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A comparative study of doxazosin versus atenolol in mild-to-moderate hypertension
volume Number
116 6, Part 2
Doxazosin
7. 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 hypertension. Br J Clin Pharmacol 1986;21(suppl 1):55S62S. 8. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S9OS. 9. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21(suppl 1):45S54S. 10. Wilner KD, Ziegler MG. Effects of alpha, inhibition on renal blood flow and sympathetic nervous activity in systemic hypertension. Am J Cardiol 1987;59:82G-6G. 11. De Leeuw PW, Van Es PN, De Bos R, Birkenhager WH. Acute renal effects of doxazosin in man. Br J Clin Pharmacol 1986;21(suppl 1):41S-3s. 12. Pool JL. Plasma lipid lowering effects of doxazosin, a new selective alpha, adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G.
us atenolol
in CHD risk reduction
13. Lehtonen A, Himanen P, Saraste M, Niittymlki K, Marniemi J. Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br J Clin Pharmacol I986:2l(sunnl 1):77S81S. 14. Frick MH, Cox DA, Himanen P, et al. Serum lipid changes in a one-year, multicenter, double-blind comparison of doxazosin and atenolol for mild to moderate essential hypertension. Am J Cardiol 1987;59:61G-7G. 15. Ott P, Storm TL, Krusell LR, Jensen H, Badskjaer J, Faeraeman 0. Multicenter. double-blind comparison of doxazosin and atenolol in patients with mild to moderate hypertension. Am J Cardiol 1987;59:73G-7G. 16. Shaw J, England JDF, Hua ASP. Beta-blockers and plasma triglycerides [Letter]. Br Med J 1978;1:986. 17. Leren P, Foss PO,- Helgeland A, Hjermann I, Holme I, Lund-Larsen PG. Effect of nronranolol and prazosin on blood lipids. The Oslo Study. Lance; 1980;2:4-6. 18. Wilson P, Castelli W. Coronary risk prediction in adults. Am J Cardiol 1987;59:91G-4G.
A comparative study of doxazosin versus atenolol in mild-to-moderate hypertension Doxarosin, a quinaroline derivative, is a selective a,-inhibitor that reduces calculated coronary heart disease risk by lowering blood pressure while favorably affecting blood lipid levels. The aim of this study was to compare the efficacy and toleration of doxazosin with atenolol, one of the most frequently used cardioselective ,&blockers in Italy. Forty patients with mild-to-moderate hypertension were treated with either atenolol (100 mg) or doxarosin (mean dose, 3.3 mg) once daily for 8 weeks. Both drugs significantly reduced supine and standing systolic and diastolic blood pressures. Atenolol induced marked bradycardia, whereas doxazosin had very little effect on heart rate. Doxarosin produced a favorable effect on blood lipid levels by decreasing triglyceride and total cholesterol levels and increasing high-density lipoprotein cholesterol and high-density lipoprotein total cholesterol ratio. Atenolol had exactly the opposite effect on blood lipid levels. Both drugs had equivalent toleration profiles. It was concluded that doxazosin was as effective as atenolol in reducing elevated supine and standing blood pressures. In addition, doxarosin had a beneficial effect on lipid proftles and minimal effect on heart rate. Therefore doxazosin may reduce calculated coronary heart disease risk in hypertensive patients. (AM HEART J 1988;116:1801.)
Gabriele Giorgi, MD, Jacopo M. Legramante, MD, Guiseppe Fioravanti, Giuseppe Paies, MD, and Alessio Legramante, MD Frascati, Italy
Doxazosin, a quinazoline derivative, is a selective cr,-inhibitor’ that reduces calculated coronary heart disease (U-ID) risk in hypertensive patients by lowering blood pressure while favorably affecting From Reprint Ospedale ltalv.
the General requests: Generale
Medicine
Division,
Hospital
Gabriele Giorgi, MD, Unita’ Provinciale, San Sebastiano
of Frascati. Sanitaria Martire,
Locale Frascati,
Rm. 29. Roma,
MD,
blood lipid levels.” The drug’s efficacy in blood pressure reduction is caused by the lowering of peripheral vascular resistance.” With a plasma halflife of approximately 22 hours, doxazosin is suitable for single daily dosing.4,5 Clinical studies in humans have shown that doxazosin is effective in lowering both systolic and diastolic blood pressures (DBPs) without significant changes in heart rate.2s6.7 In addition, the drug
1801
1802
Giorgi
et al.
American
Table I. Demographic data to-moderate hypertension No.
of patients 40
I + II
20
I Atenolol
with
mild-
yr
3-5 10 yr >lO yr Unknown
5.4 11.8
11.4 8.5
Treatment
X X x
History Physical examination BP and HR Laboratory tests Lipids ECG Toleration evaluation
12
x X X X x
x
x
3
4
68
x
x X X
xx
x
xx
x
X X X
BP, blood pressure; HR, heart rate.
induces significant beneficial effects on serum lipid levels without altering other CHD risk factors and therefore decreases calculated CHD risk.8,g Atenolol is one of the most frequently used cardioselective @-blockers in Italy, either as monotherapy or in combination with other antihypertensives, especially thiazide diuretics. The aim of this study was to comparatively assess the clinical efficacy, effect on serum lipid levels, and toleration of doxazosin and atenolol. METHODS Patients. Forty patients of both sexes, ages 18 to 70 years, with mild-to-moderate essential hypertension, were randomized into two groups. Group I consisted of 20 patients treated with atenolol* and group II of 20 patients treated with doxazosint (Table I). All patients had given their consent to be included in the study. This single-blind study included patients suffering from essential hypertension with supine DBPs ranging from 95 , ..d TV iV
II-I
MM
II&,.
1;
PaLiahts
Duration
of
hypertension
Group I (atenolol)
II. Study design
0
Ill.
Mean age f SD (range)
49.3 * 10.0 16 male/24 female 48.4 f 9.8 (18-65) 7 male: 48.0 k 13 female: 48.7 -+ 50.2 f 10.3 (30-66) 9 male: 54.1 + 11 female: 47.1 ?
II Doxazosin
Wk
Table
(years)
in
40
patients
Group
20
Table
on 40 patients
December 1988 Heart Journal
were
treated
with
other
l AtenoloI was supplied as 100 mg scored tablets. tDoxazosin was supplied by Pfizer Italiana SpA as 2, 4, and 8 mg scored tablets.
3 6 8 1 2
Group II (doxazosin) 4 8 7 1 0
antihypertensive therapy; a Z-week washout period was initiated. The main exclusion criteria for patients were as follows: pregnancy and lactation, secondary or malignant hypertension (routine basal measurement of vinylmandelic acid and creatinine clearance), recent myocardial infarction, unstable angina, cerebrovascular disorders, peripheral vascular diseases, bronchospasm, renal or hepatic insufficiency, severe concomitant diseases, and hypersensitivity to quinazoline or p-blocking drugs. Arterial blood pressure measurements were made between 10~00 AM and 12 noon during each visit: three supine blood pressure measurements were made over an S-minute period; the third measurement was taken for evaluation. Two standing blood pressure measurements were made over a P-minute period; the secondmeasurement was evaluated. The systolic arterial pressure was recorded at the appearance of sound (Korotkoff phase I), and the diastolic arterial pressure coincided with the phase V (disappearance) Korotkoff sound. Heart rate was measured for 30 seconds using a procedure similar to that for blood pressure. The aim of antihypertensive therapy was to decrease DBP below 90 mm Hg or by a reduction of 210 mm Hg below baseline in both the supine and standing positions. All patients were periodically monitored as shown in Table II. Hematochemical tests were carried out by one laboratory and included serum glucose, total serum bilirubin, alkaline phosphatase, serum and urine electrolytes, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen, serum creatinine, uric acid, serum protein electrophoresis, full blood counts, differential cell and platelet counts, urinalysis, fasting triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and creatinine clearance. ECGs were taken at the beginning and end of the study. Treatment was initiated with a single daily dose of 1 mg of doxazosin or 50 mg of atenolol (half a tablet) at 8:00 AM. If the desired therapeutic effect was achieved after 1 week, the initial dose was maintained. If efficacy was not achieved, the dosage was doubled. Subsequent review visits were made at the end of weeks 2, 3, 4, 6, and 8. Doxazosin dosage was doubled weekly until the desired therapeutic effect was achieved or up to a maximum of 16 mg/day. The maximum dosage of atenolol was 100 mg/
Volume Number
116 6, Part 2
Donazosin
Table IV. Previous antihypertensive enrolled in the study
therapy
Atenolol No treatment Diuretics @-Blockers ACE inhibitors a-Methyldopa Calcium antagonists Combinations ACE,
in 40 patients Doxazosin
6 3 2 5 2 1
9 4 1 1 4 1
1
0
BP mmHg
1801
us atenolol
SUPINE
in hypertension
1803
STANDING
160
1
80'
Doxaz&n
Atenolol
Doxazosin
Atenolol
Doxazosin ----Atenolol
angiotensin-converting enzyme.
day. The drug was taken on the day that the review visit was carried out so that there was no interruption of therapy. At the end of the study, the patients treated with atenolol continued therapy if a satisfactory response was obtained. Other antihypertensive therapy was substituted for patients receiving doxazosin, since the drug was not commercially available. An overall assessment was made for each patient on therapeutic efficacy, effect on lipids, and toleration of both drug treatments. This assessment was made by means of a semiquantitative scale of effect: none, poor, fair, good, and excellent. Eleven patients (55%) in the atenolol group had a family history of hypertension. Five patients had a family history of diabetes, associated with hypertension in three cases. In the doxazosin group 12 patients (60%) had a family history of hypertension, one of diabetes, and three of both diseases. ECG abnormalities at baseline were recorded in three patients in each group. In the atenolol group two patients showed ventricular repolarization disturbances and one sinus bradycardia at baseline. In the doxazosin group one patient showed right bundle-branch block, one Ieft ventricular hypertrophy, and one sinus bradycardia at baseline. Concomitant diseases existed in five patients before randomization to the atenolol group and in six patients before randomization to the doxazosin group. A female patient in the doxazosin-randomized group had two concomitant diseases, chronic sinusitis and renal ptosis. The duration of hypertension reported by patients in both groups was similar (Table III). Fifteen patients (37.5%) enrolled in the study had not received previous antihypertensive therapy; six in the atenolol group and nine in the doxazosin group. The remaining patients had been prescribed either diuretics, &blockers, angiotensin-converting enzyme inhibitors, omethyldopa, calcium antagonists, or combination therapies (Table IV). Statistical analyses. Two-way analysis of variance was used to assess the changes between the final and baseline parameters. Results were expressed as percentages and means (with the relevant standard deviations). The mini-
Fig. 1. Supine and standing systolic and diastolic blood pressures (BP) and heart rate (HR), at baseline, and after drug therapy for 8 weeks. All blood pressure reductions from baseline were significant (p < 0.01) for both treatment groups. Significance values indicate differences between treatment groups. mum significance limit was fixed at ~0.05. Lipid ters were logarithmically transformed before tests.
parameapplying
RESULTS
The duration of antihypertensive therapy in this study was virtually identical in both groups: 56.2 + 2.4 days for atenolol and 56.1 -+ 3.1 days for doxazosin. At the end of week 8, all patients in the atenolol group were treated with 100 mg daily. The mean daily dosage of doxazosin was 3.3 mg at week 8: nine patients (45%), 2 mg/day, nine patients (45%), 4 mg/day, and two patients (10 % ), 8 mg/day. Antihypertensive efficacy. At the end of the run-in period, both groups of patients showed similar supine blood pressure profiles. A significant decrease in systolic and DBPs was seen in both groups after the first week of therapy. At the end of the study this reduction was more than 10% of the run-in period value. Atenolol produced a more rapid antihypertensive action than doxazosin in supine and standing systolic and diastolic blood pressures, although this difference did not reach significance. Conversely, doxazosin produced a higher overall efficacy on both supine arterial pressure components, even though the difference between the two drugs was significant in favor of doxazosin for supine DBP only (p < 0.05) (Fig. 1). There were no differences in antihypertensive effect between sexes in both treatment groups. A similar trend in blood pressure reduction was seen in standing blood pressure measurements; doxazosin was more effective than atenolol, but the difference was not considered significant.
1804
Giorgi
et al.
American
12- TRIGLYCERIDES 10-
50
EZI Atenolol 0 Doxazosin
% of 40 patients
r" ,'8
846-
4
2-
December 1988 Heart Journal
W/TOTAL 3LESTEROL CHOLESTEROL
1 58 -2f -4. 8 -6-a-10-
/ Excellent
Fig.
2. Clinical
Good
assessment
Fair
Poor
of antihypertensive
None
efficacy.
Both drugs showed negative chronotropic activity in supine and standing positions; this activity was much more marked for atenolol. At the end of the study period, the mean supine heart rate in atenololtreated patients was 66 beats/min compared with 80 beats/min for doxazosin (Fig. 1). Clinical assessment of antihypertensive efficacy at the end of treatment was excellent or good in 70 % of atenolol-treated patients and 80% of the doxazosin-treated group (Fig. 2). Lipid profiles. Atenolol and doxazosin produced opposite effects on lipid profiles, with doxazosin producing favorable changes in all parameters (Fig. 3). Triglycerides. A significant increase in triglyceride levels was observed after 4 weeks of therapy with atenolol. Conversely, a significant reduction from baseline values was observed at week 8 with doxazosin (p < 0.01 vs atenolol weeks 4 and 8). Total cholesterol. Atenolol induced a moderate increase in total cholesterol (+2.2 % ), whereas doxazosin decreased levels by almost 3% from baseline values after 8 weeks. These differences were not considered significant. HDL cholesterol. Atenolol showed a progressive reduction in HDL cholesterol that reached 6.96% at week 8 (p < 0.01). The increase for doxazosin was already significant after only 4 weeks and reached 6.00% after 8 weeks (p < 0.05). The difference between the two treatments was also statistically significant (p < 0.01). HDL/total cholesterol ratio. Although this ratio gradually decreased to a maximum -8.38% tp K U.UI) at the end of study for atenolol, there was a 9.45% increase (p < 0.01) for doxazosin after the same time interval (p < 0.01 vs atenolol).
l!ii
p < 0.01
Fig. 3. Changes in lipid profiles from baseline in patients treated with atenolol and doxazosin. Significance values indicate differences between treatment groups.
Side effects. Overall, side effects were reported in six patients: three in the atenolol group (dizziness, dyspnea, and atrial fibrillation), and three in the doxazosin group (asthenia). Side effects were minor and did not require therapy or discontinuation of antihypertensive treatment. Hematologic and biochemical laboratory tests. Blood chemical and urinalyses tests showed no significant variations before, during, and after drug therapy. ECG results. A modification from baseline ECG result was recorded in one case only; a patient in the atenolol group had atria1 fibrillation but this was not considered related to drug therapy. An assessment of excellent or good was achieved in 70% of the atenolol-treated patients and in 85 % of those taking doxazosin. An assessment of fair was achieved in 20% of the atenolol-treated patients and in 15% of doxazosin-treated patients. Toleration was assessed as poor in two (10%) atenolol-treated patients only. DISCUSSION
The findings of this study show that atenolol at a mean dose of 100 mg/day and doxazosin at a mean dose of 3.3 mg/day have similar antihypertensive efficacy. Both drugs significantly reduce systolic and DBPs in supine and standing positions (p < 0.01). Overall, atenolol was more effective than doxazosin during the first half of the treatment period. However, doxazosin displayed higher efficacy at the end of the study. Atenolol has a well-documented, negative chronotropic action.lO* l1 In our study a decrease of 14.77% was noted in supine heart rate at the end of the study. Doxazosin induced only a moderate decrease in supine heart rate (81.5 to 79.4 beats/min in the supine position).
Volume Number
116 6, Part 2
The effect of each drug on lipid profiles was very interesting. At the end of the study there was an increase in triglycerides and total cholesterol and a decrease in HDL cholesterol and HDL/total cholesterol ratio in patients treated with atenolol. Conversely, doxazosin showed a reversed trend, with a reduction in triglycerides and total cholesterol and an increase in HDL cholesterol and HDL/total cholesterol ratio. There was no indication of a change in patients’ dietary habits (both qualitatively and in caloric intake) after entry into the study. Therefore, it is concluded that the effects of therapy on lipid profiles are a direct result of the two study treatments. The incidence of side effects was 15% for both drugs. Although obviously affected by the short treatment period of 8 weeks, our results show both drugs to have equivalent toleration profiles. All side effects appeared during the first days of treatment; they were mild, of short duration, and did not require specific treatment. From our results we are able to conclude that the new selective al-inhibitor doxazosin is as effective as atenolol in reducing elevated supine and standing blood pressures. In addition, doxazosin has a beneficial effect on lipid profiles, and both of these parameters reduce calculated CHD risk in hypertensive patients. Unlike atenolol, doxazosin did not reduce marked bradycardia. The good toleration profile of doxazosin and single daily dosage regimen will undoubtedly increase patient compliance.
Doxazosin
us atenolol
in hypertension
1805
REFERENCES
1. Alabaster VA, Davey MJ. The a,-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21(suppl 1):9S-17s. 2. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S9OS. 3< Davey M. Mechanism of alpha blockade for blood pressure control. Am J Cardiol 1987;59:18G-28G. 4. Cubeddu LX, Fuenmayor N, Caplan N, Ferry D. Clinical pharmacology of doxazosin in patients with essential hvper-. tension. ClmPharmacol Ther i987;41:439-49. 5. Conrad KA, Fagan FC, Mackie MJ, et al. Doxazosin in patients with hypertension. Eur J Clin Pharmacol 1988 (in press). 6. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodvnamic effects of doxazosin in hvnertension at rest and during exercise. Br J Clin Pharmaiol 1986;21(suppl 1):45S-54s. 7. Hayduk K. Efficacy and safety of doxazosin in hypertension therapy. Am J Cardiol 1987;59:35G-9G. 8. Pool JL. Plasma lipid lowering effects of doxazosin, a new selective alpha, adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G. 9. Lehtonen A, Himanen P, Saraste M, Niittymiiki K, Marniemi J. Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br J Clin Pharmacol 1986;21(suppl 1):77S-81s. 10. Floras JS, Hassan MO, Jones JV, Sleight P. Ambulatory blood pressure and ita variability during randomized doubleblind administration of atenolol, metoprolol, pindolol and long acting propranolol in subiects with mild to moderate hypertension. Drugs 1983;25 (suppl 2):19-25. 11. Greminger P, Vetter H, Boerlin HJ, et al. A comparative study between 100 mg atenolol and 20 mg pindolol slowrelease in essential hypertension. Drugs 1983;25 (suppl 2):3741.
116 6, Part 2
Doxazosin
7. 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 hypertension. Br J Clin Pharmacol 1986;21(suppl 1):55S62S. 8. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S9OS. 9. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21(suppl 1):45S54S. 10. Wilner KD, Ziegler MG. Effects of alpha, inhibition on renal blood flow and sympathetic nervous activity in systemic hypertension. Am J Cardiol 1987;59:82G-6G. 11. De Leeuw PW, Van Es PN, De Bos R, Birkenhager WH. Acute renal effects of doxazosin in man. Br J Clin Pharmacol 1986;21(suppl 1):41S-3s. 12. Pool JL. Plasma lipid lowering effects of doxazosin, a new selective alpha, adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G.
us atenolol
in CHD risk reduction
13. Lehtonen A, Himanen P, Saraste M, Niittymlki K, Marniemi J. Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br J Clin Pharmacol I986:2l(sunnl 1):77S81S. 14. Frick MH, Cox DA, Himanen P, et al. Serum lipid changes in a one-year, multicenter, double-blind comparison of doxazosin and atenolol for mild to moderate essential hypertension. Am J Cardiol 1987;59:61G-7G. 15. Ott P, Storm TL, Krusell LR, Jensen H, Badskjaer J, Faeraeman 0. Multicenter. double-blind comparison of doxazosin and atenolol in patients with mild to moderate hypertension. Am J Cardiol 1987;59:73G-7G. 16. Shaw J, England JDF, Hua ASP. Beta-blockers and plasma triglycerides [Letter]. Br Med J 1978;1:986. 17. Leren P, Foss PO,- Helgeland A, Hjermann I, Holme I, Lund-Larsen PG. Effect of nronranolol and prazosin on blood lipids. The Oslo Study. Lance; 1980;2:4-6. 18. Wilson P, Castelli W. Coronary risk prediction in adults. Am J Cardiol 1987;59:91G-4G.
A comparative study of doxazosin versus atenolol in mild-to-moderate hypertension Doxarosin, a quinaroline derivative, is a selective a,-inhibitor that reduces calculated coronary heart disease risk by lowering blood pressure while favorably affecting blood lipid levels. The aim of this study was to compare the efficacy and toleration of doxazosin with atenolol, one of the most frequently used cardioselective ,&blockers in Italy. Forty patients with mild-to-moderate hypertension were treated with either atenolol (100 mg) or doxarosin (mean dose, 3.3 mg) once daily for 8 weeks. Both drugs significantly reduced supine and standing systolic and diastolic blood pressures. Atenolol induced marked bradycardia, whereas doxazosin had very little effect on heart rate. Doxarosin produced a favorable effect on blood lipid levels by decreasing triglyceride and total cholesterol levels and increasing high-density lipoprotein cholesterol and high-density lipoprotein total cholesterol ratio. Atenolol had exactly the opposite effect on blood lipid levels. Both drugs had equivalent toleration profiles. It was concluded that doxazosin was as effective as atenolol in reducing elevated supine and standing blood pressures. In addition, doxarosin had a beneficial effect on lipid proftles and minimal effect on heart rate. Therefore doxazosin may reduce calculated coronary heart disease risk in hypertensive patients. (AM HEART J 1988;116:1801.)
Gabriele Giorgi, MD, Jacopo M. Legramante, MD, Guiseppe Fioravanti, Giuseppe Paies, MD, and Alessio Legramante, MD Frascati, Italy
Doxazosin, a quinazoline derivative, is a selective cr,-inhibitor’ that reduces calculated coronary heart disease (U-ID) risk in hypertensive patients by lowering blood pressure while favorably affecting From Reprint Ospedale ltalv.
the General requests: Generale
Medicine
Division,
Hospital
Gabriele Giorgi, MD, Unita’ Provinciale, San Sebastiano
of Frascati. Sanitaria Martire,
Locale Frascati,
Rm. 29. Roma,
MD,
blood lipid levels.” The drug’s efficacy in blood pressure reduction is caused by the lowering of peripheral vascular resistance.” With a plasma halflife of approximately 22 hours, doxazosin is suitable for single daily dosing.4,5 Clinical studies in humans have shown that doxazosin is effective in lowering both systolic and diastolic blood pressures (DBPs) without significant changes in heart rate.2s6.7 In addition, the drug
1801
1802
Giorgi
et al.
American
Table I. Demographic data to-moderate hypertension No.
of patients 40
I + II
20
I Atenolol
with
mild-
yr
5.4 11.8
11.4 8.5
Treatment
X X x
History Physical examination BP and HR Laboratory tests Lipids ECG Toleration evaluation
12
x X X X x
x
x
3
4
68
x
x X X
xx
x
xx
x
X X X
BP, blood pressure; HR, heart rate.
induces significant beneficial effects on serum lipid levels without altering other CHD risk factors and therefore decreases calculated CHD risk.8,g Atenolol is one of the most frequently used cardioselective @-blockers in Italy, either as monotherapy or in combination with other antihypertensives, especially thiazide diuretics. The aim of this study was to comparatively assess the clinical efficacy, effect on serum lipid levels, and toleration of doxazosin and atenolol. METHODS Patients. Forty patients of both sexes, ages 18 to 70 years, with mild-to-moderate essential hypertension, were randomized into two groups. Group I consisted of 20 patients treated with atenolol* and group II of 20 patients treated with doxazosint (Table I). All patients had given their consent to be included in the study. This single-blind study included patients suffering from essential hypertension with supine DBPs ranging from 95 , ..d TV iV
II-I
MM
II&,.
1;
PaLiahts
Duration
of
hypertension
Group I (atenolol)
II. Study design
0
Ill.
Mean age f SD (range)
49.3 * 10.0 16 male/24 female 48.4 f 9.8 (18-65) 7 male: 48.0 k 13 female: 48.7 -+ 50.2 f 10.3 (30-66) 9 male: 54.1 + 11 female: 47.1 ?
II Doxazosin
Wk
Table
(years)
in
40
patients
Group
20
Table
on 40 patients
December 1988 Heart Journal
were
treated
with
other
l AtenoloI was supplied as 100 mg scored tablets. tDoxazosin was supplied by Pfizer Italiana SpA as 2, 4, and 8 mg scored tablets.
3 6 8 1 2
Group II (doxazosin) 4 8 7 1 0
antihypertensive therapy; a Z-week washout period was initiated. The main exclusion criteria for patients were as follows: pregnancy and lactation, secondary or malignant hypertension (routine basal measurement of vinylmandelic acid and creatinine clearance), recent myocardial infarction, unstable angina, cerebrovascular disorders, peripheral vascular diseases, bronchospasm, renal or hepatic insufficiency, severe concomitant diseases, and hypersensitivity to quinazoline or p-blocking drugs. Arterial blood pressure measurements were made between 10~00 AM and 12 noon during each visit: three supine blood pressure measurements were made over an S-minute period; the third measurement was taken for evaluation. Two standing blood pressure measurements were made over a P-minute period; the secondmeasurement was evaluated. The systolic arterial pressure was recorded at the appearance of sound (Korotkoff phase I), and the diastolic arterial pressure coincided with the phase V (disappearance) Korotkoff sound. Heart rate was measured for 30 seconds using a procedure similar to that for blood pressure. The aim of antihypertensive therapy was to decrease DBP below 90 mm Hg or by a reduction of 210 mm Hg below baseline in both the supine and standing positions. All patients were periodically monitored as shown in Table II. Hematochemical tests were carried out by one laboratory and included serum glucose, total serum bilirubin, alkaline phosphatase, serum and urine electrolytes, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, blood urea nitrogen, serum creatinine, uric acid, serum protein electrophoresis, full blood counts, differential cell and platelet counts, urinalysis, fasting triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and creatinine clearance. ECGs were taken at the beginning and end of the study. Treatment was initiated with a single daily dose of 1 mg of doxazosin or 50 mg of atenolol (half a tablet) at 8:00 AM. If the desired therapeutic effect was achieved after 1 week, the initial dose was maintained. If efficacy was not achieved, the dosage was doubled. Subsequent review visits were made at the end of weeks 2, 3, 4, 6, and 8. Doxazosin dosage was doubled weekly until the desired therapeutic effect was achieved or up to a maximum of 16 mg/day. The maximum dosage of atenolol was 100 mg/
Volume Number
116 6, Part 2
Donazosin
Table IV. Previous antihypertensive enrolled in the study
therapy
Atenolol No treatment Diuretics @-Blockers ACE inhibitors a-Methyldopa Calcium antagonists Combinations ACE,
in 40 patients Doxazosin
6 3 2 5 2 1
9 4 1 1 4 1
1
0
BP mmHg
1801
us atenolol
SUPINE
in hypertension
1803
STANDING
160
1
80'
Doxaz&n
Atenolol
Doxazosin
Atenolol
Doxazosin ----Atenolol
angiotensin-converting enzyme.
day. The drug was taken on the day that the review visit was carried out so that there was no interruption of therapy. At the end of the study, the patients treated with atenolol continued therapy if a satisfactory response was obtained. Other antihypertensive therapy was substituted for patients receiving doxazosin, since the drug was not commercially available. An overall assessment was made for each patient on therapeutic efficacy, effect on lipids, and toleration of both drug treatments. This assessment was made by means of a semiquantitative scale of effect: none, poor, fair, good, and excellent. Eleven patients (55%) in the atenolol group had a family history of hypertension. Five patients had a family history of diabetes, associated with hypertension in three cases. In the doxazosin group 12 patients (60%) had a family history of hypertension, one of diabetes, and three of both diseases. ECG abnormalities at baseline were recorded in three patients in each group. In the atenolol group two patients showed ventricular repolarization disturbances and one sinus bradycardia at baseline. In the doxazosin group one patient showed right bundle-branch block, one Ieft ventricular hypertrophy, and one sinus bradycardia at baseline. Concomitant diseases existed in five patients before randomization to the atenolol group and in six patients before randomization to the doxazosin group. A female patient in the doxazosin-randomized group had two concomitant diseases, chronic sinusitis and renal ptosis. The duration of hypertension reported by patients in both groups was similar (Table III). Fifteen patients (37.5%) enrolled in the study had not received previous antihypertensive therapy; six in the atenolol group and nine in the doxazosin group. The remaining patients had been prescribed either diuretics, &blockers, angiotensin-converting enzyme inhibitors, omethyldopa, calcium antagonists, or combination therapies (Table IV). Statistical analyses. Two-way analysis of variance was used to assess the changes between the final and baseline parameters. Results were expressed as percentages and means (with the relevant standard deviations). The mini-
Fig. 1. Supine and standing systolic and diastolic blood pressures (BP) and heart rate (HR), at baseline, and after drug therapy for 8 weeks. All blood pressure reductions from baseline were significant (p < 0.01) for both treatment groups. Significance values indicate differences between treatment groups. mum significance limit was fixed at ~0.05. Lipid ters were logarithmically transformed before tests.
parameapplying
RESULTS
The duration of antihypertensive therapy in this study was virtually identical in both groups: 56.2 + 2.4 days for atenolol and 56.1 -+ 3.1 days for doxazosin. At the end of week 8, all patients in the atenolol group were treated with 100 mg daily. The mean daily dosage of doxazosin was 3.3 mg at week 8: nine patients (45%), 2 mg/day, nine patients (45%), 4 mg/day, and two patients (10 % ), 8 mg/day. Antihypertensive efficacy. At the end of the run-in period, both groups of patients showed similar supine blood pressure profiles. A significant decrease in systolic and DBPs was seen in both groups after the first week of therapy. At the end of the study this reduction was more than 10% of the run-in period value. Atenolol produced a more rapid antihypertensive action than doxazosin in supine and standing systolic and diastolic blood pressures, although this difference did not reach significance. Conversely, doxazosin produced a higher overall efficacy on both supine arterial pressure components, even though the difference between the two drugs was significant in favor of doxazosin for supine DBP only (p < 0.05) (Fig. 1). There were no differences in antihypertensive effect between sexes in both treatment groups. A similar trend in blood pressure reduction was seen in standing blood pressure measurements; doxazosin was more effective than atenolol, but the difference was not considered significant.
1804
Giorgi
et al.
American
12- TRIGLYCERIDES 10-
50
EZI Atenolol 0 Doxazosin
% of 40 patients
r" ,'8
846-
4
2-
December 1988 Heart Journal
W/TOTAL 3LESTEROL CHOLESTEROL
1 58 -2f -4. 8 -6-a-10-
/ Excellent
Fig.
2. Clinical
Good
assessment
Fair
Poor
of antihypertensive
None
efficacy.
Both drugs showed negative chronotropic activity in supine and standing positions; this activity was much more marked for atenolol. At the end of the study period, the mean supine heart rate in atenololtreated patients was 66 beats/min compared with 80 beats/min for doxazosin (Fig. 1). Clinical assessment of antihypertensive efficacy at the end of treatment was excellent or good in 70 % of atenolol-treated patients and 80% of the doxazosin-treated group (Fig. 2). Lipid profiles. Atenolol and doxazosin produced opposite effects on lipid profiles, with doxazosin producing favorable changes in all parameters (Fig. 3). Triglycerides. A significant increase in triglyceride levels was observed after 4 weeks of therapy with atenolol. Conversely, a significant reduction from baseline values was observed at week 8 with doxazosin (p < 0.01 vs atenolol weeks 4 and 8). Total cholesterol. Atenolol induced a moderate increase in total cholesterol (+2.2 % ), whereas doxazosin decreased levels by almost 3% from baseline values after 8 weeks. These differences were not considered significant. HDL cholesterol. Atenolol showed a progressive reduction in HDL cholesterol that reached 6.96% at week 8 (p < 0.01). The increase for doxazosin was already significant after only 4 weeks and reached 6.00% after 8 weeks (p < 0.05). The difference between the two treatments was also statistically significant (p < 0.01). HDL/total cholesterol ratio. Although this ratio gradually decreased to a maximum -8.38% tp K U.UI) at the end of study for atenolol, there was a 9.45% increase (p < 0.01) for doxazosin after the same time interval (p < 0.01 vs atenolol).
l!ii
p < 0.01
Fig. 3. Changes in lipid profiles from baseline in patients treated with atenolol and doxazosin. Significance values indicate differences between treatment groups.
Side effects. Overall, side effects were reported in six patients: three in the atenolol group (dizziness, dyspnea, and atrial fibrillation), and three in the doxazosin group (asthenia). Side effects were minor and did not require therapy or discontinuation of antihypertensive treatment. Hematologic and biochemical laboratory tests. Blood chemical and urinalyses tests showed no significant variations before, during, and after drug therapy. ECG results. A modification from baseline ECG result was recorded in one case only; a patient in the atenolol group had atria1 fibrillation but this was not considered related to drug therapy. An assessment of excellent or good was achieved in 70% of the atenolol-treated patients and in 85 % of those taking doxazosin. An assessment of fair was achieved in 20% of the atenolol-treated patients and in 15% of doxazosin-treated patients. Toleration was assessed as poor in two (10%) atenolol-treated patients only. DISCUSSION
The findings of this study show that atenolol at a mean dose of 100 mg/day and doxazosin at a mean dose of 3.3 mg/day have similar antihypertensive efficacy. Both drugs significantly reduce systolic and DBPs in supine and standing positions (p < 0.01). Overall, atenolol was more effective than doxazosin during the first half of the treatment period. However, doxazosin displayed higher efficacy at the end of the study. Atenolol has a well-documented, negative chronotropic action.lO* l1 In our study a decrease of 14.77% was noted in supine heart rate at the end of the study. Doxazosin induced only a moderate decrease in supine heart rate (81.5 to 79.4 beats/min in the supine position).
Volume Number
116 6, Part 2
The effect of each drug on lipid profiles was very interesting. At the end of the study there was an increase in triglycerides and total cholesterol and a decrease in HDL cholesterol and HDL/total cholesterol ratio in patients treated with atenolol. Conversely, doxazosin showed a reversed trend, with a reduction in triglycerides and total cholesterol and an increase in HDL cholesterol and HDL/total cholesterol ratio. There was no indication of a change in patients’ dietary habits (both qualitatively and in caloric intake) after entry into the study. Therefore, it is concluded that the effects of therapy on lipid profiles are a direct result of the two study treatments. The incidence of side effects was 15% for both drugs. Although obviously affected by the short treatment period of 8 weeks, our results show both drugs to have equivalent toleration profiles. All side effects appeared during the first days of treatment; they were mild, of short duration, and did not require specific treatment. From our results we are able to conclude that the new selective al-inhibitor doxazosin is as effective as atenolol in reducing elevated supine and standing blood pressures. In addition, doxazosin has a beneficial effect on lipid profiles, and both of these parameters reduce calculated CHD risk in hypertensive patients. Unlike atenolol, doxazosin did not reduce marked bradycardia. The good toleration profile of doxazosin and single daily dosage regimen will undoubtedly increase patient compliance.
Doxazosin
us atenolol
in hypertension
1805
REFERENCES
1. Alabaster VA, Davey MJ. The a,-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21(suppl 1):9S-17s. 2. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21(suppl 1):83S9OS. 3< Davey M. Mechanism of alpha blockade for blood pressure control. Am J Cardiol 1987;59:18G-28G. 4. Cubeddu LX, Fuenmayor N, Caplan N, Ferry D. Clinical pharmacology of doxazosin in patients with essential hvper-. tension. ClmPharmacol Ther i987;41:439-49. 5. Conrad KA, Fagan FC, Mackie MJ, et al. Doxazosin in patients with hypertension. Eur J Clin Pharmacol 1988 (in press). 6. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodvnamic effects of doxazosin in hvnertension at rest and during exercise. Br J Clin Pharmaiol 1986;21(suppl 1):45S-54s. 7. Hayduk K. Efficacy and safety of doxazosin in hypertension therapy. Am J Cardiol 1987;59:35G-9G. 8. Pool JL. Plasma lipid lowering effects of doxazosin, a new selective alpha, adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G. 9. Lehtonen A, Himanen P, Saraste M, Niittymiiki K, Marniemi J. Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br J Clin Pharmacol 1986;21(suppl 1):77S-81s. 10. Floras JS, Hassan MO, Jones JV, Sleight P. Ambulatory blood pressure and ita variability during randomized doubleblind administration of atenolol, metoprolol, pindolol and long acting propranolol in subiects with mild to moderate hypertension. Drugs 1983;25 (suppl 2):19-25. 11. Greminger P, Vetter H, Boerlin HJ, et al. A comparative study between 100 mg atenolol and 20 mg pindolol slowrelease in essential hypertension. Drugs 1983;25 (suppl 2):3741.