An open, noncomparative study of doxazosin in essential hypertension: Experience in general practice in the Netherlands

Volume 121 Number 1, Part 2

UK general practice

moderate hypertension: a randomized, parallel study with a 3-year follow up. AM HEART J 1991;121:280-5. 32. 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. 33. Frick MH, Elo 0, Haapa K, et al. Helsinki Heart Study: pri-

study

mary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237-45. 34. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationships of reduction in coronary heart disease to cholesterol lowering. JAMA 1984;251:365-75.

An open, noncomparative study of doxazosin in essential hypertension: Experience in general practice in the Netherlands The antihypertensive efficacy, safety, and lipid effects of doxarosin, a selective al-inhibitor, were assessed in a general practice setting. Three hundred twenty-six patients were entered into the study, which involved three phases: (1) a P-week baseline period, (2) an 8-week period in which patients received 1 to 8 mg of doxazosin once daily, and (3) a 4-week maintenance period. After 12 weeks, 78.8% of efficacy-evaluabie patients were considered therapy successes (sitting diastolic blood pressure either 190 mm Hg with 25 mm Hg reduction from baseline or 210 mm Hg reduction from baseline). The mean daily dose in patients considered a therapy success was 2.8 mg. By the final visit, sitting systolic/diastolic blood pressures of these patients were reduced by 16.4113.5 mm Hg from a mean baseline of 1701106 mm Hg. The investigators’ global assessment of efficacy of once-daily doxazosin therapy was excellent or good for 70% of patients. Of the 326 patients, 30.7% reported a total of 160 side effects; 78% of the side effects were mild or moderate in severity, and 24 patients (7.4%) discontinued treatment because of adverse experiences. The investigators’ global assessment of toleration was excellent or good for 67% of patients. Doxazosin produced a significant decrease in total cholesterol (p = 0.02) and triglyceride (p < 0.001) levels. From baseline to final visit there was also a highly significant reduction of 17% (p < 0.001) in calculated risk score for coronary heart disease on the basis of the Framingham Heart Study risk equation. (AM HEART J 1990;121:273-9.)

Frederick

B. Naber, MD Heemskerk,

The Netherlands

Today it is well known that hypertension, elevated serum cholesterol levels, and smoking are three major risk factors for coronary heart disease (CHD). When these risk factors are present simultaneously, the risk of CHD is increased markedly.ry2 A large number of “healthy” people are affected by these risk factors and are frequently unaware of some of them. In the Netherlands, most newly diagnosed patients with hypertension and elevated serum cholesterol levels are detected and treated by the general practitioner. In earlier days antihypertensive drugs were Reprint requests: Frederick B. Naber, MD, J. van Kuikweg 203, 1962 WD Heemskerk, The Netherlands. 410124879

selected on the basis of efficacy, safety, and toleration. However, several large-scale studies have failed to show that a reduction in blood pressure results in a reduction in the incidence of CHD.3-5 It has been suggested that the adverse effects of the antihypertensive drugs on serum lipid levels may abolish the beneficial effects of blood pressure reduction.6 Doxazosin, a new compound of the quinazoline class, is a selective postsynaptic, cyi-adrenergic receptor inhibitor.7 Doxazosin lowers blood pressure by reducing the peripheral vascular resistance without causing reflex tachycardia.8 Stroke volume and cardiac output are maintained at rest and during exercise. Well-controlled clinical studies indicate that doxazosin, administered as a single daily dose, pro273

274

Naber

Am&can

Table 1. Age, sex, and weight population

distributions

(yr)

20-35 36-50 51-60 61-70 71-75 >75 TOTAL Mean age (yr) SEM Minimum age Maximum age Mean weight (kg) SEM Minimum weight Maximum weight SEM,

Men

13 53 60 40 4 1 171 52.7 0.9 21 78 85.2 0.8 62.0 126.5

Table

II. Duration

of hypertension

on entry No.

No. Age interual

of the study

of patients Women

Total

3 42 40 54 8

16 95 100 94 12

- 8

- 9

155

57.5

1.0 29 92 73.5 1.0 50.0 120.0

326 55.0 0.7 21 92 79.7 0.7 50.0 126.5

Standard error of the mean

vides control of hypertension and has a beneficial effect on serum lipids.g The objective of this study was to assess the safety and efficacy of doxazosin in the treatment of essential hypertension in general practice. The study was also designed to determine the effect of doxazosin on the composition of serum lipids and the change in calculated CHD risk based on the Framingham Heart Study equation. The article summarizes data received to date on 326 of an expected 400 patients in The Netherlands and is part of a multicountry study, ultimately covering several thousand patients. METHODS Patient selection. Patients (n = 326) were enrolled throughout the Netherlands by 95 general practitioners. Eligible patients had an established diagnosis of essential hypertension, which was defined as a sitting diastolic blood pressure (DBP) of 95 mm Hg or greater without antihypertensive medication. Previously untreated and treated patients were included. Excluded from the study were patients with malignant or secondary hypertension, those with drug reactions or sensitivity to a-inhibitors in general and quinazolines in particular, patients with orthostatic hypotension, and patients with other medical conditions that could interfere with completion of the study. Also excluded were pregnant or nursing women; women were advised not to use oral contraceptives and to avoid pregnancy within 6 months after study entry. Study design. After an optional 2-week baseline, run-in phase, which was used to discontinue any existing antihypertensive treatment and to establish the baseline boood pressure, patients were treated with doxazosin for 10 weeks. If possible, patients were evaluated at the end of

Patients entered into study Duration category
January1991 tieart Journal

to the study

of patients 326 44 87 61 68 66 6.0 0.04-30

weeks 1 and 2 during the run-in phase. To continue in the study, the mean sitting DBP had to be 295 mm Hg, with no greater than a 10 mm Hg difference between the two baseline values. A third baseline week was allowed if the sitting DBP had not stabilized. If there was no run-in period, the initial screening visit was considered baseline. Patients eligible for continuation in the IO-week dose adjustment/maintenance phase received a starting dose of 1 mg/day of doxazosin, which could be increased at intervals of 1 or 2 weeks until one of the following conditions occurred: (1) a sitting DBP of 190 mm Hg was reached, (2) the maximum daily dose of 8 mg had been taken for 2 consecutive weeks, or (3) significant side effects precluded a further increase in dose. The defined dose-adjustment schedule was 1,2,4, and 8 mg once daily; decrease to a lower level was permitted, as necessary, if signs or symptoms of adverse experiences were evident. Once dose adjustment was complete in the three conditions specified above, subsequent visits were scheduled at 4-week intervals. If sitting DBP remained >90 mm Hg and the patient had received the maximum dose or maximum tolerated dose of doxazosin, additional antihypertensive therapy could be administered for the remainder of the study while maintaining a constant dose of doxazosin. Assessments. Blood pressure and heart rate were measured between 2 and 12 hours after dosing at each review visit. Blood pressure was measured after the patient had sat for 5 minutes and was the mean of two consecutive readings. No more than a 2 mm Hg approximation was allowed at each determination. Heart rate was determined immediately before blood pressure measurements. Patients were questioned regarding their medical history at the initial visit, and a history of left ventricular hypertrophy or glucose intolerance was recorded. Cigarette smoking habits were also noted. Patients were weighed at each visit and questioned regarding their estimation of drug compliance. Blood samples for measuring total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were taken after at least 8 hours fasting, at the last baseline visit, and at the final visit. Blood samples at the final visit were drawn no later than 24 hours after the termination of doxazosin treatment. Routine laboratory tests were carried out

Volume 121 Number 1, Part 2

Netherlands

Table III. Baseline severity of hypertension sitting DBP Severity Normal (590 mm Hg) Mild (91 to 94 mm Hg) (95 to 104 mm Hg) Moderate (105 to 114 mm Hg) Severe (115 to 129 mm Hg) Gross (2130 mm Hg) TOTAL

based on

4 0 139 136 41 6 326

The 326 adults treated with doxazosin consisted of 171 men (52.5%) and 155 women (47.5 % ), with a mean age of 55 years (range, 21 to 92

study

No. of patients

Type Circulatory Digestive Genitourinary Nervous system/sense organs Respiratory Skin/subcutaneous tissue Endocrine/metabolic, immunologic Infectious/parasitic Injury and poisoning Mental Musculoskeletal/connective tissue Neoplasms Other conditions Symptoms/signs/ill-defined conditions No. of patients with at least one concurrent illness

Table

275

IV. Summary of concurrent illnesses

No. of patients

only when clinically indicated. If patients demonstrated clinically significant abnormalities or changes, they were monitored until the condition returned to prestudy status or resolution of the problem was achieved. All side effects were recorded, such as onset date, duration, severity (mild, moderate, or severe), relation to doxazosin (yes, no, or uncertain/unknown), and outcome. Any information about concomitant illnesses and medication was recorded, including diagnosis, dates of onset, and remission, as well as the name (trade and generic), dosage, dates, and reasons for all medications whether or not they were physician prescribed. At the end of the doxazosin treatment period, an overall evaluation of efficacy and toleration was made by the investigator using a rating of excellent, good, fair, or poor. Analysis of data. Mean changes in blood pressure, heart rate, and serum lipid levels were calculated, and paired t tests (two-tailed, significance level 5%) were used to evaluate the significance of these changes. Qualitative changes in a patient’s blood pressure were categorized as follows: “control” (i.e., reduction in sitting DBP to 190 mm Hg), those patients not achieving “control” but demonstrating a reduction from baseline DBP of ~10 mm Hg, and failures (all other patients). Patients in the first two categories were regarded as therapy successes. The Framingham Heart Study risk equation was used to calculate the probability of developing CHD in 10 years.1° To include the maximum number of patients in the analysis, the following modifications to the specified ranges were made: (1) Ages within 5 years of 30 and 70 years were given an assumed value of the respective lower and upper limit; (2) the appropriate upper or lower limit was substituted for cholesterol, HDL, and blood pressure values that were outside the recommended ranges; and (3) if data were unavailable, smoking, left ventricular hypertrophy, and glucose intolerance were assumed to be absent. Each patient’s risk score was determined at baseline and final visit. Changes from baseline were assessed by applying a log-odds transformation followed by a within-group t test. RESULTS Demographics.

Table

general practice

19 16 3 5 26 2 38 4 3 9 19 2 7 21 112

V. Summary of concomitant medications No. of patients Tw

Antihistamines Antiasthma Antiinfectives Autonomies Anticoagulants Cardiovascular Central nervous system Electrolytic, caloric, and water

At entry 2 5 5 6 2 35 17 21

Started during study 1

4 1 1

balance Expectorants Gastrointestinal Hormones and synthetic substitutes Musculoskeletal Skin and mucous membrane Spasmolytic agents Unclassified Patients evaluated for concomitant medication

4 8 13 10 4 5 5 326

1 1 1

326

years). The age, sex, and weight distributions are given in Table I. The mean duration of hypertension was 6 years in the 260 patients for whom this information was available (Table II). At baseline 139 patients (42.6%) had mild hypertension (sitting DBP 95 to 104 mm Hg), 136 (41.7%) had moderate hypertension (105 to 114 mm Hg), and 41 (12.6%) had severe hypertension (115 to 129 mm Hg); Table III provides more details. One third of all patients underwent a predoxazosin run-in period of at least 3 days from the ini-

276

Naber

Table

VI. Study completion status

American

Completion

sratus

Normal completion Withdrawal before completion Lost to follow-up Patient request Hospitalization Poor compliance Inadequate efficacy Other therapy indicated Adverse event Death, not study drug related Relocation TOTAL *Whether

Table

or not considered

1 (0.3) 2 4 8 6 4 27 1 1 326

(0.6) (1.2) (2.5) (1.8) (1.2) (8.3)* (0.3) (0.3) (100)

drug related.

VII. Efficacy outcome of evaluable patients

Patients evaluable for efficacy Therapy successes Control achieved 210 mm Hg reduction Therapy failures Inadequate response at maximum Not titrated to maximum dose For any apparent reason Patient request Hospitalization Poor compliance Other therapy indicated Limited by side effects* *Includes

272 (83.4)

patients

with dose reduced

316 249 (78.8 % ) 198 (62.7%) 51 (16.1%) 67 (21.2%) dose

10 (3.2%‘) 35 (11.1%) 2 (0.6%) 3 (0.9 5%) 4 (1.3%) 1(0.3%) 12 (3.8%)

because

of side effects.

tial screening visit; most patients (68%) received their first dose of doxazosin on or within 2 days of the initial visit. There were 105 (32.2%) previously untreated patients and 213 (65.3%) who were taken off existing antihypertensive therapy before the initiation of doxazosin; only eight patients (2.5 % ) continued to receive prior medication. At least one concurrent illness was present in 112 (34.4%) patients; these were mainly endocrine and metabolic disorders and diseases of the respiratory, circulatory, digestive, and musculoskeletal systems (Table IV). Concomitant medications were taken by 108 patients (33.1%) entering the study, and 9 patients (2.8 % ) started taking concomitant medications during the study (Table V). Fifty-four patients withdrew prematurely from the study for the reasons summarized in Table VI. Early termination did not exclude patients from inclusion in the analysis of efficacy. Antihypertensive efficacy. Of the 326 patients entering the study, 316 were evaluable for efficacy; 10 were not included because of inadequate or no data

January 1991 Heart Journal

(six patients) or because baseline blood pressure was too low (four patients). The mean final dose of doxazosin in patients whose efficacy was evaluable was 2.8 mglday; 295 of 326 patients (90.5% ) received a final daily dose of 14 mg. The mean duration of therapy in efficacy-evaluable patients was 88.4 days (range, 5 to 445 days). Treatment with doxazosin reduced the sitting blood pressure from 170/106 mm Hg to 154/92 mm Hg, a reduction of 16.4/13.5 mm Hg. Changes from baseline at all visits were statistically significant (p < 0.05). There was virtually no change in heart rate throughout the treatment period (Fig. 1). Overall response in terms of therapy success or failure is summarized in Table VII. Two hundred forty-nine patients (78.8%) were considered a therapy success; 198 (62.7 % ) had a final sitting DBP 590 mm Hg (“controlled”), and 51 (16.1% ) had a reduction from baseline of at least 10 mm Hg. There were 67 therapy failures (21.2 % ), but only 10 of these were adjusted to the maximum dose (8 mg/day); for 35 of 67 patients, the investigators gave no reason for failure to achieve maximum dose adjustment. Table VIII illustrates the association between prestudy drug efficacy and the efficacy outcome with doxazosin. Two hundred twenty-one patients had received prior treatment with antihypertensive agents; 216 were evaluable for this efficacy assessment. Of the 83 patients whose response to previous treatment was “none” or “slight”, 63 (75.9 % ) were a therapeutic success on doxazosin. Changes in the hypertension severity category from baseline to final visit are shown in Table IX. Of the 136 patients with moderate hypertension at baseline, 91 (66.9%) were “controlled” with doxazosin therapy, 27 (19.9%) became mild hypertensives, in 14 (10.3 %) the severity of hypertension category was unchanged, and in 4 (2.9 % ) the severity of hypertension increased. In total, 251 patients (79.4%) demonstrated an improvement in the severity category of their hypertension. Lipid analysis. Serum lipid profiles were available for approximately 250 patients. Patients were excluded from the analyses because of concomitant hypolipemic drug therapy, absence of baseline and/or follow-up values, or if blood samples were taken outside the defined time period. At baseline, 91.3% of patients had levels of total cholesterol >200 mg/dl (5.18 mmol/L), and 70.9% of patients had levels of total cholesterol >250 mg/dl (6.48 mmol/L). After treatment with doxazosin, total serum cholesterol (p = 0.02) and triglyceride (p < 0.001) concentrations were significantly reduced from mean baseline values of 275.2 mg/dl (7.13 mmol/L) and 143.5

Volume 121 Number 1. Part 2

Netherlands

-20

4-p

/

0

2

Table

1. Mean change

VIII. Efficacy

in sitting

of doxazosin

therapy

blood pressure

relative

8

and heart

to prior

None Slight Moderate Good SUBTOTAL No previous TOTAL

Table

to previous treatment

treatment

IX. Changes

n 21 62 105 - 28 216 -100 316

in the hypertension

Controlled 9 40 54 22 125 73 198

severity

(“1) (43) (65) (52) (79) (58) (73) (63)

category

Normal Mild Moderate Severe Gross TOTAL

selwity

study

277

outcome

Reduced 4 10 19 z 35 16 51

(5)

8 12 32 4 56 11 67

(16) (16) (16)

Normal

Mild

Moderate

0 93 91 12 - 2 198

0 39 27 10 1 T I7

0 2 14 13 2 31

mg/dl(l.62 mmol/L) by 2.2 % and 8.9 % , respectively. No significant changes were observed for HDL cholesterol or the ratio of HDL/total cholesterol (Fig. 2). Calculated CHD risk. The probability of developing CHD was determined at baseline and final visit by the Framingham Heart Study risk equation. Of the 326 patients enrolled, 236 (72.4 % ) could be evaluated. As shown in Fig. 2, there was a statistically significant (p < 0.001) reduction of 17% in the lo-year

Failure

(19) (16) (18)

from baseline

Final

week

with antihypertensive

Final Baseline

12

rate after treatment

treatment

Efficacy Response antihypertensille

practice

++ 4 Therapy

Fig.

general

(%) (38) (19) (30) (14) (26) (11) (21)

with doxazosin

(n =

316).

medication Mean baseline sitting DBP (mm Hg)

Mwn

final dose (mgldayi

109.1 105.8 106.2 103.4 106.0 105.6 106.0

to final visit (efficacy-evaluable

3.8 2.8 3.1 3.2 2.7 2.4 2.8

patients)

severit) Severe 0 1 3 4 0 s

Gross

Total

0 0 1 0 1 :!

0 135 136 39 6 316

CHD risk from 24.1 to 21.1 chances per 100 as calculated from the log-odds ratio. Toleration. All 326 patients were assessed for safety; total exposure to doxazosin was 936 patient-months. As summarized in Table X, 100 patients (30.7 % ) reported 160 side effects that were possibly related to doxazosin therapy. Most side effects (78% ) were mild or moderate in severity and were tolerated or disappeared with continued treatment; 24 patients (7.4 % ) discontinued treatment because of side effects, which

278

Naber

American

January 1991 Heart Journal

NS) HDL: Total cholesterol

(n = 247, +5

1

Triglycerides p < 0.001)

(n = 250,

-20

CHD risk 1

J

(n = 236,

p < 0.001)

Fig. 2. Mean percentage change in serum lipid profile and calculated CHD risk after treatment with doxazosin. *CHD risk calculated according to the Framingham Heart Study risk equation using a log odds transformation.

X. Overall

Table

summary

of toleration

Table

Xl. Summary

of side effects

n Body

Patients studied Patient-months of drug exposure Patients with side effects* No. of side effects No. of severe side effects Patients discontinued because of side effects Patients with dose reduced *Possibly

related

to treatment

with

326 936 100 (30.7 ‘SC) 160 36 24 (7.4%)

9 (2.8%)

doxamsin.

were possibly related to the study drug, and another 9 patients (2.8 % ) had the dose of doxazosin reduced. The most common side effects were headache (7.1% ), dizziness (5.8%), and fatigue (4.6% ). Table XI provides a summary of side effects as classified by body system. Overall clinical evaluation. At the end of the study, the investigators recorded their overall impression of efficacy and toleration for all patients; the results are shown in Table XII. Of the 313 patients assessed for efficacy, 220 (70.3%) were considered to have an excellent or good response, 57 (18.2%) had a fair response, and 36 (11.5 % ) a poor response. Toleration was regarded as excellent or good in 275 of 317

No. patients

system

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

of (‘5;)

37 (11.3) 2 (0.6) 1 (0.3)

nervous system

patients (86.8%), fair in 26 patients in 16 (5.0%).

6 (1.8) 4 (1.2) 2 (0.6) 10 (3.1) 15 (4.6) 5 (1.5) 5 (1.5) 2 (0.6) 55 (16.9)

(8.2% ), and poor

DISCUSSION

The purpose of this study was to assess the safety and efficacy of doxazosin in the treatment of essential hypertension in general practice. Efficacy and toleration were good during the 12-week study period in the patients evaluated. For both previously untreated patients and those who had received antihypertensive medication, doxazosin at a mean dose of

Volume 121 Number 1, Part 2

2.8 mg once daily achieved therapeutic success. All mean blood pressures tiefe significantly (p < 0.05) reduced compared with baseline values; heart rate remained unchanged. The overall success rate, about 80%) is at least as good as that reported in the literature for various contemporary antihypertensive drugs used in this type of population. Most side effects reported were mild or moderate and of low incidence. Only 24 patients (7.4 % ) discontinued treatment because of side effects. These results, which were based on a large, representative population with varying degrees of essential hypertension, support previous data on the toleration and efficacy of doxazosin monotherapy. In treating hypertension, physicians are becoming increasingly attentive to the overall cardiovascular risk profile of their patients. In addition to the effects on blood pressure, treatment with doxazosin produced a clinically beneficial and statistically significant reduction in cholesterol and triglyceride levels. There was a significant (p < 0.001) reduction in calculated CHD risk, according to the Framingham Heart Study equation. CHD is a major cause of death and disability in many industrialized countries. A great number of studies (Framingham, l1 Multiple Risk Factor Intervention Trial [MRFIT],l and the International Prospective Primary Prevention Study [IPPPSH]*) have identified risk factors for CHD; hypertension, smoking, and elevated serum cholesterol levels (>250 mg/ dl, 6.48 mmol/L) are considered the most important. In the hypertensive population, coincidence of risk factors is by no means rare. The MRFIT study indicates that 50% of male hypertensive patients have elevated serum cholesterol levels, 35% smoke, and 21% smoke and have elevated serum cholesterol. In the present study more than 90% of hypertensive patients had baseline levels of total cholesterol >200 mg/dl(5.18 mmol/L), and more than 70% of patients had baseline levels of total cholesterol >250 mg/dl (6.48 mmol/L). The effect of combining individual risk factors is not simply additive but increases markedly the level of risk for developing CHD on the basis of the Framingham equation. Today modern management and treatment of hypertension should not adversely affect or introduce other risk factors for CHD. The favorable antihypertensive efficacy, safety, and effect on the lipid profile of once-daily doxazosin treatment indicate that dox-

Netherlands

general practice

study

279

XII. The investigators’ overall impression of efficacy and toleration

Table

No.of Parameter Efficacy*

Tolerationt

*Missing tMissing

Status Excellent Good Fair Poor Excellent Good Fair Poor

patients 74 146 57 36 141 134 26 16

(5%) (23.6) (46.6) (18.2) (11.5) (44.4) (42.3) (8.2) (5.0)

data, n = 13. data, n = 9.

azosin may be an important addition to modern antihypertensive therapy, addressing the treatment of at least two major risk factors for CHD. REFERENCES

1. Multiple Risk Factor Intervention Trial: Research Group Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA 1982;248:1465-77. 2. Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease in hypertension. In: Genest J, Koiw E, Kuchel 0, eds. Hypertension: pathophysiology and treatment. New York: McGraw-Hill, 1977:888-910. 3. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985;291:97. 4. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985;3:379-95. 5. MacMahon SW, Cutler JD, Finberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized trials. Prog Cardiovasc Dis 1986;29 (suppl 1):99-118. 6. Krone W, Nagele H. Effects of antihypertensives on plasma lipids and lipoprotein metabolism. AM HEART J 1988;116: 1729-34. 7. Alabaster VA, Davey MJ. The alpha-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21 (suppl 1):9S-17s. 8. Lund-Johansen P, Omvik P, Haughland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21 (suppl 1):45S54s. 9. Rosenthal J. Clinical experience with doxazosin in general medical practice. AM HEART J 1988:116:1748-57. 10. Levy D, Wilson PWF, Anderson KM, Castelli WP. Stratifving the patient at risk from coronary disease: new insights from the Framingham Heart Studv. AM HEART J 1990:119: 712-7. 11. Castelli WP, Anderson KM. A population at risk. Am J Med 1986;80 (suppl 2A):23-32.