Preliminary results of the Norwegian doxazosin postmarketing surveillance study: A twelveweek experience

Pool

American

patholytic drugs such as a-methyldopa. All of these would, in effect, reduce the availability of norepinephrine at the al-receptor. Did these drugs have beneficial effects on cholesterol levels? J. L. Pool. Yes. One of the earliest observations was made by Walter Kirkendall,l who was studying moderate to severe hypertension in Houston. We found that both clonidine and prazosin were associated with unexpected reductions in total serum cholesterol. P.S. Sever. Are olz-receptors involved at all in lipid metabolism? J. L. Pool. At the present time, we do not know of any role for the az-receptors in lipid metabolism. E. Burgess (Canada). In your studies of doxazosininduced increase of lz51-LDL binding, what type of cells were used in vitro? J. L. Pool. We used Hep G2 cells, a special line of human hepatoma cells.

January 1991 Heart Journal

E. Burgess. Could the decrease in foam cells induced by doxazosin relate to a systemic rather than a local cholesterol effect? J. L. Pool. The question relates to the generation of foam cells. How does the foam cell arrive in its location, by dedifferentiation and redifferentiation of tunica media smooth muscle cells, or as a result of monocytic cells that come in from the vascular compartment? This is still an area that is under intense investigation. REFERENCE

1. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults. Arch Intern Med 1988:148:36-69.

Preliminary results of the Norwegian doxazosin postmarketing surveillance study: A twelveweek experience The study was designed to investigate the safety and efficacy of doxarosin in the control of blood pressure in general medical practice; the results presented concern the first 748 patients evaluated over a 12-week period. Blood pressure was significantly reduced after treatment with doxazosin (-13/-g mm Hg), and heart rate was not significantly altered. In addition, doxazosin significantly reduced total cholesterol levels (-8.7%), reduced triglyceride levels (-lg.8%), increased high-density lipoprotein cholesterol levels (+2.5%), and the high-density lipoprotein:total cholesterol ratio (+g.7%). The calculated risk of coronary heart disease was reduced by 20.5% over a ll-week period. Thirty-five percent of patients reported at least one side effect, and the number of patients experiencing severe adverse reactions was small. Twenty patients (2.7%) discontinued treatment because of adverse events, and 2.7% had the dose of doxazosin reduced. (AM HEART J 1991;121:260-7.)

Ingar Holme, PhD, Per Fauchald, MD, Hans Erik Rugstad, Hans Petter Stokke, MD Oslo, Norway

Elevated blood pressure, high levels of serum cholesterol, and cigarette smoking are the three major risk factors for the development of coronary heart disease From

the Institute

for Medical

Statistics,

Ullevaal

Hospital.

Reprint requests: Ingar Holme, PhD, Life Insurance Companies’ Institute for Medical Statistics, Ullevaal Hospital, P. 0. Box 6.0407 Oslo 4, Norway. 410124877

260

MD, and

(CHD). According to the Framingham Study, the total risk is markedly increased if several CHD risk factors coexist.’ The aim of antihypertensive treatment is to reduce total CHD risk whether by therapy or other means. Medical experts argue that it is partitularly important to stop smoking.2s 3 It is also well documented that lowering of cholesterol by diet or medication leads to a reduced incidence of CHD.41 5

Volume

121

Number

1.

Part

Norwegian

2

20-29

30-39

40-49

50-59

60-69

70-79

doxazosin

PMS

study

26 1

80-89

Age intervals Fig.

1. Number

of patients

by age and sex (intention

Blood pressure is believed to be causally related to CHD, and a marked reduction in the potential to develop CHD is possible if blood pressure is reduced in patients with hypertension. However, several largescale intervention studies in patients with mild or moderate hypertension have failed to show that antihypertensive treatment, predominantly with thiazides and P-blockers, has a beneficial effect on CHD. One possible explanation is that known adverse effects of these drugs influence other risk factors, such as serum lipids, which may neutralize the favorable effect of reduced blood pressure.7 Doxazosin, a new compound of the quinazoline class, is a selective postsynaptic al-adrenergic receptor inhibitor. Doxazosin lowers blood pressure by reducing peripheral vascular resistance without reflex tachycardia, while stroke volume and cardiac output are maintained at rest and during exercise.8 In longterm controlled studies in comparison with thiazidesg or selective P-blockers, lo doxazosin was found to be an effective and well-tolerated antihypertensive agent suitable for first-line therapy in mild or moderate essential hypertension. The long half-life of doxazosin (22 hours)ll offers the advantage of oncedaily dosage. In several studies lowering of blood pressure with doxazosin has been associated with a beneficial effect on blood lipid levels. Lowering of cholesterol levels and/or an increase in the level of high-density lipoprotein (HDL) cholesterol by doxazosin

has resulted

in an increase

of the antiathero-

genie ratio: HDL/total cholesterol.lO, l2 When doxazosin was introduced into the Norwegian market on Jan. 1, 1989, a large study was initi-

to treat data base, n = 748).

ated involving about 600 general practitioners. The aim was to survey approximately 4500 patients treated for 12 months according to general and approved recommendations for use. The main purpose of the study was to obtain information systematically on incidences of predictable and more rare and unexpected adverse effects. Second, the study was to follow the change in calculated risk score for CHD according to the Framingham Study equation. To obtain early experience, particularly on initial toleration of doxazosin, a special interim analysis has been completed for 12-week data from the first 748 evaluable patients. These first 12-week therapeutic results are presented in this article. METHODS Inclusion and exclusion criteria. This study is an open outpatient postmarketing surveillance study with 12 months’ duration for each patient. Included in the study were adults of either sex with a diagnosis of mild or moderate hypertension for which the physician would consider pharmacologic antihypertensive therapy. Patients already taking antihypertensive treatment could be included if the physician judged it beneficial to change treatment. Doxazosin could replace or be combined with the previous therapy because of insufficient blood pressure efficacy, adverse effects, inadequate patient compliance, or high-risk score for CHD. Patients with malignant or secondary hypertension were not included in the study. Procedure. Treatment schedules comply with the principles for diagnosis, elucidation, and instruction as outlined in the “NSAM’s Handlingsprogram for Almenpraksis” (Norwegian Association for General Practice’s Program for Treatment of High Blood Pressure). Baseline blood pressure is defined as the mean of the measurements made at

262

Holme

et

al.

American

January 1991 iieart Journal

% Present

80

-

60

-

0

Angina

Stroke

Diabetes Medical

Fig.

2.

Percentage

of patients

history

LVH

Smoker

Chol>200

mg/dl

at basellne

with a history

of disease and coronary

risk.

Baseline sitting diastolic blood pressure (mm Hg) Fig.

3. Distribution

of sitting

diastolic

blood

the last two visits. Measurements were then repeated at weeks 2,4,6,12,24, and 52 of the study, of which only the first 12 weeks’ experience will be presented here. If necessary, patients could be evaluated more often. Blood pressure and heart rate were assessed between 2 and 12 hours after dosing at each review visit. Body weight was also measured at each visit. Lipid measurements were obtained by an analysis of blood samples made after a 12-hour fasting period before dosing. Total cholesterol, HDL cholesterol, low-density lipoprotein cholesterol (calculated as total cholesterol con-

pressure

(mm Hg) at baseline

in all patients.

centration minus HDL cholesterol concentration minus one fifth of the triglyceride concentration), and triglycerides were measured at baseline and at week 12. All lipid assays were analyzed at the laboratory of the National Hospital, Oslo. The risk score for CHD according to the Framingham Study equation was calculated at weeks 0,12, and 52 and was used as the basis for calculating the percentage change in estimated CHD risk during the 12 weeks.i3 Safety. The primary aim in this study was to investigate all safety aspects of doxazosin when used in general prac-

Volume 121 Number 1, Part 2

Norwegian

doxazosin

PMS study

4

8

263

!

300

200

i

--I100 Final daily

6”

’

2

Final daily

4

dose

6

”

(mg/day)

dose

(mg/day)

C-

1

2

Final daily dose

(mg/day)

4. Cumulative frequency of treatment successaccording to the last prescribed daily dose (mg) in (a) all patients (b) hypertensive patients, and (c) normotensive subjects at baseline.

Fig.

tice, with special emphasis on the early phase of its introduction. Adverse experiences, whether reported spontaneously or in response to the standard question, “Have you experienced any discomfort during therapy?,” were recorded by type, time of onset, duration, degree of severity, and consequence for further treatment. Serious events or any new or unexpected reactions were reported immediately and separately to Health Authorities, the Steering Committee, and the sponsor. Patients were excluded at the physician’s discretion if continuation of therapy was not considered to be medically justified. Also, if patients at some time were unwilling to continue in the study, were uncooperative, or were consistent violators of protocol requirements, they were withdrawn from the study. A final visit was arranged so that risk factor assessment could be made. Dosage. The dosage range of doxazosin was 1 to 16 mg

as a once-daily dose taken in the morning according to the blood pressure response. Patients were instructed to take 1 mg daily for the first week, and if therapy was well tolerated, the dose was automatically adjusted to 2 mg for the second week. At the end of week 2, patients were seen by the physician for possible adjustment of dosage. If necessary, the dose was doubled every 2 weeks. In the event of therapy-related adverse effects, the dose was reduced to the next lower level that was tolerated. Treatment success. Treatment success was defined as follows: (1) patients with baseline diastolic blood pressure (DBP) <95 mm Hg to a final DBP I 90 mm Hg; (2) patients with baseline DBP z 95 mm Hg to a final DBP I 90 mm Hg with a reduction of 25 mm Hg; or (3) patients with baseline DBP > 95 mm Hg with a final reduction of at least 10 mm Hg. Data processing and statistical methods. The primary

264

Holme

et al.

American

10

Mean dally dose (mg) “.

5

19

27

35

35

723

688

697

748

January 1991 Heart Journal

. .._ . . . . . . . . . . . . . .._..._....- . . . . . -.- . . . . . . . . . .._. .._. . . . . . . . . . . ..__.........................-.-.-...... NS

Heart rate

I

-15

! 0

2

Duration of therapy (weeks) Fig.

5. Change

in blood pressure

(mm Hg) and heart

1I II

12

6

rate (beats/min)

Final visit

1,~~,,:1P,~~~9’6~~‘~~~~~~~ NS, not slgnlflcant

after treatment

with

doxazosin.

350

I 300

Hypertensives All patients

250 y? c $ :: 5 55 -E 1

200

150

100 50

0

Change in sitting diastolic blood pressure (mm Hg) Fig.

6.

Distribution

of change

(mm Hg) in sitting

DBP

(mm Hg) for all patients

and those with hyper-

tension. aim was to estimate the prevalence of type-specific side effects; the secondary aim was to assess risk factor changes. Confidence intervals for percents were calculated by Ztransforms of binomial proportions. Confidence intervals for percentage changes were based on the geometric mean method. An intention to treat 1%week data base was established, which was comprised of all patients with a baseline assessment and at least one valid follow-up blood pressure measurement. Because the data base is not fully complete, the results reported should be considered as preliminary.

RESULTS

Results are presented for the first 748 patients recruited into the study who fulfdled the intention to treat requirements. Age and sex distribution of the study population is shown in Fig. 1. Mean age for men (n = 354) was 57.5 years and 60.7 years for women (n = 386), age data were missing for eight patients. The frequency of some diagnoses in the past medical history can be seen in Fig. 2. The prevalence of angina pectoris was 8.2%) 3.5 9%for stroke, 6.1% for di-

Volume 121 Number 1. Part 2

Table

I. Overall

Norwegian

12-week

summary

of toleration n

Patients studied Patient-months of drug exposure Patients with adverse experience(s) No. of adverse experiences No. of severe adverse experiences Patients discontinued because of adverse experiences Patients with dose reduced

748 2094 264 (35.3rcm) 444 59 20 (2.7:; ) 20 (2.7'C)

PMS study

Table II. Summary of 12-week adverse experiences ing to body system in all patients (World Health zation preferred terminology)

Body system Cardiovascular Dizziness Edema (total) Palpitation Syncope

Tachycardia

abetes, and 4.0 % for left ventricular failure; 24.2 % of patients smoked and 95.9% had serum cholesterol levels >200 mg/dl (5.2 mmol/L). The distribution of baseline DBP in Fig. 3 shows that 40.0% of patients had mild hypertension (91 to 104 mm Hg), and 38.8% had moderate hypertension (105 to 114 mm Hg). There were 14.3% of patients with normal blood pressure (190 mm Hg). Blood pressure control. Of the 748 patients treated with doxazosin, 487 (65.1% ) were considered a treatment success. Fig. 4 presents the relationship between daily dose and treatment success in all patients, hypertensive patients, and normotensive subjects at baseline. In this data set it appears that most responders received a final daily dose of 4 mg or less. The mean daily dose of doxazosin was 3.5 mg for all patients and 3.3 mg for those considered a treatment success. Blood pressure and heart rate response curves are shown in Fig. 5. Although mean values do not include the same patients at all points, the reduction from baseline to week 12 is 13.1 f 0.7 (SEM) mm Hg in systolic blood pressure (SBP), 9.1 f 0.3 mm Hg in DBP, and +0.8 + 0.4 beats/min in heart rate. If adjustments are made for hypertension status at baseline (normotensive, hypertensive), the response is slightly better (-15/-10.5 mm Hg). Fig. 6 shows the distribution of change in DBP for all hypertensive patients. A substantial number of patients experienced a reduction in DBP 120 mm Hg. Safety. Table I shows the overall summary of toleration. Adverse events were experienced by 264 patients (35.3%). The number of adverse experiences was 444 (i.e., 1.68 per patient in the group who experienced at least one side effect). Severe adverse reactions were noted 59 times (i.e., 0.08 times per patient). Twenty patients (2.7%) discontinued treatment because of adverse reactions, and 20 patients had the dose of doxazosin reduced. Table II presents a summary of adverse events by body system for all patients during the 12-week pe-

doxazosin

Vertigo Skin and appendages Musculoskeletal Central and peripheral Autonomic Hot flushes

Special senses Psychiatric Gastrointestinal Diarrhea Nausea Respiratory

Dyspnea Urinary General Fatigue Headache Weight increase

Incidence: No. of patients (0;) 143 68 28 32 2 17 14 9 2 6 29 13 11 24 27 6 11 24 19 8 106 39 53 10

(19.1) (9.1) (3.7) (4.3) (0.3) (2.3) (1.9) (1.2) (0.3) (0.8) (3.9) (1.7) (1.5) (3.2) (3.6) (0.8) (1.5) (3.2) (2.5) (1.1) (14.2) (5.2) (7.1) (1.3)

265

accordOrgani-

e;, severe 15.4

8.8 7.1 15.6 100.0 35.3 14.3

0 50.0

0 10.3 7.7 36.4 20.8 14.8

0 27.3 12.5 5.3 12.5 10.4 10.3 13.2

0

riod. Major body systems for adverse events are shown specifically. The cardiovascular system had the most frequent adverse experiences; dizziness (9.1%), edema (3.7%), and palpitation (4.3%) were typical reaction types. Syncopes were rare (two cases; 0.3%), but tachycardia appeared in 17 patients (2.3%); in six of the 17 patients, tachycardia was severe. Gastrointestinal reactions, including nausea (1.5%), were observed. Dyspnea was seen in 19 patients (2.5%). Fatigue (5.2%) and headache (7.1%) were the more general types of reactions reported. Cholesterol. In the 12-week analysis, 573 patients had evaluable cholesterol data, with mean baseline cholesterol levels of 276 mg/dl (7.14 mmol/L). The distribution was nonnormal and slightly left skewed, as shown in Fig. 7. Percentage changes in cholesterol were also nonnormal, with a slight right-skewed shape (Fig. 8). The mean reduction in total cholesterol for all patients was 6.7% + 12.4% (SD) (p < 0.001 from baseline), reflecting the large range in cholesterol response. An increase in serum cholesterol 25% was seen in 12.6% of patients, whereas a decrease in serum cholesterol ~5% was seen in 55.7% of patients.

266

January 1991 American Heart Journal

Holme et al.

183

225

266

307

349

390

431

472

514

4.75

5.82

6.89

7.96

9.03

10.10

11.17

12.24

13.31

Baseline Fig.

7. Distribution

of serum

cholesterol

cholesterol

mgidl mmol/L

levels

levels (mg/dl

and mmol/L)

at baseline

(n = 573).

Frequency

I

-47.3

-40.5

-35.6

-28.1

-20.5

-12.2

-2.0

8.3

I19.7

33.6

Mean % change from baseline cholesterol Fig. 8. (n = 572).

Distribution

of percentage

change

in serum

Table III gives a summary of the changes in serum lipid variables, body weight, and Framingham risk score during the 12-week treatment period for all efficacy-evaluable patients. The mean percentage changes in all serum lipid fractions after 12 weeks of treatment with doxazosin were significant (p < 0.001). Mean cholesterol level was reduced by 6.7 % , and triglycerides by 19.8%. HDL cholesterol was increased by 2.5 % , and the ratio of HDL to total cholesterol was raised by 9.7 % . Calculated CHD risk was reduced from 24.0 (per 100) to 20.3 (per loo), which represented an estimated 20.5% reduction in

cholesterol

after

12 weeks

of doxazosin

therapy

calculated CHD risk (p < 0.001). The mean body weight of the 678 efficacy-evaluable patients was unchanged. DISCUSSION

The results of this 12-week experience with doxazosin must be regarded as preliminary. Several variables could not be analyzed (e.g., previous medication), because such data have not been fully reviewed. The number of patients available for lipid and risk score analyses was dictated by the number of patients who had both baseline and 12-week data.

Volume 121 Number 1, Part 2

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doxazosin

PMS study

III. Mean serum lipid variables, body weight, and Framingham CHD risk score at baseline and after treatment for all efficacy-evaluable patients

Table of

267

12 weeks

12 w Variable

n

Cholesterol: mg/dl (mmol/L) Triglycerides: mg/dl (mmol/L) HDL cholesterol: mg/dl (mmol/L) HDL/cholesterol ratio Body weight Framingham CHD risk score

573 569 566 566 678 534

*Geometric

Baseline 276* (7.14) 144* (1.63) 50* (1.29) 0.18* 79.6 24.01

(70 change

from baseline) -6.7t -19.st 2.5t 9.7t 0 -20.55

95% -7.6 -22.3 1.1 8.0 -0.2 -22.4

confidence

limits -5.8 -17.2 3.9 11.4 0.2 -18.5

mean.

tp
in chances

per 100.

During the first 12 weeks of observation (more than 2000 observation months), only the previously documented side effects14* l5 of selective al-inhibitors were observed. The incidence of side effects corresponded well with other findings from observational studies and randomized trials. Indeed, this study indicated a lower incidence than in some other studies, although the duration of the study is rather short. Many of the adverse reactions may have been from doxazosin, but concomitant use of other antihypertensive drugs may have also contributed. However, the incidence of severe adverse reactions was kept to a tolerant level (0.08 events per patient). No deaths or life-threatening situations have been observed. The magnitude of the changes in blood pressure was the same in this study as that observed in another trial that compared doxazosin with placebo.16v l7 Lipid responses did not deviate from earlier findings concerning such trials with selective al-inhibitors. Thus these data suggest that responses of risk factors to treatment with doxazosin are similar in a general practice setting to those expected from experimental findings. The observed 20.5 % reduction in calculated CHD risk (according to the Framingham risk equation) is consistent with other postmarketing surveillance studies with doxazosin.18-20 REFERENCES

1. Castelli WP. The epidemiology of coronary heart disease: the Framingham Study. AM HEART J 1984;27:4-12. 2. Wilhelmsen L. Coronary heart disease: epidemiology of smoking and intervention studies of smoking. AM HEART J 1988;115:242-9. 3. Kaplan NM. Strategies to reduce risk factors in hypertensive patients who smoke. AM HEART J 1988;115:288-94. 4. Hjermann I, Holme I, Byre KV, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease. Lancet 1981;2:1303-10.

5. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Preventive Trial results: I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64. 6. Holme I. Drug treatment of mild hypertension to reduce the risk of CHD: is it worthwhile? Stat Med 1988;7:1109-20. 7. Leren P. Effect of antihypertensive drugs on lipid metabolism. Clin Ther 1987;9:326-32. 8. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br J Clin Pharmacol 1986;21:458-543. 9. Hjortdahl P, von Krogh HV, Daae L, Holme I, Hjermann I. A 24-week multicenter double-blind study of doxazosin and hydrochlorothiazide in patients with mild to moderate essential hypertension. Acta Med Stand 1987;221:427-34. 10. 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. 11. Elliot HL, Meredith PA, Reid JL, Pharmacokinetic overview of doxazosin. Am J Cardiol 1987;59:78G-81G. 12. Frick MH, Halttunen P, Himanen P, et al. A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension. Br J Clin Pharmacol 1986;21:558-628. PWF, Anderson KM, Castelli WP. Stratifying 13. Levy D, Wilson the patient at risk from coronary disease: new insights from the Framingham Heart Study. AM HEART J 1990;119:712-7. 14. Rosenthal J. Clinical experience with doxazosin in general medical practice. AM HEART J 1988;116:1748-57. in the treatment of mild and 15. van den Hogen ALCJ. Doxazosin moderate essential hypertension in general medical practice. AM HEART J 1988;116:1757-62. 16. Torvik D, Madsbu HP. Multicentre 12-week double-blind comparison of doxazosin, prazosin and placebo in patients with mild to moderate essential hypertension. Br J Clin Pharmacol 1986;21:698-758. 17. Taylor SH. Pharmacotherapeutic stature of doxazosin and its role in coronary risk reduction. AM HEART J 1988;116:1735-47. . . 18. Naber FB. An open noncomparative study of doxazosin in essential hypertension: experience in general practice in the Netherlands. AM HEART J 1991;121:273-9. 19. Maslowski AH. Clinical experience with doxazosin in general medical practice in New Zealand. AM HEART J 1991;121: 323-8. 20. Langdon CC. Doxazosin: a study in a cohort of patients with hypertension in general practice-an interim report. AM

HEART J 1991;121:268-72.