- Email: [email protected]
trandolapril combination
International
Journal
of
cardiology ELSEVIER
International Journal of Cardiology 55 (1996) 97-102
Antihypertensive efficacy of a once a day verapamil SR/ trandolapril combination ’ S. Oren”, J.R. Viskoper”, P. Zillesb ‘Department
of Internal Medicine, Barzilai Medical Centre, Ashkelon, afjliated to the Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel bResearch and Development, Knoll AG, D 67008, Ludwigshafen, Federal Republic of Germany
Received 11 September 1995; accepted 1 March 1996
Abstract Twenty-one patients with a sitting diastolic blood pressure between 100 and 114 mmHg after a single-blind 2-week placebo run-in period, started treatment under open conditions with the fixed combination of verapamil SR/ trandolapril 180/l mg o.d. for a period of 8 weeks. Patients whose conventionally measured diastolic blood pressure after 4 weeks’ treatment was not normalised (diastolic blood pressure <90 mmHg) received the higher dosage (verapamil SR/trandolapril 180/2 mg o.d.) for a further 4 weeks. Clinical evaluations including measurement of blood pressure were performed every 2 weeks. A 24-h ambulatory blood pressure monitoring (ABPM) was performed at weeks 0, 4 and 8 (end of the study). The mean office blood pressure decreased from 155 5 11/104 + 4 mmHg at baseline to 139 + 9/89 + 6 mmHg at week 8. In 12 patients (60%) the diastolic blood pressure was normalised after week 4. In eight patients, the dosage was increased and, of these, a further 25% were normalised at week 8. Response, defined as a reduction of diastolic blood pressure to 590 mmHg (normalisation) or a decrease of at least 10 mmHg compared to baseline, was recorded in 18 patients (90%). The mean 24-h ABPM was reduced from 143 ? 15185 t 9 mmHg at baseline to 131 2 11/77 ? 8 mmHg at week 8. The average systolic and diastolic blood pressure was reduced by a statistically significant amount (11/9 mmHg) during the day (8.00 am-10.00 pm) and 11/7 mmHg during the night (10.00 pm-8.00 am). Diurnal variation did not change. Only mild to moderate adverse events such as slight isolated elevations of SGPT, SGOT and potassium were observed. Two patients discontinued the study prematurely due to impotence which began during the placebo run-in period. No adverse events were serious or required any additional medical treatment. The fixed combination of verapamil SR and trandolapril appear to be a very effective and well-tolerated once-a-day antihypertensive medication. Keywords:
Verapamil SR; Trandolapril;
Combination; Efficacy; 24 h-ABP
1. Introduction Patients with essential hypertension may exhibit a more pronounced surge in the early morning blood ‘The study was supported by a grant from Knoll AG, Ludwigshafen, Germany.
pressure compared to normotensive persons. This rapid increase is potentially harmful and may increase the risk of atheriosclerotic plaque rapture and acute myocardial infarction or stroke. Therefore, antihypertensive drugs should have 24-h efficacy with sufficient control of this early morning surge. During the past 15 years, the use of verapamil SR
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO167-5273(96)02626-5
98
S. Oren et al. I International
Journal of Cardiology
(sustained release) for the treatment of hypertension has produced a sound clinical database supporting its efficacy and safety [l--8]. It has been shown that verapamil SR effectively lowers arterial blood pressure over 24 h by inducing vasodilitation without causing either reflex tachycardia, activation of the sympathetic-adrenergic system, renin angiotensinsystem, or volume expansion [9-l 11. Trandolapril effectively lowers systolic and diastolic blood pressure in patients with mild to severe hypertension [ 12,131, including the elderly and overweight or obese patients [ 14,151. Distinguishing features of the compound are its long plasma halflife and high degree of lipophilicity. Trandolapril reduces blood pressure consistently throughout the 24-h period after intake, thus the drug can be considered as a true, once-a-day antihypertensive [16,17]. The fixed combination of verapamil SR 180 mg and trandolapril 1 or 2 mg has been shown to achieve the most effective reduction of systolic and diastolic blood pressure. In these studies, the combination was significantly more effective than both monocomponents at respective dosages. The tolerability of the combination was comparable to the monocompounds. Rare adverse events included dizziness and constipation with verapamil monotherapy, headache and dizziness with trandolapril monotherapy. In combination therapy, the adverse event pattern of the monocompounds could be detected, but the overall rate of adverse events was equal for the monocompounds and the combination.
2. Aim of the study The aim of the study was to determine the 24-h efficacy of the combination of verapamil SR and trandolapril by means of 24-h ABPM in patients with mild to moderate essential hypertension.
3. Patients and methods 3.1. Patients The study was conducted in accordance with the provisions of the Declaration of Helsinki. Written
55 (1996) 97-102
informed consent of all patients and approval by the local Ethics Committee was obtained prior to the start of the study. Twenty-one outpatients (12 male, 9 female) aged 18-70 years (range: 20-65 years) were included in the study. To be entered into the study, patients’ conventionally-measured sitting diastolic blood pressure had to be in the range of lOO- 114 mmHg (mean of 3 measurements Korotkoff phase V) at the end of a 2-week single-blind placebo run-in period. Study exclusion criteria included: heart failure (NYHA IV), severe bradycardia, AV-block of any degree, myocardial infarction (<3 months), electrolyte disturbances, clinically relevant renal (creatinine i.s. >2 mg/dl) or hepatic failure. Out of 21 patients who were included in the study, 19 completed the trial. Two patients terminated the study prematurely due to adverse events which began during the placebo run-in period. Median duration of hypertension was 2 years (range O-30 years). Eleven patients were pretreated with anti-hypertensive medication consisting primarily of ACE inhibitors, Bblockers and calcium antagonists. 3.2. Methods After discontinuation of all blood pressure reducing drugs and after completion of a single-blind placebo run-in period of 2 weeks, patients were enrolled into the study and treated with verapamil SR/trandolapril 180/ 1 mg o.d. in the morning. If after 4 weeks of treatment, diastolic blood pressure was not normalised (<90 mmHg), the dosage was increased to verapamil SR/trandolapril 1SO/2 mg o.d. in the morning, and treatment continued for another 4 weeks. Systolic and diastolic blood pressure was measured both in a sitting position (three measurements after 10 min of rest) and after 2 min of standing at each check-up according to the recommendations of the 1988 AHA Committee report on blood pressure determination [18]. Twenty four h-ABPM was recorded three times with Accutracker II equipment for each patient: at the end of the placebo run-in period, after 4 weeks of treatment and at the end of treatment (after 8 weeks). The recording intervals were 20 min during daytime (X:00 am to 10:00 pm) and 30 min during night-time (10:00 pm-S:00 am).
S. Oren et al. I InternationalJournal of Cardiology5.5(1996)97-102 ECG recordings and laboratory evaluations were performed at the end of the placebo mn-in period and after 4 and 8 weeks of treatment. Clinical examination and all adverse events occurring during the clinical trial were recorded on the occasion of each 2 week visit.
3.3. Statistical methods In view of the open non-comparative design of the study, efficacy was analysed using descriptive methods. For the analysis of 24-h ABPM data, overall, daily, nightly and hourly means were calculated as AUC/time. With these values and data obtained from the three conventional recordings in sitting position, statistical characteristics were provided for the individual timepoints (visits) and with regard to their absolute and relative change versus baseline values. Frequency and percentage were computed for categorical variables; mean, standard deviation, median, extrema and quartiles for continuous variables. Twosided 95% confidence intervals were calculated for the means, medians and normalisation rates. The data of all patients treated with verapamil SR/trandolapril were included in the safety analysis. These analyses comprised the results of the resting ECG, laboratory parameters, clinical findings and documented adverse events. The parameters of the resting ECG and laboratory parameters were described by statistical characteristics and checked for individual conspicuous findings. Clinical findings and adverse events were described individually.
99
4. Results 4.1. Conventional blood pressure measurements Mean sitting blood pressure was reduced from 155 -’ ll/ 104 2 4 mmHg at baseline over 144 ? 1l/92 ? 10 mmHg (week 4) to 139 + 9189 2 6 mmHg at the end of the study (Table 1). After 4 weeks of treatment, eight patients had to be titrated to verapamil SR/trandolapril 180/2 mg o.d. After increasing the dose in these patients, blood pressure decreased from 152 t 9/102 2 9 mmHg (week 4) to 146 2 7/94 -+ 6 mmHg end of the study. Patients who had to be titrated to the higher dosage showed a slightly higher baseline blood pressure (160/ 107 mmHg vs. 151/ 102 mmHg). During active treatment, mean heart rate was reduced by 1.9 2 8.8 beats per minute.
4.2. 24-h ambulatory blood pressure measurements G&W Mean systolic and diastolic 24-h ABPM was reduced from 143 2 15/85 2 9 mmHg to 131 t 11177 ? 8 mmHg (Fig. 1). In the eight patients titrated to the higher dose, baseline 24-h ABPM profiles were higher and showed a reduction from 147 ? 15/89 + 7 mmHg to 139 5 14/73 ? 4 mmHg (Fig. 2). These findings concerning blood pressure reduction were confirmed for day-time recordings (8:00 am to 10:00 pm), showing a decrease of mean blood pressure from 147 ? 16/88 2 10 mmHg to 137 +-
Table 1 Mean sitting and standing systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) at baseline and study ttxmination (8 weeks) in patients treated with verapamil SR/trandolapril
Mean Mean Mean Mean Mean Mean
sitting DBP sitting SBP sitting MAP standing DBP standing SBP standing MAP
*P < 0.05 vs. baseline levels.
n
Baseline mmi9
Last value mw%)
Absolute difference WW9
95% Confidence interval mm3
20 20 20 20 20 20
103.95 154.95 120.90 105.20 154.70 121.60
88.55* 139.20* 105.55* 89.20* 140.25* 106.25*
-15.40 - 15.75 - 15.35 - 16.00 - 14.45 - 15.35
-18.08; -12.72 -21.29; -10.21 - 18.46; - 12.24 -18.99; -13.01 -20.54; -8.36 -18.74; -11.96
S. Oven et al. I International
100
Journal of Cardiology 55 (1996) 97-102
80
60”
” 7
9
I 11
”
” 13
”
”
15
17
”
19 24h-clock
” 21
” 23
I”’ 1
3
5
Fig. 1. Twenty four h-ABPM in patients with mild to moderate hypertension (n = 19) independent of the individual dosage.
lo/80 t 8 mmHg by 11 L 16/S ? 11 mmHg. During night-time (10:00 pm-g:00 am), mean blood pressure was lowered from 137 2 17/81 2 11 mmHg to 125 t 14/73 ? 9 mmHg by 11 + 8/7 t 10 mmHg. In none of the patients, first dose hypotension or symptomatic episodes of hypotension could be detected during treatment with the fixed combination. The pattern of diurnal variation was not changed by the medication. A slight reduction in heart rate of 2.1 + 9.1 beats per minute was found.
160
4.3. Normalisation
and response rates
Based on office recordings, normalisation (sitting diastolic blood pressure <90 mmHg) was achieved in 14 patients (70%): 12 patients on the low dose and a further two patients after titration to the higher dose of verapamil SR/trandolapril during the last 4 weeks. Response, defined as sitting diastolic blood pressure <90 mmHg or a decrease in diastolic blood pressure of at least 10 mmHg after 8 weeks of
r
80
60”
’ 7
9
11
13
15
’
’
17
19 24h-clock
’
21
I 23
1
3
5
Fig. 2. Twenty four h-ABPM in patients with mild to moderate hypertension (n = 8) titrated to verapamil SR/trandolapril after 4 weeks of treatment.
180/2 mg o.d.
S. Oren et al. I International
Journal of Cardiology
treatment compared to baseline, occurred in 18 patients (90%). Response in 24-h ABPM, defined as a decrease in mean 24-h diastolic blood pressure by 5 mmHg compared to baseline, was documented in 15 of 19 patients (79%); four patients showed no response. 4.4. Adverse events Only two of the 21 patients complained about adverse events to the extent that treatment had to be terminated prematurely. In both patients, this was due to impotence which began during the placebo run-in-period. All other adverse events were assessed as mild to moderate and transient. None of these adverse events was considered serious or required additional medical treatment or follow-up. The most frequent adverse events documented were: slight isolated elevation of liver enzymes (SGPT, SGOT) and increase of serum potassium to the upper normal range. Except for a complete right bundle branch block in one patient and a mild transient prolongation of the QT interval after 4 weeks of treatment, no clinically relevant ECG alterations were observed.
5. Discussion and conclusion Calcium antagonists are widely used as first-line drugs in the treatment of essential hypertension. However, when a satisfactory antihypertensive effect cannot be obtained by calcium antagonist therapy alone, ACE inhibitors are increasingly used concomitantly to potentiate their effect. The rationale behind the combination of an ACE inhibitor and a calcium antagonist is believed to be the inhibition of the ACE-triggered vasoconstrictor chain of events and the calcium-dependent contraction of the vascular smooth muscle. In addition to their additive effect on blood pressure reduction, there are other benefits to be gained through combining these substance classes. In this study, the antihypertensive efficacy and safety of the combination of the calcium antagonist verapamil SR and the ACE inhibitor trandolapril were investigated in 21 patients with mild to moder-
55 (1996) 97-102
101
ate essential hypertension. A significant reduction of conventionally-measured blood pressure of 16/ 15 mmHg was observed under oral administration of the combination 180/ 1 or 180/2 mg once daily, respectively. Sixty percent of the patients were normalised with the low dose (verapamil SR/trandolapril 180/l mg. o.d.) and, in addition, 25% of the non-normalised patients after titration to the higher dose (verapamil SR/trandolapril 180/2 mg o.d.) after a further 4 weeks of treatment. The overall normalisation rate was therefore 70%. Twenty four h-ABPM showed that verapamil SR/ trandolapril given o.d. effectively decreased blood pressure in these patients over a period of 24 h, especially an attenuation of the surge of blood pressure in the early morning h could be demonstrated. This may lead to a decrease in cardio- and cerebrovascular events. The individual diurnal blood pressure pattern not altered by treatment, however, had decreased to a lower level. The higher initial blood pressure in those patients who had to be titrated to the higher dose after 4 weeks probably reflected a more severe or therapeutically more resistant type of hypertension. But even in these patients, blood pressure declined further on treatment and normalisation was achieved in a further 25%. A slight reduction of heart rate was detected either with conventional blood pressure recordings or with 24-h ABPM. In none of the patients, a reflex tachycardia, as frequently seen with dihydropyridines, has been found. No consistent relationship was noted between the incidence of adverse events and the dose level. Significant but not relevant changes were observed in SGOT and SGPT, but as with all other adverse events these were mild to moderate, and transient. According to the results of this study, the optimum dose of the combination is considered to be verapamil SR/trandolapril 180/l or 180/2 mg o.d. In summary, with verapamil SR/trandolapril in a dosage of 180/l or 180/2 mg respectively given o.d., a significant blood pressure reduction during the complete dosing interval of 24 h was demonstrated without provoking reflex tachycardia. Furthermore, no serious or severe adverse events occurred under
102
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Journal of Cardiology
treatment with the combination. Thus, verapamil SRI trandolapril may be a useful treatment in hypertensives.
References VI Lewis GR, Morley KD, Lewis BM, Bones PJ. The treatment of hypertension with verapamil. Aus NZ J Med 1978; 87: 351-354. PI Leary WP, Asmal AC. Treatment of hypertension with verapamil. Curr Ther Res 1979; 25: 747. [31 Leonetti G, Sala C, Bianchini C, Terzoli L, Zanchetti A. Hypertensive and renal effects of orally administered verapamil. Em J Clin Pharmacol 1980; 8: 375-382. [41 Muiesan G, Agabiti-Rose1 E, Castellano E et al. Antihypertensive and humoral effects of verapamil and nifedipine in essential hypertension. .I Cardiovasc Pharmacol 1982; 4 (Suppl 3): S325-S329. [51 Gould BA, Mann S, Kieso H et al. The role of a slow channel inhibitor, verapamil, in the management of hypertension. Clin Exp Pharmacol Physiol 1982; 91 (suppl 6): 113121. K51Frishman WH, Klein NA, Klein P et al. Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. Am J Cardiol 1982; 50: 11641172. [71 Leonetti G, Pasotti C, Ferrary G, Zanchetti A. Verapamil and propranolol: a comparison of two antihypertensive agents. Acta Med Stand 1984; 681 (suppl): 137-141. [8] Frishman W, Charlap S, Kimmel B et al. Twice-daily administration of oral verapamil in the treatment of essential hypertension. Arch Intern Med 1986; 146: 561-565.
55 (1996) 97-102
[9] Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Cardiovascular effects of verapamil in patients with essential hypertension. Circulation 1987; 75: 1030-1036. 1101Frishman WH, Lazar EJ. Sustained-release verapamil formulations for treating hypertension. J Clin Pharmacol 1992; 32: 455-462. Ull Bemadet P, Sue JM, Durand D, Galey C, Maarek-Charbit M. Sustained-released verapamil and ambulatory recording of blood pressure in mild-to-moderate essential hypertension. Ann Cardiol Angeiol (Paris) 1992; 41: 105-112. WI Brown NL, Bade1 MY, Benzoni F et al. Angiotensin-converting enzyme inhibition, anti-hypertensive activity and hemodynamic profile of trandolapril (RU 44570). Eur J Pharmacol 1988; 148: 79-91. u31 Patat A, Surjus A, Le Go A, Granier J. Safety and tolerance of single oral doses of trandolapril (RU 44570), a new angiogtensin-converting enzyme inhibitor. Eur J Clin Pharmacol 1989; 36: 17-23. [I41 Nguyen Cong Due L, Brunner HR. Trandolapril in hypertension: overview of a new angiotensin-converting enzyme inhibitor. Am J Cardiol 1992; 70: 27D-45D. [I51 Guller B, Hall J, Reeves RL. Cardiac effect of trandolapril in hypertension. Am Heart J 1993; 125: 1536-1541. U61 Gaillard CA, de-Leeuw PW. Clinical experiences with trandolapril. Am Heart J 1993; 125: 1542-1546. u71 Conen H, Brunner HR. Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J 1993; 125: 1525-15231. U81 Frohlich ED, Grim C, Labarthe DR et al. Recommendations for human blood pressure determination by sphygmomanometers. Report of a special task force appointed by the steering committee. American Heart Association. Hypertension 1988; 11: 210A-222A.
Journal
of
cardiology ELSEVIER
International Journal of Cardiology 55 (1996) 97-102
Antihypertensive efficacy of a once a day verapamil SR/ trandolapril combination ’ S. Oren”, J.R. Viskoper”, P. Zillesb ‘Department
of Internal Medicine, Barzilai Medical Centre, Ashkelon, afjliated to the Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel bResearch and Development, Knoll AG, D 67008, Ludwigshafen, Federal Republic of Germany
Received 11 September 1995; accepted 1 March 1996
Abstract Twenty-one patients with a sitting diastolic blood pressure between 100 and 114 mmHg after a single-blind 2-week placebo run-in period, started treatment under open conditions with the fixed combination of verapamil SR/ trandolapril 180/l mg o.d. for a period of 8 weeks. Patients whose conventionally measured diastolic blood pressure after 4 weeks’ treatment was not normalised (diastolic blood pressure <90 mmHg) received the higher dosage (verapamil SR/trandolapril 180/2 mg o.d.) for a further 4 weeks. Clinical evaluations including measurement of blood pressure were performed every 2 weeks. A 24-h ambulatory blood pressure monitoring (ABPM) was performed at weeks 0, 4 and 8 (end of the study). The mean office blood pressure decreased from 155 5 11/104 + 4 mmHg at baseline to 139 + 9/89 + 6 mmHg at week 8. In 12 patients (60%) the diastolic blood pressure was normalised after week 4. In eight patients, the dosage was increased and, of these, a further 25% were normalised at week 8. Response, defined as a reduction of diastolic blood pressure to 590 mmHg (normalisation) or a decrease of at least 10 mmHg compared to baseline, was recorded in 18 patients (90%). The mean 24-h ABPM was reduced from 143 ? 15185 t 9 mmHg at baseline to 131 2 11/77 ? 8 mmHg at week 8. The average systolic and diastolic blood pressure was reduced by a statistically significant amount (11/9 mmHg) during the day (8.00 am-10.00 pm) and 11/7 mmHg during the night (10.00 pm-8.00 am). Diurnal variation did not change. Only mild to moderate adverse events such as slight isolated elevations of SGPT, SGOT and potassium were observed. Two patients discontinued the study prematurely due to impotence which began during the placebo run-in period. No adverse events were serious or required any additional medical treatment. The fixed combination of verapamil SR and trandolapril appear to be a very effective and well-tolerated once-a-day antihypertensive medication. Keywords:
Verapamil SR; Trandolapril;
Combination; Efficacy; 24 h-ABP
1. Introduction Patients with essential hypertension may exhibit a more pronounced surge in the early morning blood ‘The study was supported by a grant from Knoll AG, Ludwigshafen, Germany.
pressure compared to normotensive persons. This rapid increase is potentially harmful and may increase the risk of atheriosclerotic plaque rapture and acute myocardial infarction or stroke. Therefore, antihypertensive drugs should have 24-h efficacy with sufficient control of this early morning surge. During the past 15 years, the use of verapamil SR
0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO167-5273(96)02626-5
98
S. Oren et al. I International
Journal of Cardiology
(sustained release) for the treatment of hypertension has produced a sound clinical database supporting its efficacy and safety [l--8]. It has been shown that verapamil SR effectively lowers arterial blood pressure over 24 h by inducing vasodilitation without causing either reflex tachycardia, activation of the sympathetic-adrenergic system, renin angiotensinsystem, or volume expansion [9-l 11. Trandolapril effectively lowers systolic and diastolic blood pressure in patients with mild to severe hypertension [ 12,131, including the elderly and overweight or obese patients [ 14,151. Distinguishing features of the compound are its long plasma halflife and high degree of lipophilicity. Trandolapril reduces blood pressure consistently throughout the 24-h period after intake, thus the drug can be considered as a true, once-a-day antihypertensive [16,17]. The fixed combination of verapamil SR 180 mg and trandolapril 1 or 2 mg has been shown to achieve the most effective reduction of systolic and diastolic blood pressure. In these studies, the combination was significantly more effective than both monocomponents at respective dosages. The tolerability of the combination was comparable to the monocompounds. Rare adverse events included dizziness and constipation with verapamil monotherapy, headache and dizziness with trandolapril monotherapy. In combination therapy, the adverse event pattern of the monocompounds could be detected, but the overall rate of adverse events was equal for the monocompounds and the combination.
2. Aim of the study The aim of the study was to determine the 24-h efficacy of the combination of verapamil SR and trandolapril by means of 24-h ABPM in patients with mild to moderate essential hypertension.
3. Patients and methods 3.1. Patients The study was conducted in accordance with the provisions of the Declaration of Helsinki. Written
55 (1996) 97-102
informed consent of all patients and approval by the local Ethics Committee was obtained prior to the start of the study. Twenty-one outpatients (12 male, 9 female) aged 18-70 years (range: 20-65 years) were included in the study. To be entered into the study, patients’ conventionally-measured sitting diastolic blood pressure had to be in the range of lOO- 114 mmHg (mean of 3 measurements Korotkoff phase V) at the end of a 2-week single-blind placebo run-in period. Study exclusion criteria included: heart failure (NYHA IV), severe bradycardia, AV-block of any degree, myocardial infarction (<3 months), electrolyte disturbances, clinically relevant renal (creatinine i.s. >2 mg/dl) or hepatic failure. Out of 21 patients who were included in the study, 19 completed the trial. Two patients terminated the study prematurely due to adverse events which began during the placebo run-in period. Median duration of hypertension was 2 years (range O-30 years). Eleven patients were pretreated with anti-hypertensive medication consisting primarily of ACE inhibitors, Bblockers and calcium antagonists. 3.2. Methods After discontinuation of all blood pressure reducing drugs and after completion of a single-blind placebo run-in period of 2 weeks, patients were enrolled into the study and treated with verapamil SR/trandolapril 180/ 1 mg o.d. in the morning. If after 4 weeks of treatment, diastolic blood pressure was not normalised (<90 mmHg), the dosage was increased to verapamil SR/trandolapril 1SO/2 mg o.d. in the morning, and treatment continued for another 4 weeks. Systolic and diastolic blood pressure was measured both in a sitting position (three measurements after 10 min of rest) and after 2 min of standing at each check-up according to the recommendations of the 1988 AHA Committee report on blood pressure determination [18]. Twenty four h-ABPM was recorded three times with Accutracker II equipment for each patient: at the end of the placebo run-in period, after 4 weeks of treatment and at the end of treatment (after 8 weeks). The recording intervals were 20 min during daytime (X:00 am to 10:00 pm) and 30 min during night-time (10:00 pm-S:00 am).
S. Oren et al. I InternationalJournal of Cardiology5.5(1996)97-102 ECG recordings and laboratory evaluations were performed at the end of the placebo mn-in period and after 4 and 8 weeks of treatment. Clinical examination and all adverse events occurring during the clinical trial were recorded on the occasion of each 2 week visit.
3.3. Statistical methods In view of the open non-comparative design of the study, efficacy was analysed using descriptive methods. For the analysis of 24-h ABPM data, overall, daily, nightly and hourly means were calculated as AUC/time. With these values and data obtained from the three conventional recordings in sitting position, statistical characteristics were provided for the individual timepoints (visits) and with regard to their absolute and relative change versus baseline values. Frequency and percentage were computed for categorical variables; mean, standard deviation, median, extrema and quartiles for continuous variables. Twosided 95% confidence intervals were calculated for the means, medians and normalisation rates. The data of all patients treated with verapamil SR/trandolapril were included in the safety analysis. These analyses comprised the results of the resting ECG, laboratory parameters, clinical findings and documented adverse events. The parameters of the resting ECG and laboratory parameters were described by statistical characteristics and checked for individual conspicuous findings. Clinical findings and adverse events were described individually.
99
4. Results 4.1. Conventional blood pressure measurements Mean sitting blood pressure was reduced from 155 -’ ll/ 104 2 4 mmHg at baseline over 144 ? 1l/92 ? 10 mmHg (week 4) to 139 + 9189 2 6 mmHg at the end of the study (Table 1). After 4 weeks of treatment, eight patients had to be titrated to verapamil SR/trandolapril 180/2 mg o.d. After increasing the dose in these patients, blood pressure decreased from 152 t 9/102 2 9 mmHg (week 4) to 146 2 7/94 -+ 6 mmHg end of the study. Patients who had to be titrated to the higher dosage showed a slightly higher baseline blood pressure (160/ 107 mmHg vs. 151/ 102 mmHg). During active treatment, mean heart rate was reduced by 1.9 2 8.8 beats per minute.
4.2. 24-h ambulatory blood pressure measurements G&W Mean systolic and diastolic 24-h ABPM was reduced from 143 2 15/85 2 9 mmHg to 131 t 11177 ? 8 mmHg (Fig. 1). In the eight patients titrated to the higher dose, baseline 24-h ABPM profiles were higher and showed a reduction from 147 ? 15/89 + 7 mmHg to 139 5 14/73 ? 4 mmHg (Fig. 2). These findings concerning blood pressure reduction were confirmed for day-time recordings (8:00 am to 10:00 pm), showing a decrease of mean blood pressure from 147 ? 16/88 2 10 mmHg to 137 +-
Table 1 Mean sitting and standing systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) at baseline and study ttxmination (8 weeks) in patients treated with verapamil SR/trandolapril
Mean Mean Mean Mean Mean Mean
sitting DBP sitting SBP sitting MAP standing DBP standing SBP standing MAP
*P < 0.05 vs. baseline levels.
n
Baseline mmi9
Last value mw%)
Absolute difference WW9
95% Confidence interval mm3
20 20 20 20 20 20
103.95 154.95 120.90 105.20 154.70 121.60
88.55* 139.20* 105.55* 89.20* 140.25* 106.25*
-15.40 - 15.75 - 15.35 - 16.00 - 14.45 - 15.35
-18.08; -12.72 -21.29; -10.21 - 18.46; - 12.24 -18.99; -13.01 -20.54; -8.36 -18.74; -11.96
S. Oven et al. I International
100
Journal of Cardiology 55 (1996) 97-102
80
60”
” 7
9
I 11
”
” 13
”
”
15
17
”
19 24h-clock
” 21
” 23
I”’ 1
3
5
Fig. 1. Twenty four h-ABPM in patients with mild to moderate hypertension (n = 19) independent of the individual dosage.
lo/80 t 8 mmHg by 11 L 16/S ? 11 mmHg. During night-time (10:00 pm-g:00 am), mean blood pressure was lowered from 137 2 17/81 2 11 mmHg to 125 t 14/73 ? 9 mmHg by 11 + 8/7 t 10 mmHg. In none of the patients, first dose hypotension or symptomatic episodes of hypotension could be detected during treatment with the fixed combination. The pattern of diurnal variation was not changed by the medication. A slight reduction in heart rate of 2.1 + 9.1 beats per minute was found.
160
4.3. Normalisation
and response rates
Based on office recordings, normalisation (sitting diastolic blood pressure <90 mmHg) was achieved in 14 patients (70%): 12 patients on the low dose and a further two patients after titration to the higher dose of verapamil SR/trandolapril during the last 4 weeks. Response, defined as sitting diastolic blood pressure <90 mmHg or a decrease in diastolic blood pressure of at least 10 mmHg after 8 weeks of
r
80
60”
’ 7
9
11
13
15
’
’
17
19 24h-clock
’
21
I 23
1
3
5
Fig. 2. Twenty four h-ABPM in patients with mild to moderate hypertension (n = 8) titrated to verapamil SR/trandolapril after 4 weeks of treatment.
180/2 mg o.d.
S. Oren et al. I International
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treatment compared to baseline, occurred in 18 patients (90%). Response in 24-h ABPM, defined as a decrease in mean 24-h diastolic blood pressure by 5 mmHg compared to baseline, was documented in 15 of 19 patients (79%); four patients showed no response. 4.4. Adverse events Only two of the 21 patients complained about adverse events to the extent that treatment had to be terminated prematurely. In both patients, this was due to impotence which began during the placebo run-in-period. All other adverse events were assessed as mild to moderate and transient. None of these adverse events was considered serious or required additional medical treatment or follow-up. The most frequent adverse events documented were: slight isolated elevation of liver enzymes (SGPT, SGOT) and increase of serum potassium to the upper normal range. Except for a complete right bundle branch block in one patient and a mild transient prolongation of the QT interval after 4 weeks of treatment, no clinically relevant ECG alterations were observed.
5. Discussion and conclusion Calcium antagonists are widely used as first-line drugs in the treatment of essential hypertension. However, when a satisfactory antihypertensive effect cannot be obtained by calcium antagonist therapy alone, ACE inhibitors are increasingly used concomitantly to potentiate their effect. The rationale behind the combination of an ACE inhibitor and a calcium antagonist is believed to be the inhibition of the ACE-triggered vasoconstrictor chain of events and the calcium-dependent contraction of the vascular smooth muscle. In addition to their additive effect on blood pressure reduction, there are other benefits to be gained through combining these substance classes. In this study, the antihypertensive efficacy and safety of the combination of the calcium antagonist verapamil SR and the ACE inhibitor trandolapril were investigated in 21 patients with mild to moder-
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ate essential hypertension. A significant reduction of conventionally-measured blood pressure of 16/ 15 mmHg was observed under oral administration of the combination 180/ 1 or 180/2 mg once daily, respectively. Sixty percent of the patients were normalised with the low dose (verapamil SR/trandolapril 180/l mg. o.d.) and, in addition, 25% of the non-normalised patients after titration to the higher dose (verapamil SR/trandolapril 180/2 mg o.d.) after a further 4 weeks of treatment. The overall normalisation rate was therefore 70%. Twenty four h-ABPM showed that verapamil SR/ trandolapril given o.d. effectively decreased blood pressure in these patients over a period of 24 h, especially an attenuation of the surge of blood pressure in the early morning h could be demonstrated. This may lead to a decrease in cardio- and cerebrovascular events. The individual diurnal blood pressure pattern not altered by treatment, however, had decreased to a lower level. The higher initial blood pressure in those patients who had to be titrated to the higher dose after 4 weeks probably reflected a more severe or therapeutically more resistant type of hypertension. But even in these patients, blood pressure declined further on treatment and normalisation was achieved in a further 25%. A slight reduction of heart rate was detected either with conventional blood pressure recordings or with 24-h ABPM. In none of the patients, a reflex tachycardia, as frequently seen with dihydropyridines, has been found. No consistent relationship was noted between the incidence of adverse events and the dose level. Significant but not relevant changes were observed in SGOT and SGPT, but as with all other adverse events these were mild to moderate, and transient. According to the results of this study, the optimum dose of the combination is considered to be verapamil SR/trandolapril 180/l or 180/2 mg o.d. In summary, with verapamil SR/trandolapril in a dosage of 180/l or 180/2 mg respectively given o.d., a significant blood pressure reduction during the complete dosing interval of 24 h was demonstrated without provoking reflex tachycardia. Furthermore, no serious or severe adverse events occurred under
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treatment with the combination. Thus, verapamil SRI trandolapril may be a useful treatment in hypertensives.
References VI Lewis GR, Morley KD, Lewis BM, Bones PJ. The treatment of hypertension with verapamil. Aus NZ J Med 1978; 87: 351-354. PI Leary WP, Asmal AC. Treatment of hypertension with verapamil. Curr Ther Res 1979; 25: 747. [31 Leonetti G, Sala C, Bianchini C, Terzoli L, Zanchetti A. Hypertensive and renal effects of orally administered verapamil. Em J Clin Pharmacol 1980; 8: 375-382. [41 Muiesan G, Agabiti-Rose1 E, Castellano E et al. Antihypertensive and humoral effects of verapamil and nifedipine in essential hypertension. .I Cardiovasc Pharmacol 1982; 4 (Suppl 3): S325-S329. [51 Gould BA, Mann S, Kieso H et al. The role of a slow channel inhibitor, verapamil, in the management of hypertension. Clin Exp Pharmacol Physiol 1982; 91 (suppl 6): 113121. K51Frishman WH, Klein NA, Klein P et al. Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. Am J Cardiol 1982; 50: 11641172. [71 Leonetti G, Pasotti C, Ferrary G, Zanchetti A. Verapamil and propranolol: a comparison of two antihypertensive agents. Acta Med Stand 1984; 681 (suppl): 137-141. [8] Frishman W, Charlap S, Kimmel B et al. Twice-daily administration of oral verapamil in the treatment of essential hypertension. Arch Intern Med 1986; 146: 561-565.
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[9] Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Cardiovascular effects of verapamil in patients with essential hypertension. Circulation 1987; 75: 1030-1036. 1101Frishman WH, Lazar EJ. Sustained-release verapamil formulations for treating hypertension. J Clin Pharmacol 1992; 32: 455-462. Ull Bemadet P, Sue JM, Durand D, Galey C, Maarek-Charbit M. Sustained-released verapamil and ambulatory recording of blood pressure in mild-to-moderate essential hypertension. Ann Cardiol Angeiol (Paris) 1992; 41: 105-112. WI Brown NL, Bade1 MY, Benzoni F et al. Angiotensin-converting enzyme inhibition, anti-hypertensive activity and hemodynamic profile of trandolapril (RU 44570). Eur J Pharmacol 1988; 148: 79-91. u31 Patat A, Surjus A, Le Go A, Granier J. Safety and tolerance of single oral doses of trandolapril (RU 44570), a new angiogtensin-converting enzyme inhibitor. Eur J Clin Pharmacol 1989; 36: 17-23. [I41 Nguyen Cong Due L, Brunner HR. Trandolapril in hypertension: overview of a new angiotensin-converting enzyme inhibitor. Am J Cardiol 1992; 70: 27D-45D. [I51 Guller B, Hall J, Reeves RL. Cardiac effect of trandolapril in hypertension. Am Heart J 1993; 125: 1536-1541. U61 Gaillard CA, de-Leeuw PW. Clinical experiences with trandolapril. Am Heart J 1993; 125: 1542-1546. u71 Conen H, Brunner HR. Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J 1993; 125: 1525-15231. U81 Frohlich ED, Grim C, Labarthe DR et al. Recommendations for human blood pressure determination by sphygmomanometers. Report of a special task force appointed by the steering committee. American Heart Association. Hypertension 1988; 11: 210A-222A.