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Treatment of Hypertension With Spironolactone
Treatment of Hypertension With Spironolactone
With Spironolactone
Double-Blind Study
Robert L. Wolf, MD, Milton Mendlowitz, MD, Julia Roboz, George P. H. Styan, MA,
Peter Kornfeld, MD, and Alfred Weigl, MD
A double-blind study of patients with essential hyper- compared to that of chlorothiazide and the mer¬
tension was performed in order to determine which dosage curial diuretics.1'3 The diuretic action of either the
of spironolactone (25 mg, 100 mg, or 200 mg daily), with thiazide or the mercurial diuretics may be poten¬
or without hydrochlorothiazide, had the optimum hypo- tiated by the concomitant administration of
tensive effect. The data were analyzed by two different spironolactone.1 "°
statistical methods, in each of which multivariate analysis The mechanism whereby spironolactone admin¬
of variance was used. Both methods led to the conclusion istration produces hypotension has not been re¬
that the most efficacious treatment regimen tested was solved. It is not due solely to the depletion of
spironolactone at a daily dosage of 100 mg, without total body sodium or contraction of the plasma
hydrochlorothiazide. volume since the hypotensive effect persists despite
the experimental correction or overcorrection of
these situations.1'38 The magnitude of the anti-
erect," and "diastolic erect." We are interested in differing from each pair) ; ßu = the interaction of drug
the effect of the drugs on these blood pressures as i and patient j, as measured by the additional re¬
a whole, eg, we would like to lower all four mea¬ sponse of patient / to drug i, compared with the
surements simultaneously and obtain a measure average response of all patients to drug /; and
for this decrease on the four as a group. We are e,7;, = the random error between measurements from
also interested in examining the effects of the patient ; with drug i during visit k ( = 1,2,3).
drugs on the four pairs of blood pressures formed Each underlined quantity is a vector with four
by the sets of both systolic, both diastolic, both components corresponding to the four blood pres¬
reclining, and both erect measurements. Our in¬ sure measurements observed. The drug effect is
ference procedures are, therefore, based on multi- fixed, while the patient effect is random (we are
variate analysis.'1,13 interested in making inferences for all hypertensive
Unfortunately, each patient did not receive each patients, not just those in this study). The model
drug. This undoubtedly was because the subjects is, therefore, called "mized."15 The random error
were hospital clinic outpatients and because the vector is assumed to follow a multivariate normal
duration of the study was ten months. Of the 24 distribution11 with zero mean vector and constant
patients in the study, eight received all seven drugs. covariance matrix independent of drug i, patient
Several patients missed one out of the three j, or visit k.
visits to the clinic which they were expected to Method B: Dose-Response Relationships
Table 2.—Mean and SE of Mean Blood Pressure Measurements for Eight Patients Who Received All Drug Regimens
Daily Spironolactone Dose
Without Hydrochlorothiazide With Hydrochlorothiazide
Placebo 25 mg 100 mg 200 mg 25 mg 100 mg 200 mg
No. of observations 24 23 21 24 23 23 21
Systolic reclining, mm Hg
Means 172.71 152.26 139.14 147.38 152.48 142.70 137.86
SE of means 7.26 5.21 4.32 2.68 4.03 3.70 2.58
Diastolic reclining, mm Hg
Means 104.08 96.61 88.81 95.13 98.00 94.91 93.62
SE of means 3.35 1.76 1.89 2.54 :.69 2.09 1.97
Systolic erect, mm Hg
Means 166.17 147.22 132.14 139.88 143.35 138.09 133.57
SE of means 6.89 4.15 3.56 2.55 3.66 3.50 2.70
Diastolic erect, mm Hg
Means 103.17 96.43 96.63 97.87 95.65 94.14
SE of means 3.10 2.30 2.10 2.53 1.39 1.85
Table 3.—P-Values for Selected Hypotheses for Eight Patients Who Received All Drug Regimens
Med S Compared With"
Quadratic
Blood Pressure Med S + H Hi S Hi S + H Logarithmic Fitt Fitt
Systolic reclining 0.697 0.048 0.679 0.027 0.008
Diastolic reclining .042 .098 .078 .077 .011
Systolic erect .355 .112 .624 .029 .005
Diastolic erect .011 .133 .173 .080 .035
Both systolic responses .451 .166 .452 .104 .013
Both diastolic responses .028 .256 .220 .234 .058
Both reclining responses .107 .057 .135 .105 .040
Both erect responses .022 .086 .297 .112 .020
All four responses 0.040 0.324 0.180 Ü.415 0.049
;::Drug dosages in the comparison are Med S, 100 mg of spironolactone daily; Med S -f H, 100 mg of spironolactone and 100 mg of hydrochloro¬
thiazide daily; Hi S, 200 mg of spironolactone daily; Hi S + H, 200 mg of spironolactone and 100 mg of hydrochlorothiazide daily.
tThe logarithmic curve is determined for the regimens that included hydrochlorothiazide.
tThe quadratic curve is determined for the regimens that excluded hydrochlorothiazide.
DECREASE IN DECREASE IN
SYSTOLIC SYSTOLIC
RECLINING 10 ERECT I0
BLOOD BLOOD
-
PRESSURE PRESSURE
OVER PLACEBO OVER PLACEBO
20 -20
180
175 2. Means for four blood pres¬
sures with each of the seven
170
treatment regimens as found
165 by method B (including only
SYSTOLIC 160 eight patients who had all the
ERECT drugs), with 95% confidence
8L00D
155 regions for optimum dosages.
PRESSURE 150 Solid line, with hydrochlorothi¬
145
azide; broken /¡ne, without hy¬
drochlorothiazide.
140
135
130
25 100 200 0 25 100 200
TOTAL DAILY DOSAGE OF TOTAL DAILY DOSAGE OF
SPIRONOLACTONE (mg) SPIRONOLACTONE (mg)
105 105
DIASTOLIC
RECLINING
BLOOD
100
k DIASTOLIC
ERECT
BLOOD
100
95 95
PRESSURE PRESSURE
90 \l" 90
85 Jit !.. j_ 85
i-. J_
25 100 200 0 25 100 200
TOTAL DAILY DOSAGE OF TOTAL DAILY DOSAGE OF
SPIRONOLACTONE (mg ) SPIRONOLACTONE (mg)