Wars, War Games, and Dead Bodies on the Battlefield
Variations on the Theme of Blood Pressure Variability
Alberto Zanchetti, MD
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
See related article, pages 2860 –2865.
ntihypertensive 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
A
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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.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.626747
2722
Zanchetti
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obviously stroke or cardiovascular events could not be
recorded. Nonetheless, the conclusion of the authors is that
because of its low interindividual variability, “use of a
high-dose of a calcium channel blocker alone or in combination with other agents is likely to be particularly effective in
prevention of stroke.”
These far-reaching conclusions should be seen with the
greatest interest but also examined with a critical mind.
Rothwell’s initial analyses were post hoc interpretations of
trial data,6 –9 whereas the analyses presented in the current
article in Stroke are interpretations of nonoutcome studies
extrapolated to predict outcomes. Interpretative analyses are
justified by the wish of understanding the mechanisms of a
finding, in our case, the benefits of antihypertensive treatment. The obvious question, meritoriously raised by Rothwell
himself,6 is what mechanisms are defined by the word
“variability”? May the same word happen to be used with
different meanings in different contexts?
In its common acception, blood pressure variability is
intended as the frequent behavior-related changes in blood
pressure from moment to moment or from 1 measurement to
the next one, or from 1 hour to another, a phenomenon
already described by Riva Rocci in his classical paper.11 This
“short-term” variability was investigated in depth, particularly by our group in Milan, when ambulatory blood pressure
measurement became possible.12–14 The Milan group also
found the standard deviation of 24-hour measurements was
correlated with organ damage in hypertension.15 In their
analysis of the Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT) trial, Rothwell and associates have confirmed that
this “short-term” variability has predictive value for incident
stroke, but to a much lesser extent than the 2 new variability
indices.9
Undoubtedly, in addition to the well-studied “short-term”
variability, there also is a “longer-term” variability consisting
of blood pressure changes from day to day, from season to
season, or, in treated hypertensives, in blood pressure changes
due to drug properties, individual responsiveness to drugs,
treatment compliance, and variable success of therapy. This
“long-term” variability is more difficult to measure, and for
this reason, although its potential role has always been
recognized, only lip service has been paid to it. Is this
“long-term” variability that is now being measured by Rothwell’s intraindividual and/or interindividual variabilities?
At first glance, intraindividual visit-to-visit variability
appears as a good candidate to measure this long-term blood
pressure variability.7 However, when applied to outcome
trials to investigate its outcome predictive ability, this index is
calculated from measurements at wide time intervals (6
months in ASCOT) and whether it is measuring naturally
occurring or treatment-induced blood pressure variability or
persistency in treatment or compliance to treatment is difficult to decide. Paradoxically, supporters of the predictive role
of mean achieved blood pressure can more easily dispense
themselves from frequent measurements, whereas the same is
not the case for investigators exploring the role of long-term
variability. The ideal approach may rely on home blood
pressure measurements that can be made daily or several
times per week. In the meantime, the important observations
Variations on Blood Pressure Variability
2723
made by Rothwell and his associates cannot be disregarded,
but efforts should be made to better understand their physiological meaning, the phenomenon and the mechanism they
do measure. The stroke-predictive role Rothwell et al have
shown also for the maximum blood pressure value measured
at any of the follow-up visits during an intervention trial7
cannot be taken as demonstration of the obnoxious value of
occasional, often emotion-driven, surges in blood pressure
with the consequence of crowding the already heavily
crowded emergency rooms of our hospitals.
Separate consideration should be given to the other variability index calculated by Rothwell’s group and used in the
article published in this issue of Stroke.10 Interindividual
variability has also been found to correlate with incident
stroke in large outcome trials, and the authors have suggested
to use it as a surrogate of intraindividual variability when
individual data are not available.8 The SD or the variance of
blood pressure values in a group of patients at a follow-up
visit is another matter than individual variability on a large
timespan. Group variance of blood pressure during treatment
is likely to express variability in the blood pressure response
to treatment of the various members of the group. I have
previously suggested that even when the same average blood
pressures are achieved in the 2 treatment arms of a trial, the
distribution curves can be different, wider, or narrower and
particularly more or less skewed to the right (nonresponders
can hardly be matched in number by excessive responders).3
Width and skewedness of the distribution curve will have an
impact on outcome incidence, because it is known that blood
pressure is related to outcomes in a nonlinear way (namely,
semilogarithmically).3 The authors argue that inter- and
intraindividual variability indices are strongly correlated (the
latter would account for approximately 50% or perhaps more of
the former) and therefore interindividual variability can safely be
used as a surrogate of the intraindividual one. This does not deny
that a surrogate is a surrogate and that the 2 measures, even if
correlated, may have quite different meanings.
The use of interindividual as a surrogate of intraindividual
variability may have further limitations when applied, like in
the current article in Stroke,10 to small, short-lasting, nonoutcome pharmacological studies. The authors legitimately argue that for a specific class of antihypertensive agent, the
group SD is similar in short-term studies and long-term trials.
However, do similarities of indices calculated in such different contexts as individual visit-to-visit measurements during
several years, group blood pressure distributions at visits
during long-term follow-ups, or group blood pressure distributions only a few days or weeks after initiation of treatment
allow the conclusion that what these various indices measure
is really the same thing, the same mechanism, or the same
variation? Can a practicing physician be easily persuaded that
a blood pressure variability index measured only a few days
or weeks from initiation of therapy really predict blood
pressure variability during the large number of years chronic
antihypertensive therapy must be continued? Can we safely
exclude that similarities between different variability indices
simply indicate they have some measurement in common
(perhaps, average blood pressure?) that is too easily dismissed by excessive faith in statistical adjustments?
2724
Stroke
October 2011
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The conclusion of the current article that short-term, group
blood pressure variability can identify the most effective drug
or drug combination for individual prevention of stroke
appears hazardous. This conclusion derives from calculating
a surrogate (short-term group variability) of a surrogate
(long-term group variability) of an index (long-term intraindividual variability), the meaning of which is still largely
unknown (real variability, consistency of treatment effectiveness, treatment compliance?) and extrapolates these calculations from surrogates to outcomes such as stroke that did not
occur nor could have occurred during the study period. This
may be another case of wars substituted for by war games
with dead bodies no longer counted on the battlefield but on
a video screen. Although the statistical evidence provided by
Rothwell and associates is imposing, and perhaps intimidating for a layman (such as I), a Clausewitz of hypertension
may be tempted to doubt whether the war against hypertension is a too serious thing to be left to statisticians.
Joking aside, Rothwell and his associates deserve recognition for having raised an issue of the upmost conceptual and
practical importance. The issue deserves to be studied in
depth without hurrying to premature conclusions. More
reliable indices of “real” blood pressure variability from day
to day through the many years of treatment must be elaborated and investigated (perhaps by home blood pressure
monitoring), and a better understanding of the phenomena
underlying the current variable definitions of variability
should be achieved.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Disclosures
14.
None.
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different blood-pressure-lowering regimens on major cardiovascular
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KEY WORDS: antihypertensive agents
hypertension 䡲 stroke incidence
䡲
blood pressure variability
䡲
Wars, War Games, and Dead Bodies on the Battlefield: Variations on the Theme of Blood
Pressure Variability
Alberto Zanchetti
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Stroke. 2011;42:2722-2724; originally published online August 4, 2011;
doi: 10.1161/STROKEAHA.111.626747
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
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