KAUNAS UNIVERSITY OF MEDICINE Department of Basic & Clinical Pharmacology

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1 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 years The author: Asta Dičkutė a student of Pharmacy faculty of Kaunas University of Medicine Work supervisor: Lekt. Edmundas Kaduševičius Kaunas

2 TABLE OF CONTENTS Abbreviations Introduction and novelty of the master work Objective and tasks The renin-angiotensin aldosterone system: physiological role and pharmacologic inhibition Components of the renin-angiotensin aldosterone system Description and clasification of AT1 and AT2 receptors Classical Endocrine Pathway of Angiotensin Biosynthesis Tissue renin-angiotensin aldosterone system and Alternative Pathways of Angiotensin Biosynthesis Dysregulation of the renin-angiotensin aldosterone system in Cardiovascular Disorders Renin-angiotensin aldosterone system inhibition. Early Preclinical Findings Pharmacologic Intervention in the Renin-Angiotensin System Cascade Angiotensin converting enzyme inhibitors. History. Chemical structure. Pharmacokinetics History Chemical structure Pharmacokinetics of the ACE inhibitors Angiotensin II antagonists. History. Chemical structure. Pharmacokinetics History Chemical structure Pharmacokinetics of angiotensin II antagonists Head-to-head efficacy comparisons Results Discussion Acknowledgments Conclusions Summary Santrauka Literatures Annexes

3 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 3

4 1. INTRODUCTION AND NOVELTY OF THE MASTER WORK Cardiovascular disease is one of the main causes of death in the world in 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] 4

5 Figure 1. Population of Europe in [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 percent of disablement and 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 [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 Among the cardiovascular diseases, an ischemic heart disease is the leading cause of death (15 thousand deaths in 2005). [4] 5

6 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 [4] Almost 52 percent of all deaths (or 562 people of total deaths) are from cardiovascular diseases in Lithuania in [4] Age adjusted death rates by cause of death, 2006 Deaths per 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

7 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 million on drugs and medical goods in 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 [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

8 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 years 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-tohead comparison). 3. To evaluate utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists by ATC/DDD methodology in Lithuania during 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

9 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] 9

10 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 = chymostatinsensitive 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

11 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] 11

12 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

13 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 kallikreinlike enzymes (tonins), cathepsin G, and chymase are thought to contribute to Ang II formation in the tissue RAAS. [9] 13

14 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 pressurenatriuresis, and promotion of renal tissue growth. Under normal conditions, Ang II constricts both the 14

15 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 sodiumretaining 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

16 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 highrenin 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 (socalled 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

17 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

18 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 highrenin or volume-depleted patients with a particularly robust reactive rise in PRA. [9] 18

19 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

20 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 20

21 Captopril Enalapril maleate Lisinopril Moexipril hydrochloride Perindopril erbumine Quinapril hydrochloride Trandolapril Ramipril Benazepril 21

22 Cilazapril Fosinopri sodium Temocapril Spirapril Delapril Imidapril Pentopril Zofenopril Table.2. Chemical formulas of angiotensin converting enzyme inhibitors 22

23 4.3 Pharmacokinetics of the ACE inhibitors Drug Dosage mg Active metabolite Bioavailability % Effect of food Tmax (h) Half life (h) Protein binding % Vd (L) Excretion (Renal/fecal) [%] Benazepril 10 Benazeprilat >37 None 0, >95 8,7 20/11-12 (benezeprilat) Captopril 100 NA 70 R 0,93-1 < ,76 L/kg >95R,as disulfides Cilazapril 2,5 Cilazaprilat 57-77,5 R 0, ,4 91/and F Delapril 30(60) Delapril diacid >55 SR ,5 56/and F Delapril 5-hydroxy diacid (delapril) Enalapril 10 Enalaprilat 60 None / and F Fosinopril 10 Fosinoprilat 32 SR 3 12 > /50 Imidapril 10 Imidaprilat R /50 Lisinopril 10 NA 25 widely variable None ,4±1,4 100/0 between individuals L/kg Moexipril 15 Moexiprilat MR 1d /53 Pentopril 250 Pentopril diacid >58 1(1,28) <1 56a Perindopril 8 Perindoprilat SR 1 1, ,22 L/kg 75/25 Quinapril 40 Quinaprilat Quinapril diacid >60 R 0, ,4L/kg 61/37 Ramipril 10 Ramiprilat >60 None /40 Spirapril 6 Spiraprilat c 40/85 Temocapril 20 Temocaprilat 1b /36-44 Trandolapril 2 Trandolaprilat 10 R 0, trandolapril 18 33/ trandolaprilat Zofenopril 30 Zofenoprilat 93%. 0.4e -1,5f ,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; E Ambrosioni & C.Borghi., 2001; A. Subiss & Evangelista S & Giachett A., 1999 University of Maryland medical center; 23

24 Classifying agents by duration of action ACEIs were classified as short, intermediate, or longacting 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, Dose related Intermediate-Acting Benazepril Enalapril Moexipril Quinapril Ramipril Long-Acting Fosinopril Lisinopril Perindopril Trandolapril Table.4. Duration of action of angiotensin converting enzyme inhibitors Adapted from: Anne Stoysich & Fred Massoomi., 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] 24

25 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

26 Candesartan cilexetil Losartan Eprosartan mesylate Telmisartan Valsartan Olmesartan Irbesartan Table.5. Chemical formulas of the angiotensin II antagonists 26

27 Drug Dosage mg Active metabolite Receptor antagonism Bioavailability % Effect of food T max (h) Half life (h) Protein binding% V d (L) Excretion (Renal/fecal) [%] 5.3 Pharmacokinetics of angiotensin II antagonists Losartan E-3174 Both b 33 AUC/Cmax 10% (6 9) Both (12) 40/60 (3 4) Valsartan No Noncompetitive AUC/Cmax 40 50% /83 Irbesartan No Noncompetitive No /80 Candesartan cilexetil 8-32 Candesartan Noncompetitive 15 No > L/kg 33/67 Telmisartan No Noncompetitive AUC 6 19% > <2/98 Eprosartan No Competitive 13 AUC/Cmax 25% /90 Olmesartan medoxomil Olmesartan Competitive No /50 65 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.,

28 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] 28

29 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., 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] 29

30 Table.8. Number of included studies (number of publications) that evaluated various treatment comparisons [24] 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. [24] Key Points ARBs. Effect on Blood Pressure There was no clear difference in the blood pressure lowering efficacy between ACEIs and 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. quality of life. Effect on Quality of Life No significant difference was observed between ACEIs and ARBs in terms of their impact on 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. 30

31 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] 31

32 Table.9. Studies reporting angioedema [24] Figure 7. Studies reporting on cough with ACEIs vs. ARBs [24] 32

33 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 longterm 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

34 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 cardiovascular events Moderate Due to insufficient numbers of deaths or major 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 antihypertensive High There was no statistically evident difference in 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 other intermediate outcomes Moderate (lipid levels, markers of carbohydrate metabolism/ diabetes control, There were no consistent differential effects of ACEIs vs. ARBs on several potentially important clinical outcomes, including lipid levels, progression to type 2 diabetes mellitus, markers of carbohydrate metabolism/diabetes control, measures of LV mass or function, and 34

35 2. The differences between ACEIs and ARBs in safety, adverse events, tolerability, persistence, and adherence progression of renal disease) to Low (progression to type 2 diabetes and LV mass/function High (cough, withdrawals due to adverse events) to Moderate (persistence/ adherence) to Low (angioedema) progression of renal disease (either based on creatinine, GFR, or proteinuria). Relatively few studies assessed these outcomes over the long term. ACEIs have been consistently shown to be associated with greater risk of cough than ARBs: pooled odds ratio (Peto) = For RCTs, this translates to a difference in rates of cough of 6.7 percent (NNT = 15); however, for cohort studies with lower rates of cough, this translates to a difference of 1.1 percent (NNT = 87). This is generally consistent with evidence reviewed 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

36 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). Very low and relatively small sample sizes for ARBs, the precise magnitude of this effect is difficult to quantify. Evidence does not support conclusions regarding the comparative effectiveness, adverse events, or tolerability of ACEIs and ARBs for any particular patient subgroup. 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

37 DDD/1000 inhabitants/day 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 ,00 166,01 160,00 153,44 150,77 140,00 131,57 121,70 137,87 117,91 120,00 111,10 109,20 106,22 112,34 100,00 96,30 80,00 60,00 40,00 20,00 0,00 Lithuania Denmark Finland Norway Population: ; 2007 in Lithuania Population: ; 2006 in Lithuania Population: ; 2005 in Lithuania 37

38 DDD/1000 inhabitants/day Figure 10. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in ,00 97,57 90,00 80,00 75,34 70,00 60,00 55,10 50,00 42,89 40,00 30,97 30,62 30,00 22,10 25,36 20,00 12,52 12,50 16,82 10,00 0,00 14,74 1,005 0,001 6,70 7,35 Lithuania Denmark Finland Norway ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations 38

39 DDD/1000 inhabitants/day Figure 11. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in ,00 107,94 100,00 78,88 80,00 62,00 60,00 40,00 20,00 0,00 43,40 37,54 33,58 24,60 19,95 16,45 14,10 7,08 14,40 0,10 8,50 7,11 Lithuania Denmark Finland Norway 28,25 ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations 39

40 Figure 12. Comparison of consumption of agents acting the Renin-angiotensin-aldosterone system between states in ,00 118,33 100,00 86,20 DDD/1000 inhabitants/day 80,00 60,00 40,00 67,40 27,60 42,61 43,92 36,39 30,61 21,44 22,23 20,00 12,03 16,00 1,64 10,60 14,97 6,99 0,00 Lithuania Denmark Finland Norway ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations 40

41 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 in Lithuania 160,00 150,00 153,44 140,00 130,00 131,57 DDD/1000 inhabitants/day 120,00 110,00 111,10 100, Population: ; 2007 Population: ; 2006 Population: ;

42 Figure 14. Comparison of consumption between groups of agents acting the Renin-angiotensin-aldosterone system in in Lithuania 1,64 AIIA, combinations 0,10 0,001 AIIA, plain ACEI, combinations 12,03 7,08 1,005 21,44 16,45 12, ACEI, plain 97,57 107,94 118,33 0,00 20,00 40,00 60,00 80,00 100,00 120,00 DDD/1000 inhabitants/day 42

43 Figure 15. The actual amounts spent on agents acting on the Renin-angiotensin-aldosterone system per in Lithuania. Total ,00 Lt ,01 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,70 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,37 Lt ,00 Lt

44 7.3 Pharmacoeconomic calculations suggesting the reference price 1.Utilization of Angiotensin converting enzyme inhibitor s and Angiotensin II antagonist s per Utilization of Angiotensin converting enzyme inhibitor s combined with diuretics or calcium channel blockers and Angiotensin II antagonist s combined with diuretics per 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 quantity/ DDD DDD/1000 inhabitants/ 1 day % Nr. Agent Drug quantity, mg DDD mg Spend in (LTL) Price/DDD (LTL) 1 Captopril ,50 7,1 5,11% ,26 0,43 2 Enalapril , ,87 26,2 18,73% ,80 0,28 3 Lisinopril ,00 4,1 2,92% ,30 0,53 4 Perindopril ,50 16,4 11,76% ,05 0,77 5 Ramipril , ,60 41,8 29,90% ,06 0,33 6 Quinapril ,87 8,6 6,17% ,81 0,74 7 Fosinopril , ,21 6,3 4,52% ,40 0,88 8 Trandolapril ,00 1,5 1,06% ,60 0,90 9 Spirapril , ,00 1,1 0,78% ,85 0,82 10 Zofenopril ,00 5,2 3,71% ,54 1, Enalapril and diuretics , ,964 2,9 2,07% ,88 0,35 Perindopril and diuretics ,75 8,7 6,23% ,20 1,43 Ramipril and diuretics , ,4 0,32% ,74 0,43 Quinapril and diuretics , ,707 6,8 4,88% ,15 0,79 Fosinopril and diuretics ,333 2,1 1,51% ,17 0,89 Trandolapril and calcium channel blockers ,5 0,33% ,90 1,27 44

45 Table.12. The calculated data of Utlization of Angiotensin II antagonist s (plain and combinations with diuretics) per 2007 Nr. Agent Drug quantity, mg DDD mg Drug quantity/ DDD DDD/100 0 inhabitan ts/1 day % Spend in (LTL) Price/DDD (LTL) 1 Losartan ,9 70,74 9,7 8 % ,63 0,70 2 Eprosartan , ,00 0,1 0,61% ,16 2,61 3 Valsartan ,00 0,7 5,34% ,68 1,56 4 Irbesartan , ,00 0,4 2,86% ,62 1,99 5 Candesarta ,00 0,2 1,74% n ,73 1,39 6 Telmisartan ,00 0,4 2,62% ,06 1,65 7 Olmesartan medoxomil Losartan 8 and diuretics Valsartan 9 and diuretics Telmisartan 10 and diuretics Olmesartan 11 medoxomil and diuretics ,00 0,6 4,08% ,6 11,70 % ,04 0,29% ,001 0,01% ,003 0,02% ,56 2, ,43 0, ,12 2, ,93 2, ,41 2,56 45

46 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 10,0 5,0 7,1 4,1 8,6 6,3 1,5 1,1 5,2 0,0 Captopril Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Spirapril Zofenopril Population: ; 365 days of the

47 Figure 17. Utilization of Angiotensin II antagonist s per 2007 (DDD/1000inhabitants/day) Utilization of Angiotensin II antagonist's per 2007 (DDD/1000/day) 10,0 9,7 9,0 8,0 7,0 6,0 DDD/1000/day 5,0 4,0 3,0 2,0 1,0 0,1 0,7 0,4 0,2 0,4 0,6 0,0 Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan medoxomil Population: ; 365 days of the

48 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) 9,0 8,7 8,0 6,8 7,0 6,0 5,0 DDD/1000/day 4,0 2,9 3,0 2,1 2,0 1,6 1,0 0,4 0,5 0,04 0,001 0,003 0,0 Enalapril and diuretics Perindopril and diuretics Ramipril and diuretics Quinapril and diuretics Fosinopril and diuretics Trandolapril and calcium channel blockers Losartan and diuretics Valsartan and diuretics Telmisartan and diuretics Olmesartan medoxomil and diuretics Population: ; 365 days of the

49 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; 8% 1,64; 1% 21,44; 14% ACEI, plain ACEI, combinations AIIA, plain AIIA, combinations 118,33; 77% Population: ; 365 days of the

50 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: ; 365 days of the

51 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 ,00 Lt ,06 Lt ,00 Lt ,05 Lt ,00 Lt ,00 Lt ,00 Lt ,80 Lt ,81 Lt ,54 Lt ,00 Lt ,40 Lt ,00 Lt ,26 Lt ,00 Lt ,30 Lt ,60 Lt ,00 Lt ,85 Lt 0,00 Lt Captopril Enalapril Lisinopril Perindopril Ramipril Quinapril Fosinopril Trandolapril Spirapril Zofenopril 51

52 Figure 22. The amount of money spent on Angiotensin II antagonist s in ,00 Lt ,63 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,56 Lt ,00 Lt ,68 Lt ,62 Lt ,06 Lt ,00 Lt ,16 Lt ,73 Lt 0,00 Lt Losartan Eprosartan Valsartan Irbesartan Candesartan Telmisartan Olmesartan medoxomil 52

53 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 ,00 Lt ,20 Lt ,00 Lt ,00 Lt ,00 Lt ,00 Lt ,15 Lt ,00 Lt ,00 Lt ,43 Lt ,17 Lt ,00 Lt ,12 Lt 1 959,93 Lt 8 392,41 Lt ,88 Lt ,90 Lt ,74 Lt 0,00 Lt Losartan and diuretics Valsartan and diuretics TelmisartanOlmesartan and medoxomil diuretics and diuretics Quinapril and diuretics Fosinopril and diuretics Trandolapril and calcium channel blockers Enalapril and diuretics Perindopril and diuretics Ramipril and diuretics 53

54 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 ,03 Lt; 23% ,89 Lt; 1% ACEI plain AIIA plain ACEI combinations AIIA combinations ,43 Lt; 12% ,65 Lt; 64% 54

55 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 ,92 Lt; 24% ACEI and AIIA plain ACEI and AIIA combinations ,08 Lt; 76% 55

56 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 Name of agent DDD per DDD price Spent Reference price Spent Reference price Spent Captopril ,50 0,43 Lt ,26 Lt 0,33 Lt ,40 Lt 0,43 Lt ,26 Lt Enalapril ,87 0,28 Lt ,80 Lt 0,28 Lt ,80 Lt 0,28 Lt ,80 Lt Lisinopril ,00 0,53 Lt ,30 Lt 0,33 Lt ,29 Lt 0,53 Lt ,30 Lt Perindopril ,50 0,77 Lt ,05 Lt 0,33 Lt ,57 Lt 0,53 Lt ,34 Lt Ramipril ,60 0,33 Lt ,06 Lt 0,33 Lt ,06 Lt 0,33 Lt ,06 Lt Quinapril ,87 0,74 Lt ,81 Lt 0,33 Lt ,90 Lt 0,53 Lt ,82 Lt Fosinopril ,21 0,88 Lt ,40 Lt 0,33 Lt ,24 Lt 0,53 Lt ,09 Lt Trandolapril ,00 0,90 Lt ,60 Lt 0,33 Lt ,09 Lt 0,53 Lt ,36 Lt Spirapril ,00 0,82 Lt ,85 Lt 0,33 Lt ,22 Lt 0,53 Lt ,24 Lt Zofenopril ,00 1,45 Lt ,54 Lt 0,33 Lt ,88 Lt 0,53 Lt ,58 Lt Total ,65 Lt Total ,44 Lt Total ,84 Lt ,81 Save: Save: ,22 Lt Save: Lt 56

57 b) Reference prices of Angiotensin II antagonist s Name of agent DDD per DDD price Spent Referent price Spent Referent price Spent Losartan ,98 0,70 Lt ,63 Lt 0,70 Lt ,63 Lt 0,70 Lt ,63 Lt Eprosartan ,00 2,61 Lt ,16 Lt 0,70 Lt ,05 Lt 1,39 Lt ,29 Lt Valsartan ,00 1,56 Lt ,68 Lt 0,70 Lt ,73 Lt 1,39 Lt ,39 Lt Irbesartan ,00 1,99 Lt ,62 Lt 0,70 Lt ,08 Lt 1,39 Lt ,48 Lt Candesartan ,00 1,39 Lt ,73 Lt 0,70 Lt ,90 Lt 1,39 Lt ,73 Lt Telmisartan ,00 1,65 Lt ,06 Lt 0,70 Lt ,46 Lt 1,39 Lt ,91 Lt Olmesartan medoxomil ,00 2,61 Lt ,56 Lt 0,70 Lt ,52 Lt 1,39 Lt ,23 Lt Total ,43 Lt Total ,38 Lt Total ,65 Lt Save: ,05 Lt Save: ,78 Lt 57

58 c) Reference prices of Angiotensin converting enzyme inhibitor s combinations with diuretics or calcium channel blockers Name of agent DDD per DDD price Spent Reference price Spent Reference price Spent Enalapril and diuretics ,964 0,35 Lt ,88 Lt 0,35 Lt ,88 Lt 0,35 Lt ,88 Lt Perindopril and diuretics ,75 1,43 Lt ,20 Lt 0,35 Lt ,57 Lt 0,79 Lt ,74 Lt Ramipril and diuretics ,43 Lt ,74 Lt 0,35 Lt ,48 Lt 0,43 Lt ,74 Lt Quinapril and diuretics ,707 0,79 Lt ,15 Lt 0,35 Lt ,43 Lt 0,79 Lt ,15 Lt Fosinopril and diuretics ,333 0,89 Lt ,17 Lt 0,35 Lt ,79 Lt 0,79 Lt ,65 Lt Trandolapril and calcium channel blockers ,27 Lt ,90 Lt 0,35 Lt ,58 Lt 0,79 Lt ,89 Lt ,75 Total ,03 Lt Total ,73 Lt Total ,04 Lt Save: ,30 Lt Save: ,10 Lt 58

59 d) Reference prices of Angiotensin II antagonist s combinations with diuretics Name of agent DDD per DDD price Spent Reference price Spent Losartan and diuretics ,71 Lt ,43 Lt 0,71 Lt ,43 Lt Valsartan and diuretics ,49 Lt ,12 Lt 0,71 Lt ,45 Lt Telmisartan and diuretics 952 2,06 Lt 1 959,93 Lt 0,71 Lt 680,05 Lt Olmesartan medoxomil and diuretics ,28 Lt 4 196,21 Lt 0,71 Lt 2 340,17 Lt Total ,69 Lt Total ,09 Lt Save: ,59 Lt 59

60 e) One reference price of Angiotensin converting enzyme inhibitor s and Angiotensin II antagonist s Name of agent DDD per DDD price Spent Reference price Spent Reference price Spent Reference price Spent Captopril ,50 0,43 Lt ,26 Lt 0,33 Lt ,40 Lt 0,43 Lt ,26 Lt 0,43 Lt ,26 Lt Enalapril ,87 0,28 Lt ,80 Lt 0,28 Lt ,80 Lt 0,28 Lt ,80 Lt 0,28 Lt ,80 Lt Lisinopril ,00 0,53 Lt ,30 Lt 0,33 Lt ,29 Lt 0,53 Lt ,30 Lt 0,53 Lt ,30 Lt Perindopril ,50 0,77 Lt ,05 Lt 0,33 Lt ,57 Lt 0,53 Lt ,34 Lt 0,70 Lt ,65 Lt Ramipril ,60 0,33 Lt ,06 Lt 0,33 Lt ,06 Lt 0,33 Lt ,06 Lt 0,33 Lt ,06 Lt Quinapril ,87 0,74 Lt ,81 Lt 0,33 Lt ,90 Lt 0,53 Lt ,82 Lt 0,70 Lt ,04 Lt Fosinopril ,21 0,88 Lt ,40 Lt 0,33 Lt ,24 Lt 0,53 Lt ,09 Lt 0,70 Lt ,72 Lt Trandolapril ,00 0,90 Lt ,60 Lt 0,33 Lt ,09 Lt 0,53 Lt ,36 Lt 0,70 Lt ,50 Lt Spirapril ,00 0,82 Lt ,85 Lt 0,33 Lt ,22 Lt 0,53 Lt ,24 Lt 0,70 Lt ,58 Lt Zofenopril ,00 1,45 Lt ,54 Lt 0,33 Lt ,88 Lt 0,53 Lt ,58 Lt 0,70 Lt ,51 Lt Losartan ,98 0,70 Lt ,63 Lt 0,33 Lt ,72 Lt 0,53 Lt ,02 Lt 0,70 Lt ,63 Lt Eprosartan ,00 2,61 Lt ,16 Lt 0,33 Lt ,19 Lt 0,53 Lt ,89 Lt 0,70 Lt ,05 Lt Valsartan ,00 1,56 Lt ,68 Lt 0,33 Lt ,97 Lt 0,53 Lt ,08 Lt 0,70 Lt ,73 Lt Irbesartan ,00 1,99 Lt ,62 Lt 0,33 Lt ,57 Lt 0,53 Lt ,94 Lt 0,70 Lt ,08 Lt Candesartan ,00 1,39 Lt ,73 Lt 0,33 Lt ,82 Lt 0,53 Lt ,87 Lt 0,70 Lt ,90 Lt Telmisartan ,00 1,65 Lt ,06 Lt 0,33 Lt ,58 Lt 0,53 Lt ,99 Lt 0,70 Lt ,46 Lt Olmesartan medoxomil ,00 2,61 Lt ,56 Lt 0,33 Lt ,03 Lt 0,53 Lt ,69 Lt 0,70 Lt ,52 Lt Total ,08 Lt Total ,31 Lt Total ,34 Lt Total ,80 Lt Save: ,78 Lt Save: ,75 Lt Save: ,28 Lt 60

61 f) one reference price of Angiotensin converting enzyme inhibitor s and Angiotensin II antagonist s combinations with diuretics and calcium channel blockers Name of agent DDD per DDD price Spent Referent price Spent Referent price Spent Enalapril and diuretics ,964 0,35 Lt ,88 Lt 0,35 Lt ,88 Lt 0,35 Lt ,88 Lt Perindopril and diuretics ,75 1,43 Lt ,20 Lt 0,35 Lt ,57 Lt 0,71 Lt ,63 Lt Ramipril and diuretics ,43 Lt ,74 Lt 0,35 Lt ,48 Lt 0,43 Lt ,74 Lt Quinapril and diuretics ,707 0,79 Lt ,15 Lt 0,35 Lt ,43 Lt 0,71 Lt ,60 Lt Fosinopril and diuretics ,333 0,89 Lt ,17 Lt 0,35 Lt ,79 Lt 0,71 Lt ,77 Lt Trandolapril and calcium channel blockers ,27 Lt ,90 Lt 0,35 Lt ,58 Lt 0,71 Lt ,84 Lt Losartan and diuretics ,71 Lt ,43 Lt 0,35 Lt ,60 Lt 0,71 Lt ,43 Lt Valsartan and diuretics ,49 Lt ,12 Lt 0,35 Lt ,90 Lt 0,71 Lt ,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 ,28 Lt 4 196,21 Lt 0,35 Lt 1 148,83 Lt 0,71 Lt 2 340,17 Lt Total ,72 Lt Total ,91 Lt Total ,55 Lt Save: ,81 Lt Save: ,17 Lt 61

62 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 ,00 Lt < 1,45Lt ,00 Lt ,00 Lt < 0,53Lt ,00 Lt < 0,33Lt ,00 Lt ,00 Lt < 1,43Lt ,00 Lt < 2,61Lt < 1,39Lt < 0,70Lt < 0,79Lt < 0,35Lt ,00 Lt < 2,49Lt < 0,71Lt 0,00 Lt ACEI plain AIIA plain ACEI combinations AIIA combinations 1 DDD price ,65 Lt ,43 Lt ,03 Lt ,69 Lt 1 Reference price ,84 Lt ,65 Lt ,04 Lt ,09 Lt 2 Reference price ,44 Lt ,38 Lt ,73 Lt 62

63 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

64 Figure 27. Actual spend comparing with amount of money could be spent if one reference price was adapted for ACEI and AIIA ,00 Lt < 2,61Lt ,00 Lt < 0,70Lt ,00 Lt ,00 Lt < 0,53Lt ,00 Lt < 0,33Lt ,00 Lt ,00 Lt < 2,49Lt ,00 Lt < 0,71Lt ,00 Lt < 0,35Lt 0,00 Lt ACEI and AIIA plain ACEI and AIIA combinations 1 DDD price ,08 Lt ,72 Lt 1 Reference price ,80 Lt ,55 Lt 2 Reference price ,34 Lt ,91 Lt 3 Reference price ,31 Lt 64

65 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 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 0,71 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

66 8. Discussions The utilization of agents acting on the Renin-angiotensin-aldosterone system increased gradually on in Lithuania and in other EU countries. The ACEI and AIIA combinations are more popular in other EU countries comparing with Lithuania on Expeditures for agents acting on the Renin-angiotensin-aldosterone system increased significantly in 2007 comparing with 2005, 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

67 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 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively. 67

68 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

69 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 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 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 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 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 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively. 69

70 11. Summary Trends in the use of Angiotensin converting enzyme inhibitors and Angiotensin II antagonists in Lithuania on years Objective: To evaluate the tendencies of utilization of Angiotensin converting enzyme inhibitors and Angiotensin II receptors antagonists in Lithuania during 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 ( ) 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 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 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 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 million Litas per 2007, choosing prices of Ramipril, Lisinopril and Losartan as reference prices, respectively. 70

71 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 years in Lithuania. The expeditures for agents acting on the Renin-angiotensin-aldosterone system increased 32% from 2005 till 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

72 12. Santrauka Angiotenziną konvertuojančio fermento inhibitorių ir Angiotenzino II antagonistų suvartojimo tendencijų analizė Lietuvoje metais Tikslas: atlikti Angiotenziną konvertuojančių fermentų inhibitorių ir Angiotenzino II antagonistų suvartojimo tendencijų Lietuvoje analizę 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 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 metais. Išvados: Vadovaujantis rezultatais galime teigti, kad nuo 2005 metų, pradėjus kompensuoti Reninoangiotenzino-aldosterono sistemą veikiančius vaistus, jų suvartojimas nuolat didėjo 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

73 inhibitoriams ir Angiotenzino II antagonistams įsigyti, turime taikyti referentinių kainų taikymo ir kainų mažinimo būdus. 73

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75 Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for Treating Essential Hypertension; Comparative Effectiveness Review Number 10; November M. Bas, V. Adams, T. Suvorava, T. Niehues, T. K. Hoffmann, G. Kojda; Nonallergic angioedema: role of bradykinin; Allergy 2007: 62: Peter V. Dicpinigaitis, MD, FCCP; Angiotensin-Converting Enzyme Inhibitor-Induced Cough ACCP Evidence-Based Clinical Practice Guidelines; Chest 2006; 129; 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/ Pulmonary Complications of ACE Inhibitors; Sh. Roozitalab, M.D. Shiraz E-Medical Journal; 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): , January

76 ANNEX 1 76

77 ANNEX 2 Deaths by age group and cause of death, 2006 Cause of death Age group Codes Total (ICD-10) Unknown All causes Certain infectious and parasitic A00-B99 diseases of which: intestinal infectious diseases AQ00-A respiratory tuberculosis A15-A septicaemia A40-A human immunodeficiency virus B20-B24 (HIV) disease Malignant neoplasms C00-C of which: stomach C colon C rectum C19-C trachea, bronchus and lung C33-C breast C cervix uteri C prostate C leukaemia C Endocrine, nutritional and E00-E88 metabolic diseases of which: diabetes mellitus E10-E Mental and behavioural F01-F99 disorders of which: mental and behavioural F10 disorders due to use of alcohol mental and behavioural disorders due to psychoactive F11-F substance use Diseases of the circulatory I00-I99 system of which: 77

78 chronic rheumatic heart I05-I09 diseases hypertensive diseases I10-I acute and subsequent I21-I22 myocardial infarction other ischaemic heart diseases I20,I24-I cerebrovascular diseases I60-I atherosclerosis I Diseases of the respiratory J00-J98 system of which: influenza J10-J pneumonia J12-J chronic bronchitis and asthma J41-J Diseases of the digestive K00-K92 system of which: gastric, duodenal and peptic K25-K27 ulcer diseases of appendix K35-K alcoholic liver disease K fibrosis and cirrhosis of liver K Diseases of genitourinary N00-N98 system of which: hyperplasia of prostate N Pregnancy, childbirth and the O00-O99 puerperium of which: abortion O03-O Diseases of the perinatal period P05-P Congenital anomalies Q00-Q Symptoms and ill-defined conditions R00-R53, R55-R Senility R External causes of mortality V01-Y of which: transport accidents V01-V

79 falls W00-W accidental drowning and W65-W74 submersion accidental poisoning by and X45 exposure to alcohol intentional self-harm X60-X assault X85-Y All other diseases

80 ANNEX 3 Junior (16 29years old) mortality 2005 m. Town Country Rate per population town country women men women men women men women men All causes ,0 202,1 60,0 284,7 Certain infectious and parasitic diseases ,1 1,3 3,0 2,6 Malignant neoplasms ,0 8,0 4,9 6,0 Diseases of the circulatory system ,3 13,4 3,9 9,4 Diseases of the respiratory system ,2 2,1 2,0 11,1 Diseases of the digestive system ,2 3,8-5,1 Congenital anomalies ,2 0,4 3,0 1,7 External causes of mortality ,8 151,7 34,5 224,2 transport accidents ,4 50,8 16,7 71,6 accidental poisoning by and exposure to alcohol ,2 4,2 2,0 6,8 accidental drowning and submersion ,2 8,8 3,0 22,2 Intentional self-harm ,1 42,0 8,9 71,6 assault ,9 9,2 2,0 14,5 80

81 ANNEX 4 Medication Use: ACE Inhibitors & Angiotensin II RA 100% 90% 80% P< % 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey % 17.3% 33.8% 31.4% 46.3% 31.8% 27.4% 31.2% 31.0% Survey % 31.0% 43.7% 50.6% 58.6% 53.5% 42.9% 63.0% 49.2% Survey % 59.3% 78.9% 72.8% 80.6% 70.9% 66.5% 83.0% 74.6% S2 vs. S1 : P< S3 vs. S2 : P< S3 vs. S1 : P< 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 in nine countries, and the second in 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. 81

82 ANNEX 5 82

83 ANNEX 6 83

84 ANNEX 7 84

85 ANNEX 8 85