Curriculum

• Name : Prof. DR. Vitae

Dr. Idrus Alwi SpPD, K-KV, FACC, FESC,
FAPSIC, FINASIM, FACP.
• Current Position : President of Indonesian Society of
Internal Medicine

• Medical Student : Faculty of Medicine University of Indonesia 1986

• Internist : Faculty of Medicine University of Indonesia 1996
• Cardiovascular Consultant : The Indonesian Society of Internal Medicine , 2001
• PhD : Faculty of Medicine University of Indonesia, 2006
• FACC : American College of Cardiology, 2006
• FESC : European Society of Cardiology, 2008
• FAPSIC : Asia Pacific Society of Interventional Cardiology, 2009
• FINASIM : Indonesian Society of Internal Medicine, 2009
• FACP : American Colleague of Physician, 2013
• Advanced Course in Cardiology, Melbourne 1997
• Advanced Course on Echocardiography and Others Non Invasive Cardiology,
Melbourne 1997.
• Stem cell NOGA course, Cincinnatti, Ohio, 2009
• ASAN Interventional Cardiology Course, Seoul, 2011
Management of Hypertension to Prevent
the Risk of Cardiovascular Event

Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC

Division of Cardiology, Department of Internal Medicine,

Faculty of Medicine , University of Indonesia,
Jakarta , Indonesia
 Hypertension is the number one risk factor
for the global attributable mortality

CVD = Cardiovascular Disease World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011.
Available at: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/index.html
 Hypertension causes end-organ damage

Chobanian AV, et al. JAMA. 2003;289:2560-2572

 Ischemic Heart Disease Mortality Rate
in Each Decade of Age
SBP DBP Age at risk:
256 256
80-89 y
128 128 70-79 y
64 64 60-69 y
IHD 32 32
50-59 y
mortality 16 16
40-49 y
(floating 8 8
absolute risk
and 95% CI) 4 4
2 2
1 1

120 140 160 180 70 80 90 100 110

Usual SBP (mm Hg) Usual DBP (mm Hg)

IHD, ischemic heart disease.

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.
 Relationship Between SBP Reduction and
CV Mortality is Unequivocal
MIDAS/NICS/VHAS
1.50 P = 0.003
UKPDS C vs A

1.25 NORDIL INSIGHT

HOT L vs H
STOP ACEIs HOT M vs H MRC1
Ratio
Odds Ratio

1.00
MRC2
STOP CCBs
STONE SHEP HEP
Odds

HOPE
0.75 EWPHE
CAPPP Syst-Eur
UKPDS L vs H
Syst-China RCT70-80
0.50
PART 2/SCAT
ATMH STOP-1
0.25

-5 0 5 10 15 20 25
Difference
Difference in
in SBP
SBP (mm
(mm Hg)
Hg)
Staessen JA, et al. Lancet. 2001;358:1305-15.
ESH/ESC Guideline 2013
ESH-ESC Guideline 2013
 Stratification of total CV risk in categories of low,
moderate, high and very high risk according to SBP
and DBP and prevalence of RFs

ESC-ESH Guideine, 2013

Initiation of lifestyle changes and antihypertensive
drug treatment.

ESC-ESH Guideine, 2013

Hypertension Guidelines: an ultimate goal

Goals of treatment
“The primary goal of treatment of the hypertensive patient is to achieve
the maximum reduction in the long-term total risk of cardiovascular
morbidity and mortality.”

Therapeutic Management of Hypertension

“Antihypertensive treatment translates into significant reductions of
cardiovascular morbidity while having a less significant effect on
all cause mortality.”
Blood pressure goals in hypertensive patients
A SBP goal <140 mmHg:
a) is recommended in patients at low–moderate CV risk; I B
b) is recommended in patients with diabetes; I A
c) should be considered in patients with previous stroke or TIA;
IIa B
d) should be considered in patients with CHD; IIa B
e) should be considered in patients with diabetic or non-diabetic
CKD. IIa B
A DBP target of <90 mmHg is always recommended, except in
patients with diabetes, in whom values <85 mmHg
are recommended.
It should nevertheless be considered that DBP values between
80 and 85 mmHg are safe and well tolerated. I A
ESC-ESH Guideline, 2013
 ESH-ESC Guideline 2013

Diuretics (thiazides, chlorthalidone and indapamide),

beta-blockers, calcium antagonists, ACE inhibitors, and
angiotensin receptor blockers are all suitable and
recommended for the initiation and maintenance of
antihypertensive treatment, either as monotherapy or in
some combinations with each other.
Some agents should be considered as the preferential
choice in specific conditions
Monotherapy vs. drug combination strategies to achieve
target BP

ESC-ESH Guideine, 2013

JNC 8: Treatment Algorithm of Hypertension
American Society of Hypertension and the International Society of
Hypertension Guideline (2014)

J Hypertension 2014
WHICH ANTIHYPERTENSIVES WE
SHOULD CHOOSE?
ACEIs, ARB’s, Beta Blockers, CCBs and Diuretics
ACEI’s ARB’s B Blockers CCB’s Diuretics
• Captopril Losartan Atenolol Amlodipine Chlorthalidone
• Enalapril Valsartan Metoprolol Felodipine HCTZ
• Ramipril Irbesartan Bisoprolol Nifedipine Indapamide
• Perindopril Telmisartan Carvedilol Diltiazem Spironolactone
• Benazepril Olmesartan Verapamil
• Imidapril Candesartan
• Quinapril Eprosartan
• Trandolapril
Hypertension Management and Cardiovascular Protection:
Effect to Surrogate Endpoint
Renin-angiotensin system (RAS) blockade reduces CV
disease progression
Inhibition of angiotensin II via RAS blockade
directly reduces atherosclerosis:

Endothelial dysfunction ↓

Oxidative Stress ↓

Inflammation ↓

Tissue remodelling ↓

Schmieder et al. Lancet 2007;369:1208−1219

Image reproduced with kind permission of Professor Böhm
 PREVENT: Effect of Amlodipine Besylate on Carotid
Atherosclerosis by B-Mode Ultrasound
Mean Change in Carotid Mean Maximum IMT Over 12 Walls
During 3 Years of Follow-up*
0.10 Amlodipin Placebo

P=.007
Mean Change (mm)

0.05
at 3 Years

0.00

-0.05

-0.10

*Prespecified secondary outcome.

Pitt et al. Circulation. 2000;102:1503-1510.
 Regression of Left Ventricular Hypertrophy with
Antihypertensive Therapy by Drug Class
0 Mean % change in LV Mass from baseline (with 95% CI’s) adjusted for
change in diastolic BP & duration of treatment

* p<0.05; ** p<0.001 vs beta blocker

change in LV Mass(%)

-5

-10
* **
-15

*
-20 Diuretics b-Blockers Calcium ACE-Is ARB’s
Antagonists
Klingbeil et al 2003
Management of Hypertension to Prevent the Risk of Cardiovascular
Event :
Effect to Hard Endpoint
 Benefits of Treating Hypertension:
Metaanalysis of 14 Randomised Trials
Percentage Reduction

*
* * significant

*
Strokes
*
Fatal Non-fatal Overall
strokes CAD mortality
MacMahon et al Blood pressure, stroke and coronary heart disease.
Lancet 1990; 355: 765-774
 Previous evidence: ACE inhibitors in reducing
CV mortality and morbidity –
The HOPE study
Effectiveness of ramipril (n=4,645) versus placebo (n=4,652) in preventing major CV events
in high-risk patients with and without hypertension

Composite Death from

CV endpoint* CV causes MI Stroke
0

–4
–22% –26% –20% –32%
–8
(treatment vs. placebo)

p<0.001 p<0.001
–12 p<0.001 p<0.001

–16
% risk reduction

–20
–24
–28
–32
–36 Ramipril, n=4,645
Placebo, n=4,652
–40
* Composite CV endpoint = death from CV causes + MI + stroke
ACE = angiotensin-converting enzyme; CV = cardiovascular; HOPE = Heart Outcomes Prevention Evaluation;
MI = myocardial infarction
Yusuf S, et al. N Engl J Med 2000;342:145–153
 ARBs Markedly Reduce the
Risks of CV Endpoints*
CV
CV death
death or
or
hospitalization Total
hospitalization Total mortality
mortality2,3
2,3
Stroke
Stroke11 CV
CV death
death2,3
2,3

Losartan Valsartan
Valsartan 160
160 mg
for
for heart failure22 Valsartan
heart failure Valsartan 160
160 mg
mg
Losartan 50
50 mg/
mg/ HCTZ
HCTZ mg
Candesartan Candesartan 32 mg
Candesartan 32 mg
Candesartan Candesartan 32
32 mg
mg
25mg
25mg Candesartan 3232 mg
mg
0
Percent risk reduction

-10 -9
-12

-20

-23
-25
-30 Actual relative risk reduction/values at the lower end of a range
Values at the higher end of a range

*Risk reductions are relative to placebo, with the exception of stroke, which is relative to atenolol.
CV=cardiovascular.
1. Dahlof B et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a
randomized trial against atenolol. Lancet. 2002;359(9311):995-1003.
2. Cohn JN et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-1675.
3. Yusuf S et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved
Trial. Lancet. 2003;362(9386):777-781.
 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
Chlorthalidone
.16 Amlodipine
Rate of MI or
fatal CHD

Lisinopril
.12

.08 RR (95% CI) P-value

A/C 0.98 (0.90-1.07) 0.65
.04 L/C 0.99 (0.91-1.08) 0.81
0
0 1 2 3 4 5 6 7
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
A randomised controlled trial of the prevention
of CHD and other vascular events by BP and
cholesterol lowering in a factorial study design

B. Dahlof (Co-chair), P. Sever (Co-chair), N. Poulter (Secretary)

H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins
S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen
E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators

29
 Cardiovascular Protection and Mortality Reduction
Stronger than Classical Regimen

/Perindopril
/Perindopril

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

 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
16
death, MI, or stroke
Proportion with CV

Atenolol
12 Losartan
(%)

4
13% RRR, P=0.021
0
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
Dahlöf B et al. Lancet 2002;359:995-1003
 New Evidence Based
Systolic Blood Pressure Intervention
and Cardiovascular Protection
 Systolic Blood Pressure Intervention Trial
(SPRINT)

Principal Results

Paul K. Whelton, MB, MD, MSc

Chair, SPRINT Steering Committee
Tulane University School of Public Health and Tropical Medicine,
and School of Medicine
 SPRINT Research Question
Examine effect of more intensive high blood pressure treatment
than is currently recommended

Randomized Controlled Trial

Target Systolic BP

Intensive Treatment Standard Treatment

Goal SBP < 120 mm Hg Goal SBP < 140 mm Hg

SPRINT design details available at:

• ClinicalTrials.gov (NCT01206062)
• Ambrosius WT et al. Clin. Trials. 2014;11:532-546.
 Major Inclusion Criteria
• ≥50 years old

• Systolic blood pressure : 130 – 180 mm Hg (treated or untreated)

• Additional cardiovascular disease (CVD) risk

– Clinical or subclinical CVD (excluding stroke)

– Chronic kidney disease (CKD), defined as eGFR 20 – <60 ml/min/1.73m 2

At least one

– Framingham Risk Score for 10-year CVD risk ≥ 15%

– Age ≥ 75 years
 Major Exclusion Criteria
• Stroke

• Diabetes mellitus

• Polycystic kidney disease

• Congestive heart failure (symptoms or EF < 35%)

• Proteinuria >1g/d

• CKD with eGFR < 20 mL/min/1.73m2 (MDRD)

• Adherence concerns
 Primary Outcome and Primary Hypothesis

• Primary outcome
– CVD composite: first occurrence of
• Myocardial infarction (MI)
• Acute coronary syndrome (non-MI ACS)
• Stroke
• Acute decompensated heart failure (HF)
• Cardiovascular disease death

• Primary hypothesis*
• CVD composite event rate lower in intensive compared to standard
treatment
*Estimated power of 88.7% to detect a 20% difference
- based on recruitment of 9,250 participants, 4-6 years of follow-up and loss to follow-up of 2%/year.
 SPRINT Primary Outcome
Cumulative Hazard

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard
(319 events)

Intensive
(243 events)

During Trial (median follow-up = 3.26 years)

Number Needed to Treat (NNT)
to prevent a primary outcome = 61

Number of
Participants
 All-cause Mortality
Cumulative Hazard
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)

Standard
Adapt from Figure 2B in the(210 deaths)J Med manuscript
N Engl

Intensive
(155 deaths)
During Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)
Include NNT to Prevent a death = 90

Number of
Participants
 The Heart Outcomes Prevention
Evaluation (HOPE) – 3 Trial

Salim Yusuf, Eva Lonn, Jackie Bosch

For the HOPE-3 Investigators
Population Health Research Institute, (PHRI)
McMaster University and Hamilton Health Sciences,
Hamilton, Canada
Unrestricted grants from the Canadian Institutes of Health
Research and AstraZeneca
April, 2016
 Intermediate-Risk Population
Inclusion Criteria (Target Risk 1.0%/yr)
Women ≥ 60 yrs, men ≥ 55 yrs with at least one additional
Risk Factor
• Increased WHR • Dysglycemia

• Smoking • Mild renal dysfunction

• Low HDL-C • Family history of CHD

Exclusion Criteria:
CVD or indication(s) or contraindication(s) to study drugs

No strict BP or LDL-C criteria for entry

Uncertainty principle 5
 Baseline Characteristics
12,705 randomized
Age (yrs) 66
Female 46%
Blood Pressure (mmHg) 138/82
LDL-Cholesterol (mg/dL) 128
LDL-Cholesterol (mmol/L) 3.3
Elevated waist-to-hip ratio 87%
hsCRP (g/L) median 2.0
Ethnicity
White Caucasian 20%
Latin American 28%
Chinese 29%
Other Asian 20%
Black African 2%
11
 BP Lowering vs. Placebo:
SBP Changes
140
Systolic Blood Pressure (mmHg)

Placebo
130 135

Candesartan + HCTZ
125

Δ BP=6.0/3.0 mmHg
120

0 1 2 3 4 5 6 7
Years

Cand/HCTZ 6356 5907 5667 5446 5213 3862 1437 350

Placebo 6347 5879 5623 5442 5186 3822 1424 334

12
 CV Death, MI, Stroke, Cardiac Arrest,
Revascularization, Heart Failure

0.10
HR (95% CI) = 0.95 (0.81-1.11)
0.08

P-value = 0.51
Cumulative Hazard Rates

0.06

Placebo
0.04

Candesartan + HCTZ
0.02
0.0

0 1 2 3 4 5 6 7

No. at Risk Years

Cand + HCTZ 6356 6272 6200 6103 5968 4969 2076 522
Placebo 6349 6270 6198 6096 5967 4970 2075 488
14
 Prespecified Subgroups:
By Thirds of SBP
CV Death, MI, Stroke, Cardiac Arrest, Revasc, HF

SBP Placebo
HR (95% CI) P Trend
Cutoffs Mean Diff Event Rate%

≤131.5 122 6.1 3.5 1.25 (0.92-1.70) 0.009

131.6-143.5 138 5.6 4.6 1.02 (0.77-1.34)
>143.5 154 5.8 7.5 0.76 (0.60-0.96)

0.5 1.0 2.0

Candesartan + HCTZ Better Placebo Better

15
Conclusion
Antihypertensive treatment reduces the risk of mortality and
cardiovascular morbidity in people with diabetes mellitus and a
systolic blood pressure more than 140 mm Hg. If systolic blood
pressure is less than 140 mm Hg, however, further treatment is
associated with an increased risk of cardiovascular death, with no
observed benefit.
 Meta-analyses stratified according to baseline
systolic blood pressure

Brunstrom et al. BMJ 2016;352:i717 Favours treatment Favours control

 Kesimpulan

• Hipertensi dikaitkan dengan peningkatan

morbiditas dan mortalitas penyakit kardiovaskular
• Tujuan pengobatan hipertensi tidak hanya
menurunkan tekanan darah, tetapi juga
menurunkan morbiditas dan mortalitas
kardiovaskular ((proteksi kardiovaskular)
• Pilihan obat hipertensi seyogyanya berdasarkan
evidence based yang ada
• Target tekanan darah adalah <140/90 mmHg
(termasuk Diabetes)
 Thank You
For Your Kind Attention