doxazosin and atenolol as monotherapy in mild and moderate hypertension: a randomized, parallel...

Doxazosin and atenolol as monotherapy in mild and moderate hypertension: A randomized, parallel study with a three-year follow-up.

The efficacy and safety of doxarosin (n = 83) and atenolol (n = 81) have been compared during a 3-year period. Doxarosin (mean dose at 3 years, 5.2 mg/day) and atenolol (mean dose, 66.4 mg/day) produced a sustained and overall similar reduction in blood pressure, with no evidence of tolerance. Doxazosin decreased mean blood pressure from 158/104 mm Hg to 146190 mm Hg; with atenolol the decrease was from 160/103 mm Hg to 144/88 mm Hg. Whereas the reduction in blood pressure with atenolol was paralleled by a significant (p < 0.05) decrease in heart rate (from a mean of 74 to 60 beatslmin), doxazosin produced no clinically meaningful changes in heart rate. In contrast to atenolol, doxarosin reduced triglyceride levels by -5.9% (atenolol +22.5%), increased high-density lipoprotein cholesterol levels by +3.7% (atenolol, -11.2%), and increased the high-density lipoprotein/total cholesterol ratio by +5.9% (atenolol, -10.3%); all of these values were significantly (p <O.OOl) different from those of atenolol-treated patients. Doxazosin also reduced the calculated low-density lipoprotein cholesterol levels by -3.3% (atenolol, unchanged). The adverse effect of atenolol on lipid levels apparently negated any beneficial effect of blood pressure reduction, because the calculated coronary heart disease (CHD) risk actually increased significantly. In contrast, the reduction in calculated CHD risk in the doxarosin group was statistically significant at all points during the study. The safety profile of the drugs was similar. With the added potential of the reduction in the calculated risk of CHD among hypertensive patients, doxazosin represents an appropriate first-line drug for the treatment of essential hypertension. (AM HEART J 1991;121:280-5.)

Tore Talseth, MD, Lam Westlie, MD, and Ludwig Daae, MD OsEo, Norway

Atherosclerosis and coronary heart disease (CHD) are major risks associated with hypertension. Con- cern has been raised over the metabolic effects observed during long-term use of some antihyper- tensive drugs. Even though the initial choice of anti- hypertensive medication remains a controversial is- sue, selective q-inhibitors emerge as an attractive class of drugs because of their favorable effect on the serum lipid profile1 and their beneficial hemody- namic effects.2 Doxazosin, the most recently intro- duced q-inhibitor, has favorable kinetic properties, allowing once-daily administration.3

Results from 1-4 and 2-year follow-up5 of a long- term comparison of doxazosin and atenolol mono- therapy have been reported previously. This report concerns the data at the 3-year follow-up in those 164 patients with mild or moderate hypertension who entered the third year of the study.

From the Department of Medicine, National Hospital, Central Hospital of

dstfold. Fredrikstad, Ullev& University Hospital. Reprint requests: Tore Talseth, MD, Nycomed Pharma A/S. P.O. Box 4284 Torshov, 0401 Oslo, Norway.

410/24896

METHODS

Newly diagnosed or previously treated patients of either sex, between the ages of 18 and 70 years, were included after their consent was obtained. Hypertension was defined as sitting diastolic blood pressure (DBP) in the ranges of 90 to 105 mm Hg (18 to 29 years), 95 to 110 mm Hg (30 to 49 years), 98 to 114 mm Hg (50 to 59 years), and 102 to 118 mm Hg (60 to 70 years). The protocol excluded patients with secondary or refractory hypertension, hepatic or hematologic disease, or other conditions prohibiting the use of adrenergic inhibitors. Pa- tients who had had a myocardial infarction during the 6 months before the study or a cerebrovascular accident within less than 1 year of entry into the study were also excluded.

Study design. The study consisted of two main parts: a l-year double-blind parallel study, in which the patients were randomly assigned to treatment with either doxazosin or atenolol, and a 2-year open- label extension study of patients who completed the first year and were invited to continue.

The first-year study consisted of a washout phase,

280

Volume 121 Number 1, Part 2 Comparison of doxazosin and atenolol 28 1

Table I. Progression of patients throughout the 3 years of study

Treatment

Study period Doxazosin Atenolol

Year 1 (initial study) No. of patients entered No. of patients completing study

Year 2 (first-year extension study) No. of patients eligible for entry No. of patients entered

Year 3 (second-year extension study) No. of patients eligible for entry No. of patients entered

111 117 100 104

100 104 93 88

88 83 83 81

a single-blind placebo phase, a dose-adjustment phase, and a maintenance phase, as have been described previously.4 Baseline measurements were made during the placebo phase.

A total of 228 patients entered the double-blind phase, achieving eligibility after the placebo phase. One hundred eleven patients received doxazosin (mean age, 51.2 f 1.0 years; body weight, 78.0 * 1.4 kg; and duration of hypertension, 6.3 years). One hundred seventeen patients received atenolol (mean age, 52.6 f 0.9 years; body weight, 78.8 -t 1.1 kg; and duration of hypertension, 5.7 years). The trial was conducted by 41 general practitioners in Norway, with an average number of six patients in each cen- ter. Patients were randomized to treatment accord- ing to a computer-generated code. Tablets were given according to a double-blind double-dummy design during the first year, and the extension study was of an open design.

Both drugs were administered once daily. Dosage adjustment occurred at 2-week intervals and was based on blood pressure measurements taken ap- proximately 3 to 8 hours after the morning dose. The dose of doxazosin could be increased sequentially from 1 mglday to 2, 4, 8, or 16 mglday. Doses of atenolol could be adjusted from 50 mglday at end of the sixth week of adjustment to 100 mg/day for the duration of the study. Dose adjustment continued until one of the following occurred: (1) blood pressure control was achieved (sitting DBP of 190 mm Hg with at least 5 mm Hg reduction from baseline or, if baseline DBP had been 90 to 104 mm Hg, at least a 10 mm Hg reduction; (2) a maximum daily dose of 16 mg doxazosin or 100 mg atenolol had been adminis- tered for 2 consecutive weeks; or (3) clinically signif- icant adverse effects precluded a further increase in dosage. Patients receiving the maximum tolerated dose for whom a decrease of 15 mm Hg from base-

Table II. Patient demographics

Donazosin Atenolol (n = 83) (n = 81)

Mean age (yr) SEM

Mean weight (kg) SEM

Mean duration of hypertension (yr)

Male/female (n)

50.7 e52.1 1.2 1.0

78.6 79.1 1.6 1.4 6.6 6.6

52131 41/40

Table Ill. Summary of concomitant medications present on entry to the second year of the extension phase

Category Doxazosin Antenolol

fn) (4

Antihistamines Antiinfectives Autonomies Central nervous system Hormones and synthetic substitutes Musculoskeletal Unclassified therapeutic agents Patients evaluated for concomitant

medication Patients with concomitant

medication Total concomitant

medications

1 0 1 0 1 0 5 6 2 3 3 1 1 0

83 81

11

17

10

11

line had not-been achieved were considered to be treatment failures and were withdrawn from the study.

The 3 years of clinical study visits began with weekly visits (4 weeks) to establish baseline. Visits were then scheduled at 2-week intervals (for 14 weeks) during the dose-adjustment phase and the first visit of the maintenance phase. This was fol- lowed by sequential visits at 4- (for 16 weeks) and 8- week (for another 16 weeks) intervals for the remain- der of the maintenance phase. On entry into the extension study, visits were scheduled at 3- (for the first 12 months) and 6-month (for the second 12 months) intervals (total of 36 months).

Of the 117 patients given atenolol, 104 completed the first year of the study and were invited to enter the 2-year open-extension study; 88 accepted and were included in the first year. Of the 83 patients el- igible for the second year of the extension, 81 accepted. Of the 111 patients treated with doxazosin, 100 completed the first year and were invited to par- ticipate in the extension phase; 93 accepted. Of the 88 patients eligible for the second year of the extension

January 1991 282 Talseth, Westlie, and Daae American Heart Journal

40 , I I I 0 6 12 18 24 30 36

Treatment period (months)

Fig. 1. Sitting blood pressure and heart rate values dur- ing 3 years of treatment with doxazosin (C----O) or atenolol (O---O). All reductions in blood pressure were statistically significant (p < 0.05) from baseline.

160 1 Systolic

-4 - --- 0

: ‘, 2 60

o~---o---~---~---o--~.-o

40

I I , 1 I 0 6 12 18 24 30 36

Treatment period (months)

Fig. 2. Standing blood pressure and heart rate values during 3 years of treatment with doxazosin (CA) or atenolol (O---O). All reductions in blood pressure were statistically significant (p < 0.05) from baseline.

study, 83 accepted (Table I). The results from the first year of the open-extension phase have been re- ported separately.5 Demographic data on the study population entering the second year of the open-ex- tension phase are given in Table II.

Patient profile. Of the 83 patients taking doxazosin and 81 patients taking atenolol entering into the sec- ond year of the extension phase, 13 (15.7%) taking doxazosin and 17 (21.0%) taking atenolol had one or more concurrent illnesses. Eleven (13.3 % ) patients in the doxazosin group were taking a total of 17 con- comitant medications; 10 (12.3 % ) patients in the atenolol group were taking a total of 11 concomitant

medications (Table III). Seven patients (n = 4 dox- azosin; n = 3 atenolol) began taking concomitant antihypertensive therapy and were considered in- evaluable for efficacy at subsequent visits.

Blood pressure measurements. At each visit throughout the study, sitting and standing blood pressure measurements and heart rates were re- corded. Duplicate measurements were taken after the patient had been in the sitting position for 5 minutes and after 2 minutes standing. Body weight was also recorded at each visit.

Assessment of side effects. At each follow-up visit, including those during the placebo phase, all volun- teered and observed side effects were recorded by type, onset, and degree of severity. At intervals, pa- tients were also obliged to complete a questionaire detailing side effects that were considered relevant to the use of adrenergic inhibitors.

Laboratory analyses. Standard laboratory tests were performed at entry into the trial, at weeks 30 and 50 of the double-blind phase, and at months 18, 24, and 36 of the extension phase. Hematology, liver, and renal function were assessed. In addition, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were measured in the fasting state. Low-density lipoprotein (LDL) cholesterol levels were calculated according to De- long et a1.6

CHD risk analysis. The Framingham risk equation” was used to calculate the probability of developing CHD in 6 years. The risk score for each patient was computed at baseline, at 30 and 50 weeks of the dou- ble-blind phase, and again after 24 and 36 months of the extension phase.

Statistical methods. Differences between the two treatment groups were evaluated by Student t tests or x2 analysis. Changes from baseline were assessed by paired t tests. Lipid parameters were logarith- mically transformed before applying within- and be- tween-group t tests.

RESULTS

Effect on blood pressure. Doxazosin and atenolol significantly reduced blood pressure in the sitting and standing positions (Figs. 1 and 2). The ef- fect on blood pressure was sustained for both drugs, with a final mean change at 3 years of -151-15 mm Hg (sitting) for atenolol and -14/-14 mm Hg for doxazosin. The mean final daily doses for doxazosin and atenolol were 5.2 mg and 66.4 mg, respectively. In the doxazosin group 76.3% of patients were clas- sified as a therapeutic success at a mean daily dose of 4.8 mg, compared with 84.0% taking 62.9 mg/day atenolol; in 58.8% of the patients blood pressure

Volume 121 Number 1, Part 2 Comparison of doxazosin and atenolol 283

Table IV. Mean percent change in serum lipid levels during a 3-year period

Baseline concentration Menn 5% change from baseline

Lipid fraction mgldl mmol/L 1 (Yr) 2 W-1 3 (Yr)

Doxazosin Total cholesterol Triglycerides HDL cholesterol LDL cholesterol HDL/total cholesterol

Atenolol Total cholesterol Triglycerides HDL cholesterol LDL cholesterol HDL/total cholesterol

253.2 117.0

53.3 184.9

0.21

255.1 124.0

55.2 185.7

0.22

6.56 1.32

1.38 4.79

6.61 1.40 1.43 4.81

*Between-group significance, p < 0.001. tBetween-group significance, p < 0.0001. fWithin-group significance, p < 0.05.

normalized with doxazosin (sitting DBP 190 mm Hg with 5 mm Hg reduction from baseline) compared with 64.2 % taking atenolol. Doxazosin lowered blood pressure without virtually any change in heart rate (mean changes, -1 to +2 beats/min). In contrast, atenolol caused a significant (p < 0.05) reduction in heart rate, averaging -13 to -15 beats/min. Fluid retention was not observed clinically, and the weight gain was similar in both treatment groups (+1.31 kg with doxazosin and $1.17 kg with atenolol).

Effect on blood lipid levels. Doxazosin and atenolol did not produce any significant changes in total cho- lesterol or calculated LDL levels, although both were lowered in the doxazosin group at 3 years (Table IV). Atenolol produced a significant and sustained in- crease in triglyceride levels during the entire study period, attaining 22.5% at 3 years (p < 0.05, signifi- cantly different from baseline). At all points of mea- surement during the study atenolol also decreased HDL cholesterol levels from baseline, reaching an 11.2% decrease at the final visit (p < 0.05, signifi- cantly different from baseline). Doxazosin had the opposite effect of atenolol, increasing HDL choles- terol by 3.7 % (p < 0.0001, significant between-group difference) and lowering triglyceride levels by 5.9% (p < 0.001, significant between-group difference) at 3 years.

As a consequence of these lipid effects, the drugs changed the HDL/total cholesterol ratio in opposite directions. This ratio increased by 5.9% with dox- azosin (p < 0.05, significantly different from base- line) and decreased by 10.3 % with atenolol (p < 0.05, significantly different from baseline; p < 0.0001, be- tween-group significance).

Calculation of CHD risk. The risk, expressed as per-

-0.75 +0.08 -2.07 -8.74* -6.65t -5.91* +3.27t +8.94t$ +3.74t -1.53 -2.65 -3.30 +4.12t1 +9.17* $ +5.9ot$

-0.86 -0.07 -0.81 +14.88* f +21.59tt +22.53* 1 -10.85tl -4.61tS -11.18tI

+0.75 -1.40 +0.42 -9.8ltj -3.65* -10.34t $

Table V. The calculated probability of developing CHD*

Doxazosin Atenolol

Year n Mean baseline risk (% )t Mean risk after 1 of yr

treatment (%) Mean % change Between-group difference (p)

Year n Mean baseline risk (% ) Mean risk after 2 yr

of treatment Mean % change Between-group difference (p)

Year n Mean baseline risk (010 ) Mean risk after 3 yr

of treatment Mean % change Between-group difference (p)

56 49 7.70 6.01

6.55 6.40

-22.21 +8.8

-Co.05

60 50

7.65 6.26 5.36 6.39

-30.7$ +7.4 -co.05

60 51 7.65 6.28 6.23 7.45

-15.21 +25.4?, <0.05

*According to the Framingham 6-year risk equation.7 tvariation over the years caused by slight variation in number .of patients with complete data. ISignificantly different from baseline @ < 0.05).

cent chance of developing CHD during a g-year period, was reduced significantly (p < 0.05) with doxazosin and increased significantly 0, < 0.05) with atenolol. The difference between groups was statisti- cally significant (p < 0.05) throughout the study period (Table V).

Side effects. During the 3-year treatment period, the dropout rate as a result of side effects was similar in the two treatment groups (Table VI). Adverse drug

284 Talseth, Westlie, and Daar January 1991

American Heart Journal

Table VI. Patients withdrawing from the study because of drug-related adverse reactions*

Treatment group

First year No. of patients included 111 No. withdrawn t’, ) 13 (11.7)

Second year No. of patients included 93 No. withdrawn (‘, ) 4 (4.3)

Third year No. of patients included 83 No. withdrawn till, ) 1 (1.2)

*Side efkts related or pmsibly related tu treatment.

117 17 (14.5)

88 3 (3.4)

81 6 (7.4)

Table VII. Summary of side effects related or possibly re- lated to treatment

Doxazosin Atenolol

Typp n I’; n (‘c

Cardiovascular 13 15.7 18 22.2 ’ ‘ Skin and appendages 2 2.4 2 2.5 Musculoskeletal 4 4.8 7 8.6 Central and peripheral nervous 2 2.4 3 3.7

system Antonomic 2 2.4 13 16.0 Special senses 2 2.4 $2 2.5 Psychiatric ,5 6.0 8 9.9 Gastrointestinal 7 8.4 5 6.2 Metabolic/nutritional ‘2 2.4 0 Respiratory 7 8.4 5 6.2 Urinary 2 2.4 0 Reproductive 0 6 7.4 General 18 21.7 16 19.8

reactions were reported by 38 (45.8%) of the 83 pa- tients in the doxazosin group and 49 (60.5%) of the 81 patients in the atenolol group. Syncope was not reported with doxazosin but occurred in two patients taking atenolol; palpitations were reported by three patients taking doxazosin and one patient taking atenolol. The majority of side effects were mild or moderate and were tolerated or disappeared with time. The nature of the side effects to a certain de- gree reflected the pharmacology of the drugs em- ployed, because peripheral ischemia was more fre- quent with atenolol (9.9% vs 2.4% with doxazosin) and rhinitis occurred in 6 % of doxazosin-treated pa- tients and in none of the patients treated with atenolol. The most frequently reported side effects were fatigue (12.0%) and headache (9.6%) for dox- azosin and dizziness (16.0% ) and fatigue (14.8 % ) for atenolol. A summary of the nature of the side effects is given in Table VII.

DISCUSSION

Doxazosin and atenolol produced similar and sig- nificant, sustained decreases in blood pressure. Fur- ther comparison between doxazosin and atenolol should consequently focus on safety and metabolic effects. Because neither drug caused significant ab- normalities in routine blood test results, for practical purposes safety must be assessed from the with- drawal rate and the reported or observed incidence of adverse reactions. Of the 111 patients randomized to receive doxazosin, 29.7 % were withdrawn during the 3-year follow up; with atenolol, 40.2 % of the 117 pa- tients were withdrawn. These figures are not signif- icantly different.

Withdrawals occurred for several reasons: therapy failures, adverse reactions, or discontinuation from the study at the patient’s own request. A comparison of these subgroups did not reveal significant differ- ences between the drugs. During the entire 3-year period, 16.2% of the patients taking doxazosin and 22.2% of the patients taking atenolol were discon- tinued from the study because of drug-related ad- verse events. A dropout rate of this magnitude is to be expected in any population receiving chronic an- tihypertensive treatment. The experience accumu- lated during 5 years in the Hypertension Detection and Follow-up Program8 was that withdrawals caused by definite, probable, and possible side effects amounted to 32.7%. That study employed several different classes of antihypertensive drugs. Using a diuretic and a o-blocker, the Medical Research Coun- cil Trial9 reported a withdrawal rate of 1O’C to 15’;;) during 3 years, depending on sex and the drug studied. Our study protocol called for active ques- tioning in addition to spontaneous reports of side ef- fects. This active approach may explain why 27 7; of the entire study population reported side effects during the 4-week placebo run-in phase. During the 3-year study period, more patients taking atenolol (60.5%) than doxazosin (45.870) reported one or more adverse drug reactions. The adverse drug reac- tions were mostly mild or moderate; a first-dose ef- fect, which has been reported for prazosin,“’ did not occur. Thus from an efficacy point of view, doxazosin and atenolol performed equally. For safety, dox- azosin performed insignificantly better than atenolol under the design of this study.

The contrasting effects of doxazosin and atenolol on blood lipid levels at 1” and 2 years of follow-up:’ were sustained during the third year of the study (Table II). The magnitude and direction of the changes in lipid parameters have been reported repeatedly in short-term studies employing dox- azosin and atenolol.l,’ In this study we have docu- mented that the doxazosin effect on blood lipid lev-

Volume 121 Number 1, Part 2

els persists for 3 years of treatment, making this effect relevant for the clinical setting of chronic medication for high blood pressure.

The significant inverse relationship between HDL cholesterol levels and the risk of CHD has been con- firmed in a number of prospective studies’l and is quantified by the Framingham risk equation.7 Ac- cording to this model, so much significance is put on HDL cholesterol levels that the decrease in this lipid fraction in atenolol-treated patients more than ne- gates the expected beneficial effect of blood pressure reduction on CHD risk. The clinical significance may be questioned because clinical trials have not specif- ically addressed the relevance for CHD of isolated manipulation of HDL cholesterol levels. The issue is complicated by the inverse correlation with trigly- ceride levels,12 which is a reproducible finding over time in this study. It has been argued stronglyI that selective al-inhibitors should not be regarded as ac- ceptable first-line drugs for hypertension until it has been proved that these drugs reduce mortality rates from CHD in addition to lowering the blood pressure. However, it should be noted that these criteria have not been applied to other classes of antihypertensive agents. Thus far, all individual antihypertensive drugs that have been studied prospectively have failed to demonstrate a definite reduction in CHD mortality rates. Metaanalyses have shown that the observed reduction in CHD events is only 60% of that expected. l4 Results from such studies such as the TOMHS trial15 will serve to clarify this issue.

It can be concluded that doxazosin is a very suit- able first-line antihypertensive drug, with an effi- cacy, safety, and metabolic profile that is at least comparable with that of atenolol, a widely used first- line drug in hypertension. In addition, the kinetic and dynamic profile of doxazosin3 makes it suitable for once-daily administration, which is an attractive feature in chronic medication.

We acknowledge the contribution of Pfizer A/S (Norway) for organizing the study. The following general practitioners partici- pated: L. Aaberge, A. Aarflot, 0. Andersen, J. E. Arnstad, 0. Askildt, B. Braastad, J. Batnes, A. Dehli, A. Dyrstad, J. Fauske, D. H. Fjellestad. T. E. Franer, R. Gilhuus, T. Hansen, A. B. Hauge, T. 0. W. Hillestad, E. A. Hornback, T. Hotnes, L. Hov, 8. Imsen, I. J. Johansen. J. E. Johnson, T. J$ranli, 0. Mordal, J. Klepper, P. Kristiansen, L. Kvan, T. Lenngren, B. Lorentzen, B. Lovland, C. W. Lundbo, T. Mdrk, H. Onsum, C. Ringnes, S. Rdnsen, H. K. Sveaas, J. 0. Syvertsen, P. 0. S. Tdssebro, I. Udnaes, and H. Wahl.

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Comparison of doxazosin and atenolol 285

efficacy in mild or moderate hypertension. Drugs 1988;35:525- 41. Talseth T, Westlie L, Daae L, Vatle S. Comparison of the ef- fects of doxazosin and atenolol on blood pressure and blood lipids: a one-year double-blind study in 228 hypertensive pa- tients. AM HEART J 1988:116:1790-6. Talseth T, Westlie L, Daae L. A long-term study of atenolol and doxazosin in mild and moderate hypertension. J Hum Hypertens (in press). Delong DM, DeLong ER, Wood PD, Lippel K, Rifkind BM. A comparison of methods for the estimation of plasma low- and very low-density lipoprotein cholesterol. JAMA 1986;256: 2372-l. Wilson PWF, Castelli WP. Coronary risk prediction in adults. (The Framingham Heart Study). Am J Cardiol 1987;59:91G- 4G. Curb JD, Borhani NO, Blaszkowski TP, Zimbaldi N, Fotiu S, Williams W. Long-term surveillance for adverse effects of an- tihypertensive drugs. JAMA 1985;253:3263-8. MRC Working Party on Mild to Moderate Hypertension. Ad- verse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981;2:539-43. Graham RM, Thornell JR. Gain JM. et al. Prazosin: the first- dose phenomenon. Br Med 3 1976;2:1293-4. Gordon DJ, Rifkind BM. High-density lipoprotein: the clini- cal implications of recent studies. N Engl J Med 1989;321: 1311-6. Davies CE, Gordon D, La Rosa J, Wood PDS, Halperin M. Correlations of plasma high-density lipoprotein cholesterol levels with other plasma lipid and lipoprotein concentrations: the Lipid Research Clinics Program Prevalence Study. Circu- lation 1980;62:IV-24-30. Editorial. Alpha-blockade for hypertension: indifferent past, uncertain future. Lancet 1989;1:1055-6. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-38. Stamler J, Prineas RJ, Neaton JD, et al. Background and de- sign of the new US trial on diet and drug treatment of “mild” hypertension (TOMHS). Am J Cardiol 1987;59:51G-60G.

DISCUSSION V. D. Kuy (The Netherlands). Is it acceptable to

compare @-blockade (which increases total choles- terol levels) with doxazosin (which decreases total cholesterol levels) and calculate from this difference the probability of developing coronary heart disease, denying all other factors that would decrease athero- sclerosis?

T. Talseth. In addition to looking at total cholesterol levels, we also assessed blood pressure response, HDL cholesterol levels, smoking status, and glucose intol- erance prospectively. The most striking difference between doxazosin and atenolol was the changes in HDL cholesterol levels induced by these drugs. To date, studies have not been able to illustrate, in iso- lation, the effect of changing HDL cholesterol levels, and until this is possible a true comparison in terms of antiatherogenic effect is not possible.

M. Maniscaico (Palermo, Italy). Does the first-dose hypotensive phenomenon that may occur with pra- zosin also occur with doxazosin?

T. Talseth. No. We have not recorded one single ex- perience of syncope with doxazosin in our studies.