1. HypertensionRole of New Combination Therapy Aziz-ur-Rehman Services Institute of Medical Sciences Lahore

2. Hypertension is very prevalent

3. Hypertension is one of the easiest condition to diagnosis

4. End-stageRenal Disease Heart failure CoronaryHeart Disease PersistentlyElevated BP Stroke Left Ventricular Hypertrophy Atherosclerosis Uncontrolled hypertension may be asymptomatic but has lot of CV morbidity & mortality

5. CV Mortality Risk Doubles with Each 20/10 mmHg Increment in BP* Cardiovascular mortality risk 8 8X risk 6 4 4X risk 2 2X risk 1X risk 0 115/75 135/85 155/95 175/105 Systolic BP/Diastolic BP (mmHg) Lewington et al. Lancet 2002;360:1903–13 *Individuals aged 40–69 years

7. Treatment of Hypertension reduces CV morbidity & mortality

8. Benefits of Blood Pressure Reduction Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 years 7% reduction in risk of ischemic heart disease mortality 2 mmHg decrease in mean SBP 10% reduction in risk of stroke mortality Lewington et al. Lancet 2002;360:1903–13

9. Treatment of hypertension is very cost-effective

10. Majority of the patients are either not diagnosed or not treated adequately

11. Law of 50% Pakistan< 3%

12. Hypertension is a multifactorialdisease

15. Limitations of Agents with a Single Mechanism of Action (MoA) Inadequate in 4060% of hypertensive patients1 In majority two or more antihypertensive agents are required to achieve the recommended target BP of <130/80 mmHg2 Multiple channels are needed to be blocked3 1Materson et al. N Engl J Med 1993;328:91421 2Bakris et al. Am J Kidney Dis 2000;36:64661 3Milani. Am J Manag Care 2005;11:S2207

16. Advantages of Multiple-mechanism Therapy: Safety/Tolerability Components of multiple-mechanism therapy can add the desirable effects but not the undesirable ones1,2 Neutralize adverse events.1,2 Hyperkalaemia of ACEIs & ARBs neutralised by diuretics RAAS blockers may attenuate the oedema that is caused by CCBs Multiple-mechanism therapy may have an improved tolerability profile compared with its single-mechanism components1,2 1Sica. Drugs 2002;62:44362 2Quan et al. Am J Cardiovasc Drugs 2006;6:10313

17. Current Guidelines Recommend Combination Therapy JNC 7 guidelines state1: “When BP is more than 20/10 mmHg above goal, consideration should be given to initiate therapy with 2 drugs...” ESH/ESC guidelines state2: “A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or when CV risk is high.” ESH = European Society of Hypertension ESC = European Society of CardiologyJNC = Joint National Committee 1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587

19. Amlodipine has a Wealth of CV Outcomes Data 1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906 4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84

20. Valsartan has a Wealth of CV Outcomes Data 1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–9063Maggioni et al. Am Heart J 2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–55Cohn et al. N Engl J Med 2001;345:1667–7; 6Mochizuki et al. Lancet 2007;369:1431–9

21. Valsartan also has a Wealth of CV Protection Data 1Viberti et al. Circulation 2002;106:672–8 2Ridker et al. Hypertension 2006;48:73–9

23. Arteriodilation

24. Effective in low-renin patients

25. No renal or congestive heart failure benefits

26. Peripheral edema

28. Arterio- and venodilation

29. Effective in high-renin patients

30. Congestive heart failure and renal benefits

31. Attenuates peripheral edema

32. No effect on cardiac ischemiaSNS = sympathetic nervous system; RAS = renin-angiotensin system

33. Amlodipine/Valsartan Provides Powerful BP Reductions Moderate HTN1‡ Mild HTN1¶ Baseline SBP≥180 mmHg2 0 –10 –20 –30 –40 –50 n=69 n=15 n=140 Mean change in MSSBPfrom baseline (mmHg) –20 –30 10/160 (aml+val) –43 ¶DBP 9099 mmHg, SBP 140159 mmHg‡DBP ≥100 mmHg, SBP ≥160 mmHg BP = blood pressure; DBP = diastolic BP; SBP = systolic BP; MSSBP = mean sitting SBP 1Smith et al. J Clin Hypertens 2007;9:355–64 (Dose 10/160 mg) 2Poldermans et al. Clin Ther 2007;29:279–89 (Dose 5–10/160 mg)

34. Amlodipine/Valsartan vs. Amlodipine EX-EFFeCTS1Patients with Stage 2 Hypertension EX-STAND2Black Patients with Stage 2 Hypertension Amlodipine/Valsartan10/160–320 mg Amlodipine10 mg Amlodipine/Valsartan10/160 mg Amlodipine10 mg 0 0 N=55 N=42 N=46 N=38 −10 −10 −20 −20 −30 −30 −31.7 −40 −37.2 −40 –40.1 –43.5 p=0.0018 −50 p=0.1 LSM Change in MSSBP from baseline (mmHg) LSM Change in MSSBP from baseline (mmHg) 1.Destro et al. J Am Soc Hypertens 2008;2:294–3022.Flack et al. J Hum Hypertens 2009 (E-pub ahead of print). LSM=least square meanMSSBP=mean sitting systolic blood pressure

35. Amlodipine/Valsartan: Superior BP Across Diverse Patient Populations (EX-EFFECTS) Elderly (65 yrs) Severe (180 mmHg) ISH† Obese‡ Diabetes –5 134 145 34 36 78 98 46 55 86 89 –10 –15 –20 Mean change in MSSBP at Week 4 (mmHg) –22.0 –21.7 –22.7 –22.9 –25 –27.2 –30 –29.5 * –30.2 –29.7 –31.7 * * * –35 –40 –40.1 Amlodipine/valsartan 10/160 mg * –45 Amlodipine 10 mg *p<0.05 amlodipine/valsartan vs. amlodipine monotherapy MSSBP = mean sitting systolic BP†ISH = isolated systolic hypertension (140 and <90 mmHg) ‡Obese defined as body mass index 30 kg/m2 Destro et al. J Am Soc Hypertens 2008;2:294–302

36. Amlodipine/Valsartan Reduces Albuminuria Versus Amlodipine in Black Patients with Stage 2 Hypertension (EX-STAND) Amlodipine 5+5 mg Amlodipine/Valsartan 5+160 mg 15 10 5 0 –5 –10 –15 –20 –25 –30 –35 10 n=160 n=157 Change from baseline in UACR (%) –30 Post-hoc analysis (Week 12 data)UACR = urinary albumin-to-creatinine ratio Flack et al. J Hum Hypertens 2009 (E-pub ahead of print)

38. Tendency towards edema due to absent venodilation

40. Additional venodilation by RAS inhibitors reduces edemaMesserli. Am J Hypertens 2001;14:978–9 *Angiotensin receptor blockers or angiotensin-converting enzyme inhibitors

41. Amlodipine/Valsartan: Fewer Patients Experience Peripheral Oedema* 40 30 20 10 0 p<0.001 31% Proportion of patients experiencing peripheral edema (%) 7% n=184/591 n=39/592 Amlodipine/Valsartan 5/160 mg Amlodipine10 mg Schrader et al. J Int Clin Pract 2009;63:217225 *Week 8 data

42. SUMMARY- CCB/ARB COMBO Amlodipine/Valsartan provides powerful BP reductions across hypertension severities Up to 43 mmHg systolic BP (SBP) drop in diverse patient types Elderly (≥65 years), ISH, obese and diabetics in patients uncontrolled with monotherapy ~21 mmHg SBP drops with fewer patients experience peripheral edema

43. Single-pill combinations of Amlodipine and Valsartan approved as first-line treatments for HTN Approvals consistent with current treatment guidelines Up to 80% of patients may need multiple medications Single-pill combinations offer effective, convenient medications Single pill combination improves compliance

44. Amlodipine + Valsartan Combo

45. Make use of this powerful tool to control the menace of hypertension

46. Combination is Better Thank you Aziz-ur-Rehman