SYSTEMICHYPERTENSION

Ehlcacyand Toleranceof Spironolactone in EssentialHypertension XAVIER JEUNEMAITRE,MD, GILLES CHATELLIER, MD, CARMEN KREFT-JAIS, MD, ANNE CHARRU, MD, CLAUDE DEVRIES, MD, PIERRE-FRANCOISPLOUIN, MD, PIERRE CORVOL, MD, and JOEL MENARD, MD

The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertenston clinics between 1978 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. in 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 98.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 8.5%, p
acid level increased, but not significantly (10.5 ~moi/liter). Fasting blood glucose and total choiesteroi levels did not change, triglyceride levels increased slightly (0.1 mmoi/liter, p <0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 899 men prescribed spironolactone alone or in association with another antlhypertensive treatment, 91 cases of gynecomastia developed (13 % ). Gynecomastia was reverslble and dose-related; at doses of 50 mg or less the incidence was 8.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg. (Am J Cardiol 1987;80:820-825)

0

treatment in a large population of hypertensive patients.7 Almost 10% of the patients were given spironolactone either alone or in association with other antihypertensive treatment. To study the blood pressure (BP) and metabolic variations induced by spironolactone, the analysis included only patients who were prescribed the drug as monotherapy. Because gynecomastia is uncommon with other antihypertensive treatments, its incidence was analyzed in all men treated by spironolactone as mono- or polytherapy. Besides information gathered on the value of the drug, our results illustrate the advantages and limitations of such a study using informations of a standardized medical database, prospectively collected during the day-to-day practice of an hypertension clinic.

ver the last 20 years, spironolactone has been extensively used as a diuretic antihypertensive agent. Since 1960, it has been widely prescribed in Europe, and in France its use represented 295 million-days of treatment in 1985. However, studies of its efficacy and its metabolic and sexual adverse effects have involved only trials of short duratior+ or have included only a few subjects3p4 or patients with diseases other than hypertension5 The follow-up for 10 years of more than 20,000 patients in 2 systemic hypertension clinics by the computerized ARTEMIS system6 allowed us to analyze the efficacy and the adverse effects of an antihypertensive From the Service d’Hypertension ArttBrielle, HGptial Broussais, Paris, France. Manuscript received March 30, 1987; revised manuscript received and accepted May 28,1987. Address for reprints: Xavier Jeunemaitre, MD, Service d’Hypertension ArGrielle, HBpital Broussais, 96 rue Didot, 75014 Paris, France.

Methods Patients: From January 1, 1976, to January 1, 1986, 20,812 patients were referred to the St. Joseph and Broussais hypertension clinics in Paris. Initial evalua-

820

October

1, 1987

tion was made either in a l-day hospital stayor during a short hospitalization,and the antihypertensivetreatment was subsequentlyinitiated. After the initial period of therapeuticadjustment,patientswere examined at the hypertensionclinic on a regular yearly basis or were referred back to their physician, For patients with mild to moderate hypertension, the goal of the clinic was to achievea diastolic BP of 90mm Hg or less with the fewest drug-inducedadverseeffects.When a diuretic drug was used, the goal was to maintain a plasma potassium level of 3.9 mmol/liter or more. A total of 2,051patients were given spironolactone at least once. Of these,930patients were given spironolactone asmonotherapy;the rest were given it in association with other antihypertensivetreatment.Clinical characteristicsare listed in Table I. One hundred eighty-twopatientswere selectedaccording to the following criteria. They had been prescribed spironolactone in monotherapy, They were treated for at least 3 months (65 were followed more than 2 years).They had no initial abnormalrenal function and no diabetesmellitus. Patientswith secondary hypertension,especially primary hyperaldosteronism due to either an adenomaor a bilateral adrenalhyperplasia, were excluded on the basis of results of an extensiveclinical, radiologic and laboratory investigation Only those patients were chosenfor whom biologic data had been recorded,both before and during spironolactone treatment. Compared with the entire group of spironolactone-treatedpatients(Table I), the selected patients were slightly younger, but had the same overrepresentationof women over men and the same BP levels. Clinical and biologic records: Since 1976,a computerized system, ARTEMIS has been available for the medical managementand follow-up of hypertensive patients.For eachpatient, a prospectiveand standardized collection of medical information is maintained: patient’s medical history and initial clinical status,in-hospital work-up of hypertension,including the results of radiologic,biologic and hormonal investigations,initiation of treatment and follow-up of clinical and biologic parameters.For eachpatient selected, the initial in-hospital visit was arranged at least 2 weeks after previous treatment was discontinued.At eachsubsequentvisit to the outpatientclinic, an outpatient care questionnairewas filled in by the physician, which included clinical findings, questionson compliancewith the prescribedregimen and treatment,side effects and biologic data. At the hospital and outpatient clinic visit, systolic and diastolic (phaseV of Korotkoff sounds)BP were taken by the physicianwith a standardmercury sphygmomanometer.BP was measuredafter the patient had restedfor 10to 15minutes in the lying position and for 2 minutes in the upright position. Although several physiciansparticipatedin recordingclinical measurements, BP was always recorded under these same standardizedconditions.At the sametime, the following serum biologic data were collected:creatinine,potassium, uric acid, fasting blood glucose total cholesterol and triglyceride levels.

THE AMERICAN

TABLE I Hypertensive

JOURNAL

Characteristlcs Patients

OF CARDIOLOGY

Age Men (n) Body weight BP (mm Hg) Systolic Diastolic Dose (mg) Dose (mg/kg)

2,051 5oi 11 849 (41%) 69.6 f 14.7 187.3 98.7 52.5 0.8

60

of the 8plronolactone-Treated

All SpironolactoneTreated Patients n

Voiume

f f f f

Values are mean f standard BP = blood pressure.

28.2 15.3 32.9 0.5

Spironolactone in Monotherapy 930 55 f 12 272 (29%) 67.3 f 14.9 160.9 96.1 92.0 1.4

f f f f

23.1 13.7 57.0 0.9

Selected Patients 182 53f 11 51 (28%) 66.4 rt 14.5 162.6 98.1 96.5 1.5

f i 4~ f

20.9 11.9 52.6 0.8

deviation.

The in-hospital BP and the correspondingbiologic data obtained after at least 2 weeks of discontinuing previous treatment were taken as baseline values Thesedata were comparedwith thosemeasuredduring spironolactonetreatment, at the last complete visit (i.e., with clinical and biologic data) recorded in the computerized system. Statistics: The F and t testswere used for comparison of means for paired and unpaired data using the BDMP programs.Correlationswere calculatedby the least-squaresmethod.A p value
Results Table II is a summary of the main findings during spironolactonetreatment in 51 men and I31 women, with a mean follow-up period of almost 2 years (691 days].The mean dose of spironolactonewas 96.5mg (range25 to 300) The mean absolutedoseof the drug was larger in men than in women, but this difference disappearsif the dose is consideredper kilogram of body weight (1.5mg/kg in both groups). Blood pressure effects: Compared with pretherapeutic levels, systolic and diastolic BP were reduced significantly in the entire group (p
022

TABLE

SPIRONOLACTONE

II

Comparison

IN ESSENTIAL

of Changes

HYPERTENSION

in Baseline

Clinical

and

Biologic

Parameters

Between

Men

and

Women Significance Men vs Women

n Age Wr) Dose (mg) b’Wd Duration (days) Range

Women

51 52 f 9 118 f 68 1.5 i 0.9 621 f 632 92*3,300

131 54% 11 88 & 42 1.5 f 0.9 718 f 650 90+3,240

Before Blood pressure (mm Hg) Systolic Diastolic Body weight (kg) Plasma values (mmol/liter) Creatinine (rmollliter) Potassium Uric acid (~mollliter) Glucose Cholesterol Triglycerides

After

166.7 zk 22.3 103.3 f 12.4 79.3 f 13.4 92.9 3.5 361 5.6 6.2 1.3

f f f f f f

Basal Parameters

Men

16.4 0.5 74 0.7 1.2 0.5

: NS

Variations During Treatment

NS t NS NS NS

Before

After

142.1 f 88.5 f 78.8 f

20.1 11.1 12.9

161.0 f 96.1 f 61.5 f

20.2 11.2 11.7

$ $ t

145.7 i 88.0 f 60.4 f

17.6 9.9 11.1

NS

.

$ $

t NS

99.5 4.3 365 5.9 6.2 1.4

27.1 0.5 80 1.2 1.3 0.6

76.7 3.7 297 5.2 6.3 1.1

14.8 0.4 70 0.6 1.1 0.5

$ $ NS NS NS NS

85.9 4.2 310 5.3 6.2 1.2

18.3 0.4 71 0.6 1.0 0.6

$ *

NS

l

$

NS NS NS NS

f f f zk f f

f f rt f f f

f f f f f f

t NS NS NS NS

$ t NS t

Values are mean f standard deviation. ‘p <0.05, Tp
tion. No relation was found between plasma creatinine increase and age. Plasma creatinine level increased to more than 150 pmol/liter in only 5 patients treated with spironolactone (maximum 162 pmol/liter). The initial creatinine level of these patients was between 88 and 130 pmol/liter. In both sexes, there was a remarkable and significant increase in plasma potassium level (0.7 and 0.5 mmol/liter in men and women, respectively]. During treatment [Fig. 4, no patient had a potassium level of less than 3.0 mmol/liter; the maximal value was 5.6 mmol/liter. No complication occurred because of hyperkalemia. Variations in plasma potassium level were related to dose, with a greater increase for doses of 150 mg or more than for doses of 50 mg or less IO.76 vs 0.48 mmol/liter, p <0.05). Analyzed independently

Systolic

BEFORESPIRONOLACTONE

Diastolic

25

75

150

25

75

150

50

100

300

5-o

160

300

(86)

of the dose prescribed, there was a strong correlation (r = 0.67, n = 170, p
2.4

2.8

3.2

3.6

Illl-L 4.0

4.4

4.8

5.2

5.6

(31)

v

1

10% I

i

T

_1xx

FIGURE cording

1. Decrease in systolic and to the dose of spironolactone.

AFTER

SPIRONOLACTONE

II

ns

diastolic blood pressure ns = not significant.

Plasma ac-

FIGURE lactone

2. Plasma treatment.

potass

n (mmolll)

potassium distribution before Median values are indicated

and after by broken

splronoline.

October

TABLE III Long-Term

Absence Follow-Up

Duration (mo) Mean Follow-Up

(days)

of Change

of Clinical

Baseline

Weight (kg) 64.3 Blood pressure (mm Hg) (n = 42) Systolic 163.2 Diastolic 98.3 Plasma Values (n = 29) Greatinine (~mollliter) 76.6 Potassium (mmol/liter) 3.5 Uric acid (pmol/liter) 295.1 Glucose (mmol/liter) 5.3 Cholesterol (mmol/liter) 6.5

and

1, 1987

THE AMERICAN

Biologic

14.5

f *

17.6 13.3

f 15.4 & 0.3 z!z 66.5 zk 0.6 zl~ 1.0

Parameters

with

6-12 249

values f

JOURNAL

63.5 f

OF CARDIOLOGY

Bpirorqlactone

64.1

& 13.2

64.7 I

14.2

138.7 f 10.6” 84.1 k 7.0”

137.9 f 11.1’ 83.5 zk 13.1”

88.3 4.3 308.3 5.4 6.2

86.4 4.3 323.7 5.4 6.2

91.5 4.3 315.3 5.5 6.3

Values are mean f standard deviation. No difference was found between the changes in clinical follow-up. *Significant difference (p
A slight but insignificant increase (10.5 ~mol/liter] in plasma uric acid was noted. Eleven patients whose initial levels of plasma uric acid were between 305 and 493 pmol/liter had levels above 450 pmol/liter when treated with spironolactone. No clinical symptoms of gout were reported. No overall change in fasting blood glucose level was noted (increase of 0.1 mmol/liter), although a slight increase (0.3 mmol/liter) was observed in men (p = 0.06). Total cholesterol level did not vary in patients of either gender during spironolactone treatment. When analyzed for the entire group, triglyceride levels increased slightly (0.10 mmol/liter, p <0.05). Two patients were given fenofibrate. Neither dose of spironolactone nor duration of treatment influenced variations in the metabolic variables studied. A constant dose of spironolactone was prescribed for 42 of the 65 patients who were followed for more than 2 years (mean 46 & 17 months). Changes in BP and metabolic measurements were established in the first months and did not change during the subsequent follow-up periods (Table III). Gynecomastia: Of the 2,051 patients given spironolactone with or without other medication, 699 men were followed up for at least 2 months, which is the minimal duration expected for development of spironolactone-induced gynecomastia. Ninety-one cases (13%) of gynecomastia were observed [Table IV). By comparison with the entire group of spironolactonetreated men, patients with gynecomastia had been given larger doses of the drug (106 vs 58 mg), probably because of their mean higher BP level. Development of gynecbmastia was highly signifi: cantly dose-related (Fig. 31. Duration of treatment for development of gynecomastia was extremely variable (2 to 100 months) but was shorter for doses of 150 mg or more (9 f 12 months) than for doses of 50 mg or less (27 f 20 months, p <0.05). We did not find a relation between the cumulative dose of spironolactone and the incidence of gynecomastia. Seventy-six of the 91 patients were receiving another treatment in association with spironolactone. In 18 of these’ patients, the association with a-methyldopa (12 cases), digitalis alone (4 cases) or digitalis in association with a-methyldopa (2 cases) may have favored

and metabolic

parameters

and its pretherapeutic

TABLE

IV

It f i f +

823

>24 1,374

142.3 f 14.8’ 86.7 rt 6.7” f 17.3’ & 0.3” f 82.6 Z!Y0.6 f 0.9

60

on a

12-24 549 12.8

Volume

18.3’ 0.3” 71.0 0.7 0.8

according

* f f f f

20.0’ 0.3’ al.7 0.8 0.9

to the length of

value.

Characteristics

of the Population SpironolactoneTreated Men with Follow-Up 12 mo

n Age W) Body weight BP (mm Hg) Systolic Diastolic Dose (mg) Dose (mg/kg) Cumulative dose gr Duration (days) Range Vatues are mean f standard *p <0.05, Tp
Patients with Gynecomastia

699 54f 11 77.3 * 13.5

NS 4

167.3 4 28.7

NS

100.9 58.0 0.8 42.4

NS

f 16.1 f 35.4 f 0.5 f 61.1 682 60-3,841

t t t NS

91 53 f 9 80.8 + 14.7 172.9 k 28.1 104.0 f 17.7 106.5 f 60.2 1.4 f 0.9 57.9 f 87.6 590 60-3,000

deviation.

development of gynecomastia. However, gynecomastia disappeared when spironolactone treatment was interrupted (64 cases) or decreased [22 cases), except for 2 patients (1 with alcoholic cirrhosis and l.with digitalis treatment). Three patients were lost to followup after the appearance of gynecomastia.

Discussion The efficacy and side effects of an antihypertensive treatment are best evaluated by randomized, placebocontrplled, therapeutic trials. The results of such studies are valuable for quantifying the antihypertensive effect of a given drug, for analyzing its side effects by comparison with placebo or a reference drug, and for answering the such questions as whether mild hypertension should be treated.8 However, they are far from solving all the usual clinical problems and constitute a clinical experiment in a special environment, where patients selected are followed according to use of a standardized research protocol.g The follow-up for 10 years of 20,000 patients treated in 2 systemic hypertension clinics by the computerized ARTEMIS system allow us to analyze retrospectively the efficacy and the tolerance of antihypertensive drugs with a different approach. This standardized collection of information,

024

SPIRONOLACTONE

IN ESSENTIAL

HYPERTENSION

prospectively recorded by a fixed number of physicians over 10syears,7 reflects routine use of antihypertensive drugs in our clinics. For treating mild, uncomplicated essential hypertension, the general strategy was to use either a diuretic or a ,&blocking drug as the first-choice drug and spironolactone was preferentially prescribed in cases of hypokalemia (mean initial level 3.7 f 0.4 mmol/liter) or in postmenopausal women, in whom the problems of endocrine adverse effects do not exist [sex ratio 3.5/l]. Besides those induced by the nonrandom choice of the therapy, the main bias of such interrogation of a data bank when used to determine treatment efficacy are those introduced by the patients lost to follow-up.1° Indeed, when a patient is not followed-up at the clinic, it is almost impossible in such a retrospective study to analyze the reason for his outcome: decision of the clinic, voluntary choice of the patient or of the general practitioner, high quality of the results, drug’s side effects, complications due to the disease or the treatment. However, we already showed the validity of retrospective analysis of data in the ARTEMIS system in a study of the cost effectiveness of different methods of investigating hypertension, which provided the same results as a simultaneously performed randomized trial.ll Other authors have also shown that such pragmatic retrospective analysis could provide results similar to those obtained in randomized trials in areas as different as the results of aortocoronary bypass12 or the efficacy of tonsillectomy for recurrent throat infection.13 The results confirm the efficacy of spironolactone in treating moderate essential hypertension on a long term basis. Indeed, 60% of the patients had a diastolic BP of 90 mm Hg or less on treatment, and in only 10% was it more than 100 mm Hg with this monotherapy. The range dose of 75 to 100 mg was more effective than doses of 50 mg or less, but no further BP decrease was observed for doses of 150 mg or higher. These results are in agreement with the reports of randomized studies that concern a small number of patients.14J5 However, contrary to Schersten et al2 we did not observe

24/46

25-50 FIGURE 3. spironolactone.

Incidence

of

75-100

gynecomastia

150-300 according

to

dose

of

that patient age influenced the blood pressure response to spironolactone. That spironolactone does not adversely affect renal function in patients without renal insufficiency is shown by the slight mean increase (8.3 hmol/liter) in plasma creatinine level, which probably reflects only the negative sodium balance. On average, this increase was not dose-dependent. Slight consequences on renal function were also reported in studies of patients with mild hypertension but without renal insufficiency.16 Similarly, we found a slight but not significant increase (10.5 mmol/liter) in plasma uric acid level, similar to other studies in which no changelJ7 or only a transient reduction4 in uric acid was found. Spironolactone increased the mean plasma potassium level by 0.55 mEq/liter, a value similar to that reported in other studies. l8 The dose-dependent increase of this variable was markedly influenced by its initial level, since patients with the lowest values of serum potassium were prescribed the highest doses of spironolactone (correlation dose/K = -0.29, n = 180, p
October

1, 1987

siderably (2 to 100 months), although it was shorter for doses larger than 150 mg. The great degree of variability in spironolactone-induced hormonal alter&ion@ and the complexity of the mechanisms of development of gynecomastia24 may partly explain our results. Finally, although variations of the measurements must be cautiously interpreted in such a retrospective and nonrandomized analysis, it is interesting to compare the dose-response curve of the BP decrease induced by spironolactone td the dose-related incidence of gynecomastja. The efficacy of the drug appeared for doses larger than 75 mg, but no supplementary benefit was achieved for dqses befween 150 and 300 mg, whereas the incidence of gynecomastia greatly increased for these dosages. Therefore, the best compromise in primary hypertension appears to be ‘achieved with doses of 75 to 100 mg.

References MG, Harris JJ. Effect of spironoloctone in hypertensive patients. Am f Med Sci 1970;260:313-330. 2. Schersten B, Thulin T, Kuylinstierna J. Engstrom M, Karlberg BE, Tolagen K, Nordlander S, Nilsson G. Clinical and biochemical effects of spironolactone administered once doily in primary hypertension. Hypertension 1980;2: 672-679. 3. Fagerberg ES. Serum lipids and some metabolic parameters after treatment with spironolactone and thiazides in hypertensive patients. Curr Ther Res 1982;32:872-878. 4. Falch DK, Schreiner S. The effect of spironolactone on lipid, glucose and uric acid levels in bJood long-term administration to hypertensives. Acta Med Stand 1983;213:27-30. 5. Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1973;225:

1. Crane

40-43. 6. Degoulet

P, Chantalou JP, Chatellier G, Devries C, Goupy F, Zweigenbaum P. Structured and standardized medical records. In: Van BemmeJ /H, Ball M, Wigertz 0, eds. MEDINFO-83. Amsterdam, North-Holland, 1983;‘1164-1168. 7. Degoulet P, M&ard J, Berger C, Plouin PF, Devri& C, Hire1 JC. Hypertension management: the cpmputer as a participant. Am J Med 1980;68:559-567. 8. Byar DP, Simm RM, Friedenwald WT, Schlesselman JJ, DeMets DL, Ellenberg JH, Gail MH, Ware JH. Randomized clinical trials: perspectives on some

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recem ideas. N Engl J Med 1976;295:74-79. 9. Feinstein AR. Current problems and future challenges in randomized clinical trials. Circulation 1984;70:767-774. 10. Dambrosia JM, Ellenberg JH. Statistical considerations for a medica! data base. Biometrics 1980;36:323-332. 11. Devri& C, Chatellier G, Degoulet P, Berrard C, Ducrocq MB, Tugaye A, Plouin PF, MBnard I. Traitement de J’hypertension art&ieJJe. @ficac& compar&e de J’hapitaJ de jour et de J’hospitalisation classique. Presse Med 1983;?2:2153-2157. 12. Hammermesteir KE, DeRouen TA, Murray J, Dodge HT. Effect of aortocoronary saphenous vein bypass graft on death and sudden death: comparison of nonrandomized medically and surgically treqted cohorts with comparable coronary disease and left ventricular function. Am [ CardioJ 1977;39:925-930. 13. Paradise IL, Bluestone CD, Bachman RZ, Colborn DK. Bernard BS. Taylor FH, Rogers i
18. Morgan DB, Davidson C. Hypokalqemia and diuretics: an analysis of pubJications. Br Mea J 1980;28@905-908. 19. Conn JW. Hypertension, the potassium ion and impaired carbohydrate tolerance. N EngJ J Med 1965;273:1165-1168. 20. Weidmann P, Uehlinger DE, Gerber k. Antihypertensive treatment and serum Jipoproteins. [ Hypertensjon 1985;3:297-306. 21. Ames RP, Peacock PB. Serum cholesterol during treatment of hypertension with diuretic drugs. Arch Iritern Med 1984;144:710-734. 22. Camino-Torres R, Ma L, Snyder PJ. Gynecomastia and semen abnormcilities induced by spironolactone in normal men. f CJin Endocrinol Metab 1977;45:255-260. 23. Huffman DI& Kampmann JP, Hignite CE, Azarnoff DL. Gynecomastia induced in normal males by spironolactone. Clin Pharmaco! Ther 1978; 24:465-478. 24. Rose LI,

physiology 87:398-403.

Underwood PD, Newmark SR, Kisch ES, Williams GH. Pathoof spironolactone-induced gynecomastia. Ann Intern Med 1977;