This document discusses the management of hypertension to prevent cardiovascular events. It provides global statistics showing that hypertension is a leading cause of death worldwide. It then discusses the prevalence of hypertension, cardiovascular risk factors, target organ damage, and the link between hypertension and coronary heart disease. It reviews evidence from clinical trials on lifestyle modifications, adherence, early and aggressive blood pressure lowering, treating to target levels, and choice of drugs to prevent cardiovascular events in hypertensive patients.

1. Management of Hypertension to
Prevent Cardiovascular Events
Faris Basalamah, MD FIHA FAPSIC
Fakultas Kedokteran Universitas Muhamadiyah Jakarta
RS Mitra Keluarga Bekasi Timur

2. Global Burden of Hypertension
45% deaths due to heart disease
World Health Organization. World Health Day 2013 : A global brief on hypertension.

3. Global Burden of Hypertension (2)
51% deaths due to stroke
World Health Organization. World Health Day 2013 : A global brief on hypertension.

4. Prevalence of Hypertension
Circulation. 2016;134:441–450.

5. How about its prevalence in Indonesia?

6. CVD Risk Factors
• Hypertension
• Cigarette smoking
• Obesity (BMI >30 kg/m2)
• Physical inactivity
• Dyslipidemia
• Diabetes mellitus
• Microalbuminuria or estimated GFR
< 60 ml/min
• Age (older than 55 for men, 65 for women)
• Family history of premature CVD

7. Target Organ Damage
 Heart
Left ventricular hypertrophy
Angina or prior myocardial
infarction, heart failure
 Brain
Stroke or transient ischemic
attack
 Chronic kidney disease
 Peripheral arterial disease
 Retinopathy

8. The link between Hypertension and
Coronary Heart Disease

10. Date of download: 3/18/2017
Copyright © 2017 American Medical
Association. All rights reserved.
From: Systolic Blood Pressure Levels Among Adults With Hypertension and Incident Cardiovascular
EventsThe Atherosclerosis Risk in Communities Study
JAMA Intern Med. 2014;174(8):1252-1261. doi:10.1001/jamainternmed.2014.2482
Adjusted Hazard Ratios (HRs) of Incident Cardiovascular Events by Time-Varying Systolic Blood Pressure (SBP) Level Category Among Participants
With HypertensionThe Atherosclerosis Risk in Communities Study (1987-2010) stratified by composite event (heart failure, ischemic stroke, or
combination measure myocardial infarction/incidence of coronary heart disease death [MI/CHD]) (A), heart failure (B), ischemic stroke (C), and
MI/CHD (D). Elevated BP is defined as an SBP of 140 mm Hg or higher; standard BP, an SBP of 120 to 139 mm Hg; and low BP, an SBP of lower
than 120 mm Hg. The vertical lines through the HRs represent 95% CIs.
Figure
Legend:

11. Date of download: 3/18/2017
Copyright © 2017 American Medical
Association. All rights reserved.
From: Systolic Blood Pressure Levels Among Adults With Hypertension and Incident Cardiovascular
EventsThe Atherosclerosis Risk in Communities Study
JAMA Intern Med. 2014;174(8):1252-1261. doi:10.1001/jamainternmed.2014.2482
Unadjusted Cardiovascular Event-Free Survival Among Participants With Hypertension by Systolic Blood Pressure (SBP)
CategoryThe Atherosclerosis Risk in Communities Study (1987-2010) stratified by composite event (heart failure, ischemic stroke,
or combination measure myocardial infarction/incidence of coronary heart disease death [MI/CHD]) (A), heart failure (B), ischemic
stroke (C), and MI/CHD (D). Elevated BP is defined as an SBP of 140 mm Hg or higher; standard BP, an SBP of 120 to 139 mm Hg;
and low BP, an SBP of lower than 120 mm Hg.
Figure Legend:

12. How to prevent CV event?
• Life style modification
• Adherence concept
• Early and agresive BP lowering
• Treatment to target levels
• Drug choice

13. Life Style Modification

14. Adherence Concept
• The best adherence is in ARB treatment
• Good adherence reduces CV risks
• Fully adherence only in 30% pts after 1 year
• Poor adherence and compliance not only due
to patients and side effect, but also physician
and policy service
Chapman RH, Benner JS, Petrill AA. et al. Predictor of adherence with antihypertensive
and lipid-lowering therapy. Arch Intern Med. 2005;165:1147-1152

15. Early and Aggressive BP Lowering
• TROPHY trial :
– Pre-Hypertension pts
– Early intervention reduces CV risks
– High BP related with CVD risks
• Framingham Study :
– 31% patients stroke with normal and high normal
hypertension
• VALUE Study :
– Benefit of the study due Rapid reduction and BP
control in the beginning
 The Earlier The Better

16. Treatment to Target Levels
• The Lower the Better?

17. Source: Hansson L et al. Lancet 1998;351:1755-1762
Hypertension Optimal Treatment (HOT) Study
Diastolic BP goal
Patients without
Diabetes
MajorCVeventsper
1000patient-years
Patients with
Diabetes
Diastolic BP goal
18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized
to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg
More intensive blood pressure control provides greater benefit in diabetics
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control
BP=Blood pressure, CV=Cardiovascular

18. Source: Verdecchia P et al. Lancet 2009;374:525-533
Cardio-SIS Trial
AF=Atrial fibrillation, ESRD=End stage renal disease, CHF=Congestive heart failure,
CVA=Cerebrovascular accident, LVH=Left ventricular hypertrophy, MI=Myocardial infarction,
PAD=Peripheral artery disease, SBP=Systolic blood pressure, TIA=Transient ischemic attack
IncidenceofLVH
(%)
Usual Control
17.0
Tight Control
21
14
7
0
11.4
P=0.013
CompositeofCV
events*(%) Usual Control
9.4
Tight Control
15
10
5
0
4.8
P=0.003
*Composite of death, MI, CVA, TIA, CHF, angina, new AF,
revascularization, aortic dissection, PAD, and ESRD
1,111 patients >55 years with SBP >150 mm Hg randomized to
treatment to achieve usual BP control (SBP <140 mm Hg) or intensive
BP control (SBP <130 mm Hg)
More intensive blood pressure control provides greater benefit
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control

19. Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.
The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
Treatment to Target Levels

20. Primary Outcome and Death from Any Cause.
The SPRINT Research Group. N Engl J Med
2015;373:2103-2116
Treatment to Target Levels

21. Drug Choice
Which drugs ?
• CCB
• ARB
• Ace
inhibitor
• BB blocker
• Diuretic
RAAS versus Non-RAAS ?
HOPE
n=9,297
ALLHAT
n=33,357
LIFE
n=9,193
VALUE
n=15,245
ASCOT
n=19,342
Age (years) 66 67 67 67 63
CAD (%) 80 25 16 45 17
Diabetes 39 36 13 33 22
SBP
Difference
-10mmHg
ABPH
-3mmHg
Office
-3 to -5
mmHg
-1.3mmHg -2 to -4
mmHg
-2.9 mmHg
BP
Advantage
RAAS
Regimen
Non-RAAS
Regimen
RAAS
Regimen
Non-RAAS
Regimen
RAAS
Regimen
End Point:
CV Death
-22% No Difference -13% No Difference -24%
Wier MR. RAAS versus Non RAAS Regimens on Cardiovascular endpoints.
J Clin Hypertens 2005;7:505-512

22. Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT) Study design.
Peter S. Sever Hypertension. 2012;60:248-259
Copyright © American Heart Association, Inc. All rights reserved.

23. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)-
Blood Pressure–Lowering Arm (BPLA) summary of all end
points.
Peter S. Sever Hypertension. 2012;60:248-259
Copyright © American Heart Association, Inc. All rights reserved.

24. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)-
Lipid-Lowering Arm (LLA) 2×2 analyses.
Peter S. Sever Hypertension. 2012;60:248-259
Copyright © American Heart Association, Inc. All rights reserved.

25. Kaplan–Meier Curves
for the Second
Coprimary Outcome,
Stroke, Myocardial
Infarction, and
Coronary
Revascularization.
Yusuf S et al. N Engl J Med 2016;374:2032-2043
Combination BP and Lipid Lowering in
Patients Without CVD (HOPE-3)

26. Irbesartan dapat menghambat proses aterosklerosis, sehingga
dapat menurunkan angka kejadian kardiovaskular

27. Percent change of LVMI and voltage criteria after 18 months in
subjects treated with irbesartan or atenolol.
Markus P. Schneider et al. Hypertension. 2004;44:61-66
Copyright © American Heart Association, Inc. All rights reserved.

28. • Purpose of study : to evaluate the effect of treatment with the
angiotensin I type 1 receptor blocker irbesartan on maintaining sinus
rhythm after conversion from persistent atrial fibrillation
• Design : prospective, randomized trial
• Number of participants : 154
• Interventions :
– Group I : amiodarone 400mg/day
– Group II : amiodarone 400mg/day + irbesartan 150-300mg/day
• Follow-up period : 12 months
Circulation. 2002;106:331-336.

29. Conclusion :
Patients treated with amiodarone plus irbesartan had a
lower rate of recurrence of atrial fibrillation than did
patients treated with amiodarone alone.
Results :
After 2 months of follow-up in the
intention-to-treat analysis, the group
treated with irbesartan had fewer
patients with recurrent atrial fibrillation
(Kaplan-Meier analysis, 84.79% versus
63.16%, P=0.008). The Kaplan-Meier
analysis of time to first recurrence
during the follow-up period (median
time, 254 days [range, 60 to 710]) also
showed that patients treated with
irbesartan had a greater probability of
remaining free of atrial fibrillation
(79.52% versus 55.91%, P0.007).
Circulation. 2002;106:331-336.

30. • Purpose of study : to evaluate whether irbesartan would
reduce the risks of cardiovascular events among patients
with atrial fibrillation
• Design : double-blind, randomized trial
• Number of participants: 9.016 patients
• Interventions :
– Group I : irbesartan at a target dose of 300 mg once daily
– Group II : double-blind placebo
• Follow- up time : mean 4.1 years
N Engl J Med 2011;364:928-38.

31. Effect of Irbesartan on Hospital
Admissions.
The ACTIVE I Investigators. N Engl J Med 2011;364:928-938

33. • Purpose of study :
to evaluate irbesartan therapy in preventing protenuria in
patients with type 2 DM, hypertension and microalbuminuria.
• Design :
multicenter double-blind randomized placebo-controlled
• Participants : 590 patients with hypertension
• Intervention :
– Group I : irbesartan 150mg/day
– Group II : irbesartan 300 mg/day
– Group III : placebo
IRMA-2 Study
Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria

35. IRMA-2 SUBSTUDY

36. Irbesartan Plasebo P
CRP/ year  5,4%  10% <0,001
Fibrinogen  0,059 g/L  0,059 g/L 0,027
IL-6  1,8%  6,5% 0,005

37. THANKS

38. Forest Plot of Primary Outcome According to Subgroups.
The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
Treatment to Target Levels

40. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)-
Lipid-Lowering Arm (LLA) 11-year follow-up: cumulative
incidence of cause of death.
Peter S. Sever Hypertension. 2012;60:248-259
Copyright © American Heart Association, Inc. All rights reserved.

41. • Results :
The second coprimary outcome occurred at a rate of 7.3%
per 100 person-years among patients receiving irbesartan
and 7.7% per 100 person-years among patients receiving
placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P =
0.12). The rates of first hospitalization for heart failure (a
prespecified secondary outcome) were 2.7% per 100
person-years among patients receiving irbesartan and 3.2%
per 100 person-years among patients receiving placebo
(hazard ratio, 0.86; 95% CI, 0.76 to 0.98).
• Conclusion :
In patients with atrial fibrillation, irbesartan was
associated with a reduction in heart failure and
hospitalizations for cardiovascular causes.
N Engl J Med 2011;364:928-38.

42. Pengaruh Irbesartan Terhadap Ketebalan Ventrikel Kiri
vs Atenolol:
The CardioVascular Irbesartan Project

43. The CardioVascular Irbesartan Project
• Tujuan : membandingkan pengaruh irbesartan
vs atenolol terhadap LVH (left
ventricular hypertrophy).
• Penelitian : acak, tersamar ganda, multisenter
• Jumlah pasien: 240 pasien dengan hipertensi esensial
• Terapi :
– Kelompok I diberikan irbesartan
– Kelompok II diberikan atenolol
• Lama penelitian: 18 bulan

44. • Hasil penelitian:
Pada bulan ke 6 dan 18, penurunan massa ventrikel kiri/ (LVM, Left
Ventrikular Mass) dan perbaikan kriteria EKG untuk hipertrofi
ventrikel kiri (LVH) hanya ditemukan pada pasien yang diterapi
menggunakan irbesartan
• Kesimpulan penelitian ini:
Terapi hipertensi dengan Irbesartan menghasilkan
pengurangan yang bermakna terhadap kriteria EKG untuk
LVH, dengan kata lain terjadi penurunan penebalan
ventrikel kiri.
Pemberian atenolol tidak mengurangi ketebalan ventrikel
kiri secara bermakna pada pemeriksaan EKG.

45. 1. Mozzafarian D et al. Heart Disease and Stroke Statistics-2015 Update. AHA Circulation 2015;131:29-322.
2. Thayer C et al. Hypertension Diagnosis and Treatment Guideline. Group Health 2014 : 1-19.
Prevalence will be higher if there are no effective preventions…