Enalapril versus Hidroclorotiazida.pdf

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Enalapril versus hydro-

chlorothiazide/ amiloride inthe treatment of patients with

essential hypertension

ELIZ RABIN MD PhD FRCPC FOR THECANADIAN VASOTEC

VERSUS

MODURET

STUDY GROUP

Can J Clin Pharmacol Vol 2 No 3 Fall 1995 101

DRUGS

ABSTRACT: One hundred and eighty-tw opatients with mild to m oderate essential hy-

pertension were randomized to treatment

following a placebo washout period of four

weeks. Eligible patients received either enala-

pril 5 mg daily or hydrochlorothiazide

(HCTZ)/ amiloride 25/ 2.5 mg d aily in order to

evaluate the efficacy of these th erapies at low

dose. Patients were titrated to the m aximum

dosage of enalapril 20 mg or HCTZ/ am iloride

100/ 10 mg if blood pressure control was not

achieved at initial doses. Blood p ressure con-

trol was defined as a supine d iastolic bloodpressure of 90 mmH g or less and a d rop of at

least 10 mmH g in diastolic pressure at stud y

termina tion. Both tr eatment regimens signifi-

cantly lowered systolic and diastolic blood

pressure in the sup ine and stand ing position

at study exit compared with baseline. Pa-

tients receiving HCTZ/ amiloride, however,

tended to have greater reductions in systolic

and diastolic blood p ressure in the supine po-

sition. This was statistically significant in the

standing position after 1 min (P=0.02) and af-

ter 3 mins (P=0.009) for systolic blood pres-

sure. Although side effects were few, fourcases of hypokalemia were reported in the

HCTZ/ a miloride grou p. Thus, it is concluded

that enalapril and HCTZ/ amiloride, at the

doses studied, are equally effective in con-

trolling m ild to m oderate essential hyperten-

sion although significantly greater mean

reductions in systolic blood pressure were

demonstrated with HCTZ/ amiloride in the

standing position at the doses stud ied.

Lnalapril compar lhydrochlorothiazide-amiloride dansle traitement des patients souffrantdhypertension essentiell eRSUM:Cent quatre-vingt-deux patients souf-frant dhypertension essentielle lgre modre

ont t randomiss pour un traitement aprs une

p riode de sevrage thrape utique par placebo de

quatre semaines. Les patients ligibles ont reu soit

5 mg dnalapril pa r jou r ou une association dhy-

drochlorothiazide (HCTZ)-amiloride de 25/ 2,5 mg

pa r jou r p ou r valuer lefficacit de ces thrapies

faible dose. On a au gment la posologie des pati-

ents jusqu la dose m aximale dnalap ril de 20

mg ou de HCTZ-amiloride 100/ 10 mg si la tension

artrielle ntait pas stabilise au x doses ini tiales.

La matrise de la tension artrielle tait dfinie

Can J Clin Pharmacol

1995;2(3):101-106

Key Words:Amiloride,Comparative stu dy, Enalapril,

Hydrochlorothiazide,

Hypertension

Trademark Merck & Co, Inc/Merck

Frosst Canada Inc, R U

Ott awa Civic Hospital, University

of Ottawa, Ottawa, Ont ario

Correspondence and reprints:

Dr EZ Rabin, Div ision of

Nephrology, Ot tawa Civic Hospital,

1053 Carling A venue, Ot tawa,

Ontario K1Y 4E9

Submitted for publication N ovember

21, 1994. Accepted April 9, 1995

Enalap ril v ersus hy drochloro thiazide/am iloride Ca nadian St udy Group Inv est igators:M Burnstein, Halifax

Infirmary, Halifax, Nova Scotia; M Cohanim, Kingston General Hospital, Kingston, O ntario; A De V illiers, St Hubert,

Quebec; E Espinosa, St M arys Hospital, Montreal, Qu ebec; B Golda, Hamilton, O ntario; AL Kiss, Centre Hospitalier

Pierre Boucher, Longueuil, Quebec; R Ladouceur, Cent re Hospitalier de Verdun , V erdun, Q uebec; Z Lakhani, M isericordia

Hospital, Edmonton, A lberta; J Lalonde, Centre Hospitalier de Verdun; RA Lee-Sing, T oronto, Ontario; AT Lu tterodt,

Regina General Hospital, Regina, Saskatchewan; G Morissette Jr, Centre Hospitalier Region de lOutawais, Hull, Q uebec;

EZ Rabin, Ot tawa Civic Hospital, Ot tawa, Ontario; A Rathwell, Britt ania Medical Group, Ot tawa, Ont ario; S Rusen,

Osborne Medical Centre, W innipeg, M anitoba; C Savard, Centre Hospitalier de Verdun; MS Slobodzian, S t Pauls

Hospital, Saskatoon, Saskatchewan; M S t-Onge, Centre Hospitalier Honore Mercier, St Hyacinthe, Quebec; J Swanney,

Matsqui-Sum as-Abbotsford General Hospital, Abbotsford, British Columbia; JA Wilson, Richmond Hospital, Richmond,

British Columbia

voir page suivante


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In the p ast 10 years, the treatment of mild to m oderate essen-

tial hypertension has u ndergone fundamental changes. The

focus is now on a more individualized treatment approach,

whereas previously a stepped-care approach w as taken . Diur-

etics have been p rescribed historically w ith success; they are

still accepted as first-line agents for the treatment of hyperten-

sion and are recommended by official bod ies such as the Cana -

dian Hypertension Society (1). The use of d iuretics, how ever,

has been shown to be associated with significant metaboliccomplications such as hyperuricemia, hyperglycemia, hyper-

lipidemia (2), hypokalemia (3), and with clinical adverse ef-

fects such as impotence in ma le patients. To minimize some of

these complications potassium-sparing diuretics have been

developed and are used as mono therapy or in combina tion

with other diuretics. The traditional first-line approach has

been mod ified with the ad vent of new medications such as the

alpha-1 postsynaptic antagonists, calcium channel blockers

and th e angiotensin-converting enzyme (ACE) inhibitor s (4,5).

As indicated, hypokalemia is a characteristic side effect as-

sociated with thiazide diuretics that may be of significant con-

cern (3). This d epletion can be minimized, at least partially, by

the concomitant administration of a potassium-sparing agent

such as triamterene, spironolactone or amiloride (6). In the

present multicentre stud y, the efficacy and side effect p rofiles

of enalapril and hydrochlorothiazide (HCTZ)/ amiloride were

compared in the treatment of patients with m ild to m oderate

hypertension across a variety of dose ranges.

PATIENTS AND METHODS

A total of 206 patients were enrolled a t 20 Canadian centres

in this double-blin d , randomized, parallel design study of

enalapril versus HCTZ/ amiloride (Figure 1). Eligible patients

(182) entered an initial four-week placebo period during

which they took one enalapril placebo tablet and oneHCTZ/ am iloride placebo tablet daily.

After four weeks of placebo th erapy, any patient who w as

normokalemic with a supine diastolic blood pressure between

at least 95 mmH g and 114 mm Hg or less was randomized and

entered the double-blin d treat ment period. A normal seru m

potassium range w as established as 3.5 to 5.5 mm ol/ L for en-

rolment. Patients did not receive test m edication on the morn-

ing of their scheduled visit except when their visit was

scheduled for the afternoon and their blood pressure would

have been measured more than 30 h following the last dose of

medication. Visits were scheduled at th e same time of the day

to obtain trough blood pressure values. Duplicate supine and

standing blood pressure measurements were obtained dur ing

the physical examina tion at each visit and th e mean value of

the two determina tions was recorded as the measurement for

that v isit. The sup ine m easurement w as taken after 3 to 5 mins

of rest in the supine position; the stand ing measurements were

taken immediately upon standing and after 3 mins in the

standing position.

The active treatment period consisted of a four-, eight- or

12-week titration period, depending on the individual patient

response to a titrated dose, followed by a maintenance period

of four w eeks at optimum or maximum dose. At the beginning

of the titration period, patients were randomly assigned to

treatment w ith either enalapril 5 m g or HCTZ/ amiloride 25/

2.5 mg once daily for four w eeks. At the same time, patients

took placebo tablets that matched the comparative agent in ap-

pearance. Patients whose blood pressure was controlled at the

end of the first titration (end of w eek 8) entered the mainte-

nance period and continued w ith one tablet of active medica-

tion and one tablet of placebo daily for four m ore weeks (endof week 12). Satisfactory blood pressure control was consid-

ered to be a su pine diastolic blood pressure of 90 mm Hg or less

and a drop of at least 10 mmHg in diastolic pressure from

study baseline.

Patients whose blood pressure was not controlled by the

initial dose after four weeks were titrated to two tablets of

active m edication (enalapr il 10 mg or HCTZ/ amiloride 50/ 5 mg)

and two tablets of placebo once daily and return ed for a blood

pressure evaluation after an additional four weeks of therap y

(end of week 12). Patients whose blood pressure was con-

trolled at the en d of w eek 12 entered the maintenance period

d irectly and remained on enalapril 10 mg and placebo, or

102 Can J Clin Pharmacol Vol 2 No 3 Fall 1995

Rabin

comme une tension artrielle diastolique en dcubitus dorsal de 90

mmH g ou moins et comme un e diminu tion dau moins 10 mmH g de la

tension diastolique une fois ltude termine. Comparativement aux

valeurs de base, les deux rgimes mdicamenteux avaient nettement

fait chuter la tension artrielle diastolique et systolique en dcubitu s

dorsal et en position debou t la fin de ltu de. Cepe nd ant, les patients

recevant de lHCTZ-amiloride avaient tendance dmontrer d es dimi-

nu tions plus impo rtantes de la pression systolique et diastolique en

dcubitus dorsal. Ceci tait statistiquement significatif dans la posi-

tion debou t ap rs 1 minu te (P=0,02) et apr s 3 minutes (P=0,009) pour

la tension artrielle systolique. Quoique les effets secondaires aient

t peu nombreu x, quat re cas dhypokalimie ont t signals dans le

groupe HCTZ-amiloride. Ainsi, il a t conclu que lnalapril et

lHCTZ-amiloride, aux doses tudies, sont aussi efficaces lun que

lautre pour matriser lhypertension essentielle lgre modre. Ce-

pendant, aux doses tudies, lHCTZ-amiloride a entran des diminu -

tions moyennes nettement plus impo rtantes de la tension artrielle

systolique en position debou t.

Figure 1)Trial design. HCTZ Hydro chlorothiazide; V Visit; W Week


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HCTZ/ am iloride 50/ 5 mg and placebo for four more weeks

(end of week 16).

Patients whose blood pressure w as still not controlled after

eight weeks of treatment (end of week 12) were titrated to the

maximum dose of four tablets of active medication (enalapril

20 mg or HCTZ/ amiloride 100/ 10 mg) and four tab lets of pla-

cebo once daily for a total of eight weeks u ntil the end of the

stud y (end of week 20).

Patients were included in the stud y if they were: newly di-

agnosed or previously treated patients with mild to m oderate

essential hyper tension; ambula tory in-pat ients or ou t-

pat ien ts of either sex; and between the ages of 18 and 85 years.

After the placebo wash out period, patients were eligible to en -

ter the treatment period if serum potassium was between 3.5

and 5.5 mmol/ L, and supine d iastolic blood p ressure was at

least 95 but n ot more th an 115 mmH g. Systolic blood p ressure

was not taken into account as an entry criterion.

Patients were exclud ed if they m et any of the following cri-

teria: at risk during the placebo washout period; secondary

hypertension of any etiology; severe, complicated or malig-

nant hypertension; a myocardial infarction or uncontrolled

angina within the previous six mon ths; congestive heart fail-

ure or other significant cardiac, cerebral or liver d isease;

known diabetes mellitus requiring insu lin; severe concurrent

disease such as collagen disease or neop lasm; previously dem-

onstrated poor compliance or mental disability or those who

were not ambu latory; concomitant use of any agent known tohave an effect on blood pressure; and concomitant use of po-

tassium supplements during the titration or maintenance pe-

riods.

Laboratory studies included hematology, blood chemistry

to detect liver and kidney abnormalities, and urinalysis. These

were performed at baseline, during the titration period (after

four weeks of treatment) and at the end of the maintenance pe-

riod (after eight , 12 or 16 weeks of treatment). A partial labora-

tory examina tion was performed at the end of each titration

for any patient wh o followed the titration schema (Figure 1).

Patients w ere withdrawn from the study if any of the fol-

lowing events occurred: serum potassium increased to greater

than 5.5 mmol/ L or decreased to less than 3.0 mmol/ L;

proteinuria increased significantly (more than 200 mg/ 24 h

for patients younger than 65 years and m ore than 400 mg/ 24 h

for patients 65 years or older as determined by semiquantita-

tive protein analysis); white blood cell count fell be low

3500/ mm3; a serious adverse reaction or a serious labora tory

abnormality occurred; or the patient no longer wished to par -

ticipate.

STATISTICS

The primary efficacy analyses were performed using the

all-patien ts-treated approach and included all patients with

efficacy data both at baseline and on treatment. Baseline val-

ues were defined as the value obtained after four w eeks of pla-

cebo and exit values were defined as the values obtained after

eight continuous weeks at a maintenance dose of the active

study treatment.

Patient characteristics w ere compared using Fishers exact

test, Pearsons 2and ttest.

Treatment comparability of the efficacy variables at base-

line was assessed using t tests. Changes from baseline were

analyzed using ttests (between treatment) and paired ttests

(within treatment). The proportion of patients controlled in

each treatment group w as compared u sing Fishers exact test.

Safety analyses were based on the clinical and labora tory

ad verse experiences and on labora tory measures for all pa-

tients enrolled. Treatments were compared w ith respect to thenumber of patients with ad verse experiences using Fishers

exact test. Between treatment compar isons of continuous

clinical and labora tory measurements were made using ttests

and w ithin treatment compar isons were made using paired t

tests.

All statistical compar isons were two-sided tests and were

declared significant w hen the observed probability was below

=5%.

RESULTS

A total of 206 patients were enrolled in this stu dy; 182 were

ultimately randomized to active treatment and were eligible


Enalapril versus HCTZ in essential hypertension

TABLE 1Patient demographics

Enalapril Hydrochlorothiazide/amiloride

N (%) Mean SD Range N (%) Mean SD Range P value

Male: Age (years) 41 (45.6%) 51.9 14.2 21.1-78.1 44 (47.8%) 54.4 12.5 30.4-78.2 0.39

Female: Age (years) 49 (54.4%) 52.1 12.3 23.7-74.3 48 (52.2%) 55.7 12.8 26.1-73.0 0.16

Total: Age (years) 90 (100%) 52.0 13.1 21.1-78.1 92 (100%) 55.1 12.6 26.1-78.2 0.11Caucasian 84 (93.3%) 88 (95.7%) 0.72

Duration of disease (months) 70.9 75.7 87.1 88.6 0.20

Supine blood pressure (mmHg)

Systolic 160.5 15.9 160.5 13.5 0.97

Diastolic 99.7 4.4 100.3 5.1 0.44

Pulse rate (beats/min) 77.9 8.1 80.0 9.0 0.09

Body weight (kg) 75.2 15.6 78.9 16.2 0.12


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for evaluation. Twenty-eight of the patients randomized were

not able to complete the stu dy according to the protocol be-

cause they were ineligible, protocol violators or had early

study termina tion by virtue of premature discontinuation re-

lated to an adverse experience or loss to follow-up. Patients in

bot h tr eatment groups demonstrated no significant difference

in characteristics for age, sex, race and vital signs as presented

in Table 1. Vital sign changes for both patient groups are pre-

sented in Table 2. A significant reduction in mean systolic and

diastolic blood pressure for the supine and both stand ing posi-

tions at 1 and 3 mins w as demonstrated following study ther-apy. This mean change was evident at the end of the study

compared with baseline.

Patients receiving HCTZ/ am iloride, versus those in the ena-

lapril grou p, routinely tended to have greater mean reduc-

tions in systolic and diastolic blood pressure in the supine

position and in both standing positions after 1 and 3 mins at

weeks 8, 12 and exit. For systolic blood p ressure, this between

group mean difference at exit was approximately 5 mmHg

greater for patients treated with HCTZ/ amiloride. This was sta-

tistically significant in the standing position after 1 min

(P=0.02) and after 3 min s (P=0.009). There were no s ignificant

differences between groups regarding pu lse rate or weight at

stud y exit.

To exam ine efficacy at d oses more comparable with those

used in clinical practice today, results at week 12 for 90 pa-tients treated with enalapril 5 and 10 mg (average dose 7 mg)

were compared with those at week 8 for 92 p atients treated

with HCTZ/ am iloride 25/ 2.5 mg. At these more commonly

used dosages, no significant difference in systolic blood p res-

sure was demonstrated; however, a statistically significant

difference was evident for diastolic blood pressure taken in

the sup ine position (P=0.001) and in both stand ing positions

at 1 min (P=0.03) and 3 mins (P=0.02) in favour of enalapril

(Table 3). Moreover, at these more commonly used dosages, a

greater proportion of patients receiving enalapril was con-

trolled than those who received HCTZ/ amiloride (74.4% ver-

sus 55.4%) (Table 4).

The extent of labora tory adverse effects and chan ges were

minimal in the enalapril grou p. Alkaline phospha tase in-

creased from a mean of 83.640.5 U/ L to 87.441.1 U/ L, wh ich

was statistically significant but of no apparent clinical impor-

tance. No clinically significant changes were observed in any

hematological parameter. Similarly, serum creatinine concen-

tration increased sligh tly from a mean of 87.015.4 mol/ L to

89.116.4 mol/ L; however, this mean increase remained

within normal limits. Mean serum potassium concentration

was n oted to be slightly increased (0.09 mmol/ L) wh ich also

was not statistically significant. The remainder of labora tory


Rabin

TABLE 2Treatment comparison of changes in vital signs

Change P value

BTTreatment N Mean SD P value

Supine BP (mmHg)

Systolic Enalapril 90 15.51 14.55 0.0001

HCTZ/A 92 18.62 14.28 0.0001 0.15Dia-

stolic

Enalapril 90 14.78 7.95 0.0001

HCTZ/A 92 15.74 7.83 0.0001 0.41

Standing 0-1 min BP (mmHg)

Systolic Enalapril 90 14.38 16.22 0.0001

HCTZ/A 92 19.66 13.64 0.0001 0.02

Dia-

stolic

Enala pril 90 13.13 8.87 0.0001

HCTZ/A 92 14.54 7.39 0.0001 0.25

Standing 3 min BP (mmHg)

Systolic Enala pril 90 15.11 16.24 0.0001

HCTZ/A 92 20.82 12.91 0.0001 0.009

Dia-

stolic

Enala pril 90 13.29 8.79 0.0001

HCTZ/A 92 14.82 6.97 0.0001 0.20

Weight (kg)

Enala pril 90 0.67 2.26 0.006

HCTZ/A 92 1.06 1.63 0.0001 0.18

Pulse rate (beats/min)

Enala pril 90 1.87 8.43 0.04

HCTZ/A 92 2.30 8.39 0.01 0.73

BP Blood pressure; BT Between treatment; HCTZ/A Hydrochlorothiazide/ami-loride

TABLE 3Mean change from baseline for blood pressure

Results n

Enalapril 5

and 10 mg* n

HCTZ/amiloride

25/2.5 mg

P value

at week 12 versus 8

Supine BP (mmHg)

Systolic 90 14.5413.40 92 12.4713.99 0.31

Diastolic 90 13.788.20 92 9.768.42 0.001

Standing BP 1 min (mmHg)

Systolic 90 13.5215.28 90 13.6013.14 0.97

Diastolic 90 12.208.83 90 9.438.09 0.03

Standing BP 3 min (mmHg)

Systolic 90 13.8415.38 91 14.4812.86 0.76

Diastolic 90 11.889.13 91 8.887.86 0.02

*Average dose 7.0 mg/day;Average dose 25/2.5 mg/day. BP Blood pressure;

HCTZ Hydrochlorothiazide

TABLE 4Controlled patients

Week Do se/d ay

Average

dose

Controlled:

n (%)

Ena lapril 12 5 and 10 mg 7 mg 67 (74.4%)

HCTZ/ami loride 8 25/2.5 mg 25/2.5 mg 51 (55.4%)



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parameters were unremarkable in their mean changes du ring

the study.

A statistically significant decrease in mean serum potas-

sium concentration was observed in the HCTZ/ amiloride

group from 4.250.35 mmol/ L at baseline to 4.080.44

mm ol/ L at exit. Four cases of mild hypokalemia (potassium

3.5 mmol/ L or less) were observed. Mean serum creatinine

concentration increased slightly from 87.918.1 mol/ L to90.819.8mol/ L and this was found to be statistically signifi-

cant. This parameter was w ell within normal limits and clini-

cally not important. Mean fasting blood sugar concentration

also increased significantly from 5.641.17 mmol/ L to

5.951.55 mm ol/ L. All other biochemical labora tory parame-

ters remained relatively unchanged throughout the study.

Mean serum uric acid concentration increased significantly

during the study period and only one patient receiving

HCTZ/ am iloride reported hyperuricemia.

The overall inciden ce of clinical adverse experiences are re-

por ted in Table 5. Of the 20 adverse experiences reported by

14 patients receiving enalapril , only two event s (definitely notrelated to therapy) were noted as serious (chest pain and d is-

secting aortic aneu rysm) in one patient w ho discontinued the

dru g. For the 24 events repor ted in 18 patients who received

HCTZ/ am iloride, three events (probably not related to ther-

apy) were rated as serious (atr ial fibrillation, dizziness and he-

matemesis) in one patient who also discontinued the drug.

One adverse experience was repor ted as an u rticarial eruption

definitely associated with enalapril. Although it was classified

as mild, the patient discontinued the drug and recovered

without sequelae. One patient receiving HCTZ/ am iloride ex-

perienced an episode of gout that was considered to be possi-

bly related to the stud y drug.

DISCUSSION

The results of this multicentre study d emonstrate that the

ACEinhibitor, enalapril, an d the potass ium-sparing diuretic,

HCTZ/ am iloride, are both efficacious in th e treatment of mild

to moderate hypertension after 12 to 16 weeks of treatment. In

both tr eatment groups, over 80% of patients achieved ade-

quate blood pressure control, which is in high agr eement with

earlier repor ts (6-9).

Patients receiving HCTZ/ am iloride tended t o have a greater

mean reduction in their systolic and diastolic blood pressure

in the supine an d sta nd ing position after 1 and 3 mins versus

those receiving enalapril , at stu dy exit. This resulted in a statis-tically significant mean d ifference between the treatments for

systolic blood p ressure. This outcome d emonstrates the effi-

cacy of diu retics in treating mild to moderate forms of hyper-

tension as a first-line agent.

There are several possible explana tions to account for this

difference in favour of HCTZ/ amiloride. One may reason that

the greater efficacy demonstrated in the HCTZ/ amiloride

group m ay have been d ue to a greater number of patients in

this group receiving higher dosages but this wa s, in fact, not

the case. Patients who received HCTZ/ amiloride w ere slightly

older than those who received ena lapril an d it has been sh ow n

that older patients respond better to diuretics (9,10). The age

difference between groups in the present stud y, how ever, was

not statistically significant. Thus, the HCTZ/ am iloride combi-

na tion doses used in the present study appear to be slight ly

more potent than enalapril alone when acting on systolicblood pressure when patients are stand ing.

It is also possible th at the doses of enalapril used in th is

study may not be equivalent in potency to the doses of

HCTZ/ amiloride used in th is study. For some pa tients, because

blood pressure levels obtained were trough levels, a twice

daily administration of enalapril may have been more effec-

tive. Most likely, doses were not comparable and enalapril

was used at a suboptimal dose. Nevertheless, even at th e doses

compared in th is s tu dy, both treatments were similar in out-

come for reduction of all types of diastolic blood pressure.

When d oses closer to those u sed in clinical practice today were

compar ed (enalapril 5 or 10 m g ver sus HCTZ/ am ilorid e 25/

2.5 mg), statistically significant mean differences in diastolic

blood pressure in favour of enalapril w ere seen . Fur thermore,

a greater percentage of patients who received en alapril were

con trolled ver sus those w ho r eceived HCTZ/ amiloride at these

dosage levels.

Ad verse experiences were minimal and both drugs were

well tolerated. Four cases of hypokalemia occurred with

HCTZ/ amiloride. Although doses of HCTZin excess of 25 mg

have been associated with an increased likelihood of adverse

metabolic effects and are no longer recom mended in clinical

practice (1), the reports of hypokalemia in our stud y occurred

at the lower dosages (two cases at 25/ 2.5 mg and two cases at

50/ 5 mg). This demonstrates that a combin ed pota ssiu m-sparing diuretic and HCTZminimizes but cannot completely

eliminate the hypokalemic side effects of thiazide diuretics

(11). There were no repor ts of hyperlipidemia. A slight in-

crease in m ean serum creatinine concentration was observed

in the enalapril group. This change was not clinically signifi-

cant and remained within clinically normal range limits. Fa-

vourable renal responses have been documented with ACE

inhibitors, such as enalapril, in cluding reduction of renal vas-

cular resistance, enhancement of renal bloodflow, enhance-

ment of glomerular filtration rate and decreased urinary

protein excretion (12,13). Small increases in m ean serum cre-

atinine concentration were seen within both groups but this


Enalapril versus HCTZ in essential hypertension

TABLE 5Clinical adverse effects com parison

Enalapri l HCTZ/amiloride Total

Adverse effects

present (patients)

14 (15.6%) 18 (19.6%) 32 (17.6%)

Adverse effects

absent (patients)

76 (84.4%) 74 (80.4%) 150 (82.4%)

Total patients 90 92 182

Total adverse effect

events

20 24 44

Total laboratory

events

20 16 36

Total patients with

laboratory events

13 10 23



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was statistically significant only for patients treated with

HCTZ/ am iloride. Most likely, this greater effect with

HCTZ/ am iloride reflected a constriction of the plasma volume

consistent with the intake of a diuret ic (8,14).

At present, both of these classes of antihypertensive agents

have been r ecom mended for the treatment of mild to mod er-

ate essential hypertension. Diuretics have been shown to be

useful in all age groups but par ticularly in elderly hyperten-sive patients, wh ere they have been shown to redu ce the inci-

dence of stroke and heart d isease (10). How ever, diuretics are

not without some adverse metabolic effects that may offset the

primary benefits achieved by treatment. Combina tion

potassiu m-sparing diuretics, such as HCTZ/ amiloride, should

be p ar ticularly useful in the elderly because the possibility of

hypokalemia and its adverse consequences are diminished

(9,10). ACEinhibitors have been used widely and su ccessfully

in the management of all forms of hypertension and, notably ,

with success in the elderly (15,16).

In this study, both enalapril and HCTZ/ am iloride were

demonstrated to be equally effective in controlling mild tomoderate essential hyp er tension. The toler ability and

safety profiles of both agents were also similar except for four

cases of hypokalemia that occurred in the HCTZ/ amiloride

group.

ACKNOWLEDGEMENTS: The assistance provided by K Darbyson

BSc, D Morissette MSc and G Krip PhD for data m anagement and sta-

tistical analysis of this study is gratefully acknowledged. This study

was supported by a gran t from Mer ck Frosst Can ada Inc, Kirkland,

Quebec.

REFERENCES

1. Ogilvie RI, Burgess ED, Cusson JR, Feldma n RD, Leiter LA,

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