- 5 in 10 hypertensive patients in Singapore are not optimally controlled. Increased blood pressure variability may impact cardiovascular risk. - Consultant cardiologist will discuss implications of the SPRINT trial on optimal blood pressure management and the relationship between blood pressure variability and adverse cardiovascular outcomes. - Joint scientific session will cover optimal blood pressure control in hypertensive patients and implications of blood pressure variability based on recent studies such as the SPRINT trial.

1. Scientific Session 1:
Optimal Blood Pressure
Management
Implication of the SPRINT trial
and BP Variability
Consultant Cardiologist
Asian Heart & Vascular Centre
drgoh.pingping@asianheart.com.sg
Jointly organized by
Dr Goh Ping Ping• 5 in 10 hypertensive patients are not optimally
controlled in Singapore.1,2
• The adverse cardiovascular consequences of
hypertension may depend on increased BP
variability (BPV).3
References:
1. Nieh CC, Ho LM, J Sule, et al. Cross-sectional Study of Hypertension in a Neighborhood in Singapore. Insights Blood Press 2015, 1:1.
2. 2. Seow LSE, Subramaniam M, Abdin E, Vaingankar JA and Chong SA. Hypertension and its associated risks among Singapore elderly
residential population. Journal of Clinical Gerontology and Geriatrics 2015;6(4): 125-132
3. Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol. 2013;10:143-55.

2. Optimal Blood Pressure Management
Implication of the SPRINT Trial & Blood
Pressure Variability

3. Hypertension
3
 Leading risk factor for death and disability-adjusted life-years lost1
 Systolic hypertension is the commonest form of hypertension in individuals
aged 50 years and older2
 Systematic review and large meta-analyses of placebo-controlled randomized
clinical trials have shown that treating hypertension reduces risk of:
Stroke by 35 to 40%
Myocardial infarction by 15 to 25%
Heart failure (by up to 64%)35
1. Lim SS et al. Lancet 2012;380:2224-60; 2. Franklin SS et al. Hypertension 2001;37:869-4
3. Chobanian AV et al. JAMA 2003;289:2560-72; 4. Neal B et al. Lancet 2000;356:1955-64;
5. Psaty BM et al. JAMA 1997;277:739-45

4. CONFIDENTIAL & PROPRIETARY—INTERNAL USE ONLY.
STRATEGIES CONTAINED HEREIN ARE NOT NECESSARILY ENDORSED BY PFIZER SENIOR
MANAGEMENT AND ARE SUBJECT TO FURTHER REVIEW BEFORE IMPLEMENTATION.
Framingham Study: 6-year incidence of CHD by SBP and TC levels
Kannel WB et al. Ann Intern Med 1961;55:33-50
4

5.  Mdm Wong
52-year-old, executive
 Mother has hypertension in old age
 Trying to eat less fatty food
 Walks 30-40 minutes daily
 Comes to see you at the clinic for
upper respiratory tract infection
Clinic BP:
156/93, repeated
Comorbidities
 High normal lipids
 Not on meds
 Had high BP during
pregnancy

6. 6
How to take a proper office BP
(Canadian CHEP Guideline 2016)
Automated office BP equal to or better than manual BP
Upper arm cuff with appropriate bladder size
Lower cuff edge 3 cm above elbow crease, bladder
centred over brachial artery
Arm supported at level of the heart
Quiet room (no rest period specified)
No talking, no crossing of legs
Take readings at 1 min and 2 min intervals

7.  better reflects true BP condition than office BP by separating
from medical environment
 Use for risk stratification:
 Patients with high office BP but normal out-of-office BP
(white-coat hypertension) have lower CV risk than
patients with sustained hypertension
 Patients with normal office BP but elevated out-of-office
BP (masked hypertension) is frequently associated with
CV risk factors and has increased risk of CV events
 Close association with hypertension induced organ damage,
especially left ventricular hypertrophy
 Better prediction of CV morbidity and mortality than office BP
2013 European hypertension guidelines:
ESH/ESC emphasize out-of-office BP measurement
Mancia et al. J Hypertens 2013;31:1281-1357
7

8. Mortality with isolated and/or combined elevated
office, home, and ambulatory BP – PAMELA study
Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA)
Mancia et al. Hypertension 2006;47:846-853
8
 Analysis of office, home, and
ambulatory blood pressure in a
population from Monza, Italy
(n=2051) with outcomes of CV and
non-CV death
 69 CV and 233 all-cause deaths over
148 months
 Increased home and 24-h BP had a
greater risk of CV and all-cause
death than increased office BP
Incidence of CV and all-cause death and elevated BP over an average follow-up of 148 months.

9. Definitions of hypertension
by office and out-of-office blood pressure
Category Systolic
(mmHg)
Diastolic
(mmHg)
Office BP ≥140 and/or ≥90
Ambulatory BP
Daytime (or awake) ≥135 and/or ≥85
Nighttime (or asleep) ≥120 and/or ≥70
24-h ≥130 and/or ≥80
Home BP ≥135 and/or ≥85
9
Mancia et al. J Hypertension 2013;31:1281-1357

10. “white-coat” effect and masked hypertension
National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127:
http://www.nice.org.uk/guidance/cg127
 White-coat effect: A discrepancy of more than 20/10 mmHg
between clinic and average daytime ambulatory BP monitoring
(ABPM) or average home BP monitoring (HBPM)
 Masked hypertension: The converse of white-coat hypertension.
Normal BP measurements in the office or clinic but episodes of
elevated BP outside of the medical environment
 For people identified as having a ‘white-coat effect’ or ‘masked
hypertension’ consider daytime ABPM or HBPM as an adjunct to
clinic BP measurements to monitor response to treatment
10

11. 11
• Usual duration is 24 hours
• Ensure at least two measurements
per hour during the person’s usual
waking hours (for example, between
08:00 and 22:00).
• Use the average value of at least 14
measurements taken during the
person’s usual waking hours to
confirm a diagnosis of hypertension
• Recording is satisfactory if 70% of
values are available
• Diary on events likely to influence
BP
How to Read a 24-hour Ambulatory BP Report

12. 12Confidential & Proprietary – For Internal Use Only – Do Not Disseminate Without Approval
Reference Values for Dipper Status
<= 0% Reverse Dipper
0 to 10% Non-Dipper
10 to 15% Normal Dipper
> 15% Extreme Dipper
Calculation
%Dip = (Average day SBP – Average night SBP) x 100%
Average Day SBP

13. Kaplan-Meier curves reporting the cumulative incidence of cardiovascular events in the 4 categories of dipping pattern. Adjusted risk
of cardiovascular events was increased in reverse dippers (P=0.031) and non dippers (P=0.003) when compared with dippers, whereas
extreme dippers did not differ from dippers (P=0.73). Total mortality did not differ significantly across the dipping categories.
Verdecchia P et al. Hypertension. 2012;60:34-42
BP dipping status predicts cardiovascular events
13

14. How to Monitor Home Blood Pressure
Mancia et al. Hypertension 2006;47:846-853
14
o Two consecutive blood pressure measurements
o at least 1 minute apart
o Patient seated, without crossing legs, quiet environment
o Measure twice daily, ideally in the morning and evening
o at least 4 days, ideally for 7 days
o Discard the measurements taken on the first day and use the average
value of all the remaining measurements
o Store in log book or memory equipped device
o Possible advantage of telemonitoring

15. Item Suggestions Description
Morning
measurement
time
• Sitting BP during 1 hour after
awakening
• After urination
• Before breakfast
• Before taking medicines
• After 1‒2 minutes rest
• Morning interval is defined as the period from awakening
to around 10AM. Despite it is recommended to measure
during 1 hour, the time is not required to be controlled
strictly. Patient compliance is most important
• Keep the consistency of BP measurement: BP increases
before urination and decreases after urination
• Patient compliance: It is easier to measure during 1‒2
minutes after rest rather than 5 minutes. It can improve the
compliance of self-monitoring
• Reduce the variability of BP measurement: Diet
significantly affects BP which increases during eating and
decreases after eating
• BP measurement before taking medicines is helpful to
assess the effect of ‘surge’ on BP. It is also allowed to
measure in 5‒10 minutes after taking medicines
Measurement
frequency
• Measure 1‒3 times every time
• Weekly frequency
- Stable period: At least 3 times per
week
- Drug adjustment period: Perform
home BP monitoring at least 5
times per week
• Keep self-monitoring of BP as long as
possible
• The suggestions derived from Ohasama study. If
subtracting the results of first 3 days from 8-day single BP
measurement at home, the mean results of last 5 days are
highly reproducible
• Mandatory diary can reduce the compliance
15
Hypertension Res 2003;26:771-782

16. Summary
 Office BP is recommended for screening and diagnosis of hypertension
 Diagnosis of hypertension should be based on at least two BP
measurements per visit and on at least two visits to the office
 Out-of-office BP should be considered to confirm the diagnosis of
hypertension, identify the type of hypertension, detect hypertensive
episodes, and maximize prediction of CV risk (e.g. BP variability)
 For out-of-office BP measurements, ABPM, or HBPM may be considered
depending on indication, availability, ease, cost of use and, if
appropriate, patient preference
16

17. New evidence for controlling BPV
as part of hypertension management
Blood pressure variability (BPV) and its
management

18. What is BPV?
 Normal BP fluctuations occur in response to environmental challenges (eg,
stress or activities)1
 Blood pressure variability (BPV) can be observed:
– Over a 24-hour period with ambulatory BP monitoring (ABPM)
showing hour-to-hour variability
– Between clinic visits (visit-to-visit variability) in short and long term
 Reducing BP fluctuation in addition to mean BP has recently been
recognized as a potential target for improved management of hypertension
to prevent vascular outcomes, particularly stroke2,3
1. Schillaci et al. Hypertension 2011;58:133-135
2. Rothwell. Lancet 2010;375:938-948.
3. Muntner et al. Hypertension 2011;57:160-166
18

19. BPV differs in extent between individuals
Rothwell PM. Lancet 2010;375:938-948
Patient 1 with lower BPV Patient 2 with higher BPV
Weeks
40
60
80
100
120
140
160
180
200
220
Bloodpressure
(mmHg)
1 2 3
SBP
DBP
40
60
80
100
120
140
160
180
200
220
Bloodpressure
(mmHg)
1 2 3
Weeks
Higher
mean BP
overall
19

20. BPV : how to measure
 ABPM can identify patients with morning surge and predicts CV events
better than office BP levels1
 HBPM is a good alternative to 24-hour ABPM and variability has been
correlated with target organ damage, CV outcomes, and stroke mortality1,2
 The standard deviation (SD) and coefficient of variation (CV) of BP
measurements are commonly used parameters3
 Variation independent of the mean (VIM) is a transformation of SD
uncorrelated with mean BP (statistical tool)3
1. Grossman. Diabetes Care 2013;36 Suppl 2:S307-311
2. Parati et al. Blood Press 2013;22:345-354
3. Dolan and O'Brien. Hypertension 2010;56:179-181
BPV indices Formula/derivation
SD SD = √[∑(individual readings – sample mean)2/n]
CV CV = SD/mean
VIM SD/meanx
20

21. MBP surge: what is significant?
 MBP surge is defined as the morning BP (average of 2 hours after rising) minus the nighttime
lowest BP (average of 3 BPs)
 sleep-trough surge of >55 mmHg is significant
Kario et al. J Cardiovasc Pharmacol 2003;42:S87-S91
*P=0.001
21

22. The rapid rise of BP in the morning is one
of the critical risk variables for CV events
BP profile of untreated
hypertension patients
Mead et al. Br J Cardiol 2008;15:31-34
Incidences of MI and
stroke at different time
intervals
22
Numberofpatientswithevents(MI)n=339

23. Stroke risk and BPV are lower in patients treated with CCBs vs
other antihypertensives despite similar mean BP
Rothwell. Lancet 2010;375:938-948
Randomized trials
with CCBs vs BBs,
ACEIs, or ARBs
comparing
stroke risk and
systolic BPV (SD) Mean SBP
difference (95% CI)
A Stroke risk
Events/patients
CCB Drug B
NORDIL (vs BB/D) 159/5410 196/5471
ASCOT (vs BB) 327/9639 422/9618
ALLHAT (vs ACE) 377/9048 457/9054
Total 1326/43,623 1606/43,774
VALUE (vs ARB) 281/7596 322/7649
INVEST (vs BB) 176/11,267 201/11,309
CAMELOT (vs ACE) 6/663 8/673
0.5 1.5
0.81 (0.66 to 0.01)
0.77 (0.66 to 0.89)
0.82 (0.71 to 0.94)
0.87 (0.74 to 1.03)
0.88 (0.72 to 1.08)
0.76 (0.26 to 2.20)
0.82 (0.76 to 0.88)
Odds ratio (95% CI)
0.5 1.5
B SBP at follow-up
Mean (SD)
Variance ratio (95% CI)
CCB Drug B
NORDIL (vs BB/D) 155.2 (16.3) 151.5 (17.4) 3.70 (3.07 to 4.33)
ASCOT (vs BB) 138.4 (14.8) 140.3 (17.8) -1.90 (-2.36 to -1.44)
Total -0.21 (-0.41 to -0.01)
VALUE (vs ARB) 138.2 (13.8) 140.0 (16.2) -1.80 (-4.92 to 1.32)
INVEST (vs BB) 131.0 (11.0) 131.0 (10.0) 0.00 (-0.27 to 0.27)
CAMELOT (vs ACE) 124.5 (15.5) 123.6 (18.0) 0.60 (–1.20 to 2.40)
ALLHAT (vs ACE) 137.1 (15.0) 138.4 (17.9) -1.30 (-1.78 to -0.82)
0.88 (0.83 to 0.93)
0.69 (0.67 to 0.72)
0.70 (0.67 to 0.73)
0.73 (0.68 to 0.77)
0.83 (0.80 to 0.86)
0.74 (0.64 to 0.86)
0.76 (0.74 to 0.77)
23

24. NICE 2011 guidelines on the
management of BPV
National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127:
http://www.nice.org.uk/guidance/cg127
BPV was most effectively reduced by CCB, closely
followed by thiazide-type diuretics
Those most at risk of increased SBP SD, ie, older
hypertensive people, will already be treated with the
most effective drug classes to suppress SBP SD, ie, a
CCB
(or a thiazide-like diuretic if a CCB is not indicated or
tolerated) as Step 1 therapy
CCBs are one of the antihypertensive
classes of choice for BPV control
24

25. Amlodipine has long half-life
for the control of BPV
1. Kes et al. Curr Med Res Opin 2003;19:226-237
2. Flack et al. Eur Heart J 1996;17(Suppl. A):16-20
 Amlodipine is a long-acting CCB that blocks the calcium L-type
channel1
o Slow association and dissociation ensure gradual onset and extended
duration of pharmacodynamic activity
o Long half-life (35‒50 hours), high oral bioavailability, and low renal
clearance (7 mL/min/mg)
 It maintains a smooth and sustained dilatation of the systemic
arteriolar resistance vessels1
 Amlodipine is a forgiving agent and maintains antihypertensive
effectiveness following missed doses2
25

26. Bedtime administration of amlodipine +
olmesartan improves BPV and morning BP surge
Hoshino A, et al. Clin Exp Hypertens.2010;32:416-422.
MBP surge24-hour SBP and DBP
Hoshino et al. Clin Exp Hypertens 2010;32:416-22.
26

27. BPV in Hypertension Management
 Reducing BPV has been recognized as a potential target for improved
management of hypertension to prevent vascular outcomes,
particularly stroke
 The differential effects of CCBs compared with other agents like ACEI
and BBs on BPV may account for the disparity in observed efficacy in
reducing the risk of stroke
 The most effective approach to preventing cardiovascular event is to
use BP-lowering drugs that reduce both BPV and MBP in addition to
mean BP, and to avoid situations that increase BPV
27

28. CONFIDENTIAL & PROPRIETARY—INTERNAL USE ONLY.
STRATEGIES CONTAINED HEREIN ARE NOT NECESSARILY ENDORSED BY PFIZER SENIOR
MANAGEMENT AND ARE SUBJECT TO FURTHER REVIEW BEFORE IMPLEMENTATION.
SPRINT
(Systolic Blood Pressure Intervention Trial)
 Aim:
To assess the most appropriate systolic blood pressure targets to reduce
morbidity and mortality by comparing the benefit of treatment of SBP to a
target of <120 mmHg versus a target of <140 mmHg
 Primary hypothesis:
The CVD composite event rate would be lower in the intensive therapy group
compared with the standard therapy group

29. Guidelines for Target Blood Pressure
29
 Eighth Joint National Committee (JNC8, 2014)1,3:
<60 years or diabetes/CKD and ≥60 years: 140/90 mmHg
 Patients ≥60 years: 150/90 mmHg
 American Society of Hypertension/International Society of Hypertension
(2014)2,3:
<80 years: 140/90 mmHg
≥80 years: 150/90 mmHg
1. James PA et al. JAMA. 2014;311:507-20
2. Weber MA et al. J Hypertension. 2014;32:3-15

30. ACCORD: No difference in CV Eventsa in Patients with diabetes with
BP <120 and <140 mmHg
Cushman WC et al. New Engl J Med 2010;362:1575-85
30
n = 4733, type II DM
Intensive arm – target SBP < 120
Standard arm – target SBP < 140
Follow-up = 4.7 years
End-point: fatal MI, non-fatal stroke
or CVD
Mean baseline SBP (all participants)
=139.2±15.8 mmHg

31. SPRINT: Study Design
31
Intensive treatment
Target SBP <120 mmHg
Standard treatment
Target SBP <140 mmHg
• Age ≥50 years
• SBP 130180 mmHg (treated or untreated)
• Additional CV risk (≥1)
 Clinical or subclinical CVD (excluding stroke)
 CKD (eGFR 20<60 ml/min/1.73 m2)
 Framingham Risk Score for 10-year risk ≥15
 Age ≥75 years
Wright JT et al. New Engl J Med 2015;373:2103-16
All major antihypertensive classes can be used
Chlorthalidone encouraged as primary thiazide
Amlodipine encouraged as preferred CCB

32. SPRINT:
Enrolment and Follow-up
Ambrosius WT. Clin Trials. 2014;11:532–46
Wright JT et al. New Engl J Med 2015;373:2103-16
32
Intensive
treatment
N=4,678
Standard
treatment
N=4,683
Screened
N=14,692
Randomized
N=9,361
224
111
154
242
134
121
Consent withdrawn
Discontinued intervention
Lost to follow-up
Analyzed (ITT)
4,678 4,683

33. SPRINT: Patient Population
Wright JT et al. New Engl J Med 2015;373:2103-16
*All included in analysis (ITT)
† Increased cardiovascular risk was one of the inclusion criteria
‡ Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area.
33
Intensive Treatment
(N = 4678)*
Standard Treatment
(N = 4683)*
Criterion for increased cardiovascular risk — no. (%)†
Age ≥75 yr
Chronic kidney disease‡
Cardiovascular disease
Clinical
Subclinical
Framingham 10-yr cardiovascular disease risk score ≥15%
1317 (28.2)
1330 (28.4)
940 (20.1)
779 (16.7)
247 (5.3)
2870 (61.4)
1319 (28.2)
1316 (28.1)
937 (20.0)
783 (16.7)
246 (5.3)
2867 (61.2)
Female sex — no. (%) 1684 (36.0) 1648 (35.2)
Age — yr
Overall
≥75 yr
67.9 ± 9.4
79.8 ± 3.9
67.9 ± 9.5
79.9 ± 4.1

34. 34
SPRINT: Primary Outcome
Years
Cumulativehazard
243/4678 = 5.2%
319/4683 = 6.8%
ARR 1.6%
NNT = 61
SPRINT was terminated early (after mean follow-up of 3.26 years) on the
recommendation of the DSMB because of a clear benefit of intensive therapy
Wright JT et al. New Engl J Med 2015;373:2103-16

35. CONFIDENTIAL & PROPRIETARY—INTERNAL USE ONLY.
STRATEGIES CONTAINED HEREIN ARE NOT NECESSARILY ENDORSED BY PFIZER SENIOR
MANAGEMENT AND ARE SUBJECT TO FURTHER REVIEW BEFORE IMPLEMENTATION.35
SPRINT: All-cause Mortality
Years
Cumulativehazard
155/4678 = 3.3%
210/4683 = 4.5%
ARR 1.2%
NNT = 90
Wright JT et al. New Engl J Med 2015;373:2103-16

36. CONFIDENTIAL & PROPRIETARY—INTERNAL USE ONLY.
STRATEGIES CONTAINED HEREIN ARE NOT NECESSARILY ENDORSED BY PFIZER SENIOR
MANAGEMENT AND ARE SUBJECT TO FURTHER REVIEW BEFORE IMPLEMENTATION.
Secondary outcomes
 Significant reductions with intensive versus standard regimen in:
– Heart failure (HR [95% CI] 0.62 [0.45-0.84], p=0.002)
– Death from CV causes (HR [95% CI] 0.57 [0.38-0.85], p=0.005)
– Primary outcome or death (HR [95% CI] 0.78 [0.67-0.90], p<0.001)
Primary outcome in subgroups of interest
 The benefit of intensive therapy was consistent across pre-specified subgroups:
– Age (<75 vs. ≥75 y)
– Previous CVD (yes vs. no)
– SBP (≤132 mmHg vs. >132 but <145 mmHg vs. >145 mmHg)
– Previous CKD (yes vs. no)
Wright JT et al. New Engl J Med 2015;373:2103-16
36
SPRINT: Secondary Outcomes and Subgroups of Interest

37. 37
SPRINT: Summary
 Intensive treatment to SBP goal <120 mmHg, compared with a standard goal of <140
mmHg resulted in significantly lower rates of fatal and nonfatal CV events and all cause
mortality (trial prematurely stopped at 3.26 yrs)
 30% reduction of composite endpoint including CV death, 25% reduction in mortality
 Effect of intensive treatment was consistent across all pre-specified subgroups (age,
gender, race, presence of CVD, SBP tertiles and renal function).
One-third of patients are > 75 years old
• SAEs (hypotension, syncope, electrolyte abnormalities and acute kidney injury/renal
failure) were higher in intensive arm (38.3%) vs standard arm (31.2%); (p=0.14). Notably,
there were no between-group differences in injurious falls or bradycardia
 Overall, the authors concluded that the benefit of intensive BP lowering exceeded
potential harm

38. • Office BP and out-of-office BP (ambulatory/home BP) have
complementary roles in management of hypertension
• Reduce both mean BP and BP variability to improve cardiovascular
outcome
• New data suggest that intensive BP lowering is beneficial
38
Summary

39. Thank You
39