Optimizing Blood Pressure

Management: Target vs Variability

Iman Yulianto Suhartono
 Hypertension is an important
public health challenge worldwide
Population (in millions) with
hypertension globally
In 2000, 2000
> quarter of global Predicted
population with increase
hypertension
60%
1500

26.4%
1000

500

0
Yr 2000 Yr 2025
Kearney PM, et al. Lancet. 2005;365:217-223.
Hypertension is the most important risk factor for global disease burden
Prevalence of Hypertension

Province

RISKESDAS 2013
 Stroke and IHD mortality linked to BP levels

Systolic Blood Pressure Age at risk:

Systolic Blood Pressure
Age at risk:
256 80-89 years 80-89 years
256
(Floating Absolute Risk and 95% CI)

(Floating Absolute Risk and 95% CI)

128 70-79 years 128 70-79 years

64 60-69 years 64 60-69 years

Stroke Mortality

32

IHD Mortality
50-59 years 32
50-59 years
16 16
40-49 years
8 8
4 4
2 2
1 1
0 0
120 140 160 180 120 140 160 180
Usual Systolic BP (mm Hg) Usual Systolic BP (mm Hg)

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

 Higher risk of CHD and stroke with
high SBP in Asian Patients
1.8 Asian 1.8 Caucasian
<65
Hazard ratio
1.5 <65 1.5 < 65

CHD 1.2 1.2

65  65
65
1.0  65 1.0
p int. <0.001 0.9 p int. <0.001
0.9
1 2 3 5 10 15 1 2 3 5 10 15
2.5 Asian <65 2.5 Caucasian
< 65
2.0 2.0
Hazard ratio

<65
1.5 1.5
< 65
Stroke 65
1.2 1.2
 65
1.0 1.0
 65 65
0.9 p int. <0.001 0.9 p int. <0.001
1 2 3 5 10 15 1 2 3 5 10 15
SBP (mmHg) SBP (mmHg)
SBP: systolic blood pressure Perkovic et al. Hypertension 2007;50:991–7
 Reducing BP prevents CV outcomes
in patients with hypertension
• There is an undoubted and well-proven benefit in reducing
mean BP in patients with hypertension to prevent CV events1-3

• BP goals for patients with hypertension with or without added

CV risk are well established in the hypertension guidelines1-3

Each 2 mmHg
rise in SBP4 7% 10%

Risk of mortality from Risk of mortality

ischemic heart disease from stroke

BP, blood pressure; CV, cardiovascular.

1. Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

2. NICE Hypertension guidelines 2011 http://publications.nice.org.uk/hypertension-cg127.
3. Chobanian AV, et al. JAMA. 2003;289:2560-2572.
4. Lewington S, et al. Lancet. 2002;360:1903-1913
 Cara Mengukur TD Ideal
1. Pasien duduk dulu 3-5 menit.
2. Ukur minimal 2 kali selang 1-2 menit. Ambil nilai
rata-rata.
3. Hati-hati pada pasien aritmia.
4. Pakai manset yang tepat (utk ukuran lengan <32
cm).
5. Posisi setinggi jantung.
6. Ukur kedua lengan pada kunjungan pertama.
Ambil yang tertinggi.
1. Hpt gr 2 dan 3 wajib diberi medikasi
2. Hpt gr 1 dengan organ damage wajib diberi medikasi
3. Bila menetap (manual atau ABPM), hpt gr 1 wajib diberi medikasi
4. Pada orang tua, SBP > 160 wajib diberi medikasi
5. Hpt sistolik pada dewasa muda tidak perlu diberi obat
Target SBP < 140 dan DBP < 80 kecuali
pada orang tua dan populasi tertentu
(misal diabetes).
Number of Medicines Required to Achieve
Target BP in High-Risk Subjects
BP Goals <140/90; or <130/85 in Diabetes, CRF

ASCOT-BPLA

ALLHAT

IDNT

RENAAL

UKPDS

ABCD

MDRD

HOT

AASK

0 1 2 3 4
Dahlof, et al. Lancet 2005; 366:895-906
 Rationale for Combination Therapy
• Combining antihypertensive drugs from different classes provides
synergistic benefits and is the preferred initial strategy in the
treatment of high BP1,2
• At low doses, fixed-dose combinations may have better tolerability
than the respective high-dose monotherapies2

1. Wald DS, et al. Am J Med 2009;122:290–300;

2. Kreutz R. Vasc Health Risk Manag 2011;7:183-192
Preferred Drug Combinations
 What is blood pressure variability (BPV)?
• BP normally fluctuates during the day and can vary from day to day in response to
environmental challenges eg, stress, activity, carrying out tasks1
220 220

200 200

180 180 SBP

Blood pressure (mmHg)

Blood pressure (mmHg)

160 160

140 140 Higher

mean BP
120 120
overall
100 100
DBP
80 80

60 60

40 40
1 2 3 1 2 3
Weeks Weeks

Patient 1 with lower BPV Patient 2 with higher BPV

BP, blood pressure; BPV, BP variability.

1. Schillaci G, et al. Hypertension 2011;58:133-135. 2. Rothwell PM. Lancet 2010;375:938-948.

 BPV can be monitored in the short term
and in the long term
Short-term monitoring Longer-term monitoring

Beat-to-beat Second-to- Minute-to- Hour-to-hour BPV Day-to-day BPV Visit-to-visit BPV

BPV second BPV minute BPV
Computer analysis of BP tracing 24-hour ABPM Home BP Clinic BP
monitoring measurements

ABPM, ambulatory BP monitoring;

BP, blood pressure; BPV, BP variability.
 Pronounced BP fluctuations can occur over
short- and long-term observation periods
Different types of BP variability, their determinants and prognostic relevance

 Arterial compliance Inappropriate dosing or titration  Adherence to AHT;

 Central sympathetic drive of AHT BP measurement errors
 Arterial or cardiopulmonary reflex;
humoral, rheological, behavioral and
emotional factors; activity or sleep

Seasonal
Ventilation change

 Very short-term BPV (beat-to-beat)*  Short-term BPV (over 24 h)  Mid-term BPV (day-to-day)  Long-term BPV (visit-to-visit)

 Subclinical organ damage  Subclinical organ damage
 Cardiovascular events and  Cardiovascular events
mortality?  Cardiovascular mortality
 Renal outcomes?  All-cause mortality
 Progression of microalbuminuria
and proteinuria
 eGFR, progression to ESRD
 Subclinical organ damage
 Cardiovascular events
 Cardiovascular mortality
 All-cause mortality
 Microalbuminuria
 eGFR
 Subclinical organ damage
 Cardiovascular events
 All-cause mortality
 Microalbuminuria and
proteinuria
 eGFR

Parati G, et al. Nat Rev Cardiol 2013;10:143-155.

22
 Increased 24-hour BPV has been associated
with CV risk

1,2 1,11** 1,17*

1,07 * 1,10 *
1,03 1,03
1
Adjusted hazard ratio

0,8

0,6

0,4

0,2

0
Total mortality CV mortality CV events Cardiac events Coronary events Stroke
*P<0.05; **P<0.001

• Adjusted hazard ratios for mortality and CV events per standard deviation
of the systolic average real variability in 8938 patients

Hansen TW, et al. Hypertension 2010;55:1049–1057

 Ohasama study: Day-to-day BP variability
predictive of stroke and CV mortality
• Japanese observational study (n=2,455) found that day-to-day BP
variability, measured by home BP monitoring, was an independent predictor of
mortality from stroke, cerebral infarction or cardiovascular causes after adjusting
for mean BP
Hazard ratio* p value
Prognostic effect of increase in systolic BP variability of +1 between-subject standard
deviation
Stroke mortality 1.41 <0.001
Cardiovascular mortality 1.27 <0.01

*After adjusting for systolic BP, heart rate, sex, age, obesity, smoking and drinking, history of cardiovascular disease, diabetes mellitus,
hyperlipidemia, and treatment with antihypertensive drugs.

Kikuya M, et al. Hypertension 2008;52:1045-1050.

 Visit-to-visit variability in systolic BP was a strong predictor of
stroke, independent of mean SBP

Hazard ratios for risk of any stroke by deciles of visit-to-visit SD systolic BP based on
the first 7 measurements
Hazard ration (95% CI)

Decile of SD SBP

2 Rothwell PM, et al. Lancet 2010;375:895-905.

5
 Guidelines on BPV
• NICE 20111
– Variability in SBP when measured visit-to-visit is a strong predictor of stroke, independent of
mean SBP
– Whatever the underlying mechanisms, SBP variability appears to be an important
“Updated
independentguidance recommends
predictor of the best available evidence-based
clinical outcomes
treatment options to suppress BPV in people with hypertension”

• ESC/ESH guidelines 20132

– Consideration should be given to the evidence that visit-to-visit BPV may be a determinant
of CV risk, independently of the mean BP levels achieved during long-term treatment, and
that, thus, CV protection may be greater in patients with consistent BP control throughout
visits

BP, blood pressure; CV, cardiovascular; BPV, BP variability; SBP, systolic BP.

1. National Institute for Health and Clinical Excellence (NICE) Clinical Guideline 127. Available at: http://www.nice.org.uk/nicemedia/live/13561/56007/56007.pdf. 2. Mancia G, et al. Eur Heart J 2013;34:2159-2219.
 MBP surge: What is it?

Patients with sleep-trough surge of >55 mm Hg

were classified in the MBP surge group
MBP, morning blood pressure.
Kario K, et al. J Cardiovasc Pharmacol 2003;42 Suppl 1:S87-S91.
 Morning BP could be a potential marker for BP
variability
• Exaggerated morning BP surge was linked with overall variability in BP, but
was independent of mean BP over 24 hours

Gosse P, et al. J Hypertens 2004;22:1113-1118.

2 Kario K, et al. Hypertension 2010;56:765-773.
8
 Association between CV events and early morning
period

18:00 0:00 6:00 12:00

Time of day

CV, cardiovascular risk; EMBPS, early morning blood pressure surge.

1. Muller JE, et al. N Engl J Med 1985;313:1315–1322. 2. Marler JR, et al. Stroke 1989;20:473–476.
 Morning BP surge and stroke risk in elderly
hypertension (matching for age and 24-hr systolic BP)
Arising Silent cerebral infarcts Stroke events
（Prevalence, detected by brain MRI） (Incidence)
Sleep Awake (%)
(%)
70
25
p<0.05 p<0.05
Morning Morning BP 60
20
BP surge 57%
17% 2.7 times
(Sleep-trough)
Nighttime 50
15
Lowest
BP
40
10 7.0%
33%
30
5

20
0
Morning Non-surge Morning Non-surge
Surge group Surge group
group （n=145） group （n=145）
Morning Surge group (Top 10%: MS >55 mmHg) （n=46） （n=46）
Kario K, et al. Circulation 2003;107:1401-1406.

Japan Morning Surge ABPM Study Wave 1 30

Management of BPV & Morning Surge
• Drugs with 24h efficacy are preferred.
Long acting drug minimize BP Variability and
offer protection against progression of organ
damage and risk of CV events
• Simplification of treatment improves
adherence to therapy
 Improved long-term BPV with amlodipine
vs any other antihypertensives
SD-based BPV analysis (mm Hg) in individual studies
and from a meta-analysis

ACEI, angiotensin-converting enzyme inhibitor; BPV, blood pressure variability; CI, confidence interview; SD, standard deviation.
Wang JG, et al. J Am Soc Hypertens 2014. doi: 10.1016/j.jash.2014.02.004. [Epub ahead of print]
 CCB reduce systolic BPV more than other
classes when added to another agent

VR 95% CI N Comp pPool pHet SBP 95% CI

CCB 0.75 (0.64-0.87) 1565 12 0.0002 0.38 -3.3 (-5.4, -1.2)

DD 0.85 (0.71-1.01) 3217 17 0.07 0.005 -4.4 (-6.0, -2.7)

ARB 1.10 (0.84-1.45) 1357 9 0.49 0.009 -2.9 (-5.4, -0.4)

ACEI 1.10 (0.92-1.32) 1117 9 0.28 0.41 -3.0 (-4.8, -1.1)

BB 0.87 (0.50-1.52) 303 5 0.63 0.04 -3.7 (-7.5, -0.1)

For the control of 0.50 1.50

BPV, CCBs should be the Variance ratio (95% CI)
anchor class of drugs
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BPV, BP variability;
CCB, calcium channel blocker; CI, confidence interval; DD, non-loop diuretic drugs; SBP, systolic BP; VR, variance ratio.

Webb AJ, Rothwell PM. Stroke 2011;42:2860-2865.

 Mean Reduction in SBP at Weeks
2, 4, 6, and 8 with Olmesartan
Combinations

Chrysant et al. Clinic Ther 2008;30(4):587–604

 Amlodipine/olmesartan titration
effectively reduces BP over 24 hours

AML, amlodipine; BP, blood pressure; DBP, diastolic BP; OM, olmesartan; LOCF, last observation carried forward; SBP, systolic BP.

Punzi H, et al. Ther Adv Cardiovasc Dis 2010;4:209-221.

 Conclusion
• Hypertension is public health challenge
worldwide and in Indonesia
• Beside BP Target, the variability should also
be considered since it affect target organ
damage
• Amlodipine, a long acting anti hypertensive
therapy, is effective in control BP and BPV
• Simplification of treatment improves
adherence to therapy
Kasus 1
• Tn. A, 56 tahun
• TD: 150/80
• Riwayat merokok
• LDL 170 mg/dL, HDL 40 mg/dL, Kolesterol
total 250 mg/dL, Trigliserida 170 mg/dL
1. Apa faktor risiko pada pasien ini?

• Merokok
• Dislipidemia
2. Berapa target tekanan darah pasien ini?

<140/90
3. Strategi apakah yang dipakai?
4. Adakah hal lain yang harus diperhatikan?

• Kontrol faktor risiko lain: stop merokok dan

kontrol dislipidemia.
Kasus 2
• Ny. B, 59 tahun
• TD: 170/90
• Doing little exercise
• HbA1C 8%, GDS 250 mg/dL
• Riwayat keluarga PJK di usia muda
• Kepatuhan minum obat yang buruk
1. Apa faktor risiko pada pasien ini?

• DM tipe 2
• Sedentary lifestyle
• Riwayat keluarga
2. Berapa target tekanan darah pasien ini?

<140/85
3. Strategi apakah yang dipakai?
4. Obat mana yang ideal?
5. Kombinasi yang mana?
• ARB/ACEI + CCB
• Pilih CCB yang memiliki kerja panjang dan
dapat mengurangi BPV
• Bila tersedia kita pilih yang fixed dose
combination
• Misalnya: Olmesartan + Amlodipine
6. Adakah hal lain yang harus diperhatikan?

• Kontrol faktor risiko lain: kontrol DM dan

anjuran olah raga
• Anjuran untuk pemeriksaan ABPM
(mendeteksi BPV)
Kasus 3
• Tn. C, 25 tahun
• TD: 150/70
• Merokok
• Malas berolah raga
1. Apa faktor risiko pada pasien ini?

• Merokok
• Sedentary lifestyle
2. Berapa target tekanan darah pasien ini?

<140/90
3. Strategi apakah yang dipakai?
• Batasi garam
• Banyak makan sayur
dan buah
• Jaga BMI < 25
• Olah raga teratur
• Berhenti merokok