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BMJ

Circadian rhythm and blood pressure control: physiological and pathophysiological factors.

Coca A.J Hypertens Suppl. 1994 Jul;12(5):S13-21

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.

Arm Position

• 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

Heart Level Accurate BP

↑ 10 mmHg

↓ 10 mmHg

BP Measurement Techniques

Method Brief DescriptionOffice 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

BP monitoringIndicated for evaluation of “white coat” HTN. Absence of 10–20% BP decrease during sleep may indicate increased CVD risk.

Self-measurement

Provides information on response to therapy. May help improve adherence to therapy and evaluate “white coat” HTN.

Who Needs Lifestyle Modification?JNC 7 Recommendations

BP classification Systolic BP(mm Hg)

Diastolic BP (mm Hg)

Lifestyle 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.

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.

Why Do Patients Stop Taking BP Medication?

Reason Given

Patients (n=401)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%

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

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

Education Help a Greater Percentage of Patients Achieve BP Goals

Denver E. Diabetes Care. 2003;26:2256-2260

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Systolic goals Diastolic goals

Perc

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goal

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38%38%

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36%36%

Education program

Standard care

P=0.003

P=0.26

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.

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.

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

Effects of antihypertensive-drug class on interindividual variation in

blood 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

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

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.

Rothwell PM, Howard SC, et al. The Lancet Neurology 2010:9(5) 469-480

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

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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

Prognostic significance of visit-to-visit variability, maximum systolic blood pressure,

and episodic hypertensionIn 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

• 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.

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

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

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

• 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.

Stroke and blood-pressure variation: new permutations on an old theme

Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group.Lancet 2004; 363: 2022–31.

• 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.

• Effects of lifestyle factors

• overweight

• physical activity

• stress

• salt intake

• smoking

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