(Hypertension. 1998;32:424-429.)
© 1998 American Heart Association, Inc.
Reproducibility and Clinical Value of the Trough-to-Peak Ratio of the Antihypertensive Effect
Evidence From the Sample Study
Stefano Omboni;
Roberto Fogari;
Paolo Palatini;
Alessandro Rappelli;
Giuseppe Mancia;
; for the SAMPLE Study Group
From the Cattedra di Medicina Interna, Ospedale San Gerardo, Monza,
Università di Milano, Centro di Fisiologia Clinica e Ipertensione,
Ospedale Maggiore, and Istituto Scientifico Ospedale San Luca, Istituto
Auxologico Italiano, Milano (S.O., G.M.); Dipartimento di Medicina Interna e
Terapia Medica, Università di Pavia, Pavia (R.F.); Clinica Medica I,
Università di Padova, Padova (P.P.); and Istituto di Patologia Medica,
Ospedale Umberto I, Università di Ancona, Ancona (A.R.), Italy.
Correspondence to Giuseppe Mancia, MD, Cattedra di Medicina Interna, Ospedale San Gerardo dei Tintori, Università di Milano, Via Donizetti 106, 20052 Monza (Milano), Italy. E-mail mancia.g{at}imiucca.csi.unimi.it
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Abstract
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Abstract—The objectives of our study
were to assess the reproducibility of the trough-to-peak ratio (T/P)
and to see whether a high T/P is accompanied by more organ protection
or vice versa. The study included 175 (mean±SD age, 51±9 years)
subjects with mild-moderate essential hypertension who had
echocardiographic evidence of left
ventricular (LV) hypertrophy taken from the
SAMPLE study (Study on Ambulatory Monitoring of Blood Pressure and
Lisinopril Evaluation), an open-label multicenter study.
The study included a 3-week washout pretreatment period, a 12-month
treatment period with lisinopril (n=84) or
lisinopril plus hydrochlorothiazide (n=91)
once daily, and a 4-week placebo follow-up period. Results of 24-hour
ambulatory blood pressure monitoring and
echocardiographic determination of left
ventricular mass index (LVMI) were obtained before and
after 3 and 12 months of treatment. T/Ps were computed in each patient
by dividing the systolic and diastolic blood
pressure changes at trough (changes in the last 2 hours of the
monitoring period) by those at peak (average of the 2 adjacent hours
with the maximal blood pressure reduction between the 2nd and 8th hour
from drug intake) after 3 and 12 months of treatment. Average 24-hour
blood pressure was similarly reduced at 3 and 12 months. Trough blood
pressure changes at 3 and 12 months were closely correlated, as were
the corresponding peak blood pressure changes. However, the 3- and
12-month T/Ps correlated to a lesser degree (r<0.42).
Furthermore, the reduction of LVMI induced by treatment was similarly
correlated with the treatment-induced reduction in 24-hour average,
trough, and peak blood pressures but not with the T/Ps. This was also
evident when the contribution to LV hypertrophy regression
by 24-hour blood pressure changes and T/Ps was assessed in a
multivariate regression analysis. In patients
with a T/P 
0.5 or <0.5, the regression of LVMI was similar. In
conclusion, peak and trough blood pressure changes are reproducible and
predict the regression of LVMI induced by treatment as well as average
24-hour blood pressure. T/Ps are less reproducible, and their value
does not predict regression of organ damage by antihypertensive
treatment.
Key Words: trough-to-peak ratio • blood pressure monitoring, ambulatory • hypertrophy, left ventricular • lisinopril • hydrochlorothiazide • antihypertensive agents
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Introduction
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In 1988, the US Food
and Drug Administration stated that for an antihypertensive drug to be
acceptable, "... the drug effect at trough should be no less than
half to two thirds of the peak effect"1 to
guarantee (1) the sustained therapeutic coverage necessary to prevent
hypertension-related cardiovascular complications and
(2) that this coverage would not be obtained at the price of excessive
early hypotension that might endanger perfusion of vital
organs.2 This has meant that all antihypertensive
drugs had to be assessed not only by the absolute magnitude of their
blood pressure–lowering effect but also by their ability to reduce
systolic blood pressure (SBP) or diastolic blood
pressure (DBP) at the end of the between-dose interval in relation to
the maximal reduction early after administration of the
dose(s),3 an evaluation of their
"trough-to-peak ratio" (T/P) thus being an invariable component
of the evidence to be obtained.4 5 The importance
of the antihypertensive effect being not too dissimilar at trough and
peak has been emphasized also by the latest report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure.6
Three important questions concerning the T/P of antihypertensive drugs
have only partly been answered, however. Are trough blood pressure
changes, peak blood pressure changes, and T/Ps reproducible over time,
thereby making the results obtained in short-term studies valid also
for chronic antihypertensive treatments?5 7 8 Are
greater T/Ps associated with greater beneficial effects, eg, greater
regression of hypertension-related target organ damage? Are new methods
to assess the duration and homogeneity of the antihypertensive effect
over the 24 hours7 more reproducible and
clinically relevant than the T/Ps? We have addressed these questions by
analyzing the data collected in the SAMPLE Study (Study on Ambulatory
Monitoring of Pressure and Lisinopril Evaluation), which
provided strong evidence via a prospective controlled design that in
essential hypertension, regression of left ventricular (LV)
hypertrophy at the end of 1 year of treatment is more
closely predicted by change in average 24-hour than clinic blood
pressure.9
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Methods
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Patients
The methodology used was described in detail
previously.9 Briefly, the study was performed in
11 Italian centers, each of which was instructed to recruit male or
female patients according to the following criteria: (1) age between 24
and 65 years; (2) clinic supine DBP (average of 2 consecutive
sphygmomanometric readings) between 95 and 115 mm Hg after a 3-
or 4-week period without antihypertensive treatment (see below); and
(3) "echocardiographic" LV hypertrophy
(see below).10 Exclusion criteria were (1)
secondary hypertension; (2) history and/or signs of
cardiovascular complications (eg, congestive heart
failure, myocardial infarction, stroke, angina pectoris) or major
target organ damage (eg, serum creatinine >1.5 mg/dL); (3)
major cardiovascular or
noncardiovascular diseases beside hypertension; (4)
pregnancy or lactation; (5) contraindications to the antihypertensive
drugs to be used during the treatment period; and (6) conditions
preventing collection of technically adequate echocardiograms (eg,
obesity or pulmonary emphysema) or ambulatory blood pressure
monitoring (ABPM) (eg, atrial fibrillation or other major
arrhythmias). Patients also were excluded from the study if
previous antihypertensive treatment consisted of more than 2 drugs to
minimize patients' subsequent dropout because of lack of blood
pressure control. All patients consented to the study after being
informed of its nature and purpose. The study protocol was approved by
the ethics committees of the centers involved.
ABPM was performed on the nondominant arm with a Spacelabs 90202 or
90207 device after validation of its readings against a mercury
sphygmomanometer. The device was set to obtain automatic blood pressure
readings at 15-minute intervals during the day (6 AM to
midnight) and at 20-minute intervals during the night (midnight to 6
AM). The monitoring was performed on a work day, starting
around 9 to 10 AM. The patient was sent home with
instructions to continue with usual daily life activities but to hold
the arm still at the time of the measurements, note on a diary the
occurrence of unusual events or poor sleep at night, and return 24
hours later. Ambulatory blood pressure data were analyzed by a
single center (Milan).
The echocardiograms were obtained with the subject in a left decubitus
position. LV internal diameters, LV posterior wall thickness, and
interventricular septum thickness were measured
monodimensionally on the longitudinal parasternal view previously
identified bidimensionally according to the recommendations of the
American Society of
Echocardiography.11 LV
volumes were calculated by the cube formula, while LV mass was
calculated according to the Penn Convention10 and
indexed to body surface area by the formula of Dubois and
Dubois.12 Patients were recruited if LVMI
exceeded 110 g/m2 in women and 131
g/m2 in men.13 All
echocardiographic tracings, however, were then
centralized (Brescia and Milan) and calculated by 2 independent
observers (1 for each center). The within-observer variation
coefficients of the LV end-diastolic diameter and posterior
wall thickness (ie, the standard deviation of the average of 2 readings
obtained by the same observer divided by the average and multiplied by
100) were 0.5% and 3.4%, respectively. The corresponding values for
the between-observer variation coefficients were 0.8% and 3.9%. The
"central" calculations were those considered for the results.
Study Protocol
The protocol of the study was as follows.9
(1) After an initial medical visit, previously treated hypertensive
patients underwent a 4-week washout period from antihypertensive
treatment; previously untreated hypertensive patients underwent a
3-week period of observation. (2) After a second medical visit,
patients who met recruitment criteria were given lisinopril
in a single morning dose of 20 mg (month 0). (3) One month later,
nonresponders to lisinopril (ie, patients in whom clinic
supine DBP at trough was not reduced to <90 mm Hg or by at least
10 mm Hg) were given additional treatment with
hydrochlorothiazide in a single morning dose of 12.5 mg
(month 1). (4) After 1 more month, the dose of
hydrochlorothiazide was doubled in patients who were
still not responding to treatment (month 2). (5) Treatment was
maintained unmodified for the subsequent 10 months (month 2 through
month 12). At the end of this treatment period (month 12),
antihypertensive drugs were substituted with placebo tablets, which
were administered for 4 weeks. As mentioned in the report of the main
results of the SAMPLE study,9 this was done to
allow blood pressure to return toward pretreatment values and thus
allow collection of evidence that the blood pressure reduction seen in
the previous 12 months had been due to drug treatment.
Ambulatory blood pressure and echocardiographic data
were collected at the end of the pretreatment washout or observation
periods, after 3 months (ie, 1 month after the doubling of the
hydrochlorothiazide dose in nonresponders) and 12
months of treatment, and at the end of the final placebo period. ABPM
was started immediately before drug(s) or placebo administration.
Data Analysis
Each ABPM recording was first automatically scanned to
remove artifactual readings according to preselected editing
criteria.14 A monitoring was regarded as suitable
for further analysis if at least 70% of the expected number of
readings and/or 1 valid reading per hour was available. The
recording was then analyzed to obtain (1) 24-hour
average SBP and DBP before treatment, after 3 and 12 months of
treatment, and after the final placebo period; (2) average SBP and DBP
for each hour of the monitoring period before treatment and during
treatment (3rd and 12th month); and (3) after the final placebo period,
peak and trough changes and T/Ps for SBP and DBP after 3 and 12 months
of treatment. T/Ps were calculated as described in detail
previously.15 Briefly, peak blood pressure
changes were calculated by considering the interval between the 2nd and
8th hour after drug intake (ie, when the peak effect was expected to
occur) and by averaging, within this time window, the values for (1)
the hour in which the blood pressure fall was maximal and (2) the
adjacent hour in which the blood pressure fall was more evident,
compared with the corresponding pretreatment values. Trough blood
pressure changes were calculated by averaging pretreatment and
during-treatment blood pressure differences over the last 2 hours of
the monitoring period. Individual T/Ps were obtained by dividing, for
each patient, the blood pressure change at trough by the blood pressure
change at peak, separately for SBP and DBP. We also calculated the
"surface ratio" (SR) of the antihypertensive effect, which has
recently been reported to have advantages over the
T/P7 because it is based on the effect of
treatment on the whole 24-hour blood pressure profile. This was done by
(1) calculating the average blood pressure changes induced by treatment
for each hour of the 24-hour monitoring period, (2) dividing the area
delimited by the above hourly blood pressure changes by the maximal
hourly blood pressure reduction (ie, the maximal treatment effect), and
(3) multiplying the results by the dosing interval (ie, 24).
Blood pressure and LVMI values from individual patients were averaged
to obtain mean±SD values for the group as a whole. Group T/Ps were
obtained by either (1) dividing the average change in trough blood
pressure by the average change in peak blood pressure or (2)
calculating the median (plus the upper and lower quartile and the
extreme values of the distribution) of the individual T/Ps. The latter
approach was used also for calculation of group SRs. This was done
because the individual T/Ps15 and the
SRs7 do not show a normal distribution. The
reproducibility of peak and trough blood pressure changes after 3 and
12 months of treatment (ie, the 2 treatment periods in which treatment
was the same) was assessed by the Bland and Altman
approach.16 This consisted of calculation of the
correlation coefficients (r), the mean difference (±2 SD),
and the percent repeatability coefficients of peak blood pressure
changes, trough blood pressure changes, and T/Ps between 3 and 12
months of treatment. The percent repeatability coefficient (ie, the
inverse of the reproducibility) was obtained by (1) calculating the
difference between the 3- and 12-month data in each individual subject,
(2) calculating the SD of the mean difference in all subjects and
multiplying it by 2, (3) dividing this value by 4 times the SD of the
average value at 3 months of treatment and multiplying the result by
100 to allow it to be compared with other
coefficients.7 8 16 A similar approach was used
for the T/P and SR, although in these instances the percent
repeatability coefficient was calculated by using the 5th to 95th
percentile interval of the average 3-month value to allow for their
not-normal distribution.7 8 15 The percent
repeatability coefficient allowed cross comparisons of different
variables. A high repeatability coefficient indicated a low
reproducibility and vice versa.
The effect of treatment on blood pressure and LVMI and correlation
between blood pressure and LVMI changes were analyzed by paired
Student's t test and Pearson correlation coefficient,
respectively. The Wilcoxon test and the Spearman correlation
coefficient were used to compare the T/P and SR at 3 and 12 months and
to determine their correlation with LVMI changes. The relative
importance of T/P versus 24-hour average blood pressure changes induced
by treatment on regression of LVMI was assessed by
multivariate regression analysis. Finally, the
impact of the T/P values on the regression of LV
hypertrophy induced by treatment was analyzed by
dividing patients into groups with a more favorable (0.5) and a less
favorable (<0.5) systolic and diastolic T/P, based
on the T/P indicated by the US Food and Drug
Administration1 and recently mentioned by the
Joint National Committee Report6 as the ratio
dividing an acceptable from a not acceptable effect. The 2 groups were
compared using the unpaired Student's t test. A value of
P<0.05 was taken as the level of statistical
significance.
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Results
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Effects of Treatment on Blood Pressure and LVMI
Two hundred and six patients were given antihypertensive
treatment. Of these, 175 (113 men, 62 women; aged 51±9 years) had
valid ABPM recordings before treatment, at the 3rd month of
treatment, and at the 12th month of treatment; 154 patients had both
valid ABPM recordings and valid echocardiograms. The number of
patients was somewhat less after the final placebo period: 172 had
valid ABPM recordings and 151 had both valid ABPM
recordings and echocardiograms. Four patients withdrew because
of treatment inefficacy, 12 because of side effects; 21 patients did
not come in for follow-up examinations. In the evaluable patients, the
number of valid blood pressure readings over the 24 hours was on
average 95%, 93%, 93%, and 93% of the expected 90 readings in the
recordings performed before treatment, at 3 and 12 months of
treatment, and in the final placebo period, respectively. The
corresponding number of valid hours was 23.8, 23.9, 23.8, and 23.9,
respectively. Clinic and 24-hour average blood pressures were similarly
reduced after 3 and 12 months of treatment, whereas LVMI was
significantly reduced after 3 months and more so after 12 months. Blood
pressures, but not LVMI, returned toward pretreatment values after the
final placebo period (Table 1
).
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Table 1. BP Values and LVMI Before Treatment (Entry), After 3
and 12 Months of Treatment (TR), and After Final Placebo Period
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Reproducibility of T/Ps and SRs
Figure 1 (left panels) shows that
SBP and DBP were reduced at both peak and trough after either 3 or 12
months of treatment. The average peak and trough reductions were
superimposable at 3 and 12 months. This was the case also for the T/P,
both when obtained from average trough and peak changes and when
expressed as the median of individual T/Ps (Figure 1, middle panels).
Median SRs were also similar at 3 and 12 months of treatment (Figure 1, right panels).
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Figure 1. Changes ( ) in SBP and DBP at peak and at
trough after 3 months (open bars) and 12 months (striped bars) of
treatment in 175 patients. T/Ps and SRs at corresponding treatment
times are also shown. T/Ps were calculated as the ratio between average
peak and trough changes in the 175 patients. T/Ps were also calculated
according to the box-plot approach (median, upper, and lower quartiles
and extremes and outliers, the latter indicated by small squares)
derived from the individual T/Ps. Squares correspond to individual
outliers with no reference to their actual value. The same approach was
applied to the SR. **P<0.01, significance from
pretreatment values.
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As shown in Figure 2, peak blood pressure
changes at 3 and 12 months of treatment were closely related; this was
even more the case for trough blood pressure changes. In contrast, the
3- and 12-month T/Ps were significantly but less closely related.
Furthermore, the repeatability coefficients between 3 and 12 months of
treatment were greater for the T/P and SR than the blood pressure
changes at peak and at trough. The mean±2 SD differences and the
repeatability coefficients are shown in Table 2.
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Figure 2. Correlation between peak blood pressure changes
() after 3 and 12 months of treatment, trough blood pressure changes
after 3 and 12 months of treatment, and T/Ps after 3 and 12 months of
treatment. Data are shown separately for SBP and DBP.
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Table 2. Difference () for Peak and Trough Blood Pressure
Changes and T/P and SR Between 3 and 12 Months of Treatment
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Regression of LV Hypertrophy
As shown in Figure 3, the reduction
of LVMI after 12 months of treatment was not related to the
treatment-induced changes in clinic blood pressure, but it showed a
significant relationship with the treatment-induced changes in 24-hour
average blood pressure. Peak and trough blood pressure changes after 12
months of treatment were related to the reduction of LVMI to an extent
similar to that of 24-hour average blood pressure changes. In contrast,
the reduction of LVMI showed no relationship with the 12-month T/Ps and
a poor even though significant negative relation with SRs. On a
multivariate regression analysis, the
treatment-induced reduction in 24-hour average SBP was a determinant of
the reduction in LVMI (ß=0.39, P<0.0001) with a small
contribution from the T/P (ß=-0.15, P=NS). This was the
case also for DBP (ß=0.37, P<0.0001 for 24-hour average
change; ß=-0.10, P=NS for T/P). Furthermore, when
patients were divided into groups with a more (0.5) and less (<0.5)
favorable systolic and diastolic T/P, only small
and nonsignificant differences in the magnitude of the reduction of
LVMI were found (Figure 4).
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Figure 3. Correlation coefficients (r)
between changes () in LVMI and changes in clinic BP, changes in
24-hour average BP, peak BP changes, trough BP changes, T/P, and SR in
the 154 patients with both valid ABPM recordings and
echocardiograms after 12 months of treatment. Data are shown for SBP
(open bars) and DBP (striped bars). **P<0.01,
significance of the correlation coefficients.
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Figure 4. Average±SD 24-hour SBP and DBP and LVMI before
treatment (entry, E) and after 12 months of treatment (TR) in the
patients with T/P <0.5 (open bars, n=60) and 0.5 (striped bars,
n=94) for SBP or DBP. The median and 5th to 95th percentile interval of
the T/P distribution for the former group was 0.21 (-1.41/0.49) for
SBP and 0.25 (-1.53/0.49) for DBP; the corresponding values of the
latter group were 0.87 (0.51/1.86) and 0.83 (0.54/2.46).
**P<0.01 and *P<0.05, significance of
changes after treatment or between treatments, respectively.
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Discussion
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In our hypertensive patients, administration of
lisinopril alone or in combination with
hydrochlorothiazide reduced 24-hour average SBP and DBP
to a similar extent after 3 and 12 months. The average peak and trough
blood pressure changes induced by 3 and 12 months of treatment were
also similar, and in both instances the individual 3- and 12-month
values were closely related to each other. Thus, peak and trough blood
pressure changes associated with antihypertensive treatment are
reproducible, and their magnitude after short-term administration of
antihypertensive drugs satisfactorily reflects the magnitude
characterizing 12-month antihypertensive treatment.
This is less the case, however, for the T/P of the antihypertensive
effect. In our patients, the average T/Ps obtained after the 3-month
treatment were similar to the T/Ps obtained when treatment was
prolonged to 12 months, both when calculations were based on average
trough and peak changes and when they were based on average of
individual T/Ps. However, the percent repeatability coefficients (ie,
the reciprocal of reproducibility) were higher and the correlation
coefficients were lower for the T/Ps than for peak and trough blood
pressure changes separately considered. Thus, at variance from trough
and peak blood pressure changes, T/Ps of the antihypertensive effect
have a limited reproducibility, which may make their individual values
after short-term treatment not entirely representative
of those after 1 year of treatment. This may originate from the fact
that because it is derived from 2 relatively small blood pressure
changes, this ratio can be substantially affected by minor alterations
of the antihypertensive effect. For example, for a peak change of
10 mm Hg and a trough change of 5 mm Hg, the resulting 0.50
T/P would range from 0.36 for a T/P of 4/11 mm Hg and to 0.67 for
a T/P of 6/9 mm Hg (ie, it would show major differences for just
1 mm Hg change in the peak and trough effect from 1 treatment
period to another).
The SAMPLE study9 has previously shown that in
hypertensive patients with LV hypertrophy, regression of
the hypertrophy is much more closely related to
treatment-induced reduction of the 24-hour average than of clinic blood
pressure. The present findings additionally show, however, that
regression of LV hypertrophy is related to
treatment-induced "ambulatory" trough and peak blood pressure
reductions as closely as to 24-hour average blood pressure reduction.
Thus, 24-hour blood pressure control is superior to clinic blood
pressure control in predicting reversal of end-organ damage of
documented prognostic significance.17 18 19 Such an
advantage is shared, however, by the 2-hour blood pressure values from
which trough and peak blood pressure changes induced by
antihypertensive treatment can be calculated. This raises the question
of whether 24-hour ABPM is truly necessary or, as our data suggest,
information of similar clinical importance can be more easily (and
cheaply) obtained with shorter monitoring periods within the
between-dose interval.20
However, the T/P of the antihypertensive effect performed less well
than the separate trough and peak changes. In our hypertensive
patients, there was no significant relationship between the reduction
of LVMI induced by the 12-month treatment and the 12-month T/P of
either SBP or DBP. Furthermore, in patients with a systolic or
diastolic T/P regarded as favorable
(0.5),1 2 21 regression of LV
hypertrophy was quantitatively similar to that of the
patients with an unfavorable (<0.5) T/P. Thus, the reproducibility as
well as the clinical relevance of the T/P of the antihypertensive
effect do not mirror the trough and peak blood pressure changes from
which the ratio is derived. This indicates that these changes, rather
than their ratio, should be considered for use in evaluating in a
reproducible fashion how large, balanced, and clinically beneficial are
the effects of a given antihypertensive drug or drug combination.
Three further results of our study deserve to be mentioned. First, in
the present study we calculated the peak blood pressure effect
within a fixed time window, ie, between 2 and 8 hours after
administration of the drug(s). The question may therefore be raised
whether the peak effect may have occurred later. However, this is
unlikely because in a previous study with lisinopril in
which no "a priori" time window was used, the peak effect in
the group occurred around 11 AM and noon, ie, well within
the time window we used.8
Second, peak blood pressure changes are regarded as difficult to assess
when ambulatory blood pressure is used21 because
the sometimes short-lasting peak blood pressure fall may occur during
the interval between the automatic blood pressure readings and/or be
modified to an unpredictable and erratic degree by behavioral
influences on blood pressure. In the present study, however,
calculation of peak blood pressure changes by averaging the hour with
the maximal blood pressure reduction plus the adjacent hour with the
greater blood pressure reduction resulted in highly reproducible
values. Thus, these changes can be consistently assessed if
calculated over 2 hours within a fixed time window.
Third, our results also provide information on an alternative method to
calculate the duration and homogeneity of the antihypertensive effect
over the between-dose interval, ie, the "surface
ratio."7 Theoretically, this method has an
advantage because the calculation takes into account all blood pressure
changes during the interval between drug consumption, and according to
recent findings obtained after 1 and 2 months of treatment, it
is more reproducible than the T/P.7 In our study,
however, the reproducibility of the SR after 3 and 12 months of
treatment was not better than the T/P and worse than the trough and
peak blood pressure changes, separately considered. Furthermore, a poor
relationship was found between the SR and the magnitude of the LV
hypertrophy reduction. Thus, use of this method is not
supported by our data on long-term antihypertensive treatment.
Received December 31, 1997;
first decision February 11, 1998;
accepted April 23, 1998.
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Abstract
Introduction