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Elliott. J Clin Hypertens 2003;5(Suppl. 2):3 – 13

Strategic Choice of ARB’S To Provide Optimal Blood Pressure Management and Reduction of Cardiovascular Events Focus On Candesartan Masrul Syafri Bagian Kardiologi & Kedokteran Vaskular FK Unand-RSUP DR.M.Djamil Padang.

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Elliott. J Clin Hypertens 2003;5(Suppl. 2):3 – 13

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  1. Strategic Choice of ARB’S To Provide Optimal Blood Pressure Management and Reduction of Cardiovascular EventsFocus On CandesartanMasrul SyafriBagian Kardiologi & Kedokteran Vaskular FK Unand-RSUP DR.M.Djamil Padang

  2. ‘Controlling blood pressure with medication is unquestionably one of the most cost-effective methods of reducing premature CV morbidity and mortality’ Elliott. J Clin Hypertens 2003;5(Suppl. 2):3–13

  3. WHAT GUIDELINE SAY’S JNC 8 GUIDELINES

  4. The Earlier, The Better: Early Intervention Reduces Events Female smoker BP 180  140 mmHg No diabetes or dyslipidaemia 20 15 10 5 0 No intervention 19 12 11 CV disease deaths over 10 years (%) 6 Intervention 7 7 3 4 4 1 2 2 1 1 0 40 50 55 60 65 Age at start SCORE High Risk Region

  5. OPTIMAL BLOOD PRESSUREMANAGEMENT UPDATED GUIDELINES Publication on JAMA ( The Journal of the American Medical Association ) JAMA February 5, 2014 Volume 311, Number 5

  6. THE DIFFERENCES

  7. JAMA February 5, 2014 Volume 311, Number 5

  8. JAMA February 5, 2014 Volume 311, Number 5

  9. Strategies to Dose Antihypertensive Drugs JAMA February 5, 2014 Volume 311, Number 5

  10. JAMA February 5, 2014 Volume 311, Number 5

  11. BP LOWERING AGENT WHY ARB’S?

  12. Persistence with Antihypertensive Therapyafter1 & 4 Years of Treatment 4 years On treatment % AT1-blocker p<0.02 compared to all other classes 70 1 year 60 50 40 30 20 10 0 AT1-blocker ACE-I CCBs Beta- blockers Diuretics Conlin et al 2001

  13. Regression of Left Ventricular Hypertrophy with Antihypertensive Therapy by Drug Class 0 -5 -10 -15 -20 Mean % change in LV Mass from baseline (with 95% CI’s) adjusted for change in diastolic BP & duration of treatment * p<0.05;**p<0.001 vs beta blocker change in LV Mass(%) ** * * Diuretics b-Blockers Calcium ACE-Is ARB’s Antagonists Klingbeil et al 2003

  14. Angiotensinogen Renin Angiotensin I ACE Angiotensin II ARB Reseptor AT1 Reseptor AT2 • Sekresi Aldosteron • Vasokonstriksi • Vasodilatasi • Antiproliferasi (kinin)‏ MECHANISM OF ACTION : ACE I vs ARB ACEI Batuk Bradikinin Jalur Non-ACE Cth: khimase Fragmen inaktif Tekanan darah turun Tekanan darah naik

  15. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  16. 2014 – Evidence based guidelines for the management of High Blood Pressure in adults Report Form Panel Member Appointed of JNC - 8

  17. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  18. Number of AT1-Receptor Binding Sites for Different Angiotensin II Receptor Antagonists 3 sites - valsartan 2 sites - losartan 4 sites - candesartan Hydrogen bonds between ligand and receptor are shown as red dotted lines with hydrogen bond lengths. Carbon atoms of the ligands are coloured light blue and those of the receptors are green Bhuiyan et al 2009

  19. Insurmountable and Surmountable Antagonism: Relation to Duration of Binding 100 Candesartan 80 olmesartan EXP 3174 60 telmisartan Insurmountability (%) valsartan 40 irbesartan 20 losartan 0 0 20 40 60 80 100 120 Dissociation t1/2 Van Liefde et al 2009

  20. Candesartanvs Other ARB Perubahan Rata2 TD dari baseline hingga 6 bulan (mmHg) p<0.0001 from baseline untuk semua kelompok Efikasi penurunan tekanan darah Canderin superior dibandingkan dengan ARB lainnya, baik tekanan darah sistolik dan diastolik. Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile

  21. −10.1 ± 10.5/−4.5 ± 8.4 mmHg −13.1 ± 17.3/−6.2± 11.3 mm Hg Candesartan treatment significantly reduced the morning and office BPs compared with other ARBs in Japanese patients with morning hypertension.

  22. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  23. Goals of Hypertension Treatment • In hypertensive patients, the primary goal of treatment is toachieve maximum reduction in the long-term total risk of cardiovascular disease • This requires treatment of the raised BP per se as well as of all associated reversible risk factors • BP should be reduces to at least below 140/90 mmHg (systolic/diastolic) and to lower values, if tolerated, in all hypertensive patients Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187

  24. 30-40% Fatal and nonfatal stroke : 20% Coronary events : Event Base Trials Comparing Active Hypertensive Treatment to Placebo Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187

  25. AT II Plays a Central Role in Organ Damage Stroke Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Hypertension A II  AT1 receptor LV hypertrophy Fibrosis Remodeling Apoptosis Heart failure MI DEATH GFR Proteinuria Aldosterone release Glomerular sclerosis Renal failure *preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44, Daugherty A et al J Clin Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704, Anderson S Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB Am J Kidney Dis 2000; 35(2):179188

  26. Angiotensinogen Angiotensin I Angiotensin II Kininogens Bradykinin Metabolites Renin Kallikrein Non-renin enzymes Non-ACE enzymes ACE ACE inhibitors X X X ARBs AT1 AT2 • Vasoconstriction •Aldosterone release • Oxidative stress • Vasopressin release • SNS activation • Inhibits renin release • Renal Na+ & H2O reabsorption • Increased myocardial contractility • Cell growth & proliferation • Vasodilation • Antiproliferation • Apoptosis • Antidiuresis/antinatriuresis • Bradykinin production • NO release The Renin-AngiotensinAldosterone System (RAAS)

  27. The Cardiovascular Continuum CANDESARTAN Clinical Study

  28. CLINICAL TRIALS OF CANDESARTAN CILEXETIL (1) Vascular Health and Risk Management 2011:7 749–759

  29. CLINICAL TRIALS OF CANDESARTAN CILEXETIL (2) Vascular Health and Risk Management 2011:7 749–759

  30. Real-Life study – components of the primary composite outcome with candesartanvs. losartan Kjeldsenet al. J Hum Hypertens 2009

  31. Supramaximal Dose of Candesartan in Proteinuric Renal Disease J Am Soc Nephrol ●●: –, 2009 SMART (Supra Maximal Atacand Renal Trial)

  32. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  33. Profil Lipid • Pemakaian Candesartan mampu menurunkan tingkat total kolesterol dan LDL lebih superior dibandingkan dengan ARB lainnya. Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile

  34. BMI P=0.301 HR=0.64; 95% CI 0.43-0.97 Amlodipine Candesartan P=0.947 P=0.015 P=0.028 P=0.0034 Risk Reduction in Candesartan group months New-onset Diabetes

  35. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  36. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  37. Bioequivalence study of CANDERIN®

  38. CANDERIN® Bioekuivalen denganoriginatornya

  39. STRATEGIC CHOICE OF ARB’S The PARAMETER’s • GUIDELINES RECOMMENDATION • AT1 Affinity → Efficacy to reduce BP • Protection on Target Organ Damage (TOD) • Pleiotropic effect • Safety • Quality Assurance of Drugs • Pharmacoeconomics

  40. WHY COPY PRODUCTS EXIST? • Original products loose it’s patent protection • Copy Products have more opportunities • Definition: Branded copy products & OGB • Health Care Cost is continue to increase, needs medicines with lower price, especially for chronic disease. • Stringent GMP and BIOEQUIVALENCY requirements ensure the Quality of the products, compare to its originator

  41. Conclusions • Despite the idea that all ARBs are the same and show a ‘class’ effect, significant pharmacological differences with respect to efficacy and duration of action are apparent within the ARB class. • Such differences may translate into differences in BP reduction, and thus a reduction in CV risk. These differences should be taken into account by the prescribing physician • Long-acting ARB Candesartan have better CV outcomes. • Copy product may reduces health care cost, but must be bioequivalent compare to originator (Quality Assurance of Drugs)

  42. TERIMA KASIH

  43. New WHO Report, April 2011, highlights NCD and CVD Deaths worldwide ! • New WHO report reveals an ‘impending disaster’ caused by a rise in deaths from heart disease and other non-communicable diseases • Geneva, April 27, 2011 – The World Health Organization has today published a report on non-communicable diseases (NCDs), including cardiovascular disease (CVD) which is the number one killer worldwide, and has described them as an ‘impending disaster’ for health, society and national economies. • The World Heart Federation welcomed report recommendations for a ‘forceful response’ to the potential tragedy posed by non-communicable diseases, particularly in the developing world

  44. 7.6 Million deaths each year attributable to suboptimal blood pressure • 7.6 million deaths each year (13.5% of total) are attributable to high blood pressure. • 54% of Stroke and 47% of coronary heart disease worldwide attributed to high blood pressure. • Data obtained from Global Burden of Disease study, updated in 2008. Lawes, Hoorn, Rodgers, for ISH: Lancet 2008; 371: 1513-18

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