ORIGINAL ARTICLE
Combination of lisinopril and nifedipine GITS Increases Blood
Pressure Control Compared with Single Drugs in Essential
Hypertensive Patients
*Stefano Taddei, †Stefano Omboni, *Lorenzo Ghiadoni, ‡Alberto Caiazza, §Roberto Fogari,
储
Pierfranco Innocenti, ¶Carlo Porcellati, #Roberto Giovannetti, **Luca Corradi, ††Giuseppe Mancia, and
*Antonio Salvetti
Abstract: The present study was designed to evaluate the effect
of combination therapy using the angiotensin-converting en-
zyme-inhibitor lisinopril and the dihydropyridine calcium an-
tagonist nifedipine GITS on the degree and homogeneity of 24-
hour blood pressure reduction in essential hypertensive patients.
After a 4-week placebo run-in period, 51 patients (mean age, 54.4
± 9.4 years) with essential hypertension and clinic diastolic blood
pressure between 105 and 115 mm Hg were randomized to
4-week treatment with lisinopril (20 mg), nifedipine GITS (30
mg), or their combination according to a multicenter, random-
ized, double-blind, crossover study. Trough clinic blood pressure
and 24-hour ambulatory blood pressure were measured at the
end of the run-in period and after 4 weeks of treatment. In addi-
tion to clinic and 24-hour average blood pressure reduction, the
trough-to-peak ratio and the smoothness index, a new measure
for the homogeneity of blood pressure reduction, were also cal-
culated. Although both lisinopril and nifedipine GITS produced
a significant reduction in clinic and 24-hour average blood pres-
sure values, the reduction obtained with the combination was
significantly (P < 0.001) greater. Moreover, the combination
therapy increased (P < 0.01) the smoothness index as compared
with each single drug for both systolic (lisinopril, 1.02; nifedipine
GITS, 1.1; combination, 1.76) and diastolic (lisinopril, 0.98; ni-
fedipine GITS, 0.87; combination, 1.54) blood pressure values,
whereas trough-to-peak ratio values (expressed as median) for
systolic (lisinopril, 0.41; nifedipine GITS, 0.52; combination,
0.55) and diastolic (lisinopril, 0.35; nifedipine GITS, 0.40; com-
bination, 0.49) blood pressure values were not significantly in-
creased by the combination therapy. Thus, antihypertensive
*Department of Internal Medicine, University of Pisa, Pisa; †Istituto
Scientifico Ospedale S. Luca, Istituto Auxologico Italiano, Milan;
‡Ospedale di Fidenza, Fidenza; §Medicina Interna e Terapia Medica,
University of Pavia, Pavia; 储Ospedale di Carrara, Carrara; ¶Ospedale
Regionale Raffaello Silvestrini, Perugia; #Ospedale di Pescia, Pescia;
**Presidio Ospedaliero, Broni; and ††Cattedra di Medicina Interna,
University of Milan, Ospedale San Gerardo dei Tintori, Monza, Italy.
Received December 3, 2001; accepted August 14, 2002.
Address correspondence and reprint requests to Prof. Stefano Taddei,
Department of Internal Medicine, University of Pisa, Via Roma, 67,
56100 Pisa, Italy. E-mail: s.taddei@med.unipi.it
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
treatment with the combination of lisinopril and nifedipine GITS
is more effective and balanced over the 24 hours than the com-
bination components administered alone, confirming that the
smoothness index is superior to the trough-to-peak ratio in assess-
ing homogeneity of pharmacologic blood pressure reduction.
Key Words: Angiotensin-converting enzyme inhibitors—Blood
pressure variability—Calcium antagonists—Hypertension—
Trough-to-peak ratio.
( J Cardiovasc Pharmacol ™ 2003;41: 579–585)
D espite the awareness of the dramatic impact of essen-
tial hypertension on population mortality and mor-
bidity (1), in virtually all populations, adequate blood pres-
sure control of the hypertensive component frequently fails
to be achieved (2,3). By general agreement, this is largely
the result of poor compliance with necessarily chronic
treatment. There is also general agreement, however, that
excessive emphasis on monotherapy may be a contribut-
ing factor, because no compound used as a single therapeu-
tic agent achieves more than a 40% to 50% control rate
(2,3). Increasing the drug dose often is ineffective or impos-
sible because the compound may have a flat dose-response
curve (for instance, angiotensin-converting enzyme [ACE]
inhibitors) (4), or because higher doses may be associated
with more unpleasant side effects (5). An alternative
strategy for effective blood pressure control is to use
combination therapy (6) to associate the blood pressure-
lowering properties of two drugs and to minimize their
adverse effects, thus favorably affecting efficacy and com-
pliance (2,3,6).
In the current study, we evaluated the efficacy of
combination treatment with the ACE inhibitor lisinopril
and the dihydropyridine calcium antagonist nifedipine
GITS. Although the additive effect of this combination has
been demonstrated previously in terms of the degree of
blood pressure reduction (7,8), no data exist indicating
whether the combination also shows a better 24-hour and a
579
S. Taddei et al.
more homogeneous blood pressure control than single
drugs. The study was performed according to a double-
blind, randomized, cross-over design to compare the blood
pressure-lowering effect of the combination versus its com-
ponents in the same patients. Clinic blood pressure mea-
surements were complemented by ambulatory blood pres-
sure (ABP) monitoring (9,10), as the latter is likely to be
more important for organ protection (11–14). The ABP
data were also analyzed in terms of homogeneity of the
daily life blood pressure-lowering effect of treatment, be-
cause prevention of excessive blood pressure fluctuations
by smooth and balanced 24-hour blood pressure control is
perceived as a relevant clinical goal (15). This analysis was
based on calculation of the smoothness index (SI), which
has recently been shown to be superior to the trough-to-
peak (T/P) ratio in determining homogeneity of the anti-
hypertensive effect (16–19).
METHODS
Patient Selection and Study Design
The study was performed according to a multicenter,
double-blind, randomized, and crossover design. A total of
72 outpatients (49 men), with a mean age 54.9 ± 8.67 years
(range, 32–68 years) and moderate-to-severe essential hy-
pertension were enrolled. Never treated or previously
treated essential hypertensive patients were included if sit-
ting diastolic blood pressure (sphygmomanometer, fifth
Korotkoff sound) was found to be between 105 and 115
mm Hg at the end of the 4-week placebo run-in period to
which all patients were submitted, during which any pre-
vious antihypertensive treatment was withdrawn. Patients
were excluded from the study if they had history or clinical
evidence of malignant or secondary hypertension, coro-
nary heart disease, congestive heart failure, significant car-
diac conduction abnormalities, transient cerebral ischemic
attacks and stroke, hypo- or hyperkalemia, renal failure (se-
rum creatinine >1.5 mg/dl), hepatic or gastrointestinal dys-
function, or hypersensitivity to ACE-inhibitors or calcium
antagonists.
At the end of the placebo run-in period, patients were
randomized to receive three different treatments: lisinopril
(20 mg/day), nifedipine GITS (30 mg/day), and the com-
bination of lisinopril (20 mg/day) and nifedipine GITS (30
mg/day) for a period of 4 weeks each, according to the
crossover scheme described in Figure 1. No wash-out pe-
riod was allowed between treatments.
These drug doses were selected because (1) lisinopril
has a flat dose-response curve and the 20-mg daily dose has
been demonstrated to cover 24 hours (4); and (2) the GITS
formulation of nifedipine ensures that the compound
(which is itself characterized by a short half-life) also theo-
retically gives round-the-clock cover, even at the 30-mg
580
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
FIG. 1. Flow chart indicates treatment assignment and cross-
over scheme. Each patient was assigned to a treatment
scheme according to a randomized order.
dose, the lowest available on the market (20,21). All treat-
ments were administered at approximately 9 AM for a pe-
riod of 4 weeks each. A 4-week period was selected be-
cause theoretically full therapeutic effect is obtained within
this interval (4,20,21). Drug compliance was monitored by
pill count. Before and at the end of each treatment period,
all patients were submitted to a physical examination and
biochemistry tests. A 12-lead electrocardiogram was per-
formed at the beginning and end of the entire study. Ad-
verse events were recorded by the investigators at each
visit.
Blood Pressure Measurements
At the screening visit, after 2 weeks, at the end of the
placebo run-in period and at the end of each treatment
period, clinic blood pressure was measured in the sitting
position by a mercury sphygmomanometer. Systolic and
diastolic blood pressure values were identified by the first
and fifth Korotkoff sound, respectively. Three measure-
ments were made at 2-minute intervals after the patient had
been seated for at least 10 minutes, and the average was
used as the value of the visit. Heart rate, assessed by the
palpatory method, was likewise calculated as the mean of
three measurements. Blood pressure and heart rate mea-
surements were taken in the morning approximately 24
hours after the last placebo or drug administration.
Ambulatory blood pressure was monitored by an os-
cillometric SpaceLabs 90202 or 90207 (SpaceLabs Inc.,
Redmond, WA, U.S.A.) device at the end of the placebo
run-in period and at the end of each treatment period.
Monitoring was started after clinic blood pressure mea-
surements had been completed and the placebo or active
drug(s) administered. Blood pressure readings were ob-
tained automatically every 15 minutes during the day (6 AM
to 12 PM) and every 20 minutes during the night (12 PM to
6 AM) for a period of 24 hours. Patients were instructed
© 2003 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
not to alter their usual 24-hour schedule during the moni-
toring period but were asked to avoid unusual physical ac-
tivities and to maintain the arm still during cuff inflation
and deflation. Each ABP reading was subjected to removal
of artifactual values, as previously described (22), and was
accepted for efficacy analysis if there was at least one valid
reading per hour and at least 70% of readings were valid
over the 24 hours. Simultaneously with each blood pres-
sure monitoring, the device also measured heart rate.
Data Analysis
The primary end point of the study was the change
from the placebo run-in value of trough sitting diastolic
blood pressure at the end of each treatment period. Sec-
ondary end points were (1) the change in trough sitting
systolic blood pressure; (2) changes in mean 24-hour, day-
time and nighttime systolic and diastolic blood pressure;
and (3) T/P ratios and the SI of treatment-induced changes
in systolic and diastolic blood pressure as assessed by ABP
monitoring.
The T/P and SI were determined as previously de-
scribed (16,23). Briefly, compared with placebo run-in
data, the peak effect was identified by averaging the mean
hourly change between the second and eighth hour after
drug administration that showed the greatest blood pres-
sure decrease and the mean hourly change of the adjacent
hour with the greatest decrease. The trough effect was iden-
tified by averaging the values of the twenty-third and
twenty-fourth hour after drug administration. The SI was
obtained by (1) calculating the treatment-induced average
blood pressure change for each hour of the 24-hour moni-
toring period, as compared with the corresponding hourly
value at the end of the run-in placebo period; (2) comput-
ing the average and standard deviations of these hourly
values (n = 24); and (3) dividing the average of hourly val-
ues by the standard deviation so obtained, thereby calcu-
lating a normalized measure of homogeneity of the antihy-
pertensive effect over the entire between-dose interval.
Calculations were made separately for each treatment and
for systolic and diastolic blood pressure. Analysis of heart
rate data was similar to that of blood pressure data.
Patients were considered to be responders if, at the
end of any treatment period, clinic diastolic blood pressure
was 10 mm Hg or at least 10% lower than at the end of the
placebo run-in period. Moreover, patients were consid-
ered as normalized if, at the end of the treatment period,
blood pressure values were found to be ⱕ140 to 90 mm
Hg. Any possible crossover effect was assessed by applica-
tion of the Grizzle test. Data from individual patients were
averaged and expressed as mean ± standard deviation. In
Figures 2 and 4, results are expressed as mean ± standard
error. Differences in mean values were analyzed statisti-
© 2003 Lippincott Williams & Wilkins
Smoothness Index and Combination Therapy
cally by an analysis of variance. Because of its nonparamet-
ric distribution, the T/P ratio is reported as median and
95% confidence intervals. The Wilcoxon test was used to
evaluate the statistical difference between T/P ratio values.
A P value less than 0.05 was taken as the level of statistical
significance.
RESULTS
Of the 72 patients randomized to active treatment at
the end of the placebo run-in period, 21 patients were ex-
cluded for protocol violations (n = 5) or poor quality of
ABP data (n = 21). Thus, 51 patients (mean age, 55.2 ± 8.8
years) were considered for data analysis (Table 1). Diabetes
was present in 3% of the study group. Clinical characteris-
tics of the patients excluded from the analysis were similar
to those of included patients. Drug compliance showed no
difference during the three active treatment periods (data
not shown).
As shown in Figure 2 and Table 2, compared with the
placebo run-in data, lisinopril and nifedipine GITS caused
a similar reduction in clinic systolic and diastolic blood
pressure. However, the combination of lisinopril plus ni-
fedipine GITS caused a further reduction in blood pressure
values that was statistically significant as compared with
each single treatment. Clinic heart rate was not altered by
nifedipine GITS, but was slightly and similarly reduced by
lisinopril and by the association between lisinopril and ni-
fedipine GITS. Thirty-seven percent and 39% of patients
were found to be responders to lisinopril and nifedipine
GITS treatment, respectively. The responder rate was
greater (47%; P < 0.01) when the two drugs were given in
combination. Moreover, under lisinopril and nifedipine
GITS treatment, blood pressure was normalized (<140/90
mm Hg) in 22% and 24% of patients, respectively, whereas
the combination therapy normalized blood pressure val-
ues in 39% (P < 0.05) of patients.
TABLE 1. Characteristics of study subjects (data are
mean Ⳳ S.D.)
Essential hypertensive
Parameter patients (n = 51)
Age (years) 55.2 ± 8.8
Age range (years) 32–67
Sex (male/female) 38/13
Height (cm) 170.5 ± 7.6
Weight (kg) 74.5 ± 11.9
Plasma glucose (mg/dl) 101.7 ± 29.2
Plasma total cholesterol (mg/dl) 219.2 ± 24.6
Plasma creatinine (mg/dl) 1.0 ± 0.2
Plasma potassium (mM) 4.3 ± 0.4
Smokers (yes/no) 11/40
581
S. Taddei et al.
FIG. 2. Effect of drug treatment on clinic systolic (SBP) and
diastolic (DBP) blood pressure values measured at trough time
(upper panel) and on 24-hour average systolic (SBP) and dia-
stolic (DBP) blood pressure values (lower panel). Data are
shown as mean Ⳳ standard error changes from baseline after
1 month of treatment. Asterisks denote a significant (P < 0.01)
difference between combination and single therapy.
In Figure 2 and Table 2, 24-hour blood pressure data
are described. Compared with placebo, values for reduc-
tion in mean 24-hour, daytime, and nighttime systolic
blood pressure induced by lisinopril were similar to one
another (6.9 mm Hg, 7 mm Hg, and 6.8 mm Hg, respec-
tively). The corresponding systolic blood pressure reduc-
tions induced by nifedipine were 8.4 mm Hg, 9.1 mm Hg,
and 6.2 mmHg. The combination of lisinopril and nifed-
ipine GITS, however, lowered mean 24-hour, daytime,
and nighttime systolic blood pressure by 15.3 mm Hg, 16
mm Hg, and 13.2 mm Hg, respectively, thereby achieving
an effect that was significantly (P < 0.01) and markedly
greater than that seen with lisinopril and nifedipine GITS
alone. Similar findings were observed for mean 24-hour,
daytime, and nighttime diastolic blood pressure. At vari-
ance with results obtained for clinic heart rate, nifedipine
caused a slight increase in mean 24-hour, daytime, and
582
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
nighttime heart rate values, which were left unchanged by
both lisinopril and the association of lisinopril and nifed-
ipine GITS.
Figures 3 and 4 show the T/P and SI values for the
three treatment periods. The T/P ratio for systolic and di-
astolic blood pressure was not statistically different (al-
though close to statistical significance for diastolic blood
pressure) for the combination therapy as compared with
lisinopril or nifedipine GITS (Fig. 3) administered as
monotherapy.
The SI for systolic blood pressure was similar for lis-
inopril and nifedipine GITS, but significantly (P < 0.01)
and markedly greater for their combination. This was like-
wise the case for diastolic blood pressure SI. These results
did not change when SI was calculated in responder sub-
jects only (Fig. 4).
Safety Analysis
During the 12 weeks of treatment, there were no
dropouts from adverse events. During the study, a total of
30 adverse events were recorded in 19 patients; 19 adverse
events were judged to be probably drug related (four dur-
ing lisinopril, seven during nifedipine GITS, and eight dur-
ing lisinopril plus nifedipine GITS treatment). The most
frequent drug-related adverse event was leg edema or mild
edema (three patients during nifedipine GITS, two patients
during lisinopril, and four patients during lisinopril plus
nifedipine GITS treatment); palpitation (three patients dur-
ing nifedipine GITS treatment) and cough (one patient
during lisinopril, one patient during nifedipine GITS, and
two patients during the combination lisinopril plus nifed-
ipine GITS treatment). Laboratory data showed no clini-
cally relevant change with any type of treatment.
DISCUSSION
In the current study, both once daily lisinopril and
once daily nifedipine GITS, at the doses of 20 and 30 mg,
respectively, lowered blood pressure when administered
for 1 month as monotherapy. However, when the two
drugs were given together, the magnitude of the antihyper-
tensive effect was significantly greater. This enhanced ef-
fect was observed for clinic systolic and diastolic blood
pressure and was particularly evident for 24-hour average
systolic and diastolic blood pressure. The latter decreased
by almost twice as much during combination therapy in
comparison with the two monotherapies. Combined treat-
ment with lisinopril and nifedipine GITS is therefore an
effective means to treat hypertension. Furthermore, it is a
highly effective means to normalize daily life blood pres-
sure because, at the doses used, a near-additive ability of
the two drugs to lower blood pressure throughout the day
and night was observed. It is important to note that in our
© 2003 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003 Smoothness Index and Combination Therapy

TABLE 2. Effect of four weeks of treatment with lisinopril (20 mg daily), nifedipine GITS
(30 mg daily) and the combination of lisinopril and nifedipine GITS on clinic systolic,
diastolic blood pressure and heart rate (measured at rough time) and on 24-hour
average systolic and diastolic blood pressure and heart rate in 51 essential
hypertensive patients

Nifedipine Lisinopril +
Variables Baseline Lisinopril GITS nifedipine GITS
Clinical data
Clinic SBP (mm Hg) 167.8 ± 8.3 154.7 ± 11.9* 153.2 ± 10.3* 148.1 ± 11.4†
Clinic DBP (mm Hg) 108.8 ± 8.2 97.3 ± 9.3* 96.7 ± 7.9* 93.0 ± 7.2†
Clinic HR (beats/min) 79.9 ± 7.6 77.7 ± 6.3* 79.8 ± 5.7 77.0 ± 5.6*
24-hours average
SBP (mm Hg) 150.0 ± 12.8 143.0 ± 14.5* 141.6 ± 11.9* 134.7 ± 11.1†
DBP (mm Hg) 94.8 ± 9.7 89.1 ± 11.0* 88.8 ± 9.6* 83.6 ± 9.3†
HR (bears/min) 74.3 ± 8.6 73.9 ± 8.3 76.7 ± 8.5 76.2 ± 8.2
Data are shown as mean ± SD. DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood
pressure.
*P < 0.001 or less vs. baseline.
†P < 0.001 or less vs. lisinopril or nifedipine treatment.

study population with moderate-to-severe hypertension,
combination therapy was effective in controlling blood
pressure values in 39% of patients only, indicating the need
to add at least a third drug to achieve adequate blood pres-
sure control. However, the low rate of blood pressure nor-
malization by combination therapy is in line with the re-
sults of the Hypertension Optimal Treatment study (24),
which indicated that more than 50% of patients needed
three or more drugs to reach the target blood pressure
value of 140 to 90 mm Hg.
FIG. 3. Effect of drug treatment on trough-to-peak (T/P) ratio
for systolic (SBP) and diastolic (DBP) blood pressure values.
Because of nonparametric distribution of the T/P ratio, results
are given as median and 95% confidence intervals.
Our study provides an additional important finding.
Compared with single administration of each compound,
the association of lisinopril and nifedipine GITS substan-
tially increases SI, a parameter that gives a much clearer
picture of the distribution of 24-hour blood pressure effects
of antihypertensive treatment than do other parameters
such as T/P. The SI is highly reproducible (16), indicating
good ability to disclose possible differences in homogene-
ity of the blood pressure-lowering effect of different
treatments.
It is interesting that the SI was almost identical in
the total population and in responder patients. This find-
ing indicates that SI, at variance with T/P (25), is not
influenced by nonresponder patients, who may have a
very low standard deviation in the average fall in blood
pressure and therefore a smooth but “virtual” blood pres-
sure decrement.
The SI is therefore a suitable parameter for studies
comparing different drugs or drug regimens. Moreover,
because SI shows a direct relationship with blood pressure
variability (16) and regression of left ventricular hypertro-
phy during treatment (16) and is a predictor of changes in
carotid artery wall thickness (19), it can go beyond mere
determination of blood pressure reduction by adding cru-
cial information on the protective effect of treatment. Thus,
blood pressure variability is related to organ damage
(11,12), and because left ventricular hypertrophy is a risk
factor for cardiovascular disease (26,27), regression of the
hypertrophy possibly reflects a reduced risk (28).
The demonstration that SI can be increased by asso-
ciating lisinopril and nifedipine GITS therefore suggests

© 2003 Lippincott Williams & Wilkins 583

S. Taddei et al.
FIG. 4. Effect of drug treatment on the smoothness index for systolic (SBP) and diastolic (DBP) blood pressure values in the whole
study population (upper panel) and in responder subjects (treatment-induced blood pressure decrement more than 10% com-
pared with baseline; lower panel). Data are shown as mean Ⳳ standard error. Asterisks denote a significant (P < 0.01) difference
between combination and single therapy.
that this combination offers the advantage of improved ho-
mogeneity of the antihypertensive effect throughout the 24
hours. This is a goal of potential therapeutic importance, as
a dishomogeneous effect of treatment over the between-
dose interval may either favor an increase or oppose a re-
duction in blood pressure variability, that is, resulting in a
phenomenon that may contribute to organ damage (10–
13). With the combined administration of lisinopril and ni-
fedipine GITS, this dishomogeneity can be prevented or
reduced, leading to a more pronounced but also more
stable 24-hour blood pressure reduction.
Other findings of our study deserve to be mentioned.
The additive effect of the lisinopril and nifedipine GITS
combination was seen both for daytime and nighttime
blood pressure. This is clinically relevant because both
pressures seem to be involved in the organ damage found
in hypertension (14,29,30). Moreover, at variance with SI,
in our patients the combined administration of lisinopril
and nifedipine GITS did not significantly increase T/P as
compared with the values seen with the single administra-
tion of either compound. This provides further evidence
that T/P is a less sensitive index of the homogeneity of the
antihypertensive effect than SI (16,18). Based on previous
findings, we can speculate that this may be partly ex-
plained by the limited reproducibility of T/P. Further-
more, its nature is such as to derive homogeneity values
from only a few data within the 24 hours, so that its results
are often erratic. Its unreliability is also highlighted by the
evidence that whereas SI reflects treatment-induced
changes in overall blood pressure variability, left ventricu-
lar mass, and carotid wall thickness, T/P does not (16,18).
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J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
Finally, whereas nifedipine GITS caused a slight in-
crease in 24-hour heart rate, this variable was unchanged
either by lisinopril alone or by the nifedipine GITS plus
lisinopril combination, despite the greater hypotensive ef-
fect of the latter. Thus, the lisinopril plus nifedipine GITS
combination can lead to a better blood pressure control,
reciprocally reducing the side effects related to its compo-
nent, a finding consistent with the current concept that to
protect more effectively a hypertensive individual, blood
pressure should be decreased to less than 140/90 mm
Hg (31).
In conclusion, our study used a controlled crossover
design to assess the efficacy of the combined use of the
ACE-inhibitor lisinopril and the dihydropyridine calcium
antagonist nifedipine GITS in the same group of essential
hypertensive patients. Results show that this combination
achieves greater blood pressure reduction than combina-
tion components administered in monotherapy. The study
further shows that the antihypertensive effect of the com-
bination is particularly enhanced for ambulatory blood
pressure, which is reduced by the two drugs in an additive
and homogeneous manner. This therapeutic option is
therefore a valid means for achieving the more drastic
blood pressure reduction that is now regarded as necessary
to protect patients with high blood pressure.
ACKNOWLEDGMENTS
The authors thank the following investigators for
their participation in the study: Dr. A. Magagna (Pisa), Dr.
S. Vivaldi (Pisa), Dr. F. Ponzanelli (Carrara), Dr. G. Rastelli
© 2003 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol姠 • Volume 41, Number 4, April 2003
(Fidenza), Dr. P. Verdecchia (Perugia), Dr. A. Ciucci (Pe-
rugia), Dr. C. Borgioni (Perugia).
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