The addition of doxazosin to the treatment regimen of patients with hypertension not adequately controlled by by β-blockers

Volume 121 Number 1. Part 2

Doxazosin

Taylor SH. Pharmacotherapeutic its role in coronary risk reduction.

simultaneously induces desirable effects on the atherogenic profile of serum lipids. This has great therapeutic potential in view of the large number of patients with mild or moderate hypertension who have elevated levels of serum cholesterol and are treated for long periods of time.

M, Holzgreve H. Review of major ies in hypertension and hyperlipidemia: disease. AM HEART J 1988;116:1708-12.

stature AM

comparative

study

of doxazosin and HEART J 1988316:

1735-47.

Levy D, Wilson PWF, Anderson KM, Castelli WP. Stratifying the patient at risk from coronary disease: new insights from the Framingham Heart Study. AM HEART J 1990; 119:712-7. Rosenthal J. Clinical experience with doxazosin in general medical practice. AM HEART J 1988;116:1748-57. Talseth T, Westlie L, Daae L, Vatle S. Comparison of the effects of doxazosin and atenolol on blood pressure and blood lipids: a one-year, double-blind study in 228 hypertensive patients. AM HEART J 1988;116:1790-6.

REFERENCES

1. Middeke

and prazosin

intervention studfocus on coronary

The addition of doxazosin to the treatment regimen of patients with hypertension not adequately controlled by by ,&blockers When doxazosin was given to patients with hypertension not adequately controlled by P-blockade, blood pressure was normalized in 94% of the 34 patients (blood pressure 5 140185 mm Hg). This reduction in blood pressure was obtained with doxazosin in combination with metoprolol or oxprenolol at a mean final daily dose of 1.3 mg or pindolol or atenolol at 2.0 mg/day. Exercise-induced increase in systolic and diastolic blood pressure was also lower with combined B-blocker and doxarosin therapy than with P-blocker alone. After 12 weeks of treatment, the combination of doxazosin and p-blocker significantly reduced total serum cholesterol and triglyceride levels. All side effects were mild and only one patient was withdrawn from therapy. (AM HEART J 1991;121:31 l-6.)

Rudolf Georg Englert, MD, and Uwe Barlage, MD Kdsruhe

and Gars am Inn,

West

Germany

In the treatment of hypertension the objective is to reduce blood pressure at rest and during exercise. Generally drugs might reduce blood pressure at rest without influencing load-induced increases, whereas others might prove to be effective under load without offering particular advantages at rest. It is also possible that the negatively inotropic properties of a drug may result in limitations of load capacity or contraindications (e.g., the use of P-blockers in cardiac insufficiency). From the Clinical am Inn.

Research

Reprint requests: West Germany.

Rudolf

4/0/24a75

Pfizer/Mack. G. Englert,

Karlsruhe, MD,

and Am Markt

8096 Gars Am Inn,

11, Gars Veitlipp

3.

A combination of antihypertensive drugs can produce additive or synergistic effects and a reduced frequency and severity of side effects and may exert a balanced effect on blood pressure both at rest and during exercise. In this respect, cur-inhibitors and ,8blockers are useful complements. Nonselective a-inhibitors (phentolamine and phenoxybenzamine) and P-blockers have been used previously, but these combinations have been associated with severe side effects and the antihypertensive efficacy has been c0ntested.l Selective al-inhibitors are more suitable for combination with P-blockers because they have an antihypertensive effect that is independent of CQinduced cardiac stimulation. A number of clinical studies have confirmed this.2-g Experiments in dogs have shown that selective and nonselective a-induced 311

312

Englert and Barlage Doxazosin

American

January 1991 Heart Journal

;

10

Doxazosin

160 -4

70 ~--r--

do-h--130 i 4

6-s~

10

12

Time (weeks) Fig. 1. Baseline and final supine and standing SBP before and after the addition of doxazosin to existing P-blocker therapy (n = 33). 0-0, Supine; w, standing. *(p < 0.05), Wilcoxon test (paired data).

I. Patient demographics Existing /%blocker therapy

n

Pindolol

(M/F)

Mean

age (yr)

Mean duration hypertension (mo)

I-

6

12

Time (weeks) r- ~~~~ 0 2

Table

i

of

13 (B/5) 56 44

Atenolol 15

(10/s) 54 30

Metoprolol

Oxprenolol

3 (2/l) 60 96

3 (2/l) 56 14

vasodilatations are modified to different extents by p-blockers,1° although the selectivity of the p-cornponent does not appear to influence the antihypertensive efficacy of the combination. A lower incidence of side effects is seen with selective @1-blockers.3 Doxazosin, a quinazoline derivative, is a new, selective al-inhibitor with a favorable pharmacokinetic profile. Doxazosin has a long elimination halflife (approximately 22 hours)l’ and can be administered on a once-daily basis.12,13 The relatively long latent period between administration and onset of maximum effect is also an advantage, because a slow onset of action produces less sympathoadrenergic reflex activation.14-16 This study compares the efficacy and safety of doxazosin in combination with &blockers in frequent use (pindolol, atenolol, metoprolol, and oxprenolol) in patients whose hypertension is not adequately controlled by p-blockers ther-

Fig. 2. Baseline and final supine and standing DBP before and after the addition of doxazosin to existing p-blocker therapy (n = 33). ~0, Supine; U, standing. *(p < 0.05), Wilcoxon test (paired data).

apy alone. Blood pressure was measured at rest and during exercise, and the effect of doxazosin on serum lipid levels was examined. METHODS Study population. Male and female patients, ages 18 to 65 years with evidence of essential hypertension, were included in the study. Hypertension was not adequately controlled by P-blocker therapy; patients had a diastolic blood pressure (DBP) 295 mm Hg in the supine and standing positions. Thirty-four patients were included in the study; demographic data are presented in Table I. Patients were divided into four groups according to the @-blockers that were prescribed: pindolol (n = 13), atenolol (n = 15), metoprolol (n = 3), and oxprenolol (n = 3). Study design. In a 2-week pretreatment phase, patients received placebo, once daily, in addition to the existing p-blocker therapy. Patients with a supine and standing DBP of 95 to 120 mm Hg entered into an open IO-week doxazosin treatment phase. Doxazosin was initiated at 1 mg/day and increased at biweekly intervals, if needed, by doubling the dose up to a maximum of 8 mg/day. The objective was to achieve ~15 mm Hg decrease in systolic blood pressure (SBP) and a target SBP/DBP <140/85 mm Hg. The dose of the existing p-blocker was not changed throughout the study. Patient exclusions. Patients excluded from the study were those with known contraindications for al-inhibitors. Assessment. Blood pressure and heart rate were measured 3 to 8 hours after administration of doxazosin. Blood pressure was measured after the patient had been supine for 5 minutes and after standing for 2 minutes. Heart rate was measured immediately before blood pressure determinations. Bicycle ergometry testing in the sitting position was

“otwne

121

Number

1.

Part

Combined

2

doxazosin

Supine

Doxazosin 180

¶ *

50 0

2

I .--. ~ 4 6

140

E 120 E g 100 8

10

12

l

.

DBP ..

DBP *

60

Fig. 3. Baseline and final heart rate (HR) before and after the addition of doxazosin to existing @-blocker therapy (n = 33). O---O, Supine; w, standing.

performed on days 14 (placebo) and 70 (active treatment), at loads of 50, 75,100,125, and 150 W, each over 2 minutes. Blood pressure and heart rates were measured after 2 minutes of exercise and after 1, 2, 3, 4, and 5 minutes of rest. Total serum cholesterol, triglyceride, and blood glucose concentrations were determined at baseline and after 84 days of active treatment. All side effects that occurred during the course of the study were documented. Statistical analysis. The arithmetic mean was calculated for all parameters. Changes in blood pressure and heart rate were evaluated with the Wilcoxon test for paired data. Changes in serum cholesterol, triglyceride, and glucose values were assessed with the Student t test for paired data. For statistical significance, p < 0.05 was required.

h.

,

80

Time (weeks)

SBP . A*

. SBP . *

l

9

3I3

Standing

I

160

and +hlockade

14

84

14

84

Day

Day

Fig. 4. Baseline and final SBP and DBP before (day 14) and after (day 84) the addition of doxazosin to the pindolol (n = 12) and atenolol (n = 15) subgroup. *(p < 0.05), Wilcoxon test (paired data). 0, Doxazosin/pindolol; A, doxazosinjatenolol.

Table II. Mean daily doses of doxazosin in combination with different P-blockers at the final study visit

Mean dose of

*The

fi-hlocher

&blocker (mglday)

Pindolol Atenoloi Metoprolol Oxprenolol

4.3 57.0 67.0 53.0

dose of all &blockers

was kept

Mwn dose of doxnzosin i mg lday)

*

2.0 2.0 1.3

1.3 constant

throughout

the study.

RESULTS Changes in blood pressure and heart rate. On day 0, mean values for supine and standing SBP/DBP were 167/98 mm Hg and 172/102 mm Hg, respectively. These values did not change significantly during the 14day placebo period (Figs. 1 and 2). With the addition of doxazosin, both supine and standing blood pressure were reduced significantly (Figs. 1 and 2). After 10 weeks of doxazosin therapy, mean supine and standing blood pressures were reduced to 143/80 mm Hg and 142/80 mm Hg, respectively. Thirty-two of 34 (94%) patients achieved a DBP 585 mm Hg in both the supine and standing positions. Adequate control of SBP was also obtained in these patients; SBP stabilized at 5150 mm Hg in 31 of 34 patients (91% ). Heart rates were not significantly altered (Fig. 3). Analysis of covariance revealed statistically significant (p < 0.05) differences in blood pressure response between the doxazosinlpindolol and dox-

azosin/atenolol groups (Fig. 4). At the final visit, supine and standing SBPs and supine DBPs were significantly lower in the doxazosin/atenolol group than in the doxazosin/pindolol group. The differences, however, were slight and considered negligible in clinical practice. Because of the small numbers of patients in the doxazosin/metoprolol (n = 3) and doxazosin/oxprenolol (II = 3) groups, a betweengroup analysis was not undertaken. Dose of doxazosin. Doxazosin produced the effects on blood pressure with a mean final daily dose of 1.3 mg in combination with metoprolol or oxprenolol and at a mean daily dose of 2.0 mg in combination with pindolol or atenolol (Table II). Ergometric testing. Exercise-induced increases in SBP and DBP were less for combined doxazosin and &blockers therapy than for P-blockers alone (Fig. 5). For all patients evaluated (n = 33), the mean maxi-

3 14

Englert

and Barlage

American

January 1991 Heart Journal

Table III. Mean maximum load achieved by patients during ergometry testing before (day 14) and after (day 70) doxazosin therapy Mean

.-\i

SBP *

Group

n

All patients Doxazosin/pindolol Doxazosin/atenolol

33 12 15

maximum

loud

(WJ

Table IV. Changes in mean serum cholesterol, triglyceride, and glucose concentrations before (day 0) and after (day 84) doxazosin therapy: all patients (n = 33) Parameter

DBP --*

&-----1

-f

14

HR

70 Day

Fig. 5. Exercise-induced increase in SBP and DBP before (day 14) and after (day 70) the addition of doxazosin to existing P-blocker therapy (n = 33). *(p < 0.05), Wilcoxon test (paired data).

Cholesterol mg/dl mmol/L Triglycerides mg/dl mmol/L Glucose mgldl mmol/L *p < 1L01, Student tn = :a”.

Daq’ X3

ri, change

228 i 28 5.91 +- 0.73

“16 + 26* 5.60 t 0.67*

-5.X

197 t 18 ”-.-_‘29 i 0.20

187 * 19* 2.11 2 0.21*

-5.08

96 I 19 5.33 2 1.06

97 + 14t 5.39 i_ 0.78

+1.0-l

Day

0

t test for paired

data.

DISCUSSION

mum load was 111 W before and 121 W after the administration of doxazosin (Table III). Corresponding values for the doxazosin/pindolol group were 98 and 100 W, respectively, and for the doxazosin/atenolol group 122 and 138 W. Twenty-two patients achieved 100 W in both ergometries; 15 of these patients were in the doxazosin/atenolol group and 4 were in the doxazosin/pindolol group. Serum lipid profile. Tables IV and V show the baseline and final values and mean percent changes in cholesterol, triglyceride, and glucose concentrations after doxazosin therapy. Doxazosin produced a statistically significant reduction in mean serum cholesterol (-5.3 % ) and triglyceride (-5.1% ) levels. There were no between-group differences in the atenolol and pindolol groups. No significant changes in blood glucose values were observed. Toleration. In 14 of 34 patients, 26 side effects were documented. All were mild and included headache, vertigo, nausea, and palpitations. Only one patient was discontinued from therapy because of headache and vertigo. Side effects in individual groups are given in Table VI.

In an extensive data base, doxazosin has been shown to be highly effective as monotherapy.17 l8 In this study, doxazosin in combination with a P-blocker represents a highly effective therapeutic regimen for the treatment of essential hypertension. In 32 of 34 (94%) patients, the target DBP of 85 mm Hg was achieved; SBP was stabilized at r150 mm Hg in 31 of 34 (91% ) patients. The differences between the combinations of doxazosin/atenolol and doxazosin/pindolol were statistically significant regarding SBP (supine and standing) and DBP (supine). The differences, however, were slight and can be considered negligible in clinical practice. It is reasonable to assume that both combinations would have the same efficacy if equivalent antihypertensive doses were used. Ergometry revealed that doxazosin influenced blood pressure at rest and during exercise. A lower load-induced increase in SBP and DBP was seen with combined @-blocker and doxazosin therapy than with p-blocker therapy alone. Although an increase in the mean maximum load was observed with the addition of doxazosin, conclusions cannot be drawn regarding

Volume 121 Number

Combined

1, Part 2

doxazosin

and &blockade

3 15

Table V. Changes in mean serum cholesterol, triglyceride, and glucose concentrations before (day 0) and after (day 84) doxazosin therapy: subgroup analyses Dorazosinfpindolol Day Cholesterol mgldl mmol/L Triglycerides m&l mmol/L Glucose mg/dl mmol/L

0

Day

Doxazosinlatenolol

fn = 12) 84

s;, change

Day

0

Day

(n = 1Ei) 84

70 change

228 k 34 5.91 * 0.88

212 * 28 5.49 z!z 0.73

-7.02

229 + 27 5.94 * 0.70

218 +- 26 5.65 I!Z 0.67

-4.80

206 zt 20 2.33 t 0.23

194 k 24 2.19 -t 0.27

-5.83

191 + 16 2.16 t 0.18

181 + 16 2.04 i 0.18

-5.24

98 -t 8 5.44 * 0.44

89 k 13* 4.94 ?I 0.72*

-9.18 5.11 + 1.44

92 +- 26

100 +- 13 5.56 k 0.72

+8.70

*n = 11.

Table

VI.

The incidence of side

effects

with doxazosin and p-blocker combination therapy Doxazosinl atenolol

No.

patients with side effects’ Disappeared with continued treatment Tolerated with continued treatment Dose reduction Treatment discontinued

*Side effects

included

headache,

vertigo,

Doxazosinl pindolol

1 0 0 1 0

9 2 4 2 1

Doxazosinl netoprolol 1 1 0 0 0

Doxazosinl oxprenolol 3 0 2 1 0

nausea, and palpitations.

the effect of doxazosin on maximum load, because in most cases patients stopped exercising because of fatigue before the criteria for maximum load had been achieved. Fourteen patients reported a total of 26 side effects, with some patients having more than one. Most side effects were mild cases of headache, vertigo, nausea, and palpitations and disappeared or were tolerated with continued treatment. In four patients the dose of doxazosin was reduced and one patient was withdrawn from the study because of headache. Optimal antihypertensive treatment should aim to reduce cardiovascular risk and take into account all the risk factors for cardiovascular disease. Many extensive studies have not shown a reduced rate of morbidity or death in coronary heart disease after traditional antihypertensive treatment, because many of the therapeutic regimens negate by other mechanisms the benefit of blood pressure reducti0n.l” The effect of treatment on the serum lipid profile is particularly important.20 For example, P-blockers produce a detrimental increase in triglyceride and very low-density lipoprotein levels and a decrease in high-density lipoprotein levels and thus

increase the overall risk of coronary heart disease.20 Doxazosin, however, reduces total cholesterol, lowdensity lipoprotein, and triglyceride levels and increases high-density lipoprotein levels.21-22 Doubleblind, comparative studies have shown that the influence doxazosin exerts on total cardiovascular risk is more favorable than that of atenolol,‘2, 23,24 which because of its cardioselectivity holds a preferred position among the ,f3-blockers.20 This study shows that doxazosin exerts a favorable effect on the serum lipid profile when used in combination with /3blockers. No statistical differences between the atenolol and pindolol groups were seen. In conclusion, the combination of doxazosin and P-blocker has a pronounced antihypertensive effect. The combination is well tolerated and the addition of doxazosin to P-blockers appears to have a favorable influence on the serum lipid profile. REFERENCES

1. Drayer JIM, Weber MA. Antihypertensive agents which inhibit sympathetic activity: potentially adverse effects of combination treatment. AM HEART J 1982;104:660-4. 2. Eggertsen R, Hansson L. Vasodilators in hypertension-a review with special emphasis on the combined use of vasodilators and beta-adrenoceptor blockers. Int J Clin Pharmacol Ther Toxic01 1985;23:411-23.

3 16

Englert

and Barlage

3. Stanaszek WF, Kellerman D, Brogden RN, Romankiewicz JA. Prazosin update. Drugs 1983;25:339-84. 4. Salvadeo A, Segagni S, Villa G, Galli F, Piazza W, Bovio G. Prazosin in long-term therapy of moderate/severe hypertension. Curr Ther Res 1981;30:1055-64. 5. de Divitiis 0, Petitto M, di Somma S, Fazio S, Ruggiano A. Prazosin in therapy of arterial hypertension: double-blind comparisons and combinations. Drugs Exp Clin Res 1981;7:667-85. 6. Lund-Johansen P. Hemodynamic changes in hypertension and their modification by p-blockers and prazosin. J Cardiovast Pharmacol 1980;2(suppl 3):339-48. 7. Franz IW. Combined alpha/beta blockade with acebutolol and nrazosin. In: Rietbrock N. Woodcock BG. eds. Balanced alpha/beta blockade of adrenoceptors. Wiesbaden: Braunschweig, 1984:121-g. 8. Stokes GS, Mennie BA, Gellatly R, Hill A. On the combination of alpha- and fl-adrenoceptor blockade in hypertension. Clin Pharmacol Ther 1983;34:576-82. 9. Lund-Johansen P. Comparative haemodynamic effects of labetalol, timolol, prazosin and the combination of tolamolol and prazosin. Br J Clin Pharmacol 1979;8:107SllS. 10. Saeed M, Sommer 0, Holtz J, Bassenger E. Alpha-adrenoceptor blockade by phentolamine causes P-adrenergic vasodilation by increased catecholamine release due to presynaptic alpha-blockade. J Cardiovasc Pharmacol 1982;4:44-52. 11. Conrad KA, Fagan TC, Mackie MJ, et al. Doxazosin in patients with hypertension. Eur J Clin Pharmacol 1988;35: 21-4. 12. Frick MH, Halttunen P, Himanen P, et al. A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hvnertension. Br J Clin Pharmacol 1986;21(suppl 1):55S62S.” 13. Torvik D, Madsbu HP. Multicentre 12-week double-blind comparison of doxazosin, prazosin and placebo in patients with mild to moderate essential hypertension. Br J Clin Pharmacol 1986;21(suppl 1):69%76S. 14. Elliott HL, Meredith PA, Vincent J, Reid JL. Clinical phar-

Amencan

15.

16.

17. 18.

19.

20.

21.

22.

23.

24

January 1991 Heart Journal

macological studies with doxazosin. Br J Clin Pharmacol 1986;21(suppl 1):27%32S. Elliott HL, Meredith PA, Sumner DJ, McLean K, Reid JL. A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist-doxazosin (UK 332741in normotensive subjects. Br d Clin Pharmacol 1986:1X 699-703. de Leeuw PW, Ligthart JJ, Smout AJPM, Birkenhager WH. Within-patient comparison of prazosin and UK-33274: a new alpha-adrenoceptor antagonist. Eur J Clin Pharmacol 1982; 23:379-401. Rosenthal J. Clinical experience with doxazosin in general medical practice. AM HEART d 1988;116:1748-57. Talseth T, Westlie L, Daae L, Vatle S. Comparison of the effects of doxazosin and atenolol on blood pressure and blood lipids: a one-year, double-blind study in 228 hypertensive patients. AM HEART J 1988;116:1790-6. Weinberger MH. Treatment of hypertension in the 1990s: optimizing the benefit of blood pressure reduction by minimizing risk factors for cardiovascular disease. Am J Med 1987;82(suppl lA):44-9. Krone W, Mtiller-Weiland D, Greten H. Antihypertensive TherapieundFettstoffwechsel. Klin Wochenschr 1984:62:193202. Lehtonen A, Himanen P, Saraste M, Nittymlki K, Marniemi .J. Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br d Clin Pharmacol 1986;21(suppl 1):77SSlS. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S-90s. Nash DT, Schonfeld G, Reeves RL, Black H, Weidler DJ. A double-blind parallel trial to assess the efficacv of doxazosin, atenolol and placebo in patients with mild to moderate systemic hypertension. Am J Cardiol 1987:59:87G-90G. Mazzola C, Guerrasio E. Doxazosin versus atenolol: a randomized comparison of calculated coronary heart disease risk reduction. AM HEART J 1988;116:1797-805.