How to Achieve Better Cardiovascular Outcome in Hypertensive Patients. Seoul National University Hospital

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1 How to Achieve Better Cardiovascular Outcome in Hypertensive Patients t Yong-Jin Kim, MD Seoul National University Hospital

2 Global Burden of CV Disease Cause Millions (%) Millions (%) CHD Stroke Other CVD TOTAL CVD All Cause Death WHO:WHF

3 Rank Order of Disability y( (DALYs) 1999 Disease or Injury 2020 Disease or Injury 1.Acute lower respiratory infections 2.HIV/AIDS 3.Perinatal conditions 4.Diarrhoeal diseases 5.Unipolar major depression 1. Ischemic heart disease 2. Unipolar major depression 3. Road traffic accidents 4. Cerebrovascular disease 5. Chron obstruc pulmonary dis 6. Ischemic heart disease 6. Lower respiratory infections 7.Cerebrovascular disease 7. Tuberculosis 8.Malaria 8. War 9.Road traffic accidents 9. Diarrhoeal diseases 10.Chron obstruc pulmonary dis 10. HIV

4 Evolution of Atherosclerosis Genetic Environmental Clinical i l Events Age (yrs)

5 Atherosclerosis in Korean War Casualties 300 autopsies (mean 22.1 yrs) 77 % Coronary atherosclerosis 39% Occlusive plaques ENOS JAMA 1953

6 Individual Risk vs Proportional Attributable t bl Risk 5% People with low risk level l 70% People with average risk levell 25% People with high h risk level l Individual risk of CHD Distribution ib ti of cases

7 Primary Risk Factors for CVD Hypertension Age Modifiable Non-modifiable Diabetes mellitus CHD Family history of CHD Cigarette smoking Dyslipidemia NCEP. Circulation 1994;89: Eur Heart J 1994;15: Wood D et al. Eur Heart J 1998;19:

8 HT: A Risk Factor for CV Disease 50 Coronary disease 45.4 Stroke Peripheral artery disease Heart failure 40 Biennial Age- 30 Adjusted Rate per Patients t Risk ratio 0 Men 2.0 Women Men 3.8 Kannel WB. JAMA. 1996;275: Women 2.6 Normotensive Men 2.0 Women 3.7 Men 4.0 Hypertensive Women 3.0

9 CV Mortality Risk with BP Increment CV Mortality 4 Risk x 4x 2x 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged 40 to 69 years, starting at blood pressure 115/75 mm Hg Chobanian AV et al. JAMA. 2003;289: Lewington S et al. Lancet. 2002;360:

10 Small Difference Produces Big Impact Meta-analysis of 61 observational studies 1 million adults For every 2 mm Hg decrease in mean SBP 7% reduction in CHD mortality 10% reduction in stroke mortality Lewington S et al. Lancet. 2002;360:

11 Evolution of Management of HT HT is an important compensatory mechanism and BP should not be tampered with Dr. White PD. Heart disease. 1937

12 Headlines of the St. Louis Post-Dispatch, April 13, 1945

13 FDR s Final Picture (April 11, 1945)

14 226/118 in /150 in /78 in /105 in Thirty-Second President ( ) Franklin D. Roosevelt Messerli FH, NEnglJMed Med. 1995

15 Treatment of Hypertension β-blocker JNC 1 JNC Chlorothiazide α-blocker CCB ACEI ARB

16 Outcome in Treated HT After >20 Yrs Normotensive Treated BP ( N = 6810 ) ( N = 686 ) Screening BP (mm Hg) 145/93 185/114 Final BP (mm Hg) 145/89 CHD (%) * Stroke (%) * Cancer (%) All-cause death (%) * *P <.002. Andersson OK et al. BMJ. 1998;317:

17 CVD Survival in Treated HT Untreated BP <140/90 mm Hg Untreated BP 140/90 mm Hg Treated BP at goal <140/90 mm Hg Treated BP not at goal 140/90 mm Hg 1 %) urvival (% Su 0.96 P= P<.0001 P= Follow-up (Years) Benetos et al. J Hypertens ;21:

18 Better Outcome in HT Agents with beyond BP lowering?

19 tient Gro oup (%) Events per Pa HOPE: Events per Patient Group RR=22% 20 P< Placebo Ramipril RR=20% RR=16% P<.001 P= RR=26% 12.2 P< RR=0% RR=32% P=NS 6.1 P< Primary CV Outcome Death *MI, stroke, or CV death. Yusuf et al. N Engl J Med ;342: MI Stroke Non- CV Death Total Mortality

20 Ambulatory BP in HOPE Trial Hg) BP (mm SBP baseline SBP year 1 DBP baseline DBP year Ramipril Group (n=20) Night Δ=17/8 mm Hg (P<.001) 24-h Δ=10/4 mm Hg (P<.03) Svensson et al. Hypertension. 2001;38:e28-e32. e32. Time (hours)

21 CAD Mortality and Usual BP by Age Systolic BP Diastolic BP % CI) ity k and 95% HD Mortali olute Ris IH ating Abs (Floa years years years years years years years years years years Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg) Prospective Studies Collaboration. Lancet ;360:

22 ence) al/refere erimenta tio (Expe Odds Ra Odds Ratio for CV Events & SBP Recent trials Older trials placebo Older trials active HOPE P<.0001 < Difference (reference minus experimental) in Systolic BP (mm Hg) Staessen et al. J Hypertens ;21: Recent AASK L vs H ABCD/NT L vs H ALLHAT/Aml ALLHAT/Lis ALLHAT/Lis 65 ALLHAT/Lis Blcks ANBP2 CONVINCE DIABHYCAR ELSA IDNT2 LIFE/ALL LIFE/DM NICOLE PREVENT SCOPE Older ALLHAT/Dox ATMH EWPHE HEP HOPE HOT HOT M vs H INSIGHT MIDAS/NICS/VHAS L vs H MRC MRC2 PART2/SCAT PATS PROGRESS/Per PROGRESSION/Com RCT70-80 RENAAL SHEP STONE STOP 1 STOP2/CCBs STOP2/ACEIs Syst-China Syst-Eur UKPDS C vs A UKPDS L vs H

23 New-Onset DM With RAS Blockade 0 Lisinopril Ramipril Losartan Candesartan Valsartan Candesartan (ALLHAT) (HOPE) (LIFE) (SCOPE) (VALUE) (CHARM) -10 % Reduction in New-Onset Diabetes ALLHAT Officers and Collaborators. JAMA. 2002;288: Yusuf S et al. JAMA. 2001;286: Dählof B et al. Lancet. 2002;359: Lithell H et al. J Hypertens. 2003;21: Julius S et al. Lancet. 2004;363: Pfeffer MA et al. Lancet. 2003;362:

24 Better Outcome in HT Agents with beyond BP lowering? Rapid BP lowering in high-risk patients

25 VALUE: Primary Composite Endpoint atients ent (%) on of P st Eve oportio ith Firs Pro W Valsartan-based regimen Amlodipine-based i d regimen HR=1.03; 95% CI : P= Number at risk Time (months) Valsartan Amlodipine besylate Julius et al. Lancet.. June 2004;363.

26 ts %) Patien ent (% on of P rst Ev oportio Pro With Fi VALUE: Fatal and Non-Fatal MI Valsartan-based regimen Amlodipine-based i d regimen HR=1.19; 95% CI ; 1.38; P= Number at risk Time (months) Valsartan Amlodipine i besylate % Julius S et al. Lancet.. June 2004;363.

27 mmhg mmhg VALUE: Systolic BP in Study Sitting SBP by Time and Treatment Group Valsartan (N=7649) Amlodipine (N=7596) 135 Baseline Months (or final visit) Difference in SBP Between Valsartan and Amlodipine Months (or final visit) Julius S et al. Lancet.. June 2004;363.

28 VALUE: Outcome and SBP Differences

29 New ESC Guideline: Early Treatment

30 Better Outcome in HT Agents with beyond BP lowering? Rapid BP lowering in high-risk patients Lower BP target in high-risk patients

31 HOT - Rate of Major CV Events 000 pe erson- -years p for trend 0.5 p for trend BP goal mmhg <90 <85 <80 Rate/1 5 0 All n=18790 Diabetic n=1501 Hansson et al., Lancet 1998

32 UKPDS: Tight BP Control Tight group 144/82 mmhg vs less tight 154/87 mmhg 0 Any Diabetes- Related Diabetes- Endpoint Related Death Stroke Microvascular Endpoints Retinopathy Progression Deterioration of Vision Heart Failure P= P= P= P= P= P= P= *Compared with less tight control. Captopril and atenolol were equally effective in reducing risk and were equally safe in patients with diabetes. UKPDS Group. BMJ. 1998;317:

33 CAMELOT Study Design Comparison of Amlodipine versus Enalapril to Limit Ischemic Occurrences of Thrombosis Amlodipine 10 mg PTCA & Angiogram 2000 Patients Enalapril 20 mg Placebo 100 sites QCA 24 Months Prospective, Randomized, Double Blind, Multicenter Endpoints: CHD Death, Resuscitated t Arrest, Nonfatal MI, Stroke, TIA, CABG, Revascularization, Unstable Angina, Hospitalized CHF

34 132 CAMELOT: Systolic BP c Pres ssure (m mm Hg g) Systoli Placebo Enalapril Amlodipine Months after randomization

35 CAMELOT: Time to Major CV Event 25% 23.1% 20% 20.2% Ev vent Ra ate (% %) 15% 10% 5% Amlodipine i Enalapril Placebo 16.6% 0% Time (months)

36 ESC Guidelines for Target BP

37 Evolution of JNC Guidelines

38 Better Outcome in HT Agents with beyond BP lowering? Rapid BP lowering in high-risk patients Lower BP target in high-risk patients Improve target BP lowering: adherence

39 Target BP Lowering Patients (%) BP goal achieved BP goal not achieved England Sweden Germany Spain Italy Korea *Treated for hypertension BP goal is <140/90 mmhg Source: Wolf-Maier et al. Hypertension 2004;43:10 17; Korea National Health and Nutrition Survey 2005

40 Nonadherence With Antihypertensive Medication Patie ents (%) year retrospective study in new starters (N = 8643) Days With Drug on Hand Achieved 80% Adherence Did Not Fill Second Rx Monane M et al. Am J Hypertens. 1997;10:

41 Medication Adherence Declines When a Second Drug Is Prescribed th %) tients Wit R 0.80 (% Pat MP * Antihypertensive therapy Lipid-lowering therapy Both * * * * * * * * * 0 Month 1-2 Month 3-4 Month 5-6 Month 7-8 Month 9-10 *P <.05 vs both. Schwartz JS et al. J Am Coll Cardiol. 2003;41(6 suppl A):526A. Abstract

42 Lower Pill Burden better adherence to AHT and LLT As the number of pre-existingexisting Rx meds increased, the likelihood of adequately refilling AHT and LLT decreased Number of pre-existing Rx medications Likelihood of achieving adherence Lesser Greater Adjusted odds ratio for adherence to both AHT and LLT* (PDC 80%) (95% confidence interval) (reference group) 1.23 ( ) 1.30 ( ) 1.61 ( ) 1.96 ( ) *P<0.001 for all groups versus reference group. Retrospective cohort study of a managed care population. N=8406 patients with hypertension who added AHT and LLT to existing Rx meds within a 90-day period. Adherence to concomitant therapy: sufficient AHT and LLT Rx meds to cover 80% of days per 91-day period. Chapman RH, et al. Arch Intern Med. 2005;165:

43 ESC Guidelines on Combination Therapy More than one agent is necessary to achieve target BP in the majority of patients Fixed combinations of two drugs simplify treatment/favor compliance Task Force of ESH/ESC. J Hypertens 2007;25:

44 Adherence is fundamental to better cardiovascular (CV) health Drugs g don't work in patients who don't take them. C. Everett Koop, (Former US Surgeon General)

45 Better Outcome in HT Agents with beyond BP lowering? Rapid BP lowering in high-risk patients Lower BP target in high-risk patients Improve target BP lowering: adherence Global risk management: Add statin

46 Target BP lowering in ALLHAT

47 Global Risk Management Millions of people, p WW*, 2000 Hypertension (109 million) Dyslipidemia (138 million) Diabetes (41MM) Smoking (164 million) Obesity (91 MM) Metabolic Syndrome (100MM) *7 countries: U.S., U.K., Italy, Germany, France, Spain, and Japan; population 706 million Source:Decision Resources; Cardiovascular Outlook; DataMonitor

48 Concurrent Hypertension and Dyslipidemia id i Is Very Prevalent 24% 44M 33% 61M 15% 27M HTN DYS HTN/DYS NHANES III. Phase 2. Fasting Sample, N=185M 15% 27 Million Patients

49 Hypercholesterolemia Is Common in Patients With Hypertension * Patien nts wit th TC 250 mg/dl Normal BP 25 High BP Rx Men Women 19 Antihypertensive MacMahon SW, et al. Arteriosclerosis. 1985;5:

50 SBP and Cholesterol on CHD Death Rate Age-adjusted CHD death rates per 10, person-years <182 SBP quintile (mm Hg) Cholesterol quintile (mg/dl) Neaton JD et al. Arch Intern Med 1992;152:56-63.

51 Evolution of Management of Hypercholesterolemia

52 Evolution of Management of Hypercholesterolemia

53 The Pyramid of Recent Trials Very high chol with CHD or MI High chol in high risk CHD or MI Normal chol with CHD or MI High cholesterol without t CHD or MI No history of CHD or MI 4S 4S LIPID CARE WOSCOPS AFCAPS/ TexCAPS Low to moderate cholesterol without t CHD or MI ASCOT

54 How About in Patients with Normal Cholesterol?

55 Heart Protection Study 20,000 pt with CHD or at high risk (TC >135 mg/dl) 40 In ncidence e % % RR P= % RR p< Placebo (n=10,267) Simvastatin (n=10,269) -25% RR p< All-cause Major vascular All stroke mortality events Adapted from HPS Collaborative Group, Lancet 2002;360:7 22

56 Heart Protection Study

57 ASCOT Study Design 18,000 patients R = Randomized 9000 β-blocker ± diuretic R 9000 CCB ± ACE 5000 TC 6.5 mmol/l ( 250 mg/dl) 4000 TC >6.5 mmol/l (>250 mg/dl) TC >6.5 mmol/l (>250 mg/dl) 5000 TC 6.5 mmol/l ( 250 mg/dl) 500 open lipid lowering 500 open lipid lowering R R 2250 statin placebo 2250 placebo open lipid lowering 2250 statin These are the target numbers of patients. Sever PS, et al, for the ASCOT investigators. J Hypertens. 2001;19:

58 ASCOT LLA: BP changes DBP (mm H g) SBP (mm Hg) 170 Atorvastatin 10 mg Placebo Years Close-out Close-out Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

59 ASCOT LLA: cholesterol changes Atorvastatin 10 mg Placebo 6 Tot tal choles sterol (mmol/l L) mmol/l 1.0 mmol/l (mg/dl L) LDL chole esterol (mmo ol/l) mmol/l 1.0 mmol/l (mg g/dl) Years Close-out

60 ASCOT LLA: nonfatal MI & fatal CHD Cumu lative in cidence (%) HR=0.64 ( ) P= % reduction Atorvastatin 10mg Placebo Years Sever PS et al. Lancet 2003;361:

61 ASCOT LLA Benefits are Independent of Baseline Cholesterol Baseline TC (mg/dl) RR p < 5,0 (193) ,0 5,99 ( ) > 6,0 (231)

62 ASCOT BPLA and LLA Combined Rates/1000 Patient-Years End Point Nonfatal MI and fatal CHD Amlodipine ± Atenolol ± Relative Risk Perindopril + Thiazide + Reduction Atorvastatint ti Placebo % Fatal and nonfatal stroke % Sever P et al. Eur Heart J. 2006;27: ;

63 Global Risk Management: Add statin If perfect control of a risk factor is difficult (eg, blood pressure control in the elderly), l total t risk can still be reduced by reducing other risk factors such as smoking or blood cholesterol 10% Reduction in BP + 10% Reduction in TC = 45% Reduction in CVD Emberson J et al. Eur Heart J. 2004;25: Graham et al. Eur Heart J Advance Access Published Online August 28, 2007 Accessed at

64 Effect of Cholesterol and BP on CHD Risk Deaths/10,000 patient-years 34 N = 316, <182 < BP = blood pressure; CHD = coronary heart disease. Neaton JD et al. Arch Intern Med. 1992;152:56-64.

65 ESH Guidelines. Eur Heart J

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67 Evolution in Understanding CVD Traditional CVD Perspective Global CV Risk Perspective Hyperte ension Hyperlip pidemia Diabete es Total risk age DM LIPID HTN smoking sex Independent risk-factors treated individually Vascular Disease Is an Interplay of risk-factors

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