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Prazosin versus captopril as initial therapy: Effect on hypertension and lipid levels
Prazosin Versus Captopril as Initial Therapy Effect on Hypertension and Lipid Levels
A randomized, parallel group study evaluated the safety, efficacy, and effect of the alpha blocking agent prazosin and the angiotensin converting enzyme inhibitor captopril on serum lipid levels in patients with mild to moderate hypertension. Baseline evaluations were performed on 31 patients after a four-week placebo washout period. Patients were randomly assigned to receive either prazosin (n = 15) or captopril (n = 16). Daily doses were titrated as follows: for prazosin, 1 mg two times daily to a maximum of 20 mg per day; for captopril, 25 mg three times daily to a maximum of 450 mg per day. If diastolic blood pressure was not adequately controlled (less than 65 mm Hg) after four weeks of monotherapy, 1 mg of polythiazide was added to the daily regimen. There were no statistically significant differences between the drug groups for the measured variables in either the parallel or crossover phase of the study. Five of 15 prazosin-treated patients and six of 16 captopril-treated patients required the addition of thiazide to achieve blood pressure control.
RONALD OKUN, M.D. JEFFREY KRAUT, M.D. Los Angeles,
California
From the Department of Clinical Pharmacology at Cedars-Sinai Medical Center, Hypertension Service, Veterans Administration Hospital, and the Departments of Medicine and Pharmacology at the Center for Health Sciences, University of California at Los Angeles, Los Angeles, California. Requests for reprints should be addressed to Dr. Ponald Okun, Department of Clinical Pharmacology, Cedars-Sinai Medical Center, Box 48750, Los Angeles, California 90048-0750.
58
January
5, 1987
The American
Journal
After almost a decade of clinical use, the selective alpha, blocker prazosin is firmly established as a safe and effective antihypertensive drug when used as monotherapy or in combination with other agents [l]. Prazosin displays a favorable side-effects profile, and many controlled trials have shown it to have generally no adverse effects on serum lipid levels. When it was originally introduced into the antihypertensive market, the angiotensin converting enzyme inhibitor captopril was reserved for patients with resistant hypertension. Captopril was originally approved for use only in patients whose blood pressure was uncontrolled with other drugs, or in patients who experienced unacceptable side effects with other drug therapies. However, this agent is currently approved for use in patients with mild to moderate hypertension and is being employed as initial therapy. Although the physician’s antihypertensive armamentarium has increased greatly with the introduction of many new agents, it is essential that the drug chosen for initial antihypertension therapy be one that is well established and has a proven record of safety and efficacy. In order for a newer agent to gain acceptance in the clinical setting, it must offer benefits that the older agents do not offer, without compromising patient safety. A study was undertaken to compare the safety and efficacy of prazosin and captopril in the treatment of patients with mild to moderate hypertension. The effects of these two agents on the serum lipid profile were also evaluated.
of Medicine
Volume
82
(suppl
1A)
SYMPOSIUM
PATIENTS
AND METHODS
5, 1987
and KRAUT
chest roentgenogram were obtained at baseline. Physical examination, electrocardiography, and fundoscopy, all performed at baseline, were repeated at the end of the study. Blood pressure measurements, body weight, and clinical evidence of edema were recorded at each visit. At the end of the baseline washout phase, the monotherapy phase, and (if relevant) the combination therapy phase, measurements of blood urea nitrogen, creatinine clearance, blood neutrophils, serum potassium, urinary proteins, and serum lipids were performed. Levels of total serum cholesterol, high-density lipoprotein, high-density lipoprotein-2, high-density lipoprotein-3, low-density lipoprotein, very-low-density lipoprotein, and triglycerides were all determined on fresh specimens, drawn from patients who had fasted overnight, in the laboratory of Dr. Howard A. Eder at the Albert Einstein College of Medicine in New York using recognized methodology. Side effects reported by patients were recorded, including duration and an evaluation of relationship to drug therapy. Patients were withdrawn from the study for any of the following reasons: evidence of drug hypersensitivity or intolerance; major intercurrent illness or major surgery; pregnancy occurring during the study; and lack of cooperation. Any patient whose blood pressure was not controlled or significantly decreased by maximum doses of study drugs was withdrawn from the study and assigned to alternative therapy. Statistical Methods. The variables analyzed were sitting and standing systolic and diastolic blood pressures based on the average of three readings; sitting and standing heart rates; total cholesterol; low-density lipoprotein, high-density lipoprotein, high-density lipoprotein-2, and high-density lipoprotein-3 cholesterol levels; triglycerides; blood urea nitrogen; serum creatinine and potassium; blood neutrophils; and urinary protein. Baseline was defined as the final visit of the placebo washout period. The change from baseline to each patient’s final visit was calculated; these values were the basis of the statistical analysis. For patients who received thiazide, the change from the last prediuretic visit to the final visit on combined therapy was calculated and analyzed. Separate analyses were performed for patients receiving thiazide and for those not receiving thiazide. However, since the number of patients receiving thiazide was relatively small, the statistical analysis reflects only trends. The statistical analysis was performed using paired and two-sample t tests to assess the significance of the withingroup and between-group differences. Adverse effects were summarized by treatment to evaluate safety.
In this randomized, parallel group study, all antihypertensive medication was discontinued for a minimum washout period of four weeks, during which unmatched placebo was administered. Patients were entered into the study and baseline evaluations were performed at the end of the washout phase on those patients whose sitting diastolic blood pressure was equal to or greater than 100 mm Hg. Patients were then randomly assigned to receive either prazosin or captopril. Medication was administered by a neutral party who did not see the results. The physician and the laboratory were unaware of which medication the patients received. The initial prazosin dose was 1 mg twice daily; the initial captopril dose was 25 mg three times daily. Dosages were titrated until a sitting diastolic blood pressure of less than 85 mm Hg was achieved or until unacceptable side effects were manifested. The maximum daily doses were 20 mg of prazosin and 450 mg of captopril. Patients continued to take their respective maintenance doses for a minimum of eight weeks. Captopril-treated patients were instructed to take the study medication one hour prior to meals and to report any sign of infection such as sore throat or fever; in such cases, a neutrophil count was performed. Any patient whose blood pressure was controlled with monotherapy had final evaluations performed at the end of the eight-week maintenance period at the optimal dose. Patients whose blood pressures were not satisfactorily controlled after four weeks with prazosin or captopril alonewhether because the maximum dose was reached, side effects limited further increases in dosage, or fluid retention was detected-had clinical evaluations repeated. At that point, 1 mg of polythiazide was added to the daily regimen. If the study drug was not already titrated to the optimal dose, the dose titration was continued after the addition of the thiazide. When thiazide was added to prazosin, the prazosin dose was reduced to 6 mg daily and retitrated upwards until blood pressure control was reached. After an eight-week period with the maintenance dose of the study drug plus thiazide, final evaluations were performed. Study participants were recruited from the Hypertension Clinic at the Veterans Administration Hospital in Los Angeles. Patients included in the study ranged in age from 21 to 72 years and had an average sitting baseline (with placebo) diastolic blood pressure greater than or equal to 100 mm Hg as measured on two consecutive visits. Exclusion criteria included severe cardiovascular complications, including stroke, myocardial infarction within the past six months, congestive heart failure, or renal failure; metabolic disorders requiring drug treatment known to affect serum lipids; pregnancy, lactation, or likelihood of pregnancy during the study period; history of noncompliance; blood donation during the study period; and use of concomitant antihypertensive, sedative, tranquilizer, or oral contraceptive agents. Periodic ingestion of medications that did not interfere with the antihypertensive agents used in the study was not a disqualifying criterion. Informed written consent was obtained from all patients. As much as possible, each patient’s diet, daily activities, weight, smoking habits, and alcohol intake were kept constant throughout the study. A complete patient history and a
January
ON ALPHA BLOCKADE-OKUN
RESULTS Thirty-one patients were randomly assigned to receive the study medication. Of these, 21 were evaluated in the statistical analysis. Of the 21, 10 were also crossed-over, and thus received both study medications. Five patients were not evaluable for the following reasons: dropped out during titration (two); diabetes (two); and goiter recurrence (one). None of these five patients dropped out due to drug-related side effects. The remaining five dropped out of the study for non-medical reasons.
The
American
Journal
of Medicine
Volume
82 (suppl
1A)
59
SYMPOSIUM
ON ALPHA BLOCKADE-OKUN
TABLE I
and KRAUT
Baseline Demographics Captopril
Prazosin (n = 15) Weight (pounds)* Duration of hypertension Age (years)* Sex (male/female) Race White Black ‘Data
are mean
(years)*
period, sitting diastolic blood pressure was 80.3 k 1.4 mm Hg in the prazosin group and 79.2 k 5.5 mm Hg in the captopril group. Final sitting diastolic blood pressure in the monotherapy group was 87.8 +- 8.9 mm Hg in the prazosin group and 85.6 k 8.9 mm Hg in the captopril group. Five patients in the prazosin group required the addition of thiazide for control of blood pressure. The combination produced a mean 8.7 mm Hg decrease in sitting diastolic pressure, over and above the mean 9.8 mm Hg decrease with prazosin alone, resulting in a sitting diastolic pressure of 86.8 ~fr9.8 mm Hg. Blood pressure in six patients in the captopril group was not controlled with captopril alone; when thiazide was added to the regimen of these non-responders, the combination resulted in an exaggerated response, with a resultant sitting diastolic blood pressure of 76.4 k 8.1 mm Hg. The baseline standing diastolic blood pressures for the prazosin- and captopril-treated patients were 95.2 k 3.0 mm Hg and 97.8 -+ 4.8 mm Hg, respectively (Table Ill). At the end of the titration period, the respective corresponding values for the two groups were 78.5 k 4.5 mm Hg and 81.3 r 7.6 mm Hg. At the end of monotherapy, standing diastolic blood pressure was 84.9 L 11.1 mm Hg in the prazosin group and 85.2 i 13.4 mm Hg in the captopril group. In those patients requiring the addition of 1 mg of thiazide to the study drug regimen, the values at the end of combination therapy were 87.1 L 9.3 mm Hg in prazosin-treated patients and 76.1 -I- 8.6 mm Hg in captopril-treated patients. There was little, if any, effect on heart rate following therapy with prazosin or captopril, whether accompanied by thiazide therapy or not. Lipid Variables. Prazosin treatment resulted in a greater reduction in low-density lipoprotein cholesterol levels and a corresponding greater increase in high-density lipoprotein-2 cholesterol levels than did captopril treatment. However, there were no statistically significant differences between prazosin or captopril monotherapy in terms of
(II = 16)
186.1 ? 30.0 14.3 f 10.8 63.2 * 8.4 I.510
185.8 ZL 25.2 12.4 ? 6.9 59.5 k 9.2 1610
9 6
8 8
f SD.
The drug groups were comparable with respect to age, duration of disease, race, sex, and weight (Table I). Treatment. A total of 15 patients received prazosin therapy; five of these patients required thiazide. Six of the 16 patients assigned to captopril therapy required thiazide (Figure 1). The mean daily dose for patients receiving monotherapy with prazosin was 6.6 mg (+- 5.6 mg). Patients receiving prazosin and the I-mg dose of polythiazide required a mean daily dose of 13.2 mg (k 6.4 mg) of prazosin. The corresponding mean values for captopriltreated patients were 165.0 mg (5 136.0 mg) of captopril alone, and 150.0 mg (r 82.2 mg) of captopril in combination with 1 mg of polythiazide. The drug groups were comparable at baseline with regard to all variables. The patients were categorized as responders or non-responders according to their final sitting diastolic blood pressure; responders were required to have a value of less than 85 mm Hg diastolic. There were no significant differences between groups with respect to response. Blood Pressure Control. The efficacy of prazosin and captopril with respect to lowering blood pressure from baseline was comparable (Table II). Baseline sitting diastolic blood pressure was 99.6 k 2.9 mm Hg for both the prazosin and captopril groups. At the end of the titration 3 1 Patients
15 Prazosin
10 Controlled on Monotherapy
60
January
16 Captopril
5 Thiazide Added; Controlled on Combination
5, 1987
The
American
10 Controlled on Monotherapy
Journal
of Medicine
6 Thiazide Added; Controlled on Combination
Volume
82
(suppl 1A)
Figure 1. Schematic diagram of the number of patients whose blood pressure was controlled by monotherapy and those who required the addition of thiazide therapy.
SYMPOSIUM
TABLE
ii
Effects of Therapy
on Sitting
Diastolic
Blood
99.6 80.3 87.8 6.6
i k k t
Prazosin plus Thiazide* (n = 5)
2.9 1.4+ 8.9+§ 5.6
*Thiazide dose was 1 mg of polythiazide daily. tSignificantly different from baseline (p ~0.05). *Significantly different change from baseline, prazosin “Significantly different from end of titration (p ~0.05).
TABLE
ill
Effects of Therapy
versus
on Standing
105.2 95.5 86.8 13.2
captopril
Diastolic
95.2 78.5 84.9 6.6
k -e + 2
% t it k
Captopril plus Thiazide* (n = 6)
Captoprii (n = 10)
4.5 7.3+* 9.8+ 6.4
99.6 79.2 85.6 165.0
k f k -t
2.9 5.5+ 8.gt’ 136.0
101.4 99.2 76.4 150.0
k 3.2 I! 7.5 5 8.1t§ -+ 82.2
(p = 0.05).
Blood
Pressure
Prazosin plus Thiazide* (n = 5)
Prazosin (n = 10) Baseline (mm Hg) End of titration (mm Hg) End of maintenance (mm Hg) Average daily dose (mg rc_ SD)
and KRAUT
Pressure
Prazosin (n = 10) Baseline (mm Hg) End of titration (mm Hg) End of maintenance (mm Hg) Average daily dose (mg k SD)
ON ALPHA BLOCKADE-OKUN
3.0 4.5+ ll.l+ 5.6
108.1 100.3 87.1 13.2
+k -c ?
Captoprii plus Thiazide’ (n = 6)
Captoprii (n = 10)
7.8 9.1 9.3+’ 6.4
97.8 81.3 85.2 165.0
k 2 k -t
4.8 7.6+ 13.4+ 136.0
103.4 100.4 76.1 150.0
? 2 2 ?
5.2 7.8 8.6+* 82.2
“Thiazide dose was 1 mg of polythiazide daily. +Significantly different from baseline (p 10.05). *Significantly different from end of titration (p ~0.05).
TABLE
IV
Effects
of Monotherapy
on Lipid
Profile
Variables Prazosin
Number of patients Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides *Significantly
different
percent
Mean Percent Change lmm Baseline
Baseline (Wdl)
Parameter
change
214.3 149.9 41.7 14.1 27.5 116.2 from
baseline
2 f ? -*tk
15 52.8 48.3 11.5 6.7 7.2 29.8 (n = 14)
for prazosin
Captoprii
versus
their effects on lipid profile variables, i.e., mean percent changes from baseline in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-density lipoprotein-2 cholesterol, and high-density lipoprotein-3 cholesterol (Table IV). The lack of statistical significance of changes in these cholesterol parameters is probably due to the wide scatter among patients. It is important to note, however, that the addition of thiazide to either prazosin or captopril monotherapy resulted in an increase from baseline in total cholesterol and low-density lipoprotein cholesterol levels, and decreases in highdensity lipoprotein cholesterol, high-density lipoprotein-2 cholesterol, and high-density lipoprotein-3 cholesterol lev-
January 5,1987
-3.0 -4.5 +1.1 +50.1 t8.5 +15.1 captopril,
t 2 k -t ? f
14 11.6 14.9 14.3 177.9 30.6 27.3* (n = 13) based
on Mann-Whitney
Baseline bwdi) 204.6 138.4 37.7 11.9 25.7 142.1
16 k t + t t i
36.7 34.3 9.4 7.0 7.1 95.0
Mean Percent Change fmm Baseline +1.3 -0.1 +5.4 -3.6 +14.5 -10.6
15 2 + +-c 5 ?
13.8 17.8 22.7 28.7 68.8 29.3
test (p 10.05).
els (Tables V and Vi). This potentially adverse effect of thiazide on lipid levels has been reported elsewhere [2,3]. SIDE EFFECTS
There were a total of 139 patient complaints reported during the study. Of these, only 10 were considered by the investigator to be related to the study medication; the severity of these drug-related complaints was mild to moderate (Table Vii). Other patient complaints were sporadic in occurrence and did not demonstrate a significant relationship to the study drug. Baseline laboratory values for blood urea nitrogen, creatinine, serum potassium, urinary protein, and blood neu-
The American Journal of Medicine
Volume 82 (suppl 1A)
81
SYMPOSIUM
TABLE
ON ALPHA BLOCKADE-OKUN
V
and KRAUT
Effects of Combination
Therapy
on Lipid Profile
Variables
CaptopriiplusThiazide
PrazosinplusTltiazide
Baseline* imoW
Parameter Number of patients Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides “Baseline
TABLE
refers
VI
MeanPercent Change from Baseline
to the end-of-titration
174.0 113.5 40.8 11.5 29.3 114.8 visit (last
Effects of Monotherapy
visit before
Versus
4 -t 3I + -rt
Baseline* (mu/W
4 36.0 38.8 7.3 6.6 1.7 31.0
+14.1 +24.3 -10.4 -29.1 -2.1 +11.9
diuretic
was added).
Combination
2 -t ” + +2
Therapy
9.1 19.4 8.0 29.9 17.7 18.8
on Lipid
207.5 143.7 41.2 12.0 29.2 112.8
6 + k of: t + +
38.5 31.0 11.7 6.3 6.8 48.0
MeanPercent Change from Baseline +10.1 +17.6 -4.7 +4.5 -0.5 +33.0
6 t + f + k +
7.4 7.9 16.9 21.6 20.3 49.8
Profile
MeanPercentChangefrom Baseline+ SD Prazosin plus Thiazide
Prazosln
Parameter Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides
-3.0 -4.5 +1.1 +50.1 +8.5 +15.1
t a t t t 2
11.6 14.9 14.3 177.9 30.6 27.3
+14.1 W24.3 -10.4 -29.1 -2.1 +11.9
trophils were comparable in both groups. The effects of therapy on laboratory values, as expressed in mean change from baseline, were not significant, with the exception of blood urea nitrogen (Table VIII), which showed a statistically significant (p = 0.01) increase from baseline in patients treated with captopril plus polythiazide. Although the mean percent change between monotherapy and combination therapy attained statistical significance, the actual laboratory values for blood urea nitrogen remained within the average normal range. COMMENTS In this randomized, parallel group study, prazosin and captopril appeared to be comparable in their ability to lower elevated blood pressure in patients with mild to TABLE
VII
Patient Complaints Drug-Related
Considered
to be
Prazosin Captoprii pius plus Prazosin Thiazide Captoprii Thiezide
Complaint Dizziness Dry mouth Shortness of breath
5’ 0 1’
1’ 0 0
0 0 0
1+ 2” 0
*Mild severity. + Moderate severity.
62
January
5, 1967
The
American
Journal
of Medicine
Volume
Captopril
5 ir
9.1 19.4
+1.3 -0.1
++zc 2
8.0 29.9 17.7 16.8
+5.4 -3.6 +14.5 -10.6
Captoprii plus Thiazide
t- 13.8 ? 17.8
+10.1 +17.6
t 2
7.4 7.9
2 2 k -t
-4.7 +4.5 -0.5 +33.0
2 t t+
21.6 21.6 20.3 49.8
22.7 28.7 68.8 29.3
moderate hypertension. After eight weeks, elevated blood pressure was normalized in two thirds of the patients receiving prazosin and captopril monotherapy. In patients who did not show a response to monotherapy, the addition of thiazide produced additional blood pressure lowering effects. In the prazosin-treated patients, addition of thiazide resulted in a 9 to 13 percent reduction in sitting and standing diastolic blood pressures. In the captopriltreated patients, the addition of thiazide dramatically reduced sitting and standing diastolic blood pressures by 22 to 24 percent, in some cases approaching hypotensive levels. It is important to note that in the prazosin nonresponders, sitting and standing diastolic blood pressures decreased 7 to 9 percent before the addition of thiazide, whereas for the captopril non-responders only a 2 to 3 percent reduction resulted. This observation suggests that in the patients receiving captopril plus thiazide, captopril contributed little, if at all, to the observed 22 to 24 percent reduction in blood pressure produced by the combination therapy. The changes in lipid profiles produced by the addition of thiazide to the regimen of a small number of patients were consistent with those observed in other studies [4] that have demonstrated the negative impact thiazides can have on lipid profile variables with regard to cardiovascular heart disease risk.
62
(suppi 1A)
SYMPOSIUM
TABLE
VIII
Effects
of Therapy
on Laboratory
Values
(mean
change
from baseline
Baseline Laboratory Value Blood
urea
Creatinine
nitrogen
(mgidi)
(mgidl)
Serum
potassium
Urinary
protein
Blood
neutrophiis
“Significant
(meqiliter) (g/liter)
change
(1 ,000/mm3) from
baseline
Mean SD Mean SD Mean SD Mean SD Mean SD
Prazosin
Captoprii
15.5 4.5 1.1 0.1 4.4 0.7 0.2 0.2 59.9 8.6
12.3 4.1 1.1 0.3 4.3 0.5 0.4 0.7 57.1 12.4
2.8 2.6 -0.1 0.2 -0.6 0.8 -0.1 0.1 6.0 (n = 2) 8.5
(n = 8)
4.6 -0.0 0.1 0.2 0.9 -0.1 (n = 9) 0.3 -2.4 6.7
and KRAUT
+ SD)
Prazosin plus Thiazide (n = 4)
Prazosin (n = 10) -1.1
ON ALPHA BLOCKADE-OKUN
Captoprii (n = 9) -0.4 4.8 0.4
Captoprii plus Thiazide (n = 5) 7.4* 4.0 0.1
1.1 -0.0 (n = 8)
0.5 -0.4 (n = 8) 0.8 2.3 7.1
0.2 -0.3 0.8 -0.2 (n = 6) 0.7 3.7 (n = 6) 16.1
(p = 0.01).
In summary, this randomized, parallel group study established that the alpha blocker prazosin and the angiotensin converting enzyme inhibitor captopril have comparable antihypertensive effects in patients with mild to moderate hypertension.
REFERENCES 1. 2.
3.
4.
January
5,1987
The
Okun R: Effectiveness of prazosin as initial antihypertensive therapy. Am J Cardiol 1983; 57: 644-649. Ames RP: Coronary heart disease and the treatment of hypertension: impact of diuretics on serum lipids and glucose. J Cardiovasc Pharmacol 1984; 6 (suppi 3): S466-S473. Weinberger MH: Antihypertensive therapy and lipids: evidence, mechanisms, and implications. Arch Intern Med 1985; 145: 1102-1105. Stamler R, Stamler J, Gosch H, et al: initial antihypertensive drug therapy: alpha blocker or diuretic. Am J Med 1986; 80 (suppi 2A): 90-93.
American
Journal
of Medicine
Volume
82
(suppi 1A)
83
A randomized, parallel group study evaluated the safety, efficacy, and effect of the alpha blocking agent prazosin and the angiotensin converting enzyme inhibitor captopril on serum lipid levels in patients with mild to moderate hypertension. Baseline evaluations were performed on 31 patients after a four-week placebo washout period. Patients were randomly assigned to receive either prazosin (n = 15) or captopril (n = 16). Daily doses were titrated as follows: for prazosin, 1 mg two times daily to a maximum of 20 mg per day; for captopril, 25 mg three times daily to a maximum of 450 mg per day. If diastolic blood pressure was not adequately controlled (less than 65 mm Hg) after four weeks of monotherapy, 1 mg of polythiazide was added to the daily regimen. There were no statistically significant differences between the drug groups for the measured variables in either the parallel or crossover phase of the study. Five of 15 prazosin-treated patients and six of 16 captopril-treated patients required the addition of thiazide to achieve blood pressure control.
RONALD OKUN, M.D. JEFFREY KRAUT, M.D. Los Angeles,
California
From the Department of Clinical Pharmacology at Cedars-Sinai Medical Center, Hypertension Service, Veterans Administration Hospital, and the Departments of Medicine and Pharmacology at the Center for Health Sciences, University of California at Los Angeles, Los Angeles, California. Requests for reprints should be addressed to Dr. Ponald Okun, Department of Clinical Pharmacology, Cedars-Sinai Medical Center, Box 48750, Los Angeles, California 90048-0750.
58
January
5, 1987
The American
Journal
After almost a decade of clinical use, the selective alpha, blocker prazosin is firmly established as a safe and effective antihypertensive drug when used as monotherapy or in combination with other agents [l]. Prazosin displays a favorable side-effects profile, and many controlled trials have shown it to have generally no adverse effects on serum lipid levels. When it was originally introduced into the antihypertensive market, the angiotensin converting enzyme inhibitor captopril was reserved for patients with resistant hypertension. Captopril was originally approved for use only in patients whose blood pressure was uncontrolled with other drugs, or in patients who experienced unacceptable side effects with other drug therapies. However, this agent is currently approved for use in patients with mild to moderate hypertension and is being employed as initial therapy. Although the physician’s antihypertensive armamentarium has increased greatly with the introduction of many new agents, it is essential that the drug chosen for initial antihypertension therapy be one that is well established and has a proven record of safety and efficacy. In order for a newer agent to gain acceptance in the clinical setting, it must offer benefits that the older agents do not offer, without compromising patient safety. A study was undertaken to compare the safety and efficacy of prazosin and captopril in the treatment of patients with mild to moderate hypertension. The effects of these two agents on the serum lipid profile were also evaluated.
of Medicine
Volume
82
(suppl
1A)
SYMPOSIUM
PATIENTS
AND METHODS
5, 1987
and KRAUT
chest roentgenogram were obtained at baseline. Physical examination, electrocardiography, and fundoscopy, all performed at baseline, were repeated at the end of the study. Blood pressure measurements, body weight, and clinical evidence of edema were recorded at each visit. At the end of the baseline washout phase, the monotherapy phase, and (if relevant) the combination therapy phase, measurements of blood urea nitrogen, creatinine clearance, blood neutrophils, serum potassium, urinary proteins, and serum lipids were performed. Levels of total serum cholesterol, high-density lipoprotein, high-density lipoprotein-2, high-density lipoprotein-3, low-density lipoprotein, very-low-density lipoprotein, and triglycerides were all determined on fresh specimens, drawn from patients who had fasted overnight, in the laboratory of Dr. Howard A. Eder at the Albert Einstein College of Medicine in New York using recognized methodology. Side effects reported by patients were recorded, including duration and an evaluation of relationship to drug therapy. Patients were withdrawn from the study for any of the following reasons: evidence of drug hypersensitivity or intolerance; major intercurrent illness or major surgery; pregnancy occurring during the study; and lack of cooperation. Any patient whose blood pressure was not controlled or significantly decreased by maximum doses of study drugs was withdrawn from the study and assigned to alternative therapy. Statistical Methods. The variables analyzed were sitting and standing systolic and diastolic blood pressures based on the average of three readings; sitting and standing heart rates; total cholesterol; low-density lipoprotein, high-density lipoprotein, high-density lipoprotein-2, and high-density lipoprotein-3 cholesterol levels; triglycerides; blood urea nitrogen; serum creatinine and potassium; blood neutrophils; and urinary protein. Baseline was defined as the final visit of the placebo washout period. The change from baseline to each patient’s final visit was calculated; these values were the basis of the statistical analysis. For patients who received thiazide, the change from the last prediuretic visit to the final visit on combined therapy was calculated and analyzed. Separate analyses were performed for patients receiving thiazide and for those not receiving thiazide. However, since the number of patients receiving thiazide was relatively small, the statistical analysis reflects only trends. The statistical analysis was performed using paired and two-sample t tests to assess the significance of the withingroup and between-group differences. Adverse effects were summarized by treatment to evaluate safety.
In this randomized, parallel group study, all antihypertensive medication was discontinued for a minimum washout period of four weeks, during which unmatched placebo was administered. Patients were entered into the study and baseline evaluations were performed at the end of the washout phase on those patients whose sitting diastolic blood pressure was equal to or greater than 100 mm Hg. Patients were then randomly assigned to receive either prazosin or captopril. Medication was administered by a neutral party who did not see the results. The physician and the laboratory were unaware of which medication the patients received. The initial prazosin dose was 1 mg twice daily; the initial captopril dose was 25 mg three times daily. Dosages were titrated until a sitting diastolic blood pressure of less than 85 mm Hg was achieved or until unacceptable side effects were manifested. The maximum daily doses were 20 mg of prazosin and 450 mg of captopril. Patients continued to take their respective maintenance doses for a minimum of eight weeks. Captopril-treated patients were instructed to take the study medication one hour prior to meals and to report any sign of infection such as sore throat or fever; in such cases, a neutrophil count was performed. Any patient whose blood pressure was controlled with monotherapy had final evaluations performed at the end of the eight-week maintenance period at the optimal dose. Patients whose blood pressures were not satisfactorily controlled after four weeks with prazosin or captopril alonewhether because the maximum dose was reached, side effects limited further increases in dosage, or fluid retention was detected-had clinical evaluations repeated. At that point, 1 mg of polythiazide was added to the daily regimen. If the study drug was not already titrated to the optimal dose, the dose titration was continued after the addition of the thiazide. When thiazide was added to prazosin, the prazosin dose was reduced to 6 mg daily and retitrated upwards until blood pressure control was reached. After an eight-week period with the maintenance dose of the study drug plus thiazide, final evaluations were performed. Study participants were recruited from the Hypertension Clinic at the Veterans Administration Hospital in Los Angeles. Patients included in the study ranged in age from 21 to 72 years and had an average sitting baseline (with placebo) diastolic blood pressure greater than or equal to 100 mm Hg as measured on two consecutive visits. Exclusion criteria included severe cardiovascular complications, including stroke, myocardial infarction within the past six months, congestive heart failure, or renal failure; metabolic disorders requiring drug treatment known to affect serum lipids; pregnancy, lactation, or likelihood of pregnancy during the study period; history of noncompliance; blood donation during the study period; and use of concomitant antihypertensive, sedative, tranquilizer, or oral contraceptive agents. Periodic ingestion of medications that did not interfere with the antihypertensive agents used in the study was not a disqualifying criterion. Informed written consent was obtained from all patients. As much as possible, each patient’s diet, daily activities, weight, smoking habits, and alcohol intake were kept constant throughout the study. A complete patient history and a
January
ON ALPHA BLOCKADE-OKUN
RESULTS Thirty-one patients were randomly assigned to receive the study medication. Of these, 21 were evaluated in the statistical analysis. Of the 21, 10 were also crossed-over, and thus received both study medications. Five patients were not evaluable for the following reasons: dropped out during titration (two); diabetes (two); and goiter recurrence (one). None of these five patients dropped out due to drug-related side effects. The remaining five dropped out of the study for non-medical reasons.
The
American
Journal
of Medicine
Volume
82 (suppl
1A)
59
SYMPOSIUM
ON ALPHA BLOCKADE-OKUN
TABLE I
and KRAUT
Baseline Demographics Captopril
Prazosin (n = 15) Weight (pounds)* Duration of hypertension Age (years)* Sex (male/female) Race White Black ‘Data
are mean
(years)*
period, sitting diastolic blood pressure was 80.3 k 1.4 mm Hg in the prazosin group and 79.2 k 5.5 mm Hg in the captopril group. Final sitting diastolic blood pressure in the monotherapy group was 87.8 +- 8.9 mm Hg in the prazosin group and 85.6 k 8.9 mm Hg in the captopril group. Five patients in the prazosin group required the addition of thiazide for control of blood pressure. The combination produced a mean 8.7 mm Hg decrease in sitting diastolic pressure, over and above the mean 9.8 mm Hg decrease with prazosin alone, resulting in a sitting diastolic pressure of 86.8 ~fr9.8 mm Hg. Blood pressure in six patients in the captopril group was not controlled with captopril alone; when thiazide was added to the regimen of these non-responders, the combination resulted in an exaggerated response, with a resultant sitting diastolic blood pressure of 76.4 k 8.1 mm Hg. The baseline standing diastolic blood pressures for the prazosin- and captopril-treated patients were 95.2 k 3.0 mm Hg and 97.8 -+ 4.8 mm Hg, respectively (Table Ill). At the end of the titration period, the respective corresponding values for the two groups were 78.5 k 4.5 mm Hg and 81.3 r 7.6 mm Hg. At the end of monotherapy, standing diastolic blood pressure was 84.9 L 11.1 mm Hg in the prazosin group and 85.2 i 13.4 mm Hg in the captopril group. In those patients requiring the addition of 1 mg of thiazide to the study drug regimen, the values at the end of combination therapy were 87.1 L 9.3 mm Hg in prazosin-treated patients and 76.1 -I- 8.6 mm Hg in captopril-treated patients. There was little, if any, effect on heart rate following therapy with prazosin or captopril, whether accompanied by thiazide therapy or not. Lipid Variables. Prazosin treatment resulted in a greater reduction in low-density lipoprotein cholesterol levels and a corresponding greater increase in high-density lipoprotein-2 cholesterol levels than did captopril treatment. However, there were no statistically significant differences between prazosin or captopril monotherapy in terms of
(II = 16)
186.1 ? 30.0 14.3 f 10.8 63.2 * 8.4 I.510
185.8 ZL 25.2 12.4 ? 6.9 59.5 k 9.2 1610
9 6
8 8
f SD.
The drug groups were comparable with respect to age, duration of disease, race, sex, and weight (Table I). Treatment. A total of 15 patients received prazosin therapy; five of these patients required thiazide. Six of the 16 patients assigned to captopril therapy required thiazide (Figure 1). The mean daily dose for patients receiving monotherapy with prazosin was 6.6 mg (+- 5.6 mg). Patients receiving prazosin and the I-mg dose of polythiazide required a mean daily dose of 13.2 mg (k 6.4 mg) of prazosin. The corresponding mean values for captopriltreated patients were 165.0 mg (5 136.0 mg) of captopril alone, and 150.0 mg (r 82.2 mg) of captopril in combination with 1 mg of polythiazide. The drug groups were comparable at baseline with regard to all variables. The patients were categorized as responders or non-responders according to their final sitting diastolic blood pressure; responders were required to have a value of less than 85 mm Hg diastolic. There were no significant differences between groups with respect to response. Blood Pressure Control. The efficacy of prazosin and captopril with respect to lowering blood pressure from baseline was comparable (Table II). Baseline sitting diastolic blood pressure was 99.6 k 2.9 mm Hg for both the prazosin and captopril groups. At the end of the titration 3 1 Patients
15 Prazosin
10 Controlled on Monotherapy
60
January
16 Captopril
5 Thiazide Added; Controlled on Combination
5, 1987
The
American
10 Controlled on Monotherapy
Journal
of Medicine
6 Thiazide Added; Controlled on Combination
Volume
82
(suppl 1A)
Figure 1. Schematic diagram of the number of patients whose blood pressure was controlled by monotherapy and those who required the addition of thiazide therapy.
SYMPOSIUM
TABLE
ii
Effects of Therapy
on Sitting
Diastolic
Blood
99.6 80.3 87.8 6.6
i k k t
Prazosin plus Thiazide* (n = 5)
2.9 1.4+ 8.9+§ 5.6
*Thiazide dose was 1 mg of polythiazide daily. tSignificantly different from baseline (p ~0.05). *Significantly different change from baseline, prazosin “Significantly different from end of titration (p ~0.05).
TABLE
ill
Effects of Therapy
versus
on Standing
105.2 95.5 86.8 13.2
captopril
Diastolic
95.2 78.5 84.9 6.6
k -e + 2
% t it k
Captopril plus Thiazide* (n = 6)
Captoprii (n = 10)
4.5 7.3+* 9.8+ 6.4
99.6 79.2 85.6 165.0
k f k -t
2.9 5.5+ 8.gt’ 136.0
101.4 99.2 76.4 150.0
k 3.2 I! 7.5 5 8.1t§ -+ 82.2
(p = 0.05).
Blood
Pressure
Prazosin plus Thiazide* (n = 5)
Prazosin (n = 10) Baseline (mm Hg) End of titration (mm Hg) End of maintenance (mm Hg) Average daily dose (mg rc_ SD)
and KRAUT
Pressure
Prazosin (n = 10) Baseline (mm Hg) End of titration (mm Hg) End of maintenance (mm Hg) Average daily dose (mg k SD)
ON ALPHA BLOCKADE-OKUN
3.0 4.5+ ll.l+ 5.6
108.1 100.3 87.1 13.2
+k -c ?
Captoprii plus Thiazide’ (n = 6)
Captoprii (n = 10)
7.8 9.1 9.3+’ 6.4
97.8 81.3 85.2 165.0
k 2 k -t
4.8 7.6+ 13.4+ 136.0
103.4 100.4 76.1 150.0
? 2 2 ?
5.2 7.8 8.6+* 82.2
“Thiazide dose was 1 mg of polythiazide daily. +Significantly different from baseline (p 10.05). *Significantly different from end of titration (p ~0.05).
TABLE
IV
Effects
of Monotherapy
on Lipid
Profile
Variables Prazosin
Number of patients Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides *Significantly
different
percent
Mean Percent Change lmm Baseline
Baseline (Wdl)
Parameter
change
214.3 149.9 41.7 14.1 27.5 116.2 from
baseline
2 f ? -*tk
15 52.8 48.3 11.5 6.7 7.2 29.8 (n = 14)
for prazosin
Captoprii
versus
their effects on lipid profile variables, i.e., mean percent changes from baseline in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-density lipoprotein-2 cholesterol, and high-density lipoprotein-3 cholesterol (Table IV). The lack of statistical significance of changes in these cholesterol parameters is probably due to the wide scatter among patients. It is important to note, however, that the addition of thiazide to either prazosin or captopril monotherapy resulted in an increase from baseline in total cholesterol and low-density lipoprotein cholesterol levels, and decreases in highdensity lipoprotein cholesterol, high-density lipoprotein-2 cholesterol, and high-density lipoprotein-3 cholesterol lev-
January 5,1987
-3.0 -4.5 +1.1 +50.1 t8.5 +15.1 captopril,
t 2 k -t ? f
14 11.6 14.9 14.3 177.9 30.6 27.3* (n = 13) based
on Mann-Whitney
Baseline bwdi) 204.6 138.4 37.7 11.9 25.7 142.1
16 k t + t t i
36.7 34.3 9.4 7.0 7.1 95.0
Mean Percent Change fmm Baseline +1.3 -0.1 +5.4 -3.6 +14.5 -10.6
15 2 + +-c 5 ?
13.8 17.8 22.7 28.7 68.8 29.3
test (p 10.05).
els (Tables V and Vi). This potentially adverse effect of thiazide on lipid levels has been reported elsewhere [2,3]. SIDE EFFECTS
There were a total of 139 patient complaints reported during the study. Of these, only 10 were considered by the investigator to be related to the study medication; the severity of these drug-related complaints was mild to moderate (Table Vii). Other patient complaints were sporadic in occurrence and did not demonstrate a significant relationship to the study drug. Baseline laboratory values for blood urea nitrogen, creatinine, serum potassium, urinary protein, and blood neu-
The American Journal of Medicine
Volume 82 (suppl 1A)
81
SYMPOSIUM
TABLE
ON ALPHA BLOCKADE-OKUN
V
and KRAUT
Effects of Combination
Therapy
on Lipid Profile
Variables
CaptopriiplusThiazide
PrazosinplusTltiazide
Baseline* imoW
Parameter Number of patients Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides “Baseline
TABLE
refers
VI
MeanPercent Change from Baseline
to the end-of-titration
174.0 113.5 40.8 11.5 29.3 114.8 visit (last
Effects of Monotherapy
visit before
Versus
4 -t 3I + -rt
Baseline* (mu/W
4 36.0 38.8 7.3 6.6 1.7 31.0
+14.1 +24.3 -10.4 -29.1 -2.1 +11.9
diuretic
was added).
Combination
2 -t ” + +2
Therapy
9.1 19.4 8.0 29.9 17.7 18.8
on Lipid
207.5 143.7 41.2 12.0 29.2 112.8
6 + k of: t + +
38.5 31.0 11.7 6.3 6.8 48.0
MeanPercent Change from Baseline +10.1 +17.6 -4.7 +4.5 -0.5 +33.0
6 t + f + k +
7.4 7.9 16.9 21.6 20.3 49.8
Profile
MeanPercentChangefrom Baseline+ SD Prazosin plus Thiazide
Prazosln
Parameter Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoprotein-2 cholesterol High-density lipoprotein-3 cholesterol Triglycerides
-3.0 -4.5 +1.1 +50.1 +8.5 +15.1
t a t t t 2
11.6 14.9 14.3 177.9 30.6 27.3
+14.1 W24.3 -10.4 -29.1 -2.1 +11.9
trophils were comparable in both groups. The effects of therapy on laboratory values, as expressed in mean change from baseline, were not significant, with the exception of blood urea nitrogen (Table VIII), which showed a statistically significant (p = 0.01) increase from baseline in patients treated with captopril plus polythiazide. Although the mean percent change between monotherapy and combination therapy attained statistical significance, the actual laboratory values for blood urea nitrogen remained within the average normal range. COMMENTS In this randomized, parallel group study, prazosin and captopril appeared to be comparable in their ability to lower elevated blood pressure in patients with mild to TABLE
VII
Patient Complaints Drug-Related
Considered
to be
Prazosin Captoprii pius plus Prazosin Thiazide Captoprii Thiezide
Complaint Dizziness Dry mouth Shortness of breath
5’ 0 1’
1’ 0 0
0 0 0
1+ 2” 0
*Mild severity. + Moderate severity.
62
January
5, 1967
The
American
Journal
of Medicine
Volume
Captopril
5 ir
9.1 19.4
+1.3 -0.1
++zc 2
8.0 29.9 17.7 16.8
+5.4 -3.6 +14.5 -10.6
Captoprii plus Thiazide
t- 13.8 ? 17.8
+10.1 +17.6
t 2
7.4 7.9
2 2 k -t
-4.7 +4.5 -0.5 +33.0
2 t t+
21.6 21.6 20.3 49.8
22.7 28.7 68.8 29.3
moderate hypertension. After eight weeks, elevated blood pressure was normalized in two thirds of the patients receiving prazosin and captopril monotherapy. In patients who did not show a response to monotherapy, the addition of thiazide produced additional blood pressure lowering effects. In the prazosin-treated patients, addition of thiazide resulted in a 9 to 13 percent reduction in sitting and standing diastolic blood pressures. In the captopriltreated patients, the addition of thiazide dramatically reduced sitting and standing diastolic blood pressures by 22 to 24 percent, in some cases approaching hypotensive levels. It is important to note that in the prazosin nonresponders, sitting and standing diastolic blood pressures decreased 7 to 9 percent before the addition of thiazide, whereas for the captopril non-responders only a 2 to 3 percent reduction resulted. This observation suggests that in the patients receiving captopril plus thiazide, captopril contributed little, if at all, to the observed 22 to 24 percent reduction in blood pressure produced by the combination therapy. The changes in lipid profiles produced by the addition of thiazide to the regimen of a small number of patients were consistent with those observed in other studies [4] that have demonstrated the negative impact thiazides can have on lipid profile variables with regard to cardiovascular heart disease risk.
62
(suppi 1A)
SYMPOSIUM
TABLE
VIII
Effects
of Therapy
on Laboratory
Values
(mean
change
from baseline
Baseline Laboratory Value Blood
urea
Creatinine
nitrogen
(mgidi)
(mgidl)
Serum
potassium
Urinary
protein
Blood
neutrophiis
“Significant
(meqiliter) (g/liter)
change
(1 ,000/mm3) from
baseline
Mean SD Mean SD Mean SD Mean SD Mean SD
Prazosin
Captoprii
15.5 4.5 1.1 0.1 4.4 0.7 0.2 0.2 59.9 8.6
12.3 4.1 1.1 0.3 4.3 0.5 0.4 0.7 57.1 12.4
2.8 2.6 -0.1 0.2 -0.6 0.8 -0.1 0.1 6.0 (n = 2) 8.5
(n = 8)
4.6 -0.0 0.1 0.2 0.9 -0.1 (n = 9) 0.3 -2.4 6.7
and KRAUT
+ SD)
Prazosin plus Thiazide (n = 4)
Prazosin (n = 10) -1.1
ON ALPHA BLOCKADE-OKUN
Captoprii (n = 9) -0.4 4.8 0.4
Captoprii plus Thiazide (n = 5) 7.4* 4.0 0.1
1.1 -0.0 (n = 8)
0.5 -0.4 (n = 8) 0.8 2.3 7.1
0.2 -0.3 0.8 -0.2 (n = 6) 0.7 3.7 (n = 6) 16.1
(p = 0.01).
In summary, this randomized, parallel group study established that the alpha blocker prazosin and the angiotensin converting enzyme inhibitor captopril have comparable antihypertensive effects in patients with mild to moderate hypertension.
REFERENCES 1. 2.
3.
4.
January
5,1987
The
Okun R: Effectiveness of prazosin as initial antihypertensive therapy. Am J Cardiol 1983; 57: 644-649. Ames RP: Coronary heart disease and the treatment of hypertension: impact of diuretics on serum lipids and glucose. J Cardiovasc Pharmacol 1984; 6 (suppi 3): S466-S473. Weinberger MH: Antihypertensive therapy and lipids: evidence, mechanisms, and implications. Arch Intern Med 1985; 145: 1102-1105. Stamler R, Stamler J, Gosch H, et al: initial antihypertensive drug therapy: alpha blocker or diuretic. Am J Med 1986; 80 (suppi 2A): 90-93.
American
Journal
of Medicine
Volume
82
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