Professional Documents
Culture Documents
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
Province
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)
<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
Each 2 mmHg
rise in SBP4 7% 10%
ASCOT-BPLA
ALLHAT
IDNT
RENAAL
UKPDS
ABCD
MDRD
HOT
AASK
0 1 2 3 4
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)
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
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)
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. (%)
Age 0.32
Sex 0.45
Race 0.83
SBP 0.77
SPRINT Research Group. N Engl J Med 2015;373:2103–2116 0.50 0.75 1.00 1.20
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.
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
200 200
160 160
60 60
40 40
1 2 3 1 2 3
Weeks Weeks
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
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
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
*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
–4.55 45
–4.6 40
–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
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
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.