Blood pressure variability and stroke prevention

3. – –
– –

10. BMJ

12. Circadian rhythm and blood pressure
control: physiological and
pathophysiological factors.
Coca A.J Hypertens Suppl. 1994 Jul;12(5):S13-21

13. Cardiovascular events occur
in the early morning. Sudden
death, acute myocardial
infarction (MI), angina, silent
ischemia, and strokes all
occur between 6:00 and 10:
00 AM.
Relationship to
catecholamine levels, and in
this acute, steep period
between 6:00 and 10:00 AM,
catecholamines are going up,
platelets become stickier,
and heart rate is going up.
Important to make sure that
when blood pressure is
controlled, sympathetic tone
is reduced maximally.

16. Arm Position
↑ 10 mmHg
Heart
Accurate BP
Level
↓ 10 mmHg
• During BP measurement arms should be held at the level of the
heart
–Holding the arm too high leads to overestimation of BP
–Holding the arm too low leads to underestimation of BP

17. BP Measurement Techniques
Method Brief Description
Office After the patient rests for five minutes in a seated
position, take at least two readings a few minutes
apart. Confirm elevated reading in contralateral
arm.
Ambulatory Indicated for evaluation of “white coat” HTN.
BP monitoring Absence of 10–20% BP decrease during sleep may
indicate increased CVD risk.
Self- Provides information on response to therapy.
measurement May help improve adherence to therapy and
evaluate “white coat” HTN.

18. Who Needs Lifestyle Modification?
JNC 7 Recommendations
Systolic BP Diastolic BP Lifestyle
BP classification
(mm Hg) (mm Hg) modification
Normal <120 and <80 Encourage
Pre-HTN 120–139 or 80–89 Yes
Stage 1 HTN 140–159 or 90–99 Yes
Stage 2 HTN >=160 or >=100 Yes
JNC, Joint National Committee; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Chobanian AV, Bakris GL, Black HR, et al. JAMA. 2003;289(19):2560-2572.

19. Does Lifestyle Modification Work?
Modification Approximate SBP reduction
Weight reduction ↓ 5-20 mmHg/10 kg loss
Adopt DASH eating plan ↓ 8-14 mmHg
Dietary sodium reduction ↓ 2-8 mmHg
Physical activity ↓ 4-9 mmHg
Moderation of alcohol
consumption
↓ 2-4 mmHg
Chobanian AV, Bakris GL, Black HR, et al. JAMA. 2003;289(19):2560-2572.

20. Why Do Patients Stop Taking
BP Medication?
Patients (n=401)
Reason Given Men Women
BP reaches target 41.3% 42.3%
Side effects of medication 31.7% 24.8%
Forgetting to take medication 25.2% 20.1%
Fear of mixing alcohol and medication 23.4% 2.8%
Cost of medication 21.6% 20.1%
Ignoring the need for continuing treatment 15% 21.8%
Use of alternative treatment 11.4% 17.1%
Fear of BP going too low (hypotension) 9.6% 12%
Fear of mixing medication with other drugs 8.4% 6.1%

21. Education Resource:
The DASH Eating Plan
• The Dietary Approaches to
Stop Hypertension (DASH)
trial showed that a diet low in
fat and sodium significantly
lowers BP
• The DASH diet is effective in
lowering high BP in some
hypertension patients
• Effect on BP is seen in one
week of starting the diet
• The patient guide includes
recipes and charts for meal
planning and food shopping

22. Education Resource:
Your Guide to Lowering Blood Pressure
• A patient guide to that
explains high BP and
prehypertension
• Explains the importance of
getting BP to goal
• Offers instructions on
lowering BP with lifestyle
modification and, if
prescribed, BP medication

23. Education Help a Greater Percentage of
Patients Achieve BP Goals
Education program
P=0.26
Standard care
50
P=0.003
Percent of patients achieving BP goals (%)
45 50%
40
35 38%
36%
30
25
20
15
10
12%
5
0
Systolic goals Diastolic goals
Denver E. Diabetes Care. 2003;26:2256-2260

24. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly
hypertensive population.
DESIGN :
The Syst-Eur study was a randomized, double-blind, placebo-controlled trial, powered to detect differences in stroke rate
between participants on active antihypertensive treatment and placebo. Systolic blood pressure variability measurements
were made on 744 participants at the start of the trial. Systolic blood pressure variability was calculated over three time
frames: 24 h, daytime and night-time. The placebo and active treatment subgroups were analysed separately using an
intention-to-treat principle, adjusting for confounding factors using a multiple Cox regression model.
PARTICIPANTS:
An elderly hypertensive European population.
MAIN OUTCOME MEASURES:
Stroke, cardiac events (fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction and sudden death) and
cardiovascular mortality (death attributed to stroke, heart failure, myocardial infarction, sudden death, pulmonary embolus,
peripheral vascular disease and aortic dissection).
RESULTS:
The risk of stroke increased by 80% (95% confidence interval: 17-176%) for every 5 mmHg increase in night-time systolic
blood pressure variability in the placebo group. Risk of cardiovascular mortality and cardiac events was not significantly
altered. Daytime variability readings did not predict outcome. Antihypertensive treatment did not affect systolic blood
pressure variability over the median 4.4-year follow-up.
CONCLUSION:
In the placebo group, but not the active treatment group, increased night-time systolic blood pressure variability on
admission to the Syst-Eur trial was an independent risk factor for stroke during the trial.
Pringle E, Phillips C, Thijs L, Davidson C, Staessen JA, de Leeuw
PW, Jaaskivi M, Nachev C, Parati G, O'Brien ET, Tuomilehto J,
Webster J, Bulpitt CJ, Fagard RH; Syst-Eur investigators.
J Hypertens. 2003 Dec;21(12):2251-7.

25. Impact of blood pressure variability on cardiac and
cerebrovascular complications in hypertension.
BACKGROUND :The independent prognostic value of daytime and night-time blood
pressure (BP) variability estimated by noninvasive 24-h BP monitoring is unclear.
METHODS:
We followed 2649 initially untreated subjects with essential hypertension for up to
16 years (mean, 6). Variability of BP was estimated by the standard deviation of
daytime or night-time systolic BP (SBP) and diastolic BP (DBP). A BP variability
either less than or equal to the group median or greater than the group median
(12.7/10.4 mm Hg for daytime SBP/DBP and 10.8 and 8.9 mm Hg for night-time
SBP/DBP) identified subjects at low or high BP variability.
RESULTS:
During follow-up there were 167 new cardiac and 122 new cerebrovascular events.
The rate of cardiac events (x100 person-years) was higher (all P < .05) in the
subjects with high than in those with low BP variability (daytime SBP: 1.45 v 0.72,
daytime DBP: 1.29 v 0.91; night-time SBP: 1.58 v 0.62; night-time DBP: 1.32 v 0.85).
The rate of cerebrovascular events was also higher (all P < .05) in the subjects with
high than in those with low BP variability. In a multivariate analysis, after
adjustment for several confounders, a high night-time SBP variability was
associated with a 51% (P = .024) excess risk of cardiac events. The relation of
daytime BP variability to cardiac events and that of daytime and night-time BP
variability to cerebrovascular events lost significance in the multivariate analysis.
CONCLUSIONS:
An enhanced variability in SBP during the night-time is an independent predictor of
cardiac events in initially untreated hypertensive subjects. Verdecchia P, Angeli F, Gattobigio R, Rapicetta C, Reboldi G
Am J Hypertens. 2007 Feb; 20(2):154-61.

26. variations in people’s
blood pressure rather
than the average level
predicts stroke most
powerfully”.

27. Effects of antihypertensive-drug class on
interindividual variation in
od pressure and risk of stroke:
a systematic review and meta-analysis
Rational :
Unexplained differences between classes of
antihypertensive drugs in their effectiveness in
preventing stroke might be due to class effects on
intraindividual variability in blood pressure.
Webb AJS, Fischer U, Mehta Z, Rothwell PM. The Lancet 2010, 375: 906 - 915

28. Webb AJS, Fischer U, Mehta Z, Rothwell PM. The Lancet 2010, 375: 906 - 915

29. Drug-class effects on interindividual variation in blood
pressure can account for differences in effects of
antihypertensive drugs on risk of stroke independently
of effects on mean SBP.

30. Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT)
Rothwell PM, Howard SC, et al. The Lancet Neurology 2010:9(5) 469-480

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38. Prognostic significance of visit-to-visit variability, maximum
systolic blood pressure, and episodic hypertension
Rational
•The mechanisms by which hypertension causes vascular events are
unclear.
•Guidelines for diagnosis and treatment focus only on underlying mean
blood pressure.
Objective
to reliably establish the prognostic significance of visit-to-visit
variability in blood pressure, maximum blood pressure reached,
untreated episodic hypertension, and residual variability in treated
patients.
Rothwell PM. et al.The Lancet 2010; 375: 895 - 905

39. Prognostic significance of visit-to-visit
variability, maximum systolic blood pressure,
and episodic hypertension
In each TIA cohort
1. visit-to-visit variability in systolic blood pressure (SBP) was a
strong predictor of subsequent stroke (eg, top-decile hazard ratio
[HR] for SD SBP over seven visits in UK-TIA trial: 6·22, 95% CI
4·16—9·29, p<0·0001)
2. independent of mean SBP, but dependent on precision of
measurement (top-decile HR over ten visits: 12·08, 7·40—19·72,
p<0·0001).
3. Maximum SBP reached was also a strong predictor of stroke (HR
for top-decile over seven visits: 15·01, 6·56—34·38, p<0·0001,
after adjustment for mean SBP).
Rothwell PM. et al.The Lancet 2010; 375: 895 - 905

43. • Visit-to-visit variability in SBP and maximum SBP are
strong predictors of stroke, independent of mean SBP.
• Increased residual variability in SBP in patients with
treated hypertension is associated with a high risk of
vascular events.

44. Stroke and blood-pressure variation:
new permutations on an old theme
• First, in post-hoc analyses of randomised trials of
cardiovascular disease, visit-to-visit variability of
systolic blood pressure was a strong predictor of
stroke, independent of mean blood pressure.
Carlberg B, Hjalmar Lindholm L.The Lancet Neurology 2010; 375l: 867 – 869

45. Stroke and blood-pressure variation:
new permutations on an old theme
• Second, in a systematic review of several randomised
trials of hypertension treatment, the drugs that
brought about the greatest reduction in visit-to-visit
blood-pressure variability (calcium antagonists and
diuretics) were associated with the best stroke
prevention, independently of mean systolic blood
pressure.
- β blockers, which dose-dependently increase the
variability of blood pressure, were the least
effective in stroke prevention.
• Third, visit-to-visit variability accounted for the
difference in treatment effect on stroke in two large
hypertension trials.
Carlberg B, Hjalmar Lindholm L.The Lancet Neurology 2010; 375l: 867 – 869

46. Stroke and blood-pressure variation:
new permutations on an old theme
• In 1991, the investigators of the Swedish Trial in Old
Patients with Hypertension (STOP) noted that
antihypertensive drug therapy decreased stroke risk
more than could have been anticipated from the
attained mean blood pressure alone, and they
suggested that active drug treatment might decrease
variability in blood pressure.
• In 1993, long-term follow-up data showed that blood-
pressure variability predicted the risk of left
ventricular hypertrophy.
Ekbom T, Dahlöf B, Hansson L, et al. Blood Pressure 1992; 1: 168–72
.Frattola A, et al. J Hypertens 1993; 11: 1133–37.
Carlberg B, Hjalmar Lindholm L.The Lancet Neurology 2010; 375l: 867 – 869

47. Stroke and blood-pressure variation:
new permutations on an old theme
• Rapid effect of calcium-channel blockers on the
incidence of stroke in the Valsartan Antihypertensive
Long-term Use Evaluation trial (VALUE) has been
difficult to understand.
- Quicker reduction of blood-pressure variability by amlodipine
than by valsartan.
• Mechanisms behind the suboptimum effect of β
blockers in stroke prevention compared with other
antihypertensive drugs
- β blockers have the poorest effect on blood- pressure variation.
- Today, most hypertension guidelines recommend avoiding use of
β blockers as first-line drugs if there is no other compelling
indication.
Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group.Lancet 2004; 363: 2022–31.

48. • The effects of different classes of antihypertensive
drugs
• Relation to the risk of different types of stroke (eg,
cardioembolic, large-vessel disease, and small- vessel
disease, etc).
• The relation between long-term visit-to-visit
variability in blood pressure and arterial stiffness
should also be explored to investigate whether these
two variables measure the same underlying vascular
pathological change.

49. • Effects of lifestyle factors
• overweight
• physical activity
• stress
• salt intake
• smoking

50. Limitations of the usual blood-
pressure hypothesis and importance
of variability, instability, and
episodic hypertension
How hypertension causes end-organ damage and vascular events ?
Can usual blood pressure alone account for all blood-pressure-related
risk of vascular events and for the benefits of antihypertensive drugs?
Variability in clinic blood pressure or maximum blood pressure
reached, have been neglected, and effects of antihypertensive drugs
on such measures are largely unknown.
Clinical guidelines recommend that episodic hypertension is not
treated, and the potential risks of residual variability in blood pressure
in treated hypertensive patients have been ignored.
Importance of blood-pressure variability in prediction of risk of
vascular events and in accounting for benefits of antihypertensive
drugs, and draws attention to clinical implications and directions for
future research.
Rothwell PM.The Lancet 2010; 375: 938