In white mild to moderate hypertensive patients. Nifedipine Versus Captopril in the Management of Moderate Hypertension in Black ratients

A]H 1994; 7:440^47 Nifedipine Versus Captopril in the Management of Moderate Hypertension in Black ratients John Skoularigis, Leslie Eitzman, Jean Davis, Victor Strugo, and Pinhas Sareli The efficacy of nifedipine (20 to 40 mg twice daily) and Captopril (25 to 50 mg twice daily) was assessed during a 12-week single-blind randomized trial in 41 moderately hypertensive black patients (mean 24-h diastolic blood pressure [BP] > 90 mm Hg and < 115 mm Hg). Nifedipine and Captopril were administered as monotherapy in increasing dosage while a diuretic was added after 8 weeks in patients who failed to reach the target BP (24-h mean diastolic BP < 90 mm Hg) on monotherapy. After 8 weeks of monotherapy, the mean 24-h ambulatory BP was reduced from 156 ± 12/101 ± 5 to 128 ± 11/84 ± 7 mm Hg (P <.0001) in the nifedipine group while it remained essentially unchanged (156 ± 15/101 ± 7 to 158 ± 17/102 ± 9) in the Captopril group. Left ventricular (LV) mass index was also reduced significantly (P <.05) in the nifedipine group, while cardiac index and fractional shortening changed marginally. The addition of diuretic in the Captopril group (16/21 patients) resulted in a significant fall in BP to 123 ± 11/81 ± 7. Only 2/20 patients in the nifedipine group required the addition of diuretic. The overall incidence of side effects was similar with both treatments but the addition of diuretic in the Captopril group was followed by adverse changes in serum sodium (P <.01), urea (P <.05), and creatinine (P <.01) levels. It is concluded that nifedipine monotherapy offers an effective, safe firstline antihypertensive treatment in black patients with moderate hypertension while Captopril alone failed to control the BP. The combination of Captopril and diuretic, although more effective in controlling BP compared with Captopril alone, was associated with significant adverse metabolic effects. Am J Hypertens 1994;7:440-447 KEY WORDS: 24-h ambulatory blood pressure, nifedipine, Captopril, moderate hypertension, black patients. In white mild to moderate hypertensive patients calcium antagonists and angiotensin converting enzyme (ACE) inhibitors, commonly referred to as first-line antihypertensive agents, have approximately equal efficacy and favorable side-effect profiles. 12 Previous studies have shown that an optimal response to ACE inhibitors, especially in black patients, fairly frequently requires the addition of a Received August 16, 1993. Accepted December 20, 1993. From the Division of Cardiology, Baragwanath Hospital, Johannesburg, South Africa. Address correspondence and reprint requests to Dr. John Skoularigis, Division of Cardiology, Baragwanath Hospital, PO Bertsham 2013, Johannesburg, South Africa. diuretic. 3-6 However, most of our knowledge of the antihypertensive action of these drugs has been derived from conventional blood pressure (BP) measurements. Recently, ambulatory BP monitoring (ABPM) has become increasingly useful in the evaluation of drug efficacy because of its potential to overcome the well-known limitations inherent in conventional BP measurement. 7,8 Furthermore, the degree of BP "control" should be evaluated against the 24-h ABPM profiles of a matched control group rather than relying on an arbitrary diastolic BP value of 90 mm Hg as a measure of control. Thus, in the present study we (a) compared the BP lowering effects of tablet formulation of nifedipine 1994 by the American Journal of Hypertension, Ltd. 0895-7061/94/$7.00

Α]Η-MAY 1994-VOL. 7, NO. 5 NIFEDIPINE ν CAPTOPRIL IN BLACK HYPERTENSIVES 441 (Adalat Retard, Bayer-Miles) and Captopril (Capoten, Bristol-Myers Squibb) by using 24-h ABPM, (b) compared them to an age-matched control group, (c) investigated whether combination with a diuretic could improve their antihypertensive effect, and (d) assessed their effect on left ventricular (LV) mass and systolic function, and metabolic parameters, in 41 consecutive black patients with moderate hypertension. METHODS Patient Population Subjects were 45 consecutive black patients between 21 and 65 years of age meeting two BP criteria: (1) an average sitting diastolic BP > 95 mm Hg and < 115 mm Hg, as a mean of 10 automated readings over a 30-min screening period using the Dinamap (Critikon 1846 SX Vital Signs Monitor), and (2) a 24-h mean diastolic ABPM > 90 mm Hg and < 115 mm Hg. The BP measurements were therefore free of observer bias. Patients were excluded from the study if they had secondary hypertension, hypertensive emergency, systolic BP > 215 mm Hg, congestive heart failure, history of recent (< 3 months) myocardial infarction or stroke, previous intolerance to dihydropyridines or Captopril, or hepatic or renal disorders. Additional screening procedures for entry included a comprehensive history and physical examination, full blood count, routine blood chemistry, urinalysis, chest roentgenogram, 12-lead electrocardiogram, 24-h ABPM and echo-doppler. The 24-h BP profiles and the echocardiographic parameters before and after therapy were compared with a matched control group of 40 normotensive subjects. The 24-h ABPM profiles and echo-doppler parameters were derived for the controls at a single visit using the same equipment as used for the hypertensives. All patients gave informed consent. Ethics Committee Approval This was obtained from both the Baragwanath Hospital Prescription and Therapeutics Committee and the Ethics Committee of the University of the Witwatersrand. Study Design The study comprised two phases: (1) a 3-week placebo-controlled baseline, and (2) a 12- week prospective randomized single-blind titration period with two treatment arms (nifedipine or Captopril). At randomization an initial dose of either 20 mg nifedipine twice daily or 25 mg Captopril twice daily was given for 6 weeks, the therapeutic goal being the reduction of sitting diastolic BP to < 90 mm Hg as measured by a 30-min Dinamap. If target diastolic BP was reached, patients continued at the same dose until the 12-week visit. The patients whose 30-min mean diastolic BP remained > 90 mm Hg after 6 weeks of active medication were titrated up to 40 or 50 mg twice daily, respectively, for a further 2 weeks. A second drug was added at the end of 8 weeks if the mean diastolic BP measured by 24-h ABPM was > 90 mm Hg using the maximum dose of nifedipine or Captopril. The second drug was Moduretic (50 mg hydrochlorothiazide and 5 mg amiloride HCl, Logos Ltd., South Africa) in doses of a half tablet daily for 2 weeks, increasing to 1 tablet daily for another 2 weeks according to BP response. Follow-up during the 12- week treatment period was done on a 2-week basis. Patients who experienced significant adverse effects, or reached a mean diastolic BP > 115 mm Hg at any titration point, were withdrawn from the study and placed on alternative therapy. Echo-Doppler evaluation and 24-h ABPM were performed at the end of each phase. Blood Pressure Measurement: Dinamap Method It was hypothesized that the use of a Dinamap as a screening device, especially when an average of multiple BP measurements is taken, eliminates observer bias, terminal digit preference, and reduces "white coat" hypertension. In this study, by using the Critikon 1846 SX vital signs monitor, BP was measured by an oscillometric technique at 3-min intervals for a total of 30 min. 9 Machines were calibrated against a mercury sphygmomanometer before use in each patient with maximum acceptable difference of ± 5 mm Hg at 200 mm Hg. 10 ABPM Continuous BP was measured with (oscillometric) SpaceLabs 90202 and 90207 monitors. Machines were calibrated against a mercury sphygmomanometer before use in each patient with the monitor readings being within 3 mm Hg or 2% of the manometer readings, whichever was greater. 11 From 6 AM to midnight BP and heart rate readings were taken every 15 min, and from midnight to 6 AM every 20 min. Daytime was defined as 6 AM to 6 PM. A 24-h ABPM recording was repeated if, during the 24-h period, any single hour had less than two successful readings. Mean BP was calculated from diastolic BP + V3 (systolic BP minus diastolic BP). 12 Importantly, for comparative purposes, all recordings were done under similar conditions. Echocardiography and Doppler Analysis M-mode and two-dimensional echocardiograms were obtained with the Hewlett Packard Sonos 500 or 1000 system using a 2.5-MHz transducer. Each patient was examined in the left lateral recumbent position. With the transducer in the left parasternal position, twodimensional guided M-mode echocardiography of the LV was performed immediately below the mitral valve leaflets at the chordal level in the short-axis view. 13 In the LV outflow tract, M-mode tracings were obtained at the aortic annulus directly proximal to the insertion of the aortic leaflets. Measurement of

442 SKOULARIGIS ET AL AJH-MAY 1994-VOL. 7, NO. 5 the aortic annulus was made at the inner edge of the endocardial echoes. Using two-dimensionally guided pulsed Doppler echocardiography, cardiac output was calculated as the product of the Doppler timevelocity integral, cross-sectional area, and heart rate. 14 During echocardiographic evaluation, simultaneous three-lead electrocardiogram and BP monitoring using a Dinamap were performed. Dinamap BP measurements were used in the calculation of the systemic vascular resistance. 15 M-mode variables were analyzed according to the American Society of Echocardiography convention 16 and included LV end-diastolic and end-systolic diameters and septal and posterior wall thickness. Fractional shortening was calculated as LV end-diastolic diameter minus LV end-systolic diameter divided by LV end-diastolic diameter. Doppler and M-mode recordings were videotaped and > 90% were made by the same experienced echocardiographer (JS), who was blinded to the BP and clinical data of the patient. The LV mass was derived according to an anatomically validated regression method which corrects LV mass estimates obtained from American Society of Echocardiography measurements. 17 Statistical Analysis Where the assumption of normality was not violated, the paired and Student's t tests were used for continuous data. When no proof of normality was available, nonparametric tests, ie, the U-test of Mann Whitney and Wilcoxon's signed ranked test for matched pairs, were used for between- and within-group comparisons, respectively. Adjustment of the Ρ value according to Bonferroni was used for pairwise comparisons. RESULTS Baseline demographics and 24-h ABPM profiles for the hypertensive and the control groups are shown in Table 1 and Figure 1, respectively. The difference in LV mass index between the nifedipine and Captopril groups can be explained by the higher percentage of male patients in the latter group. Safety Effects Forty-one of the 45 randomized patients completed the study (nifedipine, η = 20; Captopril, η = 21). One patient in each group was withdrawn because of adverse drug effects. The patient on nifedipine reported headache and peripheral edema, and the Captopril patient withdrew because of dizziness. One more patient in the nifedipine group was withdrawn due to social problems, while another captopril-treated patient died suddenly. The cause of death could not be ascertained as family refused postmortem examination. Previous to his death, BP appeared to respond to Captopril monotherapy and all laboratory tests were within normal limits. The analysis includes data for all 41 patients who completed the 12 weeks of treatment. Patient compliance, measured by tablet count throughout the study, was 98%. Drug Treatment At 12 weeks, nifedipine monotherapy controlled BP in 18 patients, at a dose of 20 mg twice daily in two and 40 mg twice daily in 16. In two further patients, although diuretic was added (both TABLE 1. BASELINE CLINICAL PARAMETERS OF THE HYPERTENSIVE AND NORMOTENSIVE SUBJECTS NIF (η = 20) CAP (n = 21) Controls (n = 40) Age (years) 47 ± 11 48 ± 9 48 ± 10 Sex (males/females) 8/12 13/8 18/22 Body surface area (m 2 ) 1.75 1.80 1.75 24-h ABP (mm Hg) Systolic 156 ± 12 156 ± 15 120 ± 8 Diastolic 101 ± 5 101 ± 7 75 ± 6 Daytime ABP Systolic 162 ± 12 162 ± 15 124 ± 8 Diastolic 107 ± 6 107 ± 7 81 ± 6 Nighttime ABP Systolic 150 ± 15 150 ± 17 115 ± 9 Diastolic 94 ± 7 94 ± 8 70 ± 7 Mean arterial pressure nocturnal decline (%) 10 ± 6 9 ± 6 11 ± 6 LV mass index (g/m 2 ) 108 ± 32* 130 ± 34* 61 ± 13 LV end-diastolic diameter (mm) 47 ± 4 48 ± 6 47 ± 4 LV end-systolic diameter (mm) 31 ± 5 32 ± 6 30 ± 4 Fractional shortening (%) 34 ± 6 32 ± 5 35 ± 4 Septum (mm) 10 ± 3* 11 ± 2* 7 ± 2 Posterior wall (mm) 9 ± 2 11 ± 2* 8 ± 2 *P <.05 NIF or CAP ν control. ABP, Ambulatory blood pressure; CAP, Captopril; LV, left ventricular; NIF, nifedipine.

AJH-MAY 1994-VOL. 7, NO. 5 NIFEDIPINE ν CAPTOPRIL IN BLACK HYPERTENSIVES 443 MEAN ARTERIAL PRESSURE τ Γ 7 8 9 10 11 12 13 14 15 16 17 18 19 19 20 20 21 21 22 22 23 23 0 1 X ADALAT PRE HOURS CAPTOPRIL PRE )K ADALAT POST Φ CAPTOPRIL POST -["CONTROL FIGURE 1. Mean 24-h ambulatory mean arterial pressure profiles of the hypertensive subjects at baseline and after 8 weeks of treatment with nifedipine or Captopril ν normotensive controls. further 13 patients were controlled following the ad- dition of diuretic (seven on half a tablet daily and six on one tablet daily) while in three patients treatment failed to control the BP. on one tablet daily), BP control was not achieved. In the Captopril group, none of the patients was controlled on 25 mg twice daily, while five were controlled on monotherapy with 50 mg twice daily. A I I I I Γ TABLE 2. HEART RATE AND BLOOD PRESSURE DATA AT BASELINE AND AFTER 8 WEEKS OF TREATMENT WITH NIFEDIPINE OR CAPTOPRIL NIF (η = 20) CAP (η = 21) BLN 8 Weeks BLN 8 Weeks Dinamap BP Systolic 174 ± 15 148 ± 18* 174 ± 19 176 19 Diastolic 105 ± 5 96 7* 106 ± 6 109 ± 6 24-h ABP Systolic 156 ± 12 128 11* 156 ± 15 158 17 Diastolic 101 5 84 ± ô 101 ± 7 102 ±_ 9 Daytime ABP Systolic 162 ± 12 133 ± 11* 162 ± 15 163 17 Diastolic 107 6 89 7* 107 ± 7 107 8 Nighttime ABP Systolic 150 ± 15 122 ± 12* 150 ± 17 152 19 Diastolic 94 ± 7 77 7* 94 ± 8 86 ± 3 24-h heart rate (beats/min) 75 9 81 ± 12 74 ± 10 76 13 Mean arterial pressure nocturnal decline (%) 10 ± 6 12 ± 5 9 ± 6 11 6 *P <.0002 8 weeks ν baseline. ABP, Ambulatory blood pressure (mm Hg), BLN, baseline.

444 SKOULARIGIS ET AL A]Η-MAY 1994-VOL. 7, NO. 5 TABLE 3. COMPARISON OF CAPTOPRIL ALONE WITH CAPTOPRIL AND DIURETIC CAP CAP + DRC (n = 16) (n 16) Dinamap BP Systolic 177 ± 17 140 ± 19* Diastolic 110 ± 4 87 10* 24-h ABP Systolic 160 ± 16 123 11* Diastolic 106 ± 6 81 ± 7* Daytime ABP Systolic 164 ± 17 128 ± 12* Diastolic 110 ±7 85 7* Nighttime ABP Systolic 156 ± 17 118 ± 12* Diastolic 101 ± 6 76 6* 24-h heart rate (beats/min) 77 ± 14 79 ± 13 *P <.0001 CAP + DRS ν CAP. ABP, Ambulatory blood pressure; CAP, Captopril, DRC, diuretic. 140 MEAN ARTERIAL PRESSURE Antihypertensive Effect Nifedipine monotherapy significantly reduced both the systolic and diastolic BP at 8 weeks compared with baseline, whether pressure was measured by Dinamap (15% and 9%, respectively) or by 24-h ABPM (18% and 17%, respectively) (Table 2 and Figure 1). The reduction observed was sustained for 24 h (Figure 1) and maintained up to 12 weeks. In contrast, in the Captopril group, a significant reduction in both systolic and diastolic BP was only shown at 12 weeks and this was after the addition of diuretic (Table 3 and Figure 2). As shown in Table 4, the relative changes in BP during monotherapy were significantly greater with nifedipine compared with Captopril (Ρ <.0001), suggestive of a greater hypotensive effect of nifedipine in these middle-aged black patients with moderate hypertension. Echocardiographic Data At 8 weeks, there was a significant decline in LV mass index when compared to baseline (16%, Ρ <.05) for the nifedipine group only, and this was due to a reduction in diastolic myocardial wall thickness (Table 5). With Captopril monotherapy, although there was a 10% reduction in baseline LV mass index, this failed to become significant. Neither the reduction in LV mass nor the use of nifedipine or Captopril was associated with a deterioration in cardiac function, since cardiac index, fractional shortening, and 24-h heart rate remained similar throughout the study. HOURS CONTROL Φ Captopril alone )K Captopril +Moduretic FIGURE 2. Mean 24-h ambulatory mean arterial pressure profiles of the 15 patients who required the addition of diuretic at baseline and after 12 weeks of treatment ν normotensive controls.

AJH-MAY 1994-VOL. 7, NO. 5 NIFEDIPINE ν CAPTOPRIL IN BLACK HYPERTENSIVES 445 TABLE 4. MEAN CHANGES FOR PATIENTS ON NIFEDIPINE ν CAPTOPRIL AT 8 WEEKS NIF CAP (n = 20) (n = 21) Dinamap BP Systolic 26 15-2 17* Diastolic 10 ± 7-3 ± 8* 24-h ABP Systolic 28 ± 13-1 ± 11* Diastolic 17 ± 8-1 ± 8* LV mass index (g/m 2 ) 16 ± 28 13 ± 36 LV end-diastolic diameter (mm) -0.1 ± 4-0.2 ± 5 LV end-systolic diameter (mm) 1.1 ± 4 1.5 ± 7 Fractional shortening (%) -1.6 ± 6.7-0.8 4.0 Septum (mm) 0.2 0.2 o-.i ± 0.3 Posterior wall (mm) 0.1 ± 0.2 0.1 ± 0.3 Cardiac index (L/min/m 2 ) -0.3 ± 0.6-0.3 ± 0.5 Minus sign indicates that the baseline was smaller in value. *P <.0001 CAP ν MF. ABP, Ambulatory blood pressure; CAP, Captopril; LV, left ventricular; NIF, nifedipine. Side Effects The well-documented side-effects of headache (20% for nifedipine, 10% for Captopril), dizziness (5% for both), and pedal edema (15% and 0%, respectively) were noted at the end of the study. Only one patient in each group was withdrawn as a result of side effects. Neither treatment induced metabolic changes, although the addition of diuretic in the Captopril group was followed by adverse changes in serum sodium (P <.01), urea (P <.05), and creatinine (P <.01) levels (Table 6). No changes in serum potassium levels were observed following the combination of Captopril and a potassium-sparing diuretic (Table 6). No significant changes in physical findings or body weight were noted in either treatment group. DISCUSSION The major findings of this study were: (1) nifedipine, but not Captopril, significantly reduced both systolic and diastolic BP in middle-aged black patients with moderate hypertension as measured by 24-h ABPM; (2) the marked anithypertensive effect of nifedipine was accompanied by a reduction in LV mass on the order of 16% with no adverse effect on LV systolic performance; (3) the addition of Moduretic to Captopril produced a pronounced fall in BP and this fall was related to the dose of diuretic; and (4) the combination of Captopril and Moduretic resulted in significant adverse metabolic effects. The need for an effective, safe first-line drug that can be administered without repeated laboratory tests during chronic management of hypertension in black patients led us to evaluate in this study the relative efficacy and side effects of a calcium antagonist compared with an ACE inhibitor. Thus, for the first time, using 24-h ABPM, a direct comparison of nifedipine with Captopril has been done in black patients with moderate hypertension. Previous studies comparing calcium antagonists with ACE inhibitors were mainly done in white hypertensive patients and yielded comparable results. 1 In the study by Saunders et al, 18 the calcium antagonist verapamil, when compared with atenolol and Captopril, appeared particularly effective as monotherapy in lowering both systolic and diastolic BP in black patients with mild to moderate hypertension. Compared with our study, there are major differences, as we included patients with more severe hypertension, evaluated BP control by using 24-h ABPM, and assessed LV mass and function by echocardiography. Furthermore, the BP reduction achieved with nifedipine monotherapy in our study was not only greater than the one observed previously, 18 but was also significantly more pronounced than with Captopril, and was sustained for 24 h and maintained for up to 12 weeks. This greater responsiveness of hypertensive black patients to nifedipine than to Captopril could be related to their TABLE 5. ECHO-DOPPLER PARAMETERS BEFORE AND AFTER 8 WEEKS OF NIFEDIPINE OR CAPTOPRIL THERAPY NIF (η = 17) CAP (η = 16) BLN 8 Weeks BLN 8 Weeks Septum (mm) 10 ± 3 Posterior wall (mm) 9 ± 2 LV end-diastolic diameter (mm) 47 4 LV end-systolic diameter (mm) 31 ± 5 LV mass index (g/m 2 ) 108 ± 32 Fractional shortening (%) 34 ± 6 Cardiac index (L/min/m 2 ) 2.5 ± 0.4 Systemic vascular resistance index 40 7 (dynes-sec-cm 5 x 10 2 ) 9 ± 2* 11 ± 2 10 3 8 ± 2* 11 2 10 3 47 ± 5 48 ± 6 48 ± 6 30 ± 3 32 ± 6 31 7 91 ± 30* 130 ± 34 117 43 36 6 32 ± 5 33 ± 4 2.7 ± 0.7 2.3 0.4 2.6 0.5 32 ± 7t 45 ± 9 38 ± 8+ *P <.05 and fp <.001 8 weeks ν BLN. BLN, Baseline; CAP, Captopril; LV, left ventricular; NIF, nifedipine.

446 SKOULARIGIS ET AL AJH-MAY 1994-VOL. 7, NO. 5 TABLE 6. LABORATORY DATA BEFORE AND AFTER 12 WEEKS OF NIFEDIPINE OR CAPTOPRIL THERAPY NIF (η = 20) CAP (η = 21) Baseline 12 Weeks Baseline 12 Weeks Sodium (mmol/l) 140 ± 4 139 ± 3 141 ± 2 136 ± 5t Potassium (mmol/l) 4.0 ± 0.6 4.1 ± 0.5 4.3 ± 0.5 4.4 ± 0.7 Urea (mmol/l) 4.6 ± 1.7 4.4 ± 0.9 4.9 ± 1.1 6.2 ± 2.6* Creatinine (μιηοι/l) 78 ± 13 77 ± 13 78 ± 17 96 ± 31+ Glucose (mmol/l) 4.8 ± 1.0 4.7 ± 0.9 4.9 ± 0.8 4.8 ± 0.9 Uric acid (mmol/l) 0.4 ± 0.1 0.4 ± 0.08 0.4 ± 0.1 0.4 ± 0.1 Cholesterol (mmol/l) 5.1 ± 1.0 5.2 ± 1.3 5.0 ± 0.9 5.3 ± 1.2 *P <.05 and fp <.005 12 weeh ν baseline. CAP, Captopril; NIF, nifedipine. average low plasma renin activity. However, it is not easy to predict whether or not ACE inhibitor monotherapy would be effective in a given patient because of the multifactorial causation of hypertension and the multimechanism mode of action of ACE inhibitors. In addition, there have been studies showing that ACE inhibitor therapy becomes more effective in the presence of concurrent diuretic therapy.^ These findings were further confirmed by our study, as the combination of Captopril with Moduretic produced a significant fall in BP which was related to the dose of diuretic, as there was a further fall in BP in the six patients whose dose was increased to one tablet daily. The antihypertensive effect of nifedipine was due to a marked reduction (20%) in systemic vascular resistance (Table 5). However, although Captopril caused a significant reduction (15%) in systemic vascular resistance, it also increased the cardiac output and therefore the BP remained essentially unchanged. In the treatment of hypertension, regression of an elevated LV mass is desirable. 19 As in our previous study, 20 a reduction in diastolic myocardial wall thickness following control of BP with nifedipine resulted in a significant decrease (16%) in LV mass index (Table 5), while LV internal dimensions and systolic function were unaltered. With Captopril monotherapy, despite the failure of BP control, there was a nonsignificant reduction (10%) in LV mass index. However, this is beyond the 5.2% variation in echocardiographic measurements at our laboratory and may be attributed to a direct myocardial tissue effect. Although nifedipine or Captopril monotherapy did not affect the biochemical and hematologic variables tested, the addition of diuretic in the Captopril group was associated with significant adverse metabolic effects compared with the metabolic profile of nifedipine, raising doubts as to its use when laboratory monitoring is not readily available. These findings have practical significance in the choice of a suitable antihypertensive regimen in individual patients. A dose of 20 to 40 mg nifedipine twice daily will reduce BP steadily and without precipitous drop in most black patients with moderate essential hypertension. REFERENCES 1. Opie LH: ACE-inhibitors for hypertension, in Opie LH (ed): Angiotensin Converting Enzyme Inhibitors. New York, Authors' Publishing House, 1992, pp 20-60. 2. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154-183. 3. Bauer JH, Jones LB: Comparative studies: enalapril versus hydrochlorothiazide as first-step therapy for the treatment of primary hypertension. Am J Kidney Dis 1984;4:55-62. 4. Kayanakis JG, Baulac L: The comparative study of once-daily administration of Captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension. Br J Clin Pharmacol 1987;27: 289S-296S. 5. MacGregor G A, Markandu ND, Banks RA, et al: Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propanolol. Br Med J 1982;284:693-696. 6. Brown CL, Backhouse CI, Grippβt JC, et al: The effect of Perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the reninangiotensin system in hypertensive subjects. Eur J Clin Pharmacol 1990;39:327-332. 7. Mancia G, Omboni S, Parati G, et al: Ambulatory blood pressure monitoring in the design of studies on antihypertensive drug efficacy. Am J Hypertens 1993; 6:233S-235S. 8. White WB, Grinn JM, McCabe EJ: Clinical usefulness of ambulatory blood pressure monitoring. Am J Hypertens 1993;6:225S-228S. 9. Borow KM, Newburger JW: Noninvasive estimation of central aortic pressure using the oscillometric method for analysing systemic artery pulsatile blood flow: comparative study of indirect systolic, diastolic, and mean brachial artery pressure with simultaneous

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