Doxazosin in the treatment of essential hypertension in general medical practice in Latin America

Doxazosin in the treatment of essential hypertension in general medical practice America

in Latin

This Latin American study assessed in the general practice setting the efficacy and tolerance of once-daily doxazosin in the treatment of mild or moderate essential hypertension (sitting diastolic blood pressure, 95 to 115 mm Hg). Patients (n = 220) were treated with doxarosin for 12 weeks as monotherapy or in combination with other antihypertensive agents. At the final visit, doxazosin produced a mean change in sitting systolic/diastolic blood pressure of -18.41-14.4 mm Hg, at a mean daily dose of 4.3 mg. One hundred sixty-three (77.6%) of the 210 evaluable patients were considered a therapeutic success. Lipid analyses identified a statistically significant (p = 0.02) reduction in total serum cholesterol (4.85%) and an overall decrease in triglyceride levels (5.12%). According to the Framingham Heart Study equation, doxazosin produced a highly significant (p < 0.001) 20% reduction in the calculated probability of developing coronary heart disease in 10 years. Of the 220 patients evaluated, 54 (24.5%) reported side effects that were considered related to treatment. Ten (4.5%) patients reported side effects unrelated to treatment and 37 (16.8%) reported events of unknown relationship. Most side effects were mild or moderate and were tolerated or disappeared with continued treatment. Nine patients (4.1%) were discontinued from therapy and in 13 (5.9%) the dose was reduced. The most prevalent side effects were headache and dizziness. The investigators’ overall assessment of antihypertensive efficacy was excellent or good for 176 patients (80.4%); tolerance was considered excellent or good in 193 patients (88.5%). These results indicate that doxazosin is an effective and well-tolerated antihypertensive agent that beneficially affects the serum lipid profile and can significantly reduce the calculated risk of developing coronary heart disease. (AM HEART J 1991;121:329-35.)

Honorio Silva, MD,” Ricardo Fonseca, MD,a, h and Dennis Marshall, Caracas, Venezuela, and New York, N.Y.

Doxazosin is a new selective al-inhibitor that acts at postsynaptic adrenergic receptors to reduce blood pressure while producing little or no reflex changes in heart rate.‘,’ The antihypertensive efficacy of doxazosin has been demonstrated in patients with mild, moderate, and severe hypertension.“, 4 Doxazosin is a quinazoline derivative with an extended elimination half-life of 22 hours5 which allows for once-daily administration and facilitates patient compliance. In addition, doxazosin has been shown to beneficially affect the serum lipid profile of hypertensive patients and significantly reduce the calculated risk of developing coronary heart disesase (CHD). The pharmacokinetics of doxazosin have been studied extensively.6 A single oral dose is approximately 65 % bioavailable and gradually attains a Fnm “I’fixr

I he al’harrnacdogy S..\.. Venezurla.

Reprint reqkwts: Kirardo racas 10ML.~. Venezuela. 4/O/2.1887

Department. Central and T’fizer Intm~ational. Funsrcn.

MD, Pfizer

l’niversity of Venezuela. New York. S.A.. Apartado

f1?89.

Ca-

MS, PhD’

peak plasma concentration 3 to 4 hours after administration,7a * with an apparent volume of distribution of approximately 1 L/kg.6 Doxazosin is metabolized in the liver, with only 5% excreted unchangedeg Doxazosin has been shown to decrease total plasma cholesterol and triglyceride concentrations and to increase the levels of high-density lipoprotein (HDL) cholesterol and the HDL/total cholesterol rati0.i’.is The incidence of side effects is reported to be low and similar to that reported for a selective al-inhibitor; headache, vertigo, dizziness, and lethargy are reported most often.5T lJ, I5 The majority of side effects are mild or moderate*5,

14.15

This study evaluates the efficacy and safety of doxazosin in 220 patients from two Latin American countries (201 from Venezuela and 19 from Argentina) in an open, noncomparative, multicenter trial. Patients had mild, moderate, or severe essential hypertension and were treated in a general medical practice. Oral doses of doxazosin ranging from 1 to 8 329

January

330

Silva, Fonseca, and Marshall

Table I. Age, sex, and weight entering the study

American

distribution Patients

of patients

Table Ill. Baseline severity and standing DBP

Age interval

based on sitting

(mm

Hg)

Total Mild 91-94

0 11

0 9

48 29 12

74 28

100

119

<20 20-35 36-50 51-60 61-70

Totai Age (yr) Mean * SEM Minimum Maximum Weight (kg) Mean i SEM Minimum Maximum

Table

Female

(yr)

47.9

76.9

II. Duration Yr
0 20 122 La*

8

t 1.0 “1 69

47.1

+ 1.1

66.0

46.5 106.0

for

*Sex was not stated

1991 Journal

(n) Severity

Mu/e

of hypertension

Heart

20 220

k 0.8

47.5

-+ 0.6 21 69

71.0

t 0.8 44.0

23 69

i

1.0

44.0 98.4

106.0

one patient.

of hypertension

95-104

Moderate (105-114) Severe (115-129) Total

of study

population

Patients

(n)

19 90 60 38 13 5.3 0.08-30

mg/day were used either as monotherapy or in combination with a constant dose of another antihypertensive agent that alone was unable to control diastolic blood pressure (DBP) adequately at baseline. The goal was to obtain a sitting DBP of 190 mm Hg. METHODS Patient selection. Patients were enrolled in a general medical practice setting in Argentina (19 patients) and Venezuela (201 patients) and were entered into the trial with mild, moderate, or severe essential hypertension (sitting DBP, 95 to 129 mm Hg with or without concomitant antihypertensive therapy). Male and female patients, ages 20 to 70 years, were included. Patients were allowed to take one or more concomitant antihypertensive agents (diuretics, @-blockers, and vasodilators) provided sitting DBP was at least 95 mm Hg, and the dose was kept constant throughout the study. The protocol excluded those patients with malignant, resistant, or secondary hypertension (including estrogen-dependent hypertension); grades III and IV retinopathy; documented or clinically suspected serious or idiosyncratic reaction to &adrenergic inhibitors, thiazide diuretics, or cu-adrenergic-inhibiting drugs; renal

failure; hepatic or hematologic disease; diabetes mellitus requiring insulin therapy; unstable angina pectoris; documented myocardial infarction within 3 months of entry into the study; cerebrovascular accident within 1 year of entry into the study; neurologic convulsive disorder; chronic obstructive pulmonary disease requiring longterm drug treatment; use of estrogen or tricyclic antidepressant drugs; blood donation; or current pregnancy or lactation. Trial design. The trial was an open, multicenter study involving three phases: a 2-week baseline period (phase I), an &week dose-adjustment period (phase II), and a ii-week maintenance period (phase III). The total intended duration of active treatment was 12 weeks. During phase I, sitting and standing blood pressures and heart rates were measured each week; the mean of values served as baseline. Routine laboratory tests and serum lipid analyses’were performed before active drug was given. Phase II began with an initial dose of 1 mg doxazosin on the first day. Doses were sequentially adjusted upward from 1 to 2, 4, or 8 mg/day until one of the following occurred: blood pressure control was achieved (i.e., the sitting DBP was 590 mm Hg), a maximum daily dose of 8 mg/day had been administered, or significant side effects precluded further increases in dose. Blood pressure and heart rate measurements were made approximately 3 to 8 hours after administration of the drug. At each visit throughout the study, sitting and standing blood pressure and heart rate measurements were recorded, as were any volunteered side effects. Each blood pressure value recorded was the mean of two consecutive measurements made after the patient had been sitting for 5 minutes and standing for 2 minutes. Heart rate was determined immediately before each set of blood pressure measurements. Success of therapy in terms of blood pressure response was defined as a sitting DBP 590 mm Hg (i.e., “normalized”) with a decrease of 25 mm Hg or a 2 10 mm Hg reduction from baseline. Baseline and final laboratory tests were also performed and included an analysis of hepatic and renal functions, electrolytes, hematology, serum proteins, and serum lipids. Baseline to final changes in blood pressure and heart rate were analyzed statistically with paired t tests. Baseline and final serum lipid values were log transformed and expressed as geometric means; percent changes were derived

“D,“rnFJ

121

Number

1.

Table

Part

General

2

IV. Summary

of concurrent

diseases at baseline

Table

V. Summary

practice

study

of concomitant

in Latin

America

medications

at baseline No. of

No. of Concurrent

disease

patients

Endocrine/metabolic/immunologic Gastrointestinal Muscuioskeletal/connective tissue Respiratory Cardiovascular Renal Nervous system/sensory organs Genitourinary Skin/subcutaneous tissue Infectious/parasitic Mental

40

Concomitant

medication

pa ticw ts receirring one or more medication(s)

10

7 5 5 4

3 2 2

2 2

Hepatic

Ill-defined signs/symptoms Total No. of diseases Total No. of patients with concomitant

1 8

91 diseases

55

from the geometric means, and significance was tested with a paired t test. CHD risk analysis. The Framingham Heart Study risk equationI was used to calculate the probability of developing CHD in 10 years. The equations required the following information for the calculation of a risk score: age, sex, blood pressure, history of cigarette smoking, left ventricular mass, assessment of glucose intolerance, and total serum cholesterol and HDL cholesterol measurements. To include as many patients as possible in the analysis, the following modifications were made in the application of the equations: (1) ages I 5 years from either end point (i.e., 30 to 70 years) assumed the value of the respective upper or lower limit; (2) the appropriate upper or lower limit was substituted for cholesterol and blood pressure values that exceeded 150 to 400 mg/dl (3.89 to 10.36 mmol/L) cholesterol and 60 to 120 mm Hg sitting DBP; (3) HDL was assumed to be 47.565 mg/dl(l.23 mmol/L) in men and 57.144 mg/dl(1.48 mmol/L) in women; (4) patients were assumed to be nonsmokers if this was not specified; (5) no patients were considered to have left ventricular hypertrophy or glucose intolerance. Each patient’s risk score was evaluated at baseline and the final visit. To be included in the analysis, a patient had to be efficacy evaluable with total cholesterol and blood pressure measurements reported at both baseline and final treatment visits. The changes from baseline were assessed by first applying a log-odds transformation and then applying within-group t tests. RESULTS Patient profile. men, 119 women,

The 220 patients consisted of 100 and 1 patient of unstated sex. The mean ages for men and women were 47.9 f 1.0 and

47.1 +- 0.8 years, respectively. weight distribution of patients

33

The age, sex, and is given in Table I.

Hormones and synthetic substitutes Antidiabetics Estrogens Cardiovascular B-blockers Vasodilators Antilipemics Electrolytic caloric and water balance Diuretic (distal tubule) Diuretic (K+ sparing) Diuretic (loop) Diuretic (others) Uricosurics Gastrointestinal Antiulcer Antacids and absorbents Antiemetics Musculoskeletal Antiinflammatory Central nervous system Benzodiazepines Analgesics and antipyretics Other anticonvulsants Antiinfectives Antifungals Autonomies Parasympathomimetic Spasmolytic Respiratory No. of patients with concomitant medication(s) Total No. of concomitant medications

19

18

18

6

5 4

1 I 1 55 76

The mean duration of hypertension was 5.3 years (Table II). Baseline severity of hypertension (sitting and standing) is given in Table III. Sixty-two percent of the patients were classified as having mild hypertension (91 to 104 mm Hg) on the basis of sitting DBP. Concurrent diseases were mainly endocrine, metabolic, or immunologic disorders (Table IV). Fifty-five patients were taking a total of 76 concomitant medications on entry into the study (Table V). Only four patients started a total of six concomitant medications during the study (analgesics, antidiabetics, vitamins, and other agents), none of which was vasoactive. Discontinuation of therapy. Fourteen patients were withdrawn before completion of the study: three because of poor compliance, two because of inadequate response, and nine because of side effects. Duration of therapy, efficacy status, and dose. The mean duration of treatment for all patients was 85.1

1

332

January

Silva, Fonseca, and Marshall

1991

American Heart Journal

Table

VI.

Final dose and efficacy summary

Patients evaluable for eticacy in) Therapy successes* (n/“t ) Mean daily dose (mg) Normalized DBPt (n/‘~ ) Mean daily dose (mg) DBP reduced by ~10 mm Hg (n/’ Mean daily dose (mg) Therapy failures (n/‘(, 1 Mean daily dose (mg) L

0

2

4

6

Therapy

8

10

12

FltXI “ISIt

week * p < 0 05. from basehe

1. Effect of doxazosin on sitting systolic blood pressure, DBP, and heart rate.

Fig.

L

0

2

4

6

Therapy

8

10

12

FInal vlslt

week * p < 0 05. from baseline

2. Effect of doxazosin on standing systolic blood pressure, DBP, and heart rate.

Fig.

days (range, 5 to 125 days). The mean final dose of doxazosin for all patients was 4.3 mg/day. At the end of the study, 71% of all patients took 4 mg or less of doxazosin once daily. Of the 220 patients entered into the study, 10 were deemed inevaluable because of concomitant medication, protocol violation, low baseline blood pressure, or poor compliance. The mean duration of doxazosin therapy in the 210 efficacyevaluable patients was 85.9 days (range, 15 to 125 days). Blood pressure response. Of the 210 efficacy-evaluable patients, 163 (77.6 % ) were considered therapy successes (sitting DBP 190 mm Hg with ~5 mm Hg reduction from baseline or a decrease of L 10 mm Hg from baseline) at a mean daily dose of 3.9 mg (Table VI). Of these patients, 136 (64.8%) achieved normalized blood pressures (mean sitting DBP 190 mm Hg with ~5 mm Hg reduction from baseline) at a mean daily dose of 3.4 mg; in 27 (12.9%) patients sitting

DBP was reduced by 10 mm Hg or more from baseline, at a mean daily dose of 6.0 mg. Forty-seven patients (22.4% ) were regarded as treatment failures at a mean daily dose of 5.6 mg; 28 (13.3 % ) had an inadequate response at the maximum dose, 4 were not adjusted to the maximum dose because of side effects, and 15 were not optimally adjusted for unexplained reasons. Mean changes in blood pressure and heart rate. Doxazosin reduced mean blood pressure from a baseline of 157/104 mm Hg (sitting) and 158/105 mm Hg (standing) to 139/89 mm Hg (sitting) and 139/90 mm Hg (standing) at the end of the I2-week treatment period. Changes in sitting and standing blood pressure and heart rate are presented in Figs. 1 and 2. All reductions in sitting and standing blood pressure were significant (p < 0.05) throughout the study period. There were no clinically significant changes from baseline in mean heart rate. Changes in severity of hypertension. Eighty percent of patients showed improvement in the severity category (based on mean sitting DBP) from baseline to final visit (Table VII): blood pressure became normal in 94 (74%) of the patients with mild hypertension, and 71 (90%) of the patients with moderate hypertension became either mildly hypertensive or their blood pressures became normal. Of the four patients with severe hypertension at baseline, two improved to mildly hypertensive, one improved to moderately hypertensive, and one patient remained severely hypertensive. Lipid parameters. Of the 220 patients, 132 (60.0%) were evaluable for total cholesterol and 127 (57.7 %I) for triglyceride levels. Fifty-five patients were inevaluable for lipid levels because samples were obtained more than 24 hours after administration; 10 other patients were efficacy inevaluable and hence inevaluable for lipid analyses, and one patient was inevaluable because of a concomitant antilipemic drug. This reduced the number of patients evaluable for

Volume 121 Number

General practice

1, Part 2

Table VII. Changes in the severity of hypertension baseline to final visit in efficacy-evaluable patients Final Baseline

severity

Mild (sitting DBP 91-104 mm Hg) Moderate (sitting DBP 105-114 mm Hg) Severe (sitting DBP 115-129 mm Hg) Total

Normai

severity

from

n

Moderate

94

30

3

0

127

42

29

7

1

79

0 136

2 61

1 11

Seuere

1 2

Total

4 210

levels to 154; of these, 22 had no baseline or follow-up cholesterol value, and 27 had no baseline or follow-up triglyceride value. Doxazosin exerted beneficial effects on the serum lipid profile (Table VIII). Total cholesterol levels were reduced significantly (p = 0.02) by 4.85 % from a mean baseline level of 227 mg/dl (5.88 mmol/L). Serum triglyceride concentration was reduced by 5.12% from baseline, although this change did not attain statistical significance. Calculated reduction in CHD risk score. Calculated CHD risk score based on the Framingham Heart Study equation (probability of developing CHD in 10 years in chances per 100) is presented in Table VIII. There was a highly significant reduction of 20% (p < 0.001) in calculated CHD risk score from a mean baseline of 14.5 to 12.2 at the final visit. Side effects. The overall summary of tolerance is given in Table IX. Of the 220 patients, 101 reported side effects: 54 (24.5 % ) patients had side effects related to treatment; 47 (21.4%) were of either unknown relationship or not related to treatment. The most prevalent side effects were headache (13.6 % ) and dizziness (12.7%), the majority of which were mild or moderate and were tolerated or disappeared on continued therapy. Table X provides a summary of side effects as classified by body system. Nine (4.1%) patients discontinued therapy and in 13 (5.9 % ) the dose of doxazosin was reduced. In the nine patients who discontinued the study the adverse events were primarily headache, dizziness, tachycardia, palpitations, asthenia, or somnolence. Laboratory test results. In most cases, laboratory safety data remained unchanged after treatment with doxazosin, or minor changes were considered not significant or related to concomitant diseases or medications. In some cases, although abnormal laboratory values may have been related to doxazosin treatment, no trends with regard to organ system or correlation with dose and duration were apparent. lipids

Table VIII. Effect of doxazosin calculated CHD risk

fn)

Mild

study in Latin

Total cholesterol mmol/L mg/dl Triglycerides mmol/L mg/dl Calculated CHD risk*

Baseline

132

on serum lipid Final 5.59

5.88

226.95 121

5

333

levels and

change

p value

-4.85

0.02

-5.12

NS

-2ot


215.94

1.76

129

America

1.67

155.89

147.92

14.5

12.2

Concentrations of HDL were assumed to be 47.565 mg/dl(1.23 mmol/L) for men and 57.144 mgidl (1.48 mmol/L) for women. No patients were considered to have left ventricular hypertrophy or glucose intolerance. *Probability (chances per 100) of developing CHD in 10 years. Kalculated from log-odds ratio.

Table

IX. Overall

summary

of toleration n

Summary

Patients studied Patient months of drug exposure Patients with side effects Related to treatment Not related to treatment Unknown relationship Patients with dose reduction Patients discontinued because of side effects

Table

X. Summary

r’o

220 615

101

45.9

54

24.5 4.5 16.8

10 37 13

9

5.9 4.1

of side effects Patients

Side

n

effect

Cardiovascular General Psychiatric Autonomic Respiratory Gastrointestinal Skin and appendages Musculoskeletal Central and peripheral Reproductive Special senses

nervous system

46 46 21 6 5 4 4 2 2 2 1

?G 20.9 20.9 9.5 2.7 2.3 1.8 1.8 0.9 0.9 0.9 0.5

There was a small but statistically significant (p < 0.05) increase in body weight from baseline (70.97 kg) to final visit (71.39 kg). Overall clinical evaluation. The investigators’ global assessment of efficacy was excellent or good in 176 (80.4%) patients and fair or poor in 43 (19.6%) (one patient’s evaluation was not reported). Global assessment of tolerance was excellent or good in 193

334

Silva, Fonseca, and Marshall

(88.5%) patients and fair or poor for 25 (11.5%) (two patients’ evaluations were not reported). DISCUSSION

Worldwide selective al-inhibitors have not been used as frequently as other antihypertensive therapies, even though it has been demonstrated extensively that selective al-inhibitors have efficacy and tolerance similar to those of other antihypertensive agents. However, the increasing concern about cardiovascular risk factors and possible modification by antihypertensive therapy has recognized the need for a reevaluation of the risk/benefit balance of the different antihypertensive treatments available. Both an adverse lipid profile and hypertension are independent risk factors that must be considered when treating patients with cardiovascular disease. It is not sufficient to simply decrease the elevated levels of arterial pressure; long-term prognosis must be considered, especially with regard to the risk factors associated with cardiovascular and cerebrovascular disease.17 In a consideration of CHD risk, doxazosin is preferred compared with many antihypertensive treatments (e.g, diureticsI and /3-blockers,10-12T 18,lg). At a similar antihypertensive efficacy, doxazosin produces a favorable effect on the serum lipid profile13 and thus reduces the calculated risk of CHD. In contrast, diuretics and P-blockers, although they lower blood pressure, can adversely affect serum lipid levels, and this may negate any beneficial effects on CHD risk created by a reduction in blood pressure. This study was designed to evaluate the antihypertensive efficacy, safety, and effects on lipid levels of doxazosin in the treatment of hypertension in general medical practice. The results indicate that doxazosin can be considered an effective antihypertensive drug, taken as monotherapy or in combination with other agents. Therapeutic success was achieved in 78% of patients at a mean daily dose of 3.9 mg, and normalization of DBP was achieved in 65% of patients at a mean daily dose of 3.4 mg. Doxazosin decreased mean baseline arterial blood pressure from 157/104 mm Hg sitting and 158/105 mm Hg standing to 139189 and 139190 mm Hg, respectively, at the final evaluation. No clinically meaningful changes in mean heart rate were observed. These results are considered very good under general medical practice conditions. Doxazosin decreased the total cholesterol concentration by 4.9% (p = 0.02), triglycerides by 5.1% (difference not significant), and the calculated risk of CHD by 20% (p < 0.001). These results are in agreement with those of previous studies of doxazosin and

American

January 1991 Heart Journal

emphasize the potential long-term benefits in terms of reduction in cardiovascular risk that can be achieved with doxazosin treatment. The side effect profile of doxazosin was considered excellent or good in 193 (88 % ) of the 220 patients. Adverse events related to treatment were reported in 54 (24.5 % ) patients. Overall, the most prevalent side effects were headache (13.6% ) and dizziness (12.7 % ). Most of the side effects were mild or moderate and were tolerated or disappeared with continued treatment. Laboratory chemistry test values revealed no apparent treatment-related abnormalities. In conclusion, these study results obtained in two Latin American countries are in agreement with previously reported efficacy and safety data obtained in a general medical practice setting. Doxazosin was well tolerated and effective in controlling blood pressure in patients with essential hypertension. In addition to lowering blood pressure, the favorable effect on blood lipid levels can significantly reduce the calculated risk of developing CHD. REFERENCES

1 Torvik D, Madsbu HP. Multicentre twelve-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%75S. 2. Soltero I, Guevara J, Silva H, Velasco M. A multicenter study of doxazosin in the treatment of severe essential hypertension. AM HEART J 1988;116:1767-71. 3. Alabaster VA, Davey MJ. The al-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21(suppl l):SS-17s. 4. Ramage AG. A comparison of the effects of doxazosin and alfuzosin with those of urapidil on preganglionic sympathetic nerve activity in anaesthetised cats. Eur J Pharmacol 1986; 129:307-14. 5. Elliott HL, Meredith PA, Reid JL. Pharmacokinetic overview of doxazosin. Am J Cardiol 1987;59:‘78G-81G. 6. Elliott HL, Meredith PA, Vincent J, Reid JL. Clinical pharmacological studies with doxazosin. Br J Clin Pharmacol 1986;21(suppl 1):27S-31s. 7. Rubin PC,-Brunton J, Meredith P. Determination of vasodilator UK 33274 bv high-nerformance liauid chromatoeranhv using fluorescence detection. J Chromaiogr 1980;221:193&” 8. Cubeddu LX, Fuenmayor N, Caplan N, Ferry D. Clinical pharmacology of doxazosin in patients with essential hypertension. Clin Pharmacol Ther 1987;41:439-49. 9. Vincent J, Elliott HL, Meredith PA, Reid JL. Doxazosin, an or-adrenoceptor antagonist: pharmacokinetics and concentration-effect relationships in man. Br J Clin Pharmacol 1983; 15:719-25. 10. Svetkey LP, Brobyn R, Deedwania P, Graham RM, Morganroth ,J. Klotman PE. Double-blind comparison of doxazosin, nadolol and placebo in patients with mild-to-moderate hypertension. Curr Ther Res 1988;43:969-78. 11. Karlson BW, Henning R, Waern U. Doxazosin and atenolol in mild-to-moderate hypertension. Curr Ther Res 1988;43: 1003-s. 12. 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. 13. Pool ,JL. Plasma lipid lowering effects of doxazosin, a new se-

Volume 121 Number

General practice

1. Part 2

lective alpha-l adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:29G-34G. 14. Rosenthal JA. A multicenter trial of doxazosin in West Germany. Am J Cardiol 1987;59:40G-5G. 15. Bailev RR. Nairn PL. Walker RJ. Effect of doxazosin on blood pressure and renal haemodynamics of hypertensive patients with renal failure. NZ Med .J 1986;99:942-5. 16. 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.

study in Latin

America

17. Birkenhlger WH, de Leeuw PW. Treatment of the elderly hypertensive: a clinical perspective. Eur Heart J 1988;9(suppl D):63-7. 18. Elliott HL, Meredith PA, Sumner DJ, et al. A pharmacodynamic and pharmacokinetic assessment of a new alphaadrenoceptor antagonist, doxazosin (UK 33,274) in normotensive subjects. Br J Clin Pharmacol 1982;13:699-703. 19. Ott P, Storm TL, Krussell LR, et al. Multicenter, double-blind comparison of doxazosin and atenolol in patients with mildto-moderate hypertension. Am d Cardiol 1987;59:73G-7G.

A multicenter study of doxazosin in the treatment of essential hypertension in France This study was designed to assess the efficacy and tolerance of doxazosin in patients with mild, moderate, or severe essential hypertension in a general practice setting. Ninety-six adults of a mean age of 55% years took part in the 14-week study, consisting of a placebo phase (2 weeks), a dose-adjustment phase with doxazosin (8 weeks), and a maintenance phase (4 weeks). Doxarosin, at a final mean daily dose of 3.4 mg, produced a significant (p < 0.05) reduction in blood pressure at all points of measurement during the study. The mean change in sitting blood pressure at the end of treatment was -15.41-15.8 mm Hg. Of the 85 patients who could be categorized as a success or failure, 78 (92%) were considered a therapeutic success; 78 (Sg%) of the 88 efficacy-evaluable patients demonstrated an improvement in the severity category of their hypertension. Treatment with doxazosin produced a reduction in serum cholesterol (-3.1%) and triglyceride (-3.8%) levels, although these changes did not attain statistical significance. The calculated probability of developing coronary heart disease in 10 years (according to the Framingham equation) was significantly (p < 0.001) reduced by 22%, from 16.7 chances per 100 (baseline) to 14.3 chances per 100 (final visit). Twenty-six patients (27.1%) reported side effects that were possibly related to treatment, the most prevalent of which were vertigo (7.3%) and headache (6.3%). In four (4.2%) patients the dose of doxazosin was reduced and two (2.1%) were withdrawn prematurely. The investigators’ assessments of tolerance of doxazosin were considered to be excellent or good in 85 (88%) patients. (AM HEART J lgg1;121:335-40.)

Gerard Bonnet, MD Druueil,

France

In 1950 Dock1 wrote: “There is in fact no specific treatment for hypertension.” Since then there has been a large expansion in our knowledge of arterial hypertension, which has resulted in considerable therapeutic progress. The first antihypertensive drugs were the ganglionic blockers whose therapeutic efficacies were marred by multiple, severe side effects. Since 1950 the following antihypertensive drugs have been developed: (1) thiazides; (2) adrenergic neuron-blockFrom

the H&pita1

Dupuytren.

Reprint requests: GBrard Delacroiz, 91210 Draveil, 4/0/24889

Bonnet, France.

MD,

HBpital

Dupuytren,

1 rue Eugene

ing drugs, including the Rauwolfia alkaloids; (3) centrally acting cr-adrenergic stimulants such as CYmethyldopa; (4) clonidine, which acts by inhibiting centrally mediated inhibition of cardiovascular sympathetic drive; (5) guanethidine, which inhibits the liberation of adrenergic neurotransmitters; (6) pblockers; and (7) postsynaptic al-adrenergic inhibitors.2p 3 There are also other antihypertensive agents such as hydralazine and minoxidil that have a direct action on vascular smooth muscle, calcium antagonists, and inhibitors of angiotensin-converting enzyme that converts angiotensin I into angiotensin II. This article describes a study designed to assess the 335