Long-term efficacy and safety of terazosin alone and in combination with other antihypertensive agents

This open, multicenter phase III study was designed to assess the efficacy and long-term safety of terazosin (1 to 40 mg/day), alone or in combination with other antihypertensive drugs, in 364 patients with mild to moderate essential hypertension. Compared with baseline values, long-term terarosin monotherapy or combination therapy resulted in consistent decreases in both systolic and diastolic blood pressures, with a mean reduction in supine diastolic pressure of 12 to 14 mm Hg. The numbers of patients with controlled blood pressure at the last evaluable visit of each therapy period were as follows: terazosin alone, 106 of 246 (43%); terazosin with added diuretic, 70 of 112 (63%); diuretic with added terazosin, 47 of 68 (53%); and terazosin plus diuretic with added &blocker, 22 of 32 (69%). Most adverse events were mild or moderate in severity. Only pain in extremities had a higher incidence during long-term treatment (6%, 181 to 360-day period) than during initial short-term treatment (5%, 1 to go-day period). Three of six syncopal events occurred during the initial 180 days of treatment; this 0.8% (31384) incidence was comparable with that reported previously for short-term studies. Only one case of syncope occurred during terazosin monotherapy. Terazosin was judged to be a safe and effective long-term medication for the treatment of hypertension. (AM HEART J 1991;122:919-25.)

Jerome D. Cohen, MD St. Louis, MO.

Terazosin is a new selective al-blocker that is similar in structure to prazosin. However, compared with prazosin, terazosin shows better pharmacokinetics with more consistent absorption after oral admin- istration.’ In addition, terazosin has a relatively long half-life that supports a once-a-day treatment regimen.l The once-a-day administration of tera- zosin has been found to be safe and effective treat- ment for mild to moderate hypertension.2, 3 In a study involving 24-hour ambulatory monitoring of 191 hypertensive patients (untreated supine systolic pressures 1100 mm Hg), terazosin significantly de- creased whole-day blood pressure averages when compared with placebo. Terazosin, 5 mg, adminis- tered once in the morning, produced a consistent re- duction in blood pressure when compared with pla- cebo baseline values throughout the entire 24-hour period.4 Unlike other antihypertensive agents, tera- zosin does not produce biochemical abnormalities and has a favorable effect on plasma lipid pro- filefh3~ 5-6

From the Department of Internal Medicine, St. Louis University Medical center.

Reprint requests: Jerome D. Cohen, MD, 3525 Caroline Ave., St. Louis, MO 63104.

4/o/30197

No single agent, however, can control hypertension in all patients. Approximately 40% to 50% of patients71 8 can be expected to require a second anti- hypertensive agent eventually to adequately control blood pressure. The present study was designed to evaluate the long-term safety and efficacy of tera- zosin, alone and in combination with other antihy- pertensive agents such as thiazide diuretics and /3-blockers. Preliminary results of long-term mono- therapy with terazosin7y s were encouraging. Mersey7 observed that long-term therapy with terazosin (196 patients grouped by time intervals ending at 96,180, 360,720, and >720 days of therapy) resulted in sig- nificant 0,s 0.05) mean decreases from baseline for supine diastolic (- 10 to - 13 mm Hg) and systolic (-9 to -10 mm Hg) blood pressures. Similar results for this study were reported by Luther et al.,8 who dis- cussed 43 hypertensive patients who received tera- zosin monotherapy for 2 years or more. Terazosin was well tolerated during long-term treatment, with side effects similar to those reported in short-term studies9

METHODS

This multicenter phase III long-term study was designed to integrate patients from several short-term studies for long-term follow-up. Patients were eligible to enter this

919

920 Cohen

Table I. Summary of demographic characteristics for patients included in efficacy analyses - ~.. __--.--.- -_-_-- ..___ ----_- ___. -

Group A Group H Group (’ 1 ;r.>!r/i 1) l:r~,lrp !-. (n = 245) (12 = 11s: (n = 88) / t; z .‘:I!) : il = .‘ii9,

_.-- Age (yr)

Mean + SE 51 * 0.7 51 -+ 0.9 52 i. 1.1 :i 1 t i 7 .-I:! t 0.6 Range 21-75 22-7.5 22-72 ““-68 :!I -7.:

Race White 196 90 56 Z-1 268 Black 43 21 28 s 7R Other 6 1 4 7 I :i

Sex Male 161 69 61 19 246 Female 84 43 2: 13 113

Weight (lb) Male

Mean i SE 197.0 i 2.9 198.2 + 4.6 199.9 i 4.4 204.1 2 7.0 197.0 t 2.2 Range 123-338 127-283 149-281 170-2.54 1 ‘%1x? “I 1

Female Mean i SE 174.3 * 4.8 185.8 zk 9.6 167.5 rt- 7.3 183.7 L 18.7 173.4 -t 4.0 Range 117-330 119-324 124-253 120.274 1 17-3x0

C;roup A. Terazosin alone; (:ruup R, terazosin plus diuretic; C;roup C, diuretic plus terazosin; C;rt~up I). terazosin plus diuretic plus &hl<rkcr; C;r~~up R. all

Table II. Summary of patients who discontinued long-term therapy according to treatment regimen at time of discon- tinuation

Reason for discontinuation

from therapy

Therapy group

High RP*

Adverse High + adverse Miscel-

event BP* event laneous

Terazosin alone 21 4 0 58 Terazosin + added 27 3 2 59

diuretic Terazosin + added 5 2 1 18

diuretic + added B-blocker

Terazosin + other 6 2 0 3 Total from all 59 12 3 138

therapies

AP, Blood pressure. *High supine diastolic blood pressure that could not be controlled.

study if they had received terazosin (daily or twice daily) as part of either a dose-titration study or a double-blind study and had experienced a decrease of at least 7 mm Hg in supine diastolic blood pressure from baseline to the final visit of short-term therapy.

Terazosin was supplied in doses of 1,2,5, and 10 mg. The maximum allowable dose was 40 mg once daily or 20 mg twice daily. At the discretion of the investigator, terazosin dosage could be altered, and other antihypertensive drugs could be added to the patient’s treatment regimen. When necessary, other hypertensive drugs were added in the fol-

Table Ill. Summary of the number of evaluable patients with controlled blood pressure (supine diastolic blood pressure <90 mm Hg) at the last evaluable visit of each therapy period

Group: therap.>

A: Terazosin alone B: Terazosin + added diuretic C: Diuretic + added terazosin D: Terazosin + added diuretic +

added B-blocker

~ont.rolied

h/Wd No. of pressure

patients f’, i

“45 106 (43) 112 70 (63)

88 47 (53)

32 2” (69)

lowing sequence: methyclothiazide (Enduron) or other thiazide diuretics, propranolol or other fl-blockers, or other antihypertensive medication not including prazosin or other peripheral vasodilators.

For the first year of treatment, patients were evaluated during monthly visits. More frequent visits were scheduled if the patient’s blood pressure was not controlled (supine diastolic blood pressure <90 mm Hg) or at the discretion of the investigator. After 1 year, visits were scheduled at 2-month intervals for any patient whose blood pressure was controlled or whose regimen did not require adjustment. At each study visit, the following patient variables were eval- uated: blood pressures (supine and standing), pulse rate, body weight, and general health status. Diastolic blood pressure was usually recorded as phase V of the Korotkoff sounds unless the difference between phase IV and V sounds exceeded 15 mm Hg; in that case the phase IV

Volume 122

Number 3, Part 2 Long-term efficacy and safety of terazosin 92 1

Table IV. Summary of mean supine and mean standing blood pressures (systolic/diastolic) at baseline and mean changes from baseline as measured at the last visit of the specified regimen for each time interval

Time intervals for each therapy (days)

Groups l-90 91-180 181-360 361-720 >720

Supine blood pressures A: Terazosin alone

B: Terazosin +

added diuretic

C: Diuretic +

added terazosin

D: Terazosin -t diuretic +

P-blocker

E: All patients

Standing blood pressures A: Terazosin alone

B: Terazosin +

added diuretic

C: Diuretic +

added terazosin

D: Terazosin +

diuretic + $-blocker

E: All patients

No. of patients

Baseline (pre-TRZ)

Change No. of patients Baseline (prediuretic)

Change (from diuretic)

No. of patients

Baseline (pre-TRZ)

Change No. of patients Baseline (preblocker)

Change (from

P-blocker) No. of patients

Baseline (pre-TRZ) Change

No. of patients

Baseline (pre-TRZ) Change

No. of patients

Baseline (prediuretic) Change (from

diuretic) No. of patients

Baseline (pre-TRZ)

Change No. of patients

Baseline (preblocker) Change (from

P-blocker) No. of patients

Baseline (pre-TRZ) Change

244 172 128 88 43

153/100 151/99 150198 150198 148/98

-IO/--IO -1oi-11 -111-12 -121-13 -g/-12

112 91 78 48 20 149195 149/94 149194 150/95 150/94

-141-g -131-g -14/-8 -171-g -18/-10

87 80 61 50 27

148198 149198 148198 147198 143/96 -ll/-13 -lO/-10 -91-12 -lO/-13 -B/-l1

32 31 27 19 10 148195 147195 146194 147195 145195 -81-g -lO/-10 -111-g -71-8 -91-12

357 349 314 259 137 152/99 152199 152/99 El/99 150198

-13/-12 -14/-13 -141-14 -14/-13 -14/-13

244 172 128 88 43 149/101 147199 146198 145198 143197

-15/-11 -13/-12 -18/-14 -14/f-14 -12/-13 112 91 78 48 20

140/93 140/93 140/93 138192 141/91 -131-g -14/-9 -151-g -141-g -22/-11

87 80 61 50 27 145/101 146/101 144/100 143/99 139197

-ll/-13 -lO/-11 -12/-14 -14/-16 -91-15 32 31 27 19 10

137/94 137194 135193 133/93 128190 -8/-9 -IO/-9 -111-10 -u-9 -18/-16

357 349 314 259 137 148/101 148/101 148AOO 147llOO 145/99

-16/-13 -18/-14 -2O/-16 -201-17 -191-17

TRZ. Terazosin.

pressure was recorded. Routine clinical chemistry assays drugs, terazosin plus diuretic plus p-blocker (baseline: ter- and ECG evaluations were performed every 3 months for azosin plus diuretic); and group E (n = 364): data combined the first year and then at 4-month intervals for the dura- for all patients regardless of therapy (baseline: pre-tera- tion of the study unless more frequent intervals were zosin). Patient data were included in a therapy group (A to deemed necessary by the investigator. A complete physical E) if the patient had undergone the therapy for at least 30 examination of each patient was performed at yearly days. A patient could contribute data to one or more groups intervals. depending on treatment experience.

Patient data were categorized retrospectively into five Adverse events data were grouped as follows for analy- therapy groups for analyses (excluding adverse event anal- sis: terazosin alone (group A), terazosin plus diuretic ysis): group A (n = 249): data for study periods in which (groups B and C), terazosin plus diuretic plus B-blocker patients received terazosin alone (baseline: no medication); (group D), and any therapy (all data on all adverse events). group B (n = 112): data for study periods in which patients Adverse events were grouped by means of coding symbols received terazosin plus an added thiazide diuretic (base- for thesaurus of adverse reaction terms (COSTART)r” line: terazosin alone); group C (n = 89): data for study pe- body system classification terms. Efficacy and safety vari- riods in which patients received a thiazide diuretic plus added terazosin (baseline: diuretic alone); group D (n = 32):

ables were evaluated during each of the following time in- tervals for each therapy: 90 days or less, 91 to 180 days, 181

data for study periods in which patients received three to 360 days, 361 to 720 days, and more than 720 days. Time

922 Cohen September 1991

American Heart Journal

Table V. Summary of the number of patients and patient episodes with extreme pulse rate measurements by time

interval (days) for group E: all patients combined and for group A: terazosin alone

Baseline f-90 91-180 lHl-360 36 1 72fJ > 72ri

Supine >lOO beats/min E: Patients 171364

Episodes 2611371 A: Patients 10/249

Episodes 141877 Standing >lOO beats/min

E: Patients 431364 Episodes 67,‘1363

A: Patients 231249 Episodes 301868

Supine <50 beats/min E: Patients 21364

Episodes 2/1371 A: Patients 21249

Episodes 21877

Standing GO beats/min E: Patients O/364

Episodes O/1363 A: Patients o/249

Episodes O/868

231364 61354 161318 121261 6/l 39

3413127 911448 2712156 28/2006 16/1302 11/249 l/l74 3/130 2/89 O/44

14/2098 l/682 31852 21663 o/350

80/364 411354 541318 421261 31/139 160/3111 61/1440 112/2152 118/1995 8511297

401249 19/174 171130 9189 11144 6812091 271680 311852 241658 27/349

61364 3/354 71318 61261 6/139

lo/3127 5/1448 812156 S/2006 lo/1302 61249 21174 3/130 2/89 l/44

1012098 3/682 41852 2/663 l/350

l/364 o/354 O/318 O/261 l/139

l/3111 o/1440 o/2152 o/1995 l/l297 o/249 o/174 o/130 O/89 o/44

o/2091 O/680 O/852 O/658 o/349

intervals were not equivalent to study days but reflected the duration of treatment in each of the five therapy groups.

RESULTS

Of the 364 patients enrolled in the study, 262 received treatment with terazosin for at least 1 year, 139 received terazosin for at least 2 years, 66 received terazosin for at least 3 years, and 36 patients received treatment for 4 years or more. Demographic charac- teristics for the 359 patients included in the efficacy analyses are summarized in Table I. Data on patients who discontinued long-term therapy are summarized in Table II.

To date, 690.8 patient-years of experience have been accumulated with terazosin, including 315.4 patient-years with terazosin alone, 134.3 patient- years with terazosin plus added diuretic, 133.7 pa- tient-years with diuretic plus added terazosin, 65.0 patient-years with terazosin plus diuretic plus p- blocker, and 42.4 patient-years with terazosin plus other agents.

Approximately half of the patients in each therapy group had their blood pressure controlled (supine diastolic blood pressure <90 mm Hg) at the last evaluable visit of each treatment (Table III). Long- term treatment with terazosin, either alone or in combination with other antihypertensive agents, re- sulted in consistent reductions from baseline for all

blood pressure variables at all evaluated time inter- vals, with decreases caused by terazosin ranging from 8 to 18 mm Hg (Table IV). Monotherapy with tera- zosin produced a mean decrease in supine diastolic blood pressure of 10 to 13 mm Hg. The antihyper- tensive effects of terazosin plus a diuretic appeared to be independent of the order in which the drugs were introduced (Table IV). Similarly, the addition of ,&blocker resulted in further decreases in blood pressures. Overall terazosin alone or the combination of terazosin and other antihypertensive agents pro- duced mean decreases of 12 to 20 mm Hg. The per- centage of patients with orthostatic changes in sys- tolic blood pressure was similar among treatment groups, with approximately 36 % of all patients exper- iencing one or more such episodes.

Based on Kaplan-Meier methodology,” of the 245 patients who began treatment with terazosin alone, 59% did not require any additional hypertensive agent to achieve controlled blood pressure by the end of the first year of treatment. Similarly, 52% of pa- tients receiving terazosin monotherapy maintained controlled blood pressure without any additional hy- pertensive agent after 2 years of therapy and 45% after 3 years of treatment.

Bradycardia was a relatively uncommon event during therapy either with terazosin alone or in com- bination with other drugs (Table V). However, tachycardia, especially in the standing position, was

Volume 122

Number 3, Part 2 Long-term efficacy and safety of terazosin 923

Table VI. Summary of mean changes in body weight (pounds) from baseline for the indicated therapies by time intervals; baseline is preterazosin treatment for groups A, C, and E; prediuretic for group B; and pre+blocker for group D

No. of days

Group l-90 91-180 181-360 361- 720 >720

A: Terazosin alone Males n Change

Females n

Change B: Terazosin + diuretic Males n

Change*

Females n

Change*

C: Diuretic + terazosin Males

Change

Females n

Change

D: Terazosin + diuretic + Males n

D-blocker

Change?

Females n

Change?

E: All patients Males n

Change

Females n Change

*Change caused by diuretic when added to terazosin. tChange caused by &blocker when added to terazosin + diuretic.

162 117 88 59 31

1.1 1.3 0.3 1.3 5.6

87 57 42 30 13

1.3 1.0 1.0 2.8 3.9

69 55 47 27 11

-1.2 -2.0 -1.5 -0.5 1.0

43 36 31 21 9

-0.0 1.3 1.9 1.6 1.8 62 57 41 32 19

2.8 1.6 2.0 0.9 6.5

27 24 22 19 9

2.2 2.6 2.8 5.5 4.1

19 18 15 10 4

-0.7 -1.4 -2.0 1.6 7.3

13 13 12 9 6

1.8 0.6 0.0 5.8 -3.0

249 242 213 176 93

1.4 0.9 0.6 1.0 4.4

115 111 105 85 46

1.3 1.6 2.2 4.4 3.7

more common. The percentage of measurements that demonstrated a standing pulse rate >lOO beats/min was approximately 5% both at baseline and during treatment for all patients. As expected, when a ,&blocker was added to the regimen of 32 patients receiving terazosin and a diuretic, the percentage of measurements demonstrating standing and supine pulse rates >lOO beats/min decreased to approxi- mately 2% (data not included in Table V).

Both male and female patients tended to gain weight during monotherapy with terazosin or when terazosin was added to diuretic therapy (Table VI). Male patients tended to lose weight (mean change of -0.5 to -2.0 pounds for each of the time intervals) when a diuretic was added to terazosin therapy (Ta- ble VI). In contrast, female patients tended to gain weight (mean change of 1.3 to 1.9 pounds for each of the time intervals) when a diuretic was added to ter- azosin therapy. Terazosin had no clinically signifi- cant effects on serum glucose, uric acid, blood urea nitrogen, creatinine, aspartate aminotransferase, al- kaline phosphatase, bilirubin, or potassium levels. Changes in these variables observed when terazosin was combined with diuretics were consistent with the known effects of diuretics. There appeared to be a trend toward a decrease in hematocrit and total pro-

tein levels during the entire study, which may be in- dicative of hemodilution. None of the observed changes in clinical laboratory variables indicated any toxic drug effect.

The incidence of the most common adverse events in each treatment interval is summarized in Table VII. The events reported for terazosin during the initial time period (1 to 90 days) occurred primarily during short-term studies. Adverse events with inci- dence rates of 25 % in any long-term period include headache, dizziness, asthenia, cold symptoms, nasal congestion, chest pain, and pain in the extremities. It should be noted that the prevalence of events such as headache, cold symptoms, and flu symptoms would be expected to be high in any long-term study. To identify “delayed” or long-term effects, the incidence (not prevalence) of adverse events during the initial period (short-term studies, 1 to 90 days) was com- pared with that in other time periods. As shown in Table VII, only “pain in extremities” had a higher incidence in a long-term period (6%) 181 to 360 days) than in the short-term period (5 % , 1 to 90 days).

There were six reports of syncope during the long- term study; however, three of these events occurred during the first 180 days. This incidence (3/364, 0.8% ) is comparable with that reported previously

924 Cohen

Table VII. Summary of the incidence of the most commonly occurring adverse events (percentage) for all patients in each treatment period

Time interuals (days) for each period

Adrlerse event l-90 91-180 181-360 <161- 720

No. of patients who entered interval

Headache Dizziness Asthenia Cold symptoms Nasal congestion Chest pain Pain in extremities Back pain Nausea Peripheral edema Somnolence Dyspnea Pharyngitis Abdominal pain

Diarrhea Cough Flu Sinusitis Syncope

364 357 318 263

23 9 20 6 12 5 11 3 7 2 5 3 6 3 6 2 8 1 8 2 5 1 4 2 4 1 4 2 5 1

4 2 3 1

<1 <1

:9 12

6

6 6 4

4

2

2 <l

-8 10 4 8

4 4

<l <I

2

for short-term studies. In addition, only one of the six events of syncope occurred while the patient received terazosin monotherapy. Five of the six syncopal events occurred while patients received terazosin in combination with other antihypertensive agents.

DISCUSSION

Hypertension is a chronic disease for which there is no cure. To prevent cardiovascular complications, antihypertensive agents must be capable of main- taining blood pressure control over long periods without producing metabolic or hemodynamic ab- normalities. In this study terazosin maintained ef- fective blood pressure reductions during long-term therapy. After 2 years of treatment, approximately half of the patients did not require another antihy- pertensive agent to control blood pressure.

Terazosin, alone or in combination with other hy- pertensive agents, was well tolerated in this study. Dizziness, headache, cold symptoms, and asthenia were the most common adverse events both with ter- azosin monotherapy and combination therapy. How- ever, most of the adverse events were mild or moder- ate in severity. The incidence of syncope was less than 1% during the first 180 days of therapy and was similar to that reported in previous studies.g The in-

September 1991 American Heart Journal

cidence of tachycardia was low, which supports the finding that reflex tachycardia is more common with direct-acting vasodilators such as hydralazine.” .‘I’ The changes in hematocrit and total protein levels observed in this study suggest a hemodilution effect, which has also been reported for another selective al-blocker, prazosin.“’ Terazosin had no clinically significant effect on serum glucose, uric acid, blood urea nitrogen, creatinine, aspartate aminotrans- ferase, alkaline phosphatase, bilirubin, or potassium levels. This is in contrast to thiazide diuretics, which alter glucose tolerance, serum uric acid concentra- tion, and serum potassium concentrations.14 I7

Terazosin has a positive effect on several cardiac risk factors, a significant advantage for long-term therapy. Terazosin has a favorable effect on serum lipid levels”, T,, 6 and can minimize the negative effects of other antihypertensive agent&-“’ when given in combination therapy. Terazosin monotherapy signif- icantly decreased serum cholesterol levels and the very low-density lipoprotein cholesterol fraction while significantly increasing the ratio of high-den- sity lipoprotein cholesterol to total cholesterol in 166 hypertensive patients.2” In addition, terazosin has been found to counteract the negative serum lipid profile effects of methyclothiazide monotherapy when used in combination with this thiazide diuretic.“, 21 In contrast to terazosin and other cyl-blockers, diuretics and P-blockers have a negative effect on serum lipid profiles (increasing serum cholesterol and triglycer- ide levels and decreasing high-density lipoprotein cholesterol fractions).“. “-“’ With regard to minimiz- ing the risk of coronary heart disease, the adverse ef- fect on serum lipid levels produced by thiazide diuretics and P-blockers, alone and in combination, may negate their antihypertensive benefits.“, “‘I AS shown in the present study and other reports,7-g hy- pokalemia, which may lead to cardiac arrhythmias, is not associated with terazosin therapy. Antiadrener- gic drugs have been reported to reduce the cardiac risks associated with left ventricular hypertrophy by reducing ventricular mass.g:i Left ventricular hyper- trophy is associated with a high risk of strokes, my- ocardial infarction, renal insufficiency, and conges- tive heart failure.“%, “4 Terazosin significantly reduces septal and posterior wall thickness as well as left ventricular mass in patients with essential hyper- tension.“’

In conclusion, this study shows that terazosin, alone or in combination with other antihyperten- sives, was a safe, effective, and well-tolerated agent for the long-term treatment of mild to moderate es- sential hypertension.

Long-term efficacy and safety of terazosin 925 Volume 122

Number 3. Part 2

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