Usefulness of low Dose Guanfacine, Once a Day, for 24-Hour Control of Essential Hypertension

ROBERT E. KEENAN, MD, PAUL L. BLACK, MD, J. C. FREUDENBURG, MD, JOSEPH A. HILL, MD, C. E. HOLMBURG, MD, MICHAEL J. REITBROCK, MD,

MAURICE J. SULLIVAN, MD, MARK T. THOMPSON, MD, and DAVID L. WRIGHT, MD

The 24-hour duration of the antihypertensive effect of guanfacine, a centrally acting cu*-adrenoceptor agonist administered once a day, was demonstrated in a 12-week, multicenter, double-blind; placebo- controlled study. Two hundred and forty-nine pa- tients who remained mildly to moderately hyperten- sive following a 5-week period, during which they had been weaned from previous antihypertensive medications and stabilized on 25-mg chlorthalidone taken once a day, were Involved. Df the 249 pa- tients, 126 received guanfacine as a step-2 agent and 123 received placebo. Both groups vtrere further subdivided so that blood pressure (BP) measure- ments were determined either 12 or 24 hours after dosing. The initial dose of guanfacine was 1 mg/day, which could be raised 1 mg at 2-week in- tervals to a maximum daily dose of 3 mg/day at the

discretion of each investigator. The daily dose could also be lowered by 1 mg at P-week intervals, de- pending on patient response. The mean 24-hour re- ductions with guanfacine in sitting diastolic BP (-11 mm Hg), systolic BP (- 14 mm Hg) and mean arte- rial pressure (- 12 mm Hg) were statistically signifi- cant (p <O.Ol) compared with the reductions in BP with placebo. Heart rate also decreased with guan- facine, but no clinically relevant bradycardia (<60 beats/min) was observed. Dry mouth (47 % ), con- stipation (16 % ), fatigue (12 % ) and drowsiness (4% ) were the most frequently reported side ef- fects. The highly acceptable side-effects profile of guanfacine was also indicated by the small percent- age of patients (7 % ) who prematurely left the study because of adverse reactions.

(Am J Cardiol 1966;57:38E-42E)

R eduction of hypertension will slow the inexorable progress of end-organ damage (nephropathy, cardiac hypertrophy, retinopathy).l Further, reduction of blood pressure (BP) must be persistent since end-organ damage correlates best with N-hour BP readings2 The antihypertensive effect of guanfacine in man has been

From the Office of Medical Research, A.H. Robins Company, Richmond, Virginia, Specialty Medical Clinic of La Jolla and San Diego, San Diego, California, Longmont Clinic, Longmont, Colorado, Doctors Clinic, Vero Beach, Florida, Internal Medi- cine Department, Medical Associates Health Center, Menomo- nee Falls, Wisconsin, Internal Medicine Department, Wilkinson Clinic, Milwaukee, Wisconsin, Internal Medicine Department, Hamilton Medical Group, Lafayette, Louisiana, Internal Medi- cine Department, Redondo Beach Medical Group, Redondo Beach, California, and Internal Medicine Department, Rock- ford Clinic Ltd., Rockford, Illinois.

Address for reprints: Samuel A. Tisdale, MD, Office of Med- ical Research, A.H. Robins Co., 1407 Cummings Drive, Rich- mond, Virginia 23220.

well demonstrated.3-7 Like clonidine, guanfacine has been shown, in pharmacologic studies, to lower BP by a central a2-receptor agonist mechanism.8 Guanfacine somewhat differs from clonidine, however, both in chemical structure (Fig. 1) and in its greater and more selective affinity for bulbar sympathetic outflow re- ceptors resulting in a longer duration of action. Be- cause of its long elimination and pharmacologic half- life and prolonged receptor binding,Q guanfacine is able to control BP successfully when administered once a day to patients with mild to moderate essential hypertension.6 This report describes the results of a multicenter, double-blind, placebo-controlled clinical trial in which the antihypertensive effect seen in pa- tients taking a single daily dose of guanfacine was measured either 12 or 24 hours after oral administra- tion, and compared with placebo control values.

Methods Patients: For entry into this efficacy study, patients

had to have a diastolic BP in the range of 95 to 114 mm

30E

March26 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume57 39E

Hg, following a &week period during which they had been weaned from previous antihypertensive medica- tions and stabilized on 25 mg of chlorthalidone once a day. Patients were excluded from the study if they were obese (50% over ideal weight) or had unstable diabetes, a history of chronic alcoholism or drug addic- tion, a malignancy or other serious disease, clinically apparent gout, labile hypertension, sympatholytic therapy immediately before study entry, clinically sig- nificant abnormal laboratory test results or were preg- nant or nursing.

The duration of essential hypertension was deter- mined by medical history. Initially, 249 patients, 3 of whom discontinued during the first week, gave written informed consent and were entered into the study, 126 being assigned randomly to step-2 treatment with guanfacine and 123 to the step-2 placebo control group. The treatment and the placebo control groups were comparable in age, race, height, weight and du- ration of systemic hypertension. Table I shows demo- graphic data on the 246 patients (156 men and 90 wom- en] who were included in the efficacy analysis,

Study design: A U-week, double-blind, placebo- controlled trial followed an initial 5-week washout and diuretic stabilization period. A single daily oral dose of guanfacine or an indistinguishable placebo was added to the chlorthalidone regimen; patients were instructed to take the test medications and chlorthalidone at 9 P.M. BP and heart rate were then measured either 12 hours later in the morning, or 24 hours later in the evening just before the next dose. Patients were thus divided into an A.M. group (those guanfacine-treated patients and placebo control sub- jects whose pulse and BP were measured 12 hours after dosing) and a P.M. group (those guanfacine-treated patients and placebo control subjects whose pulse and BP were recorded 24 hours after dosing].

Dosage: The initial guanfacine dose was 1 mg/day. Doses could be raised or lowered in l-mg increments or decrements at 2-week intervals according to BP re- sponse attained as judged by each investigator. The maximum daily dose permitted in the study was 3 mg/day, and the lowest allowable dose was 1 mg/day. Chlorthalidone (25 mg) was always given with the test medication. All test medications were blister-packed and identical in appearance. Each blister-pack was labeled as level 1,2 or 3 so that neither the investigator nor the patient knew which treatment group was assigned.

Results A.M. group: Of the 61 guanfacine-treated patients

and 59 placebo control subjects in the A.M. group (BP measured 12 hours after dosing], 60 and 58 persons, respectively, were included in the endpoint efficacy analysis. Endpoint efficacy analysis was defined as the difference between mean vital signs (systolic/diastolic BP and heart rate] at the end of the step-2 treatment period or at a patient’s last evaluation after week 3 of step 2 and mean vital signs at baseline (last evaluation before initiation of step 2).

TABLE I Demographic Characteristics of Guanfacine-Treated Patients and Placebo Control Subjects

Treatment Group

Characteristic Guanfacine Placebo

Patients (no.) Sex: Male

Female Race: Non-black

Black Age (years) Height (inches) Weight (Ibs) Duration of hypertension (years)

125 80 45

122 3

46 f 9 68 f 4

188 f 34 7.3 f 7.3

120 75 45

116 5

48 f 8 68 f 4

190 f 33 8.3 f 6.8

Values for age, height, weight and duration of hypertension are mean f standard deviation.

Four patients treated with guanfacine did not com- plete the study; 3 were dropped from the study be- cause of side effects, which disappeared after discon- tinuation of guanfacine. (See results of safety studies.) The fourth patient was dropped from the study for administrative reasons. Of the 7 patients who received placebo and prematurely discontinued participation, 6 dropped out for administrative reasons and 1 terminat- ed because of therapeutic failure (diastolic BP >114 mm Hg).

Of the members of the A.M. group who had a base- line diastolic BP in the range of 95 to 99 mm Hg inclu- sive, 35 of the 46 guanfacine-treated patients (76%) and 17 of the 40 placebo control subjects (42%) had a normal sitting diastolic BP (defined as <90 mm Hg) at the end of the study. Among those with a baseline diastolic BP ranging from 110 to 114 mm Hg inclusive, BP was normalized in 9 of 14 guanfacine-treated pa- tients (64%), but in only 1 of 18 placebo controls (6%) at the end of the study.

A clinically significant decrease in sitting mean dia- stolic BP in those patients in the A.M. group who re- ceived guanfacine was observed at their first return

Cl Guanfacine /

/ NH2

CH,-CO-NH-C NNH l Ha

NH- *HCI

Cl Clonidine

FIGURE 1. Chemical structures of guanfacine and clonidine.

40E A SYMPOSIUM: GUANFACINE-A NEW CHOICE IN CENTRALLY ACTING ANTIHYPERTENSIVE AGENTS

TABLE Ii Vital Signs Endpoint Means by Treatment Category TABLE iii Means of Endpoint Diastolic Blood Pressure (DBP) by (A.M. group) Baseline Pressure and Treatment Category (A.M. group)

Treatment Group

Vital Sign Statistic Guanfacine Placebo

Sitting diastolic BP (mm W

Systolic BP (mm W

Mean arterial pressure (mm hi)

Heart rate (beatsimin)

“0. 60 58 mean 86 95 mean change -12 -5

no. 60 58 mean 126 138 mean change 16 -4

no. 60 58 mean 99 109 mean change -14 -5

no. 60 58 mean 73 78 mean change -6 -4

BP = blood pressure.

visit between 1 and 2 weeks after the initiation of guanfacine (Fig. 2). This was in response to the initial daily dose of 1 mg. Despite some subsequent increases in dosage, little further decrease in sitting diastolic BP was observed. A similar trend was seen when standing diastolic BP was evaluated (Fig. 3). Both sitting and standing heart rate decreased with guanfacine, but the magnitude of the drop in heart rate was considered clinically irrelevant. Table II summarizes the endpoint (12 week) means for 4 vital signs measured in all pa- tients in the A.M. group.

When the endpoint diastolic BP of these patients was compared with their initial diastolic pressure, it was found that guanfacine-treated individuals who started the study with a diastolic BP in the range of 95 to 99 mm Hg responded to the drug. They finished the study with a mean diastolic BP of 85 mm Hg; analysis of those who received placebo revealed a mean end- point diastolic BP of 92 mm Hg. Of patients who started the 12-week efficacy study with diastolic BP of 100 to 114 mm Hg, the mean endpoint diastolic BP was re- duced to 90 mm Hg in guanfacine-treated individuals

FIGURE 2. Decrease in sitting diastolic blood pressure (BP) in guanfacine-treated patients and placebo control subjects (A.M.

group).

Baseline DBP

Category

95 to 99 mm Hg

100 to 114 mm Hg

no. mean endpoint DBP

no. mean endpoint DBP

Treatment Group

Guanfacine Placebo

46 40 a5 92

14 ia 90 103

and to 103 mm Hg in placebo control subjects (Table III).

P.M. group: Of the 65 guanfacine-treated and 64 placebo control patients in the P.M. group (BP measured in the evening approximately 24 hours after dosing), 65 and 62 members of each group, respectively, were in- cluded in the endpoint efficacy analysis. Six patients treated with guanfacine discontinued because of com- mon side effects (i.e., dry mouth, dizziness, constipa- tion, fatigue and somnolence), which reversed rapidly after the drug was discontinued. In addition, 1 patient discontinued prematurely because of administrative reasons. Seven placebo recipients were discontinued prematurely from the study; 6 dropped out because of administrative reasons and 1 because of side effects [i.e., syncope, headache, fatigue and vertigo].

The results in the P.M. group were similar to those observed in the A.M. group. As can be seen in Figure 4, a clinically significant decrease in sitting diastolic BP occurred at the first visit after the beginning of the 12- week efficacy trial. Thus, again, the onset of the phar- macologic action of guanfacine was observed early in the course of therapy with the 1 mg/day dose, with little further decrease noted with subsequent increases in dosage. The guanfacine-associated decrease in sys- tolic BP observed at the first visit (Fig. 5) was also maintained throughout the l&week study. Heart rate again decreased with guanfacine treatment, but the reduction was, once more, not clinically relevant, nor was it statistically significant.

FIGURE 3. Decrease in standing diastolic blood pressure (BP) in guanfacine-treated patients and placebo control subjects (A.M.

group).

March 28, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 4lE

TABLE IV Vital Signs Endpoint Means by Treatment Category (P.M. group)

Treatment Group

Vital Sign Statistic Guanfacine Placebo p Value

Sitting diastolic BP no. 65 63 (mm Hg) mean 88 94 p <o.oi

mean change -11 -6

Systolic BP no. 65 63 (mm W mean 128 141 p <O.Ol

mean change -14 -6 p <O.Ol

Mean arterial pressure no. 65 63 (mm Hg) mean 101 110 p <O.Ol

mean change -12 -6

Heart rate no. 65 63 (beats/min) mean 75 81 NS

mean change -5 -3

BP = blood pressure; NS = difference not significant.

The endpoint vital signs observed in the P.M. group of guanfacine-treated patients and placebo control subjects (Table IV] demonstrate that the antihyperten- sive effect of guanfacine is well maintained for up to 24 hours, permitting once-a-day dosing with the drug in most patients.

Safety studies: Two hundred and forty-nine pa- tients participated in safety evaluations; 126 patients received guanfacine and 123 placebo (Table V]. The most common side effect associated with guanfacine therapy was dry mouth. Constipation and somnolence occurred more often at higher doses. The occurrence of other side effects was much the same as that ob- served with placebo. Nine guanfacine-treated patients dropped out of the study because of adverse reactions, compared with 1 placebo control subject. Five patients treated with 1 mg/day guanfacine discontinued be- cause of confusion (11, dry mouth (11, dizziness and headache (l), depression [l] and dry mouth and impo- tence (1). Three patients who received 2 mg/day guan- facine were dropped because of confusion and amne- sia [l], constipation, dry mouth, fatigue and taste

FIGURE 4. Decrease in sitting diastolic blood pressure (BP) in guanfacine-treated patients and placebo control subjects (P.M.

grow).

TABLE V Most Common Adverse Reactions

Treatment Group

Guanfacine Placebo

Patients (no.) Adverse experience

Dry mouth Constipation Fatigue Dizziness Somnolence Impotence

126 123

59 11 20 1 15 7 8 4 5 3 6 2

TABLE VI Summary of Electrocardiogram Results

Study Week

Guanfacine Placebo

Normal Abnormal Normal Abnormal

Baseline (end of week 4)

End of treatment (end of week 17)

107 19 110 12 (85%) (89%)

100 15 96 15

(87%) (86%)

perversion (I) and dry mouth, somnolence and testicu- lar discomfort (1). One pa-tient who received 3 mg/day guanfacine discontinued because of palpitation, dizzi- ness, headache, tinnitus and abnormal vision.

Results of laboratory tests: Routine laboratory tests done at baseline and during and after step 2 included: hemoglobin, hematocrit, white blood cell count with differential, platelet count, calcium, phosphorus, glu- cose, urea nitrogen, uric acid, cholesterol, total protein, albumin, bilirubin, alkaline phosphatase, serum glu- tamic oxaloacetic transaminase, creatinine, sodium, potassium, chloride, bicarbonate or CO2 and urinaly- sis. There were no significant drug-related changes in any laboratory test although there was a decrease in mean total serum cholesterol levels. Electrocardio- grams were done at baseline [end of week 4) and at the end of treatment (end of step 2). The interpretations of the electrocardiograms are shown in Table VI.

Discussion As in all other medical disciplines, concepts regard-

ing the diagnosis and treatment of hypertension are

FIGURE 5. Decrease in sitting systolic blood pressure (BP) in guan- facine-treated patients and placebo control subjects (P.M. group).

42E A SYMPOSIUM: GUANFACINE-A NEW CHOICE IN CENTRALLY ACTING ANTIHYPERTENSIVE AGENTS

continually evolving and generally reflect new knowl- edge. The metabolic abnormalities induced by diuret- ics (potassium loss and cholesterol, glucose and uric acid elevations) have been well known for decades. Only recently, however, has it been shown that the antihypertensive effectiveness of diuretics can be sep- arated from the metabolic derangements. For exam- ple, chlorthalidone 25 mg/day is as effective in reduc- ing BP as the more commonly used doses of 50 and 100 mg/day.lO Chlorthalidone-induced metabolic de- rangements, on the other hand, are definitely dose- related: while 100-mg chlorthalidone produces signifi- cant potassium loss, 25-mg chlorthalidone produces minimal or no potassium loss. Thus, it is now apparent that low dose (25 mg) chlorthalidone will provide max- imal (diuretic) BP decrease without inducing all of the undesirable derangements. Certainly, of all drugs now available that lower BP, diuretics are first choice be- cause they have the highest degree of patient accept- ability and the incidence of subjective side effects is relatively low. This has been further confirmed by the European Working Party on Hypertension in the El- derlyll and the recently completed feasibility study in systolic hypertension.12

Unfortunately, diuretic monotherapy is frequently unable to completely normalize high BP, thereby ne- cessitating the addition of a second (step 2] drug.

Guanfacine, like chlorthalidone, lowers BP and produces unwanted effects. Similarly, guanfacine ap- pears to produce maximal BP reductions whether ad- ministered at a dose of 1 or 3 mg/day. Again, however, unwanted effects are significantly more likely to occur at the 3 mg/day dose than at the 1 mg/day dose (which is virtually free of adverse effects). This conclusion is therefore obvious: 25-mg chlorthalidone once a day plus l-mg guanfacine once a day provides the maximal BP-lowering effect of both drugs, while at the same time minimizing the metabolic derangements and sub- jective side effects of the respective agents. Recently, a strong case has been made for the use of a rational combination of 2 drugs as the initial treatment of hypertension.13

The results of the present study demonstrate not only that guanfacine is an effective step-2 antihyper- tensive agent, but also that its antihypertensive action 24 hours after a once-a-day dose [mean decrease of 11 mm Hg over a l&week period) is similar to its effect 12 hours after a once-a-day dose (mean decrease 13 mm Hg over a l&week period]. Because its antihyperten- sive effect is maintained over a 24-hour period, guan- facine is suitable for once-a-day dosage, either alone14 or combined with chlorthalidone 25 mg/day.

Guanfacine was also shown to have a rapid onset of action, because the guanfacine-associated decrease in BP observed in this study was clinically relevant dur- ing the first 10 days therapy. The reduction in both diastolic and systolic BP seen with guanfacine was sustained over the 12-week study period.

Guanfacine was also shown to have a very accept- able side-effects profile. This was evidenced by the small number of patients who prematurely dropped out of the study because of adverse reactions.

In summary, guanfacine can be considered an ef- fective, once-a-day step-2 agent for the treatment of mild to moderate essential hypertension. Guanfacine is also well tolerated; its most common side ef- fects-dry mouth, constipation and fatigue-are al- most always mild and rarely cause patients to discon- tinue therapy. Guanfacine’s once-a-day dosing regimen, along with its favorable side-effects profile, are important factors in maximizing patient compli- ance, and thus BP control.

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9. Kiechel JR. Pharmacokinetics and metabolism of guanfacine in man: a review. Br J Clin Pharmacol 198O;lO:suppI 1:25S-32% 10. Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh JE, Moriedge J. Dose response to chlorthalidone in patients with mild hyperten- sion: efficacy of a lower dose. Clin Pharmacol Ther 1978;24:192-198. 11. Results of the European Working Party on Hypertension in the Elderly (EWPHE]. Second European Meeting on Hypertension, Milan, Italy, June 1985. 12. Buhler FR, Burhart F, Lutoid BE, Kung M, Morbet G, Pfisterer M. Antihy- oertensive a-blockinn action as related to renin and see. In: Laraeh 1. ed. ‘Topics in Hypertensyon. New York: Yorke Medical Bioks, 1980:4&&. 13. Walker BR. Approaches to antihypertensive drug therapy: initial therapy alternatives. Curr Ther Res 1984;35:1-8. 14. Jerie P, Lasance A. Long-term efficacy and tolerance of the antihyper- tensive agent guanfacine. Int J Clin Pharmacol Ther Toxicol 1984;22:170- 174.