Wars, war games, and dead bodies on the battlefield: variations on the theme of blood pressure variability.

See related article, pages 2860–2865. Antihypertensive treatment is accepted as the most effective means for preventing stroke, and its effectiveness is solidly founded on a series of large randomized controlled trials.1,2 Hypertension experts can be proud that antihypertensive therapy has been the first among cardiovascular therapies that has been tested by randomized controlled trials using so-called hard end points (ie, fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, cardiovascular death, and death by any cause), all verified by independent blind clinical event committees.3 Trials are intended to be examples of treatment in everyday life, and hard end point trials measure and compare results (or outcomes) of different interventions by simply counting dead bodies or wounded bodies on the battlefield. This is what is rightly considered solid evidence. Although trials generally cannot explore mechanisms, unavoidably (and, up to a given extent, usefully), investigators try to understand, and more often to figure out, the reasons and the mechanisms that may have led to differences in the measured outcomes. The same is the case in history: there is no uncertainty in the outcome of the battle of Waterloo, but historians take delight in interpreting (post hoc) the reasons and may conclude that Napoleon matched Wellington alone but lost to the combination Wellington plus Blücher, whereas Grouchy arrived too late to make a successful combination with Napoleon. Subtler interpretations may call on Napoleon’s bad health, on excessive raining, and the lot of mud that hampered the advantage of the French army, quick movement of troops, and the like. However, these exercises look like war games rather than real wars. Like the outcomes of Napoleon’s wars, the benefits of antihypertensive therapy shown by randomized controlled trials have also stimulated post hoc interpretations and debates about the hypothesis that all benefit is caused by blood pressure-lowering or the alternative hypothesis that part of the benefit may be due to specific properties of some class of drugs. The favorable outcome of placebo-controlled trials that have used different drug classes as an active regimen strongly supports the interpretation of the preponderant role of blood pressure reduction.1,2 Furthermore, a host of more recent trials that have compared 2 different active regimens intended to achieve similar blood pressure can also be interpreted to confirm the predominant role of blood pressures reduction (similar outcomes with the 2 compared regimens when achieved blood pressures are similar).2 However, the few trials in which different rates of outcomes occurred despite no or little blood pressure difference have allowed the few adepts of blood pressure-independent benefits of some agents to maintain their faith alive. If consensus about the paramount role of blood pressure reduction is overwhelming, there is more uncertainty about what blood pressure reduction is most relevant. Is it systolic or diastolic or pulse pressure, is it peripheral or central pressure, and is it office or out-of-office (ambulatory or home) blood pressure reduction? Furthermore, to predict outcomes of intervention, should we use the average of all values preceding the event or only the values closest to the event? In the greatest part of interpretative analyses, the mean of all blood pressures measured during treatment has been used, but the issue has not been exhaustively investigated. Against this overwhelming background of commonly shared opinion about the predictive role of average ontreatment blood pressure,2,4,5 Rothwell and his associates have recently called attention to the additive or alternative role of variability of blood pressure during treatment.6–8 This has been a welcomed challenge to common opinion, because common opinion does not necessarily mean a correct opinion. Rothwell and his associates propose 2 new measures of “variability”: (1) intraindividual visit-to-visit variability, that is, variability of an individual’s blood pressure from visit to visit7; and (2) interindividual variability, measured as the variability (the SD, variance, or coefficient of variation) of blood pressure in a group of patients on a given antihypertensive treatment.8 The 2 variability measures, when applied to large intervention trials, appear to predict incidence of stroke to a much greater extent than average blood pressure.7–9 Furthermore, in outcome trials comparing 2 antihypertensive regimens based on different drugs, the regimen associated with lower intraindividual or interindividual variabilities was also associated with a lower incidence of stroke.7–9 In an interesting article published in this issue of Stroke, Webb and Rothwell10 go even further and apply the calculation of interindividual variabilities to a number of small (an average of 100 individuals per study), short-lasting (mostly 26 weeks) studies comparing different doses or different combinations of antihypertensive agents, studies in which the primary end point was the blood pressure change, and Received July 7, 2011; accepted July 8, 2011. The opinions in this editorial are not necessarily those of the editors or of the American Heart Association. From the Istituto Auxologico Italiano and the University of Milan, Milan, Italy. Correspondence to Alberto Zanchetti, MD, Istituto Auxologico Italiano, Via L. Ariosto 13, 20145 Milan, Italy. E-mail alberto.zanchetti@auxologico. it or [email protected] (Stroke. 2011;42:2722-2724.) © 2011 American Heart Association, Inc.