vasodilatation and monotherapy with prazosin is limited by lack of efficacy. ... the Pinacidil vs Prazosin Multicenter Investigator Group* Indianapolis, Ind.
Vasodilator monotherapy in the treatment of hypertension: Comparative efficacy and safety of pinacidil, a potassium channel opener, and prazosin We compared antihypertensive effects of monotherapy with pinacidil (N = 197) or prazosin (N = 204) in a randomized, parallel, double-blind dose-titration study in which hydrochlorothiazide or propranolol could be added for adverse events or lack of efficacy. Pinacidil (12.5 to 75 mg b.i.d.) was a more potent vasodilator, producing a mean decrease in supine diastolic blood pressure (baseline = 102 to 103 ± 9 mm Hg) of 18.8 ± 10.0 (SD) mm Hg compared with 15.5 ± 92 mm Hg with prazosin (1 to 10 mg b.i.d.; p < 0.001). Patients responding to each drug had similar average blood pressure levels during 12hour monitoring (137/85 mm Hg). More patients taking pinaciclil required hydrochlorothiazide for edema (p = 0.008) and more taking prazosin required hydrochlorothiazide and propranolol for lack of efficacy (p < 0.001). Tachycardia (15% to 20%) and palpitation (13% to 15%) were frequent events with both drugs. Edema (38.2% vs 22.3%) was more frequent with pinacidil (p < 0.001) and postural hypotension (4.7% vs 1.0%) and asthenia (20.2% vs 13.2%) were more frequent with prazosin (p = 0.025; 0.062). No significant laboratory toxicity was noted. In conclusion, both pinacidil and prazosin are effective as monotherapy for hypertension. Monotherapy with pinaciclil is limited by adverse events related to vasodilatation and monotherapy with prazosin is limited by lack of efficacy. (CLIN PHARMACOL THER
1988;44:78-92.)
Michael R. Goldberg, MD, PhD, Cynthia S. Sushak, MS, Frank W. Rockhold, PhD, W. Leigh Thompson, PhD, MD, and the Pinacidil vs Prazosin Multicenter Investigator Group* Indianapolis, Ind.
Hypertension is usually associated with increased vascular resistance, making direct vasodilation a logical treatment. Vasodilators have seen limited primary utility in hypertension because their use in high doses is often associated with reflex cardiac stimulation and retention of salt and water. Of the two currently available vasodilators, one, minoxidil, produces a cosmetically unacceptable side effect, hypertrichosis, and has a narrow therapeutic index.' The other, hydralazine, induces a systemic lupus syndrome and is mutagenic, and its efficacy and toxicity are influenced by acetylator phenotype.' Thus, diuretics, p-adrenoreceptor antagonists,
From the Lilly Research Laboratories, Eli Lilly and Company. Received for publication Oct. 27, 1987; accepted Jan. 12, 1988. Reprint requests: Michael R. Goldberg, MD, Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, 1001 W. Tenth St., Indianapolis, IN 46202. *Funded by individual grants from Eli Lilly and Company.
78
and other agents have become mainstays of antihypertensive therapy in the past decade.' Recent data suggest that diuretic-induced changes in electrolyte and serum lipid concentrations can have adverse consequences in patients with mild hypertension.' p-Adrenoreceptor antagonists also have adverse effects on serum lipids and should not be used in patients with bronchospastic disease or impaired cardiac function. In some patients these latter drugs may increase peripheral vascular resistance.4 Accordingly, careful administration of a direct vasodilator as monotherapy to hypertensive patients deserves reexamination. To test this hypothesis, we compared the efficacy and safety of two drugs that reduce blood pressure by reducing peripheral vascular resistance: pinacidil, a direct vasodilator that appears to act via a novel effect on potassium conductance in vascular smooth muscle,5'6 and prazosin, an aradrenoreceptor antagonist. Pinacidil (1( )-N-cyano-N'-4-pyridinyl-]V'- (1,2,2-
VOLUME 44 NUMBER I
Vasodilators in hypertension
Study Phase
QUALIFICATION
DOSAGE ADJUSTMENT
Duration
up to 45 days
up to 21 days
EFFICACY
8
Pinacidil
POST-TREATMENT
weeks
up to
1
week
Pinacidil + Concomitant therapy
(12.5, 25, 37.5, 50, 75 mg bid)
Treatment
79
Hydrochlorothiazide and/or Propranololb Placebo + Concomitant
Placebo
Prazosin (1,
2, 3.5,
5,
Prazosin + Concomitant therapy
10 mg)
Hydrochlorothiazide and/or Propranololb
Visit No.
1
2a
3a
5
6
7
8c
9c
i
Visit Interval
10c
Ilc
12c
13c
1
15d
16d
.4 weeks+
I
17
18
I
1.5 to 15 days.
.3
to 15 days.
.1 to 3 days.
I
Fig. 1. Diagrammatic representation of study plan. Qualification and posttreatment phases were single-blind. Qualified patients were randomized at visit 4 to double-blind treatment with pinacidil or prazosin. a, Visits 2 and 3 could be skipped if supine diastolic blood pressure was - -115 mm Hg. b, Concomitant therapy could be added as follows: hydrochlorothiazide (25 or 50 mg b.i.d.) for patients with edema, dyspnea, or weight gain and propranolol (40 or 80 mg b.i.d.) for tachycardia, palpitations, or angina pectoris or both for lack of efficacy at the highest dose of pinacidil or prazosin. c, Dosage-adjustment visits could be skipped if the patient had adequate blood pressure control (supine diastolic blood pressure 110 mm Hg; n = 52). In the prazosin group, respective decrements were 13 ± 7 mm Hg (n = 150) and 24 ± 11 mm Hg (n = 43). In each stratum the decrement was significantly greater in the pinacidil group. The supine diastolic blood pressure response rate was
greater in the pinacidil group than in the prazosin group. Thus at endpoint, 83.3% (95% confidence interval, 78.2% and 88.4%) of patients in the pinacidil group had supine diastolic blood pressure below 91 mm Hg and 10 mm Hg less than baseline, compared with 75.1% (69.0% and 81.2%) in the prazosin group (p = 0.021). The difference in response rates between the two drugs was 8.2% (0.2% and 16.2%). Pinacidil did not affect the orthostatic response whereas prazosin therapy was associated with significantly greater postural decrements in systolic and diastolic blood pressure and postural increments in heart rate (Fig. 2; Table II). Although the supine heart rate increased more in the pinacidil group, the postural increment in heart rate was greater in the prazosin group resulting in similar standing heart rates.
86
CI,IN PHARMACOL THER
Goldberg et al.
JULY 1988
Table VI. Relationship between dose level of pinacidil and adverse event report: dose level of first report Pinacidd (mg b.i.d.)
n*
Headache Edema Dizziness Asthenia Tachycardia Palpitation
Placebo
12.5
204
203 12.3
16.3t 2.0 5.4 3.9 0.5 1.5
4.4 5.9 4.4 2.5 2.5
25 175
14.3 17.1 6.3
4.0 7.4 6.3
37.5 125
8.8 12.8 7.2 2.4 9.6 6.4
50
75
72
31
4.2 20.8 5.6 8.3 8.3 9.7
9.7 29.0 9.7 3.2 12.9 3.2
*n is the number of patients exposed to that dose level. One patient in each group did not return after randomization. tPercentage of patients taking the given dose who reported the event for the first time while taking that dose. Placebo is the incidence during the qualification phase
of the study.
Table VII. Relationship between dose level of prazosin and adverse event report: dose level of first report Prazosin (mg b.i.d.)
Placebo n*
Headache Edema Dizziness Asthenia Tachycardia Palpitation
193
1
192
16.7
7.3
2.6 5.7 4.7
3.1
0
2.1
5.2 3.6 2.6 2.6
2 167
6.0 7.8 3.6 1.8
3.6 2.4
3.5 146
2.1
8.2 7.5 5.5 1.4 2.7
5 123
5.7 4.9 8.1 8.1
4.9 6.5
10 97 3.1 11.3
9.3 11.3 10.3 4.1
*n is the number of patients exposed to that dose level. One patient in each group did not return after randomization.
At the efficacy visits, responding patients underwent hourly blood pressure and heart rate measurements. At each visit one half of the patients fasted until 6 hours after the dose and one half were fed breakfast. For analysis these visits were pooled because, although fed patients had 2.1 mm Hg (pinacidil group) and 2.8 mm Hg (prazosin group) greater decrements in supine diastolic blood pressure 2 to 5 hours after drug administration, there was no difference between the drugs in this regard. Fig. 3 shows the average values for supine blood pressure and heart rate at each study phase and during the 12-hour dosing interval at the efficacy visits in patients who attended these visits. Responding patients in the pinacidil and prazosin groups had generally similar average blood pressures during the dosing interval, regardless of regimen. Blood pressures were higher at the beginning and end of the dosing interval in each group, although still significantly lower than during placebo treatment at baseline. At the time of peak drug effect, differences between pinacidil and prazosin noted at end point persisted during the efficacy phase (Table II). During the active-therapy phase of the protocol,
mean body weight increased 0.5 kg in the pinacidil group and 0.4 kg in the prazosin group (p = 0.50). When the vasodilator was discontinued, weight decreased more in the pinacidil than in the prazosin group (1.4 vs. 0.3 kg; p
