Spironolactone Essential

Versus Nifedipine Hypertension

in

Michel Henry, MD, Marie Wehrlen, MD, Bruno Pelletier, MD, and Michel-Hubert Capron, MD

In a double-blind, randomized, multicenter study of 194 patients with moderate hypertension, spironolactone and nlfedipine were found to reduce blood pressure (BP) to about the same extent and in the same percentage of patients after 45 days of treatment (47 and 6656, respectively). At that point, the patients conboNed by either drug continued on their regimen for another 45 days, while patients whose BP was still elevated (diastolic BP >99 mm Hg), received the other drug in addition. After 45 days of combination therapy, 63% of the patients had normal BP, whereas those receiving monotherapy largely remained normotensive (96% in the spironolactone group and 66% in the nifedipine group). The adverse effects were not severe with either group, but the incidence was markedly higherin the nifedipine group. (Am J Cardid 1990;65:36K-36K)

he antihypertensive effect of spironolactone, used alone or in combination, has been amply demonstrated.l-3 A review of published reports of the last 20 years shows that spironolactone is especially effective when hypertension is associated with low renin levels, and when the elevated blood pressure (BP) is specifically responsive to aldosterone antagonists.4J Spironolactone is often used in combination with other diuretics, especially thiazides,3,4,6 or with other types of antihypertensive agents with good results.7 This study was conducted to (1) compare the safety and antihypertensive effectiveness of a potassium-sparing diuretic such as spironolactone with that of a calcium channel blocker (nifedipine), and (2) evaluate the safety and efficacy of the 2 drugs used in combination.

T

METHODS

A double-blind, randomized, multicenter study was conducted over a go-day period to evaluate the safety and efficacy of spironolactone and sustained-release nifedipine in 184 patients with moderate essential hypertension (165 mm Hg [1200] systolic and 100 mm Hg [1120] diastolic BP). Characteristics of the 2 patient groups are summarized in Table I. The study was preceded by a 4week washout period, after which the patients (92 in each group) were treated with either spironolactone (75 mg/ day) or sustained-release nifedipine (40 mg twice daily). At the end of 45 days of monotherapy either spironolactone or nifedipine was added to the treatment for those patients whose BP remained elevated. The effectiveness of the monotherapy and the combination treatment was evaluated again after another 45 days (90 days total). RESULTS

From the Department of Cardiology, Polyclinic, Essey-les-Nancy, Laboratories Searle, 92 Boulogne-Billancourt, France. Address for reprints: Michel Henry, MD, Clinique d’Eksey, Parmentier, 54311 Essey-b-Nancy, France.

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After 45 days of single-drug treatment, BP remained elevated (diastolic BP >90 mm Hg) in 72 patients; they then began therapy with the other drug in addition to the one they were already taking. At day 45, the decrease in BP and the percentage of patients whose BP had normalized with the single drug (diastolic BP 190 mm Hg) were comparable for the 2 drugs (47% in the spironolactone group, 50% in the nifedipine group) (Table II). At the 90day follow-up, the patients (96% of the spironolactone group and 88% in the nifedipine group) had maintained their lower pressures. Of the 72 patients who required concomitant treatment with spironolactone or nifedipine, BP in 63% reached normal levels after 45 days of combination therapy (Fig. 1, Tables II and III).

TABLE

I Characteristics

Age W Men Women Duration of hypertension (yr) Height/weight Sup SBP (mm Hg) Sup DBP (mm Hg) StdSBP(mmHg) Std DBP (mm Hg) Serum potassium (mmol/liter) Serum creatinine &mol/liter)

of Patient

Groups

Spironolactone Group

Nifedipine Group

(n = 85)

(n = 77)

60f 10 55% 45% 3f4.5

58f 56% 44% 4f4

11

2 f 177 f 105 f 175+9 105 f 4.27 f

0.3 11

5 0.36

2f 178f 106zt6 176 f 106f6 4.22 f

f 18.3

91.5i20.7

91.2

Spirono/a~tor;

p

NS = not significant;

10 0.35

59flO 55% 44% 3.6zt4

NS

2f0.3 178i 10 106i5.5 176f9 106f5.5 4.24 f 0.35

NS NS NS NS NS NS

91.4f

NS

NS

Nifedipine group (n=86)

NS

19.5

(4

SBP = systolic blood pressure;

Spirono~=too; n

Laboratory vahres: Serum potassium varied only minimally in the spironolactone group (+0.2 mmol/liter). Plasma glucose was slightly increased in both groups (+0.2 mmol/liter). Serum creatinine did not change (Table IV). Adverse effee& Adverse effects (1 or more) were recorded in 15% of the patients in the spironolactone group and in 47% of patients in the nifedipine group. In the nifedipine group these consisted chiefly of flushing or heat sensation (22%), peripheral edema (20%), erythema (8%) and headache (7%), whereas in the spironolactone group gastrointestinal distress was experienced by 4%. In the patients receiving both nifedipine and spironolactone, 1 or more adverse effects were recorded in 21%. The most frequent were peripheral edema (11%) and erythema (6%) (Table V). Three patients in the spironolactone group and 10 in the nifedipine group withdrew from the study because of untoward effects, In addition, 12 pa-

TABLE

II Blood

group

n

0.3 10 5

DBP = diastolic blood pressure: std = standing, sup = supnne.

Total (n=162)

Pressure

Before

and After

Monotherapy

Nifedipine (k42)

group

group

(sup) (std) (sup) (std)

96%

88% W

FIGURE 1. Percenl of patimts wRh blood presswe (BP) normdized(qainedlastohBP9OmmHg)with~ Wlllfdpbalone(WY). (4, pweent wllh mlmal BPatday45;(6J,pt3wmtwllhreducedBPatdaY4Bdsllll

nomalatdayS0.

tients were absent for the control visits of day 45 or day 90, but not lost at follow-up. The patients who withdrew because of adverse effects were counted as treatment failures in the analysis of the results. CONCLUSIONS

After 6 weeks of treatment, spironolactone (75 mg/ day) and sustained-release nifedipine (40 mg twice daily)

with Spironolactone

or Nifedipine

Spironolactone

SBP SBP DBP DBP

.~.~.~.~.~.~.~.~.~.~.~. . ... .. . .. .. . . . *........... . .. .. .. . . . . . . . . . ..*......... . .. . .. . .. . .. . .. . .. . .. . .. . .. . .. . .. . .. . . ::::. . ,.*....*......* .~.~.~.-.~.~.~.*.~.~.~.~. . . . . . . . . . . . .. .. . . . . . .

Sustained-Release

Nifedipine

Baseline (n = 92)

Day 45 (n = 85)

Day 90 (n = 45)

Baseline (n = 92)

Day 45 (n = 77)

Day 90 (n = 42)

177 f 10 175&9 106f5 105f5

1605 17’ 157 f 18* 93 f 10* 93 f 10*

144f 13’ 142 f 14’ 84*6* 85f6*

178f 11 176 f 10 106f6 106f6

158f 16* 155f 16* 91 f 109 92f 11*

150f 146f7” 86*6* 86f6*

10*

* Sign&cant difference vs baseline (p < 0.001). Abbreviations as in Table I. Values are expressed as mean f standard deviation.

TABLE

Ill Changes

Spironolactone (n = 72) * Significant Abbrewations

in Blood

Pressure

+ nifedipine

difference vs control as in Table I.

blood pressure

After

45 Days of Combination

Therapy

with Spironolactone

+ Nifedipine

SBP (SUP)

DBP (sup)

SBP (ski)

DBP (std)

-0.08

-0.10

-0.09

-0.11

value before

f 0.07’ initiation

of combination

therapy

f 0.09’

f 0.08*

f 0.09’

(p < 0.001).

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TABLE

ROLE

IV Laboratory

OF ALDOSTERONE

Values

Before

AND

and After

ALDOSTERONE

Treatment

ANTAGONISM

with Spironolactone

IN CARDlOVASCULAR

or Nifedipine

Spironolaotone

Serum sodium (mmol/liter) Serum Serum

potassium (mmol/liter) chloride (mmol/liter)

Plasma glucose (mmol/liter) Serum Serum Serum Serum

cholesterol (mmol/liter) triglycerides (mmol/liter) uric acid (pmol/liter) creatinine (Gmol/liter)

MEDlClNE

Sustained-Release

Nifedipine

Baseline (n = 92)

Day 45 (n = 85)

Baseline (n = 92)

Day 45 (n = 77)

14of3 4.2 f 102f3 5.5 f 5.9f 1.47 f 316f96 92.6 f

140*2*+ 4.5 f 102 f 5.7 f 6.0f 1.50f0.84 318f92*+ 92.3 f

141f2 4.2 f 103f3 5.4 f 6.1 f 1.44f0.69 312f87 91.2 f

141 4.2 103 5.6 6.0f 1.51 293 90.6

0.4 0.8 1.1 0.83 17.5

0.407 3* 1.3+ 1.0

17.3’

0.4 0.7 1.2

20.0

f f f f

29 0.4* 3” 0.7’ 1.1 *0.76+ f 78*+ f 20.3

* Significant difference between the 2 drugs (p < 0.05). 7 Significant difference vs before treatment (p < 0.05). Values are expressed as mean i standard deviation.

TABLE

V Adverse

Effects Nifedipine

Spironolactone Group

Group

(n = 92)

Spironolactone

(n = 92) No.

+ Nifedipine

Group (n= 72)

No.

% Group

Tinnitus Weakness Dry mouth Flushing, heat sensation Headache Erythema GI distress Syncope Nausea Peripheral edema Tachycardia Tremor Dizziness Other

2 2 2 20

2 2 2 22

0 1 0 0

0 1 0 0

0 2 0 1

0 3 0 1

6 7 2 2 1 18 2 2 2 9

7 8 2 2 1 20 2 2 2 10

0 1 4 0 2 1 0 0 1 6

0 1 4 0 2 1 0 0 1 7

0 4 0 0 0 8 1 0 1 3

0 6 0 0 0 11 1 0 1 4

Total

77

16

% Group

No.

% Group

20

GI = gastrointestinal.

were found to have comparable efficacy, both in terms of antihypertensive action and in the number of patients achieving controlled BP. Concomitant treatment (spironolactone + nifedipine) normalized BP in 63% of patients whose BP could not be controlled with either agent alone; however, the incidence of undesirable side effects was markedly higher with sustained-release nifedipine than with spironolactone. REFERENCES 1. Cow01 P, Menard J. Spironolactones. 2. Johnston LC, Grieble HG. Treatment diuretics: spironolactone, an aldosterone

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Sem H6p of arterial antagonist.

Paris 1987,63:1535-1542. hypertensive diseases with Arch Intern Med 1967;

OF CARDIOLOGY

VOLUME

65

119:225-238. 3. Winer BM, Lubbe WF, Colton T. Antihypertensive action of diuretics: comparative study of aldosterone antagonist and a thiazide, alone and together. JAMA 1968;204:117-121. 4. Adlin EV, Marks AD, Channick BJ. Spironolactone and hydrochlorothiazide in essential hypertension. Blood pressure response and plasma renin activity. Arch Intern Med 19?2;130:8JS-858. 5. Vaughan ED Jr, Laragh JH, Gavras I. Volume factor in low and normal renin essential hypertension. Treatment with either spironolactone or chlorthalidone. Am J Cardiol 1973;32523. 6. Dueymes JM, Eche JP, Bellanger 6. Etude cc@rative de I’efticacit6 et de la tolCrance de I’Aldactazine en monothtrapie dans I’hypertension art&rielle essentielle mod&%. Medecine Cardio- Vasculaire:60 (supplement to Quotidien du Medecin):January 31, 1986;1-7. 7. Scholn D, Wehrlen M, Petit T, Spiesser R, Assyag P, P&tier B, Capron MH. Efficacitt et toltrance de I’association Aldactazinc@-captopril dans I’hypertension artCrielle essentielle l&g&e a mod&Q. Gazette Medicale /987,94:/-X