1 TRATAMIENTO DE LA HIPERTENSION ARTERIALReunión Científica de la Sociedad de Cardiología de Tucumán (SCT) – 16 de Marzo 2006 Dr. Alberto S. Villamil ICBA Hospital Dr. Cosme Argerich

2 J of Hypertens (esp) 2001, vol 6, No 2CLatHA Prevalencia, conocimiento, tratamiento y control de la HTA en Latinoamérica País Prev. % Conoc. Trat. Control. Argentina 28.1 54 42 14.3 Brasil 26.8 50 30 10 Chile 22.8 43 26.1 8.2 Ecuador 28.7 41 23 6.7 México 26.5 28 38 22 Paraguay 30.5 33.5 18.3 7.8 Perú 40 20 Uruguay 33 68 11 Venezuela 32.4 47 37 8.5 J of Hypertens (esp) 2001, vol 6, No 2

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4 Algoritmo para el Tratamiento de la HipertensiónModificaciones del Estilo de vida Presión Arterial fuera de objetivo (<140/90 mmHg) (<130/80 mmHg para aquellos con diabetes o enfermedad renal crónica) Elección inicial de Fármacos Hipertensión Estadío 2 (PAS >160 orPAD >100 mmHg) Combinación de 2 fármacos para la mayoría (generalmente diuréticos tiazídicos e IECA, BRA, BB, BCC) Hipertensión Estadío I (PAS 140–159 o PAD 90–99 mmHg) Diuréticos tiazídicos para la mayoría Considerar IEC A, BRA, BBC, BB o combinación. Sin Indicaciones obligatorias Droga(s) para indicaciones obligatorias Otras drogas antihipertensivas (diuréticos, IECA, BRA, BB, BCC) según necesidad. Con indicaciones obligatorias Presión Arterial no controlada Optimizar dosis o agregar drogas adiconales hasta lograr la presión arterial objerivo. Considerar consulta con un especialista en hipertensión.

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6 Primera instancia terapéutica(individualizar, según las siguientes alternativas) Diuréticos Beta-bloqueantes Calcioantagonistas Inhibidores de la enzima convertidora Antagonistas receptores AT-1 Asociaciones fijas en baja dosis

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8 AB/CD Algoritmo Clasificación:  Renina  Renina DrogasInhibitorias ACE inh/ARBs o  bloqueantes No inhibitorias CCBs o diuréticos A: IECA o AAT-1 B:  bloqueantes C: bloqueantes de canales cálcicos D: diuréticos

9 Combinación de drogas en el tratamiento de hipertensión arterial

10 Estratificación del Riesgo para establecer el pronósticoOtros factores de riesgo e historia clínica Presión Arterial (mmHg) Normal Normal Alta HTA Grado 1 HTA Grado 2 HTA Grado 3 PAS <130 PAS PAS PAS PAS 180 PAD <85 PAD PAD PAD PAD 110 Sin otros factores de riesgo Riesgo promedio Bajo riesgo adicional Riesgo adicional moderado Alto riesgo adicional 1 - 2 Factores de riesgo Muy alto riesgo adicional 3 o más factores de riesgo o DOB o diabetes Condiciones Clínicas Asociadas DOB: Daño de Organos Blanco / PAS: Presión Arterial Sistólica / PAD: Presión Arterial Diastólica Fuente: Guías para el Tratamiento de la Hipertensión Arterial. Sociedad Europea de HTA / Cardiología 2003.

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12 Compliance report Time of day 24:00 20:00 16:00 12:00 8:00 4:00 0:00PATIENT ID - 37 MEMS DRUG XXXXX Start date Stop date No. days monitored - 34 Dose regimen o.d. Duration of action 24 h No. doses taken - 32 Longest interdose h % days with correct no. of doses % Taking compliance % Shortest interdose h % doses taken on schedule % Therapeutic coverage % Time of day 24:00 20:00 A compliance record derived from electronic compliance monitoring is shown for a patient with hypertension taking once-daily antihypertensive medication over a 1-month period. Overall, this patients was highly compliant, taking 94.1% of daily doses. The majority (82.4%) of doses were taken on schedule. As a result, therapeutic coverage was high (91.2%). Compliance during weekend periods (indicated by pink columns on the slide) was notably worse than throughout the working week; more late and omitted doses were clearly apparent. This pattern of compliance is a well-characterised phenomenon. 16:00 12:00 8:00 4:00 0:00 28 April 5 May 12 May 19 May 26 May Weekend

13 Compliance report Time of day 24:00 20:00 16:00 12:00 8:00 4:00 0:00PATIENT ID - 8 MEMS DRUG XXXXX Start date Stop date No. days monitored - 126 Dose regimen o.d. Duration of action 36 h No. doses taken - 73 Longest interdose h % days with correct no. of doses % Taking compliance % Shortest interdose h % doses taken on schedule % Therapeutic coverage % Time of day 24:00 20:00 Compliance was monitored in a patient with hypertension over a 4-month period. Compliance deteriorated with time, although there was an increase in compliance at the point indicated by the arrow on the slide. Overall, the patient took their medication on 57.9%of the treatment days. Towards the end of the treatment period, both the number of days that the patient took their medication and the number of times medication was taken on schedule had deteriorated markedly. 16:00 12:00 8:00 4:00 0:00 19 April 10 May 31 May 12 July 21 July 02 Aug 23 Aug

14 Posibles combinaciones de agentes antihipertensivosDiuréticos Antagonista Receptores de Angiotensina II Beta bloqueantes Antagonistas Canales de Calcio Alfa bloqueantes IECAs Las familias de drogas que se presentan demostraron beneficios en estudios clínicos controlados Fuente: Guías para el Tratamiento de la Hipertensión Arterial. Sociedad Europea de HTA / Cardiología 2003.

15 - The Metabolic Syndrome -National Cholesterol Education Program (NCEP) Definition Any 3 or more of the following features: Blood pressure > 130 systolic or 85 diastolic • Fasting plasma glucose > 110 mg/dL (> 6.1 mmol/L) (American Diabetes Assoc > 100 mg/dL or > 5.5 mmol/L) • Serum triglycerides > 150 mg/dL (> 1.7 mmol/L) • Serum HDL cholesterol: < 40 mg/dL (< 1.0 mmol/L) < 50 mg/dL (< 1.3 mmol/L) • ♂ ♀ Abdominal obesity, waist girth: > 102 cm > 88 cm • ♂ ♀

16 The Metabolic Syndrome and Mortality(Journal of American Medical Association, 288: , 2002 ) Coronary Heart Disease Cardiovascular Disease All-Cause Mortality Metabolic Syndrome Yes No Cumulative Hazard, % Follow-up, years

17 Efecto de las drogas antihipertensivas en la regresión de la HVIA more recent meta-analysis evaluating the effect of different classes of antihypertensive agent on LVH regression included trials with angiotensin II receptor blockers (ARBs).1 In this analysis, ARBs and angiotensin-converting enzyme (ACE) inhibitors produced similar reductions in LVMI, and both ARBs and ACE inhibitors were significantly superior to beta-blockers in inducing LVH regression. Klingbeil AU, et al. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 2003;115:41–46. Diureticos Beta- bloqueant. Calcio Antagonistas IECA AT1-A Klingbeil et al. Am J Med 2003;115:41–46

18 Aterogénesis – origen y eventosHipertensión Factores de riesgo Tabaco LDL TG HDL Angiotensina II Diabetes Estrés Oxidativo Disfunción Endotelial PAI 1 Fibrinógeno Agregación Plaquetaria Adipocito PPAR γ Inflamación Aterogénesis Fibrosis Proliferación Remodelación HVI Fibrilación Auricular Ruptura de Placa Aterotrombosis Cambios Metabólicos Insulino resistencia SLIDE 4 (Link Slide) Atherogenesis – origins and outcomes The pathogenesis of atherosclerosis is highly complex and incompletely understood. It involves a gradual and progressive evolution from oxidative stress and inflammation through to fibrosis, cell proliferation and plaque rupture. Although the elements of the disease process are organised sequentially here for clarity, they are in fact closely interlinked and mutually exacerbating. The most important risk factors for atherosclerosis include hypercholesterolaemia (particularly oxidised LDL), hypertension, diabetes, smoking, oestrogen deficiency and elevated levels of angiotensin II.1 In response to these risk factors, oxidative stress and inflammation develop within the endothelium. Oxidative stress is closely linked to downregulation of nitric oxide activity and is associated with endothelial dysfunction, in which resistance arterioles no longer respond efficiently to regulatory stimuli Inflammation involves the increased expression of adhesion molecules, infiltration and proliferation of monocytes and macrophages, release of a range of pro-inflammatory cytokines and chemokines, and downregulation of matrix metalloproteinases. As a consequence of the chronic inflammatory insult, frank atherosclerosis develops within the blood vessel. This includes the development of fibrosis and the formation of atherosclerotic plaques, as well as smooth muscle cell proliferation in response to growth stimuli and a downregulation of apoptosis. Two major consequences of atherogenesis are: atherothrombosis, the rupture of plaques allied with clot formation morphological changes, both within the vasculature and within organs such as the kidney (e.g. renal artery stenosis) and heart, where both left ventricular hypertrophy and atrial remodelling occur in response to dysregulation of proliferative signalling and apoptosis. Other forms of cardiovascular pathology, including platelet activation and the metabolic syndrome, are related to atherosclerosis and compound its effects, increasing the risk of cardiovascular morbidity and premature death. References 1. Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003;91(3A):7A-11A. 2. Munger MA, Hawkins DW. Atherothrombosis: epidemiology, pathophysiology, and prevention. J Am Pharm Assoc (Wash DC). 2004;44(2 Suppl 1):S5-12 3. Murtagh BM, Anderson HV. Inflammation and atherosclerosis in acute coronary syndromes. J Invasive Cardiol. 2004;16(7): 4. Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep. 2004;6(3): Eventos Cardiovasculares IAM ACV ICC Enf. Vascular Periférica I. Renal Arritmia Harrison D et al. Am J Cardiol 2003; 91(3A): 7A-11A; Munger MA et al. J Am Pharm Assoc (Wash DC) 2004; 44(2 Suppl 1): S Murtagh BM et al. J Invasive Cardiol 2004; 16(7): Shishehbor MH et al. Curr Atheroscler Rep 2004; 6(3):

19 Endothelial dysfunction and oxidative stressSLIDE 7 Endothelial dysfunction and oxidative stress Endothelial dysfunction, arising as a consequence of oxidative stress, is one of the first physiological manifestations of atherogenesis. It is revealed by an impaired ability to vasodilate in response to physiological stimuli such as acetylcholine.1 An important cause of this impaired capacity for vasodilation is depletion of nitric oxide (NO). This molecule regulates vasodilation within a healthy endothelium, but during atherogenesis it is scavenged by reactive oxygen species, notably O2- to form the potent oxidant peroxynitrite (ONOO-).2 There are many sources of reactive oxygen species which trigger oxidative stress within the endothelium. These include both circulating oxidised LDL, and angiotensin II, which stimulates the upregulation of NAD(P)H in vascular smooth muscle cells.2 As endothelial dysfunction progresses, both the endothelium itself and invading inflammatory cells contribute to a progressive exacerbation of oxidative stress. One key local effect is an increase rate of lipid peroxidation. This can be measured by the thiobarbituric acid reactive substances (TBARS) which indicate the amount of lipid-derived free radicals in the bloodstream.3 References 1. Schiffrin EL, Park JB, Pu Q. Effect of crossing over hypertensive patients from a beta-blocker to an angiotensin receptor antagonist on resistance artery structure and on endothelial function. J Hypertens 2002; 20:71-78 2. Kaysen GA, Eiserich JP. The role of oxidative stress-altered lipoprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction. J Am Soc Nephrol 2004; 15: 3. Khan BV, Navalkar S, Khan QA, Rahman ST, Parthasarathy S. Irbesartan, an angiotensin type 1 receptor inhibitor, regulates the vascular oxidative state in patients with coronary artery disease. J Am Coll Cardiol 2001; 38: Kaysen & Eiserich. J Am Soc Nephrol 2004; 15:

20 Inflammation Granger et al. Hypertens 2004; 43: 924-931 SLIDE 12Oxidative stress within the endothelium triggers a range of inflammatory responses: A range of adhesion molecules such as vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1) and various selectins are expressed, causing adhesion of leukocytes to the endothelial surface.1 Leukocyte adhesion and invasion of the endothelium significantly exacerbates the inflammatory response.1,2 A battery of inflammatory molecules is released by the endothelial cells and invading monocytes and macrophages. These include inflammatory cytokines such as IL-6, chemokines such as monocyte chemoattractant protein (MCP) and inflammatory molecules such as superoxides.1-3 Matrix metalloproteinases (MMPs) are dysregulated, causing derangement of extracellular matrix deposition.1 Atherogenic inflammation is driven by a range of processes: Depletion of NO is one major contributory factor since this key endothelial regulator has anti-inflammatory effects.4 Systemic and local RAAS activation also drives vascular inflammation by a variety of mechanisms, including the induction of adhesive molecule expression on endothelial cells, leucocytes and platelets.1,2 Once the inflammatory process is initiated it becomes a self-sustaining process, with a range of cytokines driving the response and attracting further inflammatory cells to the site of injury. A large range of markers are available to assess endothelial inflammation. These include: Inflammatory cytokines such as IL-6 and TNF-alpha Anti-inflammatory cytokines such as IL-10 Inflammatory proteins such as high sensitivity C-reactive protein (hsCRP) Adhesive molecules such as VCAM-1 Monocyte binding assays MMP expression References 1. Strawn WB, Ferrario CM. Mechanisms linking angiotensin II and atherogenesis. Curr Opin Lipidol 2002; 13: Granger DN, Vowinkel T, Petnehazy T. Modulation of the inflammatory response in cardiovascular disease. Hypertension 2004; 43: Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004; 109 (21 Suppl 1): II27-33 4. Kaysen GA, Eiserich JP. The role of oxidative stress-altered lipoprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction. J Am Soc Nephrol 2004; 15: Granger et al. Hypertens 2004; 43:

21 Lipoperóxidos de Plasma (mmol/L)Nifedipina reduce los marcadores de estrés oxidativo e incrementa la capacidad antioxidante plasmática Taddei S et al. Hypertension 2001 Lipoperóxidos de Plasma (mmol/L) 4 3 2 1 Basal Nif 3.1 1.7* Isoprostanos (pg/mL) 80 60 40 20 35 22* FRAP (mmol/L) 800 600 400 200 428 629* *p<0.05 vs referencia FRAP: Disponibilidad férrica reducida plasmática, Nif: Nifedipino

22 Calcioantagonistas y ON Liberación de ON (nmol/L)Brovkovych V et al. Hypertension 2001 Calcioantagonistas y ON Sensor electroquímico 240 120 40 80 200 160 ,000 Liberación de ON (nmol/L) Nifedipina (nmol/L)

23 Ruptura de placa y trombosisPlaquetas PAI-1 Ruptura de placa MMP 2 y 9 CD68 (macrófagos) CD3 (celulas T) SLIDE 24 Plaque rupture and thrombosis Plaque rupture is a potentially lethal complication of atherosclerosis. It gives rise to local clot formation and the resulting thrombus may cause ischaemic damage, either by blocking the immediate artery or lodging elsewhere in the body. Atherothrombosis is responsible for most cases of myocardial infarction and ischaemic stroke, (which is the key process underlying vascular disease), which is the single most common cause of human mortality.1 One of the major causes of plaque rupture is believed to be the release by infiltrating macrophages of metalloproteinases and other proteolytic enzymes.2 These degrade the fibrous cap of the plaque, making it susceptible to rupture. Several markers indicate a risk of plaque rupture. These include levels of the molecules CD68 and CD3, which indicate macrophage and T cell activity, respctively,3 and matrix metalloproteinases such as MMP-2 and MMP-9.2 Rupture of the atherosclerotic plaque exposes the subendothelial collagen to the bloodstream.4  On contact with collagen, platelets become activated, with platelet adhesion aggregation leading to thrombus formation.5 Plasminogen activator inhibitor 1 (PAI-1) is an important driver of atherothrombosis, and PAI-1 levels are indicative of atherothrombotic risk.6 PAI-I is produced by endothelial cells and production levels are increased when NO is depleted.6 C-reactive protein, a major marker of inflammation, also increases PAI-1 levels as well as promoting atherothrombosis through effects on monocytes and endothelial cells.6 AT1 blockade may have the potential to inhibit both plaque rupture and platelet aggregation. The mechanisms through which these effects are mediated are still under investigation. Studies with irbesartan, reviewed here, are helping to elucidate this complex but therapeutically critical stage of atherogenesis. References 1. The World Health Report 2001, WHO, Geneva 2001 2. Cipollone F, Fazia M, Iezzi A et al. Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity. Circulation 2004; 109: 3. Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularization? de Boer OJ, van der Wal AC, Teeling P, Becker AE. Cardiovasc Res 1999;41: 4. Kumar V, et al. Basic Pathology. 5th Edition. Philadelphia, W.B. Saunders Co., 1992 5. D'Souza D, et al. Lancet. 1994;344:991 6. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003; 107:

24 Very nice

25 Sistema nervioso central Células madre hematopoyéticasMoore M. New Engl J Med 1999 Isla sanguínea Sistema nervioso central Angioblastos Células madre hematopoyéticas Endotelio Médula ósea Timo Célula T Tronco celular Ruta de la Circulación Leucocito Plaqueta Eritrocito Célula B La médula ósea produce células madre que contribuyen a la reparación del endotelio Very nice

26 We need two or three „circulating“ endothelial progenitor cells, if possible they should chnage their colour from „circulating“ = more bluish to „endothelial = red

27 Las EPC forman vasos sanguíneos en cultivos (I)Día 4 Día 5 Día 6 Saco de la Yema endodérmica Célula mesenquimatosa Concentrado de células angiogénicas Célula sanguínea primordial Célula endotelial Formación embriónica de vasos sanguíneos Diferenciación de EPC in vitro EPC: Células endoteliales precursoras The left side of this slide shows an image how blood vessels form in the embryo. Embryonic vasculogenesis begins as a cluster formation. Growth and fusion of multiple blood islands give rise to the yolk sac capillary network. After the onset of blood circulation, this network differentiates into an arteriovenous vascular system. The centers of these clusters will generate hematopoietic cells and are termed hematopoetic stem cells. Angioblasts are located at the periphery of the blood islands and are responsible to form the vessel themselves. Endothelial progenitor cells have properties similar to those of embryonic angioblast. EPCs can be defined as migratory endothelial cells with the capacity to circulate, proliferate, and differentiate into mature endothelial cells. It is possible to mimic these sequence in vitro. On the right hand you can see mononuclear cell obtained from the peripheral blood 4 days after culturing. A great number of spindle shaped hemangioblast can be seen.These hamangioblast differentiate into endothelial progenitor cells and hematopoetic stem cells. The HSC detach from the plate, therefor the number of spindle cells like cells is decreasing. The endothelial progenitor cells start to form tube like structures. After 7 days these EPC can be trypsinated and used to induce vessel formation or reendothelialization.

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29 Los factores de riesgo cardiovascular están asociados con la disminución en el número y diferenciación de las EPC Células endoteliales precursoras (unidades formadoras de colonias) –5 5 10 15 Escala de Riesgo de Framingham 20 40 60 30 50 70 p=0.001 Hill J et al. N Engl J Med 2001 EPC: Células endoteliales precursoras Cardiovascular risk factors are associated with a decrease in EPC number and differentiation

30 Correlación entre la función endotelial y el número de EPCHill J et al. N Engl J Med 2001 Correlación entre la función endotelial y el número de EPC Células endoteliales precursoras (unidades formadoras de colonias) 2 4 6 8 Cambio en la reactividad braquial (%) 20 40 60 30 50 70 10 16 12 14 p<0.001 EPC: Células endoteliales precursoras A similar slide could be used to discuss EPCs in more detail if appropriate for target audience

31 Seguimiento (meses) Enfoque Al Suwaidi J et al. Circulación 2000 28 (11–25) Flujo coronario, diámetro epicárdico Schachinger V et al. Circulación 2000 80 (13–126) Diámetro epicárdico Neunteufl T et al. Am J Cardiol 2000 60 (52–66) Arteria braquial Heitzer T et al. Circulación 2001 53 (30–87) Microcirculación del antebrazo Halcox J et al. Circulación 2002 46 (6–96) Flujo coronario, diámetro epicárdico Resultado Gokce N et al. Circulación 2002 1 Eventos CV post cirugía vascular Eventos coronarios Eventos CV La función endotelial como marcador pronóstico de enfermedad cardiovascular Outcomes and more studies need to be added.

32 Incremento máximo total*p=0.02 vs hidroclorotiazida + amilorida Motro M et al. Hypertension 2001 INSIGHT – Nifedipino Oros retarda la aparición de calcificación coronaria Incremento máximo total de calcio (%) 100 75 50 25 27.0 46.8 77.8 * 28.5 39.9 3.2 Nifedipino Oros Hidroclorotiazida + amilorida Basal Año 1 Año 2 Año 3

33 Valor de la progresión anual del grosor íntima-media (mm/año)INSIGHT – Nifedipino Oros bloquea la progresión del engrosamiento íntima-media Valor de la progresión anual del grosor íntima-media (mm/año) 0.008 0.006 0.004 0.002 –0.002 Año 2 Año 3 Año 4 Final del Estudio Hidroclorotiazida + amilorida Nifedipino Oros * ** *p<0.01, **p<0.001 vs cero en el grupo bajo tratamiento Simon A et al. Circulation 2001 OR – nifedipine lowers rate of IMT progression

34 Aterogénesis – origen y eventosHipertensión Factores de riesgo Tabaco LDL TG HDL Angiotensina II Diabetes Estrés Oxidativo Disfunción Endotelial PAI 1 Fibrinógeno Agregación Plaquetaria Adipocito PPAR γ Inflamación Aterogénesis Fibrosis Proliferación Remodelación HVI Fibrilación Auricular Ruptura de Placa Aterotrombosis Cambios Metabólicos Insulino resistencia SLIDE 4 (Link Slide) Atherogenesis – origins and outcomes The pathogenesis of atherosclerosis is highly complex and incompletely understood. It involves a gradual and progressive evolution from oxidative stress and inflammation through to fibrosis, cell proliferation and plaque rupture. Although the elements of the disease process are organised sequentially here for clarity, they are in fact closely interlinked and mutually exacerbating. The most important risk factors for atherosclerosis include hypercholesterolaemia (particularly oxidised LDL), hypertension, diabetes, smoking, oestrogen deficiency and elevated levels of angiotensin II.1 In response to these risk factors, oxidative stress and inflammation develop within the endothelium. Oxidative stress is closely linked to downregulation of nitric oxide activity and is associated with endothelial dysfunction, in which resistance arterioles no longer respond efficiently to regulatory stimuli Inflammation involves the increased expression of adhesion molecules, infiltration and proliferation of monocytes and macrophages, release of a range of pro-inflammatory cytokines and chemokines, and downregulation of matrix metalloproteinases. As a consequence of the chronic inflammatory insult, frank atherosclerosis develops within the blood vessel. This includes the development of fibrosis and the formation of atherosclerotic plaques, as well as smooth muscle cell proliferation in response to growth stimuli and a downregulation of apoptosis. Two major consequences of atherogenesis are: atherothrombosis, the rupture of plaques allied with clot formation morphological changes, both within the vasculature and within organs such as the kidney (e.g. renal artery stenosis) and heart, where both left ventricular hypertrophy and atrial remodelling occur in response to dysregulation of proliferative signalling and apoptosis. Other forms of cardiovascular pathology, including platelet activation and the metabolic syndrome, are related to atherosclerosis and compound its effects, increasing the risk of cardiovascular morbidity and premature death. References 1. Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003;91(3A):7A-11A. 2. Munger MA, Hawkins DW. Atherothrombosis: epidemiology, pathophysiology, and prevention. J Am Pharm Assoc (Wash DC). 2004;44(2 Suppl 1):S5-12 3. Murtagh BM, Anderson HV. Inflammation and atherosclerosis in acute coronary syndromes. J Invasive Cardiol. 2004;16(7): 4. Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep. 2004;6(3): Eventos Cardiovasculares IAM ACV ICC Enf. Vascular Periférica I. Renal Arritmia Harrison D et al. Am J Cardiol 2003; 91(3A): 7A-11A; Munger MA et al. J Am Pharm Assoc (Wash DC) 2004; 44(2 Suppl 1): S Murtagh BM et al. J Invasive Cardiol 2004; 16(7): Shishehbor MH et al. Curr Atheroscler Rep 2004; 6(3):

35 de Miocardio (7,2%) (2,5%) (6,6%)COMPARACION DE LA PREVALENCIA DE ENFERMEDAD CORONARIA E.E. U.U. FRANCIA ARGENTINA Población Enf. Coronaria * (7,2%) (5,3%) (7%) Infarto Agudo * de Miocardio (7,2%) (2,5%) (6,6%) Datos correspondientes a los años *Proyecciones de acuerdo a cifras del Ministerio de Salud

36 CAUSAS DE MORTALIDAD EN ARGENTINA. Comparación según etiologíaFuente: Ministerio de Salud Pública

37 EPIDEMIOLOGÍA DE LA ENFERMEDAD CARDIOVASCULAREN ARGENTINA HIPERTENSION ARTERIAL CARDIOPATIA ISQUEMICA ANGINA CRÓNICA ESTABLE

38 TRATAMIENTO FARMACOLOGICO DE LA ANGINA CRONICA ESTABLEBETA BLOQUEANTES NITRITOS DE ACCION CORTA O PROLONGADA CALCIOANTAGONISTAS OTRAS INTERVENCIONES * ASPIRINA U OTRO ANTIAGREGANTE * ESTATINAS * IECA

39 Efecto del tratamiento en enfermedad coronariaTratamiento Randomizado Diferencia de PA (mm Hg) RR (IC 95%) Régimen activo vs control IECA vs placebo -5 / -2 0,80 (0.73-0,88) CA vs placebo -8 / -5 0,78 (0,62-0,99) Más vs menos intenso -4 / -3 0,86 (0,72-1,03) Diferentes tratamientos activos IECA vs D/BB 2 / 0 0,98 (0,91-1,05) CA vs D/BB 0 / 0 1,01 (0,94-1,08) IECA vs CA 1 / 1 0,96 (0,88-1,05)

40 Indicaciones y contraindicaciones de las principales clases de antihipertensivosCondiciones que Favorecen su uso Contraindicaciones Tipo de droga Confirmadas Posibles Antagonista Canales de Calcio (dihidropiridinas) Pacientes ancianos; HT sistólica aislada; angor; enfermedad vascular periférica; aterosclerosis carotídea; Embarazo Taquiarritmias Insuficiencia cardíaca congestiva Antagonista Canales de Calcio (verapamilo, diltiazem) Angor; aterosclerosis carotídea; taquicardia supraventricular Bloqueo A-V (Grado 2 o 3); Fuente: Guías para el Tratamiento de la Hipertensión Arterial. Sociedad Europea de HTA / Cardiología 2003.

41 ANGINA CRONICA ESTABLEMEDICINA BASADA EN EVIDENCIA NO EXISTE ESTUDIO ALGUNO QUE HALLA EVALUADO LA EFICACIA Y SEGURIDAD DEL TRATAMIENTO CON CALCIOANTAGONISTAS EN ESTOS PACIENTES

42 BASES FISIOPATOLOGICASEFECTO VASODILATADOR CORONARIO DESCENSO DE LA PRESION ARTERIAL EFECTO PROTECTOR ENDOTELIAL REDUCCION DEL ESTRÉS OXIDATIVO REDUCCIÓN DE LA MASA VENTRICULAR METABOLICAMENTE FAVORABLES INDUCTOR DE ANGIOGÉNESIS ???

43 A Coronary disease Trial Investigating Outcome with Nifedipine GITSACTION – A Coronary disease Trial Investigating Outcome with Nifedipine GITS – is the first large-scale, long-term trial to assess clinical outcomes with an anti-anginal drug in patients with symptomatic stable angina. ACTION was a multicentre, randomised, placebo-controlled, double-blind, parallel group trial comparing the effects of long-acting nifedipine GITS with placebo in patients with coronary artery disease (CAD) who were already receiving the current standard of medical care. Patients were recruited between November and December 1996 and the study was completed in September 2003.

44 Diseño (2) Nifedipina OROS 30–60mg 1 vez/día sobre la mejor terapéutica estandar n=3.825 Pacientes con angina estable 35 años n=7.665 Placebo sobre la mejor terapéutica estandar n=3.840 Study medication, which was additional to ongoing medical therapy for CAD, consisted of either nifedipine GITS or placebo. The starting dose was 30mg once daily, which was titrated to 60mg once daily within 6 weeks if well tolerated. Study medication was continued at this dose until the end of the trial (i.e., at least 4 years for the last patient started on study medication).1 The aim was to maintain patients on study medication for as long as possible; therefore, dose reduction or interruption was allowed. After the start of study medication, all patients continued to receive the concomitant treatment regimen on which they had been previously stabilised. Other CCBs could not be combined with study medication. 1. Lubsen J, Poole-Wilson PA, Pocock SJ, et al. Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Eur Heart J 1998;19(suppl I):I20–32. 1 2 3 4 5 6 Años Final del estudio

45 Selección de pacientesCriterios clave de inclusión Criterios clave de exclusión 35 años Enfermedad coronaria confirmada Condición clínica estable por 1 mes Tratamiento antisquémico usual a excepción de calcioantagonistas en las 2 semanas previas a la inclusión Fracción de eyección > 40% Recibiendo terapia hipolipemiante Atención ambulatoria Evento CV mayor o intervenciones en los 3 meses previos a inclusión Intolerancia a calcioantagonistas Enfermedad valvular, pulmonar, diabetes insulino dependiente no bien controlada y trastornos gastrointestinales (tabletas OROS) Hipotensión ortostática o PA muy elevada pese al tratamiento Drogas que interfieran con la medicación en estudio Embarazo Eligible patients were those who were ambulatory, aged 35 years or older, had angina pectoris and had been stable for at least 1 month and required treatment for anginal attacks.1 Reasons for exclusion from the trial were: Heart failure (HF) that was either symptomatic or required specific treatment Any major CV event or intervention within the last 3 months Planned coronary angiography or intervention Known intolerance to CCBs Clinically significant valvular or pulmonary disease Unstable insulin-dependent diabetes mellitus Any gastrointestinal condition that could either compromise absorption of nifedipine GITS or passage of the tablet Any condition other than CAD that limited life expectancy Symptomatic orthostatic hypotension or supine systolic blood pressure (BP) 90mmHg Systolic BP 200mmHg and/or diastolic BP 105mmHg Creatinine above twice the upper limit of normal Alanine aminotransferase or aspartate aminotransferase above three times the upper limit of normal Pregnancy. 1. Lubsen J, Poole-Wilson PA, Pocock SJ, et al. Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Eur Heart J 1998;19(suppl 1):I20–32.

46 Datos demográficos basalesNifedipina OROS Placebo Edad media (DS) (años) 63.5 (9.3) 63.4 (9.3) Historia de IAM (%, n) 52 (1,974) 50 (1,924) CRM/Angioplastía (%, n) 20 (766) 20 (759) Test esfuerzo positivo (%, n) 16 (616) 17 (646) Angina de pecho (%, n) 93 (3,544) 92 (3,526) Diabetes mellitus (%, n) 15 (565) 14 (545) PAS media (DS) (mm Hg) 137.3 (18.8) 137.6 (18.6) PAD media (DS) (mm Hg) 79.9 (9.4) 79.8 (9.5) FC media (DS) (lat/min) 64.3 (10.3) 64.4 (10.3) F. Eyección media (DS) (%) 48.3 (6.4) 48.2 (6.4) Placebo The mean age of patients was 63 years, 80% of patients were male and 98% were Caucasian. A high proportion of patients (50%) had a history of MI, making ACTION the largest trials of an anti-anginal drug in post-MI patients. Mean BP at baseline was 137/80mmHg. Treatment groups were well balanced at baseline.

47 El tratamiento previo a la inclusión cumplió los criterios de la mejor práctica clínicaMedicación Basal Pacientes (%) Antianginosos 99 Hipolipemiantes 68 IECA 20 Aspirina 86 β-bloqueantes 80 All the patients in ACTION were receiving current optimal therapy for symptomatic stable angina prior to study intervention. Medication at baseline in ACTION was far superior to other recent CAD outcome trials including IONA (Impact Of Nicorandil in Angina) and EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease), in particular the use of statins and lipid-lowering drugs. More patients received intervention than reported in the EUROASPIRE (EUROpean Action on Secondary and Primary prevention by Intervention to Reduce Events) I and II surveys. Current treatment guidelines for patients with CAD recommend an identical treatment strategy to that used in ACTION,1 with the addition of increased use of ACE inhibitors. Although 52% of patients were classified with grade 1–3 hypertension at baseline, only 30% of the study population were receiving antihypertensive therapy. Having excluded CCBs from the permitted concomitant therapy, the majority of patients with hypertension were receiving diuretics and ACE inhibitors. 1. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:159–68.

48 Comparación ACTION HOPE PROGRESS Aspirina 86 % 76 % 60 %Hipolipemiantes 68 % 29 % 16 % B-bloqueantes 80 % 39 % 17 % Antianginosos 99 % 74 % 63 % Diuréticos 11 % 15 %

49 ACTION – CaracterísticasEl estudio mas grande realizado con drogas antianginosas en pacientes con angina estable sintomática (7.665 pacientes) Más de pacientes – año Seguimiento medio de 5 años Alto nivel de adherencia al tratamiento – nifedipina OROS: 79% Se completó el protocolo sin cambios respecto al proyecto original ACTION included 7,665 patients with stable angina, making it the largest randomised trial of an anti-anginal drug to date. With more than 38,000 patient–years of follow-up, ACTION was estimated to have 95% power to detect a 18% reduction in the primary efficacy endpoint by nifedipine GITS relative to placebo at an overall 5% significance level. Patients in ACTION were followed for a mean of 5 years. Treatment compliance was 79% for nifedipine GITS – similar to perindopril in EUROPA (78%) – indicating that nifedipine GITS is well tolerated. Relief from the painful symptoms of angina, such as severe chest pain, provided by nifedipine GITS is likely to be the primary factor driving this high level of treatment compliance. The low level of adverse events experienced by patients receiving nifedipine GITS is also a contributing factor. The trial went to completion with no alteration of the protocol, in contrast to other studies such as EUROPA.

50 5 centros (128 pts) excluídos 4 no iniciaron el estudioPerfil del estudio 7.797 reclutados 5 centros (128 pts) excluídos 4 no iniciaron el estudio 7.665 en análisis de ITT 3.825 nifedipina OROS 3.840 placebo ACTION was completed as planned with no changes to protocol. In total 7,797 patients were allocated to study medication, of whom 7,665 patients were included in the intention-to-treat (ITT) analysis. 3,825 patients were started on nifedipine GITS and 3,840 on placebo. Follow-up was 97.3% complete. Patients randomised to nifedipine GITS were receiving study medication for 79% of follow-up time compared with 82% for patients receiving placebo. 179 incompletos 181 incompletos 291 muertes 310 muertes 3.334 completos 3.370 completos

51 Frecuencia de eventos clínicosPuntos finales individuales Nifedipina OROS (n) Placebo (n) Hazard ratio (p) Cambio (%) Muerte 310 291 1.07 (0.41) – IAM 267 257 1.04 (0.62) Angina refractaria 150 174 0.86 (0.18)  14 Insuficiencia cardíaca 86 121 0.71 (0.015)  29 ACV 77 99 0.78 (0.10)  22 Procedimiento de revascularización periférica 146 118 1.25 (0.073)  24 Angiografía coronaria 895 1,068 0.82 (<0.0001)  18 Angioplatía 385 417 0.92 (0.25)  8 CRM 294 371 0.79 (0.0021)  21 ACTION demonstrated unequivocal safety with nifedipine GITS in patients with CAD. For the chosen primary efficacy endpoint of the combined rate of death (any cause), MI, refractory angina, new overt HF, debilitating stroke and peripheral revascularisation procedures, there was no statistically significant benefit with additional nifedipine GITS intervention. A neutral primary efficacy endpoint may be due to several reasons: Further reduction of CV events is not realistic in patients with stable angina who are already receiving anti-anginal, antihypertensive and lipid-lowering drugs in a near optimal manner Patients with stable angina have a low mortality rate. The rate in the placebo group was 1.53/100 patient–years compared with 1.64/100 patient–years in the nifedipine GITS group with an absolute difference of 1.1 death/100 patients–years of follow-up, which was almost entirely due to non-CV causes Peripheral revascularisation procedures – a component of the combined primary endpoint – increased in the nifedipine GITS group. As peripheral vascular disease and coronary heart disease often co-exist, patients who experienced improved exercise capacity due to treatment with nifedipine GITS may then manifest the symptoms of peripheral vascular disease, thus requiring further intervention Nifedipine GITS showed a very strong trend for stroke reduction. If ACTION had a less stringent definition of stroke and had included more patients, a significant reduction in this endpoint may have been achieved.

52 Action - Control de la presión arterial74 80 1 2 3 4 5 6 PA Diastólica 125 130 135 140 PA Sistólica Nifedipina OROS Placebo p<0.0001 In addition to concomitant antihypertensive treatment, nifedipine GITS further reduced both mean systolic and diastolic BP by 6/3mmHg (p<0.0001) relative to placebo. The BP lowering achieved with nifedipine GITS in ACTION was similar to the overall BP reduction reported in the EUROPA study; however, there is evidence that the real BP effects are larger in EUROPA than described in the study. BP reduction with nifedipine GITS was rapid and sustained throughout the study period. The difference in BP levels between the two treatment groups is conclusive evidence that nifedipine GITS provides excellent BP control, and that standard intervention was not optimal for this group of CAD patients.

53 A Favor nifedipina OROSResultados I Punto final 0.41 0.54 0.0012 Hazard ratio (95% CI) p 1.07 (0.91–1.25) 0.97 (0.88–1.07) 0.89 (0.83–0.95) 0.5 1 1.5 2 Mortalidad total Punto final primario Punto final primario e intervenciones A Favor nifedipina OROS A Favor placebo Nifedipine GITS had a positive impact on two of the predefined secondary endpoints: The combined rate of death, major CV events, revascularisation and coronary angiography was reduced by 11% (p=0.0012), which was due to the marked reduction in the need for coronary angiography. The occurrence of any vascular event was reduced by 9% (p=0.027) due to the reduced need for percutaneous coronary interventions and CABG.

54 A favor nifedipina OROSResultados II Punto final 0.41 0.62 0.18 0.015 0.10 0.073 Hazard ratio (95% CI) p 1.07 (0.91–1.25) 1.04 (0.88–1.24) 0.86 (0.69–1.07) 0.71 (0.54–0.94) 0.78 (0.58–1.05) 1.25 (0.98–1.59) 0.5 1 1.5 2 Muerte IAM Angina refractaria ICC ACV invalidante Revascularización periférica A favor nifedipina OROS A favor placebo Of note, nifedipine GITS reduced the incidence of new overt HF by 29% (p=0.015). This was an unexpected result and may be explained by the long-term reduction of ischaemic episodes and additional sustained BP reduction. The incidence of debilitating stroke was reduced by 22% in the nifedipine GITS group (p=0.10). The relationship between increasing BP and incidence of stroke has been long established.1 Reasons for not reaching statistical significance in ACTION include insufficient magnitude of additional BP reduction and the stringent definition used for stroke. Nifedipine GITS was also associated with a trend for the reduction in the incidence of refractory angina compared with placebo (150 vs 174, respectively; p=0.18). This is an important finding as development of refractory angina is a measure of disease progression and is associated with an increased risk of progression to unstable angina and MI. 1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13.

55 Punto final primario en subgrupo de hipertensos0.015 0.027 0.008 Odds ratio (95% CI) p (0.768–0.993) (0.812–0.988) 0.832 (0.726–0.954) 0.5 1 1.5 2 Punto final primario Putno final primario e intervenciones Cualquier evento CV A favor nifedipina OROS A favor placebo The primary endpoint was met in the patient subgroup classified as hypertensive at baseline (systolic BP 140mmHg or diastolic BP 90mmHg) who were receiving nifedipine GITS. Nifedipine GITS significantly reduced the combined rate of death and major CV events by 13% (p=0.015) in addition to optimal therapy. Therefore, nifedipine GITS provides additional benefit in hypertensive patients, improving clinical outcomes to a greater degree than in all patients with CAD. This finding confirms the importance of stringent BP control for reducing CV risk.

56 Dual mecanismo de acción¿Protección Vascular? 21% reducción en CRM 18% reducción en angiografía coronaria 14% reducción en angina refractaria* ¿Reducción de PA? 29% reducción en nueva ICC 22% reducción en ACV invalidante* Nifedipine GITS works through its combined BP lowering and vascular-protective effects. BP lowering: The incidence of overt HF was significantly reduced by 29% with nifedipine GITS. Nifedipine GITS reduced the incidence of stroke by 22%, which was expected as significant BP lowering was achieved. The stroke definition was very stringent (debilitating with clinical signs and functional impairment present 30 days after onset of symptoms or death within 30 days), which affected the number of reported cases and likely explains why significance was not achieved. Vascular protection: Nifedipine GITS was associated with a significant reduction in the need for coronary interventions such as CABG and coronary angiograms – a positive finding for patients, as quality of life is improved, and also the healthcare system, as a reduction in revascularisation procedures has serious cost-saving implications Reduction in the need for coronary angiograms is an indicator of the anti-anginal effect of nifedipine GITS, resulting in relief from anginal pain and reduced atherosclerosis progression. This finding confirms the vascular-protective effects of nifedipine GITS Treatment with nifedipine GITS was associated with a reduction in the incidence of refractory angina, although this did not achieve statistical significance. Development of refractory angina is a measure of disease progression, but more importantly, it is associated with an increased risk of progression to unstable angina or MI. *No estadísticamente significativo

57 Aterogénesis – origen y eventosHipertensión Factores de riesgo Tabaco LDL TG HDL Angiotensina II Diabetes Estrés Oxidativo Disfunción Endotelial PAI 1 Fibrinógeno Agregación Plaquetaria Adipocito PPAR γ Inflamación Aterogénesis Fibrosis Proliferación Remodelación HVI Fibrilación Auricular Ruptura de Placa Aterotrombosis Cambios Metabólicos Insulino resistencia SLIDE 4 (Link Slide) Atherogenesis – origins and outcomes The pathogenesis of atherosclerosis is highly complex and incompletely understood. It involves a gradual and progressive evolution from oxidative stress and inflammation through to fibrosis, cell proliferation and plaque rupture. Although the elements of the disease process are organised sequentially here for clarity, they are in fact closely interlinked and mutually exacerbating. The most important risk factors for atherosclerosis include hypercholesterolaemia (particularly oxidised LDL), hypertension, diabetes, smoking, oestrogen deficiency and elevated levels of angiotensin II.1 In response to these risk factors, oxidative stress and inflammation develop within the endothelium. Oxidative stress is closely linked to downregulation of nitric oxide activity and is associated with endothelial dysfunction, in which resistance arterioles no longer respond efficiently to regulatory stimuli Inflammation involves the increased expression of adhesion molecules, infiltration and proliferation of monocytes and macrophages, release of a range of pro-inflammatory cytokines and chemokines, and downregulation of matrix metalloproteinases. As a consequence of the chronic inflammatory insult, frank atherosclerosis develops within the blood vessel. This includes the development of fibrosis and the formation of atherosclerotic plaques, as well as smooth muscle cell proliferation in response to growth stimuli and a downregulation of apoptosis. Two major consequences of atherogenesis are: atherothrombosis, the rupture of plaques allied with clot formation morphological changes, both within the vasculature and within organs such as the kidney (e.g. renal artery stenosis) and heart, where both left ventricular hypertrophy and atrial remodelling occur in response to dysregulation of proliferative signalling and apoptosis. Other forms of cardiovascular pathology, including platelet activation and the metabolic syndrome, are related to atherosclerosis and compound its effects, increasing the risk of cardiovascular morbidity and premature death. References 1. Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003;91(3A):7A-11A. 2. Munger MA, Hawkins DW. Atherothrombosis: epidemiology, pathophysiology, and prevention. J Am Pharm Assoc (Wash DC). 2004;44(2 Suppl 1):S5-12 3. Murtagh BM, Anderson HV. Inflammation and atherosclerosis in acute coronary syndromes. J Invasive Cardiol. 2004;16(7): 4. Shishehbor MH, Hazen SL. Inflammatory and oxidative markers in atherosclerosis: relationship to outcome. Curr Atheroscler Rep. 2004;6(3): Eventos Cardiovasculares IAM ACV ICC Enf. Vascular Periférica I. Renal Arritmia Harrison D et al. Am J Cardiol 2003; 91(3A): 7A-11A; Munger MA et al. J Am Pharm Assoc (Wash DC) 2004; 44(2 Suppl 1): S Murtagh BM et al. J Invasive Cardiol 2004; 16(7): Shishehbor MH et al. Curr Atheroscler Rep 2004; 6(3):

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