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Optimizing Blood Pressure

Management
Target VS Variability
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 most important risk factor for global disease burden
www.worldlifeexpectancy.com,
2014
Prevalence of Hypertension

Province

• Prevalence of HTN on people ≥ 18 y.o based on measurement


• Decrease in the prevalence can be due to :
• Difference in measurement technique from 2007 and 2013
• Awareness increase to check their condition to Healthcare Professional
RISKESDAS 2013
BP Elevation or HTN Remains One of the Most Important
Multipliers for CV Risk

• BP >140/90 mmHg associated with:


– 69% of first MIs
– 74% of cases of CHD
– 77% of first strokes
– 91% of cases of HF

• 277,000 deaths in 2003

• $63.5 billion annually


(direct/indirect)  2005 Anatomical Travelogue Inc.
Underwritten by Novartis.

BP=blood pressure; HTN=hypertension; MI=myocardial infarction;


CHD=coronary heart disease; HF=heart failure.

Adapted from Thom T et al. Circulation. 2006;113:e85–e151.


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
1.5 <65 1.5 < 65
Hazard ratio

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
 65 1.2

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
Rationale for Combination Therapy
• Monotherapy is the standard initial treatment for reducing BP, with
stepwise increases in dose if the desired decrease in BP is not
achieved 1
• Combining antihypertensive drugs from different classes provides
synergistic benefits and is the preferred initial strategy in the
treatment of high BP1,2
• Increasing the dose of a single antihypertensive agent to achieve
an adequate response may increase AEs, which can lead to
noncompliance2
• 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
Number of Medicines Required to Achieve
Target BP in High-Risk Subjects
BP Goals <140/90; or <130/85 in Diabetes, CRF, CCF

ASCOT-BPLA

ALLHAT

IDNT

RENAAL

UKPDS

ABCD

MDRD

HOT

AASK

0 1 2 3 4

Dahlof, et al. Lancet 2005; 366:895-906


Preferred Drug Combinations
When to start combination therapy and
in which population
• JNC 2014 guidelines recommend adding a second class of
antihypertensive if goal BP are not met after maximising first
agent1
– Initiate combination therapy either as two separate agents or as a single
pill combination
– Some committee members recommend starting therapy with ≥ 2 agents
when:
- SBP is >160 mm Hg and/or DBP is >100 mm Hg, or
- SBP is >20 mm Hg above goal BP and/or DBP is >10 mm Hg above goal
BP
• European treatment guidelines recommend the use of
combination therapy as an alternative to monotherapy as initial
treatment, particularly in high-CV-risk patients2
BP, blood pressure; CV, cardiovascular risk; DBP, diastolic BP; SBP, systolic BP.
1. James PA, et al. JAMA 2014;311:507-520. 2. Mancia G, et al. Eur Heart J 2013;34:2159-2219.
Another target to consider
SPRINT: Study design
• Age ≥50 years
• SBP 130–180 mmHg (treated or untreated)
• Additional CV risk factors (≥1)
 Clinical or subclinical CVD (excluding stroke)
 CKD (eGFR 20–<60 mL/min/1.73 m2)
 Framingham 10-year risk score ≥15%
 Age ≥75 years

Intensive treatment Standard treatment


Target SBP <120 mmHg Target SBP <140 mmHg
Exclusion criteria: stroke; diabetes; polycystic kidney disease; symptomatic HF or
LVEF <35%; proteinuria >1 g/d; CKD with eGFR <20 mL/min/1.73 m2 (MDRD);
adherence concerns
eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; MDRD, Modification of Diet in Renal Disease
SPRINT Research Group. N Engl J Med 2015;373:2103–2116

29
SPRINT: SBP in standard- versus
intensive-treatment groups
150
Throughout 3.26 years’
Standard treatment follow-up, mean SBP
140 was 121.5 mmHg in the
intensive-treatment
SBP (mmHg)

group versus 134.6 mmHg in the


130 standard-treatment
Intensive treatment group, and the mean number of
BP medications was 2.8 and 1.8,
120 respectively

110
0 1 2 3 4 5
No. with data Time (years)
Standard treatment 4683 4345 4222 4092 3997 3904 3115 1974 1000 274
Intensive treatment 4678 4375 4231 4091 4029 3920 3204 2035 1048 286
Mean No. of medications
Standard treatment 1.9 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.8 1.9
Intensive treatment 2.3 2.7 2.8 2.8 2.8 2.8 2.8 2.8 2.8 3.0

Mean number of medications is the number of BP medications administered at the exit of each visit
I Bars represent 95% CI
SPRINT Research Group. N Engl J Med 2015;373:2103–2116

30
SPRINT: Primary outcome – time to first CV
event (composite endpoint)
Hazard ratio with intensive treatment
0.10 0.75 (95% CI, 0.64–0.89)
p<0.001 319/4683 = 6.8%
Cumulative hazard

0.08
Standard treatment 243/4678 = 5.2%
0.06
ARR 1.6%
0.04 Intensive treatment
NNT = 61
0.02

0.00
0 1 2 3 4 5
Time (years)

SPRINT was terminated early (after mean follow-up of 3.26 years) on the
recommendation of the Data and Safety Monitoring Board because of a clear benefit of
intensive therapy

ARR, Absolute Risk Reduction; NNT, number needed to treat


SPRINT Research Group. N Engl J Med 2015;373:2103–2116

31
SPRINT: All-cause mortality
Hazard ratio with intensive treatment
0.10 0.73 (95% CI, 0.60–0.90)
p=0.003 210/4683 = 4.5%
Cumulative hazard

0.08
155/4678 = 3.3%
0.06
Standard treatment ARR 1.2%
0.04
NNT = 90
0.02 Intensive treatment

0.00
0 1 2 3 4 5
Time (years)

SPRINT Research Group. N Engl J Med 2015;373:2103–2116

32
SPRINT: Primary outcome in specified subgroups
of interest
Subgroup Intensive treatment Standard treatment Hazard ratio (95% CI) P-value for
interaction
No. of patients with primary outcome/total No. (%)

Overall 243/4678 (5.2) 319/4683 (6.8) 0.75 (0.64–0.89)

Previous CKD 0.36

No 135/3348 (4.0) 193/3367 (5.7) 0.70 (0.56–0.87)

Yes 108/1330 (8.1) 126/1316 (9.6) 0.82 (0.63–1.07)

Age 0.32

<75 years 142/3361 (4.2) 175/3364 (5.2) 0.80 (0.64–1.00)

≥75 years 101/1317 (7.7) 144/1319 (10.9) 0.67 (0.51–0.86)

Sex 0.45

Female 77/1684 (4.6) 89/1648 (5.4) 0.84 (0.62–1.14)

Male 166/2994 (5.5) 230/3035 (7.6) 0.72 (0.59–0.88)

Race 0.83

Black 62/1454 (4.3) 85/1493 (5.7) 0.77 (0.55–1.06)

Non-black 181/3224 (5.6) 234/3190 (7.3) 0.74 (0.61–0.90)

Previous CVD 0.39

No 149/3738 (4.0) 208/3746 (5.6) 0.71 (0.57–0.88)

Yes 94/940 (10.0) 111/937 (11.8) 0.83 (0.62–1.09)

SBP 0.77

≤132 mmHg 71/1583 (4.5) 98/1553 (6.3) 0.70 (0.51–0.95)

>132 to <145 mmHg 77/1489 (5.2) 106/1549 (6.8) 0.77 (0.57–1.03)

≥145 mmHg 95/1606 (5.9) 115/1581 (7.3) 0.83 (0.63–1.09)

SPRINT Research Group. N Engl J Med 2015;373:2103–2116 0.50 0.75 1.00 1.20

Intensive treatment better Standard treatment better

33
SPRINT: Adverse events
Intensive Standard
treatment treatment Hazard
(N=4678) (N=4683) ratio P-value
Serious adverse eventa
1793 (38.3) 1736 (37.1) 1.04 0.25
n (%)
Conditions of interest – serious adverse event only, n (%)
Hypotension 110 (2.4) 66 (1.4) 1.67 0.001
Syncope 107 (2.3) 80 (1.7) 1.33 0.05
Bradycardia 87 (1.9) 73 (1.6) 1.19 0.28
Electrolyte abnormality 144 (3.1) 107 (2.3) 1.35 0.02
Injurious fallb 105 (2.2) 110 (2.3) 0.95 0.71
Acute kidney injury or acute renal failurec 193 (4.1) 117 (2.5) 1.66 <0.001

aA serious adverse event was defined as an event that was fatal or life-threatening, that resulted in clinically significant or persistent disability, that required
or prolonged a hospitalization, or that was judged by the investigator to represent a clinically significant hazard or harm to the participant that might
require medical or surgical intervention to prevent one of the other events listed above.
bAn injurious fall was defined as a fall that resulted in evaluation in an emergency department or that resulted in hospitalization.
cAcute kidney injury or acute renal failure was coded if the diagnosis was listed in the hospital discharge summary and was believed by the safety officer to

be one of the top three reasons for admission or continued hospitalization. A few cases of acute kidney injury were noted in an emergency department if
the participant presented for one of the other conditions of interest.

SPRINT Research Group. N Engl J Med 2015;373:2103–2116

34
Recent evidence suggests that reducing
BPV also prevents vascular outcomes
• How BP reduction is achieved and sustained is clinically important
• Reducing BP fluctuation over time as well as mean BP has recently been
recognized as a potential target for improved management of
hypertension to prevent vascular outcomes, particularly stroke1,2

220
200
180

Blood pressure
160

(mmHg)
140 Systolic BP
Aim to reduce
both BP and BPV 120
100
80
60 Diastolic BP
40
1 2 3
Weeks

1. Muntner P et al. Hypertension. 2011;57:160-166. BP, blood pressure;


2. Rothwell PM. Lancet. 2010;375:938-948. BPV, BP variability; CV, cardiovascular.
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- Second-to- Minute-to- Hour-to-hour Day-to-day BPV Visit-to-visit


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

Less commonly Less commonly Less commonly


through home through 24-hour through 24-hour
and clinic BP ABPM or clinic ABPM and home
measurements measurements BP measurements

• Level of assessment within a treatment group


– Within-individual variability: multiple readings within each subject available
– Inter/between-individual variability: single readings for each subject
available

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

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

38
Increased 24-hour BPV has been
associated with cardiovascular damage
• In patients with mild to moderate hypertension, 24-hour BPV
has been related to the rate and severity of target organ damage
(TOD)1
– For nearly any level of 24-hour mean BP, subjects with low 24-hour
BPV had
a lower prevalence and severity of TOD than those with high 24-hour
BPV
(108 patients, P <0.05)
• Increased awake systolic BPV over a 24-hour period correlates with
subclinical TOD
– Carotid intima-media thickness and left ventricular mass index
progressively increased across tertiles of awake systolic BPV over a 24-
hour period
(180 patients, P for trend 0.001 and 0.003, respectively)
– Awake systolic BPV was identified as an independent predictor for
these endpoints2

1. Parati G, et al. J Hypertens. 1987;5:93-98. BP, blood pressure; BPV, BP variability;


2. Tatasciore A, et al. Hypertension. 2007;50:325-332. TOD, target organ damage.
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


IDACO population: Increased 24-h BP
variability was predictive of CV risk
• Incidence of mortality and cardiovascular events by fifths of the distribution of the
systolic average real variability (AVR) over 24 hours in 8,938 patients
Events per 1,000 person-years

CV, cardiovascular; NCV, noncardiovascular.


Systolic average real variability (mmHg)
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 ≤0.00143
Cerebral infarction mortality 1.46 ≤0.01
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.
4 Kikuya M, et al. Hypertension 2008;52:1045-1050.
2
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

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


3
Visit-to-visit variability in systolic BP was a strong predictor of
stroke, independent of mean SBP
UK-TIA trial

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


Increased risk of cerebrovascular disease
with increased BP and BPV
• In the WHICAP study, cerebral WMH increased across 4 groups in a linear fashion –
ie, the higher the mean/SD, the higher the WMH
• Increased mean BP and BPV were associated with increased risk of infarction

–4.55 45
–4.6 40

Percentage with infarct


relative WMH volume

–4.65 35
Log-transformed

–4.7 30
–4.75 25
–4.8 20
–4.85 15
–4.9 10
–4.95 5
–5 0
Low Low High High Low Low High High
mean, mean, mean, mean, mean, mean, mean, mean,
low SD high SD low SD high SD low SD high SD low SD high SD
BP, blood pressure; BPV, BP variability;
WMH, white matter hyperintensity
Brickman AM, et al. Arch Neurol. 2010;67:564-569.
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
independent predictor of clinical outcomes

“Updated guidance recommends the best available evidence-based


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.
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.


4 Kario K, et al. Hypertension 2010;56:765-773.
7
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.
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.
MBP surge as a cardiovascular risk

Morning surge Non-surge P-value


group (n=46) group (n=145)
Age (years) 76 76 NS
24-h systolic BP (mmHg) 142 142 NS
Baseline data
Silent cerebral infarct 70 49 0.02
prevalence (%)
Number (/person) 2.0 1.5 0.01
Multiple cerebral infarcts 54 37 0.04
prevalence (%)
Prospective data
Stroke incidence (%) 17 7.0 0.04
(relative risk = 2.7)

A 10 mm Hg increase in morning surge in SBP


increased clinical stroke risk by 22%
MBP, morning blood pressure; SBP, systolic blood pressure.
Kario K, et al. J Cardiovasc Pharmacol 2003;42 Suppl 1:S87-S91.
IDACO: Morning BP surge was a significant and independent
predictor of mortality and CV events
• Multivariable-adjusted hazard ratios (95% CIs) for all-cause mortality and
all fatal and nonfatal cardiovascular events by deciles of the morning BP
surge (n=5,645)

Sleep-trough morning BP surge (mmHg) Sleep-trough morning BP surge (mmHg)

5 Li Y, et al. Hypertension 2010;55:1040-1048.


1
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
BP surge 57% 20
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.

JMS ABPM Study Wave 1 52


Management of BPV
• 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
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
• Combination therapy and long-acting anti-
hypertensive therapy needed in the
management of BP and BPV

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