profile of trimazosin: an effective and safe antihypertensive agent

Profile of trimazosin: An effective and safe antihypertensive agent

Trimazosin, a selective alpha-l-adrenoceptor-blocking agent, has been extensively evaluated in over 1000 patients. In hypertensive patients, reduction in elevated blood pressure in both supine and standing positions, consequent to a reduction in systemic vascular resistance, persisted in long-term therapy. Progression of hypertension target organ damage did not occur. Improvement in blood lipids with decreased total serum cholesterol was noted In long-term therapy. In long-term studies, 74% of patients responded at a trfmazosin dose of 300 mg/day or less; the maximum dose was 300 mg/day or less in 52% of patients and 200 mg/day or less in 36%. Most patients received twice a day therapy. The side effect profile of trimatosin was comparable to placebo and significantly better than that of either methyldopa or propranolol. Concomitant disease or therapy did not adversely affect the trimazosin safety profile. Hematology, clinical chemistry, and urinary parameters did not indicate deleterioui effects. Because of its excellent safety and toleration profile, trimazosin may be particularly suitable in first-line therapy of patients with mild or moderate hypertension. (AM HEART J 106:1269, 1983.)

Colin R. Taylor, M.D., Joan P. Leader, Ph.D., Walter Singleton, M.B., B.S., Edward W. Munster, MS., Fred C. Falkner, Ph.D., and James A. O’Neil Groton, Conn., and Sandwich, England

PRECLINICAL FINDINGS

Trimazosin is a quinazoline antihypertensive agent that selectively inhibits the alpha-l subtype of alpha adrenoreceptors and has an additional peripheral vasodilating mechanism not mediated by alpha blockade.’ Preclinical studies showed that (1) trimazosin reduced blood pressure without evidence of tolerance to this effect with continued therapy, (2) chronic administration of doses seven times greater than the maximum therapeutic dose for humans did not produce organ toxicity, and (3) there was no evidence of carcinogenicity, mutagenic activity, or teratogenic effects.

CLINICAL STUDIES

Design and methods. Over 1000 hypertensive patients and about 300 patients with chronic heart failure have received trimazosin therapy in more than 50 clinical studies in the United States and Europe. Patients were evaluated at baseline and at periodic intervals for assessment of efficacy parameters, side effects, drug toxicity, and hypertension target organ damage.

The clinical development program consisted of double-blind and single-blind comparative trials or

From Pfizer Central Research.

Reprint requests: Cohn R. Taylor, M.D., Pfizer Central Research, Eastern Point Rd., Groton, CT 06340.

open design studies that were noncomparative. Tri- mazosin was compared with standard antihypertensive drugs and with placebo. Baseline characteristics for trimazosin, placebo, methyldopa, and proprano- 101 patients are presented in Table I. Ninety-eight percent of the patient population had essential hypertension; however, a few patients with renovascular or endocrine hypertension were studied. Most experience has been gained in mild or moderate hypertension (a diastolic blood pressure of 90 to 114 mm Hg). The duration of the double-blind studies ranged from 6 weeks to 12 months; patients in long-term open studies received trimazosin for up to 3 years.

Double-blind studies were of two main types: (1) patients had not received diuretic therapy or under- gone a washout period from previous antihypertensive medication prior to the double-blind period and (2) patients with inadequate blood pressure response to a diuretic alone at the time of entry into the double-blind study received trimazosin or placebo as concomitant medication without a change in diuretic dosage.

Analysis of the double-blind and long-term open studies conducted in the United States and in Europe compared changes from average baseline blood pressure to the average of the last three determinations made during therapy. In addition,

1269

1270 Taylor et al. November, 1983

American Heart Journal

Table I. Baseline characteristics for trimazosin, placebo, methyldopa, and propranolol patients*

TC?U2ZOSifZ Placebo Methyldopa Propranolol (N = 619) (N = 100) fN = 31) (N = 67)

Mean age 54 53 53 51 Male (‘c ) 59 79 61 51 Mean height (in) 66 68 67 68 Mean weight (pounds) 175 183 186 169

% Patients

Severity of baseline diastolic hypertension (supine)

Normal (<90 mm Hg) Mild (90 - <lOO mm Hg) Moderate (100 - <115 mm Hg) Severe (115 - <130 mm Hg) Gross (~130 mm Hg)

Severity of baseline diastolic hypertension (standing)

Normal (<90 mm Hg) Mild (90 - <lOO mm Hg) Moderate (100 - <115 mm Hg) Severe (115 - <130 mm Hg) Gross (~130 mm Hg)

*Data analyzed as of June 1982.

2 4 6 2 37 49 52 35 54 42 32 55

6 5 10 8 2 0 0 0

2 1 3 0 20 32 26 15

64 54 55 74 13 12 16 11

1 1 0 0

Table II. Differences between blood pressure (BP) responses in trimazosin (TZ) and placebo (PL) patients in double-blind outpatient studies

Mean BP change (mm Hg) with TZ minus mean change with placebo*

Study No.

Sample size Supine BP Standing BP

TZ PL Systolic Diastolic Systolic Diastolic

Individual studies

07-Z 6 6 -12.6t -10.5t -13.3t -10.8t

08-l 5 5 t.2 -2.1 -13.3 -4.2 09-l 6 6 -5.1 -4.1 -6.3 -4.1 12-2 13 13 -10.01 -6.2$ -11.4t -10.33 ‘384 8 8 -10.2$ -6.21 14.9t -9.6t 14.4l 4 4 -4.5 -3.5 14.3t -5.51 OS-7n 14 13 -13.4t -9.8s -11.9 -11.9s 14-5q 7 6 -11.8 -14.1t -13.0 -12.4t

16-39 6 5 -24.5t -10.6t 32.2t -14.3x 19-2q 7 7 -9.7 -7.5 -10.5 -11.4$

Combined multicenter common protocol studies

07-2/08-1/09-l 17 17 -6.23 -5.8t -10.9t -6.5t 08-7/14-5/16-3/19-21 34 31 -13.8s -10.2s -15.0t -12.2s

*Change from baseline to average of last three values on double-blind therapy (parallel studies) or change from end of open therapy to average of last three values on double-blind therapy (placebo withdrawal studies). tp < 0.01. $p < 0.05. §p < 0.001. INI patients on background diuretic therapy. I[Approximately half the patients were on background diuretic therapy and half on trimazosin alone; significant effects in h&h subgroups.

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Number 5, Part 2 Clinical pharmacologic profile of trimazosin 127 1

‘e;~:;o Pre- treatment BP (mm Hg.)

Fig. 1. Baseline and final standing diastolic blood pressures (BP) for each patient in the U.S. double-blind studies.

improvement was categorized as slight if there was a change from baseline of one category of hypertension severity (Table I) (e.g., severe to moderate or moderate to mild). A two-grade reduction (e.g., from severe to mild) indicated a “good” improvement; and a three-grade reduction in severity indicated a “marked” improvement over baseline.

CLINICAL RESULTS

Effect on blood pressure. Double-blind outpatient studies with trimazosin and placebo (Table II) and double-blind comparative studies of trimazosin and methyldopa or propranolol (Table III) indicated that trimazosin was clinically and statistically superior to placebo and suggested equivalence to methyldopa or propranolol in reducing blood pressure. The individual patient responses for all U.S. double- blind studies combined are displayed in Fig. 1. Similar data for a European multicenter double- blind study of trimazosin and propranolol are shown in Fig. 2.

placebo in the supine position and 13/10 mm Hg greater in the standing position. Similarly, trimazosin was significantly more effective than placebo in patients who showed an inadequate blood pressure response to diuretic alone, the effect of trimazosin being 10/7 mm Hg greater than that with placebo in the supine position and 13/9 mm Hg greater in the standing position. In the long-term open studies, about 75% of patients responded satisfactorily to trimazosin alone, whereas in the remaining 25%) investigators added diuretics to therapy to improve blood pressure control. In the U.S. combined long- term open studies, a persistent reduction in standing diastolic blood pressure was observed over a 17- month period of therapy (Fig. 3). Similar standing diastolic blood pressure changes were recorded in the European long-term open studies (Fig. 4) during an 8-month treatment period. Figs. 3 and 4 indicate blood pressure response in all patients, approximately 75% of whom received trimazosin in the absence of concomitant antihypertensive therapy.

Trimazosin was significantly more effective than For all hypertensive patients receiving trimazosin placebo in the absence of diuretics, the effect of in long-term open studies, the changes in grade of trimazosin being 11/8 mm Hg greater than that with severity of hypertension were recorded from average

post- treat - ment BP

vsaw~e ,I5 m~dera+e,~~ mild j. normal 130

Pre-treatment BP (mmHg.1

Fig. 2. Baseline and final standing diastolic blood pressures (BP) for each patient in the European double-blind studies (effect of drug k diuretic).



10

.‘...... .*.,.......*

m m Hg *. ..,a... . . . . . . . . . . . . , .

m m Hg . . . . . . . . . . . . ..’

-10 . . . . . . . . . . . . . . . . . . . . . .

*...

-20 ‘....*

. . . ...-* . . . . . . . . . . . . .._ .... . . . . . . . . .

. . . . . . . . .

-20 ..

. . . . . . . . . . . . . . .

.xl, , ,, , , , , , , , , , , , , , ,

0 80 120 180 240 300 360 420 480 30 90 150 210 270 330 390 450 510

Days on Trimazosin

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

-30 , I I I I I I I I 0 30 80 90 120 150 180 210 240

Days on Trimazosin

. . . . . . . . . ~~~ _ , SD

Avs Change . . . . . . . . . . . . Avg+lSD

Fig. 3. Change in 8tandin.g diastolic blood pressure from Fig. 4. Change in standing diastolic blood pressure from baseline in the combined U.S. long-term open hyperten- baseline in the combined European long-term open hyper- sion studies. tension studies.

Table III. Difference between blood pressure (BP) responses in trimazosin (TZ) and methyldopa or propranolol patients in double-blind outpatient studies

Mean BP change (mm Hg) with TZ minus mean change with comparative drug (CD) *

Study No.

Sample size Supine BP

TZ CD Systolic Diastolic

Individual U.S. studies vs methyldopa

Standing BP

Systolic Diastolic

07-2 08-l 09-l 16-2

6 5 +4.5 +1.7 f4.4 +1.2 5 4 +9.9 +1.7 +3.8 +4.3 6 5 -2.6 -1.9 -2.1 -2.3 4 7 +2.6 -2.3 -8.3 -3.8

Combined multicenter trials

U.S. studies vs methyIdopa 07-2/08-1/09-l 17 14 +3.5 European study vs propranolol 62-17 65 61 +4.8

None of the drug differences in the above table were statistically significant. *Change from average baseline to average of last three values on double-blind therapy. tOptim of adding diuretics in suboptimal responders.

+0.4 +1.9 +2.5

+0.6 +4.5 +0.4

baseline to the last evaluation on trimazosin, regard- less of the addition of other antihypertensive drugs to the regimen. Fig. 5 illustrates the results of trimazosin’s use in a clinical practice setting, in which other drugs, mainly thiazide diuretics, are sometimes added to a patient’s regimen to increase efficacy without increasing the trimazosin dosage. Of the 424 patients initially classed as hypertensive, 325 showed an improvement in hypertension by one or more grades, and of the 348 patients with moderate or greater baseline hypertension, 126 showed an improvement of at least two grades. Thus trimaxosin was shown to be effective in treating all grades of hypertension, with the mean fall in blood pressure being greater in patients with more severe baseline

hypertension (Table IV). A total of 165 patients who were hypertensive before trimazosin therapy became normotensive during treatment.

Limited experience from open evaluation in 11 patients with renovascular hypertension indicated effective blood pressure reduction in this hypertension subgroup (mean reduction in blood pressure: 44/25 mm Hg supine and 47/19 mm Hg standing).

In a double-blind placebo withdrawal study, effects on blood pressure with trimaxosin and placebo were compared at maximum exercise load. In patients transferred from open trimazosin therapy to placebo, exercise systolic blood pressure tended to rise, and a significant rise 03 < 0.01)

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Number 5, Part 2 Clinical pharmacologic profile of trimazosin 1273

Table IV. Baseline to final changes in standing blood pressure (BP) in patients on long-term open trimazosin therapy*

Baseline severity grade

Mean baseline

BP

(mm W

Mean change in BP (mm Hg)

No. of Systolic Diastolic patients

Gross 216/134 -38 -26 2 Severe 176/l 18 -24 -22 21 Moderate 164/106 -18 -13 319 Mild 162196 -18 -10 76 Normal 151/75 +8 +2 5

*In the majority of patients, effects are those of trimazosin alone; in about 25”; of patients, effects are those of trimazosin + diuretic.

Table V. Effects of trimazosin (20 patients) vs double- blind placebo (18 patients) on treadmill exercise performance in hypertensive patients in a multicenter double- blind placebo withdrawal study

Open trimazosin period Double-blind period

Mean SEM Mean SEM t Value

MCL exercise systolic BP (mm Hg) Trimazosin 176 5.5 174 6.8 Placebo 187 4.5 196 6.0 1.62

MCL exercise diastolic BP (mm Hg) Trimazosin 88 1.9 90 2.7 Placebo 89 2.8 100 2.1 2.a7*

MCL exercise HR X systolic BP (X10-‘) Trimazosin 28 1.0 27 1.0 Placebo 30 1.0 32 1.6 1.51

Exercise duration (set) Trimazosin 561 48 569 48 Placebo 572 35 595 35 0.46

MCL = maximum common load (i.e., maximum exercise load at which heart rate/blood pressure value was available during both open trimazosin and double-blind therapy); HR = heart rate; BP = blood pressure.

*p < 0.01.

occurred in exercise diastolic blood pressure as compared with patients who received double-blind trimazosin therapy; no significant changes occurred in rate-pressure product or in exercise duration (Table V).

Effects on other ischemic heart disease risk factors

Blood lipids. Several standard antihypertensive drugs, including oral diuretics and beta-adrenocep- ter blockers, cause undesirable effects on blood lipids: total serum cholesterol and triglycerides are increased and there is a reduction in the beneficial lipid fraction, high-density lipoprotein (HDL) cholesterol. The adverse lipid effects of diuretics and some beta blockers may prevent the reduction in coronary heart disease that could otherwise result

f

DfrERiORATiON

Fig. 5. Change in grade of severity of hypertension from baseline to the final standing blood pressure (BP) deter- mination for patients in the long-term open studies. Blood pressure categories: Gross = diastolic 2130 mm Hg; severe = diastolic <130, ~115 mm Hg; moderate = diastolic 415, ~100 mm Hg; mild = diastolic <lOO, 290 mm Hg; normal = diastolic <90 mm Hg.

from effective reduction of elevated blood pressure with these agents.

In a long-term multicenter study, the effects of trimazosin on serum lipid concentrations were evaluated in 90 patients. During an initial 12-month period of open therapy (Table VI), patients receiving trimazosin without concomitant diuretic therapy showed a reduction in total serum cholesterol with little change in HDL cholesterol, in the HDL cholesterol/total cholesterol ratio, or in total serum triglycerides. In patients in whom diuretic therapy was added to the trimazosin regimen, little change was noted in total cholesterol, in HDL cholesterol, or in the HDL/totaI cholesterol ratio, while triglyceride values increased slightly.

To evaluate lipid effects in a double-blind setting, an 8-week, double-blind evaluation was performed after completion of the l-year open-study period. Patients were randomly assigned to continue trimazosin in identical dosage or to discontinue trimazosin therapy while receiving placebo therapy. Patients receiving diuretic therapy were maintained at a constant dosage. Comparison of changes in serum lipid values in the two double-blind groups (Table VII) indicated that placebo administration was associated with a significant rise in total cholesterol (p < O.Ol), as well as nonsignificant reductions in HDL cholesterol and in the HDL/total cholesterol ratio, and a near-significant rise in total triglycerides



Table VI. Mean serum lipids at baseline and after 1 year of long-term open trimazosin therapy

Serum lipids No. of

Baseline 1 yr patients

Total serum cholesterol TMZ 226.3 217.8 48

(mg/dU TMZ + DIU 224.1 219.4 42 HDL cholesterol TMZ 50.2 51.2 22

(mg/dl) TM2 + DIU 58.8 53.5 13 HDL cholesterol/total TM2 23.4 25.1 22

cholesterol ratio TMZ + DIU 25.4 22.9 13 Total serum TM2 134.1 141.3 40

triglycerides (mg/dl) TMZ + DIU 141.0 162.3 34

TM2 = trimazosin without concomitant diuretic; TMZ + DIU = concomitant trimazosin and diuretic therapy.

Table VII. Changes in serum lipids in patients continuing long-term trimazosin (TZ) therapy as compared with those removed to double-blind placebo (PL) therapy

Mean change from end of open

trimazosin period

End End double-blind double-blind TZJPL

Serum lipids TZ PL significance

Total serum cholesterol (mddl)

HDL cholesterol

bddl) HDL cholesterol/

total cholesterol ratio

Total serum triglycerides (mg/dl)

-9.5 +11.5

(44)$ (42)

-1.1 (17) +0.3

(17)

-3.9

(44)

p < 0.01

-6.7

(18) -3.4

(18)

p > 0.10

p > 0.10

+19.9 (42)

0.05 < p < 0.10

*Numbers in parentheses indicate numbers of patients.

when compared with the change during double- blind trimazosin therapy.

In a double-blind comparison of trimazosin and propranolol,2 trimazosin was found to be superior to propranolol in its effects on HDL cholesterol and on the HDL/total cholesterol ratio. Trimazosin, therefore, has beneficial effects on two of the primary risk factors in the development of ischemic heart disease: hypertension and hyperlipidemia.

Left ventricular hypertrophy, Studies have been performed to assess regression or lack of progression of left ventricular (LV) hypertrophy, a major prog- nostic factor related to cardiovascular morbidity and mortality in hypertension. As assessed by reduction in LV voltage, double-blind placebo comparison data indicated a significant regression 0, < 0.05) of left ventricular hypertrophy with trimazosin thera-

Table VIII. Changes in LV voltage in short-term and long-term double-blind evaluation in hypertensive patients

Electrocardiographic LV voltage (SV, + RVJ mean change (mV x 10-l)

Evaluation period Trimazosin Placebo Significance

Short-term (6 wk) -1.31 +2.01 p < 0.05 Long-term (1 yr)* -2.22 -0.27 p < 0.05

*Refers to change during double-blind therapy after 1 year of open trimazosin therapy.

py as compared with placebo at both 6-week and 12-month evaluation periods (Table VIII).

Effects on renal function. Beneficial acute effects on renal function were observed with trimazosin. Statistically significant increases were noted in renal plasma flow (38% for trimazosin vs 9% for double- blind placebo) and in renal blood flow (37% vs 7 % ), accompanied by a decrease in renal vascular resistance (50% vs 3 % ) from average before dose to 3 hours after dose. In addition, trimazosin may reduce proteinuria during long-term therapy since, in long- term open studies, proteinuria was substantially reduced at the last evaluation on drug as compared with baseline.

Evaluation of other target organ damage. With long- term trimazosin therapy, there was no evidence of deterioration in other systems whose function may be impaired by the hypertensive process (e.g., reti- nopathy, cardiomegaly, and cardiac arrhythmias).

Trimazosin dosage. In early studies, a three times a day dosage was employed, but the majority of the patients in the program (81%) received twice a day dosage. Trimazosin therapy was usually initiated at a dosage of 50 mg twice a day, with increments given as determined by patient response. In long-term open studies, 74% of patients responded at a trimazosin dose of 300 mg/day or less; the maximum dose in 52% of the patients was 300 mg/day or less, whereas 36 % were maintained on 200 mg/day or less (Table IX). The percentages of patients responding to various dosages are shown in Table X. Dosage regimens up to 900 mg/day were evaluated in the clinical program and demonstrated the same favorable safety and toleration profile documented at lower dosages.

The maximum fall in blood pressure occurred substantially later than would be predicted from the time of peak drug concentration. Following acute single doses of 100 mg trimazosin, plasma levels peaked at 1 hour (11 to 14 rg/ml), with mean levels of 3 to 4 pg/ml at 4 hours. On the other hand, peak blood pressure effect was seen at 3 to 6 hours in

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4

Mun Chnga f SEM (mm Hd

8

I I I + .5 1 2 4 6 S 10 12 Hours Post Dosing 24

77s 8 6 s 3 5 No. Observations 6

Fig. 6. Mean change in standing diastolic blood pressure after placebo or trimazosin single doses of 100 to 300 mg in eight patients with essential hypertension.

Table IX. Trimazosin maximum dosage

Maximum dose* (m&day) Cumulative (% of patients)

S150 18.0 5200 36.1 5300 52.4 5400 66.5 ~600 79.2 5900 100.0

*Maximum dose in 466 patients in long-term open multicenter studies.

acute single-dose studies in hypertensive patients (Fig. 6). Table XI gives the average resting blood pressures (measured by patients at home in a seated position) at 2-hour intervals on the last day of three times a day therapy and on the first evaluation after switching to a twice a day regimen. There was no change in the total daily dose of medication. Control of blood pressure was equivalent with twice a day and three times a day therapy.

Support for twice a day dosing was also provided by the results of three small double-blind parallel studies that suggested mean reductions in diastolic blood pressure of about 7 to 12 mm Hg (compared with placebo) at the predicted time of minimum effect, i.e., prior to the 8 A.M. morning dose when the previous dose had been given 14 hours earlier (Table XII).

In a long-term open-study evaluation of 20 patients, the dose-response relationships for blood pressure effects were determined at the predicted time of minimum effect, 14 hours from the last dose

Table X. Cumulative therapeutic response rates* by dose in all long-term studies: Patients taking trimazosin without concomitant antihypertensive agents as % of all patients entered

Trimazosin dose (mglday) - 100 150 200 300 400 600 900

All long-term open 32 53 65 74 77 82 84 studies

U.S. open studies 15 50 56 68 69 77 81 European open studies 55 57 77 83 88 - - Double-blind studies 59 - 77 - 85 - -

(Europe)

- = dosage not evaluated. *Response = fall of 5 mm Hg or more in standing diastolic pressure.

(Table XIII and Fig. 7). These data showed a dose-related decrease in diastolic blood pressure with increasing dose and a further reduction in blood pressure when thiaxide was added to the trimaxosin regimen. Safety

Side effects. The side effect profile for trimazosin as evaluated in double-blind placebo comparisons was very favorable. The percentages of patients with side effects were approximately the same in the two treatment groups: trimaxosin, 24%, and placebo, 23% (Table XIV). The overall incidence of side effects reported with trimaxosin, with or without concomitant therapy such as diuretics, was 40% (Table XV). Most side effects (47 % ) were classified as mild. Side effects with an incidence of ~2% for



-2c \ I

Change in BP (mm Hd

* SEM

1 -12 I ! I t

150 300 800 so0

Trimatosin Dose (m&/day)

Fig. 7. Dose-response relationship for change in home diastolic blood pressure (BP) prior to morning trimazosin dose (approximately 14 hours since previous dose) in 20 patients with baseline home diastolic blood pressure 290 mm Hg. Patients received no concomitant antihypertensive therapy.

Table Xi. Average resting blood pressure (mm Hg) of 20 patients who switched from three times a day to twice a day trimazosin therapy*

Three times a day Twice a day

Time of day Systolic Diastolic Systolic Diastolic

8 A.M. 143 90 139 86 10 A.M. 135 86 134 83 12 noon 132 84 132 81

2 P.M. 130 82 135 82 4 P.M. 131 83 137 84 6 P.M. 128 82 137 84 8 P.M. 127 81 130 79

10 P.M. 123 78 131 80

*Measured by patients at home in a seated position.

patients receiving trimazosin treatment were as follows: headache 9.4 % , fatigue/malaise 7.7 % , dizziness 5.9 % , hypotension/postural dizziness 7.9%) drowsiness/sedation 4.1% , nausea 4.1% , and diarrhea 2.9%. The incidences of those side effects were comparable to those of placebo in controlled studies (Table XIV). Only 3.7% of trimazosin patients not requiring concomitant diuretics stopped treatment because of side effects vs 6.1% of patients receiving concomitant trimazosin and diuretic therapy.

The side effect profile of trimazosin was significantly better than that of either methyldopa or propranoiol. The incidence of side effects in doubie- blind trimazosin/methyidopa studies (Table XVI) was 23% (trimazosin) vs 45% (methyldopa); simi-

Table XII. Differences in diastolic blood pressure effect between trimazosin (TZ) and placebo (PL) patients 14 hours after last dose in three double-blind outpatient studies

Study No.

Mean change with TZ (mm Hg) minus

mean change with PL + SEM

No. of patients/group

(TZIPL)

08-l -8.8 ck 4.8 515 08-4* -11.8 + 4.6 515 14-2t -6.8 * 5.9 1415

‘TZ given in a setting of background diuretic therapy. tEvaluation of four double-blind study groups: three different TZ dosage regimens and one PL regimen.

Table XIII. Change in diastolic blood pressure in long-term open evaluation

Trimazosin dose Mean change f SEM* (mglday) (mm Hg)

No. of patients

150 -4.6 + 2.0 12 300 -5.8 + 1.9 12 600 -8.8 ?I 2.7 18 900 -9.2 f 1.9 17

900 + polythiazide -14.0 f 1.8 16

*Fourteen hours after last trimazosin dose vs baseline.

My, in the double-blind trimazosin/propranoloi evaluation (Table XVII), side effect incidence was 24 % (trimazosin) vs 48% (propranoioi).

Antihypertensive drug therapy may be associated with excessive blood pressure reduction in the standing position. Trimazosin-related postural hypotension was infrequent, and the incidence of orthostatic effect was not higher on initiation of trimazosin therapy than during long-term trimazosin therapy.

Laborutory safety. In an extensive evaluation of serial laboratory safety parameters, there was no evidence of adverse effects on hematology, clinical chemistry, or urinary parameters as a result of trimazosin treatment. There was no evidence of adverse effects on laboratory parameters frequently affected by other antihypertensive drugs (including blood lipids, potassium, plasma renin activity, glucose, antinuclear antibody, Coombs’ test, uric acid, blood urea nitrogen, and creatinine; Table XVIII).

Additional safety evaluations. The vast majority of studies included a number of special safety tests at baseline and periodically during therapy. Heart rate was slightly increased in some short-term studies, but long-term studies showed no significant heart-rate changes. No significant changes occurred

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in body weight in patients receiving trimazosin alone; therefore it is unlikely that fluid retention, a side effect of most vasodilator drugs, occurs with trimazosin therapy of hypertension. This assessment is supported by blood volume measurements in shorter term evaluations, which again showed no evidence of fluid retention, and by double-blind acute assessments of renal function, which indicated beneficial rather than deleterious effects. There was no evidence of trimazosin-related adverse effects on ophthalmologic examination, cardiopulmonary examination, chest x-ray examination, or LB-lead ECGs. There was no evidence that the presence of concomitant disease adversely affected the safety profile of trimazosin. Of particular interest, there was no evidence that trimazosin caused worsening of disease in hypertensive patients with ischemic heart disease, chronic heart failure, cardiac arrhythmias, respiratory disease predisposing to bronchospasm, hyperuricemia, gout, hyperlipidemia, diabetes melli- tus, or renal dysfunction. Trimazosin did not adversely affect treadmill exercise performance (Ta- ble V) or increase rate-pressure product (a measure of myocardial oxygen requirements). As expected in this patient population, a large number of drugs were used concomitantly in the hypertensive patients receiving trimazosin, and there was no evidence of adverse drug interactions. Concomitant therapy included diuretics, nonsteroidal anti- inflammatory drugs, potassium chloride, uric acid- lowering agents, digoxin, propranolol, methyldopa, lipid-lowering agents, and hypoglycemic agents.

SUMMARY AND CONCLUSIONS

These extensive short- and long-term studies have demonstrated that trimazosin is an effective and safe antihypertensive agent. Long-term studies have established that elevated blood pressure is reduced by trimazosin in the supine and standing positions throughout chronic therapy; a majority (74%) of patients showed an antihypertensive response to a daily dose of 300 mg or less, with the maximum daily dose being 300 mg or less in 52% of the patient population. Trimazosin was administered twice a day in most patients in these studies. Although peak trimazosin plasma concentrations occurred at about 1 hour after dosing, the maximum fall in blood pressure was observed after 3 to 6 hours. Thus the pharmacodynamics and pharmacokinetics of trimazosin may not be’directly related. The pharmacokinetics of trimazosin were described by Reid et a1.3 An initial pharmacokinetic study of a trimazosin sustained-release formulation has also been reported.4

In previously reported acute placebo-controlled

Table XIV. Double-blind trimazosin/placebo U.S. outpatient hypertension studies: Comparative side effect profile

Trimazosin Placebo

Total No. of patients 81 79 Oc, Patients with one or more side 23.5 22.8

effects “c, Patients discontinued 0 1.3

Side effects % Total patients

Cardiovascular system Hypotension/postural dizziness Dizziness Palpitations Arrhythmias

Gastrointestinal Nausea Diarrhea Dry mouth Constipation Flatulence Vomiting Flatus

Central nervous system Headache Drowsiness/sedation Vision, blurred Impotence Nervousness Anxiety Insomnia Tremor

Vasomotor Flushing Erythema

Miscellaneous Fatigue/malaise Muscle aches Libido, diminished Dyspnea Nasal congestion

4.9 1.2 3.7 1.2

1.2 3.7 1.2 1.2 1.2

8.6 7.4

2.5

1.2 1.2 1.2 1.2

1.2 1.2

4.9

1.2 1.2 1.2

6.3

1.3 1.3

2.5 1.3

7.6 2.5

2.5

1.3 1.3

5.1 1.3

1.3

investigations, De Guia et a1.5 observed that trimazosin consistently reduced blood pressure and digi- tal vascular activity in hypertensive patients. No significant changes in plasma renin activity, renal sodium excretion, or body weight were noted, and the drug was well tolerated. Additionally, Chrysant et al.,6 in a double-blind study of trimazosin vs placebo, confirmed that trimazosin lowered blood pressure through arterial dilation and reduction in peripheral vascular resistance. Renal blood flow was increased and renal vascular resistance was reduced with no effect on glomerular filtration rate or plasma renin activity.

Double-blind comparisons of trimazosin with methyldopa and placebo7eg have shown that both drugs were equally effective and signitlcantly more

1270 Taylor et al.

Table XV. Overall side effect profile of trimazosin Table XV. cont’d

Total No. of patients 796 <‘( Patients with one or more side effects 39.2

01(, Patients discontinued 4.6

No. of 7; Total Side effects patients patients

Total No. of patients 796 (‘(’ Patients with one or more side effects 39.2 “c, Patients discontinued 4.6

Side effects

Cardiovascular system Hypotension/postural dizziness Dizziness Edema Palpitations Chest pain/tightness/pressure Faintness Arrhythmias Bradycardia Dizziness on exertion Myocardial infarction Syncope

Gastrointestinal Nausea Diarrhea Abdominal discomfort Dry mouth Constipation Indigestion Abdominal pain/cramps Flatulence Vomiting Anorexia Epigastric distress Tenesmus, rectal Weight gain

Skin Rash Itching Erythema

Urogenital system Urinary frequency

Respiratory system Dyspnea

Central nervous system Headache Drowsiness/sedation Vision, blurred

135 17.0 63 7.9 47 5.9 12 1.5

8 1.0 4 0.5 4 0.5 3 0.4 2 0.3 2 0.3 1 0.1 1 0.1

94 11.8 33 4.1 23 2.9 11 1.4 11 1.4

8 1.0 7 0.9 7 0.9 6 0.8 3 0.4 2 0.3 2 0.3 1 0.1 1 0.1

21 2.6 14 1.8

5 0.6 4 0.5

2 0.3

8 1.0 147 18.5

75 9.4 33 4.1 15 1.9

effective than placebo. However, trimazosin was better tolerated. In a long-term comparison with propranolol, response rates were similar with the two drugs but, again, trimazosin was better tolerated.‘O In a further double-blind study, trimazosin, used as adjunctive therapy, was shown to be effective in patients failing to respond to prior thiazide therapy.”

The efficacy and safety profile of trimazosin, as documented here for hypertensive patients, is further supported by other reports.12-l5 In addition, trimazosin has been shown to produce subjective

November, 1993


Impotence Nervousness Twitch (tics) Depression Visual disturbances Anxiety Insomnia Paresthesia Difficulty concentrating Tinnitus Vertigo Confusion Tremor Agitation Akathisia Irritability Numbness in extremities Parkinsonism

Vasomotor Flushing Sweating Cold sweats

Eyes/ears/nose/throat Nasal congestion Eye irritation Earache Epistaxis Sore throat

Miscellaneous Fatigue/malaise Weakness Aches/pains Leg pain Burning sensation Libido, diminished Libido, increased Allergic reaction

No. of % Total patients patients

4

12 5 4 1 1

72 61

6 4 2

1.0 1.0 0.8 0.6 0.6 0.5 0.5 0.5 0.4 0.4 0.4 0.3 0.3 0.1 0.1 0.1 0.1 0.1 1.1 0.6 0.4 0.1 1.5 0.6 0.5 0.1 0.1 0.1 9.0 7.7 0.8 0.5 0.3 0.1 0.1 0.1 0.1

and functional improvemenP in short-17-25 and long- term26-33 therapy of chronic heart failure.

Special studies carried out in association with this clinical development program have revealed that trimazosin significantly decreased total serum cholesterol concentrations, while levels of HDL cholesterol were maintained. Further, in a long-term, double-blind trial,2 trimazosin was shown to be superior to propranolol in its effects on HDL cholesterol and the HDL/total cholesterol ratio after 12 weeks of therapy; when data were reanalyzed after ‘I-months of continuous therapy and after diuretics

Volume 106

Number 5, Part 2

Table XVI. Double-blind trimazosin/methyldopa hypertension studies: Comparative side effects profile

Trimazosin Methyldopa

Total No. of patients f& Patients with one or more side

effects Y Patients discontinued

Side effects

Cardiovascular system Hypotension/postural dizziness Dizziness Palpitations Chest pain/tightness/pressure

Gastrointestinal Nausea Dry mouth Constipation

Central nervous system Headache Drowsiness/sedation Vision, blurred Impotence Nervousness Depression Anxiety Hyperkinesia Insomnia Tinnitus Tremor

Vasomotor Flushing

Eyes/ears/nose/throat Sore throat Taste change

Miscellaneous Fatigue/malaise Aches/pains Burning sensation Pyrexia

31 31 22.6 45.2

0 6.5

% Total patients

3.2 6.5 3.2 3.2 3.2

6.5

3.2 3.2 9.7

3.2 6.5

6.5 6.5 3.2 9.7 3.2 3.2 6.5 3.2 3.2

3.2 3.2

3.2 3.2 3.2

3.2 3.2

3.2 3.2

3.2 3.2

3.2 9.7 3.2

3.2 3.2

had been added to some patients’ regimens, trimazosin remained superior to propranolol in effects on HDL cholesterol and the HDL/total cholesterol ratio. The use of thiaxides adversely affected HDL cholesterol and the HDL/total cholesterol ratio.

Special studies also showed that there was no apparent progression of hypertension target organ damage during trimaxosin therapy. Electrocardio- graphic voltage (an index of LV hypertrophy) was reduced, and apparent improvement in renal function was observed. In addition, Chrysant et ala previously reported that blood chemistries, blood count, plasma renin activity, plasma volume, and plasma aldosterone were not adversely affected dur-

Clinical pharmacologic profile of trimazosin 1279

Table XVII. Double-blind parallel long-term comparison study of trimazosin and propranolol: Comparative side effects profile

Trimazosin Propranolol

Total No. of patients 66 66 76 Patients with one or more side 24 48

effects % Patients discontinued 1.5 4.5

Side effects % Total patients

Cardiovascular Dizziness Palpitations Hypotension Chest pain/tightness Bradycardia Edema Ankle edema Angina Dizziness on exertion

Gastrointestinal Indigestion Nausea Dry mouth Constipation Epigastric discomfort Flatulence

Central nervous system Headache Insomnia Vertigo Tinnitus Anxiety Lacrimation Blurred vision Numbness of extremities Impotence

Vasomotor Coldness of extremities

Miscellaneous Fatigue/malaise Asthenia Dyspnea Sweating Asthma Diminished libido Dry skin Itching Gout Muscle pain Eye irritation

6.1 6.1 1.5 1.5

1.5

1.5

3.0 1.5 1.5

1.5 1.5

6.1

3.0 1.5

12.1 3.0 3.0 1.5 3.0 1.5 1.5 1.5

6.1 3.0

1.5 1.5 1.5

7.7 6.1 3.0 1.5 1.5 1.5 1.5 1.5 1.5

1.5

9.1 4.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

ing 8 weeks of trimaxosin therapy in a double-blind placebo-controlled study.

Trimaxosin has been used successfully in hypertensive patients with a variety of concomitant dis- eases and in combination with a diversity of other medications. A detailed evaluation of side effects

1280 Taylor et al.

Table XVIII. Results of laboratory evaluation of hypertensive patients being treated with trimazosin

P;. Incidence No. abnormal*

patients Test tested Increase Decrease

Hematology Hemoglobin 607 0 0 Hematocrit 600 0.3 0.3 RBC 225 0 0 Platelets 341 0 0.6 WBC 610 0.2 0.3 Neutrophils 457 0.4 0.9 Eosinophils 451 0.2 0 Basophils 452 0 0 Lymphocytes 457 0 0 Monocytes 455 0 0.2 MCV 150 0 0 MCH 150 0 0.7 MCHC 150 0 0 ESR 211 1.0 0 Reticulocytes 11 0 0

Serum protein Total protein 535 0 0 Serum albumin 491 0 0 Serum globulin 261 0 0 A/G ratio 260 0 0

Liver function Total bilirubin 587 0.2 0 SGOT 609 0.7 0 SGPT 425 0.9 0 Gamma GT 415 1.7 0 LDH 342 0.3 0 Alkaline 609 0.2 0

phosphatase Renal function

Blood urea 225 0.4 0 BUN 374 0.5 0 Serum creatinine 549 0.6 0 Uric acid 599 0.5 0 BUN/creatinine 260 0 0

Abbreviations: RBC = red blood cells; WBC = white blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; ESR = erythrocyte sedimentation rate; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; GT = gamma glutamyl transferase; LDH = lactic dehydrogenase; BUN = blood urea nitrogen; ANA = antinuclear antibody; hpf = high-power field. *Not attributable to other factors.

and laboratory parameters has revealed trimazosin to have an excellent safety profile. In view of its excellent safety and toleration profiles, trimazosin may be particularly suitable for first-line therapy of patients with mild or moderate hypertension. REFERENCES

1. Constantine JW, Hess HJ: The cardiovascular effects of trimazosin. Eur J Pharmacol 74~22’7, 1981.

2. Singleton W, Taylor CR: Effect of trimazosin on serum lipid profiles in hypertensive patients. AM HEART J 106:1265,1983.

November, 1983


Table XVIII. cont’d

Test

No. patients

tested

I:; Incidence abnormal *

Increase Decrease

Plasma renin activity

Electrolytes Chloride Sodium Potassium CO, content

Miscellaneous Serum calcium Ionized calcium Inorganic

phosphorus Cholesterol HDL cholesterol Triglycerides Glucose,

nonfasting Serum osmolality ANA Anion gap Aldosterone

Urine Albumin Glucose WBClhpf RBC/hpf Bacteria/hpf Casts/hpf Epithelial cells Proteinuria Sodium Potassium Chloride Creatinine Aldosterone

236 0 0

384 0 451 0 452 0 348 0

486 0 0.2 260 0 0 336 0 0

561 0 0 300 0 0 268 0 0 607 0.3 0.2

260 0 271 1.1 261 0

35 0

609 0.3 0 609 0.2 0 446 0.9 0 435 0.9 0 399 0 0 412 0.2 0

18 0 0 65 1.5 0 43 0 0 41 0 0 12 0 0 31 0 0 30 0 0

13 ,

4.

5.

6.

7.

8.

9.

10.

Reid J, Meredith PA, Elliott HL: The pharmacokinetics and pharmacodynamics of trimazosin in man. AM HEART J 106:1222, 1983. Flouvat B, Fodor F, Roux A, Bianchine JR: Pharmacokinetics of a sustained-release trimazosin tablet formulation. AM HEART J 106:1228, 1983. De Guia D, et ah The effect of trimazosin in essential hypertension. Curr Ther Res 15:339, 1973. Chrysant SG, Luu TM, Danisa K, Kern DC, Manion CV: Systemic and renal hemodynamic effects of trimazosin: A new vasodilator. J Cardiovasc Pharmacol 2:205, 1980. Aronow WS, et al: Comparison of trimazosin and methyldopa in hypertension. Clin Pharmacol Ther 22:425, 1977. Aronow WS, et al: Effect of trimazosin, methyldopa and placebo on hypertension. Curr Ther Res 23:448, 1978. Moyer RR: A double-blind study of trimazosin and methyldopa in hypertensive patients receiving polythiazide. AM HEART J 106:1250, 1983. Helgeland A: Double-blind comparison of trimazosin and propranolol in essential hypertension. AM HEART J 106:1253, 1983.

Volume 106

Number 5. Part 2

11. Oberman A, Pool PE: Trimazosin for the treatment of hypertensive patients failing to respond to thiazides. AM HEARTJ 106:1258,1983.

12. Pool PE, Seagren SC, Sale1 AF: Clinical hemodynamic profile of trimazosin in hypertension. AM HEART J 106:1237, 1983.

13. Chrysant SG: Autonomic, systemic, and renal hemodynamic actions of trimazosin in hypertensive subjects. AM HEART J 106:1243, 1983.

14. Vlachakis ND. et al: Treatment of essential hvnertension with trimazosm, a new vasodilator agent. Cur; -Ther Res 17~564, 1975.

15. Weber MA, et al: A vasodilator that avoids renin stimulation and fluid retention: Antihypertensive treatment with trimazosin. Clin Pharmacol Ther 31:572, 1982.

16. Taylor CR, et al: Comparative pharmacology and clinical efficacy of newer agents in treatment of heart failure. AM HEART J 102:515, 1981.

17. Franciosa JA, et al: Hemodynamic effects of trimazosin in patients with left ventricular failure. Clin Pharmacol Ther 23:1, 1978.

18. Orlando JR, et al: Effect of trimazosin on hemodynamics in chronic heart failure. Clin Pharmacol Ther 24:531, 1978.

19. Awan NA, et al: Cardiocirculatory effects of afterload reduction with oral trimazosin in severe chronic heart failure. Am J Cardiol 44:126, 1979.

20. Mason DT, et al: Comparison of cardiocirculatory actions of the oral systemic vasodilators trimazosin and prazosin: Dem- onstration of similar useful efficacy in therapy of severe heart failure. Am J Cardiol 43:403, 1979.

21. Awan NA, et al: Cardiocirculatory effects of the oral systemic vasodilators trimazosin and prazosin: Similar useful efficacy in severe heart failure therapy. Clin Res 27:14A, 1979.

22. Awan NA, et al: Comparison of oral trimazosin with nitro- prusside: Equal balanced afterload reduction in vasodilator treatment of severe congestive heart failure. Clin Res 273146, 1979.

23. Hermanovich J, et al: Balanced afterload reduction with oral trimazosin shown by cardiac catheterization and plethys-

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

Clinical pharmacologic profile of trimazosin

mography in refractory congestive heart failure patients. Clin Res 27:16A, 1979. Whitcomb C, et al: Oral trimazosin compared to nitroprus- side: Similar balanced afterload reduction in vasodilator treatment of severe congestive heart failure. Circulation 6O(suppl II):181, 1979. Ports TA, et al: Beneficial hemodynamic effects of a new oral vasodilator, trimazosin, in chronic heart failure. Clin Res 28:13A, 1980. Aronow WS, et al: Effect of the vasodilator trimazosin versus placebo on exercise performance in chronic left ventricular failure. Am J Cardiol 40:789, 1977. Aronow WS, et al: Efficacy of trimazosin and prazosin therapy on cardiac and exercise performance in outpatients with chronic congestive heart failure. Am J Med 65:155, 1978. Weber KT, et al: Long-term vasodilator therapy with trimazosin in chronic cardiac failure. N Engl J Med 303:242, 1980. Taylor DJ, et al: Treatment of refractory heart failure with trimazosin. Eur Heart J 2:127, 1981. Komajda M, et al: Trimazosin in chronic congestive cardiac failure. Symposium “Congestive Heart Failure: New Hopes,” Brussels, January, 1982. Kirlin P, et al: Chronic adjunctive trimazosin vasodilator therapy in heart failure: A six-month double-blind placebo controlled randomized trial. Am J Cardiol 49:925, 1982. Weber KT, et al: Vasodilator and inotropic agents in treatment of chronic cardiac failure: Clinical experience and response in exercise performance. AM HEART J 102:569, 1981. Chatterjee K, et al: Trimazosin in chronic congestive heart failure: Improved left ventricular function at rest and during exercise. AM HEART J. (in press.) Chrysant SG, Miller RF, Brown JL, Danisa K: Long-term hemodynamic and metabolic effects of trimazosin in essential hypertension. Clin Pharmacol Ther 30:600, 1981.

Discussion-Session III

W. H. Birkenhiiger, M.D.Gt4cderator

Professor Mattila: Dr. Pool, in your clinical studies, did you see any evidence of an excessive first-dose response with trimazosin?

Dr. Pool: No, not a genuine first-dose response. There is, as with prazosin, a small first-dose response in terms of patients noticing a hit of a postural effect for the first few days on the drug, but nothing marked, and certainly no syncope or anything like that.

Professor Rosendorff: I have never understood why there is not a reflex tachycardia with prazosin and now with trimazosin. One would expect that there would be, even if there was a resetting of the baroreceptor mechanism. It is a prominent feature of hydralazine therapy, which has a mechanism of action similar to these drugs. Why do we not get a reflex tachycardia?

Dr. PooZ: The common explanation is selective alpha,- blockade.

Professor Mallion: When we study the effect of prazosin during exercise, we realize that the higher the level of exercise, the more important the lowering of blood pressure. Did you find the same result with trimazosin?

Dr. Pool: No. At peak exercise,‘there was actually less suppression than at rest. Professor Reid.- I have a question on side effects. In Dr. Taylor’s pooled data of placebo-controlled and other trials, it was shown clearly that there is no difference in the frequency of headache or of dizziness. But headache in hypertensive patients can be caused either by severe uncontrolled hypertension or by hypotension from a peripheral vasodilator action. It is important to assess headache and dizziness in relation to drug administration. If the frequency of patients complaining of dizziness was the same in the trial groups, was there any difference in blood pressure levels recorded for these individuals while

1281

profile of trimazosin: an effective and safe antihypertensive agent

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