Management of The Patients with Hypertension and High Risk Cardiovascular Disease

Management of The Patients with Hypertension and High Risk Cardiovascular Disease Songsak Kiatchoosakun, MD. Cardiology, Medicine Khon Kaen University

CVD and Hypertension: Worldwide Morbidity and Mortality Cardiovascular disease accounted for 16.6 million deaths in 2000 7.3 million ischemic heart disease deaths 5.4 million stroke deaths High blood pressure is associated with an estimated 7.1 million deaths Estimated 690 million persons have hypertension; most remain untreated or uncontrolled

Hypertension

Effect of Systolic BP and Diastolic BP on CHD Mortality CHD Death Rate per 10,000 Person-Years : MRFIT Study (N=316,099)* 100+ 20.6 90-99 99 Diastolic BP (mm Hg) 23.8 80-89 89 31.0 16.9 10.3 11.8 75-79 79 48.3 25.5 13.9 8.8 70-74 74 37.4 24.6 12.8 8.5 34.7 25.3 12.6 9.2 <70 *Men aged 35-57 years followed for a mean of 12 years. Neaton et al. Arch Intern Med. 1992;152:56-64. 43.8 25.2 11.8 <120 38.1 24.9 80.6 160+ 140-159 120-139 Systolic BP (mm Hg)

Classification of Hypertension Definitions and Classification of Blood Pressure (BP) Levels (mmhg) ( European Society of Cardiology 2007) Category Systolic Diastolic Optimal <120 and <80 Normal 120-129 and/or 80-84 High normal 130-139 and/or 85-89 Grade1 hypertension 140-159 and/or 90-99 Grade2 hypertension 160-179 and/or 100-109 Grade3 hypertension 180 and/or 110 Isolated systolic hypertension 140 and <90

Assessment of Patient with HT Establishing blood pressure levels Identifying secondary causes of hypertension Evaluating the overall cardiovascular risk Other risk factors Target organ damage Concomitant diseases

Blood Pressure Measurement Sir, your blood pressure is OK.

Secondary Cause of Hypertension Sings suggesting secondary hypertension Features of Cushing syndrome Skin stigmata of neurofibromatosis (pheochromocytoma) Palpation of enlarged kidneys (polycystic kidney) Auscultation of abdominal murmurs (renovascular hypertension) Diminished and delayed femoral pulses and reduced femoral BP (aortic coarctation, aortic disease)

Total Cardiovascular Risk Concepts Small number of patients have hypertension alone Blood pressure and metabolic risk factors potential each other and leading to greater cardiovascular risk Goals for treatment and treatment strategies are different between high risk and low risk patients

Patients With Hypertension Are Likely To Have Additional CV Risk Factors Men Women 3 RFs 22% 4+ RFs 8% 4+ RFs None None 12% 19% 17% 2 RFs 25% 1 RF 26% 3 RFs 20% 2 RFs 24% 1 RF 27% Kannel WB. Am J Hypertens. 2000;13:3S-10S.

The Threat of Global CV Risk Dyslipidemia Hypertension TC 5.4 mmol/l X2.6 SBP 165 mm Hg (210 mg/dl) X1.9 X4.5 X1.3 X3.5 X2.3 Glucose intolerance X1.8 Hypertension SBP 195 mm Hg X3.0 X5.3 X8.7 X5.2 X2.9 Smoking X1.7 Dyslipidemia TC 6.1 mmol/l (235 mg/dl) X1.7 Risk shown above is compared with risk for a 40-year-old male nonsmoker with TC 4.7 mmol/l (185 mg/dl), SBP 120 mm Hg, and no glucose intolerance, who is ECG-LVH negative and whose probability of developing CVD is 15/1000 (1.5%) in 8 years Kannel W. In: Hypertension: Pathophysiology and Treatment. New York: McGraw-Hill, Inc.; 1977:888-909.

Factors Influencing Prognosis (1) Risk factors Systolic and diastolic BP levels and pulse pressure (in elderly) Age (M > 55 years; W > 65 years) Smoking Dyslipidemia - TC > 5.0 mmol/l (190 mg/dl) or: - LDL C >3.0 mmol/l (115 mg/dl) or: - HDL C: M < 1.0 mmol/l (40 mg/dl), W <1.2 mmol/l (46 mg/dl) or: - TG > 1.7 mmol/l (150 mg /dl) Fasting plasma glucose 5.6 6.9 mmol/l (102-125 mg /dl) Abdominal obesity (waist circumference > 102 cm (M), >88 cm (W) Family history of premature CV disease (M at age <55 years; W at age <65 years)

Factors Influencing Prognosis (2) Sub-clinical organ damage LVH by ECG or Echocardiography (LVMI M > 125 g/m 2, w > 110 g/m 2 ) Carotid wall thickening (IMT > 0.9 mm) or plaque Ankle/brachial BP index <0.9 Slight increase in plasma creatinine: M: 115 113 umol/l (1.3 1.5 mg/dl) W:107 124 umol/l (1.2 1.4 mg/dl) Low estimated glomerular filtration rate + (60 ml/min/1.73 m 2 ) or creatinine clearance (< 60 ml/min) Microalbuminuria 30 300 mg/ 24 h or albumin creatinine ratio: > 22 (M); or > 31 (W) mg/g creatinine Rike maximal for concentric LVH (left ventricular hypertrophy): increased LVMI (left ventricular mass index) with a wall thick ness/ radius ratio > 0.42.

Factors Influencing Prognosis (3) Established CV or Renal Disease Cerebrovascular disease Heart disease: CAD, CHF Renal disease: diabetic nephropathy; renal impairmant (creatinine;m > 133, W > 1 24 mmol/l); proteinuria (> 300 mg/24 h) Peripheral artery disease Advanced retinnopathy: haemorrhages or exudates, papilledema

Diagnostic Evaluation

Blood Test FBS Lipid panel Renal function Electrolyte

Waist Circumference

Electrocardiography

Proteinuria

Echocardiography: LV Hypertrophy

Carotid Plaque

Total Cardiovascular Risk

High/Very High Risk Subjects BP > 180 mmhg systolic and/or > 110 mmhg diastolic Systolic BP > 160 mmhg with low diastolic BP ( < 70 mmhg) Diabetes mellitus Metabolic syndrome > 3 cardiovascular risk factors One or more of the following sub-clinical organ damages: - LV hypertrophy - Carotid plaque detected by ultrasound - Renal impairment/micro-albuminuria or proteinuria Established cardiovascular or renal disease

Goals of Treatment Primary goal is to achieve maximum reduction in the long term total risk of cardiovascular disease BP should be reduce to at least below 140/90 mmhg Target BP should be at least <130/80 mmhg in diabetics and in high or very high risk patients such as stroke, myocardial infarction, renal dysfunction, proteinuria In order to more easily achieve goal BP, antihypertensive treatment should be initiated before significant cardiovascular damage develops

Treatment Strategies Lifestyle changes Smoking cessation Moderation of alcohol consumption Sodium restriction Other dietary changes Weight reduction Physical exercise

Antihypertensive Therapy Five major classes Diuretics Beta-blocker ACE inhibition Angiotensin receptor antagonist Calcium antagonist

Effect of Antihypertensive Therapy 0 10 Cerebrovascular Disease Coronary Heart Disease 16% % Reduction 20 30 40 50 60 48% Systematic overviews showed that reductions in blood pressure of about 10-12 mm Hg systolic and 5-6 mm Hg diastolic conferred relative reductionsinstrokeriskof38%andinriskof coronary heart disease of 16% within just a few years of beginning treatment. MacMahon SW et al. Prog Cardiovasc Dis. 1986;29(suppl 1):99 118.

Clinical Research Questions in Hypertension Is blood pressure lowering beneficial? Does it matter how elevated blood pressure is lowered?

Hypertension Treatment Significantly Reduced Mortality and Morbidity VA Cooperative Study Group Estimated Cumulative Incidence of All Morbid Events Over 5 Years Estimated Cumulative Incidence of All Morbid Events (%) 60 50 40 30 20 10 0 Control - Placebo 380 male patients diastolic blood pressure (BP) averaging 90-114 mmhg 0 1 2 3 4 5 Years Active Treatment Groups - Diuretic-based regimen and hydralazine 37% risk reduction Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.

SHEP Trial: Endpoints Active Therapy (diuretic, beta-blocker vs Placebo) Relative Risk (95% CI) 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20-13% -25% -37% -32% P=NS -54% Stroke CHD CHF CVD Death SHEP Cooperative Research Group. JAMA. 1991;265:3255; Kostis et al. JAMA. 1997;278:212-216.

Beta-blockers and Diuretic Lower Risk of Cardiovascular Mortality In hypertension, beta blockers and diuretics have proven risk reduction in cardiovascular morbidity and mortality vs. placebo (STOP, HEP, MRC) Hypertension guidelines recommend beta blockers or diuretics as one of the initial treatments for hypertension JNC-VII Guideline

Diuretic / Beta-blocker The benefits of diuretic therapy on coronary artery disease were less than than expected Metabolic side effects of diuretic/betablocker mitigated the beneficial effect of blood pressure reduction The beneficial effect of new treatment may beyond the blood pressure lowering effect

Renin-Angiotensin-Aldosterone (RAAS) and Hypertension Renin Angiotensin Converting Enzyme Angiotensinogen Angiotensin I Angiotensin II AT I receptor Vasoconstriction Sodium Retention Increase blood pressure

Manipulation of Ang II generation Angiotensinogen (Liver) Bradykinin ACEinhibitor Peptides Angiotensin I Angiotensin II AT 1 AT 2 de Gasparo et al. Pharmacol Rev. 2000; 52: 415

ACE Inhibition Blood pressure lowering Beyond blood pressure Anti-atherosclerotic effects Improvement in vascular endothelial function LV hypertrophy reduction Reduce new onset of diabetes Reduce cardiovascular complications of hypertension

The Heart Outcomes Prevention Evaluation Study: HOPE Study Aim: Effect of Ramipril (up to 10mg/d) vs placebo on CV death, MI or stroke (primary) Design:Randomized double blind, Wide entry criteria, large, simple trial Size: 9541 patients followed for 4 to 6 years Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

HOPE Study Population: Typical Office Practice Patients Patients did not have clinical of heart failure 47% of had high blood pressure Patients were 55 years or older CV events 11% had previous stroke 52% had previous MI Vascular disease 80% had history of CAD 42% had history of PVD Diabetes 39% had diabetes + 1 or more CVD risk factors The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

HOPE: Primary Outcome Reductions in MI, Stroke, or Cardiovascular Death % of Patients Reaching Endpoints 0.20 0.15 0.10 0.05 0 22% Reduction in Events P=.0001* 15% Reduction in Events at 1 year Placebo Ramipril 0 500 1000 1500 Days of Follow-up Note: Trial halted early due to the highly significant risk reductions seen with Ramipril

HOPE Study: Results (contd.) CV death MI Stroke Revasc Cardiac arrest Heart failure Total mortality Type 2 diabetes 0-5 -10-15 -20-25 -30-35 -40-26% -20% -32% -15% -37% -23% -16% -34% N Engl J Med 2000; 342: 145-153 % risk reduction

HOPE: Dose-dependent Effects of Ramipril on LV Mass and Function Mean baseline LVEF 58% in all groups Placebo (n = 151) Ramipril 2.5 mg (n = 149) Ramipril 10 mg (n = 146) LV mass (g) 10 6 5.31 8 5 8.21 7.86 LV 4 6 end 3 4 systolic 2 2 volume 1 (ml) 0 2 4 6 3.53 0 1 2 3 2.9 P Trend = 0.03 P Trend = 0.001 1.9 Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.

HOPE:Conclusions In people with high risk for CVD, addition of ramipril to other effective therapies prevents: CV death, strokes and MI Total mortality Revascularization The benefit is beyond the effect on BP (3/2 mmhg)

HOPE-TOO: Primary Outcome (CV death, MI, Stroke) Primary outcome (% HOPE-TOO patients) 30 25 20 15 10 5 Placebo Main HOPE study ends Ramipril HOPE-TOO begins RRR = 17% P = 0.0002 n Placebo Ramipril 0 0 1 2 3 4 5 6 7 4652 4645 4432 4456 4204 4256 3981 4079 3647 3789 2719 2819 1923 2075 1550 1731 Years RRR = relative risk reduction HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Additional Reduction in New-onset Diabetes 12 10 Main HOPE study ends HOPE-TOO begins New-onset diabetes (% HOPE-TOO patients) 8 6 4 2 0 Placebo Ramipril RRR 31% P = 0.0006 n Placebo Ramipril 2883 2837 1 2 3 4 2803 2763 2704 2672 2600 2587 2392 2431 5 6 7 1813 1853 1269 1324 1021 1092 Years HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

SECURE: Dose-dependent Effect of Ramipril on Carotid Atherosclerosis 0.025 P = 0.028 0.020 0.022 NS Slope of the mean maximum carotid-intima thickness (mm/y) 0.015 0.010 0.018 37% Reduction 0.014 0.005 0 Placebo Ramipril 2.5 mg Ramipril 10 mg Lonn E et al. Circulation. 2001;103:919-925.

ACE Inhibitor Evidence: Post MI with HF SAVE Radionuclide EF < 40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiogram EF < 35% Probability of Event 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 Placebo ACE-I 0 1 2 3 Years OR: 0.74 (0.66 0.83) 26 % reduction 4 ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio Flather MD, et al. Lancet. 2000;355:1575 1581

Blood Pressure Lowering Treatment Trialists Collaboration. Lancet 2000;356:1955 Comparison of ACE Inhibitors and Calcium Antagonist Stroke Coronary heart disease Heart failure ACE inhibitors based therapy may reduce risk of CAD and heart failure Total mortality 0.5 1.0 2.0 Relative risk Favor ACEI Favor calcium antagonist

Manipulation of Ang II generation Angiotensinogen (Liver) Angiotensin I ARB AT 1 receptor blocker Angiotensin II AT 1 AT 2 de Gasparo et al. Pharmacol Rev. 2000; 52: 415

The Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE Study) 9,193 hypertensive patients with LVH, aged 55-80 years Mean 4.8-year follow-up 44,119 patient-years of follow-up 945 study sites in 7 countries Dahlöf B et al Lancet 2002;359:995-1003.

LIFE: Primary Composite Endpoint Number at risk Proportion of patients with first event (%) 16 14 12 10 8 6 4 2 Composite of CV death, stroke and MI Atenolol Losartan Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009 0 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 Dahlöf B et al Lancet 2002;359:995-1003.

Stroke Proportion of patients with first event (%) 8 7 6 5 4 3 2 1 Fatal and non-fatal stroke Atenolol Losartan Adjusted Risk Reduction 24.9%, p=0.001 Unadjusted Risk Reduction 25.8%, p=0.0006 24.9 % Number at risk 0 0 6 12 18 24 30 36 42 48 54 60 66 Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925 Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897 Study Month Dahlöf B et al Lancet 2002;359:995-1003.

Proportion of patients with first event (%) 8 7 6 5 4 3 2 1 LIFE:Myocardial Infarction and Fatal and non-fatal MI Atenolol Losartan 0 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Losartan 4605 4525 4478 4430 4367 4307 4258 4196 4139 3999 1953 936 Atenolol 4588 4517 4466 4415 4364 4302 4243 4192 4134 3975 1953 937 CV Mortality Adjusted RR -7.3%, p=0.491 Unadjusted RR -5.0%, p=0.628 Proportion of patients (%) 8 7 6 5 4 3 2 1 Cardiovascular mortality Atenolol Losartan Adjusted RR 11.4%, p=0.206 Unadjusted RR 13.3%, p=0.136 0 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Losartan 4605 4563 4532 4496 4448 4410 4373 4327 4284 4152 2005 976 Atenolol 4588 4453 4513 4474 4442 4388 4341 4299 4252 4107 2006 965 Dahlöf B et al Lancet 2002;359:995-1003.

VBWG Results from ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial Blood lood Pressure Lowering Arm

ASCOT: Anglo-Scandinavian VBWG Cardiac Outcomes Trial Study 1: ASCOT-LLA Double-blind, randomized, placebo-controlled trial of a lipid-lowering agent in a sample of the total ASCOT patient population Study 2: ASCOT-BPLA Prospective, randomized, open, blinded endpoint (PROBE) design comparing two antihypertensive regimens in the total ASCOT patient population Sever PS et al. Lancet. 2003;361:1149-58. Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

VBWG ASCOT-BPLA: Study design Design: Population: Treatment: Double-blind, placebo controlled, randomized N = 19,257 with hypertension and 3 other CV risk factors Amlodipine 5 10 mg ± perindopril 4 8 mg prn (n = 9639) Atenolol 50 100 mg ± bendroflumethiazide 1.25 2.5 mg/potassium prn (n = 9618) Primary outcome: Secondary outcome: Nonfatal MI (including silent MI) and fatal CHD All-cause mortality, stroke, nonfatal MI (excluding silent MI), all coronary events, CV events/procedures, CV mortality, fatal/nonfatal HF

ASCOT-BPLA: Reduction in Primary Outcome (nonfatal MI and fatal CHD) 10 VBWG Proportion of events (%) 8 6 4 HR = 0.90 (95% CI, 0.79 1.02) RRR = 10% P = 0.1052 2 0 0 1 2 3 4 5 6 Time since randomization (years) Number at risk Amlodipine-based regimen 9639 9475 9337 9168 8966 7863 (429 events) Atenolol-based regimen 9618 9470 9290 9083 8858 7743 (474 events) *Atenolol 50 100 mg ± bendroflumethiazide 1.25 2.5 mg/potassium prn Amlodipine 5 10 mg ± perindopril 4 8 mg prn Atenolol-based regimen* Amlodipine-based regimen Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

ASCOT-BPLA: Reduction in Fatal and Proportion of events (%) 10 8 6 4 2 0 0 Nonfatal stroke HR = 0.77 (95% CI, 0.66 0.89) RRR = 23% P = 0.0003 1 2 3 4 Time (years) Number at risk Amlodipine-based regimen 9639 9483 9331 9156 8972 7863 (327 events) Atenolol-based regimen 9618 9461 9274 9059 8843 7720 (422 events) *Atenolol 50 100 mg ± bendroflumethiazide 1.25 2.5 mg/potassium prn Amlodipine 5 10 mg ± perindopril 4 8 mg prn 5 Atenolol-based regimen* Amlodipine-based regimen 6 VBWG Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

ASCOT-BPLA: Overall Results VBWG Study stopped prematurely after 5.5-year median follow-up because of higher death rate in assigned atenolol-based-regimen group Group receiving amlodipine-based regimen had nonsignificant 10% reduction in primary outcome (nonfatal MI plus fatal CHD) and significant reductions in nearly all secondary CV endpoints and new-onset diabetes Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

ASCOT-BPLA: Summary VBWG Newer antihypertensive drug regimens should be considered in preference to older beta-blocker ± diuretic therapies Amlodipine ± perindopril showed reductions in: Major CV events 16% New-onset diabetes 30% Stroke 23% Mortality 11% ASCOT results support the use of newer drugs, in multi-drug combinations, to modify risk factors and/or metabolic disturbances, especially in patients with complicated hypertension Dahlöf B et al. Lancet. 2005;366:895-906. Poulter NR et al. Lancet. 2005;366:907-13.

New Onset Diabetes: Impact of Blood Pressure Lowering Drugs

Cardiovascular Events in Treated Hypertensive Subjects Rate of events (per 100 patient years) 6 5 4 3 2 1.97 3.90 4.70 0 A B C A - without diabetes C - previously known diabetes B - new onset diabetes Total number of CV events - 63 Verdecchia, Hypertens 2004;43:963-968

Risk of DM among 3804 Hypertensive Patients with Various Antihypertensive Medications Rx Hazard Ratio* None 1.0 ACEI 0.9 B-Blocker 1.25** CCB 1.17 Thiazides 0.95 * adjusted for age, race, BMI, CV risk factors, etc. ** significant difference Gress, et al. NEJM 2000;342:905-12

Pharmacological Therapy in Hypertension Choice of antihypertensive drugs The main benefits of antihypertensive therapy are due to lowering blood pressure Beta-blockers especially in combination with thiazide diuretic, should not be used in patients with metabolic syndrome or at high risk of diabetes ESC guideline 2007

British Hypertension Society Guideline 2006 Age < 55 Age > 55 or black ACEI or ARB CCB or Diuretic Add CCB Add ACEI or ARB ACEI or ARB + CCB+ Diuretic Add beta-blocker or alpha-blocker

Conditions Favoring use of Some Antihypertensive Drugs versus Others Thiazide diuretics Beta-blockers - Isolated systolic HT - Angina pectoris - Heart failure - Post-myocardial infarction - Heart failure - Tachyarrhymias ACE inhibitors Angiotensin receptor antagonists - Heart failure - Heart failure - LV dysfunction - Post-myocardial infarction - Post-myocardial infarction - Diabetic nephropathy - Diabetic nephropathy - Proteinuria - Non-diabetic nephropathy - LV hypertrophy - LV hypertrophy - Atrial fibrillation - Carotid atherosclerosis - Metabolic syndrome - Proteinuria/Microalbuminuria - ACEI-induced cough - Metabolic syndrome

Conditions Favoring use of Some Antihypertensive Drugs versus Others Calcium antagonists (dihydropyridines) Calcium antagonists (verapamil/diltiazem) - Isolated systolic hypertension - Angina pectoris (elderly) - Carotid atherosclerosis - Angina pectoris - Supraventricular tachycardia - LV hypertrophy - Carotid/Coronary Atherosclerosis - Pregnancy - Hypertension in blacks Diuretics (anti-aldosterone) Loop diuretics - Heart failure - End stage renal disease - Post-myocardial infarction - Heart failure

Thank You for Your Attention

VALUE Valsartan Antihypertensive Long-Term Use Evaluation

VALUE: Patient Population Treated or untreated hypertensive patients entry criteria for untreated hypertension: 160 210 mmhg systolic, 95 105 mmhg diastolic Age 50 years, male or female High-risk for cardiac events one or more defined risk factors or diseases Mann J, Julius S. Blood Press. 1998;7:176 183.

Proportion of Patients With First Event (%) VALUE: Primary Composite Cardiac Endpoint 14 12 10 8 6 4 2 Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = 0.94 1.14; P = 0.49 Number at risk Valsartan 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 Amlodipine 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474 Julius S et al. Lancet. June 2004;363.

HOPE (Heart Outcomes Prevention Evaluation) Study Patients > 55 years with a history of - CAD or stroke or peripheral artery disease - Diabetes plus at least one other CV risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking or microalbuminuria) Patients did not have heart failure or LV dysfunction 9297 patients received ramipril or placebo Treatment duration: 4.5 years

Dyslipidemia Is More Common in Patients With Hypertension Patients with TC 6.5 mmol/l ( 250 mg/dl) (%) 40 35 30 25 20 15 10 5 0 Normal BP High BP Antihypertensive Rx 28 37 35 36 18 19 Men Women *Hypertension defined as BP 150/ 95 mm Hg MacMahon M, et al. Arteriosclerosis. 1985;5:391-396.

Monotherapy versus Combination Mild BP elevation Low/moderate CV risk Conventional BP target Therapy Strategies Choose between Marked BP elevation High/very high CV risk Lower BP target Single agent at low dose If goal BP not achieved Two-drug combination at low dose Previous agent Switch to different agent at full dose at low dose Previous combination Add a third drug at full dose at low dose If goal BP not achieved Two-to three-drug Combination at full dose Full dose Mono-therapy ESC guideline 2007 Two-three drug combination at full dose

Possible Combinations Between Some Classes of Antihypertensive Drugs

VALUE: Incidence of New-onset Diabetes 18 16 23% Risk Reduction With Valsartan P < 0.0001 14 New-Onset Diabetes (% of patients in treatment group) 12 10 8 6 4 13.1% 16.4% 2 0 Valsartan-based Regimen (n = 7649) Amlodipine-based Regimen (n = 7596) Julius S et al. Lancet. June 2004;363.

Rationale VBWG Cardiovascular (CV) disease continues to be the chief cause of mortality and morbidity worldwide Most of this is due to coronary heart disease (CHD) Multiple risk factors have synergistic effects in the pathogenesis of CV disease Combination treatment regimens using 2 agents are recommended to reach target BP goals Limited outcome data have led to an investigation comparing standard vs newer antihypertensive treatment options

ACE Inhibitor Evidence: CAD European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) 13,655 patients with CAD and presumed normal left ventricular function randomized to perindopril (8 mg) or placebo for 4.2 years Cardiovascular death (0.86; 0.72-1.03) Non-fatal MI (0.78; 0.20-0.90) Cardiac arrest (0.54; 0.20-1.47) Combined endpoint (0.80; 0.71-0.91) 0 0.5 1 1.5 2 Favors Perindopril Favors Placebo ACE-I=Angiotensin converting enzyme inhibitors, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction EUROPA Investigators. Lancet 2003;362:782-788

ACE Inhibitor Evidence: CAD Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial 8,290 patients with stable coronary artery disease and normal left ventricular function randomized to trandolapril (4 mg) or placebo for 4.8 years Primary End Point (%)* 30 25 20 15 10 5 0 Placebo Trandolapril 0 1 2 3 4 5 6 Years After Randomization *Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization PEACE Trial Investigators. NEJM 2004;351:2058-2068

HOPE-TOO: Rationale HOPE-TOO was an extension of the HOPE trial, which examined the effects of ACE inhibition in reducing major CV events in highrisk patients with vascular disease or diabetes HOPE-TOO was designed to assess whether the CV and metabolic benefits of ramipril were sustained over time and occurred in subgroups based on varying risk and concomitant treatment HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Study Design Heart Outcomes Prevention Evaluation The Ongoing Outcomes 4528 HOPE patients at 174 centers who agreed to further follow-up Blinded treatment ended and patients were advised to use ACEI 2.6-year post-trial extension ACEI use during extension HOPE ramipril arm (n = 2317): 72% HOPE placebo arm (n = 2211): 68% >90% of all HOPE-TOO patients used ramipril HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Major CV Events and New Diagnosis of Diabetes No. of patients (%) Ramipril (n = 3393) Placebo (n = 3393) RR (95% CI) P* MI, stroke, or CV death 699 (20.6) 820 (24.2) 0.83 (0.75 0.91) 0.0002 MI 485 (14.3) 581 (17.1) 0.81 (0.72 0.92) 0.0007 Stroke 174 (5.1) 215 (6.3) 0.79 (0.65 0.97) 0.023 CV death 327 (9.6) 374 (11.0) 0.86 (0.74 1.00) 0.045 Revascularization 767 (22.6) 880 (25.9) 0.84 (0.76 0.92) 0.0003 New diagnosis of diabetes 152 (7.3) 216 (10.3) 0.69 (0.56 0.85) 0.0006 *Calculated by log-rank test and data on all participants in the study extension, censored for period of observation HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Effect of ACEI on Major CV Events and New-onset Diabetes No. of HOPE patients (%) Event* MI, stroke, or CV death MI Stroke Ramipril (n = 2317) 220 (7.9) 146 (5.1) 59 (2.0) Placebo (n = 2211) 225 (8.4) 169 (6.1) 56 (1.9) CV death 133 (4.4) 126 (4.2) Revascularization New diagnosis of diabetes 235 (9.1) 48 (2.7) 259 (10.5) 70 (4.0) *Event rates were calculated as proportions of events in those study participants who were event-free at the end of the in-trial period. 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 RR (95% CI) HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Additional Reduction in 25 20 MI Main HOPE study ends HOPE-TOO begins MI (% HOPE-TOO patients) 15 10 Placebo 5 Ramipril RRR = 19% P = 0.0007 n Placebo Ramipril 0 0 1 2 3 4 5 6 7 4652 4645 4474 4484 4282 4309 4088 4159 3770 3875 2814 2900 1999 2137 1612 1791 Years HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Sustained Reduction 10 8 in Stroke Main HOPE study ends HOPE-TOO begins Stroke (% HOPE-TOO patients) 6 4 Placebo 2 Ramipril RRR = 21% P = 0.023 n Placebo Ramipril 0 0 1 2 3 4 5 6 7 4652 4645 4523 4539 4367 4391 4188 4263 3887 4000 2953 3011 2115 2225 1734 1876 Years HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Sustained Reduction CV death (% HOPE-TOO patients) 15 10 5 in CV Death Placebo Main HOPE study ends HOPE-TOO begins Ramipril RRR = 14% P = 0.045 n Placebo Ramipril 0 0 1 2 3 4 5 6 7 4652 4645 4569 4567 4453 4448 4309 4346 4027 4097 3061 3100 2203 2295 1808 1946 Years HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Study Conclusions The benefits of ramipril were maintained during post-trial followup for CV death, stroke, and hospitalization for heart failure Additional reductions in MI, revascularization and new-onset diabetes were also observed despite similar rates of ACEI use in the randomized groups The reduction in CV outcomes demonstrated in the HOPE trial is most likely an underestimate of the full effects of long-term ramipril therapy Subgroup analyses demonstrate the benefits observed are additive to those of other life-saving therapies, and extend to all patients with vascular disease, independent of their baseline risk HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade HOPE EUROPA ALLHAT ANBP2 INVEST LIFE GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT CONSENSUS SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT

ACE Inhibition and Anti- atherosclerotic Effect (A) Control (B) Diabetic apoe-deficient mice (C) Diabetic apoe-deficient mice ACE inhibition treated Candido R et al. Circulation. 2002;106:246-253.

Algorithm for the Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmhg) (<130/80 mmhg for those with diabetes or chronic kidney disease) Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 Hypertension (SBP 140 159 or DBP 90 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension (SBP >160 or DBP >100 mmhg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB). Drug(s) for the compelling indications* Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. *Compelling Indications Heart failure Post-MI High coronary artery disease risk Diabetes Chronic kidney disease Recurrent stroke prevention Chobanian AV et al. JAMA.. 2003;289:2560 2572 2572. JNC 7

Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin- Converting Enzyme Inhibitor to Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

ALLHAT: Entry Criteria Age >55 years old Untreated systolic and/or diastolic hypertension (>140/90 mm Hg but <180/110 mm Hg ) At least 1 additional risk factor for CV morbidity, including: Old MI or stroke History of revascularization Other documented atherosclerosis Type 2 diabetes mellitus Cigarette smoking Low HDL cholesterol(<35mg/dl) LVH Davis et al. Am J Hypertens. 1996;9:342-360.

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Cumulative CHD Event Rate.2.16.12.08.04 A/C L/C RR (95% CI) 0.98 (0.90-1.07) 0.99 (0.91-1.08) Chlorthalidone Amlodipine Lisinopril p value 0.65 0.81 0 0 1 2 3 4 5 6 7 Years to CHD Event Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

ACE Inhibitor Recommendations for Secondary Prevention I I IIa IIb III IIa IIb III Use in all patients with LVEF < 40%, and those with diabetes or chronic kidney disease indefinitely, unless contraindicated Consider for all other patients I IIa IIb III Among lower risk patients with normal LVEF where cardiovascular risk factors are well controlled and where revascularization has been performed, their use may be considered optional ACE=Angiotensin converting enzyme, LVEF= left ventricular ejection fraction

Hypertension and Dyslipidaemia Are Major Risk Factors for CHD Framingham Study 350 Age 140 Probability of CVD/1000 300 250 200 150 100 50 0 100 120 140 160 180 200 SBP (mm Hg) in men Kannel W. In: Hypertension: Pathophysiology and Treatment. New York: McGraw-Hill, Inc.; 1977:888-909; Castelli WP. Am J Med. 1984;76:4-12. 70 60 50 40 Probability of CVD/1000 120 100 80 60 40 20 0 <204 205-235- 265-234 264 294 TC (mg/dl) in men >295

Additive Effect of Cholesterol and SBP on Risk of CHD Death 34 N = 316,099 Deaths /10,000 patient-years 245+ 12 221-244 Cholesterol quintile (mg/dl)* 13 6 203-220 17 10 6 182-202 21 8 6 4 < 182 12 9 6 3 23 11 8 3 < 118 18 8 6 17 5 125-131 118-124 14 132-141 142+ SBP quintile (mm Hg) Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64. *To convert to mmol/l multiply by 0.02586

Diuretic Based Regimens Substantially reduce the risk of stroke The benefits of diuretic therapy on coronary artery disease were less than than expected Metabolic side effects of diuretic mitigated the beneficial effect of blood pressure reduction

Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade HOPE EUROPA PEACE ALLHAT ANBP2 INVEST LIFE GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS

HOPE: Benefits in All Subgroups Younger than 65 years as well as 65 years and older With/without diabetes With/without evidence of cardiovascular disease With/without hypertension With/without microalbuminuria Whether or not taking aspirin or other antiplatelet agents, beta blockers, lipidlowering agents or antihypertensive agents NEJM 2000; 342: 145-153