Effects of Reduction in Drugs or Dosage After
Long-Term Control of Systemic Hypertension

Edward D. Freis, MD, J.R. Thomas, MD, Susan G. Fisher, MS, Robert Hamburger, MD,
Richard E. Borreson, MD, Kalman C. Mezey, MD, Bangshi Mukherji, MD, William W. Neal, MD,
  H. Mitchell Perry, MD, and James T. Taguchi, MD, for the Veterans Administration
       Cooperative Study Group on Antihypertensive Agents*

The possibility of discontinuing+ompared to
reducing- antihypertensive drug treatment was in-
vestigated in 606 male hypertensive patients with
entry diastolic blood pressure (BP) in the range of
50 to 114 mm Hg. Diastolic BP was controlled at
<BO mm Hg with 1 of 4 regimens: low dose hydro-
chlorothiazide (HCTZ), 25 mg twice daily; high
dose HCTZ, 50 mg twice daily; or high dose HCTZ
plus a low or high dose of a step II drug (proprano-
loI, clonidine or reserpine). After 6 months of treat-
ment that controlled BP, dosages were reduced in
two-thirds of the patients. In those patients receiv-
ing low dose HCTZ and randomized to dose reduc-
tion, antihypertensive drugs were completely dis-
continued. Although approximately half of these
patients remained normotensive for the first 6
months, a significantly greater proportion had ele-
vation of BP compared to the control group, which
continued to receive treatment (p <O.OOOl). In the
high dose HCTZ drug group, the proportion of pa-
tients remaining normotensive did not differ among
those stepped down to low dose HCTZ and the fully
treated control group. While not achieving signifi-
cance the trend was similar with the step II regi-
mens. Although some patients remained normoten-
sive after discontinuation of step II drugs, a greater
proportion returned to elevated BP than when step
II dosage was unchanged. Therefore, while stop-
ping therapy may be effective in some patients, a
decreased dosage is significantly more effective as
a method for maintaining an antihypertensive ef-
fect. Decreasing drug dosages offers the dual bene-
fit of minimizing side effects and reducing drug
CO&S.

(Am J Cardiol 1989;63:702-708)

From the Veterans Administration Medical Center, Washington, DC,
Memphis, Tennessee, Hines, Illinois, Boston, Massachusetts, Houston,
Texas, East Orange, New Jersey, Oklahoma City, Oklahoma, Dallas,
St. Louis, Missouri, and Dayton, Ohio. This study was funded by the
Cooperative Studies Program of the Veterans Administration's Medi-
cal Research Service. Manuscript received July 19,1988; revised manu-
script received and accepted December 7, 1988.

Address for reprints: Edward D. Freis, MD, Hypertension Re-
search, Veterans Administration Medical Center, 50 Irving Street
N.W., Washington, DC 20422.
*See Appendix.

702  THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

B ecause antihypertensive drugs are customarily
  given for life and are often expensive, it is desirable
  to reduce them if possible. Perry and Schroeder'

reported in 1956 that the dose requirement of antihy-
pertensive drugs diminished following long-term treat-
ment. Later investigators assessed the effects of com-
plete discontinuation of antihypertensive drugs.le6 Un-
fortunately, hypertension returned in nearly all patients
although the return was often delayed for months. Few
trials have studied the effects of dosage reduction as an
alternative to drug discontinuation.`,7s8 The present trial
was designed to evaluate the effect of dosage reduction
compared to complete discontinuation of drugs on blood
pressure (BP) control in patients with mild to moderate
hypertension.

METHODS

Endpoint measurement: Goal BP was defined as a
diastolic BP <90 mm Hg except for newly diagnosed
patients with entry diastolic BP between 90 and 94 mm
Hg. In them goal BP was defined as diastolic BP at
least 5 mm Hg below that at entry. If at any time dur-
ing the study a patient had 2 consecutive visits with a
diastolic BP greater than goal BP and the average was
at least 5 mm Hg greater than the baseline level, the BP
was considered to be uncontrolled.

Drug regimens: The protocol drug regimens consist-
ed of the following: (1) low dose (25 mg twice daily)
hydrochlorothiazide (HCTZ); (2) high dose (50 mg
twice daily) HCTZ; (3) high dose HCTZ plus low dose
step II drug (low dose step II); and (4) high dose
HCTZ plus high dose step II drug (high dose step II).
The step II drugs were titrated as necessary. Low dose
step II medications were propranolol 40 mg twice daily,
clonidine 0.1 mg twice daily or reserpine 0.1 mg once
daily. High dose step II medications were propranolol
80 mg increased if necessary to 160 twice daily, cloni-
dine 0.2 mg increased to 0.3 twice daily if needed or
reserpine 0.25 mg once daily.

Prerandomization: Study candidates included previ-
ously diagnosed patients whose diastolic BP was < 115
mm Hg and newly diagnosed patients with a diastolic
BP between 90 and 109 mm Hg on 3 consecutive visits
each 2 weeks apart, or between 110 and 114 mg Hg, on
2 consecutive visits 1 week apart. Screened patients with
malignant hypertension, hemorrhagic stroke, recent
myocardial infarction, history of alcoholism or drug
abuse, contraindication to study medication or who re-


fused to participate were ineligible. Of the 1,316 pa-
tients initially screened for this study 872 met these cri-
teria for entry into the prerandomization drug titration
phase.

Depending on the patient's previous treatment, 1 of
3 types of titration procedures was used as follows.

1. Of those patients entering the titration phase, 329
were previously treated with a regimen similar to one of
the study regimens; these patients were switched to that
study regimen without a washout period. For example,
a patient already receiving HCTZ 50 mg plus propran-
0101 80 mg once daily would be switched to the protocol
regimen of HCTZ 50 mg plus propranolol 80 mg twice
daily. If BP remained above the goal BP, study medica-
tion was titrated upward.

2. Patients previously treated with regimens dissimi-
lar to study regimens (n = 384) had all medications
tapered off and withdrawn over a l- to 2-week period.
They were then begun on low dose HCTZ and titrated
upward to high dose HCTZ and then to the step II
regimens as necessary to achieve goal BP.

3. The 159 previously untreated patients were fol-
lowed weekly for 2 to 4 weeks to establish that the study
criteria for hypertension were met. Those qualifying
were then begun on low dose HCTZ and titrated up-
ward as necessary.

During drug titration 147 patients were determined
to be ineligible for the study due to failure to meet study
criteria for hypertension (n = 27), adverse drug reac-
tions (n = 13), failure to return to clinic (n = 58) and
other, nonmedical reasons (n = 49).

Following successful titration to goal BP, the pa-
tients entered a 6-month prerandomization baseline
phase. Its purpose was to maintain a prolonged period
of continuous normotension before medication reduc-
tion. Patients excluded during this phase included 6 pa-
tients in whom BP rose above goal BP, 29 with medical
problems, 33 lost to follow-up and 51 in whom treat-
ment was interrupted for >14 days. Candidates com-
pleting this 6-month baseline phase with maintenance of
BP control (n = 606) were included in the core study
sample.

Randomization and postrandomization phases:
Two-thirds of the study patients were randomly as-
signed to either dose reduction or drug discontinuation
depending on drug regimen; the other one-third of the
patients continued to receive their unchanged drug regi-
men as a control group (Figure 1). This 2:l randomiza-
tion scheme ensured adequate sample size for a second
randomization of the dose reduction group later in the
study. Patients in the low dose HCTZ group had the
diuretic discontinued while high dose HCTZ patients
were switched to low dose HCTZ. Low dose step II pa-
tients had the step II drug discontinued but remained
on high dose HCTZ and high dose step II patients re-
ceived a low dose of the step II medication and contin-
ued on high dose HCTZ. The appearance of all medica-
tions and placebos was kept uniform to maintain the
double-blinded design. This first postrandomization
lasted 6 months, as did all subsequent study phases.

Patients maintaining goal BP were continuously
treated and followed. Patients not maintaining goal BP

Screened for Eligibility (1316) ----- lnellglble (444)
   +

Titrated on Study Drugs (672) ----w Excluded*
   1                      (147)

       Entered Baseline (725) ----- Excluded o (119)
       I
  I                           I            I
LD HCTZ (209,           HD "C,Z 1146)         LD step II 1135,        HD step II 11161

FIGURE 1. Flow sheet showing the prerandomization drug titration phase using the 4 step regimens as needed to control dii-
stolic blood pressure to <66 mm Hg followed by 6-month treatment maintenance phase. Eligible patients then entered the post-
randomization period where drugs were reduced in two-thirds of patients and remained unchanged in one-third. After 6 months,
two-thirds of eligible patients underwent a second medication reduction. *Excluded patients include those in whom blood pres-
sure was not controlled within study limits and patients with other medical or nomnediil problems. **Reasons for postran-
domization terminations are similar to prerandomization reasons with the addiion of patients being unable to complete the 6-
month phase because the study ended (see text). LD = low dose.

THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 15,1989   703


REDUCTION VERSUS DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS

TABLE I Background Characteristics of Randomized Patients

Pts
(n)

Mean Age
Ws)

Race

White

Black     Other

Before Randomizatron
BP* (mm Hg)

Prior Rx

Yes      No

Low dose HCTZ
No change         72     58f8        31       38      3       126/80 i 13/6         67      5
Dose reduced       137     57f9        60       75      2       129/82 zk 13/6         124     13
High dose HCTZ
No change         47     56i9        22       25      0       128/84&13/5         45      2
Dose reduced        99     59k8        44       54      1       129/82 k 15/5          88     11
Low dose step II
No change         48     56zk 10       24       22      2       126/82 zk 10/6          44      4
Dose reduced        87     56% 10       40       47      0       126/83 f 13/5          84      3
Hugh dose step II
No change         34     56i9        19        15      0       125/84f11/5         32      2
Dose reduced       82     55* 10       43       38      1       128/84 f 14/5         81      1
All treatment arms     606     57f9       283       314      9       127/83 f 136          565     41

' Durq treatment to lower BP.
All f values are mean * standard d&&on.
No slgnlflcant differences I" background characteristics between treatment groups.
BP = blood pressure; HCTZ = hydrochlorothwide.

TABLE II Percent of Patients Remaining Under Blood
Pressure Control at Various Times During 30 Months After
Randomization

Percent Controlled After
Randomization (months)

Group

Low dose HCTZ unchanged
Low dose HCTZ drscontinued
High dose HCTZ unchanged
High dose HCTZ reduced to LD
High dose HCTZ second stepdown
Low dose STEP II unchanged
Low dose STEP II discontinued
High dose STEP II unchanged
High dose STEP II reduced to LD
Hugh dose STEP II second stepdown

6      18

94f3 89i4
55f4 35zk4
79*7 55k9
84zk4 58+9
*      20f6
96i3 84k6
56k5 37i6
85i6 70fll
62i6 47f9
*      17 i 6

30

86f4
23f5

12f7
84i6
16f8
70f 11
47 f 9

* Pabents were randomized to Mial drug reduction for first 6 months after ran-
domlzatlon. Second reduction began after this period.
iSome data were omitted at the Dmonth follow-up because the number of
patents were too few to provide a reliable statement.

I

were considered to have reached a study endpoint; their
drugs were unblinded and appropriate increases were
made in study medication to achieve control of BP. Pa-
tients unable to maintain goal BP on the maximum
study regimen were treated in hypertension clinics on
nonprotocol regimens.

Following the first 6-month postrandomization
phase, patients maintaining BP control in whom medi-
cation was originally reduced but not discontinued-i.e.,
the high dose HCTZ and the high dose step II regi-
mens-were randomized a second time. Thus, two-
thirds received a second dose reduction/drug discontin-
uation while one-third remained on the same dosage. In
that way, two-thirds of the high dose HCTZ patients
initially reduced to low dose HCTZ now had it discon-
tinued. High dose step II patients, in whom the step II
medication had been previously reduced, now had the
step II medication discontinued although these patients
continued to receive high dose HCTZ. After this second
randomization no further changes in medication were
made unless a study endpoint was reached. Patients

704  THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

who maintained control BP were followed for up to 30
months after randomization.

Throughout the study medication compliance was
measured. Patients had to return their medication bot-
tles containing the remaining unused tablets (we delib-
erately provided a small excess of tablets). Patients were
considered compliant if they returned <30% of the
number of tablets that should have been taken without
exceeding 110% of the number to be taken. The return
of an empty bottle was considered a violation. Tablet
counts were done on every visit throughout the trial.

In cases in which therapy was stopped because of
illness, surgery, trauma, etc., the code-labeled medica-
tions could be reinstituted if the interruption was 17
days during the prerandomization phases or 114 days
during the postrandomization period. Otherwise, pa-
tients were terminated from the trial.

Data analysis: Descriptive statistics including 95%
confidence intervals were used to describe the percent-
age of patients maintaining BP control in each study
phase. Long-term maintenance of BP was estimated us-
ing Kaplan-Meier techniques. Differences between
background characteristics, laboratory values and side
effects were examined by the chi-square test of homoge-
neity and the Student t test. Logistic regression proce-
dures were used to identify variables as potential predic-
tors of a patient's ability to maintain BP control. In all
cases a 2-tailed p value of 0.05 was considered statisti-
cally significant. All patients entering the trial signed an
informed consent statement after the procedure had
been fully explained.

RESULTS

After the 6-month baseline treatment period 606 pa-
tients maintained BP control and were therefore eligible
for randomization. Of these, 209 were receiving the low
dose HCTZ, 146 the high dose HCTZ, 135 the low
dose step II regimen and 116 the high dose step II regi-
men.

The major characteristics of randomized patients are
listed in Table I. There were no significant differences


between treatment groups. The mean age of the sample
was 56.9 years. The racial distribution was 52% black
and 47% white. There was no significant difference in
pretreatment BP between the control group and the
drug reduction group within each drug regimen cate-
gory. Ninety-three percent of the patients entering the
trial had been receiving antihypertensive therapy previ-
ously.

First six-month postrandomization phase: Depend-
ing on the therapeutic regimen 55 to 84% of patients on
reduced dosage remained within the acceptable levels of
diastolic BP during the first 6 months (Table II). Low
dose HCTZ was the only regimen in which all antihy-
pertensive drug therapy had been discontinued. Al-
though 55% of these patients maintained goal BP
throughout this treatment phase (Figure 2), this propor-
tion was significantly less than the fully treated low dose
HCTZ control patients (p <O.OOOl). The high dose
HCTZ patients who were reduced to low dose HCTZ
had the greatest percentage remaining controlled at or
below goal BP (84%) after 6 months (Figure 3). At the
end of 6 months, 56% of the low dose step II patients in
whom step II medication was discontinued maintained
BP control (Figure 4). Among the high dose step II
patients in whom the step II drug was reduced, 62%
remained controlled during the 6-month period (Figure
5). Both low and high dose step II groups were signifi-
cantly different from their unchanged dose controls.
There was no significant difference, either before or af-
ter dose reduction, among any of the 3 antihypertensive
drugs used in the step II regimens.

Among patients remaining within goal BP criteria,
the greatest average increase in BP occurred among
those in whom medication was reduced from low dose
HCTZ to no active treatment. Six months after ran-

,-

I-

, -
0

domization these patients increased BP by 13.9 mm Hg
systolic and 3.6 mm Hg diastolic. The 2 treatment
groups who were stepped down to a lower dose and re-
mained controlled exhibited only small increases in BP
(approximately 5/2 mm Hg).

FIGURE 3. Percent of high dose HCTZ patii remaining un-
der diastolic BP control during 20 months after randomiza-
tion. The so/id line represents the patients whose dose of 60
mg HCTZ twice daily remained unchanged. The broken he
with frequent interruptions indicates the patients whose
HCTZ was reduced from 50 to 26 mg twii daily but was not
discontinued. The broken line with few interruptions repre-
sents the patients who, after 6 months of initial dose reduc-
tin, had active medication discontinued. Blood pressure con-
trot is well maintained in the dose reduced group but not in the
drug discontinued patii, i.e., after the first but not the sec-
ond reduction.

PERCENT MAINTAINING BP CONTROL

1.00 -

    \
     \ \
0.75 - `1 \
        \ \ \
         `. .-
0.50 -          `\
            `\ em- ----
                          ----a-,-,-

0.0         6       12       18       24      30
                  MONTHS

FIGURE 2. Percent of low dose HCTZ patii maintaining
diastolic BP control during 24 months of follow-up. The so/id
line indicates the patients remaining on 26 mg HCTZ twice
daily. The broken line indicates the patients whose HCTZ was
discontinued. A high rate of loss of blood pressure control
occurred when HCTZ was discontinued.

FIGURE 4. Percent of patients on low dose step II drugs re-
maining under diastolic BP control during 30 months fdlowing
randomization. The so/id he represents the patients remain-
ing on HCTZ 50 mg twice daily plus step II dntg. The broken
line indicates patii whose step II drug, but not HCTZ, was
discontinued.

THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 15.1989   705


REDUCTION VERSUS DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS

t

TABLE Ill Patfents Entering and Patient Attrition on Each Regimen During the First 18 Months After Randomization

                        Patient Attntron Dunng Study Phase

Time from       No. of Pts Entered         Elevated BP            Other Causes
Randomization
(months)        04    6-12    12-18    O-6    6-12    12-18    04    6-12

Low dose HCTZ    209    135     110      63    15      10      10     5
Hugh dose HCTZ    146    103     52      23    31      9      15     10
Low dose step II    135     91      62      39    11      4       2     5
High dose step II    116     72     40      33    23      2       7     3
Total          606    401     264     158    80     25      34     23

* Patients entering late who were unable to complete all phases of the study before the termlnaton date

12-18

11
5
4
2
22

End of Study*

06    6-12

1     5
5     10
3     13
4     6
13    34

12-18

11
16
18
17
62

For causes other than an increase above goal BP,  minations for other causes including medical problems

terminations from the study were uncommon: 6% of the
control patients and 5% of the reduced dosage group
had to be terminated. The most frequent reason was
failure to return to the clinic. Other terminations in-
cluded major cardiovascular complications (5) of which
4 were in patients receiving HCTZ at the time; adverse
drug reactions (2) both in patients receiving only place-
bo; and BP >114 mm Hg on 2 visits or >119 mm Hg
on 1 visit (2).

Long-term follow-up: Patients were followed for a
maximum of 30 months after randomization. Table III
lists the number of patients available for entry into the
first 3 postrandomization phases by regimen. Patient at-
trition during these phases is also shown. The 3 main
reasons for a constantly decreasing pool of patients are
elevated BP, which was the major study endpoint; ter-

  -NO CHANGE
`I  ----STEP 2 REDUCED
  -- STEP 2 REDUCED

ONCE
TWICE

0          0         12         18        24
                MONTHS

FIGURE 5. Percent of patients on high dose step II regimens
remaining under diastolic BP control during 20 months after
randomization. During the first reduction (line with frequent
interruptions) the step II drugs were reduced but not discon-
tinued. HCTZ dosage remained unchanged. At 6 months some
of the patients were subjected to a second reduction in whiih
the step II drug was discontinued. Discontinuation of step II
drug, despite continuation of HCTZ, was followed by a steep
decline of patients remaining under diastolic BP control.

706  THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

such as cardiovascular complications, or administrative
reasons such as refusal to return to clinic; and inability
to complete all phases before the end of the study be-
cause of sequential enrollment. Although 30-month re-
sults are listed in Table II, it should be recognized that
due to attrition these results are based on a very small
sample of patients.

Table II lists the decreasing percent of patients re-
maining under BP control at 6-month intervals up to 30
months from the time of randomization. Among the low
and high dose HCTZ groups the patients most effec-
tively maintaining their BP over time were those in
whom doses were reduced rather than discontinued. In
fact, up to 18 months after randomization, the percent
of high dose HCTZ patients remaining normotensive
was essentially the same between the dose reduction and
the dose unchanged control groups. Also, among the
step II patients in whom dosage was reduced but not
discontinued, nearly half maintained BP control up to
30 months.

The long-term results in the patients whose drug was
discontinued were not as favorable. Among patients
having low dose HCTZ discontinued 23% were able to
maintain BP control as long as 30 months (Table II).
The patients originally given high dose HCTZ and who
after 2 dose reductions were receiving no active drug
fared worse: the percentage with BP control decreased
to 12% after 30 months of follow-up (Table II, Figure
3). Results of discontinuation of low dose step II drug
were also poor (Table II), even though patients contin-
ued to take HCTZ. Some of these patients had begun
prerandomization treatment with step II regimens.
Many others who had begun with HCTZ failed to show
BP control on the single drug and were, therefore, ad-
vanced to step II. Over 30 months, major complications
averaged 3% (n = 6) in the control group and 2% (n =
8) in the reduced dosage group. Thus, dose reduction
did not appear to increase the risk of major complica-
tions over the period of the study.

Reestablishment of blood pressure control: During
the course of the study there were 202 patients on re-
duced drug dosages whose BP increased above the per-
missible limits of goal BP and at least 5 mm Hg above
the prerandomization level. These patients had their
dosages retitrated. Of these 202 patients, 172 were re-
controlled on their prerandomization medication and
dosage. Thus, the great majority of the patients re-


TABLE IV Biochemical Changes After Six Months of Study Treatment

                            Low Dose HCTZ     High Dose HCTZ    Low Dose Step II    High Dose Step II

                            No             No             No             No
                      Change   Reduction  Change   Reduction  Change   Reduction  Change   Reduction

Glucose (mg/dl) (X 0 05551 mmol/llter)       -3.7    -7.7       3.8     2.5      -7.0     3.4     -1.9     0.5
Potassium (mEq/L) X 1.0 mmol/llter)        -0 1     0 6+      0.2     0.2       0.1    -0.1       0.1    -0 1
Cholesterol (mg/dl) (X 0 02586 mmol/llter)    -15.4   -19.9      -2.0     0.3     -18.9    -3.o*    -21.9     1.3
Triglycerides (mg/dl) (X 3.397 mmol/llter)     -35.2   -43.1      14.0     1.0     -1.2    32.7      31.2   -54.6
Unc Acid (mg/dl) (X 59.48 pmol/liter)        -0.2    -0.9+     -0.2    -0.6      -0.1    -0.0       0     -0.2
Alkalme phosphatase (unlts/llter) (X 7.1 U/liter)   -1.1     7.5'      2.1     2.4     -2.2     1.8      -2.1    -3.0

* p <0.05. f p <O.col.
To obtm the results in SI units multIply the values shown by the appropriate factor I" parentheses.

gained BP control on the same dosage they required
during initial titration.

Biochemical changes: Table IV lists the mean
changes in biochemical serum levels from the time of
randomization to 6 months after. Significant differences
between treatment groups most frequently occurred in
the low dose HCTZ patients in whom all medication
was withdrawn. In these patients there was a significant
increase in serum potassium levels, a decrease in serum
uric acid and an increase in alkaline phosphatase. These
changes were not seen in the high dose HCTZ patients
possibly because their dosage was only reduced rather
than discontinued during the first 6-month postrandom-
ization phase. Serum cholesterol decreased with some
regimens and not with others. The reason for the de-
creases was not apparent. There was considerable varia-
tion within groups since only the difference between the
control and reduced low dose step II patients was signif-
icant (p <0.05). There were no significant changes in
fasting blood glucose. Changes in biochemical levels
during later postrandomization phases were similar to
those in Table IV.

Side effects and compliance: Patient-reported side
effects were minimal. Headache was reported on >l
visit by 4% of patients. Gout and dizziness occurred in-
termittently in 3% and 2% of the patients, respectively.
There were no significant differences in the incidence of
side effects between the drug reduction and the control
groups or between the different regimens. No particular
side effect was associated with any specific drug or regi-
men. As estimated by pill counts there was no differ-
ence in the level of compliance between the various
treatment groups.

Factors predictive of successful dose reduction:
Characteristics predictive of successful reduction in
medication were investigated using univariate and mul-
tivariate analyses. Characteristics differing (p <0.20)
between patients in whom medication was successfully
reduced or discontinued and those with unsuccessful
drug reduction were selected for inclusion in a logistic
regression analysis. These characteristics included mean
diastolic BP during baseline, variability of BP during
baseline, patient compliance, time since diagnosis, he-
moglobin, hematocrit, alkaline phosphatase, potassium,
white blood cell count and pulse rate. Other factors con-
sidered as potential covariates included in the statistical
model were race, age, each drug regimen and treatment

assignment, i.e., reduction of drug dosage or discontinu-
ation. Variables that contributed significantly to the
model included treatment assignment (p <O.OOOl),
baseline diastolic BP (p = 0.003) and compliance (p =
0.0528). The statistical significance of the randomiza-
tion treatment assignment rather than the specific drug
regimen suggested that drug dosage reduction was more
successful than drug discontinuation, regardless of drug
regimen group. Patients with a lower diastolic BP dur-
ing baseline were more likely to maintain BP control, as
were compliant patients.

DISCUSSION

There were no significant differences in major pa-
tient characteristics between the various treatment
groups. Sample sizes were adequate in all groups and
remained adequate up to 18 months after randomiza-
tion. Black patients equalled 52% of the total. The study
was limited to men. After randomization the patients
whose drugs were reduced but not entirely discontinued
maintained more effective BP control than those whose
drugs were completely discontinued. The latter group
included patients whose sole medication of HCTZ 25
mg twice daily was suddenly discontinued. The second
most frequent group to develop BP elevation was pa-
tients receiving the low dose step II regimens. These pa-
tients continued to take HCTZ (only the step II drug
was discontinued). The failure of HCTZ alone to con-
trol BP in these patients may have been due, at least in
part, to their more resistant hypertension. They had
failed to achieve normalization of BP with HCTZ alone
during titration of dosage. The percent of step II pa-
tients maintaining BP control was slightly greater
among the high dose step II patients in whom step II
medication was reduced rather than discontinued. After
6 months, however, the difference was not significant.
The greatest percent of patients maintaining control BP
despite dose reduction was achieved in the high dose
HCTZ group. Their dose was reduced from 50 to 25
mg twice daily. These patients maintained levels of BP
that closely approximated the control group whose dos-
age was not reduced.

The highest percentage of patients whose BP in-
creased to hypertensive levels was those whose medica-
tion was completely discontinued. Within each treat-
ment regimen, the patients most likely to increase dia-
stolic BP to >89 mm Hg were those with higher levels

THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 15.1989   707


REDUCTION VERSUS DISCONTINUATION OF ANTIHYPERTENSIVE DRUGS

of diastolic BP at randomization. By the time of the
second dose reduction most patients were receiving min-
imal or no therapy. In the patients receiving HCTZ
alone and randomized to medication reduction, HCTZ
had been stopped, while in the patients on step II treat-
ment only HCTZ was maintained. No further reduc-
tions in dosage were made after the second randomiza-
tion. Despite minimal or no medication the rate at
which patients exhibited return of hypertension dimin-
ished after the first 12 months following randomization.
This was probably because no further dosage reductions
occurred during that period and also because patients
most susceptible to lose BP control had experienced BP
elevations during their first year in the trial. However,
following the second reduction, at 6 months many of the
patients failed to maintain normal BP when most anti-
hypertensive drugs were discontinued (Figures 3 and 5).
The critical factor, therefore, seemed to be whether the
medication was reduced or completely discontinued.
It is possible that after the first 6 months following
the initial reduction, the patients remaining in the trial
represented a population that for various reasons were
better able to maintain their BP within normal limits
following treatment discontinuation. Although not insti-
tuted in this study, weight reduction and sodium restric-
tion have been used with some success in preventing the
return of elevated blood pressure after drug withdraw-
al."

The relative lack of purely drug-related side effects
in this study applied to all drug regimens including re-
serpine plus HCTZ. However, more than half of the
patients received only 0.1 mg reserpine daily. These re-
sults confirm our former study of small doses of reser-
pine with HCTZ.`O

The present results suggest that degree of elevation
of the prerandomization diastolic BP was significantly
related to the return of hypertension. The patient's BP
variability before randomization also directly correlated
with return of hypertension. It is also possible that some
of the mildly hypertensive patients had only temporary
elevations of BP when admitted to the trial and they
returned spontaneously to normal after repeated visits.`*
The present results suggest that after long-term treat-
ment, dosage reduction is more effective in preserving
antihypertensive control than is discontinuation of medi-
cations. Dose reduction should be advantageous over the
long term because smaller doses reduce the risk of ad-
verse effects and decrease the cost of treatment.

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APPENDIX

The following persons participated in the study.
Chairman's Office: Barbara Gregory, BSN, Washington,
DC.

Consultant: Barry J. Materson, MD, Miami, Florida.
Clinic Associates: Debbie Ohlen, PA, Patricia Kershen, PA,
Dallas, Texas; Ruth Collins, RN, Houston; Phyllis Mangas,
FNP, Dayton, Ohio; Lorretta Hoerman, PA, St. Louis, Missou-
ri; Mary Jo Barsotti-Tracey, MS, Barbara Lesniak, East Or-
ange, New Jersey; Anne M. Faiella, BSN, Catherine Cum-
mings, RN, Boston, Massachusetts.
Cooperative Studies Program Coordinating Center: Wil-
liam G. Henderson, PhD, Jean Rowe, Laura Weber, MS, Mary
Ellen Vitek, Hines, Illinois.

Cooperative Studies Program Clinical Research Pharma-
cy: Larry M. Young. RPh, Jane Weber-San-Hamel, PharmD,
Dennis Toussaint, RPh, Mike Sather, RPh, Albuquerque, New
Mexico.

Operations Committee: Morten H. Maxwell, MD, Chair-
man, Walter M. Kirkendall, MD, Theodore Colton, ScD.
Cooperative Studies Program Central Administration:
Daniel Deykin, MD, Janet Gold, Boston; James A. Hagans,
MD, PhD, Ping Huang, PhD, Washington, DC.
Hines Cooperative Studies Program Coordinating Center's
Human Rights Committee: Lauren Lawson, PhD (Chairper-
son), Hines Veterans Administration Medical Center, Hines,
Illinois; Edgard Perez, Horace C. Dudley, PhD, Nancy Cahill,
Paul Peterson, MD, William Upholt, PhD.

708  THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63