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PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE Get to Goal, Achieve Control.

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Presentation on theme: "PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE Get to Goal, Achieve Control."— Presentation transcript:

1 PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE Get to Goal, Achieve Control

2 WHO World Health Report 2004 CV diseases Cancer Infectious and parasitic diseases Other non-infectious diseases Injuries Respiratory diseases Respiratory infections Maternal and perinatal conditions Nutritional deficiencies Cardiovascular diseases leading causes of global mortality

3 Prevalence of Hypertension

4 Proportion of Patients Treated/Not Treated for Hypertension in Europe* Wolf-Maier et al. Hypertension 2004;43:10–17 Patients (%) EnglandSwedenGermanySpainItaly *Age adjusted; patients aged 35–64 years Hypertension = 140/90mmHg threshold

5 Prevalence of Hypertension Increases with Age Brown. BMJ 2006;332:833 6 20 3940 59 60 Prevalence of Hypertension (%) Age (years) Estimated non-institutionalized US adults, 1999 2002 Adapted from Centers for Disease Control and Prevention

6 Stroke & IHD* Mortality Rate in Each Decade of Age, vs Usual Systolic BP at the Start of that Decade *IHD= Ischaemic Heart Disease

7 Cardiovascular Mortality Risk Systolic BP/Diastolic BP (mmHg) 115/75135/85155/95175/105 0 2 4 8 6 Lewington et al. Lancet 2002;360:1903–13 Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic BP* *Individuals aged 40–69 years 4X risk 8X risk 2X risk 1X risk

8 BP Reduction of 2 mmHg Decreases the Risk of CV Events by 7–10% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 2 mmHg decrease in mean SBP 10% reduction in risk of stroke mortality 7% reduction in risk of ischaemic heart disease mortality Lewington et al. Lancet 2002;360:1903–13

9 Hypertension in Egypt Hypertension is a major health problem in Egypt with a prevalence rate of 26.3% among the adult population (> 25 years) 1. Only 8% of hypertensive Egyptians have their blood pressure controlled 1. 1- Ibrahim MM, Rizk H, Apple LJ, et al. For the NHP investigation team. Hypertension, prevalence, awareness, treatment and control in Egypt. Results from the Egyptian National hypertension Project (NHP). Hypertension 1995; 26:880.

10 More Than 80% Of hypertensive Patients have additional Co-morbidities

11

12 Controlling SBP Is the Main Problem Adapted from Lloyd-Jones DM, et al. Hypertension. 2000;36:594–599. DBP, mmHg SBP, mmHg 20601001201408040 67% did not reach SBP goal 4% 13% 29% 54% 80 100 120 140 160 180 200 220 90 140 Not at SBP or DBP goal At SBP and DBP goal

13 <140 140–159 160–179 180 Relative risk Predictive Power of Systolic BP on Cardiovascular Mortality Alli et al. Arch Intern Med 1999;159:1205–12 Relative risk 0.511.522.5 0.511.522.5 <90 90–99 100 Prognosis better Prognosis worse Prognosis better Prognosis worse Systolic BP (mmHg)Diastolic BP (mmHg)

14 11-Year Increase in Risk of CV Death for 10 mmHg Increase in SBP at Different Baseline SBP Values 11-Year Increase in Risk of CV Death for 10 mmHg Increase in SBP at Different Baseline SBP Values Sega et al., Circulation 2005 Increase in risk of CV death (%) Baseline SBP (mmHg) 0.6 0.8 1.1 0.9 1.3 2.0 1.8 2.4 4. 5

15 Evolution of Cardiovascular Risk in Hypertension Low RiskHigher RiskHighest Risk Clinical Trial Treatment Guidelines Disease Evolution; 20 – 50 years Hypertension: No TOD No CVD Younger Target Organ Damage: LVH Vascular Structure Albuminuria Cardiovascular Disease: CHD / CHF Stroke / TIA Renal Disease Hard EndpointsSurrogate Endpoints Drug Treatment Atrial Fibrillation Systolic Dysfunction Diastolic Dysfunction Metabolic Syndrome to Diabetes

16 Hypertension Diabetes Dislipidemia Central Obesity Arteriosclerosis Vascular remodeling LVH > IM thickness Lacunar infarcts Microalbuminuria MI, Angina Stroke Congestive Cardiac Failure Renal Failure Periferal Artery Disease Non-fatal recurrent events CRF Dialysis Dementia Treatment of Cardiovascular Risk Factors Genes Life style Death Life Style Changes Treatment of Silent Lesions To Interrupt Vascular Disease Progression Treatment of Clinical Events Natural History of Cardiovascular Disease

17 Angiotensin II Plays a Central Role in Organ Damage A II Atherosclerosis* Vasoconstriction Vascular hypertrophy LV hypertrophy Fibrosis Remodeling Apoptosis Stroke DEATH GFR Proteinuria Aldosterone release Glomerular sclerosis Renal failure Hypertension Heart failure MI AT 1 Receptor *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. 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.

18 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

19 Associated risk factors

20 Blood Pressure and Cardiovascular Risk: ESH ESC Guidelines Other RF, OD or disease BP (mmHg) Normal SBP 120–129 or DBP 80–84 High normal SBP 130–139 or DBP 85–89 Grade 1 SBP 140–159 or DBP 90–99 Grade 2 SBP 160–179 or DBP 100– 109 Grade 3 SBP 180 or DBP 110 No other RF Average risk Low added risk Moderate added risk High added risk 1–2 RF Low added risk Moderate added risk Very high added risk 3 RF, MS, OD or diabetes Moderate added risk High added risk High added risk Very high added risk Established CV or renal disease Very high added risk MS = metabolic syndrome OD = subclinical organ damage RF = risk factors Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87; Copyright © 2007, with permission from Lippincott Williams and Wilkins

21 Factors influencing prognosis in hypertension. Subclinical organ damage 2007 Guidelines for the management of arterial hypertension Electrocardiographic LVH –Sokolow-Lyon >38 mm –Cornell >2440 mm x ms Echocardiographic LVH (Left ventricular mass index): –125 g/m 2 (males) –110 g/m 2 (females) Carotid wall thickening (IMT >0.9 mm) or plaque Carotid-femoral pulse wave velocity >12 m/s Ankle / brachial blood pressure index >0.9 Mancia G, et al. J Hypertens. 2007;25:1105-87 LVH: Left ventricular hypertrophy IMT: Intima media thickness

22 ESH/ESC & JNC 7 Summary: Target BP Goals Types of HypertensionBP Goal (mmHg) Uncomplicated<140/90 Complicated Diabetes mellitus <130/80 Kidney disease <130/80* Other high risk (stroke, myocardial infarction) <130/80 Task Force of ESH–ESC. J Hypertens 2007;25:1105 87 Chobanian et al. JAMA 2003;289:2560 72 *Lower if proteinuria is >1 g/day

23 Blood Pressure Thresholds (mmHg) for Definition of Hypertension with Different Types of Measurement SBPDBP Office or Clinic14090 24-hour125-13080 Day130-13585 Night12070 Home130-13585

24 Cont…

25 Causes of Inadequate Responsiveness to Therapy…. cont.

26 Patient-Related Barriers to Effective Antihypertensive Treatment Limited access to health care –Lack of health insurance –Lack of a regular provider Nonadherence to therapy –Knowledge deficits –Medication cost –Complicated regimens –Side effects –Medication not taken by patient –Poor physician-patient communication –Lack of social support Increased susceptibility –Advanced age –Obesity Secondary causes (less common) –Sleep apnea –Drug side effects –Chronic kidney disease –Primary aldosteronism –Renovascular disease –Cushing syndrome –Pheochromocytoma –Coarctation of the aorta –Thyroid/parathyroid disease Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662; Chobanian AV, et al. JAMA. 2003;289:2560-2572.

27 Physician-Related Barriers to Effective Antihypertensive Treatment Unfamiliarity with current treatment guidelines –B–Blood pressure thresholds –I–Isolated systolic hypertension –T–Threshold for diabetic patients –U–Use of monotherapy to treat patients with difficult-to-control blood pressure Belief that in-office blood pressure tends to be higher than at-home blood pressure Lack of time at office visits Therapeutic inertia Overestimation of adherence to guidelines Disagreement with guidelines –Isolated systolic hypertension –Concern about the relationship between diastolic blood pressure and myocardial infarction (i.e., the J curve) Reluctance to treat a seemingly asymptomatic condition Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662; Chobanian AV, et al. JAMA. 2003;289:2560-2572; Okonofua EC, et al. Hypertension. 2006;47:345-351.

28 Recommended Lifestyle Modifications and Their Individual Effects on Blood Pressure Chobanian AV, et al. JAMA. 2003;289:2560-2572; Blumenthal JA, et al. Arch Intern Med. 2000;160:1947-1958. Modifications*Recommendation Approximate SBP Reduction Reduce weight Maintain normal body weight (BMI of 18.524.9 kg/m 2 ) 320 mm Hg Adopt DASH diet Rich in fruit, vegetables, and low-fat dairy; reduced saturated and total fat content 814 mm Hg Reduce dietary sodium <100 mmol (2-4 g)/day 28 mm Hg Increase physical activity Aerobic activity >30 min/day most days of the week 49 mm Hg Moderate alcohol consumption Men: 2 drinks/day Women: 1 drink/day 24 mm Hg *Combining 2 or more of these modifications may or may not have an additive effect on blood pressure reduction. SBP = systolic blood pressure; BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension

29 Causes of Essential Hypertension Age Excess Sodium Consumption Overweight Excess Alcohol Consumption Physical Inactivity Elevated Systolic and/or Diastolic Blood Pressure Family History Stress

30 Pathophysiology of Hypertension Sever P. J Cardiovasc Pharmacol. 1998;31(suppl 2):S1-S4.

31 Hypertension Syndrome!! Its More Than Just Blood Pressure Decreased Arterial Compliance Endothelial Dysfunction Abnormal Glucose Metabolism Neurohormonal Dysfunction Renal-Function Changes Blood-Clotting Mechanism Changes Obesity Abnormal Insulin Metabolism LV Hypertrophy and Dysfunction Accelerated Atherogenesis Abnormal Lipid Metabolism Hypertension Kannel WB. JAMA. 1996;275:1571-1576. Weber MA et al. J Hum Hypertens. 1991;5:417-423. Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5.

32 Blood Pressure Regulation

33 Short Term Regulation of Blood Pressure: Pressure Natriuresis Arterial pressure is a signal for regulation of NaCl excretion. Arterial pressure NaCl reabsorbed in the proximal tubule more NaCl to Macula Densa Tuboglomerular Feedback (TGF) autoregulation RBF, GFR ECFV: Extracellular fluid volume, a function of Na+ reabsorption ; RBF: Renal blood flow; PT: Proximal tubule; GFR: Glomerular filtration rate; TGF: tubuloglomerular feedback In addition, there is an accompanying increase in urine Na+, volume output: pressure natriuresis/diuresis. Pressure natriuresis can normalize BP by decreasing the effective circulating volume – this response connects BP and ECFV.

34 Predicted Long-Term Effects of a Hypertensive Stimulus Renal function curve Predicted long-term effects of a hypertensive stimulus, caused by increased total peripheral resistance (normal renal-pressure natriuresis mechanism). Blood pressure is initially elevated (from point A to point B), but hypertension cannot be sustained because sodium excretion exceeds intake, thereby reducing extracellular fluid volume until blood pressure returns to normal and intake and output of sodium are balanced. Hall et al. Kidney Int Suppl, Volume 49 Supplement 55.June 1996.S-35-S-41

35 The Renin Angiotensin Aldosterone System (RAAS) Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409

36 ACE Inhibition S., et al. J Renin Angiotensin Aldosterone Syst–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 200H2000;1:147anon 4;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409 Bradykinin/NO Inactive fragments Vasodilation Tissue protection ACE Inhibitor Angiotensin I Angiotensin II Chymase tPA Cathepsin AT 1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Angiotensin II escape AT 2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis

37 Selective AT 1 Receptor Blockade (ARB) Bradykinin/NO Inactive fragments ACE Angiotensin I Angiotensin II Chymase tPA Cathepsin ARB Bradykinin? NO? AT 1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis AT 2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409

38 Rationale for Dual RAAS Blockade with ACEI & ARB Bradykinin/NO Inactive fragments Vasodilation Tissue protection ACE Inhibitor Angiotensin I Angiotensin II Chymase tPA Cathepsin AT 1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Angiotensin II escape AT 2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis ARB Bradykinin? NO? Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409

39

40 Consider: BP level before treatment Absence or presence of TOD and risk factors Choose between If goal BP not achieved 2–3-drug combination at full doses ESH/ESC Algorithm for the Treatment of Hypertension TOD = target organ damage Marked BP elevation High/very high CV risk Lower BP target Mild BP elevation Low/moderate CV risk Conventional BP target Task Force of ESH/ESC. J Hypertens 2007;25:1105–87 2-drug combination at low dose Single agent at low dose Previous combination at full dose Add a third drug at low dose Full-dose monotherapy 2-3 drug combination at full dose Previous agent at full dose Switch to different agent at low dose

41 Advantages of Multiple-mechanism Therapy: Efficacy Components with a different mechanism of action interact on complementary pathways of BP control 1 Each component can potentially neutralize counter- regulatory mechanisms, e.g. Diuretics reduce plasma volume, which in turn stimulates the renin angiotensin system (RAS) and thus increases BP; addition of a RAS blocker attenuates this effect 1,2 Multiple-mechanism therapy may result in BP reductions that are additive 2 1 Sica. Drugs 2002;62:443 62 2 Quan et al. Am J Cardiovasc Drugs 2006;6:103 13 Multiple-mechanism therapy results in a greater BP reduction than seen with its single-mechanism components 1,2

42 Advantages of Multiple-mechanism Therapy: Safety/Tolerability Components of multiple-mechanism therapy can be given at lower dosages to achieve BP goal than those required as monotherapy therefore better tolerated 1,2 Compound-specific adverse events can be attenuated, e.g., 1,2 RAS blockers may attenuate the edema that is caused by CCBs 1 Sica. Drugs 2002;62:443 62 2 Quan et al. Am J Cardiovasc Drugs 2006;6:103 13 Multiple-mechanism therapy may have an improved tolerability profile compared with its single-mechanism components 1,2

43 *Lower doses generally used in fixed-dose combinations + = potential advantage *Lower doses generally used in fixed-dose combinations + = potential advantage Advantages of Fixed Versus Free Combinations of Two Antihypertensive Drugs FixedFree Simplicity of treatment+– Compliance+– Efficacy++ Tolerability+*– Price+– Flexibility–+

44 Better Compliance with Antihypertensive Drugs Leads to a Lower Risk of Hospitalization Level of compliance (%) All-cause hospitalization risk (%) *p<0.05 vs 80–100% compliant group n=5,804 n=921 n=562 n=344 n=350 * * * Sokol et al. Med Care 2005;43:521–30 *

45 Average no. of antihypertensive medications 1234 Multiple Antihypertensive Agents are Needed to Reach BP Goal Trial (SBP achieved) Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906; Jamerson et al. Blood Press 2007;16:80–6 ASCOT-BPLA (136.9 mmHg) ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg) ABCD (132 mmHg) MDRD (132 mmHg) HOT (138 mmHg) AASK (128 mmHg) ACCOMPLISH* (132 mmHg) Initial 2-drug combination therapy *Interim 6-month data

46 Recommendations for Multiple-mechanism Therapy: What the Treatment Guidelines Say: ESH–ESC More than one agent is necessary to achieve target BP in the majority of patients Treatment can be initiated with monotherapy or a combination of two drugs at low doses Drug dose or number of drugs may be increased if necessary A combination of two drugs at low doses preferred 1st step when Initial BP in grade 2–3 range Total CV risk high/very high Fixed combinations of two drugs simplify treatment/favor compliance Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

47 Interaction of CCBs and ARBs on Vascular and Renal Function, SNS and RAS Activity CCB ARB Vasodilation Natriuresis Arterial Arterial + Venous RAS RAS SNS SNS RAS RAS SNS SNS

48 CCB Arteriodilation Peripheral edema Effective in low-renin patients Reduces cardiac ischemia CCB RAS activation No renal or congestive heart failure benefits CCB/ARB: Synergy of Counter-regulation ARB Venodilation Attenuates peripheral edema Effective in high-renin patients No effect on cardiac ischemia ARB RAS blockade Congestive heart failure and renal benefits

49 Tolerability and Risk Factor Modification: CCB-induced Peripheral Edema Minimized by the ARB Single mode of action of the CCB Dual mode of action of the CCB/ARB Illustration modified from www.lotrel.com ARB dilates arteries and veins Reduces CCB-induced peripheral edema Capillary overload forces fluid into surrounding tissue CCB dilates arteries Veins remain constricted Messerli et al. Am J Hypertens 2001;14:978–9

50 12418 M The importance of BP control for CV protection calls for use of effective antihypertensive drugs in the context of effective antihypertensive treatment strategies

51 Choose the treatment…!!!

52 Maximum home blood pressure: a novel indicator of target-organ damage in hypertension Blood pressure variability has recently been shown to be a strong predictor of stroke and cardiovascular events, independently of the mean systolic blood pressure level. 1 The clinical implication of variability in blood pressure, as measured by home blood pressure monitoring, has never been reported. A new study has investigated the association between maximum home blood pressure and target-organ damage in 356 never-treated hypertensive subjects. 1. Rothwell PM et al. Lancet. 2010;375:938-948. 2. Matsui Y et al. Hypertens, 2011;57: in press

53 Maximum home systolic blood pressure measurements were observed up to 50 times per day Number of episodes per/day Matsui Y et al. Hypertens. 2011;57: in press

54 High incidence of maximum home systolic blood pressure is associated with a high degree of cardiac and vascular remodeling Matsui Y et al. Hypertens. 2011;57: in press

55 Conclusion This study provides additional information on the importance of blood pressure stabilization to prevent cardiovascular complication in hypertensive patients: Transiently high blood pressure readings at home should be taken seriously as meaningful indicators for hypertensive damage in the heart and artery. 1 The variability in systolic blood pressure can be simply assessed by home blood pressure measurements. 1 This study confirms, that effective antihypertensive treatment should not only reduce, but also stabilize blood pressure. 2 1. Matsui Y et al. Hypertens. 2011;57: in press; 2.Rothwell PM. et al. Lancet. 2010;375:938-948.

56 Conditions favoring use of some antihypertensive drugs versus others:

57 Effects of RAS blockade on stroke: meta-analysis of ARBs and ACE inhibitors MI Cardiovascular mortality All-cause mortality Stroke Favours ARB Favours ACE inhibitor Reboldi et al. J Hypertension 2008;26:1282–1289 N=63,409 Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET

58 Better stroke protection with ARBs than with ACEIs Suggests AT2-receptor mediated cerebroprotection

59 Spansk studie ARB less severe strokes The multiple regression analysis showed that Previous treatment with ARB was independently associated with reduced stroke severity: OR: 0.40; 95% CI 0.240.65, p<0.001 and against poor outcome: OR: 0.41; 95%CI 0.23-0.78, p=0.003

60 There is no such thing as a simple Class Effect that explains,all about a particular molecule Every molecule is unique

61 21 1. VALUE 2. VALIANT 3. NAVIGATOR 4. Val-HeFT 5. JIKEI HEART 6. KYOTO HEART* 7. VART* 8. VALISH* 27. IDNT 28. ACTIVE-I* 29. NID-2 30. SUPPORT* 31. COLM* 32. OSCAR* 33. ORIENT* 34. MOSES Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007; 6. http://clinicaltrials.gov (NCT00149227); 7. Nakayama et al. 2008; 8. NCT00151229; 9. ONTARGET Investigators 2008; 10. Yusuf et al 2008; 11. TRANSCEND Investigators 2008; 12. http://clinicaltrials.gov (NCT00283686); 13. Dahlöf et al. 2002; 14. Dickstein et al. 2002; 15. Pitt et al. 2000; 16. Brenner et al. 2001; 17. http://clinicaltrials.gov (NCT00090259); 18. http://clinicaltrials.gov (NCT00555217); 19. Pfeffer et al 2003; 20. Papademetriou et al. 2004; 21. http://clinicaltrials.gov (NCT00120003); 22. Ogihara et al. 2008; 23. http://clinicaltrials.gov (NCT00108706); 24. Laufs et al. 2008; 25. Suzuki et al. 2005; 26. Massie et al 2008; 27. Lewis et al. 2001; 28. http://clinicaltrials.gov (NCT00249795); 29. http://clinicaltrials.gov (NCT00535925); 30. http://clinicaltrials.gov (NCT00417222); 31. http://clinicaltrials.gov (NCT00454662); 32. http://clinicaltrials.gov (NCT00134160); 33. http://clinicaltrials.gov (NCT00141453); 34. Schrader et al. 2005...35. Kunihiro Matsushita,et al, J of Cardiology Volume 56, Issue 1, July 2010, Pages 111-117Volume 56, Issue 1 1. 9. ONTARGET 10. PRoFESS 11. TRANSCEND 12. HALT-PKD* 13. LIFE 14. OPTIMAAL 15. ELITE II 16. RENAAL 17. NCT00090259* *Expected enrolment Ongoing and completed randomized controlled trials with death or hard CV events as or part of the primary endpoint ¶ Valid as of January 2009 Mortality and Morbidity Endpoint Trials¶ with ARBs 18. VA NEPHRON-D* 19. CHARM 20. SCOPE 21. SCAST* 22. CASE-J 23. ACCOST 24. HIJ-CREATE 25. E-COST 26. I-PRESERVE Number of patients Valsartan TelmisartanLosartanCandesartanIrbesartanOlmesartanEprosartan 57,781 52,896 24,841 23,940 6,577 1,405 15,693 1 2 5 4 3 7 8 6 9 10 16 12 11 17 18 15 13 14 22 23 25 19 20 34 31 30 32 33 29 28 27 26 24 35. NAGOYA Heart S 35

62 VALUE: Incidence of New-onset Diabetes New-onset diabetes (% of patients in treatment group) Julius S et al. Lancet. June 2004;363. 0 2 4 6 8 10 12 14 Valsartan-based regimen (n = 7,649) Amlodipine-based regimen (n = 7,596) 13.1% 16.4% 23% risk reduction with valsartan 16 18 P < 0.0001

63 Valsartan Improves Insulin Sensitivity in Hypertensive Patients* *All patients in study group received valsartan 80 mg once daily. P <0.001 vs hypertensive pretreatment. HOMA-IR = homeostasis model assessment – estimated insulin resistance. Top C et al. J Int Med Res. 2002;30:15-20. Normotensive (n = 20) Hypertensive pretreatment (n = 20) Hypertensive posttreatment (n = 20) HOMA-IR 0 5 10 15 20 25 9.8 19.6 8.7 2.2 1.9 4.4 0 5 10 15 20 25 Fasting Insulin (µlU/mL)

64 Valsartan ® Improves Insulin Sensitivity & Decreases Leptin in Obese Patients with HTN Results from a 16-week study in 91 obese patients with mild-to-moderate essential HTN BMI 30kg/m 2 ; DBP >90 and <110 mmHg; *p<0.01, **p<0.05, ***p=NS vs. placebo; § p<0.01 vs. DIOVAN; BMI=Body mass index; HOMA-IR=Homeostasis model assessment of insulin resistance index Fogari et al. Hypertens Res 2005;28:209-214 Change from baseline (%) BMIPlasma Leptin HOMA-IRPlasma norepinephrine DIOVAN 80-160 mg od (n=46) Felodipine 5-10 mg od (n=45) * -20 -10 0 10 20 30 40 -4.7* 0.1 -10.1** 0.6 -20.0** -3.8 -13.8*** 38.8* §

65 Change in plasma levels from baseline to 12 weeks Adiponectin (ng/mL) Resistin (ng/mL) Leptin (ng/mL) DIOVAN 160 mg/day (n=36) Valsartan ® Significantly Increases Adiponectin in Obese Patients with HTN Results from a 12-week study in 72 obese § patients with mild-to-moderate HTN # § BMI 30kg/m 2 ; # DBP >90 mmHg and <110 mmHg; *p<0.05 vs. baseline Fogari et al. Am J Hypertens 2005;18:196A (abstract P-521) Amlodipine 10 mg/day (n=36) -4 -3 -2 0 1 2 1.1* 0.3 -0.3 -3.7* -0.2 -1.1* -0.2 -1.0* HOMA-IR

66 Valsartan: Wealth of CV Outcomes Data 1 Julius et al. Lancet 2004;363:2022–31; 2 Pfeffer et al. N Engl J Med 2003;349:1893–906; 3 Maggioni et al. Am Heart J 2005;149:548–57; 4 Wong et al. J Am Coll Cardiol 2002;40:970–5; 5 Cohn et al. N Engl J Med 2001;345:1667–7; 6 Mochizuki et al. Lancet 2007;369:1431–9 VALUE 1 15,245 high-risk HTN patients; Double-blind, randomized study vs. amlodipine No difference in composite of cardiac mortality and morbidity (primary) 23% new-onset diabetes VALIANT 2 14,703 post-myocardial infarction patients; Double- blind, randomized study vs. captopril and vs. captopril + valsartan No difference vs. captopril in all-cause mortality (primary) (valsartan is as effective as standard of care) Val-HeFT 3–5 5,010 heart failure II–IV patients; Double-blind, randomized study vs. placebo 13% morbidity and mortality (primary) left ventricular remodeling 37% atrial fibrillation occurrence heart failure signs/symptoms 28% heart failure hospitalization JIKEI HEART 6 3,081 Japanese patients on conventional treatment for hypertension, coronary heart disease, heart failure or combination of these; Multicenter, randomized, controlled trial comparing addition of valsartan vs. non-ARB to conventional treatment 39% composite CV mortality and morbidity 40% Stroke/transient ischemic attack 47% Hospitalization for heart failure 65% Hospitalization for angina

67 Amlodipine: Wealth of CV Outcomes Data 1 Pitt et al. Circulation 2000;102:1503–10; 2 Nissen et al. JAMA 2004;292:2217–26; 3 Dahlof et al. Lancet 2005;366:895–906 4 Williams et al. Circulation 2006;113:1213–25; 5 Leenen et al. Hypertension 2006;48:374 – 84 PREVENT 1 825 CAD patients (30%): Multicenter, randomized, placebo controlled Primary outcome: No difference in mean 3 yr coronary angiographic changes vs. placebo 35% hospitalization for heart failure + angina 33% revascularization procedures CAMELOT 2 1,991 CAD patients (>20%): Double-blind, randomized study vs. placebo and enalapril 20 mg Primary outcome: 31% in CV events vs. placebo 41% hospitalization for angina 27% coronary revascularization ASCOT-BPLA/CAFE 3,4 19,257 HTN patients: Multicenter, randomized, prospective study vs. atenolol Primary outcome: 10% in non-fatal MI & fatal CHD 16% total CV events and procedures 30% new-onset diabetes 27% stroke 11% all-cause mortality central aortic pressure by 4.3 mmHg ALLHAT 5 18,102 HTN patients: Randomized, prospective study vs. lisinopril Primary outcome: No difference in composite of fatal CHD + non-fatal MI vs. lisinopril 6% combined CVD 23% stroke

68 Non-fatal MI (excluding silent) + fatal CHD Total coronary endpoint Total CV events and procedures All-cause mortality CV mortality Fatal/non-fatal stroke Fatal/non-fatal HF Development of renal impairment 0.5 12 ASCOT BPLA 1 Amlodipine-based better Atenolol-based better Valsartan and Amlodipine in High-risk Hypertension Have Proven Endpoint Benefits 0.5 2 Primary cardiac composite endpoint Cardiac mortality Cardiac morbidity All MI All congestive heart failure All stroke All-cause death New-onset diabetes 1 VALUE trial 2 Favors valsartan Favors amlodipine Development of diabetes 1 Dahlöf et al. Lancet 2005;366:895–906; 2 Julius et al. Lancet 2004;363:2022–31

69 Exforge Clinical data

70 Page 70 Amlodipine/Valsartan: BP Reductions Across All Grades of Hypertension - (Exzellent Trial 1 ) DBP (mmHg) –17 –18 –29 n = 1800 n = 2293 n = 890 1 Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008. -19 -32 -49

71 Page 71 Amlodipine/Valsartan FDC: BP Reductions for Patients with Diabetes – (Exzellent Trial 1 ) n = 639 n = 795 n = 295 1 Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008. -19 -32 -48 DBP (mmHg) –11 –15 –18 syst.BP reduction (mmHg)

72 Amlodipine/Valsartan: Powerful SBP Drops of Over 40 mmHg in Patients with Baseline MSSBP 180 mmHg LSM Change in MSSBP from baseline (mmHg) p=0.1 20 10 0 Amlodipine/Valsartan 10/160 mg Amlodipine 10 mg p=0.0018 40 30 N=55 31.7 N=46 –40.1 LSM=least square mean MSSBP=mean sitting systolic blood pressure EX-EFFeCTS 1 Patients with Stage 2 Hypertension 20 10 0 N=42 Amlodipine/Valsartan 10/160–320 mg Amlodipine 10 mg –43.5 40 30 50 37.2 N=38 EX-STAND 2 Black Patients with Stage 2 Hypertension 1. Destro et al. J Am Soc Hypertens 2008;2:294–302 2. Flack et al. J Hum Hypertens 2009 (E-pub ahead of print).

73 Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP Goal <140/90 mmHg Amlodipine/Valsartan 5/160 mgAmlodipine/Valsartan 10/160 mg Diabetic patients with BP <130/80 mmHg at Week 8 were 47.0% and 49.2% for 5/160 mg and 10/160 mg doses, respectively Patients (%) Data shown are at Week 8 No hydrochlorothiazide add-on was permitted until after Week 8 Randomized, double-blind, multinational, parallel-group, 16-week study n=440n=369n=71n=449n=375n=74 80.0 Adapted from Allemann et al. J Clin Hypertens 2008;10:185–94

74 Amlodipine/Valsartan: Additional BP Drops in Non- responders to Ramipril/Felodipine –30.7 mmHg –14.3 mmHg –15.4 mmHg p<0.0001 –7.0 mmHg p<0.0001 Week0510 N=133 After Amlo/Val 10/160 After Ram 5 + Fel 5 Open, sequential, non- responder, 10-week study After Amlo/Val 10/160 After Ram 5 + Fel 5 Week0510 Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261)

75 Page 75 *p<0.01 vs. amlodipine Fogari et al. J Hum Hypertens 2007;21:220-4 EXFORGE ® Significantly Reduces Fluid Retention Vs Amlodipine Monotherapy 25 20 15 10 5 0 Ankle-foot volume increase (%) Amlodipine 10 mg EXFORGE® 10/160 mg n=80 70% difference

76 Amlodipine/Valsartan: Powerful SBP Drops of 43 mmHg in Patients with a Baseline MSSBP 180 mmHg *p<0.001; p<0.002 vs. baseline Change from baseline in MSSBP at 6-week endpoint (mmHg) Endpoint BP (mean) 0 –10 –20 –30 –40 –50 Amlodipine (5–10 mg) + valsartan (160 mg) 145.4 mmHg157.4 mmHg Lisinopril (10–20 mg) + HCTZ (12.5 mg) n=15n=11 Change in MSDBP (mmHg)–26.1*–21.7* Poldermans et al. Clin Ther 2007;29:279–89 Baseline mean sitting systolic BP (MSSBP): 188 mmHg Baseline mean sitting diastolic BP (MSDBP): 113 mmHg Randomized, double-blind, multicenter, active-controlled study

77 Page 77 Blood Pressure and Cardiovascular Risk: ESH ESC Guidelines Other RF, OD or disease BP (mmHg) Normal SBP 120–129 or DBP 80–84 High normal SBP 130–139 or DBP 85–89 Grade 1 SBP 140–159 or DBP 90–99 Grade 2 SBP 160–179 or DBP 100–109 Grade 3 SBP 180 or DBP 110 No other RFAverage risk Low added risk Moderate added risk High added risk 1–2 RF Low added risk Moderate added risk Very high added risk 3 RF, MS, OD or diabetes Moderate added risk High added risk High added risk Very high added risk Established CV or renal disease Very high added risk MS = metabolic syndrome OD = subclinical organ damage RF = risk factors Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87 Copyright © 2007, with permission from Lippincott Williams and Wilkins

78 Summary of Amlodipine/Valsartan Clinical Data Amlodipine/Valsartan – the first antihypertensive agent available to physicians that reduces BP via dual calcium channel and angiotensin receptor blockade Data on Amlodipine/Valsartan demonstrate Powerful BP reductions across all grades of hypertension 1,2 Up to 43 mmHg drop in patients with a mean sitting systolic BP (SBP) 180 mmHg 2 Incremental BP drops over reductions achieved with previous medications ~21 mmHg SBP drop in patients uncontrolled on monotherapy 3 ~15 mmHg SBP drop in patients uncontrolled on combination therapy 4 1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89 3 Allemann et al. J Clin Hypertens 2007 (In press); 4 Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261); 5 Philipp et al. Clin Ther 2007;29:563–80

79 Summary of Amlodipine/Valsartan Clinical Data Up to 9 out of 10 patients achieved BP <140/90 mmHg 3 Well tolerated with a reduction in the incidence of peripheral edema compared with amlodipine monotherapy 5 ARB at least the same efficacy as ACEI but better tolerability/safety and potentially a stroke benefit Valsartan can preferably be combined with Amlodipine, HCTZ and Aliskiren SPC to a majority 1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89 3 Allemann et al. J Clin Hypertens 2007 (In press); 4 Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261); 5 Philipp et al. Clin Ther 2007;29:563–80

80 The Best Marker to Monitor in Treating Blood Pressure …. Is Blood Pressure Itself

81 Every two seconds, one person dies from cardiovascular disease

82 …are frightened to death of cancer and AIDS…or H1N1 …and ultimately die of cardiovascular diseases The Paradox of Diseases The majority of people continuously complain of allergic problems…

83 Thank You


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