Reprinted from the Archives of internal Medicine
      June 1988, Volume 748
Copyright 1988, American Medical Association

Original Investigations

Thiazide Therapy Is Not a Cause of Arrhythmia
in Patients With Systemic Hypertension

Vasilios Papademetriou, MD; James F. Burris, MD; Aldo Notargiacomo;
Ross D. Fletcher, MD; Edward D. F&s, MD

o Forty-four patients with uncomplicated systemic hyper-
tension underwent 48-hour electrocardiographic monitoring
before and after four weeks of treatment with hydrochlorothi-
azide, 100 mg daily. Plasma potassium concentration de-
creased from 4.07-cO.26 mmollL (4.07kO.26 mEq/L) to
3.36 2 0.44 mmol/L (3.36 + 0.44 mEq/L). The average number of
premature ventricular contractions, couplets, or ventricular
tachycardia episodes did not change significantly. Twenty
patients had more than mintmat ventricular ectopy (class 2 to
5) before and 17 after diuretic therapy. Further analysis
revealed that following diuretic therapy, neither patients with
plasma potassium levels of 3.4 mmol/L or less (53.4 mEq/L)
nor patients with left ventricular hypertrophy had increased
ectopy as compared with baseline. At baseline, patients wlth
left ventricular hypertrophy had more arrhythmias than pa-
tients without. We conclude that the results of this study
provide no evidence that diuretic therapy or diuretic-Induced
hypokalemia results in increased ventricular ectopy, and that
patients with left ventricular hypertrophy may have more
ventricular ectopy than patients wlthout, but these arrhyth-
mias are not adversely effected by diuretic therapy.

(Arch Intern Med 1988;148:1272-1276)

D iuretics have been widely used in the management of
  systemic hypertension for more than 20 years. In
general, they have been considered to be safe and effective
with rather a low side effect profile. They have been used
in most studies that showed beneficial effects from the

For editorial comment see p 1265.

treatment of hypertension,112 and diuretics have been rou-
tinely recommended as initial therapy in the stepped-care
approach.3 In recent years, however, the safety of diuretics
in the management of hypertension has been questioned.
While biochemical consequences such as hyperuricemia,
hyperglycemia, or increase in cholesterol levels cause some

Accepted for publication NW 22, 1987.
From the Georgetown University and Veterans Administration (VA)
Medical Centers, Washington, DC.
Reprint requests to Hypertension Research, VA Medical Center, 50
Irving St NW Washington, DC 20422 (Dr Papademetriou).

1272  Arch Intern Med-Vol 148, June 1988

concern, hypokalemia became a major issue. Fears that
mild-to-moderate hypokalemia may aggravate cardiac ar-
rhythmias have resulted in the extensive administration of
potassium supplements and potassium-sparing diuretica
and more recently, these fears have initiated a trend away
from the use of diuretics in the treatment of hypertension.
This trend gained popularity even though an association
between hypokalemia and cardiac arrhythmias not only
remains unproved but also has been challenged.4m6 Although
some studies suggested an increased risk of cardiac ar-
rhythmias in patients with diuretic-induced hypokale-
rnia,?ra others failed to confirm iW0 and the subject remains
controversial. The original publication of the Multiple Risk
Factor Intervention Trial11 has been interpreted as indicat-
ing an increased risk of sudden death in hypertensive
patients with resting electrocardiographic (ECG) abnor-
malities when treated aggressively with diuretics. Al-
though this interpretation has been criticized,5 this study
greatly influenced the medical community.

The present study was designed to investigate the effect
of diuretic therapy and diuretic-induced hypokalemia on
cardiac arrhythmias by direct recording methods in pa-
tients with uncomplicated essential hypertension. Some
data from the first 31 patients have been previously
published.`* This article presents complete analysis of the
expanded series of 44 patients; particular emphasis has
been placed on the influence of diuretic-induced hypoka-
lemia on cardiac arrhythmias.

PATIENTS AND METHODS

Forty-seven patients with essential hypertension entered the
study. All patients were black males. Patients with a history of
myocardial infarction, angina pectoris, congestive heart failure,
renal insufficiency (creatinine level ~176.8 kmol/L r~2.0 mg/dL]),
inability to give informed consent, or patients who required
digitalis therapy were excluded from the study. Three patients
were terminated from the trial because of noncompliance and
failure to attend clinic visits.

Screening Phase

Following the history and physical examination, a chest roent-
genogram, M-mode echocardiogram, ECG, complete blood cell
count, and blood chemistry studies were obtained from all patients.
Patients with evidence of heart disease other than left ventricular
hypertrophy were excluded from the study. The presence or

Thiazide Therapy-Papademetriou et al


absence of left ventricular hypertrophy was determined from the
echocardiogram by measuring the left ventricular posterior wall
thickness prior to the mechanical contraction of the left atrium.13
Left ventricular hypertrophy was considered present if the pos-
terior wall thickness was equal or more than 12 mm. Echocardio-
grams with evidence of asymmetric hypertrophy or dilated car-
diomyopathy were not acceptable. The presence or absence of left
ventricular hypertrophy was also determined by ECG criteria
using Estes' scoring system.14

Study Protocol

Phase 1: Baseline.-After eligibility for the study was deter-
mined, all drug therapy was discontinued and potassium chloride,
40 mEq, was given to all patients for ten days. Three weeks later
patients were seen for baseline studies. Sitting blood pressure,
heart rate, body weight, and plasma creatinine, sodium, potas-
sium, and chloride levels were determined. Blood samples, which
were collected in sterilized lo-mL tubes that contained 143 U of
lithium heparin, were analyzed within 30 minutes. Shortly after
blood samples were obtained, a 48-hour ambulatory ECG monitor-
ing was initiated. Immediately after the completion of the 48-hour
recording, a second blood sample for electrolyte determination
was obtained. The average plasma potassium level of these two
measurements constituted the plasma potassium value of this
phase.
Phase 2: Hydrochlorothiazide Therapy.-Following the com-
pletion of phase 1, all patients were started on a regimen of
hydrochlorothiazide. 50 mp twice dailv, that continued for four
weeks. At the end bf this-period and while hydrochlorothiazide
therapy continued, all studies described in phase 1, including 48-
hour ECG monitoring, were repeated.

Ambulatory ECG Monitoring.-Ambulatory ECG monitoring
was carried out for 48 hours during each phase using a double-
channel recorder (model 445B; Del Mar Avionics. Irvine, Calif)
and analysis was performed on a two-channel cardioxanner'(mode1
MK3 Cardiodata Corn. Malboro. Mass). Analvsis of all taues was
carried out by an exp&ienced technician. For quality contiol, 10%
of the tapes were analyzed by a second technician. Less than 10%
interobserver variability was found in premature beats and no
difference was found in couplets or ventricular tachycardia epi-
sodes. In addition, samples from each hour recording, including
the important arrhythmias, were printed on hard copy in real time
and were reviewed by one of us. Ventricular arrhythmias were
tabulated in two ways. The first way is modification of Lown's
classification as used by Singh et a1,15 which is as follows: 0
indicates no arrhythmias; 1, premature ventricular contractions
(PVCs) of 1 to 29/h; 2, PVCs of 30 or more/h; 3, multifocal PVCs;
4, couplets; and 5, ventricular tachycardia. From this grading
system an average grade per hour was calculated. The second way
is the average number of premature ventricular contractions per
hour, total number of couplets, and total number of ventricular
tachycardia episodes.

BW kg     92.22175 90.1?17.6+ 61.1+14.4 79.8214.lt
PK, mmol/L
(mWL)   4.00k0.22 3.08?0.24t 4.2OkO.26 3.81 k0.28t
PVC/h      16.6?50.7  9.1 k22.9   2.6 + 5.9   5.1 k9.2
Total couplets    124       12       5        6

Total VT
episodes       2       2       5        1

AGR/h     0.72kO.76 0.59r0.64 0.46kO.54 0.57r0.76

J

*BW indicates body weight; PK, plasma potassium; PVC, premature
ventricular contractions; VT, ventricular tachycardia; and AGR, average
grade.
tPc.001; statistics compare values before and after diuretic therapy

rothiazide (P = not significant). A total of 129 couplets and
seven brief episodes (three to five beats) of ventricular
tachycardia was noted before and 18 couplets and three
runs of ventricular tachycardia were noted after diuretic
therapy. The average grade per hour was similar between
the two phases.

Statistical analysis of the results was performed where appro-
priate using the Student t test for paired observations, or the x2
test. The study was approved by the Research and Development
Committee at the Veterans Administration Medical Center, Wash-
ington, DC.

        Assessment of the Effect of
   Hypokalemia on Ventricular Arrhythmias
To further evaluate the role of low potassium levels on

RESULTS

At baseline, all patients studied had mild-to-moderate
hypertension, normal plasma potassium levels, and normal
renal function. Twenty-eight of these patients had evidence
of left ventricular hypertrophy by echocardiography and
20 by ECG criteria. The remaining 16 patients had normal
left ventricular wall thickness by echocardiography and
only one met the ECG criteria for left ventricular hyper-
trophy. In the group as a whole, body weight and blood
pressure decreased significantly as expected with diuretic
therapy (Table 1). The plasma potassium level also de-
creased from 4.07kO.26 mmol/L (4.07 +0.26 mEq/L) at
baseline to 3.36+ 0.44 mmol/L (3.36? 0.44) (P<.OOl) with
hydrochlorothiazide. Premature ventricular contractions
averaged 11.3 * 40.2 before and 7.5 2 18.8 after hydrochlo-

ventricular ectopy patients have been grouped into those
who developed hypokalemia while receiving diuretic ther-
apy and those who maintained plasma potassium levels
within the normal range (Table 2). Of the 44 patients, 27
had potassium levels of 3.4 mmol/L or less (~3.4 mEq/L)
following thiazide therapy, The decrease in body weight
and plasma potassium level was highly significant in both
groups (Pc.001). Ventricular ectopy, and the average grade
per hour decreased substantially in the hypokalemic group,
although the changes did not reach statistical significance.
The distribution of patients into the Lown classes did not
change with thiazide therapy (Table 3). In the hypokalemic
group, 12 patients had more than minimal ectopy (class 2
to 5) before thiazide therapy and 11 patients had more than
minimal ectopy after thiazide therapy. Similarly, in the
normokalemic group, eight patients had class 2 to 5 ectopy
before thiazide therapy and six patients had it after.

Arch Intern Med-Vol148, June 1988                       Thiazide Therapy-Papademetriou et al   1273

Table I.-Ventricular Ectopy Before and After
Muretk Therapy: All Patients (n = 44)

Variable*

Baseline

Diuretic

SBP, mm Hg             154?16        136+12t
DBP, mm Hg             96k6         69+6t
W kg                67.6? 16.9       85.9e 16.9t
PK, mmol/L (mEq/L)        4.07~0.26       3.36 f 0.44t
  PVC/h                11.3-c40.2        7.5218.0
Total couplets              129             16
Total VT episodes             7             3

  AGRlh                0.63 to.70       0.58 k 0.67

*SBP indicates systolic blood pressure; DBP, diastolic blood pressure;
BW. bodv weioht: PK. olasma ootassium: PVC. oremature ventricular
co~tractirks; VT vkntrkuiar tachykardia; and AGR,' average grade.
tP<.ool.

Table 2.-Ventricular Ectopy in Patients With or
WEthou? Hypokalemia Receiving Diuretic Therapy

Variable*

  Hypokalemla
   (n=27)

Baseline   Diuretic

No Hypokalemla
   (n = 17)

Baseline   Diuretic


Table 3.-Patient Distribution: Modified Lown
        Classifica%3ri*

Hypokaiemlc Group

Normokalemic Group

_.                              I

Class

Baseline

Diuretic

Baseline

Diuretic 1

0         3         4        0         0

1        12        12        9         11

2         1         1         0         0

3         5         3        3         2

4         4         6         1          3

5         2         1         4         1

1

*Difference within or between groups not statistically significant. Modifi-
cation of classification as used by Smgh et al.13

Table 4.-Ventricular Ectopy in Patients With or
Without LVH Before and After Hydroohlorothiazide*

LVH (n = 28)      No LVH (n=16)

Variable    Baseline   Diuretic   Baseline   Diuretic

LVPWT     1.39+0.14        1.03-to.07     

W kg    86.3k14.7 85.4-cl4.7t 90.0?20.8 88.1 -c20.6+
PK, mmoi/L
(mEW   4.06~0.23 3.39-cO.45t 4.1OkO.32 3.33-cO.43t
PVC/h      16.6k49.8  10.1 +22.9   2.1 k5.0   3.0 + 5.9
Total couplets    123       15       6        3

Total VT
episodes       5       3       2        0

AGRlh     0.79iO.78 0.88-tO.74 0.34+0.40t 0.41 eO.54

L

*LVH indicates left ventricular hypertrophy; LVPWT, left ventricular pos-
terior wail thickness; BW, body weight; PK, plasma potassium; PVC,
premature ventricular contractions; VT, ventricular tachycardia; and AGR,
average grade.
tP<.OOl, compare values before and after diuretic; Pc.05, compare
values between groups at baseline.

     Effect of Diuretic Therapy in Patients
   With or Without Left Ventricular Hypertrophy
Since some studies suggested a higher incidence of
ventricular arrhythmias in patients with left ventricular
hypertrophy, patients were also grouped into those with
and those without left ventricular hypertrophy as assessed
by echocardiography (Table 4). Twenty-eight patients met
the echocardiographic criteria for left ventricular hyper-
trophy. Of these patients, 20 also had ECG evidence of left
ventricular hypertrophy. In the remaining 16 patients, left
ventricular wall thickness was normal, but one patient met
ECG criteria for left ventricular hypertrophy. Comparing
the ventricular ectopy between the two groups, patients
with left ventricular hypertrophy determined by echocar-
diography had more PVCs per hour and more repetitive
beats than patients without left ventricular hypertrophy,
but the differences did not reach statistical significance.
The difference in the average grade per hour, however,
which is an alternative way of quantitating the severity of
arrhythmias, was statistically significant. The average
grade per hour at baseline was 0.7920.78 for the first
group and 0.3420.40 for the second (Pc.05). There were
no statistically significant differences in arrhythmias be-
tween patients with or without left ventricular hypertro-
phy determined by ECG.
Diuretic therapy resulted in a significant decrease in
body weight and the plasma potassium level in both groups.
&rrhythmias, however, did not change significantly. Table
b I&XYS the patient distribution into arrhythmia classes

b        155         18

3
a         8          1

b         3         

4
a         33         

b         90         4

5
a         6                      2

b          2         
6
a         8                      1

  b         2                      
*PVC indicates premature ventricular contractions; VT, ventricular tachy-

carala.

ta indicates first Hoiter monitoring; b, second Holter monitoring.

before and after diuretic therapy in the two groups. Overall,
in the left ventricular hypertrophy group, there were 15
patients with more than minimal ventricular ectopy (class
2 to 5) at baseline and 12 after diuretic therapy. In the
second group, there were five patients with more than
minimal ectopic activity at baseline and five after diuretic
therapy. These differences were not statistically significant
either within groups or between groups.

Data of this study demonstrated no correlation between
plasma potassium level and any type of arrhythmias or
arrhythmia grade. Even the eight patients with overt
hypokalemia (plasma potassium level 2.5 to 2.9 mmol/L
[2.5 to 2.9 mEq/L]) had no worsening of their arrhythmias
with diuretic therapy. Arrhythmias worsened in some
patients following diuretic therapy but improved in many
others. In some patients, there was considerable variability
between Holter recordings obtained during the same
phase. As shown in Table 6, the number of PVCs per hour
varied up to fourfold between consecutive recordings
whereas couplets or ventricular tachycardia runs could be
present on one but not the other recording. (Individual
results for each of the 44 patients are available on request.)

k$@T4  Arch Intern Med-Vol 148, June 1988                      Thiazide Therapy-Papademetriou et al

    Table 5.-Pat&tit Distdbutkm: Modified town
~

                                 . .

Class    Baseline    Diuretic    Baseline    Diuretic

0         2         2         1         2

1        11         14        IO        9

2         1         0         0         1

3         6         3         2        2

4         4         7         1         2

   5         4         2         2        0  I
*Difference between groups or within groups did not reach statistical
significance by x2 test. Modification of classification as used by Singh et
al.`5
tLVH indicates left ventricular hypertrophy

Tab@ ea.---Spontaneous Vadabifity Bsiweatn 24~How
   Ho&w Re&ording Obtained Ourif@
    the same twee of the s?udp

Patientf    PVC/h   Total Couplets   Total VT Episodes
1
a         55         10             1

b         99                      

2
a        359         63             


COMMENT

In a previously published study,0 we found no change in
ventricular arrhythmias when overt diuretic-induced hy-
pokalemia was corrected in patients with systemic hyper-
tension. In that study, approximately one third of the
patients with overt hypokalemia (average plasma potas-
sium level, 2.8eO.3 mmol/L 12.8~0.3 mEq/LI) had more
than minimal ventricular ectopy that remained unaffected
by correction of plasma potassium levels. We hypothesized
then that those arrhythmias were not related to the low
plasma potassium level.

The present study was designed to determine whether
diuretic therapy, per se, without hypokalemia or diuretic
therapy with hypokalemia has adverse effects on the
cardiac rhythm. F'or the purpose of the study, patients
with systemic hypertension and no other major disease
were selected. Although ambulatory ECG monitoring rep-
resents the best method for detection of spontaneous
cardiac arrhythmias, the technique is still limited by
considerable day-to-day va~abilit~`~I' Therefore, to in-
crease its sensitivity, two consecutive 24-hour monitorings
were performed during each phase of the study. The close
temporal relationship between the plasma potassium mea-
surement and recording of arrhythmias was assured by
obtaining blood samples for plasma potassium levels at the
beginning and at the end of each 48hour ECG monitoring.
Furthermore, interference with arrhythmias by any other
pharmacologic agents was excluded by discontinuing treat-
ment with all medications prior to including patients in the
study so that only hydrochlorothiazide was administered
during the experimental phase.

Data in this study were examined for the group as a
whole and in subgroups; that is, patients were separated
into hypokalemic and nonhypokalemic groups and into
patients with or without left ventricular hypertrophy
Although we realize the limitations of subgroup analysis,
these separations were helpful in differentiating the effects
of hypokalemia from any other independent effects of
diuretic therapy on the cardiac rhythm and any adverse
effects of diuretics in patients with left ventricular hyper-
trophy.

Results in this study provide no evidence that diuretic
therapy or diuretic-induced hypokalemia results in in-
creased ventricular eetopy Neither the group as a whole
nor the subgroups exhibited increased arrhythmias with
hydroehlo~thiazide therapy. In fact, the hypokalemic
group manifested a trend toward decreased arrhythmias
with hydrochlorothiazide. More patients had complex ar-
rhythmias at baseline than during hypokalemia. Even the
eight patients who exhibited plasma potassium levels of
2.5 to 2.9 mmol/L (2.5 to 2.9 mEq/L) with hydrochlorothi-
azide therapy did not have any change in the frequency of
ventricular ectopy. Two patients with considerable ventric-
ular ectopy at baseline, if anything, improved with diuretic
therapy, which also resulted in marked hypokalemia. Pa-
tients with left ventricular hypertrophy had considerably
more ventricular ectopy at baseline than patients without
left ventricular hypertrophp Although the differences did
not reach statistical significance for any individual category
of arrhythmias, the average grade per hour was signifi-
cantly higher in the first group of patients. These findings
are in accord with the data published by Messerli et al,`8
who found more severe and complex arrhythmias in hyper-
tensive patients with left ventricular hypertrophy, It is
important to emphasize, however, that even patients with
left ventricular hypertrophy did not demonstrate increased
ventricular ectopy following thiazide therapy.

Arch Intern Med-Vol 148, June 1988

Data in Table 2 indicate an impressive difference in
premature beats at baseline between hypokalemic and
normokalemic patients. This difference was not statistically
significant due to the large SD. Careful examination of the
individual data demonstrated no correlation between base-
line arrhythmias and subsequent development of hypoka-
lemia. In fact, the difference at baseline was due to the
high premature beat count demonstrated by three patients
(257, 76, and 40 PVCs per hour). In the remaining 24
patients constituting the hypokalemic group, baseline
PVCs averaged 3,3/h.

Considerable day-to-day variability has been noted in
consecutive Holten recordings.`%" The sensitivity of the
technique increases with the number of monitorings per-
formed. Although a large number of recordings in each
phase would be desirable, this is difficult for technical
reasons. Most of the previously published studies utilized
only one Holter monitoring in each phase, whereas in the
present study two recordings were obtained in each phase.

With respect to the variability in arrhythmias noted in
this study, the following are noteworthy. The large SD
noted in the group as a whole and in the hypokalemic group
at baseline has been greatly effected by one patient who
demonstrated a very high PVC count at baseline (257/h).
This admittedly decreases the statistical power of the
study to detect changes. However, if this patient was not
to be included, the mean ( 2 SD) of the difference would be
1.2k11.6 for the 43 patients. This would give an 80%
statistical power to detect a change of 4.9 premature beats
per hour. Although small changes would not have been
detected, the clinical significance of such changes is ques-
tionable. Furthermore, a trend toward less rather than
more arrhythmias was noted after diuretic therapy.

Results in this trial are supported by other similarly
designed studies. Lief et al9 performed 48-hour ECG
monitoring in 13 patients with uncomplicated systemic
hypertension before and after treatment with hydrochlo-
rothiazide. Plasma potassium levels decreased from
4.0 r 0.1 to 3.0 2 0.1 mmol/L (4.0 2 0.1 to 3.0 rf: 0.1 mEq/L),
but no change in ventricular ectopy was noted. Madias et
allo performed 24-hour ECG monitoring in 20 patients with
hypertension who were receiving placebo, and at two and
four weeks of hydrochlorothiazide therapy. Plasma potas-
sium level was 4.4 ~fr 0.1 mmol/L (4.4+- 0.1 mEq/L) with
placebo, 3.4 r 0.1 mmol/L (3.4 t 0.1 mEq/L) at two weeks,
and 3.0?0.1 mmol/L (3.01tO.l mEq/L) at four weeks of
hydrochlorothiazide therapy Ventricular ectopic activity
did not change significantly with hydrochlorothiazide ther-
apy Caralis et alIs studied 16 hypertensive patients before
and after thiazide therapy. Eight patients with no clinical
evidence of organic heart disease had no change in ventric-
ular eetopy following diuretic therapy, The remaining eight
patients had findings consistent with organic heart disease
and they demonstrated increased ventricular ectopy with
diuretics. In a 1983 publication, the Medical Research
Council of Britain- reported on two studies with rather
contradictory results. In the first study, patients with
uncomplicated hypertension were subjected to 24-hour
ECG monitoring before and after eight to ten weeks of
therapy with bendroflumethiazide. This study showed no
evidence of increased ventricular ectopy with diuretic
treatment. The second study compared results of 24-hour
ECG monitoring of patients receiving long-term treatment
with thiazides with a group of placebo-treated patients.
The investigators noted an overall increased incidence of
ventricular ectopy in the diuretic-treated patients. How-
ever, this increase in ventricular ectopy could not be
att~buted to hypokalemia since there was no correlation

Thiazide Therapy-Papademetriou et al  7275


with plasma potassium in this particular subgroup and
these patients had no baseline pretreatment ECG record-
ings.

The study most frequently quoted as providing evidence
linking diuretic-induced hypokalemia to cardiac arrhyth-
mias is that by Holland et a1.8 That investigation, using 24-
hour ECG monitoring, showed increased ventricular ectopy
in thiazide-treated, hypokalemic patients, as compared
with their control pretreatment recordings. Holland's
study, however, failed to take into account the considerable
day-to-day variability in arrhythmic activity.16 Patients
with more than six premature ventricular beats per hour
at baseline, prior to diuretic therapy, were excluded from
the study. Bias, therefore, was introduced by selecting
baseline recording with low levels of ventricular ectopy.
Because of possible day-to-day variability,16 the likelihood
of finding increased arrhythmias on the second recording
would be increased simply due to regression toward the
mean rather than to hypokalemia per se. In our study,
patients with more than minimal baseline ventricular
ectopy were not excluded. It is noteworthy that up to a
fourfold difference in the frequency of PVCs was noted in
the same patient during the same phase on consecutive 24-
hour recordings. More importantly, couplets or runs of
ventricular tachycardia were noted on one but not the
other 24-hour monitoring during the same phase.

Much of the controversy surrounding diuretic therapy
with or without hypokalemia and increased risk of sudden
death has been derived from the results of the Multiple
Risk Factor Intervention Trial" that was published in 1982.
That study has been interpreted as having shown increased
mortality in a subgroup of patients with ECG abnormalities
at rest when aggressively treated with diuretics. Although
the author@' of that study cautioned that their findings

were inconclusive and further investigation was needed,
these data have frequently been used as establishing an
association between thiazide therapy and increased risk of
sudden death in patients with baseline ECG abnormali-
ties.21 This finding, however, has not been substantiated by
other studies. In fact, the recent retrospective analysis of
the Hypertension Detection and Follow-up Program2* failed
to confirm the findings of the Multiple Risk Factor Inter-
vention Trial. Furthermore, the final report of the Medical
Research CounciP reporting on the results of treatment
of mild hypertension could not demonstrate any adverse
effects of diuretic therapy on patient mortality.

Although the electrophysiologic changes associated with
diuretic therapy are of uncertain significance, theoretically
at least, it is possible that mild-to-moderate, diuretic-
induced hypokalemia in patients with uncomplicated sys-
temic hypertension could be associated with more electrical
stability and less cardiac arrhythmias. It has been shown
by many investigators that diuretic therapy is mainly
associated with a decrease of extracellular potassium but
only minimal change in intracellular potassium concentra-
tion.24.2' The changes result in hyperpolarization of the cell
membrane,28~29 which could lead to an increased threshold
of excitation, increased rate of rise of phase 0, and improve-
ment in conduction, which could eliminate reentrant cir-
cuits and thus improve electrical stability.

In conclusion, the results of this study provide no
evidence that diuretic therapy, per se, or mild-to-moderate,
diuretic-induced hypokalemia are associated with in-
creased ventricular ectopy. Furthermore, diuretic therapy
did not result in increased ventricular ectopy in patients
with left ventricular hypertrophy, although these patients
appear to have more arrhythmias at baseline as compared
with patients with normal left ventricular wall thickness.

1. Veterans Administration Cooperative Study Group on Antihyperten-
sive Agents: Effects of treatment on morbidity in hypertension: Results in
patients with diastolic blood pressures averaging 115 through 129 mm Hg.
jAMA 1967;202:1028-1034. -          - -

2. Veterans Administration Cooperative Study Group: Effects of treat-
ment on morbiditv in hvnertension: III. Influence of ace. diastolic nressure
and prior cardio&c&; disease. Circulation 1972;45;941-1004.  L

3. The 1984 report of the Joint National Committee on Detection,
Evaluation, and Treatment of High Blood Pressure. Arch Intern Med

1984;144:1045-1057.

4. Harrington JT, Isner JM, Kassirer JP: Our national obsession with
potassium. Am J Med 1982;`73:155-159.
5. Papademetriou V: Diuretics, hypokalemia, and cardiac arrhythmias:
A critical analysis. Am Heart J 1986;111:1217-1224.
6. Papademetriou y Fletcher R, Khatri IM, et al: Diuretic-induced
hypokalemia in uncomplicated hypertension: Effect of plasma potassium
correction on cardiac arrhythmias. Am J CarWol 1983;52:1017-1022.
7. Hollifield JW, Statou PE: Thiazide diuretics, hypokalemia and cardiac
arrhythmias. Acta Med Stand 1981$647:67-73.
8. Holland OB, NixonJv Kuhnert I: Diuretic-induced ventricular ectopic
activity. Am J Med 1981;70:762-768,
9. Leif PD, Beligon I, Mates J, et al: Diuretic-induced hypokalemia does
not cause ventricular ectopy in uncomplicated essential hypertension,
abstracted. Kidney Int 1984;25:203.
10. Madias JE, Madias NE, Gavras HP: Nonarrhythmogenicity of
diuretic-induced hypokalemia. Arch Intern Med 1984;144:2171-2176.
11. Multiple Risk Factor Intervention Trial: Risk factor changes and
mortality results. JAMA 1982;248:1465-1476.
12. Papademetriou s Price M, Notargiacomo A, et al: Effect of diuretic
therapy on ventricular arrhythmias in hypertensive patients with or without
left ventricular hypertrophy. Am Heart J 1985;110:595-599.
13. Feigenbaum H: Echocardiography, ed 3. Philadelphia, Lea & Febiger,
1981, pp 129-131.
14. Lipman BS, Massie E, Kleiger RE: Clinical Scalar Electrocardiog-
rap& ed 6. Chicago, Year Book Medical Publishers Inc, 1972,
pp 103.104.
15. Singh SN, DiBianco R, Davidov ME, et al: Comparison of acebutolol
and propranolol for treatment of chronic ventricular arrhythmia: A placebo-
controlled, double-blind, randomized crossover study Circulation 1982;
65:1356-1364.
16. Michelson EL, Morganroth J: Spontaneous variability of complex

1276  Arch Intern Med-Vol 148, June 1988

References

ventricular arrhythmias detected by long-term electrocardiographic re-
cording. Circulation 1980;61:690-695.
17. Morganroth J, Michelson EL, Horowitz LN, et al: Limitations of
routine long-term electrocardiographic monitoring to assess ventricular
ectopic frequency. Circulation 1978;58:408-414.
18. Messerli FH, Ventura HO, Elizardi DJ, et al: Hypertension and
sudden death: Increased ventricular ectopic activity in left ventricular
hypertrophy. Am JMed 1984;77:18-22.
19. Caralis VP, Materson BJ, Perez-Stable E: Potassium and diuretic
induced ventricular arrhythmias in ambulatory hypertensive patients.
Miner Electrolyte Metab 1984;10:148-154.
20. Medical Research Council Working Party on Mild to Moderate
Hypertension: Ventricular extra systole during thiazide treatment: Sub-
study of MRC mild hypertension trial. Br Med J 1983;28'7:1249-1253.
21. Kaplan NM: Our appropriate concern about hypokalemia. Am J Med

1984;77:1-4.

22. The Hypertension Detection and Follow-up Program Cooperative
Research Group: The effect ofantihypertensive drug treatment on mortality
in the presence of resting electrocardiographic abnormalities at baseline:
The HDFP experience. Circulation 1984;70:996-1003.
23. Medical Research Council Trial of Treatment of Mild Hvoertension:
Principle results: Medical Research Council Working Part;`& Med J
19x5:291:97-104.

24. Kassirer PJ, Harrington TJ: Diuretics and potassium metabolism: A
reassessment ofneed, effectiveness and safety ofpotassium therapy. Kidney
Id 1977;11:505-515.
25. Leemhuis MP. VanDamme KJ. Stravrebere A: Effects of chlorthali-
done on serum and'total body pot&si& in hypertensive patients. Acta
Med Stand 1976;200:37-45.
26. Hersp R, Wilkinson PR: Potassium supplementation of thiazide
therapy. Lancet 1976;2:1144.
27. Dareie HJ, Boddv K. Kennedy AC. et al: Total body potassium in
long-termlfurosemide therapy: Is p&ass&m supplementation necessary?
Br Med J 1974;4:316-319.
28. Dyckner T, Wester PO: Ventricular extrasystoles and intracellular
electrolytes in hypokalemic patients before and after correction of the
hypokalemia. Acta Med Sand 1973;204:357-359.
29. Dyckner T, Wester PO: Ventricular extrasystoles and intracellular
electrolytes before and after magnesium infusion in patients on diuretic
treatment. Am Heart J 1979;97:12-18.

Thiazide Therapy-Papademetriou et al

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