Spironolactone Versus Nifedipine in Essential Hypertension

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, spirono- lactone 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 treat- ment (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 monother- apy 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 high- erin the nifedipine group.

(Am J Cardid 1990;65:36K-36K)

From the Department of Cardiology, Polyclinic, Essey-les-Nancy, and Laboratories Searle, 92 Boulogne-Billancourt, France.

Address for reprints: Michel Henry, MD, Clinique d’Eksey, 7, rue Parmentier, 54311 Essey-b-Nancy, France.

T he antihypertensive effect of spironolactone, used alone or in combination, has been amply dem- onstrated.l-3 A review of published reports of the

last 20 years shows that spironolactone is especially effec- tive 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.

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 nifedi- pine 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 4- week 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 spironolac- tone 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 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 normal- ized 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 90- day 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 treat- ment with spironolactone or nifedipine, BP in 63% reached normal levels after 45 days of combination thera- py (Fig. 1, Tables II and III).

36K THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

TABLE I Characteristics of Patient Groups

Spironolactone Nifedipine Group Group Total (n = 85) (n = 77) (n=162) p

Age W 60f 10 58f 11 59flO NS Men 55% 56% 55% Women 45% 44% 44%

NS

Duration of hyper- 3f4.5 4f4 3.6zt4 NS tension (yr)

Height/weight 2 f 0.3 2 f 0.3 2f0.3 NS Sup SBP (mm Hg) 177 f 10 178f 11 178i 10 NS Sup DBP (mm Hg) 105 f 5 106zt6 106i5.5 NS

StdSBP(mmHg) 175+9 176 f 10 176f9 NS Std DBP (mm Hg) 105 f 5 106f6 106f5.5 NS

Serum potassium 4.27 f 0.36 4.22 f 0.35 4.24 f 0.35 NS (mmol/liter)

Serum creatinine 91.2 f 18.3 91.5i20.7 91.4f 19.5 NS &mol/liter)

DBP = diastolic blood pressure: NS = not significant; SBP = systolic blood pressure; std = standing, sup = supnne.

Laboratory vahres: Serum potassium varied only minimally in the spironolactone group (+0.2 mmol/li- ter). Plasma glucose was slightly increased in both groups (+0.2 mmol/liter). Serum creatinine did not change (Ta- ble 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-

Spirono/a~tor; group n

Nifedipine group (n=86)

(4

.~.~.~.~.~.~.~.~.~.~.~. . . . . . . . . . . . *........... . . . . . . . . . . . . . . ..*......... . . . . . . . . . . . . . . . . . . . . . . . . . . ::::. . . . . . . . . . . . . . . . . . . 96%

Spirono~=too; group ,.*....*......* .~.~.~.-.~.~.~.*.~.~.~.~. . . . . . . . . . . . . . . . . . . . . .

n

Nifedipine group (k42)

W

88%

FIGURE 1. Percenl of patimts wRh blood presswe (BP) nor- mdized(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)

TABLE II Blood Pressure Before and After Monotherapy with Spironolactone or Nifedipine

Spironolactone

Baseline Day 45 (n = 92) (n = 85)

SBP (sup) 177 f 10 1605 17’ SBP (std) 175&9 157 f 18* DBP (sup) 106f5 93 f 10* DBP (std) 105f5 93 f 10*

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

Day 90 (n = 45)

144f 13’ 142 f 14’

84*6* 85f6*

Sustained-Release Nifedipine

Baseline Day 45 Day 90 (n = 92) (n = 77) (n = 42)

178f 11 158f 16* 150f 10* 176 f 10 155f 16* 146f7” 106f6 91 f 109 86*6* 106f6 92f 11* 86f6*

TABLE Ill Changes in Blood Pressure After 45 Days of Combination Therapy with Spironolactone + Nifedipine

SBP (SUP) DBP (sup)

Spironolactone + nifedipine -0.08 f 0.07’ -0.10 f 0.09’ (n = 72)

* Significant difference vs control blood pressure value before initiation of combination therapy (p < 0.001). Abbrewations as in Table I.

SBP (ski) DBP (std)

-0.09 f 0.08* -0.11 f 0.09’

THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 19, 1990 37K

A SYMPOSIUM: ROLE OF ALDOSTERONE AND ALDOSTERONE ANTAGONISM IN CARDlOVASCULAR MEDlClNE

TABLE IV Laboratory Values Before and After Treatment with Spironolactone or Nifedipine

Spironolaotone Sustained-Release Nifedipine

Baseline Day 45 Baseline Day 45 (n = 92) (n = 85) (n = 92) (n = 77)

Serum sodium (mmol/liter) Serum potassium (mmol/liter) Serum chloride (mmol/liter) Plasma glucose (mmol/liter) Serum cholesterol (mmol/liter) Serum triglycerides (mmol/liter) Serum uric acid (pmol/liter) Serum creatinine (Gmol/liter)

* 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.

14of3 4.2 f 0.4

102f3 5.5 f 0.8 5.9f 1.1

1.47 f 0.83 316f96

92.6 f 17.5

140*2*+ 4.5 f 0.407

102 f 3* 5.7 f 1.3+ 6.0f 1.0

1.50f0.84 318f92*+

92.3 f 17.3’

141f2 4.2 f 0.4

103f3 5.4 f 0.7 6.1 f 1.2

1.44f0.69 312f87

91.2 f 20.0

141 f 29 4.2 f 0.4*

103 f 3”

5.6 f 0.7’ 6.0f 1.1

1.51 *0.76+ 293 f 78*+

90.6 f 20.3

TABLE V Adverse Effects

Tinnitus Weakness Dry mouth Flushing, heat

sensation Headache Erythema GI distress Syncope Nausea Peripheral edema Tachycardia Tremor Dizziness Other

Total

GI = gastrointestinal.

Nifedipine Spironolactone Spironolactone + Nifedipine Group Group Group

(n = 92) (n = 92) (n= 72)

No. % Group No. % Group No. % Group

2 2 0 0 0 0 2 2 1 1 2 3 2 2 0 0 0 0

20 22 0 0 1 1

6 7 0 0 0 0 7 8 1 1 4 6 2 2 4 4 0 0 2 2 0 0 0 0 1 1 2 2 0 0

18 20 1 1 8 11 2 2 0 0 1 1 2 2 0 0 0 0 2 2 1 1 1 1 9 10 6 7 3 4

77 16 20

were found to have comparable efficacy, both in terms of 119:225-238.

antihypertensive action and in the number of patients achieving controlled BP. Concomitant treatment (spiro- nolactone + 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

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1. Cow01 P, Menard J. Spironolactones. Sem H6p Paris 1987,63:1535-1542. 7. Scholn D, Wehrlen M, Petit T, Spiesser R, Assyag P, P&tier B, Capron MH. 2. Johnston LC, Grieble HG. Treatment of arterial hypertensive diseases with Efficacitt et toltrance de I’association Aldactazinc@-captopril dans I’hypertension diuretics: spironolactone, an aldosterone antagonist. Arch Intern Med 1967; artCrielle essentielle l&g&e a mod&Q. Gazette Medicale /987,94:/-X

3. Winer BM, Lubbe WF, Colton T. Antihypertensive action of diuretics: com- parative 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.

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