension, women, African Americans, and patients with type 2 diabetes, as well as among patients with chronic renal parenchyma disease. Although such patients often have lesser blood pressure lowering benefit from RAAS blocking agents, there is evidence that the circulating levels of PRA might not necessarily reflect tissue activities of the system. This is particularly evident with regard to the kidney, with several lines of evidence pointing to substantial involvement of intrarenal Ang II in progression of renal damage (and substantial benefit of RAAS blockade), despite low circulating levels of renin and Ang II. [9] The RAAS also plays a pivotal role in several nonhypertensive conditions, and in particular in CHF and the other oedematous disorders (cirrhosis with ascites and the nephrotic syndrome). In these conditions, all characterized by under perfusion of the kidneys due to reduced ―effective arterial volume,‖ secondary hypersecretion of renin leads to secondary aldosteronism, which makes an important contribution to progressive edema. In addition, with regard to heart failure, the contribution of Ang II to increased peripheral vascular resistance (cardiac after load) also plays a major role in progressive ventricular dysfunction. [9] Beyond progression of renal disease, there is additional clear evidence (again from responses to RAAS blockade) of involvement of Ang II in development of both vascular and cardiac hypertrophy and

16 remodeling, as well as on mechanisms that contribute to vascular damage and atherosclerosis, effects that appear to have major impact on morbidity and mortality. Unlike the case for secondary hypertensive syndromes where the nature of RAAS dysregulation is well defined, the reasons for these pathologic effects of Ang II are uncertain since they often occur in the absence of any perturbation of the circulating RAAS. It has been inferred that there may be dysregulation of some component(s), such as of ACE levels, the balance of AT-receptor subtypes, or even local synthesis of renin or angiotensinogen, to account for such phenomena, but clear cut evidence of such derangements are mostly lacking. It also remains possible that the RAAS plays a ―passive‖ role in such events—that is, that tissue injury can be accelerated even in the presence of ―normal‖ Ang II levels. [9]

3.6. RAAS Inhibition. Early Preclinical Findings Because renin is the initial and rate-limiting step in the RAAS cascade, it has long been considered the logical therapeutic target for blocking the system. Preclinical studies with antirenin antibodies and then with early synthetic renin inhibitors established the potential utility of RAAS inhibition. In these studies, renin inhibition induced decreases in plasma renin levels (generally measured in these early studies as plasma renin activity or PRA), Ang I, Ang II, and aldosterone, along with decreases in blood pressure.25 These studies also provided evidence that blood pressure-lowering activity was due to inhibition of PRA.25 However, pharmacologic activity of the early renin inhibitors could only be achieved with intravenous infusion, and the development of an orally active direct renin inhibitor was fraught with numerous difficulties arising from issues of potency, low bioavailability, duration of action, and costs of synthesis. As a result, further development of these agents was halted in the mid-1990s. Concurrently, other strategies for inhibiting the RAAS progressed to clinical use. [9]

3.7. Pharmacologic Intervention in the Renin-Angiotensin System Cascade Inhibition of the RAS as part of an effective BP lowering regimen is also a successful strategy for preventing or delaying end-organ damage. Two drug classes directly target angiotensin II through complementary mechanisms. ACE inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. ARBs selectively antagonize angiotensin II at AT 1 receptors. The beneficial effects of ARBs may also include increased activation of the AT 2 receptor and modulation of the effects of angiotensin II breakdown products.[18] See Figure 2. A dry, persistent cough is a well-described class effect of the angiotensin-converting enzyme (ACE) inhibitor medications. The mechanism of ACE inhibitor-induced cough remains unresolved, but likely involves the protrusive mediators bradykinin and substance P, agents that are degraded by ACE and therefore accumulate in the upper respiratory tract or lung when the enzyme is inhibited, and prostaglandins, the production of which may be stimulated by bradykinin.[26]

17 Angiotensin-converting enzyme (ACE) inhibitors can cause bradykinin-induced angioedema. See Figures 3 and 5.

Figure 5. Detrimental and beneficial effects of activation of BKR-2 in humans. [25]

ACEIs also decrease aldosterone and vasopressin secretion and sympathetic nerve activity, but there is controversy regarding their efficacy in blocking other ―tissue‖ actions of the RAAS. [9] Short-term ACEI therapy is associated with a decrease in Ang II and aldosterone and an increase in renin release and Ang I. There is some evidence, however, that over the long term ACE inhibition may be associated with a return of Ang II and aldosterone toward baseline levels (―ACE escape‖)—perhaps, it is proposed, through activation of the so-called alternate pathways. See Figure 3. [9] Such pathways rely on chymase and other proteases to independently produce angiotensin-II in myocardial and vascular tissue. [16] Undoubtedly this phenomenon has been greatly exaggerated, particularly from early studies using faulty methodology that did not specifically measure Ang II, and the relevance of alternate pathways of Ang II synthesis in the intact human is unclear at present. [9] On the other hand, because ACEIs are all competitive inhibitors of the enzyme, it is possible that increased levels of Ang I (provoked by the compensatory increase in PRA due to loss of negative feedback inhibition) can tend to partially overcome the blockade. This would be especially likely in high- renin or volume-depleted patients with a particularly robust reactive rise in PRA. [9]

4. ANGIOTENSIN - CONVERTING ENZYME INHIBITORS. HISTORY. CHEMICAL STRUCTURE. PHARMACOKINETIC.

4.1 History Early studies performed in the 1960s showed that peptides from the venom of the Brazilian arrowhead viper (Bothrops jararaca) inhibited kinase II, an enzyme that facilitates degradation of bradykinin, and which was later shown to be identical to ACE. [9] Mixtures of peptides from the venom of South American pit vipers are effective at lowering blood pressure when injected, but inactive orally. Even though the snake venom peptides were not active orally the realization that peptides could inhibit ACE initiated the search for smaller peptide based inhibitors which could be administered orally. A screen of N-acylated tripeptides led to the discovery that N-acylated tripeptides could be inhibitors. [19] Synthetic analogues of the peptide fraction of snake venom, such as the nonapeptide teprotide, were shown to lower blood pressure in patients with hypertension and produce beneficial hemodynamic effects in patients with heart failure. [9]

Figure 6. The structure of teprotide and N-acylated tripeptides [19]

These findings encouraged the search for orally active inhibitors of ACE; the first of these, captopril, was designed based on known inhibitors of another zinc-containing metalloprotease, carboxypeptidase A, and included a sulfhydryl-containing amino acid to serve as ligand for the zinc moiety. Because many of the unacceptable side effects of captopril, such as proteinuria, skin rashes, and altered taste, were attributed to the sulfhydryl group, subsequent work led to the development of ACEIs that replaced this group with a carboxyl group (e.g., lisinopril, benazepril, quinapril, ramipril, perindopril, cilazapril, trandolapril) or phosphoryl group (fosinopril). The presence of the carboxyl group conferred greater lipophilicity, which actually improved binding to ACE, and improved tissue penetration. [9]

19 4.2 Chemical structure ACE inhibitors can be divided into three groups based on their molecular structure. For example, the active chemical side group or ligand on captopril, which binds to ACE, is a sulfhydryl group; for fosinopril, it is a phosphinyl group, with the remaining ACEIs containing a carboxyl group. [16] Classification according to chemical structure: I. Sulfhydryl-containing agents Captopril, the first ACE inhibitor Zofenopril II. Dicarboxylate-containing agents Enalapril, Ramipril, Quinapril, Perindopril (Non-thiol), Lisinopril, Benazepril, Cilazapril, Moexipril, Trandolapril, Spirapril III. Phosphonate-containing agents Fosinopril

Captopril

Enalapril maleate

Lisinopril

Moexipril hydrochloride

Perindopril erbumine

Quinapril hydrochloride

Trandolapril

Ramipril

Benazepril

21 Cilazapril

Fosinopri sodium

Temocapril

Spirapril

Delapril

Imidapril

Pentopril

Zofenopril

Table.2. Chemical formulas of angiotensin converting enzyme inhibitors

22 4.3 Pharmacokinetics of the ACE inhibitors Drug Dosage mg Active metabolite Bioavailability % Effect Tmax Half life Protein binding Vd (L) Excretion of food (h) (h) % (Renal/fecal) [%] Benazepril 10 Benazeprilat >37 None 0,5 10-11 >95 8,7 20/11-12 (benezeprilat) Captopril 100 NA 70 R 0,93-1 <2 25-30 0,76 >95R,as L/kg disulfides Cilazapril 2,5 Cilazaprilat 57-77,5 R 0,83 9 25,4 91/and F Delapril 30(60) Delapril diacid >55 SR 1.0–1.1 0,5 56/and F Delapril 5-hydroxy diacid (delapril) Enalapril 10 Enalaprilat 60 None 1 11-13 50-60 94/ and F Fosinopril 10 Fosinoprilat 32 SR 3 12 >95 10 50/50 Imidapril 10 Imidaprilat R 2 7-9 85 40/50 Lisinopril 10 NA ≈25 widely variable None 7 11-12 10 2,4±1,4 100/0 between individuals L/kg Moexipril 15 Moexiprilat 13-22 MR 1d 2-9 50 180 13/53 Pentopril 250 Pentopril diacid >58 1(1,28) <1 56a Perindopril 8 Perindoprilat 65-95 SR 1 1,5-3 60 0,22 L/kg 75/25 Quinapril 40 Quinaprilat >60 R 0,63 2 97 0,4L/kg 61/37 Quinapril diacid Ramipril 10 Ramiprilat >60 None 1 13-17 73 60/40 Spirapril 6 Spiraprilat 28-69 1 25-35 89 28c 40/85 Temocapril 20 Temocaprilat 1b 1.6 17- 24/36 - 44 Trandolapril 2 Trandolaprilat 10 R 0,5-1 6-10 80 trandolapril 18 33/66 65-94 trandolaprilat Zofenopril 30 Zofenoprilat 93%. 0.4e -1,5f 5.5 88 1,3L/kg 69/26 a. Estimated value obtained by calculation or by averaging a representative set of results; b. Reported as median; c. intravenous dose; d. Estimated value obtained from graph in study; e-solution; f-tablet tmax = time to Cmax; Vd = apparent volume of distribution; R = reduced, SR = slightly reduced, MR =markedly reduced; NA-not available Table.3. Comparative pharmacokinetics of the ACE inhibitors Adapted from: Luca Cavalieri & Giovanni Cremonesi., 2007; Paul L. McCormack and Gillian M. Keating., 2006 ; William H.Frishman, Angela Cheng-Lai, James Newarskas.,2005; Jessica C. Song &C. Michael White., 2002; Anne Stoysich & Fred Massoomi., 2002; Преображенский Д.В., 2000 ; UK Drug Information Pharmacists Group.,1999; HITOSHI ISHIZUKA., 1997; www.rxlist.com; E Ambrosioni & C.Borghi., 2001; A. Subiss & Evangelista S & Giachett A., 1999 University of Maryland medical center; www.umm.edu/altmed/drugs. 23 Classifying agents by duration of action— ACEIs were classified as short, intermediate, or long- acting based on five characteristics: onset of action, time-to-peak effect, half-life, duration of action, and dosing interval. Several characteristics of chosen medicines are in Table 4. [] Short-Acting Onset of action(h) T peak(h) Duration of action(h) Captopril 0,2-03 1 Dose related Intermediate-Acting

Benazepril 1 2-4 16-24 Enalapril 1 4-6 18-24 Moexipril 1 2 12-24 Quinapril 1-2 4 18-24 Ramipril 1-2 3-6 18-24 Long-Acting Fosinopril 1 2-6 24 Lisinopril 1 4-6 24 Perindopril 1 3-4 24 Trandolapril 2-4 6-8 24 Table.4. Duration of action of angiotensin converting enzyme inhibitors Adapted from: Anne Stoysich & Fred Massoomi., 2002.

KEY FACTORS EXAMINED IN ACEI CLASS COMPARISON Enalaprilat is the only ACEI available for intravenous dosing; Captopril was classified as the only short-acting agent; Captopril and lisinopril are the only ACEIs that are not prodrugs and therefore do not require hepatic activation; In patients with severe renal dysfunction, dosage adjustment may be necessary for all ACE inhibitors except fosinopril (because of its dual and equal routes of elimination); Lisinopril is the optimal agent for patients with hepatic dysfunction because its parent compound is exclusively renally eliminated; Fosinopril does not significantly accumulate in patients with hepatic impairment because it has compensatory dual routes of elimination; Only captopril and moexipril have shown potential drug-food interactions, with a decrease in the rate but not in extent of absorption. [20] Moreover, like captopril, but unlike all other ACE inhibitors, zofenopril contains a sulfhydryl moiety, which has been associated with the capacity to scavenge oxygen-free radicals. [27]

5. ANGIOTENSIN II ANTAGONISTS. HISTORY. CHEMICAL STRUCTURE. PHARMACOKINETICS.

5.1 History

In 1982, Furakawa, Kishimoto, and Nishikawa first described a nonapeptide angiotensin II receptor antagonist, S-8307, that became the structural model for what was to become an entirely new class of antihypertensive agents. Further development led to a panoply of promising orally active substances with improved effectiveness, optimised receptor kinetics, and longer durations of action. In the mid-1990s, losartan was the first of these pharmacological agents to be licensed and marketed, followed soon thereafter by valsartan, eprosartan, irbesartan, candesartan, and telmisartan (Table 2). Based on the convincing evidence of their safety and efficacy, angiotensin II type 1 (AT1) receptor antagonists have recently been included in the World Health Organisation's recommendations for the treatment of high blood pressure. [15]

5.2 Chemical structure The ARBs are non-peptide compounds with varied structures. There are some structural similarities among the ARBs: (a) candesartan, irbesartan, losartan, valsartan [21] and olmesartan [22] have a common tetrazolobiphenyl structure;

(b) candesartan and telmisartan have a common benzimidazole group;

(c) with the exception of irbesartan, all active ARBs have a free carboxylic acid group. The structure of eprosartan is distinct from other ARBs. [21]

25 Candesartan cilexetil

Losartan

Eprosartan mesylate

Telmisartan

Valsartan

Olmesartan

Irbesartan

Table.5. Chemical formulas of the angiotensin II antagonists

26 5.3 Pharmacokinetics of angiotensin II antagonists

abolite

Drug mg Dosage met Active Receptor antagonism Bioavailability% of food Effect (h) Tmax (h) Halflife binding% Protein (L) d V Excretion [%] (Renal/fecal) Losartan 25-100 E-3174 Both b 33 AUC/Cmax ↓ 10% 1–2 1–3 (6–9) Both ≥99 34 (12) 40/60 (3–4) Valsartan 80-320 No Non- 10-35 AUC/Cmax ↓40–50% 2–4 6–9 94–97 17 13/83 competitive Irbesartan 150-300 No Non- 60-80 No 1.5–2 11–15 90–96 53–93 20/80 competitive Candesartan 8-32 Candesartan Non- 15 No 3–5 5–9 >99 0.13 L/kg 33/67 cilexetil competitive Telmisartan 20-80 No Non- 40–60 AUC ↓ 6–19% 0.5–1 20–38 >99.5 500–2000 <2/98 competitive Eprosartan 400-800 No Competitive 13 AUC/Cmax ↓ 25% 1–3 5–9 98 13 7/90 Olmesartan 20-40 Olmesartan Competitive 26–29 No 1–3 10–15 99 17 35–50/50–65 medoxomil

b Losartan = competitive; E-3174 = non-competitive. ↓ indicates decrease;  indicates increase. Table.6. Comparative pharmacokinetics of the angiotensin II antagonists Adapted from: G. Neil Thomas, Paul Chan and Brian Tomlinson., 2006.

27 KEY FACTORS EXAMINED IN AIIA CLASS COMPARISON

Candesartan cilexetil and olmesartan medoxomil are the ester prodrugs Eprosartan, olmesartan and losartan are competitive or surmountable antagonists of the receptor. All these agents are still effective with once daily administration, although losartan and eprosartan may provide better 24-hour effect if given twice daily, especially when lower doses are used. AT1 receptor antagonists are predominantly eliminated by biliary excretion, although compared with others in the class, losartan and olmesartan medoxomil show more substantial renal excretion. [22]

6. HEAD-TO-HEAD EFFICACY COMPARISONS Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) play a role in the treatment of hypertension (HTN) and heart failure (HF). The literature shows that in patients with HTN with co morbidities, such as HF, myocardial infarction (MI), diabetes mellitus, chronic kidney disease, and stroke, ACE inhibitors and ARBs appear to provide added benefit beyond solely lowering blood pressure. In addition, clinical trials have also demonstrated that ACE inhibitors and ARBs may be beneficial in the prevention of diabetes, atrial fibrillation (AF), and recurrent stroke. [23]

Table.7. Licensed indications of ACE inhibitors and angiotensin II receptor antagonists and WHO Defined Daily Doses for Hypertension Adapted from: APC/DTC Briefing Document., 2008

1. The differences between ACEIs and ARBs in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes for adult patients with essential hypertension. 2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence for adult patients with essential hypertension. 3. The differences of effectiveness and tolerability of ACEIs or ARBs for subgroups of patients based on demographic characteristics (age, racial and ethnic groups, sex). [24]

Table.8. Number of included studies (number of publications) that evaluated various treatment comparisons [24]

Key Points

Effect on Blood Pressure • There was no clear difference in the blood pressure lowering efficacy between ACEIs and ARBs.

Mortality and Major Cardiovascular Events • Few deaths or major cardiovascular events occurred in the identified studies comparing ACEIs to ARBs; this precluded any assessment of a differential effect of ACEIs and ARBs on these events.

Effect on Quality of Life • No significant difference was observed between ACEIs and ARBs in terms of their impact on quality of life.

Effect on Rate of Use of a Single Antihypertensive Agent • There was no statistically evident difference in rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs.

Effect on Lipid Levels • Available evidence suggests that ACEIs and ARBs have a similar lack of impact on lipid levels for individuals with essential hypertension.

Diabetes Control • Available evidence suggests that ACEIs and ARBs have a similar lack of impact on glucose levels or HgbA1c for individuals with essential hypertension.

LV mass/function outcomes • Evidence does not demonstrate a difference between ACEIs and ARBs with regard to their effect on LV mass or function for individuals with essential hypertension.

Renal disease • There are no consistently demonstrated differential effects related to renal function as measured by creatinine or GFR with use of ACEIs versus ARBs. • There is a consistent finding of no differential effect related to reduction of urinary protein or albumin excretion among patients with essential hypertension with use of ACEIs versus ARBs. [24]

2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence for adult patients with essential hypertension. [24]

Key Points

• Cough was modestly more frequently observed as an adverse event in groups treated with ACEIs than in groups treated with ARBs. • Withdrawals due to adverse events were modestly more frequent for groups receiving an ACEI rather than an ARB; this is consistent with differential rates of cough. • No significant between-class differences were observed in the rates of any other commonly reported adverse events. • Angioedema was reported only in patients treated with ACEIs; however, because angioedema was rarely explicitly reported in the included studies, it was not possible to estimate its frequency in this population. [24]

Table.9. Studies reporting angioedema [24]

Figure 7. Studies reporting on cough with ACEIs vs. ARBs [24]

Figure 8. Studies reporting withdrawals due to adverse events for ACEIs vs. ARBs [24]

3. The differences of effectiveness and tolerability of ACEIs or ARBs for subgroups of patients based on demographic characteristics (age, racial and ethnic groups, sex). [24]

Key Points • Evidence does not support conclusions regarding the comparative effectiveness, adverse events, or tolerability of ACEIs and ARBs for any particular patient subgroup.[24]

Key question Strength of Conclusions evidence 1. The differences between ACEIs and ARBs in the following health outcomes: a. Blood pressure control High ACEIs and ARBs appear to have similar long- term effects on blood pressure among individuals with essential hypertension. This conclusion is based on evidence from 50 studies (47 RCTs, 1 nonrandomized controlled clinical trial, 1

33 retrospective cohort study, and 1 case-control study) in which 13,532 patients receiving an ACEI or an ARB were followed for periods from 12 weeks to 5 years (median 16.5 weeks). Blood pressure outcomes were confounded by additional treatments and varying dose escalation protocols. b. Mortality and major Moderate Due to insufficient numbers of deaths or major cardiovascular events cardiovascular events in the included studies, it was not possible to discern any differential effect of ACEIs vs. ARBs for these critical outcomes. In 9 studies that reported mortality, MI, or clinical stroke as outcomes among 3,356 subjects, 16 deaths and 13 strokes were reported. This may reflect low event rates among otherwise healthy patients and relatively few studies with extended followup. c. Quality of life Low No differences were found in measures of general quality of life; this is based on 4 studies, 2 of which did not provide quantitative data. d. Rate of use of a single High There was no statistically evident difference in antihypertensive the rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs. The trend toward less frequent addition of a second agent to an ARB was heavily influenced by retrospective cohort studies, where medication discontinuation rates were higher in ACEI-treated patients, and by RCTs with very loosely defined protocols for medication titration and switching e. Risk factor reduction and Moderate (lipid There were no consistent differential effects of other intermediate outcomes levels, markers ACEIs vs. ARBs on several potentially important of carbohydrate clinical outcomes, including lipid levels, metabolism/ progression to type 2 diabetes mellitus, markers diabetes of carbohydrate metabolism/diabetes control, control, measures of LV mass or function, and

34 progression of progression of renal disease (either based on renal disease) creatinine, GFR, or proteinuria). Relatively few to Low studies assessed these outcomes over the long (progression to term. type 2 diabetes and LV mass/function 2. The differences between High (cough, ACEIs have been consistently shown to be ACEIs and ARBs in safety, withdrawals associated with greater risk of cough than ARBs: adverse events, tolerability, due to adverse pooled odds ratio (Peto) = 0.32. For RCTs, this persistence, and adherence events) to translates to a difference in rates of cough of 6.7 Moderate percent (NNT = 15); however, for cohort studies (persistence/ with lower rates of cough, this translates to a adherence) to difference of 1.1 percent (NNT = 87). This is Low generally consistent with evidence reviewed (angioedema) regarding withdrawals due to adverse events, in which the NNT is on the order of 27—that is, 1 more withdrawal per 27 patients treated with an ACEI vs. An ARB. There was no evidence of differences in rates of other commonly reported specific adverse events.

Angioedema was reported only in patients treated with ACEIs; however, because angioedema was rarely explicitly reported in the included studies, it was not possible to estimate its frequency in this population.

ACEIs and ARBs have similar rates of adherence based on pill counts; this result may not be applicable outside the clinical trial setting. Rates of continuation with therapy appear to be somewhat better with ARBs than with ACEIs; however, due to variability in definitions, limitations inherent in longitudinal cohort studies,

35 and relatively small sample sizes for ARBs, the precise magnitude of this effect is difficult to quantify. 3. The differences of Very low Evidence does not support conclusions regarding effectiveness and tolerability of the comparative effectiveness, adverse events, or ACEIs or ARBs for subgroups tolerability of ACEIs and ARBs for any particular of patients based on patient subgroup. demographic characteristics (age, racial and ethnic groups, sex).

Abbreviations: ACEI(s) = angiotensin-converting enzyme inhibitor(s); ARB(s) = angiotensin II receptor blocker(s)/antagonist(s); GFR = glomerular filtration rate; LV = left ventricular; MI = myocardial infarction; NNT = number-needed-to-treat; RCT(s) = randomized controlled trial(s) Table.10. Summary of evidence on comparative long-term benefits and harms of ACEIs vs. ARBs for essential hypertension [24]

36 7. RESULTS 7.1 Comparison of consumption over the three years period

Figure 9. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2005-2007

180,00 166,01

153,44 150,77 160,00

137,87 131,57 140,00 121,70 117,91

112,34 111,10 109,20 120,00 106,22

96,30 100,00

80,00

DDD/1000 inhabitants/day DDD/1000 60,00

40,00

20,00

0,00 Lithuania Denmark Finland Norway

2005 2006 2007

Population: 3.375.700; 2007 in Lithuania Population: 3.403.300; 2006 in Lithuania Population: 3.425.300; 2005 in Lithuania

37 Figure 10. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2005

97,57 100,00

90,00

75,34 80,00

70,00

55,10 60,00

50,00 42,89

40,00 30,97 30,62

DDD/1000 inhabitants/day DDD/1000 25,36 30,00 22,10

16,82 20,00 12,52 12,50

14,74 10,00 1,005 0,001 6,70 7,35 0,00 Lithuania Denmark Finland Norway

ACEI, ACEI, AIIA, AIIA, plain combinations plain combinations

38 Figure 11. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2006

120,00 107,94

100,00

78,88

80,00

62,00

60,00

43,40

37,54 33,58

DDD/1000 inhabitants/day DDD/1000 40,00 28,25 24,60 19,95 16,45 14,10 20,00 7,08 14,40 0,10 8,50 7,11 0,00 Lithuania Denmark Finland Norway

ACEI, ACEI, AIIA, AIIA, plain combinations plain combinations

39 Figure 12. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in 2007

118,33 120,00

100,00 86,20

80,00 67,40

60,00

42,61 43,92

36,39

DDD/1000 inhabitants/day 40,00 27,60 30,61

21,44 22,23

16,00 20,00 12,03 14,97 1,64 10,60 6,99 0,00 Lithuania Denmark Finland Norway

ACEI, ACEI, AIIA, AIIA, plain combinations plain combinations

40 7.2 Comparison of consumption over the three years period in Lithuania Figure 13. Utilization of Agents acting on the Renin-angiotensin-aldosterone system in 2005-2007 in Lithuania

160,00

153,44 150,00

140,00

131,57 DDD/1000 130,00 inhabitants/day

120,00

111,10 110,00

100,00 2005 2006 2007

Population: 3.375.700; 2007 Population: 3.403.300; 2006 Population: 3.425.300; 2005

Figure 14. Comparison of consumption between groups of agents acting the Renin-angiotensin-aldosterone system in 2005-2007 in Lithuania

1,64

AIIA, 0,10 combinations 0,001

12,03

AIIA, 7,08 plain 1,005 2007 2006 21,44 2005 ACEI, 16,45 combinations 12,52

118,33 ACEI, 107,94 plain 97,57

0,00 20,00 40,00 60,00 80,00 100,00 120,00 DDD/1000 inhabitants/day

42 Figure 15. The actual amounts spent on agents acting on the ReninTotal-angiotensin-aldosterone system per 2005-2007 in Lithuania.

120 000 000,00 Lt 116 620 998,01 Lt

115 000 000,00 Lt

110 000 000,00 Lt

105 000 000,00 Lt

100 000 000,00 Lt 97 327 882,70 Lt 95 000 000,00 Lt

90 000 000,00 Lt

85 000 000,00 Lt

80 000 000,00 Lt 79 436 195,37 Lt 75 000 000,00 Lt

70 000 000,00 Lt 2005 2006 2007

43 7.3 Pharmacoeconomic calculations suggesting the reference price 1.Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s per 2007. Utilization of Angiotensin converting enzyme inhibitor‘s combined with diuretics or calcium channel blockers and Angiotensin II antagonist‘s combined with diuretics per 2007.

Table.11. The calculated data of Utlization of Angiotensin converting enzyme inhibitor‘s (plain and combinations with diuretics and calcium channel blockers) per 2007

Drug DDD/1000 Drug DDD quantity/ inhabitants/ Spend in Price/DDD Nr. Agent quantity, mg mg DDD 1 day % (LTL) (LTL) 1 Captopril 440346125 50 8806922,50 7,1 5,11% 3 819 908,26 0,43 2 Enalapril 322600168,7 10 32260016,87 26,2 18,73% 9 164 817,80 0,28 3 Lisinopril 50347050 10 5034705,00 4,1 2,92% 2 643 673,30 0,53 4 Perindopril 81019590 4 20254897,50 16,4 11,76% 15 560 019,05 0,77 5 Ramipril 128708074 2,5 51483229,60 41,8 29,90% 16 835 944,06 0,33 6 Quinapril 159296398 15 10619759,87 8,6 6,17% 7 860 526,81 0,74 7 Fosinopril 146442983,2 15 7783336,21 6,3 4,52% 6 879 577,40 0,88 8 Trandolapril 3647616 2 1823808,00 1,5 1,06% 1 634 913,60 0,90 9 Spirapril 8032019,994 6 1338670,00 1,1 0,78% 1 098 601,85 0,82 10 Zofenopril 191604840 30 6386828,00 5,2 3,71% 9 247 214,54 1,45 Enalapril and 11 diuretics 35709899,64 10 3570989,964 2,9 2,07% 1 252 277,88 0,35 Perindopril and 12 diuretics 42909675 4 10727418,75 8,7 6,23% 15 312 229,20 1,43 Ramipril and 13 diuretics 1379035 2,5 551614 0,4 0,32% 236 504,74 0,43 Quinapril and 14 diuretics 126048595,6 15 8403239,707 6,8 4,88% 6 625 851,15 0,79 Fosinopril and 15 diuretics 38891120 15 2592741,333 2,1 1,51% 2 304 817,17 0,89 Trandolapril and calcium channel 16 blockers 1144360 2 572180 0,5 0,33% 726 259,90 1,27

44 Table.12. The calculated data of Utlization of Angiotensin II antagonist‘s (plain and combinations with diuretics) per 2007

DDD/100 Drug Drug 0 quantity, DDD quantity/ inhabitan Spend in Price/DDD Nr. Agent mg mg DDD ts/1 day % (LTL) (LTL) 11914583,9 70,74 1 Losartan 595729199 50 9,7 8 % 8 313 815,63 0,70 2 61958400 0,6 Eprosartan 103264,00 0,1 0,61% 269 482,16 2,61 3 71977920 80 Valsartan 899724,00 0,7 5,34% 1 407 699,68 1,56 4 72231600 0,15 Irbesartan 481544,00 0,4 2,86% 957 756,62 1,99 Candesarta 5 2344160 8 293020,00 0,2 1,74% n 406 634,73 1,39 6 17680320 40 Telmisartan 442008,00 0,4 2,62% 729 186,06 1,65 Olmesartan 7 13729520 20 686476,00 0,6 4,08% medoxomil 1 794 760,56 2,61 Losartan 11,70 8 and 98498900 50 1969978 1,6 % diuretics 1 407 226,43 0,71 Valsartan 9 and 3888640 80 48608 0,04 0,29% diuretics 120 947,12 2,49 Telmisartan 10 and 38080 40 952 0,001 0,01% diuretics 1 959,93 2,06 Olmesartan medoxomil 11 65520 20 3276 0,003 0,02% and diuretics 8 392,41 2,56

45 1. DDD/1000inhabitants/day Figure 16. Utilization of Angiotensin converting enzyme inhibitor‘s per 2007 (DDD/1000inhabitants/day)

45,0 41,8

40,0

35,0

30,0 26,2

DDD/1000/day 25,0

20,0 16,4

15,0

7,1 8,6 10,0 6,3 5,2 4,1 5,0 1,5 1,1

0,0 Captopril Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Spirapril Zofenopril

Population: 3.375.700; 365 days of the 2007.

Figure 17. Utilization of Angiotensin II antagonist‘s per 2007 (DDD/1000inhabitants/day) Utilization of Angiotensin II antagonist's per 2007 (DDD/1000/day)

9,7 10,0

9,0

8,0

7,0

6,0

DDD/1000/day 5,0

4,0

3,0

2,0 0,7 0,4 0,6 1,0 0,1 0,2 0,4

0,0 Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan medoxomil

Population: 3.375.700; 365 days of the 2007.

47 Figure 18. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics or calcium channel blockers per 2007 (DDD/1000inhabitants/day)

8,7 9,0

8,0 6,8

7,0

6,0

5,0

4,0 DDD/1000/day 2,9

3,0 2,1

1,6 2,0

1,0 0,4 0,5 0,04 0,001 0,003

0,0 Enalapril Perindopril Ramipril Quinapril Fosinopril Trandolapril Losartan Valsartan Telmisartan Olmesartan and and and and and and calcium and and and medoxomil diuretics diuretics diuretics diuretics diuretics channel diuretics diuretics diuretics and blockers diuretics

Population: 3.375.700; 365 days of the 2007.

48 Figure 19. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s and combinations with diuretics and calcium channel blockers per 2007 (DDD/1000inhabitants/day)

DDD/1000 inhabitants/day

12,03; 1,64; 8% 1% 21,44; 14%

ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations

118,33; 77%

Population: 3.375.700; 365 days of the 2007.

49 Figure 20. Utilization of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s (plain and combinations with diuretics and calcium channel blockers) per 2007 (DDD/1000inhabitants/day)

13,6; 9%

ACEI (plain and combinations with diuretics or calcium channel blockers) AIIA (plain and combinations with diuretics)

139,7; 91%

Population: 3.375.700; 365 days of the 2007.

50 2. The actual amounts of money spent on Angiotensin converting enzyme inhibitor’s and Angiotensin II antagonist’s in 2007 Figure 21. The amount of money spent on Angiotensin converting enzyme inhibitor‘s in 2007

18 000 000,00 Lt 16 835 944,06 Lt

15 560 019,05 Lt 16 000 000,00 Lt

14 000 000,00 Lt

12 000 000,00 Lt

9 247 214,54 Lt 10 000 000,00 Lt 9 164 817,80 Lt 7 860 526,81 Lt

8 000 000,00 Lt 6 879 577,40 Lt

6 000 000,00 Lt 3 819 908,26 Lt

4 000 000,00 Lt 2 643 673,30 Lt 1 634 913,60 Lt

1 098 601,85 Lt 2 000 000,00 Lt

0,00 Lt Captopril Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Spirapril Zofenopril

Figure 22. The amount of money spent on Angiotensin II antagonist‘s in 2007

9 000 000,00 Lt 8 313 815,63 Lt

8 000 000,00 Lt

7 000 000,00 Lt

6 000 000,00 Lt

5 000 000,00 Lt

4 000 000,00 Lt

3 000 000,00 Lt 1 794 760,56 Lt

1 407 699,68 Lt 2 000 000,00 Lt 957 756,62 Lt 729 186,06 Lt

406 634,73 Lt 1 000 000,00 Lt 269 482,16 Lt

0,00 Lt Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan medoxomil

52 Figure 23. The amount of money spent on Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics or calcium channel blockers in 2007

16 000 000,00 Lt 15 312 229,20 Lt

14 000 000,00 Lt

12 000 000,00 Lt

10 000 000,00 Lt

8 000 000,00 Lt 6 625 851,15 Lt

6 000 000,00 Lt

4 000 000,00 Lt 1 407 226,43 Lt 2 304 817,17 Lt

1 252 277,88 Lt 2 000 000,00 Lt 726 259,90 Lt 120 947,12 Lt 236 504,74 Lt 1 959,93 Lt 8 392,41 Lt 0,00 Lt Losartan Valsartan TelmisartanOlmesartan Quinapril Fosinopril Trandolapril Enalapril Perindopril Ramipril and and and medoxomil and and and and and and diuretics diuretics diuretics and diuretics diuretics calcium diuretics diuretics diuretics diuretics channel blockers

53 Figure 24. The amount of money spent on Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s and combinations with diuretics and calcium channel blockers in 2007

1 538 525,89 Lt; 1% 26 457 940,03 Lt; 23%

ACEI plain AIIA plain ACEI combinations AIIA combinations

13 879 335,43 Lt; 12% 74 745 196,65 Lt; 64%

54 Figure 25. The amount of money spent on of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s (plain and combinations with diuretics and calcium channel blockers) in 2007

27 996 465,92 Lt; 24%

ACEI and AIIA plain ACEI and AIIA combinations

88 624 532,08 Lt; 76%

55 3. Pharmacoeconomic analysis of angiotensin converting enzyme inhibitor‘s and angiotensin II receptor antagonist‘s by cost minimisation and reference price analysis. a) Reference prices of Angiotensin converting enzyme inhibitor‘s

DDD per 1DDD Reference Name of agent 2007 price Spent Reference price Spent price Spent Captopril 8806922,50 0,43 Lt 3 819 908,26 Lt 0,33 Lt 2 880 022,40 Lt 0,43 Lt 3 819 908,26 Lt Enalapril 32260016,87 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt Lisinopril 5034705,00 0,53 Lt 2 643 673,30 Lt 0,33 Lt 1 646 439,29 Lt 0,53 Lt 2 643 673,30 Lt 15 560 019,05 10 635 644,34 Perindopril 20254897,50 0,77 Lt Lt 0,33 Lt 6 623 716,57 Lt 0,53 Lt Lt 16 835 944,06 16 835 944,06 16 835 944,06 Ramipril 51483229,60 0,33 Lt Lt 0,33 Lt Lt 0,33 Lt Lt Quinapril 10619759,87 0,74 Lt 7 860 526,81 Lt 0,33 Lt 3 472 852,90 Lt 0,53 Lt 5 576 329,82 Lt Fosinopril 7783336,21 0,88 Lt 6 879 577,40 Lt 0,33 Lt 2 545 291,24 Lt 0,53 Lt 4 086 952,09 Lt Trandolapril 1823808,00 0,90 Lt 1 634 913,60 Lt 0,33 Lt 596 418,09 Lt 0,53 Lt 957 663,36 Lt Spirapril 1338670,00 0,82 Lt 1 098 601,85 Lt 0,33 Lt 437 769,22 Lt 0,53 Lt 702 922,24 Lt Zofenopril 6386828,00 1,45 Lt 9 247 214,54 Lt 0,33 Lt 2 088 607,88 Lt 0,53 Lt 3 353 659,58 Lt 74 745 196,65 46 291 879,44 57 777 514,84 Total Lt Total Lt Total Lt 16 967 681,81 Save: Save: 28 453 317,22 Lt Save: Lt

56 b) Reference prices of Angiotensin II antagonist‘s DDD per 1DDD Name of agent 2007 price Spent Referent price Spent Referent price Spent Losartan 11914583,98 0,70 Lt 8 313 815,63 Lt 0,70 Lt 8 313 815,63 Lt 0,70 Lt 8 313 815,63 Lt Eprosartan 103264,00 2,61 Lt 269 482,16 Lt 0,70 Lt 72 056,05 Lt 1,39 Lt 143 303,29 Lt Valsartan 899724,00 1,56 Lt 1 407 699,68 Lt 0,70 Lt 627 813,73 Lt 1,39 Lt 1 248 580,39 Lt Irbesartan 481544,00 1,99 Lt 957 756,62 Lt 0,70 Lt 336 014,08 Lt 1,39 Lt 668 256,48 Lt Candesartan 293020,00 1,39 Lt 406 634,73 Lt 0,70 Lt 204 464,90 Lt 1,39 Lt 406 634,73 Lt Telmisartan 442008,00 1,65 Lt 729 186,06 Lt 0,70 Lt 308 426,46 Lt 1,39 Lt 613 390,91 Lt Olmesartan medoxomil 686476,00 2,61 Lt 1 794 760,56 Lt 0,70 Lt 479 012,52 Lt 1,39 Lt 952 648,23 Lt 13 879 335,43 10 341 603,38 12 346 629,65 Total Lt Total Lt Total Lt Save: 3 537 732,05 Lt Save: 1 532 705,78 Lt

57 c) Reference prices of Angiotensin converting enzyme inhibitor‘s combinations with diuretics or calcium channel blockers DDD per 1DDD Reference Name of agent 2007 price Spent Reference price Spent price Spent Enalapril and diuretics 3570989,964 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 15 312 229,20 Perindopril and diuretics 10727418,75 1,43 Lt Lt 0,35 Lt 3 761 900,57 Lt 0,79 Lt 8 458 437,74 Lt Ramipril and diuretics 551614 0,43 Lt 236 504,74 Lt 0,35 Lt 193 440,48 Lt 0,43 Lt 236 504,74 Lt Quinapril and diuretics 8403239,707 0,79 Lt 6 625 851,15 Lt 0,35 Lt 2 946 855,43 Lt 0,79 Lt 6 625 851,15 Lt Fosinopril and diuretics 2592741,333 0,89 Lt 2 304 817,17 Lt 0,35 Lt 909 224,79 Lt 0,79 Lt 2 044 344,65 Lt Trandolapril and calcium channel blockers 572180 1,27 Lt 726 259,90 Lt 0,35 Lt 200 652,58 Lt 0,79 Lt 451 156,89 Lt 26 457 940,03 19 068 573,04 26418183,75 Total Lt Total 9 264 351,73 Lt Total Lt Save: 17 193 588,30 Lt Save: 4 952 827,10 Lt

58 d) Reference prices of Angiotensin II antagonist‘s combinations with diuretics

DDD per 1DDD Name of agent 2007 price Spent Reference price Spent Losartan and diuretics 1969978 0,71 Lt 1 407 226,43 Lt 0,71 Lt 1 407 226,43 Lt Valsartan and diuretics 48608 2,49 Lt 120 947,12 Lt 0,71 Lt 34 722,45 Lt Telmisartan and diuretics 952 2,06 Lt 1 959,93 Lt 0,71 Lt 680,05 Lt Olmesartan medoxomil and diuretics 3276 1,28 Lt 4 196,21 Lt 0,71 Lt 2 340,17 Lt 2022814 Total 1 534 329,69 Lt Total 1 444 969,09 Lt Save: 89 360,59 Lt

59 e) One reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s Name of DDD per 1DDD Reference Reference Reference agent 2007 price Spent price Spent price Spent price Spent Captopril 8806922,50 0,43 Lt 3 819 908,26 Lt 0,33 Lt 2 880 022,40 Lt 0,43 Lt 3 819 908,26 Lt 0,43 Lt 3 819 908,26 Lt Enalapril 32260016,87 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt 0,28 Lt 9 164 817,80 Lt Lisinopril 5034705,00 0,53 Lt 2 643 673,30 Lt 0,33 Lt 1 646 439,29 Lt 0,53 Lt 2 643 673,30 Lt 0,53 Lt 2 643 673,30 Lt Perindopril 20254897,50 0,77 Lt 15 560 019,05 Lt 0,33 Lt 6 623 716,57 Lt 0,53 Lt 10 635 644,34 Lt 0,70 Lt 14 133 559,65 Lt Ramipril 51483229,60 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt 0,33 Lt 16 835 944,06 Lt Quinapril 10619759,87 0,74 Lt 7 860 526,81 Lt 0,33 Lt 3 472 852,90 Lt 0,53 Lt 5 576 329,82 Lt 0,70 Lt 7 410 307,04 Lt Fosinopril 7783336,21 0,88 Lt 6 879 577,40 Lt 0,33 Lt 2 545 291,24 Lt 0,53 Lt 4 086 952,09 Lt 0,70 Lt 5 431 093,72 Lt Trandolapril 1823808,00 0,90 Lt 1 634 913,60 Lt 0,33 Lt 596 418,09 Lt 0,53 Lt 957 663,36 Lt 0,70 Lt 1 272 625,50 Lt Spirapril 1338670,00 0,82 Lt 1 098 601,85 Lt 0,33 Lt 437 769,22 Lt 0,53 Lt 702 922,24 Lt 0,70 Lt 934 103,58 Lt Zofenopril 6386828,00 1,45 Lt 9 247 214,54 Lt 0,33 Lt 2 088 607,88 Lt 0,53 Lt 3 353 659,58 Lt 0,70 Lt 4 456 631,51 Lt

Losartan 11914583,98 0,70 Lt 8 313 815,63 Lt 0,33 Lt 3 896 283,72 Lt 0,53 Lt 6 256 229,02 Lt 0,70 Lt 8 313 815,63 Lt Eprosartan 103264,00 2,61 Lt 269 482,16 Lt 0,33 Lt 33 769,19 Lt 0,53 Lt 54 222,89 Lt 0,70 Lt 72 056,05 Lt Valsartan 899724,00 1,56 Lt 1 407 699,68 Lt 0,33 Lt 294 225,97 Lt 0,53 Lt 472 436,08 Lt 0,70 Lt 627 813,73 Lt Irbesartan 481544,00 1,99 Lt 957 756,62 Lt 0,33 Lt 157 473,57 Lt 0,53 Lt 252 853,94 Lt 0,70 Lt 336 014,08 Lt Candesartan 293020,00 1,39 Lt 406 634,73 Lt 0,33 Lt 95 822,82 Lt 0,53 Lt 153 861,87 Lt 0,70 Lt 204 464,90 Lt Telmisartan 442008,00 1,65 Lt 729 186,06 Lt 0,33 Lt 144 544,58 Lt 0,53 Lt 232 093,99 Lt 0,70 Lt 308 426,46 Lt Olmesartan medoxomil 686476,00 2,61 Lt 1 794 760,56 Lt 0,33 Lt 224 490,03 Lt 0,53 Lt 360 461,69 Lt 0,70 Lt 479 012,52 Lt Total 88 624 532,08 Lt Total 51 138 489,31 Lt Total 65 559 674,34 Lt Total 76 444 267,80 Lt Save: 37 486 042,78 Lt Save: 23 064 857,75 Lt Save: 12 180 264,28 Lt

60 f) one reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics and calcium channel blockers DDD per 1DDD Name of agent 2007 price Spent Referent price Spent Referent price Spent Enalapril and diuretics 3570989,964 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 0,35 Lt 1 252 277,88 Lt 15 312 229,20 Perindopril and diuretics 10727418,75 1,43 Lt Lt 0,35 Lt 3 761 900,57 Lt 0,71 Lt 7 662 982,63 Lt Ramipril and diuretics 551614 0,43 Lt 236 504,74 Lt 0,35 Lt 193 440,48 Lt 0,43 Lt 236 504,74 Lt Quinapril and diuretics 8403239,707 0,79 Lt 6 625 851,15 Lt 0,35 Lt 2 946 855,43 Lt 0,71 Lt 6 002 737,60 Lt Fosinopril and diuretics 2592741,333 0,89 Lt 2 304 817,17 Lt 0,35 Lt 909 224,79 Lt 0,71 Lt 1 852 088,77 Lt Trandolapril and calcium channel blockers 572180 1,27 Lt 726 259,90 Lt 0,35 Lt 200 652,58 Lt 0,71 Lt 408 728,84 Lt Losartan and diuretics 1969978 0,71 Lt 1 407 226,43 Lt 0,35 Lt 690 833,60 Lt 0,71 Lt 1 407 226,43 Lt Valsartan and diuretics 48608 2,49 Lt 120 947,12 Lt 0,35 Lt 17 045,90 Lt 0,71 Lt 34 722,45 Lt Telmisartan and diuretics 952 2,06 Lt 1 959,93 Lt 0,35 Lt 333,85 Lt 0,71 Lt 680,05 Lt Olmesartan medoxomil and diuretics 3276 1,28 Lt 4 196,21 Lt 0,35 Lt 1 148,83 Lt 0,71 Lt 2 340,17 Lt 27 992 269,72 18 860 289,55 Total Lt Total 9 973 713,91 Lt Total Lt Save: 18 018 555,81 Lt Save: 9 131 980,17 Lt

61 4. Predictable savings Figure 26. Actual spend comparing with amount of money could be spent if reference prices were adapted for ACEI and AIIA separately

80 000 000,00 Lt < 1,45Lt

70 000 000,00 Lt

< 0,53Lt 60 000 000,00 Lt

< 0,33Lt 50 000 000,00 Lt

40 000 000,00 Lt

< 1,43Lt 30 000 000,00 Lt < 0,79Lt < 2,61Lt 20 000 000,00 Lt < 1,39Lt < 0,70Lt < 0,35Lt

10 000 000,00 Lt < 2,49Lt < 0,71Lt

0,00 Lt ACEI plain AIIA plain ACEI combinations AIIA combinations 1 DDD price 74 745 196,65 Lt 13 879 335,43 Lt 26 457 940,03 Lt 1 534 329,69 Lt 1 Reference price 57 777 514,84 Lt 12 346 629,65 Lt 19 068 573,04 Lt 1 444 969,09 Lt 2 Reference price 46 291 879,44 Lt 10 341 603,38 Lt 9 264 351,73 Lt

62 Table.13. The reference prices of Angiotensin converting enzyme inhibitor‘s Name of agent 1DDD price 1 Reference price 2 Reference price Captopril 0,43 Lt 0,43 Lt 0,33 Lt Enalapril 0,28 Lt 0,28 Lt 0,28 Lt Lisinopril 0,53 Lt 0,53 Lt 0,33 Lt Perindopril 0,77 Lt 0,53 Lt 0,33 Lt Ramipril 0,33 Lt 0,33 Lt 0,33 Lt Quinapril 0,74 Lt 0,53 Lt 0,33 Lt Fosinopril 0,88 Lt 0,53 Lt 0,33 Lt Trandolapril 0,90 Lt 0,53 Lt 0,33 Lt Spirapril 0,82 Lt 0,53 Lt 0,33 Lt Zofenopril 1,45 Lt 0,53 Lt 0,33 Lt

Table.14. The reference prices of Angiotensin II antagonist‘s Name of agent 1DDD price 1 Reference price 2 Reference price Losartan 0,70 Lt 0,70 Lt 0,70 Lt Eprosartan 2,61 Lt 1,39 Lt 0,70 Lt Valsartan 1,56 Lt 1,39 Lt 0,70 Lt Irbesartan 1,99 Lt 1,39 Lt 0,70 Lt Candesartan 1,39 Lt 1,39 Lt 0,70 Lt Telmisartan 1,65 Lt 1,39 Lt 0,70 Lt Olmesartan medoxomil 2,61 Lt 1,39 Lt 0,70 Lt

Table.15. The reference prices of ACEI combinations with diuretics and calcium channel blockers Name of agent 1DDD price 1 Reference price 2 Reference price Enalapril and diuretics 0,35 Lt 0,35 Lt 0,35 Lt Perindopril and diuretics 1,43 Lt 0,79 Lt 0,35 Lt Ramipril and diuretics 0,43 Lt 0,43 Lt 0,35 Lt Quinapril and diuretics 0,79 Lt 0,79 Lt 0,35 Lt Fosinopril and diuretics 0,89 Lt 0,79 Lt 0,35 Lt Trandolapril and calcium channel blockers 1,27 Lt 0,79 Lt 0,35 Lt

Table.16. The reference prices of AIIA combinations with diuretics Name of agent 1DDD price 1 Reference price Losartan and diuretics 0,71 Lt 0,71 Lt Valsartan and diuretics 2,49 Lt 0,71 Lt Telmisartan and diuretics 2,06 Lt 0,71 Lt Olmesartan medoxomil and diuretics 1,28 Lt 0,71 Lt

63 Figure 27. Actual spend comparing with amount of money could be spent if one reference price was adapted for ACEI and AIIA

90 000 000,00 Lt < 2,61Lt

80 000 000,00 Lt < 0,70Lt

70 000 000,00 Lt < 0,53Lt 60 000 000,00 Lt

50 000 000,00 Lt < 0,33Lt

40 000 000,00 Lt

30 000 000,00 Lt < 2,49Lt

20 000 000,00 Lt < 0,71Lt

10 000 000,00 Lt < 0,35Lt

0,00 Lt ACEI and AIIA plain ACEI and AIIA combinations 1 DDD price 88 624 532,08 Lt 27 992 269,72 Lt 1 Reference price 76 444 267,80 Lt 18 860 289,55 Lt 2 Reference price 65 559 674,34 Lt 9 973 713,91 Lt 3 Reference price 51 138 489,31 Lt

64 Table.17. One reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s

Name of agent 1DDD price 1 Reference price 2 Reference price 3 Reference price Captopril 0,43 Lt 0,43 Lt 0,43 Lt 0,33 Lt Enalapril 0,28 Lt 0,28 Lt 0,28 Lt 0,28 Lt Lisinopril 0,53 Lt 0,53 Lt 0,53 Lt 0,33 Lt Perindopril 0,77 Lt 0,70 Lt 0,53 Lt 0,33 Lt Ramipril 0,33 Lt 0,33 Lt 0,33 Lt 0,33 Lt Quinapril 0,74 Lt 0,70 Lt 0,53 Lt 0,33 Lt Fosinopril 0,88 Lt 0,70 Lt 0,53 Lt 0,33 Lt Trandolapril 0,90 Lt 0,70 Lt 0,53 Lt 0,33 Lt Spirapril 0,82 Lt 0,70 Lt 0,53 Lt 0,33 Lt Zofenopril 1,45 Lt 0,70 Lt 0,53 Lt 0,33 Lt

Losartan 0,70 Lt 0,70 Lt 0,53 Lt 0,33 Lt Eprosartan 2,61 Lt 0,70 Lt 0,53 Lt 0,33 Lt Valsartan 1,56 Lt 0,70 Lt 0,53 Lt 0,33 Lt Irbesartan 1,99 Lt 0,70 Lt 0,53 Lt 0,33 Lt Candesartan 1,39 Lt 0,70 Lt 0,53 Lt 0,33 Lt Telmisartan 1,65 Lt 0,70 Lt 0,53 Lt 0,33 Lt Olmesartan medoxomil 2,61 Lt 0,70 Lt 0,53 Lt 0,33 Lt

Table.18. One reference price of Angiotensin converting enzyme inhibitor‘s and Angiotensin II antagonist‘s combinations with diuretics and calcium channel blockers

1 Reference 2 Reference Name of agent 1DDD price price price Enalapril and diuretics 0,35 Lt 0,35 Lt 0,35 Lt Perindopril and diuretics 1,43 Lt 0,71 Lt 0,35 Lt Ramipril and diuretics 0,43 Lt 0,43 Lt 0,35 Lt Quinapril and diuretics 0,79 Lt 0,71 Lt 0,35 Lt Fosinopril and diuretics 0,89 Lt 0,71 Lt 0,35 Lt Trandolapril and calcium channel blockers 1,27 Lt 0,71 Lt 0,35 Lt Losartan and diuretics 0,71 Lt 0,71 Lt 0,35 Lt Valsartan and diuretics 2,49 Lt 0,71 Lt 0,35 Lt Telmisartan and diuretics 2,06 Lt 0,71 Lt 0,35 Lt Olmesartan medoxomil and diuretics 1,28 Lt 0,71 Lt 0,35 Lt

65 8. Discussions The utilization of agents acting on the Renin-angiotensin-aldosterone system increased gradually on 2005-2007 in Lithuania and in other EU countries. The ACEI and AIIA combinations are more popular in other EU countries comparing with Lithuania on 2005-2007. Expeditures for agents acting on the Renin-angiotensin-aldosterone system increased significantly in 2007 comparing with 2005, 2006. The amount spent on plain ACEI (64%) contains the biggest part of total expeditures spent on agents acting on the Renin-angiotensin-aldosterone system in 2007, on the contrary the smallest amount was spent on AIIA combinations in the same year, as we can see in Fig.24. ACEIs are the leading group in the consumption of renin-angiotensin acting drugs from 2005 till 2007 in Lithuania. In addition the same trends in use are in other countries. This may be due to the lower price of ACEIs, however side effects (dry cough, angioedema) of ACEIs are more frequent than using AIIA. As we can see in Table 9; Fig. 7 and Fig. 8. In ACEI group, Ramipril was prescribed most commonly (which accounted for 29,90% of all ACEI) in 2007, but Ramipril combinations with diuretics were the most undersubscribed agents of all ACEI in the same year. Our study showed the significant difference in the amounts of prescribed plain Perindopril and Ramipril per 2007 but the sums spent on are quite similar. Ramipril was the most popular agent of total utilization of ACEI, while part of Perindopril was only 11,76%, as we can see in Table 11; Fig.21. In addition Ramipril is low-priced agent comparing with Perindopril or other agents, as we can see in Table 11. This is due to the different 1DDD prices of two preparats dependent to the same pharmacological subgroup. Both agents depends to the same pharmacological group, so they have similar pharmacological effects. Losartan was the most popular and low-priced agent among plain AIIA, as we can see in Table 12; Fig 17. In addition Losartan with diuretics was the most popular and low-priced agent among AIIA combinations, as we can see in Table 12; Fig.18. However angiotensin converting enzyme inhibitors and angiotensin II antagonist are from different pharmacological subgroups, there is now significant differences in therepeutic effects comparing ACEIs and AIIAs (as it shown in Table.8), differs the side effects. In concordance with 1DDD prices ACEIs are lower priced than AIIA, but ACEIs can cause a dry cough and angioedema. On the other hand, maybe buying the ACEIs is cocominant with buying drugs reducing dry cough or angioedema. Spent amount on ACEIs and drugs reducing adverse effects could be bigger than the amount of money spent on AIIAs at once. On the other hand it is important how many people don‗t buy any drugs because of adverse effects caused by ACEIs.

66 A non-productive cough can occur in 5% to 15% of all patients who use ACE inhibitors. It usually appears within the first several weeks to months of therapy but can also appear after one or even several years of treatment. Cough predominantly occurs at night and is due to mucosal irritation secondary to overproduction of bradykinin and PGE2. This complication usually disappears 1-2 weeks after discontinuation of treatment and recurs within days of rechallenge. Change of drug to another one in this category may reduce the risk of this adverse effect. If therapy should be continued or if cough doesn't disappear after discontinuation of therapy, treatment with opiates, sodium cromoglycate or ipratropium bromide can reduce or abolish cough. It is emphasized that other causes of cough must be considered and ruled out. ACE inhibitors should be implicated only after the physician confirms that the cough disappears after withdrawal of drug and recurs with rechallenge.[28] Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema. [29] Genetic factors also can be the reason of angioedema, so all the opportunities must be evaluated. Patients with such reactions appear to be sensitive to all of these drugs. Most reactions begin within the initial weeks of therapy, but reactions have been reported as late as 7 years after usage of these drugs. Fatal episodes have been reported, and therapy with alternative ACE inhibitor drugs should not be attempted. Corticosteroids, antihistamines and epinephrine are used for treatment and none of ACE inhibitors should be used again. [28] According to meta-analysis, number of included studies (number of publications) that evaluated various treatment and head-to-head efficacy comparisons found in literature no consistent differential effects of ACEIs versus ARBs on risk factor reduction and other intermediate outcomes were determined. No differences were found in measures of general quality of life also. Considering the similar effects of ACEIs versus ARBs on general quality of life, risk factor reduction and other intermediate outcomes and experience of other EU countries on reference pricing for ACEIs and AIIA it‘s very important to implement in practice reimbursement of ACEIs and AIIA based on reference price methodology. According to our calculations such implementations makes possibility to rationalize 12.180 – 23.064 – 32.486 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively.

67 9. Acknowledgments

Special thanks to Edmundas Kaduševičius for consultations and contribution to this work. We offer special thanks to the company SoftDent, JSC for the collected data of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists‘ utilization in Lithuania.

68 10. Conclusions

According to meta-analysis, number of included studies (number of publications) that evaluated various treatment and head-to-head efficacy comparisons found in literature no consistent differential effects of ACEIs versus ARBs on risk factor reduction and other intermediate outcomes were determined. No differences were found in measures of general quality of life also.

The total consumption of AIIA (plain and combinations) increased from 1,3 DDD/1000 inhabitants/day in 2005 and reached the value 13,6 DDD/1000 inhabitants/day in 2007.

The total consumption of ACEIs (plain and combinations) decreased from 146,1 DDD/1000 inhabitants/day in 2005 till 124,4 DDD/1000 inhabitants/day in 2006, and reached the value 139,8 DDD/1000 inhabitants/day in 2007.

The total consumption of agents acting on the Renin-angiotensin-aldosterone system increased from 111,1 DDD/1000 inhabitants/day in 2005 and reached the value 153,4 DDD/1000 inhabitants/day in 2007.

The expenditures for agents acting on the Renin-angiotensin-aldosterone system were almost 80 million Litas in 2005 and reached the value 116,6 million Litas in 2007.

The pharmacoeconomical calculations done for Angiotensin converting enzyme inhibitors and Angiotensin II antagonists expenditures using cost-minimization analysis and reference based pricing showed the possibility to rationalize 12.180 – 23.064 – 32.486 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively.

11. Summary

Trends in the use of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists in Lithuania on 2005 – 2007 years

Objective: To evaluate the tendencies of utilization of Angiotensin converting enzyme inhibitors and Angiotensin II receptors antagonists in Lithuania during 2005-2007 years.

Methods: MEDLINE database was searched to identify and evaluate all literature relating to pharmacokinetic and pharmacodynamic characteristics of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists. Utilization data of Angiotensin converting enzyme inhibitors (plain and combinations) and Angiotensin II antagonists (plain and combinations) in Lithuania over three years (2005 – 2007) period were obtained from SoftDent, JSC database. The retail prices of agents acting on the Renin-angiotensin-aldosterone selected from Reimbursed Medical Products Reference Prices Lists of 2005, 2006, 2007 years. Drugs were classified according to the Anatomic Therapeutic Chemical system and use was quantified in terms of defined daily doses (ATC/DDD). Consumption of Angiotensin converting enzyme inhibitors (plain and combinations) and Angiotensin II antagonists (plain and combinations) was calculated by DDD methodology and expressed as DDD per 1.000 inhabitants per day. Pharmacoeconomic calculations were done according to cost minimization and reference price methodologies.

Results: According to meta-analysis, number of included studies (69 publications) that evaluated various treatment and head-to-head efficacy comparisons found in literature no consistent differential effects of ACEIs versus ARBs on risk factor reduction and other intermediate outcomes were determined. No differences were found in measures of general quality of life also. The total consumption of agents acting on the Renin-angiotensin-aldosterone system increased from 111,1 DDD/1000 inhabitants/day in 2005 and reached the value 153,4 DDD/1000 inhabitants/day in 2007. The expenditures for agents acting on the Renin-angiotensin-aldosterone system were almost 80 million Litas in 2005 and reached the value 116,6 million Litas in 2007. The pharmacoeconomical calculations done for Angiotensin converting enzyme inhibitors and Angiotensin II antagonists expenditures using cost-minimization analysis and reference based pricing showed the possibility to rationalize 12.180 – 23.064 – 32.486 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively.

70 Conclusions: The findings suggest that from 2005 even as the government began to reimburse the agents acting on the Renin-angiotensin-aldosterone system the utilization increased gradually on 2005-2007 years in Lithuania. The expeditures for agents acting on the Renin-angiotensin-aldosterone system increased 32% from 2005 till 2007. Due to gradually increasing utilization of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists, on purpose to reduce the expeditures for Angiotensin converting enzyme inhibitors and Angiotensin II antagonists it is important to adapt reference prices and cost minimisation methods.

71 12. Santrauka

Angiotenziną konvertuojančio fermento inhibitorių ir Angiotenzino II antagonistų suvartojimo tendencijų analizė Lietuvoje 2005 – 2007 metais

Tikslas: atlikti Angiotenziną konvertuojančių fermentų inhibitorių ir Angiotenzino II antagonistų suvartojimo tendencijų Lietuvoje analizę 2005 – 2007 metais.

Metodai: Duomenys apie Angiotenziną konvertuojančio fermento inhibitorių ir Angiotenzino II antagonistų farmakokinetines ir farmakodinamines savybes buvo surinkti iš MEDLINE elektroninių duomenų šaltinių. Duomenys apie AKF inhibitorių (paprastų ir sudėtinių) ir Angiotenzino II antagonistų (paprastų ir sudėtinių) suvartojimą Lietuvoje per 2005 – 2007 metus gauti iš UAB SoftDent duomenų bazės. Renino-angiotenzino-aldosterono sistemą veikiančių vaistų mažmeninės kainos išrinktos iš Lietuvos kompensuojamų vaistinių preparatų 2005, 2006, 2007 metų kainynų. Vaistai buvo suklasifikuoti pagal anatominę terapinę cheminę (ATC) klasifikaciją. AKFI inhibitorių (paprastų ir sudėtinių) ir Angiotenzino II antagonistų (paprastų ir sudėtinių) suvartojimas buvo vertinamas pagal apibrėžtos dienos dozės (DDD – daily defined dose) metodiką, o duomenys įvertinti pagal DDD skaičių, tenkantį 1000 gyventojų per vieną dieną. AKF inhibitorių (paprastų ir sudėtinių) ir Angiotenzino II antagonistų (paprastų ir sudėtinių) farmakoekonominei analizei atlikti buvo taikytas kainų mažinimo bei standartinės kainos nustatymo metodai.

Rezultatai: Vadovaujantis metaanalizių, įvairių klinikinių tyrimų 69 publikacijomis bei išsamia AKF inhibitorių ir Angiotenzino II antagonisų efektyvumo palyginimo analize galima teigti, kad šių vaistų grupių poveikis prilygsta vienas kitam rizikos faktorių, vidutinių pasekmių atsiradimu, bei gyvenimo kokybės gerinimu. Bendras Renino-angiotenzino-aldosterono sistemą veikiančių vaistų suvartojimas padidėjo nuo 111,1 DDD/tūkstančiui gyventojų per dieną 2005 metais iki 153,44 DDD/tūkstančiui gyventojų per dieną 2007metais. Išlaidos Renino-angiotenzino-aldosterono sistemą veikiantiems vaistams sudarė iki 80mln. litų 2005 metais ir padidėjo iki 116,6 mln. 2007 metais.

Išvados: Vadovaujantis rezultatais galime teigti, kad nuo 2005 metų, pradėjus kompensuoti Renino- angiotenzino-aldosterono sistemą veikiančius vaistus, jų suvartojimas nuolat didėjo 2005-2007 metų laikotarpiu. Išlaidos Renino-angiotenzino-aldosterono sistemą veikiantiems vaistams nuo 2005 iki 2007 metų išaugo 32 %. Esant tolygiam Angiotenziną konvertuojančio fermento inhibitorių ir Angiotenzino II antagonistų suvartojimo augimui, siekdami sumažinti išlaidas Angiotenziną konvertuojančio fermento

72 inhibitoriams ir Angiotenzino II antagonistams įsigyti, turime taikyti referentinių kainų taikymo ir kainų mažinimo būdus.

73 REFERENCES: 1. World Health Organization 2006; World Health Statistics 2006 Part 1. Ten Statistical Highlights in Global Public Health 9; 5. Cause of death and burden of disease: global epidemic of chronic noncommunicable diseases14 2. Wilma Scholte op Reimer, Maarten L. Simoons, Eric Boersma, Anselm K. Gitt Sophia Antipolis, France 2006 Euro Heart Survey Cardiovascular diseases in Europe 8-14pg 3. British Heart Foundation Statistics Database. Coronary heartdisease statistics, 2006. Available from: URL: http://www.heartstats.org/ 4. Statistikos Departamentas prie Lietuvos Respublikos Vyriausybes; www.stat.gov.lt 5. Euro Heart survey – ESC congress, Vienna September 2007; Slide: Medication Use: ACE inhibitors & Angiotensin II RA; 6. Dolila B.Corry MD; Ronald J.De Bellis, PharmD, FCCD. Advances in the management of cardiovascular disease: Understanding the Effect of the Renin-Angiotensin-Aldosterone System; www.princeton.com/program/2006-194/page/357 7. Journal of Inflammation 30 September 2004; Cancer, inflammation and the AT1 and AT2 receptors 8. Richard E. Klabunde, Ph.D. Concepts Cardiovascular Physiology Renin-Angiotensin-Aldosterone System; www.cvphysiology.com 9. The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition Steven A. Atlas, MD J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20 Copyright© 2007, Academy of Managed Care Pharmacy 10. Kristina Garuolienė VLK vaistų kompensavimo skyriaus vedėja; Vaistų kompensavimas 2005 metais; www.vlk.lt 11. "Sveikatos drauda" 2007 Nr.1; www.vlk.lt 12. www.kmu.lt; 13. Journal of Human Hypertension (2006) 20, 101–108.doi:10.1038/sj.jhh.1001960; published online 5 January 2006 14. Irena Milvidaitė, Dalia Lukšienė, Birutė Šlapikienė, Marija Rūta Babarskienė, Valdas Liukaitis, Romas Mačiulaitis, Edmundas Kaduševičius, Rugilė Pilvinienė. Antrinė išeminės širdies ligos profilaktika persirgus miokardo infarktu (medikamentinio gydymo įvertinimas remiantis anketinės apklausos duomenimis); Medicina (Kaunas) 2007; 43(2) 15. W. Kirch, B. Horn and J. Schweizer; Review Comparison of angiotensin II receptor antagonists; Technical University of Dresden, Germany European Journal of Clinical Investigation (2001) 31, 698±706 16. Domenic A. Sica, MD; Class Effects of Angiotensin-Converting Enzyme Inhibitors; THE AMERICAN JOURNAL OF MANAGED CARE; VOL. 6, NO. 3, SUP. 2000 17. Toutain, P. L., Lefe`bvre, H. P. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships for angiotensin-converting enzyme inhibitors. J. vet. Pharmacol. Therap. 27, 515–525; 2004 18. Matthew R. Weir, MD; Effects of Renin-Angiotensin System Inhibition End-Organ Protection: Can We Do Better? Clinical Therapeutics/Volume 29, Number 9, 2007 19. TRENDS in Pharmacological Sciences (2003) 24, 391-394 20. Anne Stoysich, PharmD, and Fred Massoomi, PharmD; Automatic interchange of the ACE inhibitors: Decision-making process and initial results; Formulary January 2002 21. ZH Israili., Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension; Journal of Human Hypertension (2000) 14 22. G. Neil Thomas,1 Paul Chan2,3 and Brian Tomlinson4., The Role of Angiotensin II Type 1 Receptor Antagonists in Elderly Patients with Hypertension; Drugs Aging 2006; 23 (2): 23. Amy E. Miller, PharmD, BCPS, Mark Cziraky, PharmD, FAHA, Sarah A. Spinler, PharmD, ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection considerations; Formulary Jun 1, 2006 24. David B. Matchar, Douglas C. McCrory, Lori A. Orlando, Manesh R. Patel, Uptal D. Patel, MeenalB. Patwardhan, Benjamin Powers, Gregory P. Samsa, Rebecca N. Gray; Comparative Effectiveness of

74 Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for Treating Essential Hypertension; Comparative Effectiveness Review Number 10; November 2007 25. M. Bas, V. Adams, T. Suvorava, T. Niehues, T. K. Hoffmann, G. Kojda; Nonallergic angioedema: role of bradykinin; Allergy 2007: 62: 842–856 26. Peter V. Dicpinigaitis, MD, FCCP; Angiotensin-Converting Enzyme Inhibitor-Induced Cough ACCP Evidence-Based Clinical Practice Guidelines; Chest 2006; 129; 169-173 27. Claudio Borghi, Ettore Ambrosioni, Department of Internal Medicine, University of Bologna, Bologna, Italy; Zofenopril: A Review of the Evidence of its Benefits in Hypertension and Acute Myocardial Infarction; Clinical Drug Investigation; Posted 11/01/2000 28. Pulmonary Complications of ACE Inhibitors; Sh. Roozitalab, M.D. Shiraz E-Medical Journal; 2003 29. Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema. Byrd, James Brian; Touzin, Karine; Sile, Saba; Gainer, James V.; Yu, Chang; Nadeau, John; Adam, Albert; Brown, Nancy J. Hypertension. 51(1):141-147, January 2008

ANNEX 1

ANNEX 2

Deaths by age group and cause of death, 2006

Cause of death Age group Codes Total (ICD-10) 0-14 15-44 45-64 65+ Unknown All causes 44813 374 3842 10927 29670 -

Certain infectious and parasitic A00-B99 514 6 129 224 155 - diseases of which: intestinal infectious diseases AQ00-A09 3 - - 1 2 - respiratory tuberculosis A15-A16 263 - 72 133 58 - septicaemia A40-A41 78 - 10 29 39 - human immunodeficiency virus B20-B24 6 - 6 - - - (HIV) disease

Malignant neoplasms C00-C97 8148 18 305 2480 5345 - of which: stomach C16 740 - 26 216 498 - colon C18 486 - 9 93 384 - rectum C19-C21 433 - 5 100 328 trachea, bronchus and lung C33-C34 1477 - 19 525 933 - breast C50 515 - 32 191 292 - cervix uteri C53 236 - 42 96 98 - prostate C61 552 - - 74 478 - leukaemia C91-95 249 6 16 51 176 -

Endocrine, nutritional and E00-E88 362 8 43 96 215 - metabolic diseases of which: diabetes mellitus E10-E14 330 3 39 83 205 -

Mental and behavioural F01-F99 82 - 34 21 27 - disorders of which: mental and behavioural F10 34 - 11 17 6 - disorders due to use of alcohol mental and behavioural disorders due to psychoactive F11-F19 18 - 18 - - - substance use

Diseases of the circulatory I00-I99 24321 6 579 3880 19856 - system of which:

77 chronic rheumatic heart I05-I09 149 - 6 58 85 - diseases hypertensive diseases I10-I13 479 - 16 140 323 - acute and subsequent I21-I22 1346 - 28 290 1028 - myocardial infarction other ischaemic heart diseases I20,I24-I25 13680 - 183 1871 11626 - cerebrovascular diseases I60-I69 5844 - 95 702 5047 - atherosclerosis I70 885 - - 56 829 -

Diseases of the respiratory J00-J98 1710 16 132 449 1113 - system of which: influenza J10-J11 4 - - - 4 - pneumonia J12-J18 660 14 97 231 318 - chronic bronchitis and asthma J41-J46 944 1 19 176 748 -

Diseases of the digestive K00-K92 2341 2 409 986 944 - system of which: gastric, duodenal and peptic K25-K27 224 - 16 45 163 - ulcer diseases of appendix K35-K38 12 2 - 2 8 - alcoholic liver disease K70 693 - 195 411 87 - fibrosis and cirrhosis of liver K74 527 - 97 308 122 -

Diseases of genitourinary N00-N98 309 - 9 63 237 - system of which: hyperplasia of prostate N40 18 - - - 18 -

Pregnancy, childbirth and the O00-O99 - - - - - puerperium - of which: abortion O03-O08 ------

Diseases of the perinatal period P05-P96 74 74 - - - -

Congenital anomalies Q00-Q99 140 100 20 9 11 -

Symptoms and ill-defined R00-R53, 549 14 185 180 170 - conditions R55-R99

Senility R54 61 - - - 61 -

External causes of mortality V01-Y89 5336 108 1878 2253 1097 - of which: transport accidents V01-V99 899 38 473 253 135 -

78 falls W00-W19 555 2 101 256 196 - accidental drowning and W65-W74 335 24 113 136 62 - submersion accidental poisoning by and X45 486 - 156 284 46 - exposure to alcohol intentional self-harm X60-X84 1049 6 415 407 221 - assault X85-Y09 254 4 126 91 33 -

All other diseases 866 22 119 286 439 -

ANNEX 3

Junior (16–29years old) mortality 2005 m.

Town Country Rate per 100 000 population town country women men women men women men women men All causes 119 481 61 334 49,0 202,1 60,0 284,7 Certain infectious and parasitic diseases 5 3 3 3 2,1 1,3 3,0 2,6 Malignant neoplasms 17 19 5 7 7,0 8,0 4,9 6,0 Diseases of the circulatory system 8 32 4 11 3,3 13,4 3,9 9,4 Diseases of the respiratory system 3 5 2 13 1,2 2,1 2,0 11,1 Diseases of the digestive system 3 9 - 6 1,2 3,8 - 5,1 Congenital anomalies 3 1 3 2 1,2 0,4 3,0 1,7 External causes of mortality 70 361 35 263 28,8 151,7 34,5 224,2 transport accidents 35 121 17 84 14,4 50,8 16,7 71,6 accidental poisoning by and exposure to alcohol 3 10 2 8 1,2 4,2 2,0 6,8 accidental drowning and submersion 3 21 3 26 1,2 8,8 3,0 22,2 Intentional self-harm 10 100 9 84 4,1 42,0 8,9 71,6 assault 7 22 2 17 2,9 9,2 2,0 14,5

ANNEX 4

Medication Use: ACE Inhibitors & Angiotensin II RA

100%

90% P<0.0001 80%

70%

60%

50%

40%

30%

20%

10%

0% Nether- Czech Rep. Finland France Germany Hungary Italy Slovenia ALL lands

Survey 1 28.1% 17.3% 33.8% 31.4% 46.3% 31.8% 27.4% 31.2% 31.0% Survey 2 47.1% 31.0% 43.7% 50.6% 58.6% 53.5% 42.9% 63.0% 49.2% Survey 3 76.1% 59.3% 78.9% 72.8% 80.6% 70.9% 66.5% 83.0% 74.6%

S2 vs. S1 : P<0.0001 S3 vs. S2 : P<0.0001 S3 vs. S1 : P<0.0001 Euro Heart Survey - ESC congress, Vienna, September 2007

EUROASPIRE III is a 22 country - Belgium, Bulgaria, Croatia, the Czech Republic, Cyprus, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, the Netherlands, Poland, Romania, Russia , Slovenia, Spain, Turkey and the UK – survey of the practice of preventive cardiology. The first EUROASPIRE survey of preventive cardiology practice in 1995-1996 in nine countries, and the second in 1999-2000 in fifteen countries showed a high prevalence of unhealthy lifestyles, modifiable risk factors and inadequate use of drug therapies to achieve blood pressure, lipid and glucose goals in patients with established CHD.

ANNEX 5

ANNEX 6

ANNEX 7

ANNEX 8

ANNEX 9