Permanent blood pressure control over the 24 h by trandolapril

AJH 1995; 8:715-745

Permanent Blood Pressure Control Over the 24 h by Trandolapril Stefano Omboni, Antonella Ravogli, Ales5andra Villani, and Giuseppe Manda Noninvasive ambulatory blood pressure monitoring (ABPM) has proved to be an innovative tool for the assessment of the efficacy of antihypertensive drugs. It enables evaluation of the magnitude of the drug-related blood pressure fall and also of the duration of this effect throughout 24 h. Moreover, ambulatory blood pressures have advantages compared to office blood pressure: they are not affected by the white coat effect occurring at the time of the doctor's visit, are devoid of a placebo effect, are more reproducible than occasional clinic measurements, and may yield important information on the prognosis of hypertensive patients. Ambulatory blood pressure recordings were used to test the antihypertensive effect of a novel angiotensin converting enzyme, trandolapril, in 62 mild to moderate essential hypertensive outpatients. After a 4 week wash-out, period, patients were randomized to 2 mg trandolapril or placebo

for 6 weeks. A 4-week wash-out period was scheduled at the end of the treatment period. Ambulatory blood pressure recordings were performed at the end of each period, starting in the morning. Trandolapril (n = 31) significantly reduced 24 h systolic and diastolic blood pressure as compared to pre- and posttreatment periods and to placebo (n = 17). The reduction involved both the daytime and nighttime blood pressure values and was evident also in the last hours of the recording, the trough-topeak ratio being 0.6 for systolic and 0.7 for diastolic blood pressure. Thus, trandolapril at a dose of 2 mg once daily is an effective long-lasting antihypertensive drug. Am J Hypertens 1995;8:715-745 Ambulatory blood pressure measurement, peak to trough ratio, trandolapril, angiotensin converting enzyme inhibitor, essential hypertension.

KEY WORDS:

mbulatory blood pressure measurement zyme (ACE) inhibitor (trandolapril)4 has been tested, (ABPM) is not yet widely used in clinical and finally the difference between the 24 h blood practice because of the relative lack of con- pressure effects of trandolapril and those of other clusive data on the range of ABPM blood ACE inhibitors. pressure value and the lack of conclusive results on ABPM AND DRUG TRIALS the prognostic value of ABPM compared to casual measurement. Conversely, this technique is routinely Several investigators believe ABPM is an important employed to test the effects of new antihypertensive tool to assess the efficacy of new antihypertensive drugs on daily life blood pressure. l -3 In this paper, drugs and to indicate whether they can be adminiswe will discuss the potential advantages of ABPM for tered once daily. The 24-h blood pressure seems to as its value is antihypertensive drug studies, the results obtained in reflect patient's actual blood pressure 5 not affected by the white coat effect. The white coat a study in which a novel angiotensin converting eneffect pressor response can lead both to a false diagnosis of hypertension and to an underestimation of the efficacy of drug treatment. ~rom t~e Istituto Scientifico Ospedale San Luca, Centro AuxoABPM allows the assessment of the effectiveness of logtco Italiano, Milan (SO, AV), and Cattedra di Medicina Intema Universit~ di Milano, Ospedale San Gerardo Dei Tintori Mo~ the antihypertensive regimen not only over 24 h but (AR, GM), Italy. ' also over various subperiods within the 24 h (eg, dayAddr~ss c~rrespondence and reprint requests to Dr. Stefano p~bom, Istituto Scientifico Ospedale San Luca, Centro Auxo- time and nighttime). This allows a better evaluation ogtco Italiano, Via Spagnoletto 3, 20149 Milano, Italy. also of the duration of the antihypertensive effect and

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«:> 1995 by the American Journal of Hypertension, Ltd.

0895-7061/95/$9.50

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AJH-OCTOBER 1995-VOL. 8, NO. 10, PART 2

TABLE 1. EFFECT OF 4 WEEKS OF PLACEBO ADMINISTRATION ON CLINIC AND AMBULATORY SYSTOLIC (SBP) AND DIASTOLIC BLOOD PRESSURE (DBP) IN 63 ESSENTIAL HYPERTENSIVE OUTPATIENTS

SBP Baseline Placebo DBP Baseline Placebo

Average Daytime (mm Hg)

Clinic (mm Hg)

Average 24 h (mm Hg)

160.1 ± 1.9 153.1 ± 2.0**

140.2 ± 1.6 138.8 ± 1.7

143.4 141.6

102.2 ::t 0.7 96.0 ± 1.1**

87.9 ::t 1.1 87.4 ± 1.2

90.4 89.2

::t ::t ::t ::t

Average Nighttime (mm Hg)

1.6 1.7

127.2 ± 1.8 128.3 ± 1.9

1.1 1.2

77.6 ± 1.2 78.2 ± 1.4

Data are shown as means ± SEM. The asterisks refer to the statistical significance (P < .01) of the changes induced by placebo (modified from Manda et al 17 with permission).

the occurrence of hypotensive episodes within the dosing interval. At variance from office blood pressure, 24-h average blood pressure is largely devoid of the blood pressure reduction caused by treatment with placebo (Table 1).6,7 Also, it has been shown that when blood pressure is measured weeks apart the average 24 h value is more reproducible than the office value. 8-10 Finally, ABPM provides information on 24 h blood pressure variability. This is of clinical importance because both 24 h blood pressure and blood pressure variability are more closely related to the end organ damage of hypertension than casual blood pressure measurement,1 ,12 This suggests that ABPM values are prognostically more important than office blood pressure, although final confirmation of this will have to await longitudinal studies currently in progress. 13-15 Recently, however, a follow-up study performed in 73 essential hypertensive patients reexamined after 7 years of treatment has shown that the initial 24 h blood pressure variability was capable of predicting the cardiovascular complications of hypertension. 16 ANTIHYPERTENSIVE EFFECT OF TRANOOLAPRIL ON AMBULATORY BLOOD PRESSURES Methods We assessed the effect of once-a-day trandolapril versus placebo on ABPM in 62 mild to moderate essential hypertensive outpatients (mean age ± SO, 50.7 ± 8.6). After an initial 4 week wash-out period, patients were randomly allocated to receive trandolapril at a dose of 2 mg once daily (n = 42) or placebo (n = 20) for a period of 6 weeks. Active drug or placebo control were given at approximately 9 AM. The 6 weeks of treatment were followed by a washout period of 4 weeks. 17 At the end of each 24 h period blood pressure was measured in ambulatory conditions by an oscillometric device (SpaceLabs 90202 or 90207, SpaceLabs Inc., Redmond, WA) programmed to obtain blood pressure readings at 15 min intervals during the day (from 6 AM to midnight) and at 20 min intervals during the night (from midnight to 6 AM). Each recording started

at 9 or 10 AM immediately after placebo or drug intake. ABPM data were analyzed in the 48 patients in whom the 24 h recording was regarded as qualitatively acceptable. For each recording, average 24 h, daytime, nighttime, and hourly mean values were obtained separately for systolic blood pressure and heart rate. Peak and trough blood pressure changes were also considered separately for the active treat-

24 hours

mmHg

155

....

Q)

~

135

a:

115

en

Q)

'0

g

al

95

** ** 75..L--------------bpm

**

Baseline

Treatment

After Treatment

FIGURE 1. The 24 h systolic and diastolic blood pressure and heart rate values obtained at baseline, during treatment with placebo (open bars), or trandolapril (striped bars), and after a final 4 week wash-out period. Data are shown as means ± SEM. Asterisks refer to the statistical significane of the difference between baseline and treatment and between posttreatment and treatment: ** P < .01, * P < .05. Modified from Mancia et al 17 with permission.

TRANDOLAPRIL FOR 24 H BP CONTROL

ATH-OCTOBER 1995-VOL. 8, NO. 10, PART 2

PIIClbo

TrlndotllpriJ In-31)

In-171

SBP

mmHg

SBP

mmHg

170

170

leo

1&0

150

150

140

140

130

130

120

120

110

110

mmHg

mmHg

DBP

120

120

110

110

100

100

FIGURE 2. Hourly average systolic blood pressure (SBP) and diastolic blood pressure (DBP) values at baseline (open circles, dashed lines) and after 6 weeks of treatment (full circles, continous lines) with placebo or trandolapril. Data are shown as means ± SEM.

DBP

gO

gO

eo

eo

70

10 &0

73S

10

14

18

22

10

60

10

1.

18

ment and the placebo group. Peak changes were computed by averaging the blood pressure values obtained during treatment between the 2nd and the 6th hour after drug intake and subtracting the resulting value from the corresponding value obtained during the initial wash-out phase. Trough changes were computed in the same fashion by considering the last 4 h of the recording. Trough-to-peak ratios were obtained in the active treatment group by dividing the average trough change by the average peak change, expressed as a percentage. Comparisons between the different timepoints were made by paired Student's t test. Results As shown in Figure 1, in contrast to placebo, trandolapril significantly reduced 24 h average systolic and diastolic blood pressure as compared to the baseline and post-treatment period. Compared to baseline and posttreatment period, trandolapril also significantly reduced the daytime average blood pressure (9.0 ± 1.9 mm Hg systolic and 7.6 ± 1.1 nun Hg diastolic blood pressure; P < .01) and nighttime average blood pressure (5.3 ± 2.4 and 4.3 ± 1.4 mm Hg; p < .01). Twenty-four hour average heart rate was also slightly reduced by the drug. In contrast to placebo, trandolapril reduced blood pressure also for every hour of the 24 h monitoring period (Figure 2). The antihypertensive effect was greater in the first than in the last hours after drug intake, for both the peak and trough blood pressure. Placebo had a small lowering effect on systolic blood pressure at peak (p < .01), but did not significantly affect trough blood pressure (Figure 3).

22

10 houri

DISCUSSION: TRANDOLAPRIL VERSUS OTHER ACE INHIBITORS Table 2 shows the effects on 24 h ABPM of 2 mg trandolapril and two other ACE inhibitors (20 mg

-

0)

::I:

E E

5

2nd-6th hour

20th-24th hour

0 -5

0-

m -10

(f)

**

-15

-

C)

J:

E

-

E

5

*

0 -5

0CD

c -10

**

-15 FIGURE 3. Average systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes at peak (between the 2nd and the 6th h after drug intake) and at trough (from the 20th to the 24th h) in the group of patients treated with placebo (open bars) or trandolapril (striped bars). Data are shown as means ± SEM. Asterisks refer to the statistical significance versus baseline: .... P <

.01, .. P

< .05.

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TABLE 2. AVERAGE 24 H AND PEAK AND TROUGH SYSTOLIC (SBP) AND DIASTOLIC BLOOD PRESSURE (DBP) CHANGES AFTER TREATMENT WITH TRANDOLAPRIL (2 MG ONCE DAILY, N = 31), ENALAPRIL (20 MG ONCE DAILY, N = 49) OR FOSINOPRIL (20 MG ONCE DAILY, N = 39). TROUGH-TO-PEAK RATIOS ARE ALSO SHOWN SEPARATELY FOR SYSTOLIC AND DIASTOLIC BLOOD PRESSURE (TIP)

Drug

n

24 h SBP (mmHgl

24 h DBP (mmHgl

Peak SBP (mmHgl

Trough SBP (mm Hgl

TIP

Peak DBP (rom Hg)

Trough DBP (mm Hgl

TIP

Trandolapril Enalapril Fosinopril

31 49 39

-8.4:t 1.9 -9.5 :t 1.9 -11.8 ± 1.3

-7.0 :t 1.0 -7.0 ± 1.3 -9.0 ± 0.9

-10.3 :t 2.1 -17.0 ± 2.5 -13.7 :t 1.7

-6.6 :t 2.5 -11.0 ± 2.0 -8.0::t 1.9

0.6 0.7 0.6

-8.5 :t 1.3 -11.0 ± 1.7 -1O.3:t 1.1

-5.9:t 1.4 -7.6 ± 1.3 -5.3::t 1.3

0.7 0.7 0.5

Data refer to three different studies and are shown as means :t SEM. Changes after treatment were always statistically significant, while no differena was obsenJed between changes induced by trandolapril and by the other two ACE inhibitors (Data from Mancia et a117•1B and Omboni et al19 with permission).

enalapril and 20 mg fosinopril) studied in our laboratories. 18,19 The drugs were administered once daily (between 9 and 10 AM) for a period of 6 to 8 weeks following a wash-out period of 3 to 4 weeks. There was no significant difference among the falls in 24 h average blood pressure induced by trandolapril, enalapril, and fosinopril. This was the case for both systolic and diastolic blood pressure, although visually the reduction in systolic blood pressure caused by the three drugs appeared to differ more than the reduction in diastolic blood pressure. The peak blood pressure effect also appeared to be different among the three drugs, but the trough-ta-peak ratios were similar, suggesting a long duration for the antihypertensive effect. CONCLUSIONS Trandolapril at a dose of 2 mg once daily reduced 24 h ambulatory blood pressure in mild to moderate essential hypertensives. As compared to the pre- and posttreatment periods and placebo controls, the reduction involved systolic and diastolic blood pressures and elevated daytime and reduced nighttime blood pressure values. Furthermore, a significant reduction in blood pressure was evident also in the last 4 h after drug administration. The trough-to-peak ratio was 0.6 for systolic and 0.7 for diastolic blood pressure. Finally, no significant difference was observed between the effect of trandolapril on average 24 h blood pressure and trough-to-peak ratio. REFERENCES 1.

2. 3. 4. 5.

Mancia G, Di Rienzo M, Parati G: ABPM use in hypertension research and clinical practice. Hypertension 1993;21:510-524. Mancia G, Casadei R, Mutti E, et al: ABPM in the evaluation of antihypertensive treatment. Am J Med 1989;87(suppl 6B):645-695. Omboni 5, Ravogli A, Manda G: ABPM and antihypertensive treatment. J Human Hypertens 1992;6(suppl 2):59-513. Conen H, Brunner HR: Pharmacologic profile of trandolapril, a new angiotensin converting enzyme inhibitor. Am Heart J 1993;125:1525-1531. Mancia G, Bertinieri G, Crassi C, et al: Effects of blood pressure measurements by the doctor on patient's blood pressure and heart rate. Lancet 1983;ii:695-698.

6. 7. 8.

9.

10.

11. 12.

Could BA, Mann 5, Davies AB, et al: Does placebo lower blood pressure? Lancet 1981;ii:1377-1381. Manda C, Omboni 5, Parati C, et al: Lack of placebo effect on ambulatory blood pressure. Am J Hypertens 1995;8:311-315. Conway J, Johnston J, Coats A, et al: The use of ABPM to improve the accuracy and reduce the numbers of subjects in clinical trial of antihypertensive agents. J Hypertens 1988;6:111-116. Trazzi 5, Mutti E, Frattola A, et al: Reproducibility of noninvasive and intra-arterial blood pressure monitoring: implications for studies on antihypertensive treatment. J Hypertens 1991;9:115-119. Manda G, Omboni S, Parati G, et al: Limited reproducibility of hourly blood pressure values obtained by ABPM: implications for studies on antihypertensive drugs. J Hypertens 1992;10:1531-1535. Pedoff 5, Sokolow M, Cowan R: The prognostic value of ambulatory blood pressure. JAMA 1983;249:2792-2798. Parati G, Pomidossi G, Albini F, et al: Relationship of 24 h blood pressure mean and variability to severity of target organ damage in hypertension. J Hypertens 1987;5:9~98.

13. Clement DL, on behalf of the Steering Committee: Home versus office monitoring of blood pressure: a European multicentre study of high blood pressure. J Hypertens 1989;7(suppl 3):549-551. 14. Amery A, Birkenhager W, Bulpitt q, et al: 5ysteur: a multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organisation. Aging 1991;3:287-302. 15. Mancia G, Zanchetti A, Agabiti-Rosei E, et al: Prognostic value of ambulatory blood pressure. The sample study. High Blood Pressure 1992;1:297-301. 16. Frattola A, Parati G, Guspidi C, et al: Prognostic value of 24-hour blood pressure variability. J Hypertens 1993;1l:1l3~1137.

17. Mancia G, De Cesaris R, Fogari R, et al: Evaluation of the antihypertensive effect of once-a-day trandolapril by 24-hour ABPM. Am J CardioI1992;70:60D--66D. 18. Mancia G, Bazzato G, 5canferla F, et al: 24-Hour antihypertensive effect of verapamil sustained release 240 mg versus nitrendipine and enalapril in essential hypertension. High Blood Pressure 1993;2:241-248. 19. Omboni 5, Ravogli A, Fogari R, et al: Effects of oncea-day fosinopril on 24-hour ambulatory blood pressure in mild and moderate essential hypertension. High Blood Pressure (in press).