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© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: May 2005

eprosartan mesylate. eprosartan and hydrochlorothiazide. Eprosartan in the treatment of essential hypertension, with special emphasis on systolic blood pressure and the secondary prevention of stroke. © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: May 2005.

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© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: May 2005

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  1. eprosartan mesylate eprosartan and hydrochlorothiazide Eprosartan in the treatment of essential hypertension, with special emphasis on systolic blood pressure and the secondary prevention of stroke © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: May 2005

  2. Please see Summary of Product Characteristics before prescribing eprosartan Other tradenames include Tevetens®, Tevetenz®, Teveten® HCT, Teveten® Comp, and Tevetens® Plus References cited in this slide set are numbered to correspond with those in the companion eprosartan e-monograph

  3. Hypertension - is it well controlled? “a large body of evidence suggests that, in overall terms, blood pressure is not well controlled, and in particular, that elevated systolic blood pressure is poorly controlled”13 “surveys continue to show substantial underdiagnosis, undertreatment and poor rates of blood pressure control”2 2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19

  4. HYPERTENSION Why should hypertension be treated? • ischaemia • myocardial infarction • cardiac hypertrophy • congestive heart failure • stroke • TIA (transient ischaemic attack) • PRIND (prolonged, reversible, ischaemic, neurological deficit) • retinopathy • lesions • swelling of optic disc • blindness • nephrosclerosis • atrophy of nephrons • renal failure

  5. A major risk factor for CVD “The relationship between BP and risk of cardiovascular disease (CVD) events is continuous, consistent, and independent of other risk factors”14 “elevated systolic blood pressure is a particularly strong predictor for risk of stroke”13 14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19

  6. Mortality and morbidity • 12-14% of deaths from coronary heart disease are due to high blood pressure … 6% of these deaths could be avoided if the incidence of hypertension was reduced by 50%1 • Approximately 20% of people die within the first few months after a stroke • Up to 35% of stroke victims will be dependent at 1 year2 1. Petersen S, Rayner M. Coronary heart disease statistics 2002 edition. British Heart Foundation Statistics Database Annual Compendium., 2. Williams B, et al. J Hum Hypertens 2004;18:139-185

  7. Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Classification of hypertension2,15 140-159 mmHg systolic 90-99 mmHg diastolic 160-179 mmHg systolic 100-109 mmHg diastolic >180 mmHg systolic >110 mmHg diastolic The JNC-7 Report14 combines Grades 2 and 3 2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 15. ESH Guidelines Committee. J Hypertens 2003;21(6):1011-1053

  8. Isolated systolic hypertension (ISH)2,15 • ISH means raised systolic BP with normal or low diastolic BP • Most older hypertensive patients have isolated systolic (or systolic predominant) hypertension Grade 1 ISH = 140-159/<90 mmHg Grade 2 ISH = >160/<90 mmHg 2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 15. ESH. J Hypertens 2003;21(6):1011-1053

  9. Importance of SYSTOLIC hypertension • Systolic blood pressure (SBP) is a powerful predictor of all-cause mortality, coronary artery disease, stroke and renal disease16 • SBP is regarded as the major factor to control in patients over 50 years of age2,14 • Optimal therapy for these patients should be to reduce SBP while minimising the reduction of DBP18 2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 18. Kannel W. Drugs Aging 2003;20:277-286

  10. MRFIT study – importance of SBP4 MRFIT showed a strong correlation between risk of stroke and increased blood pressure, especially SBP 4. Stamler J, et al. Arch Intern Med 1993;153:598-615 (This diagram shows SBP and DBP at baseline and adjusted stroke mortality for men. Relative Risk was adjusted to take into account several factors including age, race, serum cholesterol, smoking and diabetic medication)

  11. Benefits of reducing raised SBP • Syst-Eur20 • 4,695 elderly patients with ISH • treatment with the Ca-blocker nitrendipine gave a 42% risk reduction for total stroke • SHEP19 • 4,736 elderly patients with ISH • antihypertensive treatment reduced stroke by 36%, CAD by 27%, and CHF by 49% 19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;350:757-764

  12. Syst-Eur (elderly patients with ISH)20 6 Fatal or non-fatal stroke (events per 100 patients) placebo * p=0.003 5 4 3 * active treatment 2 1 0 0 1 2 3 4 Time since randomisation (years) 20. Staessen JA, et al. Lancet 1997;350:757-764

  13. Arterial compliance and raised SBP • A major factor contributing to raised SBP is decreased arterial compliance, associated with altered aortic wave travel and reflection16,21 • Reduced arterial compliance is generally caused by arterial stiffening • This is usually a consequence of aging or atherosclerosis, which may be why hypertension in older people is predominantly systolic 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 21. London GM, Guerin A. J Hypertens 1999;17(Suppl 2):S3-S6

  14. RAS and SNS both control of SBP16 RAS = renin-angiotensin system; SNS = sympathetic nervous system; HTN = hypertension; CHF = congestive heart failure; ESRD = end-stage renal disease; CAD = coronary artery disease; LVH = left ventricular hypertrophy 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32

  15. presynaptic AT1 receptor sympathetic neurone angiotensin II postsynaptic AT1 receptor (+) norepinephrine postsynaptic alpha-1 receptor blood vessel The neuro-effector junction16 Angiotensin II … postsynaptic and presynaptic effects 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32

  16. Renin-angiotensin system (RAS)

  17. Primary intervention studies • Early trials found that treatment with diuretics or Ca-blockers reduced blood pressure and decreased morbidity and mortality19,20 • It became a common conclusion that any drug which reduced blood pressure would reduce the risk of cardiovascular disease25 • However, it has since been found that this is not the case for beta-blockers26-29 or the ACE inhibitor perindopril30 19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;360:757-764., 25. Messerli F. XXVI ESC, Munich, 2004., 26. MRC Working Party. BMJ 1985;291:97-104., 27. MRC Working Party. BMJ 1992;304:405-413., 28. The Dutch TIA trial study group. Stroke 1993;24:543-548., 29. Eriksson S, et al. Cerebrovasc Dis 1995;5:21-25., 30. PROGRESS Collaborative Group. Lancet 2001;358:1033-1041

  18. AIIA intervention studies -1 LIFE31 Stroke rate was 5% with losartan and 7% with atenolol (RRR=25%) SCOPE32 Candesartan significantly reduced the risk of non-fatal stroke in elderly patients by 27.8% 31. Dahlöf B, et al. Lancet 2002;359:995-1003., 32. Lithell H, et al. J Hypertens 2003;21:875-886

  19. AIIA intervention studies -2 VALUE33 No significant differences between valsartan and amlodipine in CVD; valsartan significantly reduced the number of new cases of diabetes CHARM34 Candesartan significantly reduced all-causes mortality and the number of patients developing new diabetes 33. Julius S, et al. Lancet 2004;363:2022-2031., 34. Kulbertus H. Rev Med Liege 2003;58(10):646-652

  20. AIIA intervention studies -3 PRIME35 Irbesartan reduced the risk of progressing to more advanced stages of kidney disease in hypertensive patients with type-2 diabetes and kidney disease It also significantly reduced the number of hospitalisations due to congestive heart failure 35. Program for irbesartan mortality and morbidity evaluations (PRIME). Data on file.

  21. eprosartan mesylate eprosartan and hydrochlorothiazide

  22. Eprosartan - unique dual action10,11,16 blockade of postsynaptic AT1 receptor inhibits action of angiotensin II blockade of presynaptic AT1 receptor inhibits norepinephrine release into the synapse 10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251., 11. Balt JC, et al. J Hypertens 2001;19(3):465-473., 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32

  23. Affinity for AT1 receptors • Inhibition of AT1 receptors by eprosartan is dose-dependent and ‘surmountable’ 37 • Eprosartan can be displaced if angiotensin II output increases, eg. in response to a fall in blood volume • Most other AIIAs bind non-competitively to AT1 receptors and are not readily displaced by increased angiotensin II output38 37. Edwards RM, et al. J Pharmacol Exp Ther 1992;260:175-181., 38. Hollenberg NK. Pharmacotherapy 1999;19(4 Pt 2):71S-72S

  24. Dose-related inhibition of AT1 in man39 Percentage inhibition of the effects of angiotensin II by various doses of eprosartan in healthy volunteers 100 - 80 - 60 - 40 - 20 - 0 - Inhibition of angiotensin II (%) 86% 71% 56% 70mg 100mg 200mg eprosartan dosage 39. Ilson B. Am J Hypertens 1998;11(4 Pt 2):108A (Abstract E051)

  25. Sympatho-inhibitory effects10 Acute effects on the pressor response to spinal cord stimulation in pithed rats of eprosartan, losartan, valsartan irbesartan (0.3mg/kg iv; n=4 for each AIIA) 40 - 20 - 0 - - 20 - - 40 - Change in DBP vs controls (%) eprosartan losartan valsartan irbesartan Sympathetic stimulation at 1Hz. Drugs were given intravenously 10 min before stimulation (acute effect) p<0.05 10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251

  26. Sympathetic inhibition in man40 • Randomised, double-blind, crossover study • 16 healthy male volunteers received a single dose of eprosartan 600mg or placebo, followed by insulin-induced hypoglycaemia • The pulse pressure response to sympatho-adrenal activation was significantly reduced by eprosartan compared with placebo (p=0.02) 40. Christensen M, et al. Clin Sci 2005;108:113-119

  27. Overview of efficacy • Effect on SBP and pulse pressure • Studies versus active comparators • Studies versus placebo • Efficacy in older patients • Efficacy in black patients • Long-term efficacy • Efficacy in combination with other drugs • Secondary prevention of stroke (MOSES) • Effect on blood platelets / fibrinolytic function • Renoprotective effects

  28. Sega – more effective than enalapril5 • 118 patients with severe hypertension • Randomised, parallel group study • 8-week double-blind titration phase was followed by a 2-week maintenance phase • - eprosartan 400mg/day (up to 600 or 800mg) • - enalapril 10mg/day (up to 20 or 40mg) • - HCTZ 25mg/day added at week 6 in patients not achieving target BP 5. Sega R, et al. Blood Pressure 1999;8:114-121

  29. Sega – more effective than enalapril5 Mean reduction from baseline of sitSBP and sitDBP, following treatment with eprosartan or enalapril in severe hypertension sitting systolic BP sitting diastolic BP - 0 - - 10 - - 20 - - 30 - Reduction in blood pressure from baseline (mmHg) -16.2 -20.1 -21.2 N.S. -29.1 p=0.025 enalapril 10-40mg/day (n=46) eprosartan 400-800mg/day (n=43) 5. Sega R, et al. Blood Pressure 1999;8:114-121

  30. Ruilope – effective control of SBP41 • 12-week, double-blind, randomised trial in 334 patients aged >65 years with predominantly systolic hypertension • Eprosartan (600-800mg/day) and enalapril (5-20mg/day) reduced sitSBP to a similar extent • At week 3 there were significantly more responders with eprosartan than with enalapril for SBP (30% versus 20%, p=0.033) 41. Ruilope L, et al. Blood Pressure 2001;10:223-229

  31. Punzi – effective control of SBP42 Mean change from baseline in sitSBP in ISH patients >60yrs of age: 9 weeks of monotherapy followed by 4 weeks in combination with HCTZ week 3 week 6 week 9 week 13 - 0 - - 5 - - 10 - - 15 - - 20 - - 25 - Mean change in sitSBP from baseline (mmHg) placebo * ** eprosartan * p<0.0001 between treatments ** p<0.002 between treatments 42. Punzi HA, et al. J Human Hypertens 2004:1-7

  32. Teitelbaum – effective control of SBP43 • Evaluated eprosartan (600mg/day alone or with HCTZ) in 195 patients aged 60-84yrs with ISH or combined systolic-diastolic hypertension • SBP was significantly reduced at study endpoint from baseline (p<0.0001) • Reduction in DBP was significantly greater in patients with combined systolic-diastolic hypertension than in those with ISH (12.2 versus 5.0 mmHg, respectively, p<0.0001) 43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C

  33. Teitelbaum – pulse pressure reduction43 Mean pulse pressure during eprosartan treatment in patients with ISH or combined systolic-diastolic hypertension * p<0.0001 ISH versus non-ISH ISH non-ISH ** p<0.05 ISH versus non-ISH 90 - 80 - 70 - 60 - 50 - 40 - Mean pulse pressure (mmHg) p<0.0001 versus baseline * ** week 2 week 4 week 6 week 10 baseline follow-up (weeks) 43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C

  34. de la Sierra – pulse pressure reduction46,47 • 3,133 hypertensive patients in primary care • Eprosartan significantly reduced pulse pressure at 12 weeks (mean -13.5 mmHg from baseline, p<0.001) • In 895 patients with ISH, mean SBP and pulse pressure were reduced by 25.6 mmHg and 22.5 mmHg (both p<0.05 versus baseline) • DBP decreased by 3.1 mmHg in ISH patients (versus 16.7 mmHg for non-ISH patients) 46. de la Sierra A, et al. Can J Cardiol 2004;20(Suppl C):17C-22C., 47. de la Sierra A, et al. Blood Pressure 2004;13(Suppl 2):5-10

  35. Robles – pulse pressure reduction48 Reduction in mean pulse pressure, arterial pressure, SBP and DBP in a 16-week open-label study (n=566) pulse pressure arterial pressure systolic pressure diastolic pressure - 0 - - 10 - - 20 - - 30 - Reduction in blood pressure from baseline (mmHg) -13 -13 -17.4 -26 all changes p<0.0001 versus pretreatment baseline 48. Robles NR, et al. Int J Clin Pract 2005;59(4):478-484

  36. Elliott – study versus enalapril8 Responders to eprosartan (400-600mg/day) and enalapril (5-20mg/day) at the end of 26 weeks of treatment in 528 patients with mild-to-moderate hypertension % responders p=0.018 100 - 80 - 60 - 40 - 20 - 0 - 81.7% 73.4% 70.3% 62.6% eprosartan monotherapy eprosartan + HCTZ enalapril monotherapy enalapril + HCTZ 8. Elliott WJ, et al. J Hum Hypertens 1999;13:413-417

  37. Oparil – study versus enalapril9 Reduction in sitDBP from baseline to endpoint after 6 weeks of eprosartan (600mg/day), enalapril (20mg/day) or placebo in 136 patients with mild-to-moderate essential hypertension eprosartan 600mg/day enalapril 20mg/day placebo - 0 - - 2 - - 4 - - 6 - - 8 - - 10 - Reduction in sitDBP from baseline (mmHg) - 4.4 - 7.9 - 8.7 p<0.002 p<0.035 9. Oparil S. Curr Ther Res 1999;60(1):1-14

  38. Puig – study versus losartan49 • Compared 4 weeks of treatment with eprosartan (600mg/day) or losartan (50mg/day) in a randomised, double-blind study in 60 outpatients with mild-to-moderate hypertension • Mean sitting BP was reduced by 12.4/12.7 mmHg with eprosartan and by 9.6/10.9 mmHg with losartan (N.S.) • At study endpoint there were 73% eprosartan responders and 53% losartan responders (N.S.) 49. Puig JC, et al. J Hypertens 1999;17:1033-1039

  39. Hedner – study versus placebo50 Reduction in sitDBP from baseline to endpoint after 13 weeks treatment with eprosartan 400-800mg bd or od compared with placebo in 243 patients with mild-to-moderate hypertension eprosartan 400-800mg once-daily eprosartan 400-800mg twice-daily placebo • 0 - • 2 - • 4 - • 6 - • 8 – • - 10 - Reduction in sitDBP from baseline (mmHg) - 4 - 9 - 9 p<0.0001 p<0.001 50. Hedner T, et al. J Hypertens 1999;17(1):129-136

  40. Hedner – study versus placebo50 Overall response rate after 13 weeks treatment with eprosartan 400-800mg bd or od compared with placebo in 243 patients with mild-to-moderate hypertension * p=0.05 46.8%* Response rate (%) 50 - 40 - 30 - 20 - 10 - 0 - 35.1% eprosartan once-daily placebo 50. Hedner T, et al. J Hypertens 1999;17(1):129-136

  41. Gradman – study versus placebo51 Change in mean sitSBP and sitDBP from baseline after 8 weeks of treatment with eprosartan (600mg/day) or placebo in 243 patients with mild-to-moderate hypertension SYSTOLIC BP DIASTOLIC BP eprosartan placebo eprosartan placebo • 2 - • 0 - • 2 - • 4 - • 6 - • 8 - • - 10 - Change in sitBP from baseline (mmHg) 0.8 - 1.9 - 6.0 - 7.5 p<0.0001 p<0.0001 51. Gradman AH, et al. Clin Ther 1999;21:442-453

  42. Argenziano – study in older patients52 Percentage of elderly and younger responders after 26 weeks of treatment with eprosartan (400-600mg/day) and enalapril (5-20mg/day) in patients with mild-to-moderate hypertension % responders 100 - 80 - 60 - 40 - 20 - 0 - 87.3% 80.0% 77.4% 72.1% eprosartan < 65 yrs eprosartan > 65 yrs enalapril < 65 yrs enalapril > 65 yrs 52. Argenziano L, Trimarco B. Curr Med Res Opin 1999;15(1):9-14

  43. Levine – study in black patients53 Response in black patients after 26 weeks of treatment with eprosartan (400-600mg/day) or enalapril (5-20mg/day) with or without HCTZ in patients with mild-to-moderate hypertension % responders p<0.018 p<0.05 100 - 80 - 60 - 40 - 20 - 0 - 66.7% 52% 42.1% 26% eprosartan monotherapy eprosartan + HCTZ enalapril monotherapy enalapril + HCTZ 53. Levine B. Curr Med Res Opin 1999;15:25-32

  44. Levine – long-term study54 Mean sitSBP and sitDBP in a 24-month study in patients with mild-to-moderate hypertension who received eprosartan (400-800mg/day) with or without HCTZ (12.5-25mg/day) mean sitDBP mean sitSBP 160 - 120 - 80 - 40 - 0 - Mean BP (mmHg) 145.9 139.5 136 136.7 94.9 88.7 86.4 86.9 baseline (n=591) titration endpoint (n=577) 12 months (n=571) 24 months (n=300) 54. Levine B. Curr Med Res Opin 2001;17(1):8-17

  45. Sachse – combination with HCTZ55 Mean change in sitDBP from baseline after 8 weeks treatment with eprosartan 600mg/day with or without HCTZ 12.5mg/day eprosartan (n=156) eprosartan + HCTZ (n=149) Mean change in sitDBP from baseline (mmHg) • 0 - • 2 - • - 4 - • - 6 - • 8 - • - 10 - • - 12 - - 7.9 - 10.7 p=0.001 55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176

  46. Sachse – combination with HCTZ55 Percent responders after 8 weeks treatment with eprosartan 600mg/day with or without HCTZ 12.5mg/day p=0.004 % responders 100 - 80 - 60 - 40 - 20 - 0 - 73.2% 57.1% eprosartan eprosartan + HCTZ 55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176

  47. Secondary stroke prevention (MOSES)6 • Eprosartan (n=710) versus nitrendipine (n=695) (the calcium channel blocker shown to reduce strokes in Syst-Eur) • The study included hypertensive patients with proven ischaemia, TIA/PRIND or intracerebral haemorrhage during the previous 24 months MOrbidy and mortality after Stroke - Eprosartan compared with nitrendipine for Secondary prevention 6. Schrader J, et al. Stroke 2005;36: (In Press). Additional information: ESC, Munich, 2004/data on file

  48. Secondary stroke prevention (MOSES) • Combined primary endpoint: total mortality plus the total cardiovascular and cerebrovascular events, including all recurrent events • Secondary endpoints: The single components of the combined primary endpoint, and an assessment of functional status and cognitive function • Mean follow-up: 2.5 years • Mean dosages: 623mg eprosartan 16mg nitrendipine

  49. MOSES - blood pressure changes Effect of eprosartan and nitrendipine on blood pressure in hypertensive patients with previous stroke/TIA/PRIND eprosartan nitrendipine Blood pressure (mmHg) 160 - 140 - 120 - 100 - 80 - 60 - SBP DBP 0 3 6 3 6 12 18 24 36 48 weeks months 76% of patients on eprosartan had their BP normalised. This was higher than in LIFE (46%) or VALUE (64%)

  50. MOSES - primary endpoint Reduction in total mortality, cardiovascular and cerebrovascular events during treatment with eprosartan or nitrendipine in hypertensive patients with previous stroke/TIA/PRIND 21% risk reduction with eprosartan (p=0.014) Number of events nitrendipine 300 - 250 - 200 - 150 - 100 - 50 - 0 - eprosartan 0 250 500 750 1000 1250 1500 1750 days

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