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Comparison of labetalol versus enalapril as monotherapy in elderly patients with hypertension: results of 24-hour ambulatory blood pressure monitoring
Comparison of Labetalol Versus Enalapril as Monotherapy in Elderly Patients with Hypertension: Results of 24-Hour Ambulatory Blood Pressure Monitoring WILLIAM B. APPLEGATE,M.D., Memphis, Tennessee, NEMATBORHANI,M.D., Davis, California, VINCENTDEQUATTRO,M.D., LosAngeles, California, PAULM. KAIHLANEN,M.D., SanAnfonio, Texas, SEICHIOISHI, M.D., Kumamafo City, Japan, DEBORAHL. DUE, MARKA. SIRGO,Pharm.D., Research Triangle Park, North Carolina
PURPOSE: This study compared the safety and efficacy of labetalol and enalapril as antihypertensive therapy for elderly patients. PATIENTSANDMETHODS: Arandomized,openlabel, parallel controlled trial was conducted. After completing a g-week placebo phase, 79 elderly (65 years or older) patients with an average standing diastolic blood pressure (BP) 95 mm Hg or above and 114 mm Hg or less were randomized to receive a 12-week course of either labetalol or enalapril in an open-label design. The patients’ BP and heart rate were evaluated biweekly by trained observers unaware of the treatment status, and drug dosage was titrated (up to 400 mg twice a day of labetalol or 40 mg daily of enalapril) to achieve a standing diastolic BP of less than 90 mm Hg and a decrease of 10 mm Hg from baseline. Patients underwent 24hour ambulatory BP monitoring (ABPM) at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS: The treatment groups were comparable in their reduction of supine diastolic BP, with no significant differences between the two treatments. Labetalol demonstrated a significantly greater reduction (p <0.05) in standing diastolic BP at the end of the titration period compared to enalapril, but this difference was not significant by the end of the study period. Based on 24-hour ABPM readings, labetalol reduced mean 24-hour diastolic BP (p <0.05) and From the University of Tennessee, Memphis (WBA), Memphis, Tennessee; School of Medicine (NB), University of California, Davis, California: Hypertension Service, Los Angeles County, and University of Southern California Medical Center (VD), Los Angeles, California: San Antonio, Texas (PMK); Kumamato University Medical School (SO), Kumamato City, Japan: and Glaxo, Inc. (DLD, MAS), Research Triangle Park, North Carolina. This work was funded by Glaxo, Inc., Research Triangle Park, North Carolina. Requests for reprints should be addressed to William B. Applegate, M.D., Division of Geriatric Medicine, University of Tennessee, Memphis, 66 North Pauline, Suite 232, Memphis, Tennessee 38163. Manuscript submitted May 25, 1990, and accepted in revised form October 1. 1990.
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mean heart rate (p <0.05) more than enalapril. The labetalol-treated patients were significantly less often above their diastolic BP goal throughout the 24-hour ABPM period (p X0.01). The two treatments were equally well tolerated. CONCLUSIONS: The results indicate that labeta101 and enalapril are equally effective in lowering supine diastolic BP in the elderly, but labetalol is more effective in lowering ambulatory BP and heart rate throughout the day.
H
ypertension is a major health care problem for the elderly, affecting almost 50% of those individuals aged 65 years or older [1,2]. Essential hypertension in the elderly differs from that found in the younger patient. Hypertension in the elderly is generally characterized by elevated total peripheral resistance and reduced cardiac output and renal blood flow [3]. Elderly hypertensive patients tend to have reduced plasma renin activity and their responsiveness to norepinephrine is impaired [4]. Elevation of either systolic or diastolic blood pressure (BP) is a well-recognized risk factor for cerebrovascular and cardiovascular morbidity and mortality in elderly patients [5-111. In the Framingham Study, elderly patients with hypertension had a threefold greater incidence of coronary heart disease, congestive heart failure, and cerebrovascular accidents as compared to normotensive patients [8]. Several trials have documented the value of diastolic BP control for the elderly patient, while the impact of drug treatment of isolated systolic hypertension is still under study [g-12]. The efficacy of antihypertensive medication is typically evaluated by mean BP measurement during clinical visits. However, 24-hour ambulatory BP monitoring (ABPM) may more accurately assess BP control throughout the day and during the early morning hours when BP typically rises [13]. Control of BP and heart rate during this morning “acceleration period” may be important because a relatively higher number of coronary heart disease and stroke 90
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events occur within the first few hours after awakening [14-191. Labetalol possesses both selective cri- and nonselective P-blocking properties [20,21]. It reduces peripheral vascular resistance and BP while preventing reflex tachycardia. Recent studies have shown that it is an effective antihypertensive agent when used for either diastolic [22] or isolated systolic hypertension [23] in elderly patients and prevents the early morning acceleration in BP [24]. Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, also reduces peripheral resistance and BP [25] and has been shown to be effective in treating elderly patients with diastolic hypertension in short-term clinical trials [26]. The present study was designed to compare the effects of labetalol to enalapril on BP and heart rate in elderly patients with diastolic hypertension using 24-hour ABPM. In addition, the safety profile of each drug was compared in this group of elderly patients.
PATIENTS AND METHODS Enrollment Elderly male and female outpatients with a history of hypertension were eligible for enrollment into this open-label, controlled multicenter trial. Female candidates were either postmenopausal or had a previous hysterectomy. Inclusion criteria required patients to be 65 years or older and have an average standing diastolic BP 95 mm Hg or above and 114 mm Hg or less at the end of the third and fourth weeks of the initial placebo phase. Exclusion criteria were as follows: uncontrolled diabetes mellitus or congestive heart failure; unstable angina pectoris; major cardiac conduction abnormalities including atrioventricular blockade greater than first degree; severe arrhythmia or bradycardia (less than 50 beats/minute); recent (within the previous 6 months) myocardial infarction or cerebrovascular accidents; bronchial asthma or bronchospastic chronic obstructive pulmonary disease requiring bronchodilator therapy; secondary or complicated hypertension requiring surgical intervention; systolic BP more than 220 mm Hg; clinically significant hepatic or renal disease; or a history of alcoholism, drug abuse, psychosis, or other personality problems that would limit the validity of consent to participate in the study. Patients with a history of intolerance to P-blockers or ACE inhibitors, recent treatment (within the prior 2 weeks) with guanethidine or rauwolfia agents, or treatment with an investigational drug within the prior month were not eligible for study participation. Randomized patients were not permitted to take any antihypertensive agent other than the study medications during the study period.
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The study protocol was reviewed and approved by the participating institutions’ review committees. All patients provided written informed consent prior to enrolling in the study. The study was conducted in two phases. Phase 1 was a single-blind, 4-week placebo washout phase. Enrolled patients were switched from their current antihypertensive regimen to placebo (one tablet twice a day). BP was measured at Weeks 0,2,3, and 4 during the placebo period. The Visit 4 BP at the end of the placebo period was the baseline BP. Phase 2 was an open-label, 12-week, active treatment period in which eligible patients were randomized to receive either oral labetalol, 100 mg twice a day, or enalapril, 5 mg once daily. Individualized dosage adjustments were made every 2 weeks over the first 6 weeks of active treatment if necessary to meet BP control criteria. The treatment goals were to decrease the standing diastolic BP by 10 mm Hg from baseline (end of the placebo phase) and to less than 90 mm Hg. The protocol allowed doses ranging from 100 to 400 mg twice daily of labetalol or 5 to 40 mg once daily of enalapril. Data Collection Medical personnel taking BPS and heart rate and eliciting adverse events were unaware of the identity of the study treatment. BPS were measured by a trained nurse or technician using a mercury sphygmomanometer. Supine BPS were taken after a 5minute rest period. Standing measurements with the arm at the level of the heart were taken in succession after 1 minute of standing. The average of three supine and standing measurements for both diastolic and systolic BPS was computed and recorded at each clinic visit. None of the patients were found to have postural hypotension at baseline (defined as a postural drop of systolic BP of 20 mm Hg or more). Pulse rate was also recorded. Patient’s usage of other drugs as well as concomitant illnesses and adverse events was evaluated at each clinic visit. The investigators determined the relationship between a reported adverse event or laboratory abnormality and active drug therapy based on clinical judgment. Compliance with the prescribed regimen was assessed by tablet counts of unused medication and recorded at each clinic visit. Patients underwent 24-hour ABPM measured by an AccutrackerTM recorder (Suntech, Raleigh, North Carolina) once at the completion of the placebo phase and again at the end of 8 weeks of active treatment. The Accutracker is an R-wave gated device that utilizes a piezoelectric microphone to measure phase 1 and phase 5 Korotkoff sounds [27]. When the ABPM device was applied, the first diastolic BP displayed by the Accutracker was re-
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TABLEI Mean Differences in Blood Pressure (Standing and Supine) and Heart Rate from Baseline to the End of the Titration and Treatment Periods Standing Labetalol Enalapril Mean SEM Mean SEM To end of titration period (baseline to Week 8) SBP (mm Hg) DBP (mm Hg) HR (beats/minute)
2.5 1.47
2.06
-2E
To end of treatment period (baseline to Week 12) SBP (mm Hg) DBP (mm Hg) HR (beats/minute)
pVa1ue-t
(n = 37)”
(n = 34)*
-22.62*
Supine Labetalol Enalapril Mean SEM Mean SEM
-16.08$ -10.97* 0.27
(n = 31)’
(n = 34)”
3.09 1.25 2.27
oNi4
2.21
-11.41$
1.35
-3.68
3.25
-1;t:g:
1.21 1.70
1.88
-12.7* -1o.o* -0.95
(n = 31)”
(n = 36)*
-19.26*
(n = 37)*
-16.44*
0.07
1:;:;;: -0.11
3.08
NS
1.12
NS
2.17
-13.48* -2;:;;:
p Value?
2.78 1.24 1.71
NS
3.0
NS
Ii:
(n = 36)*
3.24
-18.14*
1.25
1.71
1.34 -3:~;
2.06
O.“os
I SBP = svstalic blood oressure: DBP = diastolic blood pressure; HR = heart rate: NS = not significant. * Sample size differences due to dropouts. t Two-sample t-test (labetalol versus enalapril). T p CO.01 (baseline versus follow-up within treatment group).
differential, and urine sample for urine protein determination were obtained at the beginning and end of phase 1 and at the end of Weeks 8 and 12 of phase 2.
TABLE II Mean Differences in Blood Pressure, Heart Rate, and Area Under the Curve for ABPM Readings for Labetalol Versus Enalapril from Baseline to Week 8 Labetalol (n = 24)* Mean SEM Mean 24-hour values SBP (mm Hg) DBP (mm Hg) HR (beats/minute) Area under the curve SBP DBP HR
-12.0
-8.8 -6.4
3.0 1.3 1.3
-281.7
68.7
-202.6
29.4
-145.2
27.6
Enalapril ,‘,“,; 26)* SEM -8.0 -4.9 -1.8 -187.5
-117.3 -39.3
pValuet
1.9
0.26
1.0 1.2
0.01
39.1 21.2 25.9
0.02 0.12 0.01
0.004
3PM = ambulatory blood pressure monitoring; other abbreviations as in Table I. Includes only those patients who had ABPMs performed on both occasions. t Two-sample t-test.
quired to match within f5 mm Hg with the average indirect sphygmomanometer readings for that day. One reading was taken every 20 minutes from 6 AM to 12 PM and every 30 minutes for the remainder of the 24-hour period. Readings had to fall in the following ranges to be considered valid: diastolic BP 50 to 140 mm Hg, systolic BP 90 to 255 mm Hg, pulse pressure 10 to 100 mm Hg, and heart rate 40 to 160 beats/minute. Also, the maximum change from the previous reading allowed was: diastolic BP 30 mm Hg or less, systolic BP 60 mm Hg or less, and heart rate 60 beats/minute or less. At least 70% of the hourly BP recordings had to be valid [28]; if not, the 24-hour ABPM measurement was repeated, or the patient’s data were excluded from the ABPM analysis. A medical history, a physical examination, and 12-lead electrocardiogram were undertaken prior to the initiation of phase 1 and at the end of phase 2. A chest radiograph was obtained at the initiation of phase 1 only. A fasting SMA-12 profile, serum creatinine measurement, complete blood count with 200
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Statistical Analysis A two-tailed t-test was used to compare the two treatment groups for age, weight, systolic and diastolic BPS, and heart rate. Group distributions of sex, race, and hypertension history were compared using Fisher’s exact test. A two-sample t-test was used to compare the diastolic and systolic BPS and heart rate of the two treatment groups at baseline versus at the end of the eighth and 12th weeks of the study. Standing diastolic BP was used to determine primary efficacy. The SAS procedure REG was used to fit a linear regression model for systolic, diastolic, and mean arterial BPS and heart rate as a function of the hour in which the readings were taken [29]. A one-sample t-test was used to analyze mean differences between the first and second ABPM data. A two-sample ttest was used to compare the hourly heart rates and BPS as well as areas under the curve for ABPM readings of labetalol-treated and enalapril-treated patients. The Pearson chi-square test was used to compare the percentages of patients with ABPM readings above preselected levels by time period from baseline to the eighth week of treatment. Mean differences in laboratory values from baseline to study completion were compared using a two-sample t-test. The frequencies of adverse events in the two treatment groups were compared using Fisher’s exact test.
RESULTS Of the 132 patients screened, 79 (51 men, 28 womcriteria and were enrolled into
en) met all inclusion
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Figure 1. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory systolic blood pressure by hour. Vertical line indicates a significant difference (p <0.05) between
labetalol
and
130 0
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enalapril.
the study. The patients’ ages ranged from 62 to 79 years. An exception was made to the inclusion criteria for one 62-year-old patient who satisfied all criteria except that of age 65 years or older. Thirtynine patients were randomized to labetalol and 40 patients to enalapril. There were no differences between the labetalol and enalapril groups with regard to sex (67% versus 63% males, respectively), age (70.2 years versus 69.8 years), weight (79.8 kg versus 80.2 kg), race (69% versus 65% whites), prior hypertension history (74% versus 70% with diagnosis for 6 years or more), baseline standing diastolic BP (lb0 mm Hg versus 100.3 mm Hg), or baseline standing systolic BP (163.9 mm Hg versus 163.4 mm Hg). Labetalol and enalapril both effectively (p
tion of the study. These declines were approximately 7 beats/minute. Enalapril had no effect on heart rate. BP control at study completion occurred at a mean (SEM) daily dose of 322 mg (29) and 12 mg (2) of labetalol and enalapril, respectively. ABPM cif the 79 patients enrolled in the study, 50 completed both 24-hour ABPMs with valid readings: 24 patients who were receiving labetalol and 26 patients who were receiving enalapril. These treatment subgroups were comparable based on sex, age, weight, race, and prior hypertension history. Sixteen of the 24 (67%) labetalol-treated patients and 13 of the 26 (50%) enalapril-treated patients were normotensive based on clinic BP measures prior to the second 24-hour ABPM. There were no differences in the proportion normotensive between those who did and did not complete valid ABPM studies at the Week 8 visit for either treatment group. At 8 weeks, labetalol-treated patients showed a significantly greater decrease in mean 24-hour diastolic BP (8.8 mm Hg versus 4.9 mm Hg, p = 0.02) and mean 24-hour heart rate (6.4 beats/minute versus 1.8 beats/minute, p = 0.01) than the enalapriltreated patients (Table II). The labetalol group
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Figure ?. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory diastolic blood pressure by hour. Vertical line indicates a significant difference (p <0.05) between labetalol and enalapril.
showed a significantly (p
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interval (Figures 1 and 2). Similar, significantly greater reductions were also noted for mean arterial pressure. The heart rate of patients taking labetalol was significantly lower than that of the enalapriltreated patients at every hour except hours 0,3 AM, and 5 PM (p <0.05) (Figure 3). Adverse Events and Laboratory Abnormalities Two patients randomized to receive enalapril left the study due to adverse effects including dizziness, fainting, fatigue, and depression. One patient receiving labetalol discontinued treatment prematurely due to fatigue and weakness. Another labetalol-treated patient was dismissed from the study after 6 weeks of active treatment due to weight gain, headache, fatigue, shortness of breath, and peripheral edema. Six labetalol-treated and five enalapriltreated patients experienced adverse events thought to be related to drug therapy. There was no significant difference between the two treatment groups with regard to frequency of adverse effects (Table III). Analysis of mean differences in laboratory parameters between baseline and completion of the
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Figure 3. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory heart rate by hour. Vertical line indicates a significant difference (p <0.05) between labetalol and enalapril.
0
2
.
6
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12
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14
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24
HOUR
.
.n.
,I
4
1
study demonstrated statistically sigmrlcant but relatively small differences between the treatment groups for red blood cell and platelet counts.
r
TABLE
III
Number and Percentageof AdverseEventsRelatedto Drug Therapy
COMMENTS Both labetalol and enalapril effectively lowered standing and supine systolic and diastolic BPS in older patients with hypertension. Labetalol significantly decreased heart rate, which was unchanged by enalapril. These effects of labetalol are consistent with findings from other studies [22,23]. Both drugs were well tolerated, with equal numbers of withdrawals from treatment due to side effects. Comparison of the drugs’ effects on BP as measured by 24-hour ABPM showed that labetalol more consistently maintained control of BP and heart rate throughout the day and demonstrated a significantly greater decrease in mean 24-hour diastolic BP and a significantly greater decrease in mean AUC for 24-hour diastolic BP and heart rate. In addition, labetalol showed a nonsignificant tendency to blunt the early morning increase in BP so that BP did not rise quite as high as with enalapril in the early morning hours. The early morning increase in heart
Reported
Labetalol (n = 39)
Adverse Effect
Dizziness/lightheadedness Tiredness/fatigue Headache Weakness Drained feeling Tendency to faint Depression Impotence Dryness of mouth Uncontrolled blood pressure
Enalapril (n = 40) 1(2.5%) ; (5.o%) 0
0 i Fl 0
rate was significantly less with labetalol than with enalapril. Relatively few studies have directly compared different antihypertensive agents as monotherapy in elderly patients [30]. Most of the studies that do exist have compared antihypertensive agents versus hydrochlorothiazide or placebo [23,26,31]. Although diuretics are effective in lowering BP in the elderly, questions remain about the metabolic side
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effects [32]. Recently, 105 hypertensive patients (mean age 55) were randomized to labetalol or prazosin. Although there were no significant differences in the amount of reduction in BP measured in the clinic, ABPM revealed that the labetalol-treated patients had significantly greater reductions of systolic and diastolic BP during the daytime hours [33]. Several studies have compared ACE inhibitors versus diuretics in elderly patients with hypertension and have generally found that either drug class is equally effective in controlling BP based on clinic BPS but the diuretics generally cause more metabolic side effects [26,34,35]. In this study, the fact that labetalol showed greater control of the early morning increase in heart rate and demonstrated betber control of BP throughout the day could be due to its combined (YIand ,&adrenoreceptor blocking activity [36]. It has been postulated that part of the pathophysiology of hypertension in the elderly may involve the possibility that peripheral a-adrenergic vasoconstriction is relatively unaffected by age [37], while ,f%adrenergic vasodilatation may be blunted [38]. There are several potential limitations of the current study. This was an open-label randomized study and the possibility of bias in observation of clinic BPS measured with a mercury sphygmomanometer cannot be excluded. Nonetheless, efforts were made to ensure the clinical personnel performing BP measurements were unaware of treatment status. Also, any bias that might have existed would not have affected the ABPM results. Second, the study treatment goals were based on standing BP, which could potentially bias the results in favor of labetalol, which is thought to have more of a postural effect. However, both supine and standing BP results are reported here. When clinic BPS were examined, the drugs were equally effective in lowering supine BP, while labetalol showed an early tendency to cause greater reductions in standing BP (which disappeared by the end of the total treatment period). The ABPM measures would appear to resolve this issue since BPS were recorded at regular intervals throughout the day, allowing for a variety of activities. Also, the ABPM measures were made at Week 8, when differences in standing diastolic BP between the two treatment groups were the greatest. It is possible that the differences seen between the two groups with ABPM could have diminished if these measures were repeated at the end of the study. On the other hand, at times, differ ences between treatment regimens may be detected by ABPM but not by clinic measures [33,39]. Finally, although a number of subjects did not successfully complete ABPM, there would appear to be no inherent bias since the remaining treatment sub204
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groups continued to be evenly matched on a number of demographic and clinical variables and the rate of BP control within the two groups did not differ between those who did and did not have valid ABPM recordings. In conclusion, results of this study suggest that labetaiol and enalapril are both well tolerated and effective in lowering elevated diastolic and systolic BP in elderly hypertensive patients. Both drugs are equally effective in lowering supine office BP measures. However, labetalol appears to more consistently maintain BP and heart rate control as assessed by ABPM compared to enalapril.
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32. Pollare T, Lithell H, Berne C. A comparison of the effect of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension, N Engl J Med 1989; 321: 868-73. 33. Gray JM, Silberman HM, Gorwit JI. Comparison of labetalol and prazosrn in hypertensive patients using automated ambulatory monitoring. Am J Med 1988; 84: 904-10. 34. Verza M, Cacciapuoti F, Spieza R, eta/. Effects of the angiotensrn converting enzyme inhibitor enalapril compared with diuretic therapy in elderly hypertensive patients. J Hypertens 1988; 6 (Suppl 1): 597-9. 35. Fries ED for the Veterans Administration Cooperative Study Group on Antihypertensive Agents. Age and antihypertensive drugs (hydrochlorothiazide, bendroflumethiazide, nadolol, and captopril). Am J Cardiol 1988; 61: 117-21. 36. Koch G. Hemodynamic changes after acute and long term combined alphabeta adrenoreceptor blockade with labetaiol as compared with beta receptor blockade. J Cardiovasc Pharmacol 1981; 3 (Suppl 1): S30-41. 37. Abrass IB. Catecholamine levels and vascular responsiveness in aging. In: Horan MJ. Steinberg GM, Dunbar JB, Hadley EC, eds. Blood pressure regulation and aging, an NIH Symposium. New York: Biomedical Information Corporation, 1986: 123-30. 38. Bertel 0, Buhler FR. Kiowski W. Lutold BE. Decreased beta-adrenoreceptor responsiveness as related to age, blood pressure, and plasma catecholamines in patients with essential hypertension. Hypertension 1980; 2: 130-8. 39. Weber MA, Cheung DG, Graettinger WF, Lipson JL. Characterization of antihypertensive therapy by whole-day blood pressure monitoring. JAMA 1988; 259: 3281-5.
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PURPOSE: This study compared the safety and efficacy of labetalol and enalapril as antihypertensive therapy for elderly patients. PATIENTSANDMETHODS: Arandomized,openlabel, parallel controlled trial was conducted. After completing a g-week placebo phase, 79 elderly (65 years or older) patients with an average standing diastolic blood pressure (BP) 95 mm Hg or above and 114 mm Hg or less were randomized to receive a 12-week course of either labetalol or enalapril in an open-label design. The patients’ BP and heart rate were evaluated biweekly by trained observers unaware of the treatment status, and drug dosage was titrated (up to 400 mg twice a day of labetalol or 40 mg daily of enalapril) to achieve a standing diastolic BP of less than 90 mm Hg and a decrease of 10 mm Hg from baseline. Patients underwent 24hour ambulatory BP monitoring (ABPM) at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS: The treatment groups were comparable in their reduction of supine diastolic BP, with no significant differences between the two treatments. Labetalol demonstrated a significantly greater reduction (p <0.05) in standing diastolic BP at the end of the titration period compared to enalapril, but this difference was not significant by the end of the study period. Based on 24-hour ABPM readings, labetalol reduced mean 24-hour diastolic BP (p <0.05) and From the University of Tennessee, Memphis (WBA), Memphis, Tennessee; School of Medicine (NB), University of California, Davis, California: Hypertension Service, Los Angeles County, and University of Southern California Medical Center (VD), Los Angeles, California: San Antonio, Texas (PMK); Kumamato University Medical School (SO), Kumamato City, Japan: and Glaxo, Inc. (DLD, MAS), Research Triangle Park, North Carolina. This work was funded by Glaxo, Inc., Research Triangle Park, North Carolina. Requests for reprints should be addressed to William B. Applegate, M.D., Division of Geriatric Medicine, University of Tennessee, Memphis, 66 North Pauline, Suite 232, Memphis, Tennessee 38163. Manuscript submitted May 25, 1990, and accepted in revised form October 1. 1990.
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mean heart rate (p <0.05) more than enalapril. The labetalol-treated patients were significantly less often above their diastolic BP goal throughout the 24-hour ABPM period (p X0.01). The two treatments were equally well tolerated. CONCLUSIONS: The results indicate that labeta101 and enalapril are equally effective in lowering supine diastolic BP in the elderly, but labetalol is more effective in lowering ambulatory BP and heart rate throughout the day.
H
ypertension is a major health care problem for the elderly, affecting almost 50% of those individuals aged 65 years or older [1,2]. Essential hypertension in the elderly differs from that found in the younger patient. Hypertension in the elderly is generally characterized by elevated total peripheral resistance and reduced cardiac output and renal blood flow [3]. Elderly hypertensive patients tend to have reduced plasma renin activity and their responsiveness to norepinephrine is impaired [4]. Elevation of either systolic or diastolic blood pressure (BP) is a well-recognized risk factor for cerebrovascular and cardiovascular morbidity and mortality in elderly patients [5-111. In the Framingham Study, elderly patients with hypertension had a threefold greater incidence of coronary heart disease, congestive heart failure, and cerebrovascular accidents as compared to normotensive patients [8]. Several trials have documented the value of diastolic BP control for the elderly patient, while the impact of drug treatment of isolated systolic hypertension is still under study [g-12]. The efficacy of antihypertensive medication is typically evaluated by mean BP measurement during clinical visits. However, 24-hour ambulatory BP monitoring (ABPM) may more accurately assess BP control throughout the day and during the early morning hours when BP typically rises [13]. Control of BP and heart rate during this morning “acceleration period” may be important because a relatively higher number of coronary heart disease and stroke 90
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events occur within the first few hours after awakening [14-191. Labetalol possesses both selective cri- and nonselective P-blocking properties [20,21]. It reduces peripheral vascular resistance and BP while preventing reflex tachycardia. Recent studies have shown that it is an effective antihypertensive agent when used for either diastolic [22] or isolated systolic hypertension [23] in elderly patients and prevents the early morning acceleration in BP [24]. Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, also reduces peripheral resistance and BP [25] and has been shown to be effective in treating elderly patients with diastolic hypertension in short-term clinical trials [26]. The present study was designed to compare the effects of labetalol to enalapril on BP and heart rate in elderly patients with diastolic hypertension using 24-hour ABPM. In addition, the safety profile of each drug was compared in this group of elderly patients.
PATIENTS AND METHODS Enrollment Elderly male and female outpatients with a history of hypertension were eligible for enrollment into this open-label, controlled multicenter trial. Female candidates were either postmenopausal or had a previous hysterectomy. Inclusion criteria required patients to be 65 years or older and have an average standing diastolic BP 95 mm Hg or above and 114 mm Hg or less at the end of the third and fourth weeks of the initial placebo phase. Exclusion criteria were as follows: uncontrolled diabetes mellitus or congestive heart failure; unstable angina pectoris; major cardiac conduction abnormalities including atrioventricular blockade greater than first degree; severe arrhythmia or bradycardia (less than 50 beats/minute); recent (within the previous 6 months) myocardial infarction or cerebrovascular accidents; bronchial asthma or bronchospastic chronic obstructive pulmonary disease requiring bronchodilator therapy; secondary or complicated hypertension requiring surgical intervention; systolic BP more than 220 mm Hg; clinically significant hepatic or renal disease; or a history of alcoholism, drug abuse, psychosis, or other personality problems that would limit the validity of consent to participate in the study. Patients with a history of intolerance to P-blockers or ACE inhibitors, recent treatment (within the prior 2 weeks) with guanethidine or rauwolfia agents, or treatment with an investigational drug within the prior month were not eligible for study participation. Randomized patients were not permitted to take any antihypertensive agent other than the study medications during the study period.
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The study protocol was reviewed and approved by the participating institutions’ review committees. All patients provided written informed consent prior to enrolling in the study. The study was conducted in two phases. Phase 1 was a single-blind, 4-week placebo washout phase. Enrolled patients were switched from their current antihypertensive regimen to placebo (one tablet twice a day). BP was measured at Weeks 0,2,3, and 4 during the placebo period. The Visit 4 BP at the end of the placebo period was the baseline BP. Phase 2 was an open-label, 12-week, active treatment period in which eligible patients were randomized to receive either oral labetalol, 100 mg twice a day, or enalapril, 5 mg once daily. Individualized dosage adjustments were made every 2 weeks over the first 6 weeks of active treatment if necessary to meet BP control criteria. The treatment goals were to decrease the standing diastolic BP by 10 mm Hg from baseline (end of the placebo phase) and to less than 90 mm Hg. The protocol allowed doses ranging from 100 to 400 mg twice daily of labetalol or 5 to 40 mg once daily of enalapril. Data Collection Medical personnel taking BPS and heart rate and eliciting adverse events were unaware of the identity of the study treatment. BPS were measured by a trained nurse or technician using a mercury sphygmomanometer. Supine BPS were taken after a 5minute rest period. Standing measurements with the arm at the level of the heart were taken in succession after 1 minute of standing. The average of three supine and standing measurements for both diastolic and systolic BPS was computed and recorded at each clinic visit. None of the patients were found to have postural hypotension at baseline (defined as a postural drop of systolic BP of 20 mm Hg or more). Pulse rate was also recorded. Patient’s usage of other drugs as well as concomitant illnesses and adverse events was evaluated at each clinic visit. The investigators determined the relationship between a reported adverse event or laboratory abnormality and active drug therapy based on clinical judgment. Compliance with the prescribed regimen was assessed by tablet counts of unused medication and recorded at each clinic visit. Patients underwent 24-hour ABPM measured by an AccutrackerTM recorder (Suntech, Raleigh, North Carolina) once at the completion of the placebo phase and again at the end of 8 weeks of active treatment. The Accutracker is an R-wave gated device that utilizes a piezoelectric microphone to measure phase 1 and phase 5 Korotkoff sounds [27]. When the ABPM device was applied, the first diastolic BP displayed by the Accutracker was re-
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TABLEI Mean Differences in Blood Pressure (Standing and Supine) and Heart Rate from Baseline to the End of the Titration and Treatment Periods Standing Labetalol Enalapril Mean SEM Mean SEM To end of titration period (baseline to Week 8) SBP (mm Hg) DBP (mm Hg) HR (beats/minute)
2.5 1.47
2.06
-2E
To end of treatment period (baseline to Week 12) SBP (mm Hg) DBP (mm Hg) HR (beats/minute)
pVa1ue-t
(n = 37)”
(n = 34)*
-22.62*
Supine Labetalol Enalapril Mean SEM Mean SEM
-16.08$ -10.97* 0.27
(n = 31)’
(n = 34)”
3.09 1.25 2.27
oNi4
2.21
-11.41$
1.35
-3.68
3.25
-1;t:g:
1.21 1.70
1.88
-12.7* -1o.o* -0.95
(n = 31)”
(n = 36)*
-19.26*
(n = 37)*
-16.44*
0.07
1:;:;;: -0.11
3.08
NS
1.12
NS
2.17
-13.48* -2;:;;:
p Value?
2.78 1.24 1.71
NS
3.0
NS
Ii:
(n = 36)*
3.24
-18.14*
1.25
1.71
1.34 -3:~;
2.06
O.“os
I SBP = svstalic blood oressure: DBP = diastolic blood pressure; HR = heart rate: NS = not significant. * Sample size differences due to dropouts. t Two-sample t-test (labetalol versus enalapril). T p CO.01 (baseline versus follow-up within treatment group).
differential, and urine sample for urine protein determination were obtained at the beginning and end of phase 1 and at the end of Weeks 8 and 12 of phase 2.
TABLE II Mean Differences in Blood Pressure, Heart Rate, and Area Under the Curve for ABPM Readings for Labetalol Versus Enalapril from Baseline to Week 8 Labetalol (n = 24)* Mean SEM Mean 24-hour values SBP (mm Hg) DBP (mm Hg) HR (beats/minute) Area under the curve SBP DBP HR
-12.0
-8.8 -6.4
3.0 1.3 1.3
-281.7
68.7
-202.6
29.4
-145.2
27.6
Enalapril ,‘,“,; 26)* SEM -8.0 -4.9 -1.8 -187.5
-117.3 -39.3
pValuet
1.9
0.26
1.0 1.2
0.01
39.1 21.2 25.9
0.02 0.12 0.01
0.004
3PM = ambulatory blood pressure monitoring; other abbreviations as in Table I. Includes only those patients who had ABPMs performed on both occasions. t Two-sample t-test.
quired to match within f5 mm Hg with the average indirect sphygmomanometer readings for that day. One reading was taken every 20 minutes from 6 AM to 12 PM and every 30 minutes for the remainder of the 24-hour period. Readings had to fall in the following ranges to be considered valid: diastolic BP 50 to 140 mm Hg, systolic BP 90 to 255 mm Hg, pulse pressure 10 to 100 mm Hg, and heart rate 40 to 160 beats/minute. Also, the maximum change from the previous reading allowed was: diastolic BP 30 mm Hg or less, systolic BP 60 mm Hg or less, and heart rate 60 beats/minute or less. At least 70% of the hourly BP recordings had to be valid [28]; if not, the 24-hour ABPM measurement was repeated, or the patient’s data were excluded from the ABPM analysis. A medical history, a physical examination, and 12-lead electrocardiogram were undertaken prior to the initiation of phase 1 and at the end of phase 2. A chest radiograph was obtained at the initiation of phase 1 only. A fasting SMA-12 profile, serum creatinine measurement, complete blood count with 200
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Statistical Analysis A two-tailed t-test was used to compare the two treatment groups for age, weight, systolic and diastolic BPS, and heart rate. Group distributions of sex, race, and hypertension history were compared using Fisher’s exact test. A two-sample t-test was used to compare the diastolic and systolic BPS and heart rate of the two treatment groups at baseline versus at the end of the eighth and 12th weeks of the study. Standing diastolic BP was used to determine primary efficacy. The SAS procedure REG was used to fit a linear regression model for systolic, diastolic, and mean arterial BPS and heart rate as a function of the hour in which the readings were taken [29]. A one-sample t-test was used to analyze mean differences between the first and second ABPM data. A two-sample ttest was used to compare the hourly heart rates and BPS as well as areas under the curve for ABPM readings of labetalol-treated and enalapril-treated patients. The Pearson chi-square test was used to compare the percentages of patients with ABPM readings above preselected levels by time period from baseline to the eighth week of treatment. Mean differences in laboratory values from baseline to study completion were compared using a two-sample t-test. The frequencies of adverse events in the two treatment groups were compared using Fisher’s exact test.
RESULTS Of the 132 patients screened, 79 (51 men, 28 womcriteria and were enrolled into
en) met all inclusion
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Figure 1. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory systolic blood pressure by hour. Vertical line indicates a significant difference (p <0.05) between
labetalol
and
130 0
2
4
6
8
10
12
14
16
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32
24
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enalapril.
the study. The patients’ ages ranged from 62 to 79 years. An exception was made to the inclusion criteria for one 62-year-old patient who satisfied all criteria except that of age 65 years or older. Thirtynine patients were randomized to labetalol and 40 patients to enalapril. There were no differences between the labetalol and enalapril groups with regard to sex (67% versus 63% males, respectively), age (70.2 years versus 69.8 years), weight (79.8 kg versus 80.2 kg), race (69% versus 65% whites), prior hypertension history (74% versus 70% with diagnosis for 6 years or more), baseline standing diastolic BP (lb0 mm Hg versus 100.3 mm Hg), or baseline standing systolic BP (163.9 mm Hg versus 163.4 mm Hg). Labetalol and enalapril both effectively (p
tion of the study. These declines were approximately 7 beats/minute. Enalapril had no effect on heart rate. BP control at study completion occurred at a mean (SEM) daily dose of 322 mg (29) and 12 mg (2) of labetalol and enalapril, respectively. ABPM cif the 79 patients enrolled in the study, 50 completed both 24-hour ABPMs with valid readings: 24 patients who were receiving labetalol and 26 patients who were receiving enalapril. These treatment subgroups were comparable based on sex, age, weight, race, and prior hypertension history. Sixteen of the 24 (67%) labetalol-treated patients and 13 of the 26 (50%) enalapril-treated patients were normotensive based on clinic BP measures prior to the second 24-hour ABPM. There were no differences in the proportion normotensive between those who did and did not complete valid ABPM studies at the Week 8 visit for either treatment group. At 8 weeks, labetalol-treated patients showed a significantly greater decrease in mean 24-hour diastolic BP (8.8 mm Hg versus 4.9 mm Hg, p = 0.02) and mean 24-hour heart rate (6.4 beats/minute versus 1.8 beats/minute, p = 0.01) than the enalapriltreated patients (Table II). The labetalol group
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Figure ?. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory diastolic blood pressure by hour. Vertical line indicates a significant difference (p <0.05) between labetalol and enalapril.
showed a significantly (p
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interval (Figures 1 and 2). Similar, significantly greater reductions were also noted for mean arterial pressure. The heart rate of patients taking labetalol was significantly lower than that of the enalapriltreated patients at every hour except hours 0,3 AM, and 5 PM (p <0.05) (Figure 3). Adverse Events and Laboratory Abnormalities Two patients randomized to receive enalapril left the study due to adverse effects including dizziness, fainting, fatigue, and depression. One patient receiving labetalol discontinued treatment prematurely due to fatigue and weakness. Another labetalol-treated patient was dismissed from the study after 6 weeks of active treatment due to weight gain, headache, fatigue, shortness of breath, and peripheral edema. Six labetalol-treated and five enalapriltreated patients experienced adverse events thought to be related to drug therapy. There was no significant difference between the two treatment groups with regard to frequency of adverse effects (Table III). Analysis of mean differences in laboratory parameters between baseline and completion of the
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Figure 3. Effects of labetalol (L) and enalapril (E) on mean 24-hour ambulatory heart rate by hour. Vertical line indicates a significant difference (p <0.05) between labetalol and enalapril.
0
2
.
6
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10
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12
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14
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24
HOUR
.
.n.
,I
4
1
study demonstrated statistically sigmrlcant but relatively small differences between the treatment groups for red blood cell and platelet counts.
r
TABLE
III
Number and Percentageof AdverseEventsRelatedto Drug Therapy
COMMENTS Both labetalol and enalapril effectively lowered standing and supine systolic and diastolic BPS in older patients with hypertension. Labetalol significantly decreased heart rate, which was unchanged by enalapril. These effects of labetalol are consistent with findings from other studies [22,23]. Both drugs were well tolerated, with equal numbers of withdrawals from treatment due to side effects. Comparison of the drugs’ effects on BP as measured by 24-hour ABPM showed that labetalol more consistently maintained control of BP and heart rate throughout the day and demonstrated a significantly greater decrease in mean 24-hour diastolic BP and a significantly greater decrease in mean AUC for 24-hour diastolic BP and heart rate. In addition, labetalol showed a nonsignificant tendency to blunt the early morning increase in BP so that BP did not rise quite as high as with enalapril in the early morning hours. The early morning increase in heart
Reported
Labetalol (n = 39)
Adverse Effect
Dizziness/lightheadedness Tiredness/fatigue Headache Weakness Drained feeling Tendency to faint Depression Impotence Dryness of mouth Uncontrolled blood pressure
Enalapril (n = 40) 1(2.5%) ; (5.o%) 0
0 i Fl 0
rate was significantly less with labetalol than with enalapril. Relatively few studies have directly compared different antihypertensive agents as monotherapy in elderly patients [30]. Most of the studies that do exist have compared antihypertensive agents versus hydrochlorothiazide or placebo [23,26,31]. Although diuretics are effective in lowering BP in the elderly, questions remain about the metabolic side
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effects [32]. Recently, 105 hypertensive patients (mean age 55) were randomized to labetalol or prazosin. Although there were no significant differences in the amount of reduction in BP measured in the clinic, ABPM revealed that the labetalol-treated patients had significantly greater reductions of systolic and diastolic BP during the daytime hours [33]. Several studies have compared ACE inhibitors versus diuretics in elderly patients with hypertension and have generally found that either drug class is equally effective in controlling BP based on clinic BPS but the diuretics generally cause more metabolic side effects [26,34,35]. In this study, the fact that labetalol showed greater control of the early morning increase in heart rate and demonstrated betber control of BP throughout the day could be due to its combined (YIand ,&adrenoreceptor blocking activity [36]. It has been postulated that part of the pathophysiology of hypertension in the elderly may involve the possibility that peripheral a-adrenergic vasoconstriction is relatively unaffected by age [37], while ,f%adrenergic vasodilatation may be blunted [38]. There are several potential limitations of the current study. This was an open-label randomized study and the possibility of bias in observation of clinic BPS measured with a mercury sphygmomanometer cannot be excluded. Nonetheless, efforts were made to ensure the clinical personnel performing BP measurements were unaware of treatment status. Also, any bias that might have existed would not have affected the ABPM results. Second, the study treatment goals were based on standing BP, which could potentially bias the results in favor of labetalol, which is thought to have more of a postural effect. However, both supine and standing BP results are reported here. When clinic BPS were examined, the drugs were equally effective in lowering supine BP, while labetalol showed an early tendency to cause greater reductions in standing BP (which disappeared by the end of the total treatment period). The ABPM measures would appear to resolve this issue since BPS were recorded at regular intervals throughout the day, allowing for a variety of activities. Also, the ABPM measures were made at Week 8, when differences in standing diastolic BP between the two treatment groups were the greatest. It is possible that the differences seen between the two groups with ABPM could have diminished if these measures were repeated at the end of the study. On the other hand, at times, differ ences between treatment regimens may be detected by ABPM but not by clinic measures [33,39]. Finally, although a number of subjects did not successfully complete ABPM, there would appear to be no inherent bias since the remaining treatment sub204
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groups continued to be evenly matched on a number of demographic and clinical variables and the rate of BP control within the two groups did not differ between those who did and did not have valid ABPM recordings. In conclusion, results of this study suggest that labetaiol and enalapril are both well tolerated and effective in lowering elevated diastolic and systolic BP in elderly hypertensive patients. Both drugs are equally effective in lowering supine office BP measures. However, labetalol appears to more consistently maintain BP and heart rate control as assessed by ABPM compared to enalapril.
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2. Hulley SB, Furberg CD, Gurland D, et al. Systolic hypertension in the elderly program (SHEP): antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985; 56: 913-20. 3. Messerli FH, Sundgaard-Riise K, Ventura HO, eta/. Essential hypertension in the elderly: hemodynamics. intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet 1983: 2: 983-6. 4. Drayer JI, Weber MA. Hypertension in the elderly: a new understanding. Drug Ther Bull 1981; 11: 91-8. 5. The Working Group on Hypertension in the Elderly: Statement on hypertension in the elderly. JAMA 1986; 256: 70-4. 6. Amery A, Birxko P, Clement D, et a/. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; 1: 1349-54. 7. Curb JD. Borhani NO, Schnaper H, et al. Detection and treatment of hypertension in older individuals. Am J Epidemiol 1985; 121: 371-6. 8. Kannel WB, Wolf PA, McGee DL, eta{. Systolic blood pressure, arterial rigidity and risk of stroke: the Framingham study. JAMA 1981; 245: 1225-9. 9. Hypertension Detection and Follow-up Program Cooperative Group: Fiveyear findings of the Hypertension Detection and Follow-up Program: II, Mortality by race, sex and age. JAMA 1979; 242: 2572-7. 10. Management Committee of the National Heart Foundation of Australia: Treatment of mild hypertension in the elderly. Med J Aust 1981; 2: 398-402. 11. Hypertension Detection and Follow-up Program Cooperative Group: Fiveyear findings of the Hypertension Detection and Follow-up Program: Ill. Reduction in stroke incidence among persons with high blood pressure. JAMA 1982; 247: 633-8. 12. Systolic Hypertension in the Elderly Program Cooperative Research Group. Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension. J Clin Epidemiol 1988; 41: 1197-208. 13. Weber MA. Drayer JIM, Nakamura DK, Wyle FA. The circadian blood pressure pattern in ambulatory normal subjects. Am J Cardiol 1984; 54: 1115-g. 14. Meyers A, Dewars HA. Circumstances attending 100 sudden deaths from coronary artery disease with coroners’ necropsies. Br Heart J 1975; 37: 113343. 15. Muller JE, Stone PH, Turi ZG, et a/. Circadian variations in the frequency of onset of acute myocardial infarction. N Engl J Med 1985; 313: 1315-22. 16. Muller JE, Ludmer PL, Willich SN, eta/. Circadian variation in the frequency of sudden cardiac death. Circulation 1987; 75: 131-8. 17. Willich SN, Linderer T, Wegscheider K, et al. Increased risk of myocardial infarction in the morning [Abstract]. J Am Coll Cardiol 1988; 11: 28A. 18. Willich SN, Levy D, Rocco MB, et al. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol 1987; 60: 801-6. 19. Tsementzis SA, Gill JS, Hitchcock ER, et a/. Diurnal variation of activity and onset of stroke. Neurosurgery 1985: 17: 901-4. 20. Blakeley AGH, Summers RJ. The effects of labetalol (AH 5158) on adrenergic transmission in the cat spleen. Br J Pharmacol 1977; 59: 643-50. 21. Richards DA. Pharmacological effects in labetalol in man. Br J Clin Pharma-
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32. Pollare T, Lithell H, Berne C. A comparison of the effect of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension, N Engl J Med 1989; 321: 868-73. 33. Gray JM, Silberman HM, Gorwit JI. Comparison of labetalol and prazosrn in hypertensive patients using automated ambulatory monitoring. Am J Med 1988; 84: 904-10. 34. Verza M, Cacciapuoti F, Spieza R, eta/. Effects of the angiotensrn converting enzyme inhibitor enalapril compared with diuretic therapy in elderly hypertensive patients. J Hypertens 1988; 6 (Suppl 1): 597-9. 35. Fries ED for the Veterans Administration Cooperative Study Group on Antihypertensive Agents. Age and antihypertensive drugs (hydrochlorothiazide, bendroflumethiazide, nadolol, and captopril). Am J Cardiol 1988; 61: 117-21. 36. Koch G. Hemodynamic changes after acute and long term combined alphabeta adrenoreceptor blockade with labetaiol as compared with beta receptor blockade. J Cardiovasc Pharmacol 1981; 3 (Suppl 1): S30-41. 37. Abrass IB. Catecholamine levels and vascular responsiveness in aging. In: Horan MJ. Steinberg GM, Dunbar JB, Hadley EC, eds. Blood pressure regulation and aging, an NIH Symposium. New York: Biomedical Information Corporation, 1986: 123-30. 38. Bertel 0, Buhler FR. Kiowski W. Lutold BE. Decreased beta-adrenoreceptor responsiveness as related to age, blood pressure, and plasma catecholamines in patients with essential hypertension. Hypertension 1980; 2: 130-8. 39. Weber MA, Cheung DG, Graettinger WF, Lipson JL. Characterization of antihypertensive therapy by whole-day blood pressure monitoring. JAMA 1988; 259: 3281-5.
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