Nighttime Blood Pressure Is the Blood Pressure

Michael E. Ernst, Pharm.D.

Key Words: blood pressure, nighttime, nocturnal, ambulatory blood pressuremonitoring, ABPM.(Pharmacotherapy 2009;29(1):3–6)

The greatest danger to a man with high bloodpressure lies in its discovery, because then some foolis certain to try to reduce it.

John Hay, M.D., FRCP1

Blood pressure measurement has an illustrioushistory, which undoubtedly had its origins withthe observation of the changing characteristics ofpulse noted by early Egyptians. The actualdetection of a measurable blood pressure camemuch later, beginning in 1733 when a countryparson from England, Reverend Stephen Hales,performed his famous experiment demonstratingthe rise of blood to a height of 8 feet 3 inches in aglass column inserted into the artery of a horse.2

Remarkably, his findings remained largelyunnoticed by the scientific community duringthe ensuing 150 years until 1896, when theItalian physician Scipione Riva-Rocci developedthe mercury sphygmomanometer. Riva-Rocci’smethod employed manual palpation to observethe pulse disappearance when the artery wasfully constricted, and in 1905 the Russiansurgeon Nicolai Korotkoff improved on thistechnique by outlining the characteristic soundsrepresenting systolic and diastolic pressures,which bear his name to this day.

This noninvasive sphygmomanometry methodof measuring blood pressure has remained theconventional method of blood pressuremeasurement for more than 100 years. Themeasurement of blood pressure is one of the focalevents of nearly every encounter in a physician’soffice, with the presumption that the reading

obtained reflects the true blood pressure of thepatient. Epidemiologically, beginning at a bloodpressure of 115/75 mm Hg, the relationshipbetween cardiovascular risk and blood pressureincreases in a graded and continuous manner.3

This relationship has endured in large, inter-vention-based, landmark hypertension studies,beginning in the 1960s and continuing to thisday, that have unequivocally revealed office bloodpressure to be a reliable and predictable surrogateand that lowering of office blood pressure leadsto lower rates of cardiovascular events.

For good reason then, measurement of bloodpressure in the physician’s office has remainedthe gold standard for interventions on which tobase cardiovascular risk and to strategize treat-ments. However, conventional office bloodpressure measurement is in danger of becomingan antiquated clinical assessment, and theinformation obtained reveals only a portion ofthe cardiovascular risk imparted by bloodpressure.

The accuracy of office blood pressure measure-ments has long been known to suffer fromproblems such as improper technique, terminal-digit preference, miscuffing, and a variety ofexternal influences.4 From a clinical decisionperspective, it is particularly alarming to considerthat inattentiveness to proper technique withoffice measurement of blood pressure lends itselfto the commission of two equally egregiouserrors: first, hypertension may be misdiagnosedand the patient given lifelong pharmacologictherapy based on a few potentially inaccuratedata points; and second, patients withhypertension may be treated suboptimally on themisassumption of a controlled office bloodpressure.

With regard to the latter, one of the inherentproblems with office blood pressure is that it istoo often used as a “floor” (i.e., clinicians seem

From the Division of Clinical and AdministrativePharmacy, College of Pharmacy, and the Department ofFamily Medicine, Carver College of Medicine, TheUniversity of Iowa, Iowa City, Iowa.

Address reprint requests to Michael E. Ernst, Pharm.D.,Department of Family Medicine, 01291-A PFP, University ofIowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City,IA 52242; e-mail: michael-ernst@uiowa.edu.

PHARMACOTHERAPY Volume 29, Number 1, 2009

content just to reduce systolic blood pressure to140 mm Hg, or 130 mm Hg in the case ofdiabetes mellitus) when it should really be a“ceiling” (i.e., we should try to keep systolicblood pressure from going above those thresholds).In fact, a recent study reveals that a greater amountof time that blood pressure is spent under control,or consistency of effect, is associated with improvedoutcomes.5 In a post hoc analysis of the Inter-national Verapamil SR-Trandolapril (INVEST)study, the risk of cardiovascular morbidity andmortality, stroke, and myocardial infarction wasinversely related to the percentage of on-treatment visits in which blood pressure wascontrolled.5 These findings provide renewedsupport for the critical importance of office bloodpressure control, yet they fail to account forimportant out-of-office differences, as singlepoint-in-time measures, which are used in theoffice and in clinical trials, are not alwaysreflective of full 24-hour control. Numerousstudies have observed nighttime and/or 24-hourdifferences on ambulatory blood pressuremonitoring (ABPM) that were not apparent withoffice blood pressure measurements.6–8

Technologic and scientific advancements in thelast 30 years have allowed a greater under-standing of the chronobiology of blood pressureand more detailed analysis of the individualblood pressure risk profile of a patient. Foremostamong these advancements include ABPM, andmore recently, noninvasive methods of estimatingcentral aortic pressures.9, 10 Although theliterature on the practical incorporation ofnoninvasive central pressure measurements intoclinical decision making is in its infancy, theevidence supporting ABPM is definitive.

A more thorough picture of the cardiovascularrisk burden of elevated blood pressure can beobtained from ABPM than from single orrepeated office assessments. Studies over the lastdecade have revealed some very importantfindings regarding the typical 24-hour bloodpressure profile. One of the strongest amongthese findings is the ability of the night:day ratioof systolic blood pressure to more accuratelypredict risk for cardiovascular events comparedwith office blood pressure.11

The importance of nighttime blood pressurefirst came to attention with the observation that“non-dippers,” or those patients with a less than10% decrease in blood pressure during sleep,were at higher risk for stroke than “dippers.”12

Since then, an impressive evidence base hasaccrued regarding the prognostic value of ABPM

in both treated and nontreated subjects, withmost studies evaluating 24-hour blood pressureas a predictor.11, 13–22 However, nighttime bloodpressure and stratification by dipping statusappear even more closely related to prediction ofstroke, myocardial infarction, and incidentchronic heart failure.11, 14, 15, 20–22

Although the elevated risk associated withuncontrolled blood pressure at night receivesmost of the attention in discussions about theprognostic role of ABPM, an equally importantarea with direct relevance to the pharmaco-therapy of hypertension that has received lessattention—but is no less important—is the issueof nocturnal hypotension. One group of authors,who first described optic nerve ischemiaassociated with low blood pressure at night,hypothesized that the reduction in blood flowbelow a critical level plays a role in the multi-factorial pathogenesis of anterior optic neuropathyand glaucomatous neuropathy.23, 24 The contri-bution of antihypertensive therapy to nocturnalhypotension was directly implicated in theirfindings. Anterior ischemic optic neuropathy isnot the only potential collateral damage occurringfrom excessive lowering of blood pressure atnight; a higher rate of cerebral lacunae has alsobeen reported in extreme dippers.25 No doubt, asblood pressure goals inch lower and multidrugregimens with long-acting agents become thenorm rather than the exception, the issue ofiatrogenic harm must be addressed with morestudy. Future clinical trials such as the soon-to-be-launched National Institutes of Health–sponsored Systolic Blood Pressure InterventionTrial (SPRINT), which will investigate aggressivereduction of systolic blood pressure to less than120/80 mm Hg, must be careful to examine thisrisk:benefit ratio. In the meantime, it is prudentto use caution when dosing antihypertensives atnight, particularly if uncertainty exists regardingthe patient’s diurnal blood pressure profile.

It remains to be seen whether prospectivestudies using chronotherapy specifically tonormalize the circadian blood pressure profile toa dipping status will provide superior resultscompared with the targeting of office bloodpressure or daytime ambulatory blood pressures.Intuitively, one would expect that conversion ofnondippers to dippers through targeted pharmaco-therapy should yield superior outcomes,although definitive answers to this question awaitthe results of ongoing studies.26 As attractive asit may seem, this approach neglects the possibleharm that may also occur. To date, prospective

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NIGHTTIME BLOOD PRESSURE IS THE BLOOD PRESSURE Ernst

studies with ABPM are based primarily on 24-hour versus office blood pressure comparisons,with investigation of nighttime blood pressuresas a covariate or post hoc outcome. There is agreat need for intervention studies basedspecifically on targeting nighttime blood pressurereadings as the marker of control and safety.Until then, optimal nighttime blood pressures,such as the less than 100/65 mm Hg suggested bythe International Database on Ambulatory BloodPressure Monitoring in Relation to CardiovascularOutcomes (IDACO) Investigators,27 can only bederived from population-based studies and willremain subject to debate.

The question of whether clinicians shouldcontinue measuring blood pressure in the officehas been raised recently in the hypertensioncommunity.28 It is certainly difficult to imagine avisit to the doctor without the assessment mostvisible and central to the visit, the blood pressuremeasurement, not being performed. Despite allof its limitations, conventional sphygmomanometryhas an incredibly respectable track record ofperformance as a surrogate for estimating cardio-vascular risk and stratifying treatment whenperformed correctly. It is a cost-effectivescreening tool and should not be abandonedcarelessly. However, the time has arrived to movebeyond the simplistic belief that office bloodpressures are solely what we should basepharmacotherapy decisions on, and realize that a19th century methodology can be improved on inthis 21st century era of “personalized medicine.”

Technologic advancements and the resultantenhanced understanding of the chronobiology ofblood pressure necessitate that it is time toredefine our definitions of hypertension controland consider what numbers are most relevant onwhich to base our pharmacotherapy. Officeblood pressure should no longer be considered areliable enough indicator of the patient’s trueblood pressure to be used as the only data sourcefor making clinical decisions. Outcome trialsthat rely solely on single point-in-time measure-ments of blood pressure to explain differencesbetween treatments should become historicalrelics. It is time for research studies to beundertaken that specifically dose therapy toensure 24-hour and, in particular, nighttimeblood pressure control.

Blood pressure measurement is long overduefor a paradigm shift. Accruing evidence indicatesthe risk:benefit ratio of hypertension treatmentseems most closely defined by blood pressure atnight. Clinicians should consider routine

incorporation of out-of-office assessments intotheir practices to obtain this information.Nocturnal blood pressures are most consistentlycorrelated with prediction of cardiovascular riskand provide more close surveillance of safety.For these reasons, evidence clearly points to thefact that nighttime blood pressure is, indeed, theblood pressure.

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