Doxazosin: A study in a cohort of patients with hypertension in general practice—An interim report

Doxazosin: A study in a cohort of patients with hypertension in general practice-An interim report The objective of this study was to assess the safety and efficacy of doxarosin in a substantial cohort of hypertensive patients drawn from general practice. A total of 4027 patients entered the study, 1472 of whom (36.6%) were untreated hypertensive patients. Patients were not advised to change diet, smoking habit, or life-style during the study. Twenty-one percent were cigarette smokers, and concurrent diabetes was present in 2.3%. Baseline blood cholesterol exceeded 200 mg/dl (5.2 mmol/L) in 90% and 250 mg/dl (6.5 mmol/L) in 56% of patients. The mean decrease in blood pressure produced by doxarosin was 22/15 mm Hg after 10 weeks of therapy; there was a mean decrease in heart rate of 1 beat/min. The mean maintenance dose for all patients was 3.1 mg/day. Side effects considered related or possibly related to treatment were reported in 705 patients. Treatment was discontinued in 233 patients (5.6%) because of adverse events related or possibly related to treatment with doxazosin. Doxarosin produced a significant (p < 0.001) decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and a significant increase in high-density lipoprotein cholesterol and the ratio of high-density lipoprotein:total cholesterol. The potential reduction in lo-year coronary heart disease risk (according to the Framingham equation) was calculated to be 20.4%. (AM HEART J 1991;121:266-73.)

Christopher

G. Langdon,

MB Maidenhead,

England

Doxazosin is a highly selective inhibitor of sympathetic stimulation of postsynaptic al-adrenoreceptors. Doxazosin produces a reduction in blood pressure by decreasing peripheral vascular resistance without causing reflex tachycardia.lm3 The plasma half-life of the drug is between 1g4 and 22 hours5 and does not appear to be influenced by age6, 7 or renal dysfunction.8 Thus a single daily dose of doxazosin is sufficient to control hypertension. Controlled double-blind studies have shown that doxazosin produces a significant reduction in standing and supine blood pressure, which is maintained throughout the 24-hour dosing interval.g Hypertension is only one of a number of risk factors implicated in coronary heart disease (CHD); elevated serum cholesterol, reduced high-density lipoprotein (HDL) cholesterol, smoking, and glucose intolerance increase the risk of CHD and often coexist in the hypertensive population to produce a more than additive effect on the risk of CHD.‘O-13 Doxazosin has a potentially favorable effect on the serum From

the Symons

Reprint Frascati 4/O/24878

268

Medical

requests: Christopher Way, Maidenhead,

Centre. G. Langdon, MB, Symons Medical Berkshire SL6 4AB, England.

Centre,

5

lipid profile and has been found to reduce total plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels and to increase the levels of HDL cholesterol and the HDL:total cholesterol ratio.14 This is in contrast to some other antihypertensive agents, in particular @blockers and diuretics, which can adversely affect serum lipids.15-l8 This study was designed to evaluate the safety and efficacy of doxazosin in a substantial cohort of hypertensive patients drawn from general practice. Selection criteria were sufficiently broad to ensure that patients were representative of those seen routinely by family practitioners. This article is an interim report of the principal results in 4027 patients. METHODS Study design. The study was an open, noncomparative, multicenter evaluation of doxazosin in patients with mild or moderate hypertension (sitting diastolic blood pressure [DBP] 95 to 114 mm Hg). Patients over 18 years of age, of either sex, and with untreated or inadequately controlled hypertension, gave informed consent to participate in the study. Patients already receiving antihypertensive treatment could discontinue this at or before trial entry or could

continue to take the therapy at a constant dose and administration schedule throughout the study. The fol-

Volume 12 1 Number 1, Part 2

UK general practice

lowing criteria excluded a patient from entering into the study: malignant or secondary hypertension, risk of pregnancy, pregnancy, lactation, cerebrovascular accident or acute myocardial infarction within the past 3 months, unstable angina pectoris, known significant hepatic, renal, endocrine, gastrointestinal, or hematologic disease, orthostatic hypotension, or a previous history of intolerance to a-inhibitors. Patients were not advised to change their diet, smoking habits, or life-style during the study. There was a 2-week observation period between screening and baseline, after which patients could receive doxazosin if they still met the selection criteria. Assessments were performed at screening, baseline, and after 2,4,6, and 10 weeks of treatment with doxazosin. Initially patients received 1 mg as a single daily dose, which could be increased by doubling to a maximum of 8 mg/day of doxazosin. The dose was increased at intervals of 2 weeks until DBP was <90 mm Hg, the maximum daily dose of 8 mg was achieved, or significant side effects precluded a further increase in dose. Patients then continued the optimum dose of doxazosin until the end of the study. Patients received doxazosin either in the morning or evening as monotherapy or added to an existing antihypertensive regimen (combination therapy). Blood pressure and heart rate were assessed at 2-week intervals. Blood pressure was determined after 5 minutes of sitting, and the mean of two consecutive measurements was taken. Heart rate was recorded immediately before blood pressure was measured. All patients with at least one evaluable reading on doxazosin in addition to the baseline reading were included in the efficacy analysis. Blood pressure and heart rate readings taken within 24 hours of the last dose of doxazosin and within 7 days of the scheduled visit date were considered evaluable. The final visit was the last evaluable visit. Paired t tests were performed on the change from baseline to final visit. All adverse events at baseline and at each subsequent visit were recorded in terms of onset date, duration, severity, and whether they were considered drug related. Information about concomitant illnesses and medications was also recorded. Blood lipid measurements included total and HDL cholesterol and triglycerides; LDL cholesterol was calculated by Friedewald’s formula,ig and the ratio HDL:total cholesterol was determined. Nonfasting blood samples were taken at baseline and at the final visit. The risk score for CHD according to the Framingham Study equationzO was also calculated. Baseline blood lipid samples had to be taken on or no more than 2 weeks before the start of doxazosin to be considered evaluable, and final samples had to be after at least 28 days of doxazosin treatment and no later than 1 week after treatment was stopped. Log-odds transformation was applied to the calculated probability of developing CHD in the subsequent 10 years, and paired t tests were performed on these transformed data for the change from baseline to final measurement. RESULTS Demographic

data and baseline

tal of 4027 patients

characteristics.

from 461 practices entered

A tothe

Table

study

269

I. Baseline demographic data

No. of patients

4027

Untreated hypertensives Smokers Diabetics Total cholesterol 2200 mg/dl (5.2 mmol/L) Total cholesterol 2250 mg/dl (6.5 mmoliL) Mean duration of hypertension (yr) Mean age (yr)

1472

36.6

836

20.8 2.3

Mean weight (kg)

(1889 males, 2138 females)

92 3622

89.9

2251

55.9

4.5 (range,
study, 1472 of whom (36.6%) were untreated hypertensive patients. A total of 3687 patients (92 % ) completed the study. There were 2138 women (53%) and

1889 men (47%); 1096 patients (27%) were more than 65 years of age. The mean age of the total cohort was 58.3 years (range, 19 to 87 years), and the mean duration of hypertension was 4% years (range, 65 years old), the mean fall in blood pressure of 23/15 mm Hg

270

Langdon

American

January 1991 Heart Journal

80 l/U

160 E ki s r"

150 140 130 120 110 100 90 80

70 60 50

u

6

I

Week of treatment Systolic 01---e Fig. 1. Changes in blood pressure pressure; HR, heart rate.

‘2; 6 5v) f a x$ 75 8 5 -0 .2 -

and heart rate after treatment

with doxazosin

(n = 3943). BP, Blood

IO 9 8 7 6 5 4 3 2 1 0 Dizziness Headache

Fig.

Diastolic Heart rate

2. Side effects related

Fatigue

or possibly

related

(baseline: MO/103 mm Hg) was similar to the mean decrease of 21/14 mm Hg in those patients 165 years old. The mean daily maintenance dose was slightly lower in the older than in the younger group (2.7 mg/ day vs 3.2 mglday, respectively). Toleration. Side effects considered by the investigator to be related or possibly related to doxazosin were reported in 705 (17.5% ) patients and were a cause of discontinuation of treatment in 233 (5.8%). Toleration was good, with more than 75% of elderly and younger patients free from side effects. The incidence of the most common side effects is summarized in Fig 2. The most frequently experienced side effect was dizziness, which occurred in 234 patients (5.8% ) and

Nausea PalpitationsSomnolence Edema to treatment

with

doxazosin

(n = 4027).

was considered severe in 41 (1.0%). Other events possibly related to postural hypotension occurred in 28 patients (0.7 % ) and were classified as severe in 8 (0.2%). Headache (4.2%), fatigue (2.4%), nausea (1.7%), palpitations (1.6%), somnolence (1.4% ), and edema (1.2 % ) were also reported. Toleration in the elderly group was generally similar to that in patients 565 years old. Dizziness occurred in 150 patients (5.1% ) 565 years of age and in 84 patients (7.7%) >65 years old. Other effects possibly related to postural hypotension occurred in 18 younger (
Volume 121 Number 1, Part 2

was 258 mg/dl(6.68 mm&L). In 56% of patients this value was >250 mg/dl (6.5 mmol/L), a level considered by the British Hyperlipidaemia Association and the British Cardiac Society to require some type of intervention213 22 In 90% of patients, mean baseline plasma cholesterol exceeded 200 mg/dl(5.2 mmol/L), the level now generally considered the upper limit of normal in Western societies.22 Doxazosin affected all the lipid parameters assessed. The mean baseline and final values and the percentage changes in blood lipid variables are presented in Table II. Statistically significant decreases occurred in total cholesterol (4.1%), LDL cholesterol (4.9 % ), and triglyceride levels (8.4 % ), and there were statistically significant increases in HDL cholesterol (2.8%) and the ratio of HDL:total cholesterol (7.1%). Estimation of CHD risk (Framingham). When the changes in CHD risk factors, blood pressure, total cholesterol, and smoking habits, are considered together in the context of the Framingham equation for the calculation of CHD risk, the potential reduction in risk in the next 10 years is 20.4 % . DISCUSSION

These findings from more than 450 general practices throughout the United Kingdom and Ireland are probably representative of the performance of doxazosin in routine practice. The antihypertensive effect of doxazosin when given alone was of the order expected from controlled studies and comparable with that of other first-line agents, including angiotensin-converting enzyme inhibitors and calcium antagonists.23-25 The effect was similar when doxazosin was added to an existing antihypertensive regimen and whether it was given in the morning or evening. A reassuring finding in this large sample of hypertensive patients was the good toleration of doxazosin. Although dizziness and other events potentially related to postural hypotension have sometimes been proposed as reasons limiting the usefulness of al-inhibitors as first-line antihypertensive drugs, the results of the present study largely discount this as a problem of clinical relevance. Almost 80 % of patients reported no side effects; adverse effects were a probable cause for discontinuation of treatment in 5.8%. Dizziness was reported in 5.8% of patients and was considered severe in only 1% of patients. That doxazosin is also well tolerated in elderly subjects is important. In a large group of 1096 patients whose age exceeded 65 years old, the frequency of adverse effects overall and that of severe or postural side effects differed little from that in younger subjects. These results provide strong sup-

UK general practice

study

27 1

Table II. Blood lipid levels at baseline and after treatment with doxazosin n Cholesterol mg/dl mmol/L HDL cholesterol mg/dl mmol/L LDL cholesterol mg/dl mmol/L Triglycerides mg/dl mmol/L HDL cholesterol:total

Baseline

Final

3520

258 6.68

247 6.41

-4.06*

3474

47 1.22

48 1.25

+2.80*

3463

189 4.89

179

182 2.05 0.18

167 1.88 0.20

3506 3472

7; change

-4.9*

4.65

-8.39* +7.14*

*p < 0.001.

port for the use of doxazosin as initial antihypertensive therapy in all age groups. The characteristics of this population before treatment with doxazosin underscore the frequent coexistence of multiple CHD risk factors in hypertensive subjects in the United Kingdom and Ireland. Baseline blood cholesterol exceeded 200 mg/dl(5.2 mmoll L) in 90% and 250 mg/dl(6.5 mmol/L) in 56% of patients. In addition, 21% were smokers, and concurrent diabetes was present in 2.3 % . Thus at least two CHD risk factors were present in at least 56 % of this cohort of hypertensive subjects and in 90% or more if the upper limit for normal blood cholesterol in a Western society is accepted as 200 mgldl(5.2 mmol/ L).21* 22 These results should be considered together with those of another British study,26 in which 35% of subjects were smokers and 70 % had elevated total serum cholesterol levels. If the figure of 70% to 90% is representative of the hypertensive population in the United Kingdom and Ireland, this has a significant impact on the choice of antihypertensive agent. Blood lipid levels were measured on nonfasting blood samples, which are widely considered acceptable for assay of total cholesterol. Although a fasting blood sample is considered preferable and more accurate for the measurement of HDL cholesterol and triglycerides in an individual subject, it has been shown on a number of occasions and in two recent large British studies 27,28 that there is not significant loss of accuracy when measurements are performed on nonfasting samples in large groups of subjects. Thus the lipid profile of populations such as that in the present study can be observed with sufficient accuracy in nonfasting blood samples. There were modest but statistically significant

272

Langdon

American

changes in blood lipid levels after treatment with doxazosin; total and LDL cholesterol were reduced by 4.1% and 4.9 % , respectively, HDL cholesterol was increased by 2.8%) and the ratio HDL:total cholesterol by 7.2%. Plasma triglyceride levels decreased by 8.4 % . Because these potentially beneficial changes are in accordance with those described in placebocontrolled studies2g, 3o and in comparative trials,31s 32 they were probably attributable to doxazosin rather than any other factor. Patients had been advised not to change their diet, smoking habits, or life-style during the study. It is interesting that the baseline lipid values observed in this study were similar to those reported in the Helsinki Heart Study.33 In both this study and the Lipid Research Clinics study,34 positive lipid changes were shown to have a significant association with a decline in CHD incidence. The clinical significance of the lipid changes induced by doxazosin in this study remains uncertain. However, it is possible to consider them, together with changes in blood pressure and smoking habit, in the context of the Framingham equation for the calculation of CHD risk.20 If these changes were maintained, potential reduction in risk over the next 10 years would be 20.4%. Thanks are due to the many in this study and Keal-Newley ganization and monitoring.

general practitioners who took Evaluations for their efficient

part or-

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

REFERENCES

W, Caxton CAPD, Hernandez J, Prichard BNC. 1. Singleton Postjunctional selectivity of alpha-blockade with prazosin, trimazosin and UK-33,274 in men. J Cardiovasc Pharmacol 1982;4:S145-s51. VA, Davey MJ. The alpha-adrenoceptor antagonist 2. Alabaster profile of doxazosin: pre-clinical pharmacology. Br J Clin Pharmacol 1986;21:98-179. PBMWM, Kwa HY, Karamat Ali F, van 3. Timmermans Zwieten PA. Prazosin and its analogues UK-18,596 and UK33,274: a comparative study on cardiovascular effects and alpha-adrenoceptor blocking activities. Arch Int Pharmacodyn Ther 1980;245:218-35. LX, Fuenmayor N, Caplan N, Ferry D. Clinical 4. Cubeddu pharmacology of doxazosin in patients with essential hypertension. Clin Pharmacol Ther 1987;41:439-49. HL, Meredith PA, Reid JL. Pharmacokinetic overview 5. Elliott 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;21:278-318. Vincent J, Elliott HL, Meredith PA, Reid JL. The pharmacokinetics of doxazosin in elderly normotensives. Br J Clin Pharmacol 1986;21:521-4. Carlsson RV, Bailey RR, Begg EJ, Cowlishaw MG, Sharman JR. Pharmacokinetics and effect on blood pressure of doxazosin in normal subjects and patients with renal failure. Clin Pharmacol Ther 1986;40:561-6. Smyth P, Pringle S, Jackson G, Lorimer AR. 24-hour control of blood pressure by once daily doxazosin: a multicentre dou-

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January 1991 Heart Journal

ble-blind comparison with placebo. Eur J Clin Pharmacol 1988;34:613-8. Modan M, Hackin H, Almog S, et al. Hyperinsulinemia, a link between hypertension, obesity and insulin intolerance. J Clin Invest 1985;75:809-17. Eto T, Tsutsu N, Abe I, et al. Glucose intolerance in middleaged Japanese males with uncomplicated hypertension. J Clin Epidemiol 1988;41:835-41. Zavaroni I, Dall’Aglio E, Bonora E, et al. Evidence that multiple risk factors for coronary artery disease exist in persons with abnormal glucose tolerance. Am J Med 1987:83:609-12. Shaper AG, Pocock SJ, Walker M, Phillips AN, Whitehead TP, Macfarlane PW. Risk factors for ischaemic heart disease: the prospective phase of the British Regional Heart Study. J Epidemiol Comm Health 1985;39:197-209. Cox DA, Leader JP, Milson JA, Singleton W. The antihypertensive effects of doxazosin: a clinical overview. Br J Clin Pharmacol 1986;21:838-908. Levy RI, Leren P. Selection of initial antihypertensive therapy: new perspectives on coronary heart disease. Risk factors provide new insights. Am J Med 1985;8O(suppl 2A):l-125. Pool JL. Plasma lipid lowering effects of doxazosin, a new selective alpha1 adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G. Frick MH. Cox DA. Himanen P. et al. Serum livid 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. Leren P. Comparison of effects on lipid metabolism of antihypertensive drugs with alpha- and beta-adrenergic antagonist properties. Am J Med 1987;82(suppl lA):31-5. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502. 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. Shepherd J, Betteridge DJ, Durrington P, et al. Strategies for reducing coronary heart disease and desirable limits for blood lipid concentrations: guidelines of the British Hyperlipidaemia Association. Br Med J 1987:295:1245-6. British Cardiac Society Working Group on Coronary Prevention. Conclusions and recommendations. Br Heart J 1987; 57:188-g. Young RA, Brogden RN. Doxazosin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in mild or moderate hypertension. Drugs 1988:35:52541. Nechwatal W, Berger J, Blumrich W, et al. A double-blind comparative study of doxazosin and nitrendipine in patients with mild-to-moderate essential hypertension. AM HEART J 1988;116:1806-14. Taylor SH, Lee PS, Sharma SK. A comparison of doxazosin and enalapril in the treatment of mild and moderate essential hypertension. AM HEART J 1988;116:1820-5. Poulter N. Management of multiple risk factors for coronary heart disease in patients with hypertension. AM HEART J 1991;121:246-50. Thelle DS, Shaper AG, Whitehood TP, et al. Blood lipids in middle-aged British men. Br Heart J 1983;49:205-13. Mann JI, Lewis B, Shepherd J, et al. Blood lipid concentrations and other cardiovascular risk factors: distribution, prevalence, and detection in Britain. Br Med J 1988;296:1702-6. Cubeddu LX, Pool JL, Bloomfield R, et al. Effect of doxazosin monotherapy on blood pressure and plasma lipids in patients with essential hypertension. Am J Hypertens 1988;1:158-67. Pool JL, Leuz ML, Taylor AA. q-Adrenoreceptor blockade and the molecular basis of lipid metabolism alterations. AM HEART J 1991;121:251-60. Talseth T. Doxazosin and atenolol as monotherapy in mild and

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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-

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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