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Evaluation of the antihypertensive effect of once-a-day trandolapril by 24-hour ambulatory blood pressure monitoring
Evaluation of the Antihypertensive Effect of Once-a-Day Trandolapril by 24-Hour Ambulatory Blood Pressure Monitoring Giuseppe Mancia, MD, Raffaele De desaris, MD, Roberto Fogari, MD; Salvatore Lattuada, MD, Giuseppe Montemurro, MD, Carlo Palombo, MD, Carlo Porcellati, MD, Giuseppe Ranieri, MD, France Tettamanti, MO, Paolo Verdecchia, MD, Claudio Marelli, MD, Stefano Omboni, MD, Antonella Ravogli, MD, Albedo Zanchetti, MD, for the Italian Trandolapril Study Group
The aim of this study was to evaluate the effects of tranddaprii on P&hour biood ptessure in patients wfth mild-to-moderate essential h-ension, After a washout period of 4 weeks, 42 patientswere randomized to receive 2 mgof t&lolapril once daiiy and 20 to re&ve placebo Ona doumblind fashbn for 6 ww&s. This was foilowedbya-dwashoutperkdof4wwks. At the end of each period, cJink blood pressure was assessed ti 24 hours after the last dose and 24hour ambulatory blood pressurewars measured noninvasiveiy, taking blood pWsure readings every I5 minutes during the dajr and every 20 mlnutesduriilgthe night, TWo patIentswere dropped out before any biowl pressure evaluaAnalysis of ambulatory tion under Matmeut, biowipressurewasperformedin4Spatientswho met the crB@ia for the minimal number of ambw Jatory blood pressure data (2 valu6s per hour durlng the day and 1 value per hour in the night). in tb tranMapril=treated group (n = 41) clinic sysl tolk/dlastoik blood pressures were 1159,s & 2.0/ lO2,4 t 0.&U&6.8 t 2.3/94.8 2 l& and 155.7 t 2.0/99.2 t 0.7 mm Hg in the pretreatment, treatment, and post-treatment s respectiveiy. lhe correqponding values for P&hour mean blood pressure (n = 31) were 239.5 * L9/9L2 t 1.5, l3LO k 2,0/843 t l.2, and 139.7 2 l.Sl90.9 t Ll mm Hg. The difFerewes between the ktir
From the Italian Trandolapril Study Group: Cattedra di Medicina Interna and Clinica Medica Generale, Universita’ degli Studi di Milan0 (G.M., SO., A,R., AZ.); Cattedra di Fisiopatologia Medica, Universita’ degli Studi di Bari (R.D.C., G,R.); Clinica Medica, Universita’ degli Studi di Pavia (R,F., FT.); Clinica Medica, Universita’ degli Studi di Milano (S.L.); Divisione di Cardiologia, Ospedale de1 Ponte, Varese (G.M.); Istitbto di Fisiologia Clinica, Universita’ degli Studi di Pisa (C.P.); Divisione di Medicina, Ospedale Silvestrini, Perugia (C.P., P.V.); Direzione Medica, Roussel Pharma Italia (CM.); Milano, Italy. Address for reprints: G. Mancia, MD, Centro di Fisiologia Ciinica e Ipertensione, via F. Sforza, 35,20122 Milano, Italy. 60D
THE AMERICAN
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70
treatment, versus the higher pre- and po&treatmerit, values were all statistkally signlfkant (p ~0.01). The traindoiapril-induced blood prey sure fall was sfmii& during the day and niglrt and statistkaiiy signifkamt also during the last 4 hoursofthe2M&Br monito& pefiod (-6.6 * 0,3 and -5,9 2 0,2 mm Hg far systolk and diastoik blood pressure, resp&l& p ~0.05). Trandolapril did not affect clink heart rate but signifkantiy lowered 24hour heart ratevalues. In the piacebo group the clink (n = 19) and amm b&tory (n = 17) blood pressure and heart rate values obtainedat theendofthe3 periods mre similar, Thus, at the d0w of 2 mg once dally, trandolapril reduce6 blood pressure in mildto-moderate hypertensive patients. This antihypertenslve efkct is manifest throughout the 24 hOUlrs.
(Am J Cardioll992;70:6O~D)
T
randolapril is a newly developed angiotensin converting enqme (ACE) inhibitor characterized by being a prodrug and having a relatively long half-life in plasma? Whether this makes the drug effective in reducing 24-hour blood pressure by once-a-day dosing has not been conclusively established, however. In tHi=present study we have set out to examine this issue. MEFHODS Study pop~latlon:
Our studjr was done on 62 outpatients with mild or mode&e essential hypertension. The subjects (46 males and 16 females) had a mean age of 5 1.3 -+ 1.5 iears (range 29-67 years). They were recruited if their supine and standing diastolic blood pressure values, as assessed in the outpatient clinic, were > 95 mm Hg at the end of the run-in period (see below). Other inclusion criteria were: (1) a body weight within the OCTOBER
29, 1992
normal limits for age, sex, and body surface; (2) no history or evidence of severe target organ damage (transient ischemic attacks, stroke, coronary heart disease, renal insufficiency, congestive heart failure, intermittent claudication, etc.); (3) no evidence of severe diseases in addition to hypertension; and (4) no history of hypersensitivity to ACE inhibitors. Each subject gave his or her consent to the study after explanation of its nature and purpose. After randomization to placebo or active treatment two patients were dropped out before any blood pressure evaluation under treatment. Therefore efficacy analyses were performed on 60 patients. Study design: The study, which was a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, had the following protocol. After an initial medical visit had shown a blood pressure elevation, the subjects were submitted to a run-in period of 4 weeks to allow washout from any previgus treatment and to ensure diagnosis of the essential nature of their hypertension. The subjects were randomly assigned in a 2:l ratio to trandolapril 2 mg once daily or to placebo for 6 weeks. The dose of trandolapril or ‘placebo was administered at about 9 A.M. At the end of the 6 weeks, treatment was withdrawn and the patients were followed for another 4 weeks. Clinkal assessments Before treatment, at the end of treatment, and after the treatment periods all patients had a physical examination, a 12-lead resting ECG, and biochemical, hematologic and urinary laboratory examinations. Adverse events were recorded at each visit upon enquiry from the investigator. At the end of each period, systolic and diastolic blood pressures were measured 3 times by sphygmomanometry (1st and 5th Korotkoff sounds, respectively), 10 minutes after assumption of the supine and 1 minute after assumption of the upright posture. The average of the last 2 readings in the supine position was taken as the reference clinic value. The concomitant heart rate values were assessed by the palpatory method over 1 minute. The measurements were obtained between 8 and 9 A.M., which for the treatment period corresponded to about 24 hours after dosing. Ambulatory blood pressure monitoring: Ambulatory blood pressure and heart rate were monitored electronically (Spacelabs 5200; Spacelabs Inc., Redmond, Washington, USA). The monitoring started between 9 and 10 A.M., i.e., after completion of the clinic blood pressure measurements and, during the treatment period, immediately after the ingestion of the active drug or
TABLE I Demographic Characteristics of the Patients Placebo In = 20) Sex (male/female) Age (years)
Trandolapri I (n = 42)
1515
31/11
51.1 2 1.7
51.4 +: 1.5
Weight (kg)
77.6 2 2.8
73.4 2 1.6
Height (cm)
169.0 + 1.4
170.0 * 1.2
Data are means 2 SE.
placebo. The ambulatory blood pressure monitoring device was set to obtain one measurement every 15 minutes between 6 A.M. and 12 P.M. and one measurement every 20 minutes between 12 P.M. and 6 A.M. A recording was regarded as satisfactory if at least two readings per hour during the day and one reading per hour during the night ( i.e., from midnight to 6 A.M.) were acceptable according to previously established criteria? St&is&al methods: Ambulatory blood pressure data were analyzed as (1) 24-hour average systolic/diastolic blood pressure, mean arterial pressure, and heart rate; (2) daytime (6 A.M. to midnight) and night-time (midnight to 6 A.M.) average blued pressures and heart rates; and (3) hourly average systolic/diastolic blood pressure, mean arterial pressure, and heart rate. The analysis included the day-time and night-time mean arterial pressure and heart rate standard deviations of the mean values, which were taken as indices of blood pressure and heart rate variability. Data from single subjects were averaged to obtain the means (-+ SE) of the group. A paired Student’s l test was used to locate the differences between data obtained during treatment and before or after treatment. The statistical significance of the differences in the average hourly values was assessed by 2-way analysis of variance. A p <0.05 was taken as the minimum level of statistical significance throughout the study. RESULTS Demographic and medical history characteristics: Table I shows the demographic characteristics of the patients randumly treated with trandolapril or placebo. All data were comparable between the two groups. As shown in Table II, in Clinic blood pressure: the group randomized to placebo, supine clinic systolic/diastolic blood pressures were not significantly different at the end of the run-in or baseline period, the treatment period, or the final treatment withdrawal period. In contrast, in the group randomized to trandolapril both systolic and diastolic A SYMPOSIUM:
HYPERTENSION
AND ACE INHIBITORS
TABLE II Clinic Systolic/Diastolic Mood Pressure and Heart Rate Values at Run-in or Baseline, After Treatment with Placebo or Trandolapril, and After Washout After Baseline
Treatment
158.0 2 3.1 102.3 2 1,l 73.9 2 1.9
151.7 k 3.2 101.1 2 0.9
158.5 L 1.9
72.5 + 1.8
72.8 ZL 1.7
(n = 41) SBP (mm Hg)
159.8 2 2.0
DBP (mm Hg)
102.4 -t 0.8
146.8 2 2.3* 94.8 2 Ll*
155.7 i 2.0 99.2 k 0.7
72.0 zt 1.2
72.1 -+ 0.8
Treatment
Ptacebo (n = 19) SBP (mm Hg)
DBP (mm Hg) HR (bpm)
103.0 -+ LO
Trandolaprit
72.1 2 1.3
t-W @pm)
Data are shown as means L SE. Asterisks refer to statistical significance of differences between baseline and treatment values (*p < 0.01). bpm = beats per minute; SBP, DBP = systolic, diastolic blood pressure; HR = heart rate.
blood pressures decreased significantly in the treatment as compared to the baseline period, a significant increase being observed following treatment mmklg
SBP
withdrawal. Heart rate was not significantly different throughout the study in either the placebo or the trandolapril-treated group, Similar results were obtained when considering blood pressure and heart rate values taken in the upright position (data not shown). Ambulatory blo@ pressure: Twelve patients did not meet the criteria for the minimal number of ambulatory blood pressure data (see Methods). Thus, the analysiswas carried out in 48 patients, 31 randomized to trandolapril and 17 to placebo. Figure 1 shows that in the placebo group, 24-hour averagesystolic/diastolic blood pressuresand mean arterial pressure obtained at the end of the baseline period, the treatment period, and the posttreatment periods were superimposable. In contrast, in the trandolapril group all 24-hour average blood pressures were significantly less during the treatment period compared with the run-in and DBP
mmHg
160
110 1
150
I I*+1
1
l
-I
T
**-
I
mu
I**1
!
T
80 -
60 -
MAP
mmHg
120
1
HR
bPm 90 -
I*+1
-*++
I
-
*+1
I*1
80 -
701
60 -
80 -
40Baseline
q
62D
Placebo (n47)
Treatment
q
Trandolapril
Baseline
After treatment h-31)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
Treatment
After treatment
meansfSE
OCTOBER 29, 1992
*
p<0.05
**
p4.01
MAP
HR Trandolapril (n=31)
Placebo (n=17)
mmHg 120 -
Placebo (n=l7)
bPm 90 -
Trandolapril In=31)
3
80 -
I Night
1 Day
I
r Nighi
w
50 -
I Day
I Night
I Day
I Night
FIGURE 2. Day-and nlg@Mime me&n artwlal pressure (MAP) and heart rate (HR) values at basehm (qmm chh) after treatment (solid ckks) with placdm w tramdolapril. Dash am Mown as mmms 2 SE. Astddc8~tathestatb tkals@nlfkanceafthedWfemmcm betweentlm2cmdRlam
Placebo mmHg
Trando ilapril (n=31)
(n=17)
SBP
170
mmHg 170
160
160
150
150
140
140
130
130
120
120
110
I10
mmHg
and
SBP
mmHg
DBP
120
120
110
110
100
100
DBP
* ri
90 80 70
70
60
60 10
14
18
22
2
6
10
FlGuRE3. Houriysy~WkbImdpmssure (SRP)anddhstoHc after~(solld~)~plaoeboort~nddaprl.Dataaredwmrazrmeans~8E. tkal8l@lmcanceafthe cMhencmInt~last4hwrs m
10
14
18
22
2
6
10
hours
blowi pmssure(DBP)val~at~~(openc~~)and A4MMk8~tathe8tatlsthe2 condm. A SYMPOSIUM:
I-IYPERTENSION
AND ACE INHlBITORS
63p
Placebo mmHg 130
h=17)
Trandolapril
MAP
(n=3 1)
MAP
1
80 1
100
100
60
60
10 o----o
14
18
Baseline
22 -
2
6
Treatment
10 means&SE
14
IO
18
22
2
6
10 hours
* pco.05
FlWRE 4. Hourly mean attaial pressure (MAP) and heart rate (RR) v&es at basdb(opend~)and~treatnrent (sdiddmks)wRhpkceboortmmldaprll. Data areshown ammans *SE.Forhrtherexpla~seeFlgure3.
MAP
HR Trandolapril (n=31)
Placebo (n=17)
mmHg 14
Placebo (n=17)
bPm 13
Trandolapril (n=31)
T
i IIc 9,
6
-. P
7-
8
1
r
I
I
Day
Night
Day
Night
5'
I Day
meansiS
840
TI-IE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
OCTOBER 29, 1992
1 Night
I
1
Day
Night
post-treatment periods. In contrast to placebo, trandolapril caused a significant reduction of both the elevated day-time and the reduced night-time blood pressure values (Figure 2). The trandolaprildependent reduction in blood pressure was evident during almost every hour during 24 hours and significant also for the last 4 hours of the 24-hour monitoring period (Figures 3 and 4). Average 24-hour, day-time, night-time, and hourly heart rates were not significantly affected by placebo and only slightly, although significantly, reduced by trandolapril (Figures l-4). Blood pressure and heart rate variabilities were less during the night than during the day-time. In both instances placebo and trandolapril had no significant effect (Figure 5). safety: After randomization to placebo or trandolapri12 patients dropped out: one patient had a stroke during placebo treatment while the second withdrew for reasons not related to the study treatment. The laboratory examinations and the ECG patterns were not significantly modified by treatment compared with the pretreatment values. In the trandolapril group, 3 patients complained of symptoms that were not considered to be related to the study drug (headache, gastric pain, and tinnitus). In the placebo group, one patient reported flushing and conjunctival hyperemia.
In our hypertensive subjects, once-a-day administration of t randolapril at the dose of 2 mg caused a signi .ficant reduction in 24-hour average blood pressure values compared with the pre- and posttreatment values. The reduction involved both systolic and diastolic blood pressures. It was evident with respect to the elevated day-time and the reduced night-time blood pressures, and it was manifest for the blood pressure values occurring in the last few hours of the 24-hour dosing interval. This permits the conclusion that at the dose employed, once-daily administration of trandolapril is therapeutically effective over 24 hours. Several other data of our study deserve to be mentioned: (1) In our patients, trandolapril caused a significant although small reduction in 24-hour mean heart rate. This is not an invariable finding for antihypertensive treatment with ACE inhibitors. However, in some studies ACE inhibitors have been reported to potentiate vagal cardiac drive, which would account for the slight bradycardia we observed? (2) Trandolapril had no significant effect on either the elevated or the reduced blood pressure variability occurring during the day
and night, respectively. This may have clinical relevance, because in the setting of systemic hypertension, blood pressure variability is related to organ damage. 7y8It should be emphasized, however, that noninvasive ambulatory blood pressure monitoring may not accurately measure blood pressure variability, because blood pressure readings obtained at 15 or 20 minute intervals miss a large number of blood pressure values and do not allow the resulting standard deviation to closely reflect the actual degree of the blood pressure oscillations.9 This may account for the fact that different effects on blood pressure variability have been reported in ambulatory blood pressure monitoring studies with several antihypertensive drugs? It should also be emphasized that in a study in which blood pressure was measured beat-to-beat, trandolapril was shown to cause a reduction in blood pressure variability? The findings of the present trial may thus underestimate the effect of the drug on this phenomenon. Finally, in the patients randomized to placebo, clinic blood pressure fell whereas 24-hour mean blood pressure remained unchanged. Further, in the patients treated with trandolapril, treatment withdrawal was accompanied by an increase in clinic blood pressure, whereas no blood pressure effect occurred in the placebo group. Thus at variance from clinic blood pressure, 24.hour average blood pressure is devoid of any substantial placebo or time-related effect.12J3In other words, 24-hour blood pressure reflects the absence or presence of active treatment more adequately than clinic blood pressure. This emphasizes the advantages of using the former approach when investigating new antihype rtensive drugs. REFERENCES L Patat A, Sujus A, Le Go A, Granier J. Safety and tolerance of single oral dosesof trandolapril (RU 44570),a new angiotensinconverting enzymeinhibitor. Eur J Clin Phamcol1989;36:17-23. 2. Lenfant B, Mouren M, Boyce T, De Lauture D, Strauch G. Trandolapril: pharmacokineticsof a single oral dose (O.%Img) in male healthy volunteers. J Cardovmc Phmmacul1993, in press. 3. Amer P, Wade A, Engfeldt, Mouren M, StepniewskiJP, Sultan E, Bryce T, Lenfant B, Pharmacakineticsand pharmacodynamicsof trandolapril after repeated administration of 2 mg to young and older patients with mild-tomoderate hypertension.J Cardbvmc Phmnacul1993, in press. 4. Nguyen Cong Due L, Banner HR. Pharmacologiccharacteristicsof trandolapril, a new angiotensin-convertingenzymeinhibitor. Am J Cardd 1992,69: 8. Casadei R, Parati G, Pomidossi G, Groppelli A, Trazzi S,Di Rienzo M, Mancia G. 24hour blood pressure monitoring: evaluation of Spacelabs5300 monitor by comparison with intra-arterial recording in ambulant subjects.J lT&pm.s 1988;6:797-803. 6. Perondi R, Saino A, Tio RA, Pomidossi G, Gregorini L, Ale&o P, Morganti A, Zanchetti A, Mancia G. ACE inhibition attenuatessympatheticcorenary vasrxonstriction in patients with coronary artery disease.Circulation 1992; 85:20#4-2013. 7. Parati G, PomidossiG, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressuremean and variability to severity of target-organ damage in hypertension,J Hyptem 1987;5:93-98. A SYMPOSIUM: HYPERTENSION AND ACE tNHIBtTORS
8. Mancia G, Parati G, AIbini F, Villani A. Circadian bl& pressurevariations and their impact on disease.J Cardtbvax Phamzacol 1988;12(suppI7):SlI-S17. 9. Di Rienzo M, Grassi G, Pedotti A, Mancia G. Continuous vs intermittent blood pressure measurementsin estimating 24-hour average bl& pressure. Hyptierkn 1983;5:2&269. I.0. Mancia G, Casadei R, Mutti E, Trazzi S, Parati G. Ambulatory bl& pressuremonitoring in the evaluation of antihypertensivetreatment.Am J Med 1989;87(suppl68):64ti9S.
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Tt-tE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
1L Dutrey-Dupagne C, Guard A, Ulmann A, Elghozi JL. Effects of the converting enzyme inhibitor trandolapril on short-term variability of bI& pressurein essentialhypertension.Cfin Auton Res 1991;1:30,%307. I2. Gould BA, Mann S, Davies AB, Altman B, Raftery EB. Does placebo lower blood pressure?Lancet 1981;ii:1377-1381. 13. Mutti E, Trazzi S, Omboni S, Parati G, Mancia G. Effect of placebo on 24hour non-invasiveambulatory blood pressure.J H~tien,s 1991;9:361-3@.
OCTOBER 29, 1992
The aim of this study was to evaluate the effects of tranddaprii on P&hour biood ptessure in patients wfth mild-to-moderate essential h-ension, After a washout period of 4 weeks, 42 patientswere randomized to receive 2 mgof t&lolapril once daiiy and 20 to re&ve placebo Ona doumblind fashbn for 6 ww&s. This was foilowedbya-dwashoutperkdof4wwks. At the end of each period, cJink blood pressure was assessed ti 24 hours after the last dose and 24hour ambulatory blood pressurewars measured noninvasiveiy, taking blood pWsure readings every I5 minutes during the dajr and every 20 mlnutesduriilgthe night, TWo patIentswere dropped out before any biowl pressure evaluaAnalysis of ambulatory tion under Matmeut, biowipressurewasperformedin4Spatientswho met the crB@ia for the minimal number of ambw Jatory blood pressure data (2 valu6s per hour durlng the day and 1 value per hour in the night). in tb tranMapril=treated group (n = 41) clinic sysl tolk/dlastoik blood pressures were 1159,s & 2.0/ lO2,4 t 0.&U&6.8 t 2.3/94.8 2 l& and 155.7 t 2.0/99.2 t 0.7 mm Hg in the pretreatment, treatment, and post-treatment s respectiveiy. lhe correqponding values for P&hour mean blood pressure (n = 31) were 239.5 * L9/9L2 t 1.5, l3LO k 2,0/843 t l.2, and 139.7 2 l.Sl90.9 t Ll mm Hg. The difFerewes between the ktir
From the Italian Trandolapril Study Group: Cattedra di Medicina Interna and Clinica Medica Generale, Universita’ degli Studi di Milan0 (G.M., SO., A,R., AZ.); Cattedra di Fisiopatologia Medica, Universita’ degli Studi di Bari (R.D.C., G,R.); Clinica Medica, Universita’ degli Studi di Pavia (R,F., FT.); Clinica Medica, Universita’ degli Studi di Milano (S.L.); Divisione di Cardiologia, Ospedale de1 Ponte, Varese (G.M.); Istitbto di Fisiologia Clinica, Universita’ degli Studi di Pisa (C.P.); Divisione di Medicina, Ospedale Silvestrini, Perugia (C.P., P.V.); Direzione Medica, Roussel Pharma Italia (CM.); Milano, Italy. Address for reprints: G. Mancia, MD, Centro di Fisiologia Ciinica e Ipertensione, via F. Sforza, 35,20122 Milano, Italy. 60D
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
treatment, versus the higher pre- and po&treatmerit, values were all statistkally signlfkant (p ~0.01). The traindoiapril-induced blood prey sure fall was sfmii& during the day and niglrt and statistkaiiy signifkamt also during the last 4 hoursofthe2M&Br monito& pefiod (-6.6 * 0,3 and -5,9 2 0,2 mm Hg far systolk and diastoik blood pressure, resp&l& p ~0.05). Trandolapril did not affect clink heart rate but signifkantiy lowered 24hour heart ratevalues. In the piacebo group the clink (n = 19) and amm b&tory (n = 17) blood pressure and heart rate values obtainedat theendofthe3 periods mre similar, Thus, at the d0w of 2 mg once dally, trandolapril reduce6 blood pressure in mildto-moderate hypertensive patients. This antihypertenslve efkct is manifest throughout the 24 hOUlrs.
(Am J Cardioll992;70:6O~D)
T
randolapril is a newly developed angiotensin converting enqme (ACE) inhibitor characterized by being a prodrug and having a relatively long half-life in plasma? Whether this makes the drug effective in reducing 24-hour blood pressure by once-a-day dosing has not been conclusively established, however. In tHi=present study we have set out to examine this issue. MEFHODS Study pop~latlon:
Our studjr was done on 62 outpatients with mild or mode&e essential hypertension. The subjects (46 males and 16 females) had a mean age of 5 1.3 -+ 1.5 iears (range 29-67 years). They were recruited if their supine and standing diastolic blood pressure values, as assessed in the outpatient clinic, were > 95 mm Hg at the end of the run-in period (see below). Other inclusion criteria were: (1) a body weight within the OCTOBER
29, 1992
normal limits for age, sex, and body surface; (2) no history or evidence of severe target organ damage (transient ischemic attacks, stroke, coronary heart disease, renal insufficiency, congestive heart failure, intermittent claudication, etc.); (3) no evidence of severe diseases in addition to hypertension; and (4) no history of hypersensitivity to ACE inhibitors. Each subject gave his or her consent to the study after explanation of its nature and purpose. After randomization to placebo or active treatment two patients were dropped out before any blood pressure evaluation under treatment. Therefore efficacy analyses were performed on 60 patients. Study design: The study, which was a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, had the following protocol. After an initial medical visit had shown a blood pressure elevation, the subjects were submitted to a run-in period of 4 weeks to allow washout from any previgus treatment and to ensure diagnosis of the essential nature of their hypertension. The subjects were randomly assigned in a 2:l ratio to trandolapril 2 mg once daily or to placebo for 6 weeks. The dose of trandolapril or ‘placebo was administered at about 9 A.M. At the end of the 6 weeks, treatment was withdrawn and the patients were followed for another 4 weeks. Clinkal assessments Before treatment, at the end of treatment, and after the treatment periods all patients had a physical examination, a 12-lead resting ECG, and biochemical, hematologic and urinary laboratory examinations. Adverse events were recorded at each visit upon enquiry from the investigator. At the end of each period, systolic and diastolic blood pressures were measured 3 times by sphygmomanometry (1st and 5th Korotkoff sounds, respectively), 10 minutes after assumption of the supine and 1 minute after assumption of the upright posture. The average of the last 2 readings in the supine position was taken as the reference clinic value. The concomitant heart rate values were assessed by the palpatory method over 1 minute. The measurements were obtained between 8 and 9 A.M., which for the treatment period corresponded to about 24 hours after dosing. Ambulatory blood pressure monitoring: Ambulatory blood pressure and heart rate were monitored electronically (Spacelabs 5200; Spacelabs Inc., Redmond, Washington, USA). The monitoring started between 9 and 10 A.M., i.e., after completion of the clinic blood pressure measurements and, during the treatment period, immediately after the ingestion of the active drug or
TABLE I Demographic Characteristics of the Patients Placebo In = 20) Sex (male/female) Age (years)
Trandolapri I (n = 42)
1515
31/11
51.1 2 1.7
51.4 +: 1.5
Weight (kg)
77.6 2 2.8
73.4 2 1.6
Height (cm)
169.0 + 1.4
170.0 * 1.2
Data are means 2 SE.
placebo. The ambulatory blood pressure monitoring device was set to obtain one measurement every 15 minutes between 6 A.M. and 12 P.M. and one measurement every 20 minutes between 12 P.M. and 6 A.M. A recording was regarded as satisfactory if at least two readings per hour during the day and one reading per hour during the night ( i.e., from midnight to 6 A.M.) were acceptable according to previously established criteria? St&is&al methods: Ambulatory blood pressure data were analyzed as (1) 24-hour average systolic/diastolic blood pressure, mean arterial pressure, and heart rate; (2) daytime (6 A.M. to midnight) and night-time (midnight to 6 A.M.) average blued pressures and heart rates; and (3) hourly average systolic/diastolic blood pressure, mean arterial pressure, and heart rate. The analysis included the day-time and night-time mean arterial pressure and heart rate standard deviations of the mean values, which were taken as indices of blood pressure and heart rate variability. Data from single subjects were averaged to obtain the means (-+ SE) of the group. A paired Student’s l test was used to locate the differences between data obtained during treatment and before or after treatment. The statistical significance of the differences in the average hourly values was assessed by 2-way analysis of variance. A p <0.05 was taken as the minimum level of statistical significance throughout the study. RESULTS Demographic and medical history characteristics: Table I shows the demographic characteristics of the patients randumly treated with trandolapril or placebo. All data were comparable between the two groups. As shown in Table II, in Clinic blood pressure: the group randomized to placebo, supine clinic systolic/diastolic blood pressures were not significantly different at the end of the run-in or baseline period, the treatment period, or the final treatment withdrawal period. In contrast, in the group randomized to trandolapril both systolic and diastolic A SYMPOSIUM:
HYPERTENSION
AND ACE INHIBITORS
TABLE II Clinic Systolic/Diastolic Mood Pressure and Heart Rate Values at Run-in or Baseline, After Treatment with Placebo or Trandolapril, and After Washout After Baseline
Treatment
158.0 2 3.1 102.3 2 1,l 73.9 2 1.9
151.7 k 3.2 101.1 2 0.9
158.5 L 1.9
72.5 + 1.8
72.8 ZL 1.7
(n = 41) SBP (mm Hg)
159.8 2 2.0
DBP (mm Hg)
102.4 -t 0.8
146.8 2 2.3* 94.8 2 Ll*
155.7 i 2.0 99.2 k 0.7
72.0 zt 1.2
72.1 -+ 0.8
Treatment
Ptacebo (n = 19) SBP (mm Hg)
DBP (mm Hg) HR (bpm)
103.0 -+ LO
Trandolaprit
72.1 2 1.3
t-W @pm)
Data are shown as means L SE. Asterisks refer to statistical significance of differences between baseline and treatment values (*p < 0.01). bpm = beats per minute; SBP, DBP = systolic, diastolic blood pressure; HR = heart rate.
blood pressures decreased significantly in the treatment as compared to the baseline period, a significant increase being observed following treatment mmklg
SBP
withdrawal. Heart rate was not significantly different throughout the study in either the placebo or the trandolapril-treated group, Similar results were obtained when considering blood pressure and heart rate values taken in the upright position (data not shown). Ambulatory blo@ pressure: Twelve patients did not meet the criteria for the minimal number of ambulatory blood pressure data (see Methods). Thus, the analysiswas carried out in 48 patients, 31 randomized to trandolapril and 17 to placebo. Figure 1 shows that in the placebo group, 24-hour averagesystolic/diastolic blood pressuresand mean arterial pressure obtained at the end of the baseline period, the treatment period, and the posttreatment periods were superimposable. In contrast, in the trandolapril group all 24-hour average blood pressures were significantly less during the treatment period compared with the run-in and DBP
mmHg
160
110 1
150
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mu
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701
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40Baseline
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After treatment h-31)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
Treatment
After treatment
meansfSE
OCTOBER 29, 1992
*
p<0.05
**
p4.01
MAP
HR Trandolapril (n=31)
Placebo (n=17)
mmHg 120 -
Placebo (n=l7)
bPm 90 -
Trandolapril In=31)
3
80 -
I Night
1 Day
I
r Nighi
w
50 -
I Day
I Night
I Day
I Night
FIGURE 2. Day-and nlg@Mime me&n artwlal pressure (MAP) and heart rate (HR) values at basehm (qmm chh) after treatment (solid ckks) with placdm w tramdolapril. Dash am Mown as mmms 2 SE. Astddc8~tathestatb tkals@nlfkanceafthedWfemmcm betweentlm2cmdRlam
Placebo mmHg
Trando ilapril (n=31)
(n=17)
SBP
170
mmHg 170
160
160
150
150
140
140
130
130
120
120
110
I10
mmHg
and
SBP
mmHg
DBP
120
120
110
110
100
100
DBP
* ri
90 80 70
70
60
60 10
14
18
22
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6
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FlGuRE3. Houriysy~WkbImdpmssure (SRP)anddhstoHc after~(solld~)~plaoeboort~nddaprl.Dataaredwmrazrmeans~8E. tkal8l@lmcanceafthe cMhencmInt~last4hwrs m
10
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AND ACE INHlBITORS
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h=17)
Trandolapril
MAP
(n=3 1)
MAP
1
80 1
100
100
60
60
10 o----o
14
18
Baseline
22 -
2
6
Treatment
10 means&SE
14
IO
18
22
2
6
10 hours
* pco.05
FlWRE 4. Hourly mean attaial pressure (MAP) and heart rate (RR) v&es at basdb(opend~)and~treatnrent (sdiddmks)wRhpkceboortmmldaprll. Data areshown ammans *SE.Forhrtherexpla~seeFlgure3.
MAP
HR Trandolapril (n=31)
Placebo (n=17)
mmHg 14
Placebo (n=17)
bPm 13
Trandolapril (n=31)
T
i IIc 9,
6
-. P
7-
8
1
r
I
I
Day
Night
Day
Night
5'
I Day
meansiS
840
TI-IE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
OCTOBER 29, 1992
1 Night
I
1
Day
Night
post-treatment periods. In contrast to placebo, trandolapril caused a significant reduction of both the elevated day-time and the reduced night-time blood pressure values (Figure 2). The trandolaprildependent reduction in blood pressure was evident during almost every hour during 24 hours and significant also for the last 4 hours of the 24-hour monitoring period (Figures 3 and 4). Average 24-hour, day-time, night-time, and hourly heart rates were not significantly affected by placebo and only slightly, although significantly, reduced by trandolapril (Figures l-4). Blood pressure and heart rate variabilities were less during the night than during the day-time. In both instances placebo and trandolapril had no significant effect (Figure 5). safety: After randomization to placebo or trandolapri12 patients dropped out: one patient had a stroke during placebo treatment while the second withdrew for reasons not related to the study treatment. The laboratory examinations and the ECG patterns were not significantly modified by treatment compared with the pretreatment values. In the trandolapril group, 3 patients complained of symptoms that were not considered to be related to the study drug (headache, gastric pain, and tinnitus). In the placebo group, one patient reported flushing and conjunctival hyperemia.
In our hypertensive subjects, once-a-day administration of t randolapril at the dose of 2 mg caused a signi .ficant reduction in 24-hour average blood pressure values compared with the pre- and posttreatment values. The reduction involved both systolic and diastolic blood pressures. It was evident with respect to the elevated day-time and the reduced night-time blood pressures, and it was manifest for the blood pressure values occurring in the last few hours of the 24-hour dosing interval. This permits the conclusion that at the dose employed, once-daily administration of trandolapril is therapeutically effective over 24 hours. Several other data of our study deserve to be mentioned: (1) In our patients, trandolapril caused a significant although small reduction in 24-hour mean heart rate. This is not an invariable finding for antihypertensive treatment with ACE inhibitors. However, in some studies ACE inhibitors have been reported to potentiate vagal cardiac drive, which would account for the slight bradycardia we observed? (2) Trandolapril had no significant effect on either the elevated or the reduced blood pressure variability occurring during the day
and night, respectively. This may have clinical relevance, because in the setting of systemic hypertension, blood pressure variability is related to organ damage. 7y8It should be emphasized, however, that noninvasive ambulatory blood pressure monitoring may not accurately measure blood pressure variability, because blood pressure readings obtained at 15 or 20 minute intervals miss a large number of blood pressure values and do not allow the resulting standard deviation to closely reflect the actual degree of the blood pressure oscillations.9 This may account for the fact that different effects on blood pressure variability have been reported in ambulatory blood pressure monitoring studies with several antihypertensive drugs? It should also be emphasized that in a study in which blood pressure was measured beat-to-beat, trandolapril was shown to cause a reduction in blood pressure variability? The findings of the present trial may thus underestimate the effect of the drug on this phenomenon. Finally, in the patients randomized to placebo, clinic blood pressure fell whereas 24-hour mean blood pressure remained unchanged. Further, in the patients treated with trandolapril, treatment withdrawal was accompanied by an increase in clinic blood pressure, whereas no blood pressure effect occurred in the placebo group. Thus at variance from clinic blood pressure, 24.hour average blood pressure is devoid of any substantial placebo or time-related effect.12J3In other words, 24-hour blood pressure reflects the absence or presence of active treatment more adequately than clinic blood pressure. This emphasizes the advantages of using the former approach when investigating new antihype rtensive drugs. REFERENCES L Patat A, Sujus A, Le Go A, Granier J. Safety and tolerance of single oral dosesof trandolapril (RU 44570),a new angiotensinconverting enzymeinhibitor. Eur J Clin Phamcol1989;36:17-23. 2. Lenfant B, Mouren M, Boyce T, De Lauture D, Strauch G. Trandolapril: pharmacokineticsof a single oral dose (O.%Img) in male healthy volunteers. J Cardovmc Phmmacul1993, in press. 3. Amer P, Wade A, Engfeldt, Mouren M, StepniewskiJP, Sultan E, Bryce T, Lenfant B, Pharmacakineticsand pharmacodynamicsof trandolapril after repeated administration of 2 mg to young and older patients with mild-tomoderate hypertension.J Cardbvmc Phmnacul1993, in press. 4. Nguyen Cong Due L, Banner HR. Pharmacologiccharacteristicsof trandolapril, a new angiotensin-convertingenzymeinhibitor. Am J Cardd 1992,69: 8. Casadei R, Parati G, Pomidossi G, Groppelli A, Trazzi S,Di Rienzo M, Mancia G. 24hour blood pressure monitoring: evaluation of Spacelabs5300 monitor by comparison with intra-arterial recording in ambulant subjects.J lT&pm.s 1988;6:797-803. 6. Perondi R, Saino A, Tio RA, Pomidossi G, Gregorini L, Ale&o P, Morganti A, Zanchetti A, Mancia G. ACE inhibition attenuatessympatheticcorenary vasrxonstriction in patients with coronary artery disease.Circulation 1992; 85:20#4-2013. 7. Parati G, PomidossiG, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressuremean and variability to severity of target-organ damage in hypertension,J Hyptem 1987;5:93-98. A SYMPOSIUM: HYPERTENSION AND ACE tNHIBtTORS
8. Mancia G, Parati G, AIbini F, Villani A. Circadian bl& pressurevariations and their impact on disease.J Cardtbvax Phamzacol 1988;12(suppI7):SlI-S17. 9. Di Rienzo M, Grassi G, Pedotti A, Mancia G. Continuous vs intermittent blood pressure measurementsin estimating 24-hour average bl& pressure. Hyptierkn 1983;5:2&269. I.0. Mancia G, Casadei R, Mutti E, Trazzi S, Parati G. Ambulatory bl& pressuremonitoring in the evaluation of antihypertensivetreatment.Am J Med 1989;87(suppl68):64ti9S.
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1L Dutrey-Dupagne C, Guard A, Ulmann A, Elghozi JL. Effects of the converting enzyme inhibitor trandolapril on short-term variability of bI& pressurein essentialhypertension.Cfin Auton Res 1991;1:30,%307. I2. Gould BA, Mann S, Davies AB, Altman B, Raftery EB. Does placebo lower blood pressure?Lancet 1981;ii:1377-1381. 13. Mutti E, Trazzi S, Omboni S, Parati G, Mancia G. Effect of placebo on 24hour non-invasiveambulatory blood pressure.J H~tien,s 1991;9:361-3@.
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