Before the early 1970s, intraarterial recordings provided the only means of following changes in blood pressure (BP) during the typical activities of daily living over a period of time. The development and commercial availability of lightweight, quiet, easy-to-wear automated noninvasive BP recorders has facilitated the collection of large volumes of data (∼100 measurements in 24 hours) while a subject pursues his or her everyday activities. Data derived from ambulatory BP monitoring (ABPM) have made important contributions to our understanding of the pathophysiology of hypertension and its complications, the definition of daytime and nighttime normotension, the prognostic value of ambulatory BP, and the evaluation of therapies.
Circadian Variation of Blood Pressure
The circadian variation in BP and its association with cardiovascular events, including both myocardial infarction and stroke, are well-established. Blood pressure follows a highly reproducible pattern characterized by: (1) a low period during sleep; (2) an early morning, postawakening rise, coinciding with the transition from sleep to wakefulness; and (3) a higher, sustained and more variable period thereafter. Evidence for the circadian periodicity of BP being synchronized with the sleep–wake cycle also comes from observations in shift workers. For example, a complete and immediate reversal of the circadian BP rhythm occurs on the first occasion of a session of night shifts. As a result of the shift in work schedules (and sleep times), the peak systolic blood pressure (SBP) in night workers is recorded at about 11 pm and the diastolic blood pressure (DBP) peaks at about 10 pm . Night shift work is also associated with a conversion from a dipping to nondipping pattern in BP which is reversed when the nocturnal work is stopped. Night shift and rotating patterns in shifts have been associated with an increased incidence of metabolic syndrome, inflammatory markers and dyslipidemia.
Clinical Importance of Nighttime Decline (“Dipping”) in Blood Pressure
A dipping pattern is characterized by nighttime BP reductions of 10% to 30% relative to the “awake” period and is consistently found in the majority of normotensive and hypertensive people. However, about 25% to 35% of hypertensive patients (and probably a smaller proportion of normotensive people) do not display this decline in nocturnal BP. Instead, this population expresses a blunted or total absence in decline in nocturnal BP. The absence of a nocturnal decline in BP varies according to the patient population and is more prevalent in the older persons, African Americans, and postmenopausal women (especially African-American women). The term “nondippers” was coined by O’Brien to describe those individuals in whom the decline in nighttime BP is less than 10% of the daytime value; such people were found to be at increased risk for stroke. There is strong evidence that a persistent nondipping pattern is associated with more pronounced cardiac involvement, particularly left ventricular hypertrophy (LVH). It has been proposed that the nondipping pattern may be associated with atherosclerosis, cardiovascular and kidney disease. Of particular relevance is a large cohort study of 8711 patients demonstrating that even in normotensive people, isolated nocturnal hypertension predicts cardiovascular outcomes. However, patients with blunted nocturnal dipping patterns frequently belong to high-risk categories that confound outcomes; they are often older, obese, diabetic, or have overt cardiovascular or renal disease. Nondipping also confounds the higher cardiovascular risk observed in African Americans. Even among patients with treated hypertension, half do not adequately drop their nocturnal BPs. After adjusting for age, sex and diabetes, a mean 5 mm Hg reduction in systolic nocturnal BP is associated with a 17% drop in cardiovascular risk.
Despite the clinical findings associated with the lack of decline in BP during sleep, the validity of an arbitrary proportional threshold to define dipping status has been questioned. The reproducibility of the fall in nighttime BP compared with daytime values has been poor in some studies, because sleep quality and depth of sleep may influence the degree of dipping. Rather than a proportional reduction in BP, an absolute BP value may be more appropriate to define nocturnal hypertension. Many years ago, a consensus panel of the American Society of Hypertension originally proposed a definition of nocturnal hypertension as being a mean nighttime BP of greater than 125/80 mm Hg, based on epidemiologic and cross-sectional studies of target organ disease at that time. A committee, later organized by the American Heart Association, suggested using a value of 125/75 mm Hg. This threshold was further lowered by the European Society of Hypertension (ESH) updated practice guidelines that considered a nighttime BP of greater than 120/70 mm Hg to be abnormal.
In the past decade, the examination of ambulatory BP data has established the reproducibility of an absolute definition of nocturnal hypertension compared with proportional decreases. Data were extracted from high-quality 24-hour recordings obtained during the placebo run-in phase of a series of clinical trials conducted in hypertensive patients diagnosed according to the standard office BP. Patients with nocturnal hypertension were identified using three different criteria: those with a less than 5% decrease in nighttime BP compared with daytime; those with a less than 10% decrease in nighttime compared with daytime; and those with a mean nocturnal BP of greater than 125/80 mm Hg. The analyses confirmed that a mean nighttime BP of greater than 125/80 mm Hg is more reproducible than the other two criteria. About half of the patients identified as nondippers on the first ABPM assessment were considered nondippers on the second assessment performed after 4 to 8 weeks. The dipper status was more reproducible using absolute criteria for SBP rather than similar criteria for DBP ( Fig. 11.1 ). These findings suggested that the absolute nocturnal BP may have provided a more appropriate approach than proportional declines in BP for evaluating the efficacy of antihypertensive agents.
Clinical Importance of the Early-Morning Blood Pressure Surge
In most individuals who sleep at night, a rapid rise in both BP and heart rate occurs in the morning upon awakening. During this period of the “early morning BP surge,” there is also an increase in the incidence of cardiovascular events, including myocardial infarction and stroke. Many non-hemodynamic factors, including plaque vulnerability and increased coagulability, contribute to the early morning prothrombotic state. Studies have consistently shown that acute myocardial infarction is more prevalent between 6 am and noon than at other times of the day or night. In addition, the incidence of subarachnoid hemorrhage, ischemic stroke, hemorrhagic stroke, and transient ischemic attacks is highest in the morning period after awakening.
The primary evidence for a link between a steep increase in BP and morbidities associated with hypertension comes from a study conducted in elderly Japanese hypertensive patients. Using ABPM, the early morning BP surge was defined as the difference between the SBP during the 2 hours after awakening minus the lowest sleep SBP. The 519 patients studied were divided into two groups, according to the extent of the surge. In the group of 53 patients who had a surge of 55 mm Hg or more (average 69 mm Hg) at baseline, there was a 57% incidence of silent cerebral infarcts, as opposed to only 33% in the remaining patients whose average increase in SBP was a more modest 29 mm Hg. During the follow-up period that averaged 41 months, 19% of patients with a large early-morning BP surge suffered a stroke, compared with 7.3% of those with a relatively small surge. The control of the early-morning BP surge was regarded as being an important stratagem to prevent vascular disease in hypertensive patients. The authors concluded that, in the future, large randomized trials should investigate the ability of antihypertensive agents to suppress the morning BP surge. Later, larger studies in more diverse populations exposed an increased risk for renal disease and even death associated with a morning blood pressure rise. However, a relationship between morning BP surge and cardiovascular outcomes has been controversial. A diminished surge in morning BP has been associated with a blunting in dipping pattern and with worse cardiovascular outcomes. Importantly, there are no data showing that inhibiting this surge pharmacologically is of specific benefit to patients. The logical approach to treatment would be to prescribe an antihypertensive medication that is effective for 24 hours or longer, to provide target organ protection throughout the dosing interval. Controlling morning BP is a reasonable therapeutic target, if assisted by the use of ABPM and home BP, as well as appropriate timing of medications that mirror the circadian variation of both the renin-angiotensin and the sympathetic nervous systems.
Prognostic Value of Ambulatory Blood Pressure
Data from both prospective clinical and population-based studies show that ambulatory BP predicts the risk for a cardiovascular event, after adjustment for conventional (office) BP. A now-historic prospective study by Perloff and associates established that cardiovascular risk was greater in patients with higher daytime ambulatory BP than in those with lower daytime value, independent of the office BP values. Subsequent outcomes-based studies have shown that ambulatory BP is superior to conventional clinic BP measurements in predicting adverse cardiovascular clinical events. Of these, two considered the prognostic value of ambulatory BP in the general population. In both studies, after adjustment for gender, age, smoking status, baseline clinic BP, and antihypertensive treatment, ambulatory BP proved to be a superior predictor of cardiovascular death compared with clinic BP. In addition, the BP at night and the ambulatory SBPs were the best predictors of cardiovascular death. Similar results were also observed in the Dublin outcome study that followed over 5000 patients for 5 years.
In most studies, ambulatory BP data used to predict cardiovascular endpoints were recorded in untreated subjects participating in clinical trials while receiving placebo during the run-in phase. The absence of data on the prognostic value of ambulatory BP in patients with treated hypertension was addressed in the Office versus Ambulatory Blood Pressure Study. This study followed 1963 patients for a median of 5 years, during which 157 patients had documented new cardiovascular events. After adjustment for age, sex, body mass index, use of lipid-lowering drugs, and a history of cardiovascular events, higher 24-hour mean ambulatory SBPs and DBPs were independent risk factors for new cardiovascular events. Even after adjusting for clinic BP, 24-hour and daytime SBP and DBP predicted outcomes. Patients with a 24-hour mean ambulatory SBP of less than 135 mm Hg had higher cardiovascular risk than those with a mean value of 135 mm Hg or higher. This was true especially when the patients were classified according to their clinic BPs.
Use of Ambulatory Blood Pressure Monitoring in the Management of Hypertension
Diagnosis of hypertension and the decision to initiate drug treatment are traditionally based on office BP measurements. Prospective cohort studies clearly show that the prognostic capabilities of office BP, however, are inferior to ambulatory BP. Most notably, clinic BP measurements correlate poorly with 24-hour mean ambulatory BP, especially in men both before and during antihypertensive treatment. The Spanish ABPM Registry, which has incorporated 190,000 clinical records of people with hypertension, shows that the use of ABPM in clinical practice may double the rates of hypertension control. The findings of both the Office versus Ambulatory Blood Pressure Study and the Spanish registry support more extensive utilization of ABPM in clinical practice. ABPM has potential advantages, but its use needs to be considered in relation to the cost of the equipment and data evaluation, poor insurance coverage in most countries, information gained, additional consultations required, and possible inconvenience to the patient. A developed algorithm for the use of self-monitoring of BP and ABPM may help to minimize the excessive use of ABPM while identifying patients who would benefit from antihypertensive therapy ( Fig. 11.2 ).
Self-monitoring of BP may restrict the use of ABPM to those patients in whom there is a large disparity between clinic measurements and out-of-clinic values. Ideally, patients should measure their BP twice daily at home and/or while at work over a minimum of a 1-week period. In 2015, for the first time, the U.S. Preventive Services Task Force recommended the use of ABPM to confirm the diagnosis of hypertension in people with an elevated office BP. The National Clinical Guideline Centre in the United Kingdom had already issued a similar recommendation in 2011 to use ABPM to diagnose hypertension in any person with an elevated office blood pressure and also to consider its use for therapeutic monitoring. Other societies, including, the World Health Organization, British Hypertension Society, American Heart Association, American Society of Hypertension, and European Society of Hypertension, have not recommended the use of ABPM to diagnose hypertension in all patients but in many instances these groups do not have recent updates to their guidelines. In most guidelines the indications for ABPM had been limited to: ruling out white-coat hypertension, ascertaining resistant hypertension, evaluating episodic hypotension or hypertension and assessing dipping patterns. The major impediments to recommending ABPM for all patients with an elevated BP have been costs, coverage and practical concerns of device acquisition and maintenance. The recent U.S. Preventive Services Task Force recommendations now clearly encourage practitioners to look beyond these logistic difficulties and develop programs and protocols for ABPM to be disseminated more into the hypertension and cardiovascular communities.
Impact of Ambulatory Blood Pressure Monitoring on Advances in Treatment
In addition to its use in everyday clinical practice for the identification of patients at risk, ABPM has become the gold standard for the evaluation of drug therapy in clinical trials. ABPM reveals important differences between antihypertensive agents, most notably regarding duration of action; many commonly used once-daily antihypertensive drugs were determined to provide suboptimal control toward the end of the dosing interval. With once-daily dosing and drug administration in the morning on arising to encourage patient adherence to therapy, incomplete BP control at the end of the dosing interval could actually coincide with the time of the greatest risk of an acute cardiovascular event.
To illustrate the utility of ABPM to differentiate antihypertensive therapies, we evaluated two angiotensin receptor blockers (ARB): valsartan, an ARB with a half-life of about 7 hours, versus telmisartan, an ARB with a half-life of 24 hours. The study proved that telmisartan provided better BP control at the end of the once-daily dosing interval. A clear benefit of ABPM in clinical trials is its enhanced reproducibility compared with office BP measurements; this leads to improved precision in evaluating drug effects, and a smaller number of subjects, especially when comparisons are made between two drugs.
Analyses of Ambulatory Blood Pressure Data in Antihypertensive Drug Trials
Data from ambulatory BP studies in hypertension trials may be analyzed in a number of ways. Despite numerous attempts by different committees across the globe, a consensus regarding a single superior method of analysis for ABPM data has never been reached. The use of 24-hour means, daytime and nighttime means (or preferably awake and sleep values), BP loads (the proportion of values above a cutoff value during wakefulness [typically >140/90 mm Hg] or sleep [typically >120/80 mm Hg] divided by the total number of BP readings), area under the 24-hour BP curve, and smoothing techniques designed to remove some of the variability from the raw BP data analysis are among the most popularly used methods of analysis.
Features of any method of analysis for ambulatory BP data should include the statistical ease of calculation, clinical relevance of the measure, and relationship of the parameter to the hypertensive disease process. Many of these analytic methods meet all of these criteria. For example, the 24-hour mean BP remains an important parameter for evaluation in antihypertensive drug trials because it appears to be a strong predictor of hypertensive target organ disease, is easy to calculate, uses all of the ambulatory BP data, and, as previously mentioned, is remarkably reproducible in both short-term and long-term studies.
The BP load has been used as a simple method of analysis in evaluating the effects of antihypertensive drugs. BP load has been defined in our laboratory as the percentage of BPs exceeding 140/90 mm Hg while the patient is awake, plus the percentage of BPs exceeding 120/80 mm Hg during sleep. A number of years ago, we evaluated the relationship between this BP load and cardiac target organ indices in previously untreated hypertensives. At a 40% DBP load, the prevalence of LVH was nearly 80%, but below a 40% DBP load, it was only about 8%. In contrast, the office BP and even the 24-hour average BP were not as discriminating in predicting LVH in this group of previously untreated patients. Thus, in most stage 1 hypertensive patients, one would desire a low BP load (conservatively, <30%), during treatment with antihypertensive drug therapy.
In studies in which the patient population has a greater range in BP, the proportional (or percentage) BP load becomes unhelpful. Because the upper limit of the BP load is 100%, this value may represent a substantial number of individuals with broad ranges of high stage 2 hypertension. To overcome this problem, we devised a method to integrate the area under the ambulatory BP curve and relate its values to predicting hemodynamic indices in untreated essential hypertensives. Areas under the BP curve (AUC) were computed separately for periods of wakefulness and sleep, and combined to form the 24-hour area under the BP curve. Threshold values were used to calculate AUC such as 135 or 140 mm Hg systolic while awake and 85 or 90 mm Hg diastolic while awake. Values during sleep were reduced to 115 and 120 mm Hg systolic and 75 and 80 mm Hg diastolic. This method allowed simplification of the data processing and improved the diagnostic performance of the ABPM.
Smoothing of ambulatory BP data may be used to aid in the identification of the peak and trough effects of an antihypertensive drug. The extent of variability in an individual’s BP curve may be large because of both mental and physical activity; thus evaluating the peak antihypertensive effect of a short- or intermediate-acting drug may be difficult. Other than the benefits associated with examining pharmacodynamic effects of new antihypertensive drugs, data and curve smoothing for 24-hour BP monitoring appear to have little clinical relevance. Furthermore, editing protocols are not uniform in the literature and missing data may alter the balance of mean values for shorter periods of time. To avoid excessive data reduction in a clinical trial, one statistical expert suggested that data smoothing should be performed on individual BP profiles rather than on group means.
Useful Situations for Ambulatory Blood Pressure Monitoring in Antihypertensive Drug Trials
Utility of Ambulatory Blood Pressure Monitoring in Dose-Finding Studies
Since the early 1990s, numerous studies have been performed with ABPM to fully assess the efficacy of a wide range of doses of new antihypertensive agents. The advantage of ABPM in dose-finding studies is related in part to the improved statistical power to show differences among the treatment groups compared with clinic pressures. Examples are shown in the following section.
Eprosartan
To determine the dose responsiveness of the then-new angiotensin II receptor antagonist eprosartan during phase II of development, the drug was studied at doses of 100, 200, 300, and 400 mg daily (in twice-daily divided doses) using ABPM. Compared with placebo, only the 400-mg daily dose showed consistently significant reductions in ambulatory systolic and diastolic BP. These findings led to the use of higher doses in the phase III clinical development program and a larger trial using 600 and 1200 mg once daily versus placebo. The trough BP (last 4 hours of the dosing period) changes from baseline were significantly greater than placebo for both doses of the drug, with a trend for greater reductions at 1200 mg versus 600 mg once daily. When assessing the changes from baseline using clinic BPs, the differences for 1200 mg versus 600 mg once daily against placebo were not significant.
Eplerenone
The efficacy of a novel selective aldosterone receptor antagonist, eplerenone, was studied in 417 patients with essential hypertension using a multicenter, randomized, placebo-controlled design. In this trial, the drug was assessed using either a once daily dosing regimen of 50, 100, or 400 mg or a twice-daily dosing regimen of 25, 50, or 200 mg. Clinic and ambulatory BPs were compared with both baseline values and with the effects of placebo. As shown in Fig. 11.3 , there was a dose-related reduction in SBP at trough for both clinic and ambulatory BP (similar results were seen for the changes in DBP). Twice daily dosing of eplerenone led to greater reductions in BP compared with the once-daily dosing regimen, but these differences were not statistically significant.
Utility of Ambulatory Blood Pressure Monitoring in Clinical Comparator Trials
ABPM has been very helpful in comparing antihypertensive drugs, especially when assessing their duration of action. There are numerous examples in the literature that now illustrate this benefit, including the superiority of ambulatory BP over clinic BP in assessing the trough to peak ratio of various agents.
Comparisons within the Same Class
In a now-classic multicenter study, Neutel and associates compared the beta-blockers bisoprolol and atenolol in 606 patients using both clinic and ambulatory BPs. Following therapy, trough BP in the clinic was reduced 12/12 mm Hg by bisoprolol and 11/12 mm Hg by atenolol. Although these changes were significantly different from baseline, they were not significantly different between drugs. In contrast, daytime systolic and diastolic BPs (6 am to 10 pm ) and the last 4 hours of the dosing interval (6 am to 10 pm ) were lowered to a significantly greater extent by bisoprolol than by atenolol. This finding was present whether the assessment was made by examination of the overall means, area under the curve, or BP loads. These data demonstrated that despite no difference in office BPs, bisoprolol had significant differences in efficacy and duration of action compared with atenolol when assessed by 24-hour BP monitoring.
More recently, the antihypertensive efficacy of the selective angiotensin II receptor antagonists azilsartan medoxomil, valsartan, and olmesartan medoxomil were compared with placebo in randomized, parallel group, double-blind trial of 1291 patients with stages I and II hypertension. After 2 to 3 weeks of single-blind placebo treatment, patients were randomized to receive azilsartan medoxomil at either 40 or 80 mg, valsartan 320 mg, olmesartan 40 mg, or placebo once daily. Based on ambulatory SBP measurements, the reductions in BP were significantly greater with azilsartan 80 mg daily compared with both other angiotensin receptor blockers ( Table 11.1 ). The ability of ABPM to reveal small but statistically significant changes between treatment groups is most likely related to the lower variance that occurs with repeated ambulatory BP studies compared with repeated clinic BPs.
