- Email: [email protected]
Initial antihypertensive drug therapy: Alpha blocker or diuretic: Interim report of a randomized, controlled trial
Initial Antihypertensive Drug Therapy: Alpha Blocker or Diuretic Interim Reportof a Randomized,ControlledTrial
A two-center, randomized, controlled trial designed to evaluate and compare an ‘alpha blocker and a dluretlc as initial antihypertensive drug treatment is currently in progress. Approximately 100 men and women, aged 30 to 69 years, are being randomly assigned to treatment with either of these two agents. If diastolic blood pressure is not reduced to Its target level and is 65 mm Hg or higher, the alternate agent is added. The alternate. agent is substituted if a patient does not tolerate the assigned agent. This preliminary report presents data concMnlng 62 patients who completed at least three of the planned 12 months of drug treatment. ,At that point, the alpha blocker prazosin and the diuretic hydrochlorothiaxide were similar in their ability to lower the average diastolic blood preasure to normal levels. Serum total cholesterol and tiiglyceride levels declined in praxosln-treated patients but Increased In hydrochlorothlazlde treated patients, a difference that was statlstlcally significant. No significant weight change, a possible confounding variable, occurred In either group. More patients were unPble to tolerate praxosin than were unable to tolerate hydrochlorothlaxide (10 of 30 receiving praxosin, compared with three of 32 receiving hydrochlorothiazide). For those able to continue tilth praxosin, the favorable lipid response appears to be an asset In regard to reducing possible atherogenic effects of treatment.
ROSE STAtvILER, MA. JEREMIAH STAMLER, M.D. FLORA c. Gosc~, M.D. DAVID M. BERKSON, M.D. ALAN DYER, Ph.D. PATRICIA HERSHINOW, R.N. Chicago,
Illinois
From the Department of Community Health and Preventive Medicine, Northwestern University Medical School and St. Joseph’s Hospital, Chicago, Illinois. This work &as supix&d by a grant from Pfizer Inc. Requests for reprints should be addressed to Professor Rose Stamler, Department of Community Health and Preventive Medicine, Northwest&n University Medical School, 303 East Chicago Avenue, Chicago, Illinok 60611.
90
Februmy
14,1&W
The
Amertcan Journal
Tens of millions of people in the United States have hypertension, whichif uncontrolled-carries markedly increased risks of morbidity, disability, and premature death [I -71. When pharmacologic intervention to control this risk factor is indicated, the next step involves choosing the most appropriate initial drug. At least four issues are involved in this choice: efficacy in control of blood pressure, presence or absence of unwanted biologic effects, acceptability to patients, and long-term efficacy in preventing major complications of hypertension. The current study examines the first three of these issues by comparing two drugs, an alpha blocker and a diuretic. In this interim report, in addition to describing the overall efficacy and acceptability of the drugs, data are presented regarding the biologic effect of the drugs on serum lipids, since this effect has been a recurring concern in antihypertensive therapy [8,9]. PATIENTS AND METHODS Sample. The study jnvolves 100 (interim report sample size is 62) hypertensive men and women, aged between 30 and 64 years, randomly assigned to receive either an alpha blocker (prazosin hydrochloride) or a diuretic (hydrochlorothiazide). To minimize the need to add other drugs, eligibilityis confined to those with a baseline diastolic blood pressure of 90 to 130 mm Hg, who are
ol Mdclne
&lumo
60 (suppl2A)
SYMPOSIUM
not receiving antihypertensive drugs, and who do not have major cardiovascular complications. Blood pressure eligibility is based on the mean diastolic level measured twice on each of two consecutive visits. Measurement is made on the right arm with the patient seated, after a five-minute rest for the first reading and a 15minute rest between the first and second readings. The Hawksley Random Zero sphygmomanometer is used to measure blood pressure. Those excluded from the study are pregnant or lactating women, those with metabolic disorders known to affect serum lipids, and those taking drugs affecting either blood pressure or lipids, e.g., other antihypertensive medication, oral contraceptives, or lipid-lowering drugs. Baseline and Randomization. Baseline evaluation includes a comprehensive history and physical examination, electrocardiography, radiography, and fundoscopy. Fasting blood samples are drawn so that a lipid profile and a comprehensive set of standard biochemical measurements can be obtained using the automated Technicon instrument (SMAC
20). After baseline evaluation, those who are eligible and who have signed a consent form are randomly assigned to groups by a computer-generated code and stratified by sex and initial diastolic blood pressure (90 to 104 mm Hg for one group, 105 to 130 mm Hg for the other). Treatment. Patients who are randomly assigned to the prazosin group are given an initial dose of a single 1 -mg capsule to be taken before bedtime to avoid the possible “first-dose” effect. Thereafter, 1 mg twice daily is prescribed. The dosage may then be increased progressively at visits two weeks apart until target blood pressure is achieved, or until a maximum dosage (10 mg twice daily) is reached or limiting side effects occur. The step-up schedule is 1 mg twice daily, 2 mg twice daily, 5 mg twice daily, and 10 mg twice daily. For the group receiving hydrochlorothiazide, the initial dose is 25 mg per day. If target blood pressure is not achieved in four weeks, this dosage is increased to 50 mg per day. The target blood pressure is designated as less than or equal to 89 mm Hg or 10 mm Hg below entry mean diastolic blood pressure, whichever is lower. For patients in both groups whose diastolic blood pressure is not at target level and is 85 mm Hg or higher after at least four weeks of treatment with the maximum dosage, blood pressure is recorded, a blood sample is drawn to determine lipid levels with the assigned drug, and the alternate drug is added using the step-up schedule just described. If diastolic blood pressure remains at the same level with these two drugs, ‘an appropriate third drug is used. If the originally assigned drug needs to be discontinued because of unacceptable side effects, the alternate drug is substituted after blood pressure is measured and a blood sample is drawn for determination of lipid levels. A modest effort, consistent with good medical practice, is made to help patients in both groups adopt a nutritional pattern that reduces excess intake of calories, sodium, and alcohol. Advice on these measures is offered after drug treatment has been stabilized, but not earlier than three months after starting drug therapy. Ongoing Evaluation. After baseline evaluation and adjustment of medication to reach targeted blood pressure values,
February
14, 1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
subsequent visits are scheduled every three months. At each of these visits, blood pressure is recorded (two measurements in the sitting position and one in the standing position) using the Hawksley Random Zero sphygmomanometer. Body weight is also measured. At baseline, at three- and six-month visits, and at six-month intervals thereafter, a 12-hour fasting blood sample is drawn for lipid determinations. When the alternate agent to ttia! originally assigned is added or substituted, blood sarnples are drawn prior to the change and at three, six, and 12 months after the change. In addition to lipid analysis, standard biochemical measurements are obtained at baseline and sixmonth intervals. The serum potassium level is measured every three months. A review of symptoms, including patients’ volunteered compl&nts, is recorded at each visit. Women who become pregnant during the study are referred to their personal physician for manager&nt of hypertension during pregnancy and withdrawn from the study. Llpid Analytical Methods. Total cholesterol and triglycerides are analyzed by the enzymatic method with the SMAC autoanalyzer (Technicon) [lo]; the total high-density lipoprotein cholesterol level is measured after precipitation with heparin manganese chloride; high-density lipoprotein cholesterol subclass 3 is measured after precipitation with dextran sulfate, molecular weight 15,000. High-density lipoprotein cholesterol subclass 2 is calculated by subtracting the value for high-density lipoprotein cholesterol subclass 3 from the total high-density lipoprotein cholesterol [l 11. Both internal and external (blind-replicate) quality-control procedures are used in the analytic laboratory. Laboratory technical error will be presented in the final report, after a larger number of replicates have been analyzed.
RESULTS The 62 persons whose data are included in this interim report were selected on the basis of having completed at least three months of follow-up after starting drug treatment (average 4.5 months). The sample includes 53 men and nine women, with a mean age of 50.1 years; 53 are white, nine are black. By randomization, 30 individuals were assigned to receive prazosin and 32 were assigned to receive hydrochlorothiazide. The distributions for age, sex, and initial diastolic blood pressure were similar in the two groups. Blood Pressure Control. Both drugs succeeded in reducing mean diastolic pressure from 97 mm Hg at baseline to high-normal levels at the most recent follow-up, with a decline of 10.3 mm Hg for the prazosin-treated group and 8.6 mm Hg for the hydrochlorothiazide-treated group, a nonsignificant difference (Table I). Weight remained stable during this period. The need to add or change drugs is described in a later section of this article. Effects on Total Lipids. Mean serum total cholesterol was reduced by 4.? mg/dl in patients receiving prazosin who completed at least three months in the trial, but in-
creased by 8.2 mg/dl for those receiving hydrochlolothiazide (Tabli II). This difference in change while rec@ving a
The American
Journal
of Medlclne
Volume
99 (euppl
U)
91
SYMPOSIUM
TABLE I
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
Diastolic Blood Pressure at Entry and during Trial with Prazosin and Hydrochlorothiazide* Prazosin
Hydmcblorothiazide (n = 32)
(n = 30)
Mean Baseline average (mm Hg) Trial average with assigned drug+ (mm W Change (mm W
SD
Mean
SD
96.9
5.0
97.1
8.1
86.6
6.9
88.5
7.9
0.8 (SE)
-8.6
1.4 (SE)
-10.3
Note: t value for difference in change is equal to 1.03 (NS). ‘Values are for patients completing at least three months in the trial. +Patients had two to three visits after starting drug therapy. Diastolic blood pressures for these visits were averaged to provide individual values. Data from visits subsequent to the use of an alternate agent are not included.
TABLE II
Serum Total Cholesterol at Entry and during Trial with Prazosin and Hydrochiorothlazide* Prazosin (n = 30) Mean
Baseline average Owl) Trial average with assigned drug O-Wdl) Change (mg/dl)
SD
SD
40.6
230.6
40.3
220.3
39.2
238.8
41.5
-4.2
4.5 (SE)
+8.2
4.3 (SE)
to 2.01; p ~0.05. months in the trial.
Serum Total Triglycerides at Entry and during Trial wlth Prazosin and Hydrochlorothiazide* Prazosin (n = 30)
Baseline average (mcW Trial average with assigned drug hW-4 Change (mUdI)
HydmchlorothiazCde (n = 32)
Mean
SD
Mean
SD
165.0
72.4
160.8
72.6
141.0 -24.0
76.7
178.0
69.4
10.2 (SE)
+17.2
7.8 (SE)
Note: t value for difference in change is equal ‘Values are for patients completing at least three
92
Mean
224.5
Note: t value for difference in change is equal ‘Values are for patients completing at least three
TABLE Ill
Hydmchiorothiazide (n = 32)
February 14,1986
to 3.24; p
The American Journal of Medicine
drug was significant at the 0.05 level in a two-tailed t test. Mean serum triglyceride response showed the greatest difference between the two groups. There was a reduction of 24 mg/di for those receiving prazosin but a 17.2 mg/dl increase for those receiving hydrochlorothiazide (Table Ill). This difference in change after initiation of drug treatment was significant (p ~0.01). There was no weight change in either group. Effects on high-density lipoprotein cholesterol, highdensity lipoprotein cholesterol subclass 2 and subclass 3, and derived low-density lipoprotein will be included in later reports. Change in Drug Regimen. The grounds for addition to or substitution for the original drug were insufficient blood pressure control and patient intolerance. When diastolic blood pressure could not be reduced to its target level and remained at 85 mm Hg or higher at the maximum tolerable drug dosage, the alternate drug was added. This occurred in seven of the 30 prazosin-treated patients and in 14 of the 32 hydrochlorothiazide-treated patients (Table IV). Of the seven prazosin-treated patients, six had diastolic blood pressures of 95 mm Hg or higher at the visit prior to changing the drug regimen, and none had pressures below 90 mm Hg at that visit. The average diastolic blood pressure for these seven patients at that time was 98.3 mm Hg. Of the 14 hydrochlorothiazide-treated patients who required a change in the regimen, six had blood pressures of 95 mm Hg or greater, and four had blood pressures below 90 mm Hg although these were not at the target level. The average diastolic blood pressure for these 14 hydrochlorothiazide-treated patients at the time the regimen was changed was 93 mm Hg. As to side effects and patient complaints leading to discontinuation of the assigned drug, the number of changes was greater for those receiving prazosin than for those receiving hydrochlorothiazide: 10 out of 30 and three out of 32, respectively (Table IV). The number of side effects reported was, in fact, considerably higher than in previously published reports [12]. The most common complaints among those in whom prazosin was discontinued were headache (some severe), dizziness, fatigue, gastrointestinal disturbance, irritability, and mood change. One case each of diaphoresis and priapism occurred. Among the three hydrochlorothiazide-treated patients in whom diuretic treatment was discontinued, a rash developed in one, impotence in another, and marked fatigue in the third. COMMENTS Prazosin and hydrochlorothiazide appear to be similar in their ability to lower elevated diastolic blood pressure in those whose hypertension is not severe. After four and a half months of observation, normalization of blood pressure with use of a single agent has been achieved in a majority of patients in both groups. Although this propor-
Volume 80 (suppl 2A)
SYMPOSIUM
TABLE
tion was somewhat higher among those receiving prazosin, the reduction in mean pressure in the two groups was essentially the same. The effect of antihypertensive drugs on serum lipids is an important concern in optimal treatment, since several agents have been found to raise cholesterol and/or triglyceride levels and reduce high-density lipoprotein levels [8,9]. Thus, the benefit of decreasing cardiovascular risk through a reduction in blood pressure could be offset or even outweighed by the increase in risk that accompanies a rise in lipid levels. At this point in the study, prazosin-treated patients on average have a reduction in total cholesterol and triglyceride levels, whereas these lipid levels are increased in the hydrochlorothiazide group. The differences between the two groups in these changes are statistically significant. Overall, prazosin appears to have a better effect on the lipid profile than does hydrochlorothiazide, and it has an equivalent ability to control elevated blood pressure in those able to continue to receive the drug. However, about one third of the prazosin-treated patients reported side effects that led to drug cessation, compared with 10 percent of hydrochlorothiazide-treated patients who showed intolerance to the drug. Although all of the reported symptoms may not be directly attributable to the drugs, they have all been described previously. Without a placebo group for comparison, a more definitive statement on this issue is not possible. In conclusion, prazosin’s efficacy as monotherapy and its favorable effect on lipids are desirable assets to be considered in the selection of initial antihypertensive drug therapy for patients who can receive the drug on a long-
1. 2.
3.
4.
5.
6.
14, 1986
IV
THERAPY-STAMLER
Changes in the Regimen Hydrochlorothiazide’
of Prazosin
Prazosin-treated group (n = 30) Hydrochlorothiazide added because of insufficient blood pressure control Prazosin discontinued because of reaction or intolerance Hydrochlorothiazide-treated group (n = 32) Prazosin added because of insufficient blood pressure control Hydrochlorothiazide discontinued because of reaction or intolerance ‘For patients with three or more months of follow-up treatment. +lncludes four patients with diastolic blood pressure Hg, but not at target blood pressure.
ET AL
and
7 10
14+ 3
after start of drug less than 90 mm
term basis. Further observations should provide additional information regarding the effects of combined therapy using a diuretic plus an alpha blocker on lipids and other biochemical variables, and the ability of such a combination to maintain normal blood pressure over the long term. ACKNOWLEDGMENT
Appreciation is expressed to the staffs of the two cooperating centers: Jean Civinelli, Doris Fine, Joan Fishman, Evelyn Gaskins, Patricia La Salle, Catherine McMillan, Angeline Merlo, Joan Sciacchitano, Cheryl Westbrook, Ruth Willis, and Rebecca Zaccard. Thanks are also expressed to the following persons for their assistance in the study: Dr. Youlian Liao, Dan Garside, Dr. William Levine, Dr. Kiang Liu, and Ron Hoeksema.
7.
Build and Blood Pressure Study, vol 1. Chicago: Society of Actuaries, 1959. The Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chron Dis 1978; 31: 201-306. Keys A: Seven countries-a multivariate analysis of death and coronary heart disease. Cambridge, Massachusetts: Harvard University Press, 1980. Stamler J, Stamler R, Liu K: High blood pressure: role in coronary heart disease and implications for prevention and control. In: Connor W, Bristow D, eds. Coronary heart disease. Philadelphia: JB Lippincott, 1985; 85-109. Smith WM: Treatment of mild hypertension: results of a ten-year intervention trial. U.S. Public Health Service Hospitals Cooperative Study Group. Circ Res 1977; 40 (suppl I): 98-105. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: 10281034.
February
ON INITIAL ANTIHYPERTENSIVE
8.
9.
10.
11.
12.
The
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 11431152. Grimm RH Jr, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. A double-blind controlled trial. Ann Intern Med 1981; 94: 4-l 1. Lasser NL, Grandits G, Caggiula AW, et al: Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76 (suppl 2A): 52-66. Vlastelica D, Bucolo G, Yabut J, Kessler G: Total automated enzymatic assay of serum triglycerides (abstr). Clin Chem 1974; 20: 907. Gidez LI, Miller GH, Burstein M, Slagle S, Eder HA: Separation and quantitation of subclasses of human plasma high-density lipoproteins by a simple precipitation procedure. J Lipid Res 1982; 23: 1206-1223. Okun R: Effectiveness of prazosin as initial antihypertensive therapy. Am J Cardiol 1983; 51: 844-850.
American
Journal
of Medicine
Volume
60
(euppl 2A)
93
A two-center, randomized, controlled trial designed to evaluate and compare an ‘alpha blocker and a dluretlc as initial antihypertensive drug treatment is currently in progress. Approximately 100 men and women, aged 30 to 69 years, are being randomly assigned to treatment with either of these two agents. If diastolic blood pressure is not reduced to Its target level and is 65 mm Hg or higher, the alternate agent is added. The alternate. agent is substituted if a patient does not tolerate the assigned agent. This preliminary report presents data concMnlng 62 patients who completed at least three of the planned 12 months of drug treatment. ,At that point, the alpha blocker prazosin and the diuretic hydrochlorothiaxide were similar in their ability to lower the average diastolic blood preasure to normal levels. Serum total cholesterol and tiiglyceride levels declined in praxosln-treated patients but Increased In hydrochlorothlazlde treated patients, a difference that was statlstlcally significant. No significant weight change, a possible confounding variable, occurred In either group. More patients were unPble to tolerate praxosin than were unable to tolerate hydrochlorothlaxide (10 of 30 receiving praxosin, compared with three of 32 receiving hydrochlorothiazide). For those able to continue tilth praxosin, the favorable lipid response appears to be an asset In regard to reducing possible atherogenic effects of treatment.
ROSE STAtvILER, MA. JEREMIAH STAMLER, M.D. FLORA c. Gosc~, M.D. DAVID M. BERKSON, M.D. ALAN DYER, Ph.D. PATRICIA HERSHINOW, R.N. Chicago,
Illinois
From the Department of Community Health and Preventive Medicine, Northwestern University Medical School and St. Joseph’s Hospital, Chicago, Illinois. This work &as supix&d by a grant from Pfizer Inc. Requests for reprints should be addressed to Professor Rose Stamler, Department of Community Health and Preventive Medicine, Northwest&n University Medical School, 303 East Chicago Avenue, Chicago, Illinok 60611.
90
Februmy
14,1&W
The
Amertcan Journal
Tens of millions of people in the United States have hypertension, whichif uncontrolled-carries markedly increased risks of morbidity, disability, and premature death [I -71. When pharmacologic intervention to control this risk factor is indicated, the next step involves choosing the most appropriate initial drug. At least four issues are involved in this choice: efficacy in control of blood pressure, presence or absence of unwanted biologic effects, acceptability to patients, and long-term efficacy in preventing major complications of hypertension. The current study examines the first three of these issues by comparing two drugs, an alpha blocker and a diuretic. In this interim report, in addition to describing the overall efficacy and acceptability of the drugs, data are presented regarding the biologic effect of the drugs on serum lipids, since this effect has been a recurring concern in antihypertensive therapy [8,9]. PATIENTS AND METHODS Sample. The study jnvolves 100 (interim report sample size is 62) hypertensive men and women, aged between 30 and 64 years, randomly assigned to receive either an alpha blocker (prazosin hydrochloride) or a diuretic (hydrochlorothiazide). To minimize the need to add other drugs, eligibilityis confined to those with a baseline diastolic blood pressure of 90 to 130 mm Hg, who are
ol Mdclne
&lumo
60 (suppl2A)
SYMPOSIUM
not receiving antihypertensive drugs, and who do not have major cardiovascular complications. Blood pressure eligibility is based on the mean diastolic level measured twice on each of two consecutive visits. Measurement is made on the right arm with the patient seated, after a five-minute rest for the first reading and a 15minute rest between the first and second readings. The Hawksley Random Zero sphygmomanometer is used to measure blood pressure. Those excluded from the study are pregnant or lactating women, those with metabolic disorders known to affect serum lipids, and those taking drugs affecting either blood pressure or lipids, e.g., other antihypertensive medication, oral contraceptives, or lipid-lowering drugs. Baseline and Randomization. Baseline evaluation includes a comprehensive history and physical examination, electrocardiography, radiography, and fundoscopy. Fasting blood samples are drawn so that a lipid profile and a comprehensive set of standard biochemical measurements can be obtained using the automated Technicon instrument (SMAC
20). After baseline evaluation, those who are eligible and who have signed a consent form are randomly assigned to groups by a computer-generated code and stratified by sex and initial diastolic blood pressure (90 to 104 mm Hg for one group, 105 to 130 mm Hg for the other). Treatment. Patients who are randomly assigned to the prazosin group are given an initial dose of a single 1 -mg capsule to be taken before bedtime to avoid the possible “first-dose” effect. Thereafter, 1 mg twice daily is prescribed. The dosage may then be increased progressively at visits two weeks apart until target blood pressure is achieved, or until a maximum dosage (10 mg twice daily) is reached or limiting side effects occur. The step-up schedule is 1 mg twice daily, 2 mg twice daily, 5 mg twice daily, and 10 mg twice daily. For the group receiving hydrochlorothiazide, the initial dose is 25 mg per day. If target blood pressure is not achieved in four weeks, this dosage is increased to 50 mg per day. The target blood pressure is designated as less than or equal to 89 mm Hg or 10 mm Hg below entry mean diastolic blood pressure, whichever is lower. For patients in both groups whose diastolic blood pressure is not at target level and is 85 mm Hg or higher after at least four weeks of treatment with the maximum dosage, blood pressure is recorded, a blood sample is drawn to determine lipid levels with the assigned drug, and the alternate drug is added using the step-up schedule just described. If diastolic blood pressure remains at the same level with these two drugs, ‘an appropriate third drug is used. If the originally assigned drug needs to be discontinued because of unacceptable side effects, the alternate drug is substituted after blood pressure is measured and a blood sample is drawn for determination of lipid levels. A modest effort, consistent with good medical practice, is made to help patients in both groups adopt a nutritional pattern that reduces excess intake of calories, sodium, and alcohol. Advice on these measures is offered after drug treatment has been stabilized, but not earlier than three months after starting drug therapy. Ongoing Evaluation. After baseline evaluation and adjustment of medication to reach targeted blood pressure values,
February
14, 1999
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
subsequent visits are scheduled every three months. At each of these visits, blood pressure is recorded (two measurements in the sitting position and one in the standing position) using the Hawksley Random Zero sphygmomanometer. Body weight is also measured. At baseline, at three- and six-month visits, and at six-month intervals thereafter, a 12-hour fasting blood sample is drawn for lipid determinations. When the alternate agent to ttia! originally assigned is added or substituted, blood sarnples are drawn prior to the change and at three, six, and 12 months after the change. In addition to lipid analysis, standard biochemical measurements are obtained at baseline and sixmonth intervals. The serum potassium level is measured every three months. A review of symptoms, including patients’ volunteered compl&nts, is recorded at each visit. Women who become pregnant during the study are referred to their personal physician for manager&nt of hypertension during pregnancy and withdrawn from the study. Llpid Analytical Methods. Total cholesterol and triglycerides are analyzed by the enzymatic method with the SMAC autoanalyzer (Technicon) [lo]; the total high-density lipoprotein cholesterol level is measured after precipitation with heparin manganese chloride; high-density lipoprotein cholesterol subclass 3 is measured after precipitation with dextran sulfate, molecular weight 15,000. High-density lipoprotein cholesterol subclass 2 is calculated by subtracting the value for high-density lipoprotein cholesterol subclass 3 from the total high-density lipoprotein cholesterol [l 11. Both internal and external (blind-replicate) quality-control procedures are used in the analytic laboratory. Laboratory technical error will be presented in the final report, after a larger number of replicates have been analyzed.
RESULTS The 62 persons whose data are included in this interim report were selected on the basis of having completed at least three months of follow-up after starting drug treatment (average 4.5 months). The sample includes 53 men and nine women, with a mean age of 50.1 years; 53 are white, nine are black. By randomization, 30 individuals were assigned to receive prazosin and 32 were assigned to receive hydrochlorothiazide. The distributions for age, sex, and initial diastolic blood pressure were similar in the two groups. Blood Pressure Control. Both drugs succeeded in reducing mean diastolic pressure from 97 mm Hg at baseline to high-normal levels at the most recent follow-up, with a decline of 10.3 mm Hg for the prazosin-treated group and 8.6 mm Hg for the hydrochlorothiazide-treated group, a nonsignificant difference (Table I). Weight remained stable during this period. The need to add or change drugs is described in a later section of this article. Effects on Total Lipids. Mean serum total cholesterol was reduced by 4.? mg/dl in patients receiving prazosin who completed at least three months in the trial, but in-
creased by 8.2 mg/dl for those receiving hydrochlolothiazide (Tabli II). This difference in change while rec@ving a
The American
Journal
of Medlclne
Volume
99 (euppl
U)
91
SYMPOSIUM
TABLE I
ON INITIAL ANTIHYPERTENSIVE
THERAPY-STAMLER
ET AL
Diastolic Blood Pressure at Entry and during Trial with Prazosin and Hydrochlorothiazide* Prazosin
Hydmcblorothiazide (n = 32)
(n = 30)
Mean Baseline average (mm Hg) Trial average with assigned drug+ (mm W Change (mm W
SD
Mean
SD
96.9
5.0
97.1
8.1
86.6
6.9
88.5
7.9
0.8 (SE)
-8.6
1.4 (SE)
-10.3
Note: t value for difference in change is equal to 1.03 (NS). ‘Values are for patients completing at least three months in the trial. +Patients had two to three visits after starting drug therapy. Diastolic blood pressures for these visits were averaged to provide individual values. Data from visits subsequent to the use of an alternate agent are not included.
TABLE II
Serum Total Cholesterol at Entry and during Trial with Prazosin and Hydrochiorothlazide* Prazosin (n = 30) Mean
Baseline average Owl) Trial average with assigned drug O-Wdl) Change (mg/dl)
SD
SD
40.6
230.6
40.3
220.3
39.2
238.8
41.5
-4.2
4.5 (SE)
+8.2
4.3 (SE)
to 2.01; p ~0.05. months in the trial.
Serum Total Triglycerides at Entry and during Trial wlth Prazosin and Hydrochlorothiazide* Prazosin (n = 30)
Baseline average (mcW Trial average with assigned drug hW-4 Change (mUdI)
HydmchlorothiazCde (n = 32)
Mean
SD
Mean
SD
165.0
72.4
160.8
72.6
141.0 -24.0
76.7
178.0
69.4
10.2 (SE)
+17.2
7.8 (SE)
Note: t value for difference in change is equal ‘Values are for patients completing at least three
92
Mean
224.5
Note: t value for difference in change is equal ‘Values are for patients completing at least three
TABLE Ill
Hydmchiorothiazide (n = 32)
February 14,1986
to 3.24; p
The American Journal of Medicine
drug was significant at the 0.05 level in a two-tailed t test. Mean serum triglyceride response showed the greatest difference between the two groups. There was a reduction of 24 mg/di for those receiving prazosin but a 17.2 mg/dl increase for those receiving hydrochlorothiazide (Table Ill). This difference in change after initiation of drug treatment was significant (p ~0.01). There was no weight change in either group. Effects on high-density lipoprotein cholesterol, highdensity lipoprotein cholesterol subclass 2 and subclass 3, and derived low-density lipoprotein will be included in later reports. Change in Drug Regimen. The grounds for addition to or substitution for the original drug were insufficient blood pressure control and patient intolerance. When diastolic blood pressure could not be reduced to its target level and remained at 85 mm Hg or higher at the maximum tolerable drug dosage, the alternate drug was added. This occurred in seven of the 30 prazosin-treated patients and in 14 of the 32 hydrochlorothiazide-treated patients (Table IV). Of the seven prazosin-treated patients, six had diastolic blood pressures of 95 mm Hg or higher at the visit prior to changing the drug regimen, and none had pressures below 90 mm Hg at that visit. The average diastolic blood pressure for these seven patients at that time was 98.3 mm Hg. Of the 14 hydrochlorothiazide-treated patients who required a change in the regimen, six had blood pressures of 95 mm Hg or greater, and four had blood pressures below 90 mm Hg although these were not at the target level. The average diastolic blood pressure for these 14 hydrochlorothiazide-treated patients at the time the regimen was changed was 93 mm Hg. As to side effects and patient complaints leading to discontinuation of the assigned drug, the number of changes was greater for those receiving prazosin than for those receiving hydrochlorothiazide: 10 out of 30 and three out of 32, respectively (Table IV). The number of side effects reported was, in fact, considerably higher than in previously published reports [12]. The most common complaints among those in whom prazosin was discontinued were headache (some severe), dizziness, fatigue, gastrointestinal disturbance, irritability, and mood change. One case each of diaphoresis and priapism occurred. Among the three hydrochlorothiazide-treated patients in whom diuretic treatment was discontinued, a rash developed in one, impotence in another, and marked fatigue in the third. COMMENTS Prazosin and hydrochlorothiazide appear to be similar in their ability to lower elevated diastolic blood pressure in those whose hypertension is not severe. After four and a half months of observation, normalization of blood pressure with use of a single agent has been achieved in a majority of patients in both groups. Although this propor-
Volume 80 (suppl 2A)
SYMPOSIUM
TABLE
tion was somewhat higher among those receiving prazosin, the reduction in mean pressure in the two groups was essentially the same. The effect of antihypertensive drugs on serum lipids is an important concern in optimal treatment, since several agents have been found to raise cholesterol and/or triglyceride levels and reduce high-density lipoprotein levels [8,9]. Thus, the benefit of decreasing cardiovascular risk through a reduction in blood pressure could be offset or even outweighed by the increase in risk that accompanies a rise in lipid levels. At this point in the study, prazosin-treated patients on average have a reduction in total cholesterol and triglyceride levels, whereas these lipid levels are increased in the hydrochlorothiazide group. The differences between the two groups in these changes are statistically significant. Overall, prazosin appears to have a better effect on the lipid profile than does hydrochlorothiazide, and it has an equivalent ability to control elevated blood pressure in those able to continue to receive the drug. However, about one third of the prazosin-treated patients reported side effects that led to drug cessation, compared with 10 percent of hydrochlorothiazide-treated patients who showed intolerance to the drug. Although all of the reported symptoms may not be directly attributable to the drugs, they have all been described previously. Without a placebo group for comparison, a more definitive statement on this issue is not possible. In conclusion, prazosin’s efficacy as monotherapy and its favorable effect on lipids are desirable assets to be considered in the selection of initial antihypertensive drug therapy for patients who can receive the drug on a long-
1. 2.
3.
4.
5.
6.
14, 1986
IV
THERAPY-STAMLER
Changes in the Regimen Hydrochlorothiazide’
of Prazosin
Prazosin-treated group (n = 30) Hydrochlorothiazide added because of insufficient blood pressure control Prazosin discontinued because of reaction or intolerance Hydrochlorothiazide-treated group (n = 32) Prazosin added because of insufficient blood pressure control Hydrochlorothiazide discontinued because of reaction or intolerance ‘For patients with three or more months of follow-up treatment. +lncludes four patients with diastolic blood pressure Hg, but not at target blood pressure.
ET AL
and
7 10
14+ 3
after start of drug less than 90 mm
term basis. Further observations should provide additional information regarding the effects of combined therapy using a diuretic plus an alpha blocker on lipids and other biochemical variables, and the ability of such a combination to maintain normal blood pressure over the long term. ACKNOWLEDGMENT
Appreciation is expressed to the staffs of the two cooperating centers: Jean Civinelli, Doris Fine, Joan Fishman, Evelyn Gaskins, Patricia La Salle, Catherine McMillan, Angeline Merlo, Joan Sciacchitano, Cheryl Westbrook, Ruth Willis, and Rebecca Zaccard. Thanks are also expressed to the following persons for their assistance in the study: Dr. Youlian Liao, Dan Garside, Dr. William Levine, Dr. Kiang Liu, and Ron Hoeksema.
7.
Build and Blood Pressure Study, vol 1. Chicago: Society of Actuaries, 1959. The Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chron Dis 1978; 31: 201-306. Keys A: Seven countries-a multivariate analysis of death and coronary heart disease. Cambridge, Massachusetts: Harvard University Press, 1980. Stamler J, Stamler R, Liu K: High blood pressure: role in coronary heart disease and implications for prevention and control. In: Connor W, Bristow D, eds. Coronary heart disease. Philadelphia: JB Lippincott, 1985; 85-109. Smith WM: Treatment of mild hypertension: results of a ten-year intervention trial. U.S. Public Health Service Hospitals Cooperative Study Group. Circ Res 1977; 40 (suppl I): 98-105. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: 10281034.
February
ON INITIAL ANTIHYPERTENSIVE
8.
9.
10.
11.
12.
The
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 11431152. Grimm RH Jr, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. A double-blind controlled trial. Ann Intern Med 1981; 94: 4-l 1. Lasser NL, Grandits G, Caggiula AW, et al: Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76 (suppl 2A): 52-66. Vlastelica D, Bucolo G, Yabut J, Kessler G: Total automated enzymatic assay of serum triglycerides (abstr). Clin Chem 1974; 20: 907. Gidez LI, Miller GH, Burstein M, Slagle S, Eder HA: Separation and quantitation of subclasses of human plasma high-density lipoproteins by a simple precipitation procedure. J Lipid Res 1982; 23: 1206-1223. Okun R: Effectiveness of prazosin as initial antihypertensive therapy. Am J Cardiol 1983; 51: 844-850.
American
Journal
of Medicine
Volume
60
(euppl 2A)
93