CASE STUDY

01 Study ClickCase to edit Master title style

A 55 y.o man complained of chest discomfort when exercising since
the last 2 months.. He admitted suffering from both hypertension and DM2 . No history of MI, CHD or stroke. He is a heavy smoker. Currently he is on Glibenclamide 5 mg (1-0-) and Rampiril 1 x 10 mg.

BP 150/90 mmHg HR 78/m

ECG : SR, LVH LDL 126 mg/dL, TG 144 mg/dL. The kidney function and liver
function are normal

02 What are the Patients Problem?

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1. Cigarette smoker
2. Hypertension

3. Diabetes Mellitus 4. Dyslipidemia

5. Chest discomfort

03 What are the Patients Problem?

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Cigarette smoker Yes
Hypertension Yes

Diabetes Mellitus Yes Dyslipidemia

Yes ! Yes

Chest discomfort

04

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Is there any way to prevent cardiovascular event, considering CVD is the leading causes (67%)1 of morbidity and mortality among Hypertension and DM patients? A. Yes B. No

1. Alexander CM, Antonello S. Pract Diabet. 2002;21:21-8 2. Colhoun HM et al. Lancet. 2004;364:685-696

05 Click to edit Master title style

Is there any way to prevent cardiovascular event, considering CVD is the leading causes (67%)1 of morbidity and mortality among Hypertension and DM patients?

Yes

1. Alexander CM, Antonello S. Pract Diabet. 2002;21:21-8 2. Colhoun HM et al. Lancet. 2004;364:685-696

The cardiovascular continuum of events

ACS
Secondary prevention Coronary Thrombosis

Stroke

Arrhythmia and Loss of Muscle

Myocardial Ischemia

Remodeling

Important

CAD

Ventricular Dilatation Congestive Heart Failure End-stage Heart Disease

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Atherosclerosis
Primary prevention

Risk Factors ( Dyslipidemia, BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Progression of HT to LVH to HF

06 Click to edit Master title style

BAGAIMANA PASIEN HARUS DIKELOLA?

Tentukan risiko pasien ini. Bagaimana caranya? Apakah perlu diperiksa marker untuk sindrom koroner akut?

2007 ESH/ESC Guidelines: Definitions & Classification of Blood Pressure Levels (mmHg)

Category Optimal Normal High normal Grade 1 hypertension Grade 2 hypertension Grade 3 hypertension ISH

Systolic <120 120129 130139 140159 160179 180 140 and and/or and/or and/or and/or and/or and

Diastolic <80 8084 8589 9099 100109 110 <90

Assessment of the overall cardiovascular risk Cardiovascular Risk Factors Presence of Risk Factors
Increasing age Male gender Smoking Family history of premature cardiovascular disease (age< 55 in men and < 65 in women) Dyslipidemia Sedentary lifestyle Unhealthy eating Abdominal obesity Dysglycemia (diabetes, impaired glucose tolerance, impaired fasting glucose)

Presence of Target Organ Damage

- Microalbuminuria or proteinuria - Left ventricular hypertrophy - Chronic kidney disease (glomerular filtration rate < 60 ml/min/1.73 m2) - Previous stroke or TIA - Coronary Heart Disease - Peripheral arterial disease

Presence of atherosclerotic vascular disease

CV Risk Factors that may alter thresholds and targets in the treatment of HTN

2009 CHEP Recommendations

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CKMB dan Troponin dalam batas

normal

Adakah pemeriksaan lain diperlukan?

Chest PA view of Heart - LVH Click to edit Master title style

C/T ratio > 50%

13

BAGAIMANA RISIKO PASIEN INI?

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RENDAH ? SEDANG ? TINGGI? SANGAT TINGGI ?

Cardiovascular Risk Stratification

Blood pressure (mm Hg) Other risk factor, organ damage, or disease
No other risk factors High normal Average risk Grade 1 HT Low added risk Moderate added risk High added risk Grade 2 HT Moderate added risk Moderate added risk High added risk

Normal Average risk

Grade 3 HT High added risk Very high added risk Very high added risk

1-2 risk factors

3 risk factors, mets, organ damage, or diabetes

Low added Low added risk risk Moderate added risk High added risk

Established CV or renal disease

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

HT: hypertension; mets: metabolic syndrome; CV: cardiovascular

Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187

BAGAIMANA SEHARUSNYA PASIEN INI DIKELOLA?

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Merokok

Stop Merokok Merubah gaya hidup

Obat Anti-hypertensive Hypertensi Diabetes Mellitus Obat Hypoglicaemic Dyslipidemia Obat Hypolipidemic Chest discomfort Obat anti-hipertensi Obat anti iskemia

Hypertension and subcinical organ damage

data obtained in the LIFE study, in which hypertensive patients in whom treatment was accompanied by regression of echocardiographic

LVH or a delayed increase in LVM had less incident cardiovascular events, including sudden death, than those in whom no regression from or earlier progression to LVH occurred.

Mancia et al Reappraisal of ESC/ESH 2007 Guidelines on Hypertension

Cardiac Hypertrophy in Hypertension

Cardiac hypertrophy (LVH)
1. Regression of cardiac hypertrophy leads to an improvement in prognosis. 2. Any antihypertensive drug can induce the regression of cardiac hypertrophy by maintaining a sufficient decrease in blood pressure. The target of blood pressure control should be <140/90mmHg. 3. RA system inhibitors and long-acting Ca channel blockers,in particular, are effective for the regression of cardiac hypertrophy.
Japanese Society of Hypertension Guideline 2009

Hypertension and coronary heart disease

1. Careful and sufficient reduction of blood pressure is important

in coronary artery disease. The target of blood pressure control should be <140/90mmHg, in principle.

2. In patients with old myocardial infarction, b-blockers, reninangiotensin (RA) system inhibitors (ACE inhibitors, ARBs) and aldosterone antagonists reduce the mortality rate and improve prognosis. Careful reduction of blood pressure to <130/80mmHg is desirable.

3. Hypertension complicated by angina pectoris due to organic coronary artery stenosis is a good indication for long-acting Ca channel blockers and b-blockers with no endogenous sympathomimetic action.

4. Vasospastic angina pectoris is a good indication for Ca channel blockers.

Japan society of Hypertension Guideline 2009

Whats New for 2009 The Hypertensive Diabetic

Treating hypertension in the diabetic patient reduces death and disability and reduces health care system costs

TARGET <130 systolic and <80 mmHg diastolic

Patients with diabetes are at high cardiovascular risk

Up to 80% of diabetic patients die of cardiovascular disease

Most patients with diabetes have hypertension Between 35 and 75% of diabetic complications have been attributed to hypertension. Treatment of hypertension in patients with diabetes reduces total mortality, myocardial infarction, stroke, retinopathy and progressive renal failure rates. More intensive reduction in blood pressure reduces major cardiovascular events and total mortality by 25%
2009 Canadian Hypertension Education Program Recommendations

Blood Pressure Evidence: Primary Prevention

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
33,357 patients with HTN and >1 CHD risk factor randomized to chlorthalidone, amlodipine, or lisinopril for 5 years

.20 Rate of MI or fatal CHD .16

.12
.08

Chlorthalidone Amlodipine Lisinopril

RR A/C 0.98 0.99 (95% CI) (0.90-1.07) (0.91-1.08) P-value 0.65 0.81

.04 0 0 1 2

L/C

3 4 Years to CHD Event

There is similar efficacy among BP lowering agents

BP=Blood pressure, CHD=Coronary heart disease, HTN=Hypertension, MI=Myocardial infarction

ALLHAT Investigators. JAMA 2002;288:2981-97

Blood Pressure Evidence: Primary Prevention

Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study
9,193 high-risk hypertensive* patients with LVH randomized to losartan (100 mg) or atenolol (100 mg) for 5 years Proportion with CV death, MI, or stroke (%)
16 12 8 4 0

Atenolol Losartan

13% RRR, P=0.021

0 6 12 18 24 30 36 42 48 54 60 66

Study Month An ARB provides greater efficacy in patients with LVH

ARB=Angiotensin receptor blocker, CV=Cardiovascular, DBP=Diastolic blood pressure, LVH=Left ventricular hypertrophy, MI=Myocardial infarction, SBP=Systolic blood pressure *Defined by SBP=160-200 mmHg or DBP=95-115 mmHg

Dahlf B et al. Lancet 2002;359:995-1003

Blood Pressure Evidence: Primary Prevention

Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA)
19,342 high-risk hypertensive patients with 3 additional CV risk factors randomized to amlodipine (10 mg) & perindopril (8 mg) or atenolol (100 mg) & bendroflumethiazide (2.5 mg) for 5.5 years

Nonfatal MI and fatal CHD (%)

Atenolol-based regimen
Amlodipine-based regimen

4
2 0 0

RRR = 10%, P = 0.1052

Time since randomization (years) There is similar efficacy with both BP lowering regimens
BP=Blood pressure, CV=Cardiovascular, CHD=Coronary heart disease, MI=Myocardial infarction

Dahlf B et al. Lancet 2005;366:895-906

HOPE Study (Usefulness of ACEi) Relative Risk Reduction of Cardiovascular Endpoints in high risk patients (angina, DM, HTN, PAOD) with normal LV Fx.
Combined Cardiovascular Cardiovascular Myocardial mortality infarction endpoints

Stroke

-22% p <0.001

-20% p <0.001

-26% p <0.001

Ramipril n=4645 Placebo n=4652

-32% p <0.001

Weber et al. AJC 2002;89:suppl:27A

Blood Pressure Evidence: Secondary Prevention

Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial
15,245 patients with untreated HTN and high CV risk randomized to a BP

lowering strategy with valsartan (160 mg) or amlodipine (10 mg) for 4.2 years

Primary cardiac composite endpoint Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2 Favors valsartan Favors amlodipine
There is similar efficacy with an ARB and CCB
ARBS=Angiotensin receptor blocker, CCB=Calcium channel blocker, CV=Cardiovascular

Julius S et al. Lancet 2004;363:2022-2031

Blood Pressure Evidence: Secondary Prevention

Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) Trial
1,991 patients with CAD and a DBP <100 mmHg randomized to amlodipine (10 mg), enalapril (20 mg), or placebo for 2 years

CV event rate*

0.25

0.20
0.15 0.10

Placebo Enalapril Amlodipine

130/78 124/77 125/77

Follow-up BP (mmHg)

0.05
0 0 6 12 18 24

Months

A BP <130/80 mmHg is associated with fewer CV events*

*Includes CV death, myocardial infarction, cardiac arrest, coronary revascularization, hospitalization for heart failure or angina pectoris, stroke, transient ischemic attack, development of peripheral arterial disease BP=Blood pressure, CAD=Coronary artery disease, CV=Cardiovascular, DBP=Diastolic BP Nissen S et al. JAMA 2004;292:2217-26

ARB Evidence: Secondary Prevention

Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial
2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo for 34 months 50 CV Death or Hospitalization for HF 40 30 Placebo

Candesartan

20
10 0 0 1

HR 0.77 p=0.0004

2 3 Years ARB reduce CV events in those intolerant of ACE-I

ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction Granger CB et al. Lancet 2003;362:772-777

ARB Evidence: Secondary Prevention

Valsartan in Acute Myocardial Infarction Trial (VALIANT)
14,703 patients with post-MI HF or LVSD (EF <0.40) randomized to captopril (50 mg tid), valsartan (160 mg bid), or captopril (50 mg tid) plus valsartan (80 mg bid) for 2 years

0.4
All Cause Mortality

Captopril
Valsartan Valsartan and Captopril

0.3 0.2
0.1 0.0

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 0

12

18

24

30

36

ARB provide similar efficacy to ACE-I in Post-MI LVSD

ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction

Months

Pfeffer M et al. NEJM 2003;349:1893-1906

Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA): Study Design

Patient population Men and women aged 40-79 years
Untreated HTN
(SBP 160 mm Hg, DBP 100 mm Hg, or both)

Treated HTN

(SBP 140 mm Hg, DBP 90 mm Hg, or both)

19,342 patients with HTN

10,305 patients with TC 251.4 mg/dL

Atorvastatin 10 mg (n=5168)

Placebo (n=5137)
5 years Trial stopped at 3.3 years, 2 years earlier than expected

TC 251.4 mg/dL
At least 3 additional CVD risk factors Primary efficacy end point

Nonfatal MI, including silent MI, and fatal CHD

HTN=hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; TC=total cholesterol; CVD=cardiovascular disease. Sever PS et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA: Atorvastatin Reduced the Occurrence of First Major CV Events

4 Patients with nonfatal MI and fatal CHD (%)

Placebo

36% RRR in nonfatal MI and fatal CHD P=.0005 Atorvastatin (10 mg)

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

RRR=relative risk reduction.

Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.

Baseline Characteristics JIKEI Click to edit Master title style

Clinical characteristics Male Female
Age (years) Current smoker

Valsartan arm (n=1,541) 1,020 (66%) 521 (34%)

65 (10) 259 (17%)

Non-ARB arm (n=1,540) 1,023 (66%) 517 (34%)

65 (10) 262 (17%)

Systolic BP [SBP] (mmHg)

Diastolic BP [DBP] (mmHg) Heart rate (beats/min) BMI (kg/cm2)

139.2 (11.4)
81.4 (10.5) 71 (11) 24(3)
Note: Data are mean (Standard Deviation) or Number (%)

138.8 (10.6)
81.4 (10.8) 72 (11) 24(3)

Medical History at Baseline Click to edit Master title style

Valsartan arm (n=1,541) 1,358 (88%) 514 (33%) 176 (11%) 812 (53%) 315 (20%) Non-ARB arm (n=1,540) 1,341 (87%) 522 (34%) 174 (11%) 813 (53%) 314 (20%)

Concomitant Diseases
Hypertension Coronary heart disease Heart failure Hyperlipidaemia Diabetes mellitus

Clickof toTreatment edit Master title style Effect on Endpoints JIKEI STUDY
Primary endpoint Composite endpoint Secondary endpoints Stroke/TIA Myocardial infarction Hospitalisation for angina pectoris

P-value
0.0002

0.0280 0.7545 0.0001

0.0293

Hospitalisation for Heart Failure Dissecting aortic aneurysm Transition to dialysis, doubling of serum creatinine levels All cause mortality Cardiovascular mortality
0.125

0.0340
0.8966 0.7537

0.9545
0.25 0.5
1

Incidence of endpoint reduced

TIA = transient ischaemic attack

Incidence increased

Primary Endpoint Click to edit Master title style

15 Valsartan arm (92 events) Non-ARB arm (149 events)

Event rate (%)

10

5
HR=0.61, p=0.0002 95% CI 0.470.79

39%

0
0 6 1,504 1,502 12 1,441 1,447 18 1,257 1,262 24 1,092 1,075 30 855 835 36 689 657 42 368 344 48 368 343

Number at risk Valsartan 1,541 Non-ARB 1,540

Hospitalisation for Angina Pectoris Click to edit Master title style

4 Valsartan arm 19 events Non-ARB arm 53 events
3 Event rate (%)

1 HR=0.35, p=0.0001 95% CI 0.200.58

65%

0
0 6 1,504 1,504 12 1,441 1,450 18 1,257 1,265 24 1,092 1,078 30 855 837 36 689 658 42 368 343 48 368 343

Number at risk Valsartan 1,541 Non-ARB 1,540

Source: Kaplan Meier Curve adopted from Dr Dahlof ESC 2006 Hotline presentation

Hospitalisation for Heart Failure Click to edit Master title style

2.5 Valsartan arm 19 events Non-ARB arm 36 events 2.0
Event rate (%)

1.5

1.0

47%
HR=0.53, p=0.029 95% CI 0.310.94

0.5

0.0
0 6 1,504 1,502 12 1,441 1,448 18 1,257 1,264 24 1,093 1,077 30 856 837 36 690 657 42 369 343 48 368 343

Number at risk Valsartan 1,541 Non-ARB 1,540

Source: Kaplan Meier Curve adopted from Dr Dahlof ESC 2006 Hotline presentation

b -blocker Evidence: Secondary Prevention

Summary of Secondary Prevention Trials of b -blocker Therapy
Phase of Treatment Acute treatment
Secondary prevention Overall

Total # Patients
28,970

RR (95% CI) 0.87 (0.77-0.98)

24,298 53,268 0.5

0.77 (0.70-0.84) 0.81 (0.75-0.87) 2.0

CI=Confidence interval, RR=Relative risk

1.0 RR of death b-blocker Placebo better better

Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.

ASPIRIN IN HYPERTENSION

the prudent recommendations of the 2007 ESH/ESC guidelines can be reconfirmed: antiplatelet therapy, in particular low-dose aspirin, should be prescribed to hypertensive patients with previous cardiovascular events;

it can also be considered in hypertensive patients without a history of cardiovascular disease with reduced renal function or with a high cardiovascular risk.

In patients receiving aspirin, careful attention should always be given to the increased possibility of bleeding,particularly gastrointestinal.

Mancia et al. Reappraisal of 2007 ESC/ESH Guidelines on Hypertension

2nd Prevention of aspirin

- CV death 17%
- AMI 34%

- CVA 35% - All CV disease 35%

AHA ecommendation :Anyone with atherosclerosis

Initial Tx: 160-325mg at 1st day Subsequent Tx: 75-160 mg/day

Anti-anginal Drug

JADI, BAGAIMANA GARIS BESAR PENGOBATAN?

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ASPIRIN / ANTIPLATELET ?

THIAZIDE BETA BLOCKER CALCIUM CHANNEL BLOCKER NITRAT ACE-INHIBITOR ARB

VASODILATOR LAIN ANTI DIABETIK HIPOLIPIDEMIK LAIN-LAIN ?

Terapi Kombinasi

ADAKAH PEMERIKSAAN LAIN YANG DIPERLUKAN? Click to edit Master title style
Laboratorium : ?? Treadmill Test ?

Ekhokardiogram MSCT ?
Angiografi koroner/kateterisasi jantung ?