Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension

doi:10.1016/S0140-6736(10)60309-1

The Lancet

Volume 375, Issue 9718, 13–19 March 2010, Pages 938-948

https://doi.org/10.1016/S0140-6736(10)60309-1 Get rights and content

Summary

Although hypertension is the most prevalent treatable vascular risk factor, how it causes end-organ damage and vascular events is poorly understood. Yet, a widespread belief exists that underlying usual blood pressure can alone account for all blood-pressure-related risk of vascular events and for the benefits of antihypertensive drugs, and this notion has come to underpin all major clinical guidelines on diagnosis and treatment of hypertension. Other potentially informative measures, such as 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. This Review discusses shortcomings of the usual blood-pressure hypothesis, provides background to accompanying reports on the 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.

Introduction

Hypertension is the most prevalent treatable cause of vascular events,¹ accounting for about 50% of risk.² In developed countries, it affects half of adults,³ and is the leading indication for prescribed drugs.⁴ Yet, we understand little about how hypertension leads to vascular events. Nevertheless, one hypothesis has come to dominate research and practice—that all of us have an underlying usual blood pressure (panel 1)5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 that is the main determinant of blood pressure-related vascular risk and of benefit from antihypertensive drugs (the usual blood-pressure hypothesis). For example, the American Heart Association guidelines⁹ on measurement of blood pressure state that “it is generally agreed that conventional clinic readings, when made correctly, are a surrogate marker for a patient's true blood pressure, which is conceived as the average over long periods of time, and which is thought to be the most important component of blood pressure in determining its adverse effects.” All major guidelines recommend that treatment should be on the basis of estimates of this true blood pressure, with or without consideration of other risk factors.9, 10, 11, 12, 13 By contrast, visit-to-visit variability in blood pressure is dismissed as random, merely an obstacle to reliable estimation of usual blood pressure.5, 6, 14, 15, 16, 17

Proponents of the usual blood-pressure hypothesis make three main points. First, average blood pressure differs between individuals, can be tracked from childhood to middle age,¹⁸ and predicts risk of vascular events. Second, reliable estimation of mean blood pressure or of usual blood pressure strengthens this risk association. Third, the benefits of antihypertensive drugs are correlated reasonably well with reduction in mean blood pressure during follow-up.19, 20, 21 This Review questions the interpretation of this evidence and provides background to accompanying reports that patients with only episodic hypertension have a high risk of vascular events,7, 8 that residual visit-to-visit variability in blood pressure on treatment has poor prognosis despite good control of mean blood pressure,7, 8 and that benefits of some antihypertensive drugs are due partly to reduced variability in blood pressure.8, 22 As the outcome that is most strongly related to blood pressure, stroke is used to illustrate some of the arguments.

Section snippets

Application of the hypothesis in practice

Blood pressure often varies greatly from visit to visit,23, 24, 25, 26 and so several readings are needed to estimate a usual value.9, 10, 11, 12, 13 The joint European guidelines state that, in the absence of substantially raised blood pressure, repeat readings “should be obtained over several months to define the patient's usual blood pressure as accurately as possible”.¹² Hypertension should not be diagnosed on the basis of episodic rises in blood pressure, unless home monitoring or 24-h

Epidemiological evidence

Mean blood pressure is a very powerful risk factor for vascular events, but much other epidemiological evidence suggests that instability and variability in blood pressure are also important. First, the predictive value of estimated usual blood pressure falls with age (figure 2), even though adjustment for regression-dilution bias increases with age,6, 14, 15, 16, 24, 25, 41 whereas incidence of stroke increases 100-fold from age 40–80 years,²⁷ and the relative benefit of antihypertensive drugs

Statistical basis

Prediction of risk of vascular events on the basis of one blood-pressure reading is usually improved by use of the average of several readings from ABPM31, 32, 33 or home monitoring,37, 38 but the strongest risk relations result from indirect statistical adjustment for the error in estimation of usual blood pressure, on the basis of the extent to which grouped baseline blood-pressure readings regress to the mean when repeated after follow-up.5, 6, 73 This correction for regression-dilution bias

Trial evidence

The usual blood-pressure hypothesis also relies on the finding that in trials of antihypertensive drugs, effects on vascular risk are usually correlated with differences in mean blood pressure during follow-up.19, 20, 21 However, this result could partly be an artefact of the design of trials, which have often recruited only patients with blood pressure consistently within a specific range on repeated screening visits. After exclusion of patients with variable blood pressure, treatment effects

Mechanisms and causation

Although accelerated atherosclerosis is often cited as the mechanism by which hypertension affects vascular risk, strong risk factors for atherosclerosis, such as smoking and raised lipid concentrations, are weak risk factors for stroke. Increased atrial fibrillation and small-vessel disease might also play a part, but regression of these chronic pathological findings would not account for why stroke risk falls within weeks of starting of calcium-channel blockers.46, 47, 76, 77, 78 Reduced

Implications for guidelines, practice, and research

Incidence of stroke exceeds that of coronary events in developed countries,⁶⁸ and is rising steeply in developing countries. Yet, hypertension guidelines, based on the usual blood-pressure hypothesis, are poorly suited to prevention of stroke. First, diagnostic strategies should take into account the effect of increased visit-to-visit variability in blood pressure and episodic hypertension on vascular risk. More research is needed into how to quantify variability and instability in routine

Conclusion

Increased mean blood pressure is an important cause of arterial disease, but the usual blood-pressure hypothesis is inconsistent with much of the epidemiology of hypertension and stroke, and its clinical application is questionable in patients with variable blood pressure. Variability and instability in blood pressure also have important roles in the progression of organ damage and in triggering of vascular events. Further research is needed to refine understanding of the causes, consequences,

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We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated.
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4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.
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View full text

ReviewLimitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension

Summary

Introduction

Section snippets

Application of the hypothesis in practice

Epidemiological evidence

Statistical basis

Trial evidence

Mechanisms and causation

Implications for guidelines, practice, and research

Conclusion

Lancet

Lancet

Lancet

J Clin Epidemiol

Lancet

Lancet

Lancet

Lancet

Lancet

Lancet

Lancet

J Clin Epidemiol

Am J Hypertens

Lancet

Lancet Neurol

Lancet

Lancet

J Clin Epidemiol

Lancet

Lancet

Am J Hypertens

Am J Hypertens

J Am Coll Cardiol

Clinical hypertension

Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study

JAMA

National ambulatory medical care survey: 2002 summary

Adv Data

Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

Lancet

Effects of β blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke

Lancet Neurol

Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research

Circulation

Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement

J Hypertens

Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Hypertension

2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)

J Hypertens

European Society of Hypertension guidelines for blood pressure monitoring at home: a summary report of the Second International Consensus Conference on Home Blood Pressure Monitoring

J Hypertens

Blood pressure variability causes spurious identification of hypertension in clinical studies: a computer simulation study

Am J Hypertens

When measurements are misleading: modelling the effects of blood pressure misclassification in the English population

BMJ

Long term monitoring in patients receiving treatment to lower blood pressure: analysis of data from placebo controlled randomised controlled trial

BMJ

Serial changes in blood pressure from adolescence into adulthood

Am J Epidemiol

Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

BMJ

Medium-term variability of BP and potential underdiagnosis of hypertension in patients with previous transient ischemic attack or minor stroke

Stroke

Systolic hypertension in the elderly: an epidemiological assessment

Circulation

Variability of blood pressure and the results of screening in the hypertension detection and follow-up program

J Chronic Dis

Difficulties in diagnosing hypertension

J Hypertens

Twenty-four-hour ambulatory blood pressure profiles of high-risk patients in general practice: data from an ambulatory blood pressure monitoring registry

J Hypertens

Ambulatory blood pressure monitoring in hypertensive patients with high cardiovascular risk: a cross-sectional analysis of a 20 000-patient database in Spain

J Hypertens

Antihypertensive treatment based on conventional or ambulatory blood pressure measurement. A randomized controlled trial

JAMA

Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators

JAMA

Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension

Review
Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension