Ambulatory Blood Pressure for Cardiovascular Risk Stratification
Ambulatory blood pressure (ABP) monitoring is increasingly recognized as a valuable tool to refine prediction of cardiovascular risk related to blood pressure (BP).1 After the first landmark study published by Perloff and colleagues 24 years ago,2 several longitudinal event-based studies provided unequivocal evidence of an independent association between ABP and risk of cardiovascular disease. Although experimental procedures and statistical analyses varied from study to study, ABP generally improved cardiovascular risk stratification over and beyond traditional risk factors, including clinic BP.3 The Table, obtained through an electronic search of literature using the terms “ambulatory blood pressure” and “prognosis,” shows a list of longitudinal event-based studies performed by independent groups. It is worth noting that the list of available studies is longer because each group generally published other analyses of their database. Only the first-appearing or main contribution from each group has been included in the Table.
Article p 2145
Three aspects of available investigations deserve special mention. First, the prognostic value of ABP has been examined not only in subjects with clinical diagnosis of hypertension but also in the general population and in a variety of settings, including diabetes mellitus, renal failure, and cerebrovascular disease. Second, subjects could be untreated or treated at the time of ABP monitoring. This point may raise concerns, because drug treatment could exert unpredictable effects on 24-hour ABP profile and, consequently, interpretation and applicability of results. Third, although a continuous relation emerged in most studies between ABP and cardiovascular risk, several investigators tried to define clinical categories based on arbitrary thresholds of ABP. Although such categories are potentially useful to make diagnostic and therapeutic decisions in clinical practice, their prognostic role requires confirmation from large and independent cohort studies. Unfortunately, most of the above studies were quite limited in size and hence inadequate to provide universally acceptable clinical implications.
The Role of International Databases
To overcome the limitations related to relatively small single-center studies, a valuable attempt is being made to join individual data from longitudinal studies that used comparable experimental procedures. For example, one of these databases merged individual data from 4 prospective cohort studies that used similar methodology for recruiting patients and performing 24-hour ABP monitoring.4 In the specific context, the analysis of the database failed to detect differences in the risk of stroke between subjects with white coat hypertension and clinically normotensive control subjects, although the incidence of stroke showed a trend to increase in the long run in the group with white coat hypertension.4 The conclusions of such analysis may be applied to initially untreated subjects with clinical diagnosis of hypertension because of the features of subjects in the database.
This issue of Circulation reports the results of the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) study, a large international database currently composed of 5682 subjects included in prospective population studies from Denmark, Belgium, Japan, and Sweden.5 Of note, all of these studies comprised a random sample of the general population, and all included a longitudinal follow-up with ascertainment of fatal and nonfatal cardiovascular outcome events. The authors ran complex multivariate analyses to determine the ABP thresholds, which resulted in 10-year cardiovascular risks similar to those associated with an optimal (120/80 mm Hg), normal (130/85 mm Hg), and high (140/90 mm Hg) clinic BP. To establish easily recallable thresholds, estimates for cardiovascular events were also reported as rounded to an integer value ending in 0 or 5. In summary, average daytime ABP levels below 120/80 mm Hg were suggested as “optimal,” levels <130/85 mm Hg as “normal” and levels ≥140/85 as denoting “ambulatory hypertension.” Corresponding thresholds for nighttime ABP were 105/65, 110/70, and 120/70 mm Hg.5 The authors also calculated separate thresholds in the subjects who were untreated at the time of ABP monitoring. As expected, values were slightly higher, particularly for systolic BP, than those obtained in the total sample. Unfortunately, a separate analysis in subjects who were undergoing drug treatment at the time of ABP monitoring is not available.
As recognized by the authors, the calculated thresholds were generally lower than those suggested by a working group of the European Society of Hypertension on BP monitoring,6 which, for example, set the daytime ABP normalcy to <135/85 mm Hg, with optimal levels to <130/80 mm Hg. Similar threshold values for daytime ABP normalcy have been suggested by a working group of the American Society of Hypertension.7
The findings of IDACO confirm the conclusions of a previous study from our group8 in which the incidence of cardiovascular events did not differ between a normotensive control group and a clinically hypertensive group with white coat hypertension (defined by an average daytime ABP <130/80 mm Hg), whereas the event rate increased significantly in association with higher ABP levels, even if only modestly higher. In a population study by Mancia and coworkers,9 however, each isolated elevation in clinic BP, home BP, or ABP carried an increased risk for mortality that added to that of the other BP elevations.
Applicability of Results to Well-Defined Populations
The clinical applicability of results of longitudinal studies is a topic of utmost importance. What is the rationale prompting us to require 24-hour ABP monitoring in an individual subject? ABP monitoring may be required in untreated subjects with clinical diagnosis of high BP in the clinical setting with the aim of selecting individuals at low (white coat hypertension) or high (blunted BP fall from day to night, excessive BP variability, high pulse pressure) cardiovascular risk whose identification would be difficult or impossible to accomplish on the basis of clinic BP measurements.1,3 Categorization of subjects based on ABP is potentially important because it may drive the decision of withholding or immediately commencing a drug treatment.7,10 In contrast, the kind of information required for ABP monitoring may be different in subjects who are under treatment at the time of monitoring. In these subjects, although self-measured BP at home may be preferable to monitoring BP outside the clinic in the very long term,6 ABP may still be of help in tailoring individual drug treatment based on 24-hour ABP profile. This holds particularly true in subjects with apparent drug resistance, excessive variability between traditional BP measurements, symptoms of hypotension, or marked discrepancies between BP recorded in the clinic and out of the clinic.6,11
Therefore, in order to optimize the applicability of results of longitudinal studies with ABP monitoring to the clinical practice, it is important that studies be performed in well-defined populations of untreated or treated subjects at the time of qualifying ABP monitoring. As stated above, conclusions from studies merging treated and untreated populations may raise concerns about the applicability of results to individual subjects.
Validation of operational thresholds is a vital step for implementation of ABP in the clinical practice. The operational thresholds obtained by the IDACO investigators in the general population now should be validated in the specific clinical setting for which they are intended, ie, subjects with clinical diagnosis of hypertension. To this purpose, large international databases like the one mentioned above4 may be valuable. At the same time, the use of ABP in clinical practice should continue to be driven by the concept that ABP normalcy is markedly lower than clinic BP normalcy. For example, the average ABP recorded during the daytime period should not be considered normal if >130 mm Hg for systolic BP and 80 (or perhaps 85) mm Hg for diastolic BP.
However, the real challenge with ABP monitoring in the year 2007 would be the implementation of a randomized intervention trial to test the hypothesis that a diagnostic and therapeutic strategy based on ABP and home BP is superior to one based solely on traditional BP measurements in the clinical setting. Progression of target-organ damage and, hopefully, the incidence of cardiovascular events should be the primary end points of such a study. Unfortunately, such a project is something like a “mission impossible,” because costs would be very high, and industry may not be interested in supporting such a study in the absence of a potentially adequate return on investment. For example, the hypothesis of a 4-year outcome trial with an anticipated event rate of 2.40 per 100 patient-years in the group guided by clinic BP alone and 2.10 per 100 patient-years in the group guided by ABP and home BP monitoring (ie, a 13% reduction) would require a type I error set to 5% and a power of 90%, which would require 11949 subjects in each group to complete the study and 2144 total events. The number of subjects to randomize would be even higher in relation to the anticipated dropout rate.
It is therefore up to scientific societies, working groups and public health authorities to make such a study possible. Given the high prevalence of hypertension and the growing diffusion of ABP monitoring and self-measured BP, such a study would provide invaluable clinical information in the field of preventive cardiology.
We thank the Associazione Umbria Cuore e Ipertensione for financial support, Carla Jaspers and Francesca Saveri for secretarial help, and Marie Quinn for nursing support.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Verdecchia P. Prognostic value of ambulatory blood pressure: current evidence and clinical implications. Hypertension. 2000; 35: 844–851.
Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, Imai Y, Ohkubo T, Kario K. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005; 45: 203–208.
Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, Richart T, Torp-Pedersen C, Lind L, Ibsen H, Imai Y, Staessen JA; on behalf of the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) Investigators. Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Circulation. 2007; 115: 2145–2152.
O’Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, Myers M, Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G, Verdecchia P; on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens. 2005; 23: 697–701.
Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long-term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure. Hypertension. 2006; 47: 846–853.
Verdecchia P, Angeli F. How can we use the results of ambulatory blood pressure monitoring in clinical practice? Hypertension. 2005; 46: 25–26.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.