24-hour blood pressure control with ramipril: comparison of once-daily morning and evening administration

24-hour blood pressure control with ramipril: comparison of once-daily morning and evening administration

CURRENT THERAPEUTIC RESEARCH ~ VOL. 56, NO. 12, DECEMBER 1995 24-HOUR BLOOD PRESSURE CONTROL WITH RAMIPRIL: C O M P A R I S O N OF O N C E - D A I L ...

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CURRENT THERAPEUTIC RESEARCH ~ VOL. 56, NO. 12, DECEMBER 1995

24-HOUR BLOOD PRESSURE CONTROL WITH RAMIPRIL: C O M P A R I S O N OF O N C E - D A I L Y M O R N I N G A N D EVENING ADMINISTRATION D I R K P E T R U S M Y B U R G H , 1 MATTI VERHO, 2 J O A N H. BOTES, 3 T H E O D O R U S P H I L I P P U S ERASMUS, 4 A N D H E R M A N U S G E R H A R D U S L U U S 4

1Department of Cardiology, University of Pretoria, and Department of Cardiology, Institute of Aviation Medicine, Pretoria, Republic of South Africa, 2Hoechst AG, Frankfurt, Germany, 3Noristan Ltd., Pretoria, and 4Division of Biometry, FARMOVS Research Centre for Clinical Pharmacology and Drug Development, University of the Orange Free State, Bloemfontein, Republic of South Africa.

ABSTRACT

The antihypertensive efficacy of ramipril administered once daily, either in the morning or in the evening, was compared in an open, randomized, crossover trial in 33 patients with mild-to-moderate essential hypertension. A 24-hour ambulatory blood pressure monitoring device was used. A significant (P < 0.05) decrease from baseline blood pressure values was observed with both dosing regimens. A slight, but discernible difference in the effectiveness of the two regimens was observed in the mean daytime (10 AM to 8 PM) blood pressure for both diastolic and systolic values. The mean daytime blood pressure decreased from 145.8/95.4 mm Hg to 139.7/89.7 mm Hg following morning administration and to 142.3/91.8 mm Hg following evening administration. The mean nighttime (midnight to 6 AM) blood pressure was slightly lower in patients receiving ramipril in the evening than in those receiving the drug in the morning. The mean blood pressure during the critical time (4 AM to 8 AM) Was similar for the two dosing regimens. Ramipril proved to be an efficacious antihypertensive treatment with once-daily dosing and provided as good, or slightly better, blood pressure control when administered in the morning than in the evening. INTRODUCTION

T h e t r e a t m e n t of e s s e n t i a l h y p e r t e n s i o n is a i m e d a t l o w e r i n g blood press u r e c o n s i s t e n t l y a n d r e d u c i n g excessive p e a k s in p r e s s u r e , w h i c h m a y pose a n a d d i t i o n a l c a r d i o v a s c u l a r risk. A m b u l a t o r y blood p r e s s u r e m o n i t o r i n g (ABPM) is a v a l u a b l e t e c h n i q u e for e v a l u a t i n g a n t i h y p e r t e n s i v e efficacy in p a t i e n t s s e e n in clinical practice, as well as in a r e s e a r c h setting. 1 T h i s t y p e of m o n i t o r i n g h a s s e v e r a l a d v a n t a g e s o v e r t r a d i t i o n a l cuff Address correspondence to: Prof. DP Myburgh, Department of Cardiology, Private Bag X169, Pretoria, 0001 Republic of South Africa. Receivedfor publication on September29, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1298

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D. P. MYBURGH ET AL.

blood pressure measurement: it allows the assessment of duration of action of antihypertensive agents, it makes it possible to exclude from pharmacotherapy those patients who have white coat hypertension, and finally, it allows the evaluation of the consistency of the antihypertensive effect of new drugs. 2 Angiotensin-converting enzyme (ACE) inhibitors are widely used for the treatment of essential hypertension.3 There is, however, no general agreement concerning the time of day when ACE inhibitors should be given. Furthermore, the duration of action of some ACE inhibitors is problematic. For the short-acting ACE inhibitor captopril, contradictory resuits have been reported. In some studies, a decrease in antihypertensive efficacy was seen prior to the end of the dosing period, 4'5 while in others 24-hour efficacy with once-daily administration was demonstrated, e'7 For longer-acting ACE inhibitors, the efficacy of once-daily administration has been acceptable, s-ll By utilizing ABPM, the antihypertensive effect of a drug can be evaluated over the entire 24-hour period, making it possible to determine which dosing regimen (morning or evening administration) is more effective in reducing blood pressure. Ramipril is an ACE inhibitor with a prolonged duration of action. 9'1°'12'13 The primary aim of the present study was to determine the difference, if any, in antihypertensive potency of ramipril over 24 hours when administered as a single daily dose, either at 8 AM or at 8 PM. P A T I E N T S AND M E T H O D S

Thirty-nine patients (35 men, 4 women) with mild-to-moderate essential hypertension, aged 24 to 73 years (mean age, 49 years), entered the study after clinical examination and laboratory tests had been performed. Patients with an average sitting diastolic blood pressure (DBP) I>95 mm Hg and <114 mm Hg were enrolled. The average blood pressure was calculated from three readings taken at 3-minute intervals on at least two separate visits. The study conformed to the recommendations for clinical trials specified in the Declaration of Helsinki, and was approved by the local ethics committee. All patients gave their informed consent. After a 4-week run-in phase, a baseline 24-hour ABPM profile was obtained. Thereafter, the patients were randomly allocated to one of two treatment groups: ramipril 2.5 mg at 8 AM or ramipril 2.5 mg at 8 PM. After 4 weeks of treatment, only three patients had not responded sufficiently to the 2.5-mg dose; their dose of ramipril was increased to 5 mg. These three patients were not included in the analysis. (Three further

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B L O O D PRESSURE C O N T R O L W I T H RAMIPRIL

patients who were withdrawn because of adverse events were also excluded from the analysis.) The criteria for nonresponse were a DBP >95 mm Hg after 4 weeks of t r e a t m e n t or a decrease in DBP of <10 mm Hg, as compared with baseline values. In patients with an adequate decrease in blood pressure, 24-hour ABPM was performed, whereafter the patients were crossed over to the alternate t r e a t m e n t group (morning or evening administration). Patients were treated with ramipril 2.5 mg for 4 more weeks, after which the final 24-hour ABPM was performed, using the same ABPM device throughout the study. All patients were instructed to take the ramipril within the same 3-hour period (8 AM to 11 AM or 8 PM to 11 PM) daily. Also, all patients began and ended each of their 24-hour ABPM procedures at the same time of the day (-+60 min), and each monitoring procedure had to cover a mini m u m of 24 hours. Blood pressure was always measured on the same arm for each patient with a 24-hour ABPM device (model 90207, Spacelabs Inc., Redmond, Washington). The location of the cuff and microphone was marked in pencil on the patient's arm, and the patient was instructed to m a i n t a i n the cuff in the marked position. With the aid of a Y-piece, the ABPM reading was verified with the auscultatory Riva-Rocci method; the difference between the two readings had to be less t h a n 5 mm Hg. The following efficacy variables were calculated from the measurements t a k e n during the 24-hour ABPM for both systolic blood pressure (SBP) and DBP: (1) average 24-hour blood pressure; (2) average daytime (10 AM to 8 PM) blood pressure; (3) average nighttime (midnight to 6 AM) blood pressure; and (4) average critical-time (4 AM to 8 AM) blood pressure. Each variable was calculated as the area under the blood pressure versus time curve (AUC) divided by the period of time over which the AUC was calculated. Additional efficacy variables were calculated for the duration of blood pressure control as follows: (1) the amount of time during the 24-hour period with DBP <90 mm Hg and SBP <140 mm Hg; (2) the amount of time during the 10-hour daytime period (10 AM to 8 PM) with DBP <90 m m Hg and SBP <140 mm Hg; and (3) the amount of time during the 6-hour nighttime period (midnight to 6 AM) with DBP <80 mm Hg and SBP <120 mm Hg. The two t r e a t m e n t regimens (morning versus evening administration) were compared with reference to the efficacy variables using analysis of variance with t r e a t m e n t group, period, sequence, and patient within sequences as the main effects. Also, 95% two-sided confidence intervals (CIs) for the difference "morning a d m i n i s t r a t i o n - e v e n i n g administration" were calculated using methods described by Jones and Kenward 14 and Gardner and Altman. 15

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D.P. M Y B U R G H

ET A L

RESULTS

Thirty-nine patients were enrolled in the study and randomly assigned to a treatment group. Fifteen patients from the morning/evening sequence and 18 patients from the evening/morning sequence completed both active treatment phases. The mean 24-hour blood pressure profiles for the two treatment regimens are shown in Figure 1 (DBP) and Figure 2 (SBP). The results of the measurements of the daytime, nighttime, and critical-time blood pressures are summarized in Table I. A slightly better control of the daytime blood pressure was observed with the morning administration than with the evening administration. The mean decrease in daytime DBP was 2.1 mm Hg (95% CI: - 0 . 0 4 to - 4 . 2 mm Hg) greater following morning administration; the corresponding figure for SBP was 3.3 mm Hg (95% CI: - 0 . 3 to - 6 . 3 mm Hg). The mean decrease in nighttime DBP was 1.8 mm Hg (95% CI: - 1 . 9 to 5.4 mm Hg) greater, and in SBP was 2.6 mm Hg (95% CI: - 2.6 to 7.7 mm Hg) greater with the evening administration than with the morning administration. For the mean critical-time blood pressure, antihypertensive efficacy was similar with the evening and the morning administration of ramipril. Table II summarizes the duration of blood pressure control over 24 hours, during daytime, and during nighttime. Over a 24-hour period, the duration of control was longer with the morning administration than with the evening administration; the differences being 0.9 hour (95% CI: - 1.0 to 2.6 hour) for DBP, and 1.0 hour (95% CI: - 0.6 to 2.6 hour) for SBP. The duration of blood pressure control during daytime was also longer with the morning administration than with the evening administration of the drug. The difference between the treatments was 1.1 hour (95% CI: - 0 . 0 2 to 2.1 hours) for DBP and 1.0 hour (95% CI: 0.03 to 2.0 hours) for SBP. The duration of blood pressure control during the nighttime was similar for the two treatment regimens; the mean values for DBP being 4.4 -+ 2.0 hours and 4.6 -+ 1.8 hours with morning and evening administration, respectively. The corresponding values for SBP were 3.5 -+ 2.3 hours and 3.2 -+ 2.3 hours.

Safety Results Ramipril was generally well tolerated. Adverse events were reported by three patients, all of whom were receiving ramipril in the morning during the first treatment phase of the study. These patients were all withdrawn from the study. One patient was withdrawn because of cough, one patient experienced gastric discomfort, and another patient experienced headache, listlessness, and fatigue. 1301

BLOOD PRESSURE CONTROL WITH RAMIPRIL

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DISCUSSION

A B P M is widely used to determine whether a patient has persistently elevated blood pressure levels. This method is also used to assess the severity of hypertension and to ascertain the effectiveness of the therapy aimed at reducing blood pressure.18 Earlier trials have shown the antihypertensive efficacy of ramipril. 9'1°'12'13 Due to its tight binding with the ACE receptor, ramipril is usually prescribed as a once-daily treatment. In the present study, the aim was to determine whether the time of administration of ramipril would have any influence on the antihypertensive efficacy of the drug. For some ACE inhibitors, the time of administration has a significant influence on the duration of blood pressure control. 17-19 Middeke et a117 investigated the chronopharmacology of captopril plus hydrochlorothiazide in the treatment of hypertension. This combination therapy was administered as an evening dose for 3 weeks and subsequently as a morning dose for the same period. The mean daytime blood pressure values (systolic and diastolic) of the ABPM were significantly higher with evening administration compared with morning administration. Palatini is and colleagues 19 evaluated the effect of the time of administration on the antihypertensive efficacy of quinapril. Quinapril 20 mg was given at 8 AM or 10 PM for 4 weeks in a double-blind, crossover study. The resulting 24-hour blood pressure profiles showed a more sustained antihypertensive action with evening administration of quinapril compared with morning administration. With the morning administration, a partial loss of effectiveness was observed during the nighttime hours. The authors concluded that an evening administration appeared to be preferable. The present study illustrates that morning administration of ramipril Table I. Effects of once-daily administration of ramipril 2.5 m g either in the morning or in the evening for at least 4 weeks on 33 hypertensive patients.

Daytime/tOP (10 m.-8 PM) DBP (ram HO) Baseline (mean -+ SD) 95.4 +- 7.5 Morning administration (mean - SD) 89.7 -+ 7.2 Evening administration (mean ± SD) 91.8 ± 7.7 Morning-evening difference (Mean) -2.1 95% CI (-4.2; -0.04) P value 0.046

NiGhttime ABP (midnight-6 AM)

SDP (ram HO)

DBP (mm HO)

SBP (ram Hg)

Critical-Time ABP (4 AM-8 AM)

DBP (ram Ha)

124.1 + 12.8 85.1 -+ 8.8

SBP (mm Hg)

145.8 -+ 11.4

75.7 +- 7.3

139.1 ± 11.5

74.6 +- 12.5 122.6 +- 20,5 82.0 -+ 10.5 129.3 -+ 15.2

142.3 -+ 12.5

72.7 +_ 9.4

-3.3 (-6.3;--0.3) 0.030

1.8 (-1,9; 5.4) 0,328

119.8 +_ 15.3 81.8 ± 9.5 2,6 (-2.6; 7.7) 0.323

0.2 (-3.2; 3.5) 0.924

134.2 ± 12.8

130.1 ± 15.5 -0.9 (-4.9; 3.1) 0,643

ABP = ambulatory blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; SO = standard deviation; CI = conficlenceinterval.

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D. P. MYBURGHET AL.

Table II. Duration (hours) of blood pressure control in 33 hypertensive patients following once-daily administration of ramipril 2.5 mg either in the morning or in the evening for at least 4 weeks. Daytime ABP (10 AO~-8PM)

24-hour ABP

Baseline (h) (mean -+ SD)

Nighttime U P (midnight-6 AN)

DBP

SBP

DBP

SBP

DBP

SBP

12.9 _+ 4.7

13.1 -+ 6,3

3,0 -+ 2.7

3.3 ± 3.3

4,3 ± 1.9

2.4 -+ 2.1

16.0 ± 5.6

16.0 ± 6.7

5.4 -+ 3.2

5,4 -+ 3.6

4.4 ± 2.0

3.5 ± 2.3

15.1 +_ 5.3

150 -+ 6.6

4.4 ± 3.4

4.4 -+ 3.8

4.6 - 1.8

3.2 -+ 2,3

-0.2 ( - 0 . 7 ; 0,5) 0,686

0.3 ( - 0 . 3 ; 0.9) 0.358

Morning administration (h) (mean ± SD) Evening administration (h) (mean ± SD) Morning-evening

Difference (Mean)

95% CI P value

0.9

1.0

1.1

1.0

( - 1 , 0 ; -2.6) 0.315

( - 0 . 6 ; 2.6) 0.231

(-0,02; 2.1) 0,054

(0.03; 2.0) 0,043

ABP = ambulatory blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; $D = standard deviation; CI = confidence interval.

may be slightly more effective in controlling the 24-hour blood pressure profile than evening administration. This may be explained by the fact that during physical activity more vasoactive hormone systems are activated than while lying down or sleeping. This explanation seems quite logical as the morning drug administration induces concentrations of the active drug to reach the receptors, counteracting the stronger daytime hormonal responses in comparison with the lower concentrations with evening administration, and the antihypertensive effects are more apparent. The opposite happens with the evening administration, as the counterregulatory mechanisms in the supine or sleeping state are weaker, rendering these effects less apparent. In conclusion, ramipril provides effective 24-hour antihypertensive control with once-daily administration. This study indicates that when administered in the morning, blood pressure control is as good as or slightly better than control achieved with evening administration. References: 1. O'Brien E, Cox J, O'Malley K. The role of twenty-four-hour ambulatory blood pressure measurement in clinical practice. J Hypertens. 1991;9(Suppl 8):$63-$65. 2. Canter DA, Texter MJ, McLain RW. Short report: Ambulatory blood pressure monitoring can play an integral role in patient selection, dosage adjustment and efficacy assessment in clinical trials of antihypertensive agents. J Hypertens. 1994;12:491-494. 3. Kostis JB. Angiotensin converting enzyme inhibitors. II. Clinical use. A m HeartJ. 1988; 116:1591-1605. 4. Whelton A. Application of ambulatory blood pressure monitoring to clinical therapeutic decisions in hypertension. J Hypertens. 1991;9(Suppl 1):$21-$25. 1305

BLOOD PRESSURE CONTROL WITH RAMIPRIL

5. Whelton A. 24-hour activityof lisinopril:Clinicaladvantage in blood pressure control. Cardiology. 1991;79(Suppl 1):10-15. 6. Frewin DB, Ryan GJ, Rennie GC. A comparison of the efficacyof captopriland enalapril given once daily for the treatment of hypertension: A study using 24-hour ambulatory blood pressure monitoring. J Clin Pharmacol. 1991;31:327-332. 7. Hofling B, Grimm CM, Gross R, et al. Comparison of the efficacyand safetyof diltiazem and captoprilin mild to moderate essentialhypertension.Herz Kreislauf 1994;26:295299. 8. Van den Meiracker AH, Admiraal PJJ, Derkx FHM, et al. Comparison of blood pressure and angiotensin responses to the renin inhibitorro 42-5892 and the angiotensinconverting enzyme inhibitorenalaprilin essentialhypertension.JHypertens. 1993;11:831-838. 9. Burris JF. The effectof ramipril on ambulatory blood pressure: A multicenter trial.J Cardiova,sc Pharmacol. 1991;18(Suppl 2):S131-$133. 10. McCarron D. The Ramipril Multicentor Study Group. 24-hour blood pressure profilesin hypertensive patients administered ramipril or placebo once daily: Magnitude and duration of antihypertensive effects.Clin Cardiol. 1991;14:737-742. 11. Whelton A, Dunne B Jr, Glazer N, et al. Twenty-four hour blood pressure effect of once-dailylisinopril,enalapril,and placebo in patients with mild to moderate hypertension.J H u m Hypertens. 1992;6:325-331. 12. Modesti PA, Said AM, Cecioni I, et al. Twenty-four hour antihypertensive efficacyof ramipril and enalapril.Curr Ther Res. 1993;53:137-143. 13. Burris JF. Lessons learned with ambulatory blood pressure monitoring: A focus on ramipril.Clin Ther. 1993;15:476-485. 14. Jones B, Kenward MG. Designs and Analysis of Cross-Over Trials. London: Chapman and Hall; 1989. 15. Gardner MJ, Altman DG. Confidence intervalsrather than P values: Estimation rather than hypothesis testing.Br M e d J. 1986;292:746-750. 16. PerloffD, Sokolow M. Ambulatory blood pressure:Mortality and morbidity.JHypertens. 1991;9(Suppl 8):$31-$33. 17. Middeke M, KlfiglichM, Holzgreve H. Chronopharmacology of captoprilplus hydrochlorothiazide in hypertension: Morning versus evening dosing. Chronobiol Int. 1991;8:506510. 18. Palatini P. Can an angiotensin-converting enzyme inhibitor with a short half-life effectively lower blood pressure for 24-hours? A m Heart J. 1992;123:1421-1425. 19. Palatini P, Racioppa A, Raule G, et al. Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril. Clin P l m r ~ o l Ther. 1992;52:378-383.

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