The Long-Term Antihypertensive Effects of Prazosin and Atenolol HAROLD D. ITSKOVITZ, M.D., KATHY KRUG, R.N., SALIW KHOURY, M.D., JOSEPH L. MOLLURA, M.D. Va/ha//a. New pork

The efficacy and tolerability of the alpha-blocker prazosin was compared with that of atenolol, a beta-blocker, in the long-term treatment of un- complicated, essential hypertension. Twelve pa- tients were randomly assigned to prazosin treat- ment and 15 to treatment with atenolol. Drug therapy was titrated to reduce diastolic blood pressure by 10 mm Hg or to below 89 mm Hg, whichever was lower. If monotherapy with either study drug failed to do this, hydrochlorothiazide was added to the regimen. Once blood pressure control was established, patients received mainte- nance therapy at that dosage and were followed for up to 12 months. Blood pressure, side effects, and plasma lipid levels were monitored during this period. Seventy-five percent of patients re- ceiving prazosin monotherapy attained blood pressure goals, compared with 60 percent of pa- tients given atenolol monotherapy. With the addi- tion of low-dose hydrochlorothiazide, those pa- tients not having an adequate response to mono- therapy attained blood pressure control. Blood pressure reductions were maintained without dos- age adjustment throughout the maintenance pe- riod; patient acceptance was good, and there was no evidence of tolerance. Treatment with atenolol produced slight increases in plasma triglyceride levels and little change in total or low-density lipoprotein cholesterol. In contrast, patients treated with prazosin demonstrated no adverse effects with regard to lipid levels. Although a higher percentage of patients reached goal blood pressure with prazosin monotherapy than with atenolol, the response rates were comparable when hydrochlorothiazide was added to the regi- mens.

From the Hyperiens~on SectIon, Department of Medwe. New York Medical College. Valhalla New York, and the Hyperterwon Clonic, Department of Medicine, Flushing Hospital MedIcal Center. Flushing. New York This work was supported by a grant from Pfizer Laboratories Requests for reprints should be addressed to Dr Harold D ltskovltr. D~won of ClinIcal Pharmacology and Hypertension. New York Medical Cal

T he sympathetic nervous system is an important determinant of blood pressure regulation, since it

affects cardiac output, peripheral vascular resistance, and the release of various vasoactive hormones [ 1,2]. Drugs that reduce the activity or the effects of the sympathetic nervous system, therefore, frequently are used for treatment of hypertension. The sympa- thetic nervous system may be altered by two contrast- ing niechanisms-alpha- or beta-adrenergic blockade. Alpha-blockers, especially those selective for the alpha, receptor, have little effect on cardiac output and reduce blood pressure by decreasing peripheral vascular resistance [3]. Beta-blockers, on the other hand, tend to increase peripheral vascular resistance and reduce blood pressure by decreasing cardiac out- put 141.

The present study compared the long-term antihy- pertensive effects of prazosin, an alpha]-blocking agent, with atenolol, a beta-blocker, to determine each agent’s efficacy in reducing high blood pressure and the need, if any, for supplemental diuretics to achieve blood pressure control. Drug-related side ef- fects and patient tolerance were evaluated as well. Finally, since elevated blood cholesterol levels pose an additional risk for coronary artery disease, the long- term effects of prazosin and atenolol on plasma lipids also were measured.

MATERIALS AND METHODS Randomization and Titration of Medication

Twenty-seven patients with untreated or neLvly di- agnosed uncomplicated essential hypertension were enrolled in this study (patients \vho were receiving pharmacotherapy for hypertension entered a minimal eight-week placebo washout period). Informed con- sent was obtained from all study participants. Base- line sitting diastolic blood pressure had to average between 95 mm Hg and 109 mm Hg for inclusion in the study. Patients were randomly selected by computeI*- generated code to receive either prazosin or atenolol as initial therapy. During the initial four- to six-week titration phase, dosages of the study medications were adjusted until diastolic blood pressure goals of either 89 mm Hg or less or a decrease of 10 mm Hg, which- ever was lower, were met. Patients randomly as- signed to prazosin therapy received 1 mg twice dail>l to start, increasing progressively (2 mg, 5 mg, and 10 mg twice daily) until blood pressure goals were met, a maximal close of 20 mg per d;ly was reached, or limit- ing side effects occurred. Patients randomly assigned to atenolol therapy started at a dose of 50 mg per day, increasing as necessary until blood pressure goals were attained, a maximal dose of 100 mg per day was reached, or limiting side effects occurred. Patients who failed to meet blood pressure goals on maximal doses of prazosin or atenolol received hytlrochlorothia-

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SYMPOSIUM ON CHD AND HYPERTENSION i ITSKOVITZ ET AL

zide 25 mg per day in addition. Doses of the diuretic subsequently were adjusted down to the lowest dose necessary to attain adequate blood pressure control.

Laboratory Tests After the titration period, all patients received

maintenance drug therapy for a minimum of three months. A complete history, physical examination, and routine blood, urine, and electrocardiographic studies were completed at baseline to ensure that each patient had uncomplicated essential hypertension. In addition, total cholesterol, triglyceride, ant1 low- density lipoprotein cholesterol levels were measured ]5-71 after a 12-hour fast at baseline and after three, six, nine, and 12 months of maintenance therapy. Stu- dent t test was used to determine the significance of differences between mean values in each group.

RESULTS Table I compares the baseline characteristics of the

prazosin and atenolol groups. In general, both treat- ment groups were comparable, except for racial clistri- bution, which differecl despite randomization. Table II summarizes the antihypertensive efficacy of each drug. A higher percentage of patients in the prazosin- treated group (75 percent) met blood pressure goals on monotherapy than clid those in the atenolol-treated group (60 percent). Furthermore, the prazosin- treated patients who attained blood pressure goals on monotherapy did so at the lowest prescribed dose (1 mg twice daily); whereas two of the nine atenolol- treated patients who met blood pressure goals on monotherapy required the higher dosage, i.e., 100 mg per day. ,411 three prazosin-treated patients who re- quired the addition of hydrochlorothiazide to achieve blood pressure control needed only 25 mg per clay; one of six patients receiving atenolol, who required hydro- chlorothiazicle supplementation, needed 50 mg per clay. Ease of titration was similar in both groups. Pra- zosm-treated patients needed an average of 3.25 ? 0.24 (SEM) visits before bloocl pressure control was attained, compared with 3.67 * 0.34 for patients in the atenolol-treated group.

Antihypertensive Response Figures 1, 2, and 3, respectively, compare the aver-

age systolic, diastolic, and mean blood pressure levels of patients treated with prazosin or atenolol at base- line, at the end of titration (with and without hvdro- chlorothiazicle), at the end of monotherapy, and fkr up to 12 months of maintenance therapy. As can be seen, treatment with prazosin monotherapy produced con- sistent and significantly loiver blood pressure levels compared with atenolol alone. Blood pressure levels between the two groups did not differ significantly after titration with hydrochlorothiazide and during the maintenance period, however, blood pressure was consistently lower in the prazosin-treated group.

Since the two groups were not comparable racially, attempts were macle to stratify patients according to race in terms of blood pressure response. These data are illustrated in Figures 4, 5, and 6. Although the number of persons studied was too small to reach sta- tistical significance when analyzed by race, white pa- tients treated with prazosin tended to have lower blood pressure than those treated with atenolol. Fur- thermore, the antihypertensive response of black pa-

/ TABLE I

Baseline Characteristics (mean f SEM)

Prazosin Atenolol

Number of patients 15 Men:women ti’; Age (years) 52 15 d8 Race

8lack:whlte 1.11 105 Systol~cid~astollc blood pressure (mm Hg) 159 =4:99 t 1 157 r 3.100 I2 Weight (pounds) 187? 10 185 i 8

TABLE II

Antihypertensive Efficacy

Prazosin (n = 12) Atenolol (n = 15)

1: ii

2 (n = 9) 50 (n = 7) 100 (n = 2)

2in= 11 4 in = 2j

50 in = 21 100 in = 4i

25 (n = 3) 25 [n = 5) 50 (n = 1)

Achieved blood pressure goal (percent) Monotherapy Comblnatlon therapy

Dose required (mg!day] Monotherapy

Comblnatlon therapy Studv medlcatlon

Hydrochlorothlazlde

Number of vlslts to obtain maintenance dose 3.25 2 0 24 3.67 I 0.34

1

tients treated with atenolol alone tended to be less than that of white patients given the same medication.

Side Effects Side effects, listed in Table III, ivere minor and

transient in both study groups. No patient withdrew from therapy as a result of persistent or intolerable side effects. During the initial week of treatment, more patients experienced postural dizziness while taking prazosin, compared with those taking atenolol, but this complaint disappeared with continued ther- apy. Three patients in each group experienced edema in the lower extremities during monotherapg, but after the addition of thiazides, the swelling disap- peared in every case. Four patients receiving atenolol experienced headaches, and two in the prazosin- treated group noted recluced energy levels.

Lipid Parameters The effects of treatment on plasma lipid patterns

are illustrated in Figure 7. Total cholesterol, low- density lipoprotein cholesterol, and triglyceride levels tended to decrease in the prazosin group, but the changes were not significant in the small number of patients studied. Patients receiving atenolol showed a trend toward higher triglyceride levels. At six ancl 12 months, the differences in plasma triglyceride levels between prazosin-treated patients and atenolol- treated patients approached or reached significance whether or not the patients received supplemental hyclrochlorothiazicle.

COMMENTS The results presented here reaffirm the usefuhless

of antihypertensive drugs that alter sympathetic ner-

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SYMPOSIUM ON CHD AND HYPERTENSION i ITSKOVITZ ET AL

L

Blood Pressure 90 , (mm Hg)

n p=12 8=12 HP=12 rnP=12 8P=ll W=ll rnP=7 q A=l5 q =15 +HCTZ=3 +HCTZ=3 tHCTZ=3 +HCTZ=3 +HCTZ=P

q A=l5 q A=l5 q A=l3 q =ll q A=9 +HCTZ=B +HCTZ=B tHCTZ=B +HCTZ=4 +HCTZ=4

160

160 mod

Pressure (mm W

140

130

Baseline Monotherapy Titration 3 mos. 6 mos. 9 mos. 12 mos.

IP=12 1=12 rnP=12 rnP=12 n P=ll n =11 rnP=7 q A=l5 0 = 15 +HCTZ=J +HCTZ=3 +HCTZ=3 +HCTZ=3 +HCTZ=P

q A=l5 OA=15 q A=l3 q =ll q A=9 +HCTZ=B +HCTZ=B +HCTZ=5 +HCTZ=4 tHCTZ=4

60

Baseline Monotherapy Titration 3 mos. 6 mos. 9 mos. 12 mos.

n p=12 n =12 rnP=12 8P=12 n P=il n =11 rnP=7 q A=l5 q =15 tHCTZ=J +HCTZ=J +HCTZ=J +HCTZ=3 +HCTZ=P

OA=15 CIA=15 q A=l3 q =ll q A=9 tHCTZ=B +HCTZ=6 tHCTZ=5 +HCTZ=4 +HCTZ=4

120

P<.lO

110 mod

Pressure (mm 4

100

90 End End

Baseline Monotherapy Titration 3 mos. 6 mos. 9 mos. 12 mos.

Figure 1. Monotherapy with prazosln was asso- elated with a better hypotenslve response of systolk blood pressure (p ~0.10) than mono- therapy with atenolol. Comblnatlon therapy with hydrochlorothlazlde appeared equally effective. BP = blood pressure; P = prazosin; A = atenolol; HCTZ = hydrochlorothlazlde, mos = months. Numbers refer to patients In each group.

Figure 2. Monotherapy with prazosln was asso. elated with greater reduction of diastolic blood pressure than monotherapy with atenoiol (p CO.05).

Figure 3. Monotherapy with prazosin was asso- ciated with greater reduction of mean arterial pressure than monotherapy with atenolol. See Figure 1 for abbreviations.

vow system activity. Each of the 27 patients included of patients receiving atenolol monotherapy. The in this study attained a diastolic blood pressure either greater efficacy seen with prazosin monotherapy, below 89 mm Hg or reduced by at least 10 mm Hg compared with atenolol monotherapy, may be clue, in fl-om baseline. Blood pressure reductions were accom- part, to the large number of black patients included in plished without the addition of a diuretic in 75 percent the atenolol treatment group. In general, beta- of patients treated with prazosin alone and 60 percent blockade is less effective in black patients then in

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SYMPOSIUM ON CHO AND HYPERTENSION / ITSKOVITZ ET AL

Figure 4. Systolic blood pressure responses (mean -t SEM) by treatment group and race. Data lndlcate trend for decreased antlhyperten- slve efficacy of atenolol monotherapy in black patients (B] compared with white patients (W). After the addition of hydrochlorothiazide (titra- tlon to 12 months), however, the difference dls- appeared. Efficacy pf prazosin was at least as great as that of atenolol In white and black pa- tients. From baseline to three months. n values are 15 (atenolol, B and W): 10 (atenolol. B); five (atenolol. W): and 12 (prazosln). At SIX, nine. and 12 months, respectively, corresponding n values for each group are 13, eight, five, and 11 (SIX months); 11, eight. three, and 11 (nine months), and nine, seven, two, and seven (12 months)

Figure 5. Diastolic blood pressure responses (mean -t SEM) by treatment group and race. See Figure 4 for abbreviations.

Figure 6. Mean blood pressure responses (mean i SEM) by treatment group and race. See Figure 4 for abbreviations

160

Systolic 150 Blood

Pressure (mm W

140

130

E3 Atenolol-B 0 Atenolol-W

61 Atenolol B + W I Prazosin

End End Baseline Monotherapy Titration 3 mos 6 mos. 9 mos 12 mos

•a Atenolol-B 0 Atenolol-W

N Atenolol B - W I Prazosm

Diastolic Blood

Pressure 90 (mm Hg)

Rrl -- Baseline Monotherapy Titration 3 mos. 6 mos. 9 mos. 12 mos.

120 q Atenolol B t W I Prazosin

Mean 1 IO Blood

Pressure (mm 4)

100

90 End End

Basellne Monotherapy Titration 3 mos. 6 mos. 9 mos. 12 mos.

•3 Atenolol-B 17 Atenolol-W

TABLE III

Side Effects

The present data are consistent with previous re- Prazosin (n = 12) Atenolol (II = 15)

ports in \\-hich atenolol monotheral?y was associated Postural dizziness (initial visit) 2 I with lower blood pressure levels m white patients Edema than in black patients and in which racial differences hilonotherapy in drug responses disappeared with diuretic supple- Comblnatlon therapy i i

mentation. Although the number of patients studied Headache 0

here was too small to reach a statistically significant Decreased energy 2 r:

difference, further analysis showed that even among an all-Lvhite patient population, prazosin monotherapy 12 months without the development of tolerance 01 tended to reduce blood pressure more than atenolol loss of antihypertensive efficacy. therapy did. Once blood pressure goals were The occurrence of various side effects was similar in achieved. dosages were maintained in both groups fol both treatment groups (Table III). All adverse reac-

J

white patients, since h,vpertension is often volume- dependent in black patients and beta-blockers may be associated with reduced renal perfusion, which can lead to greater salt and water retention [g-11].

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SYMPOSIUM ON CHD AND HYPERTENSION / ITSKOVITZ ET AL

150-• z P<.os P-z.10 P<.lO

II T 1

yi 150- P<.o25 P-c.10 PC.025

mgldl 125 -I 125 - . l

. 11 ~x-=I

loo - I loo-.’ . . .

. 75 ’ ’ ’ ’ ’ ’ ’ ’ 75’ ’ ’ ’ ’ ’ ’ ’ ’

3 6 9 12 3 6 9 12 Months of Therapy Months of Therapy

Figure 7. Prazosrn therapy was assocrated wrth a trend toward lower plasma total cholesterol, low-densrty lrpoprotern cholesterol, and trrglycer- Ide levels. whereas atenolol therapy tended to Increase plasma trrglycerrde levels The length of arrows reflects mean changes from basellne measurements for those patrents in whom lrprd values were determlned after various periods of marntenance therapy. SEM IS Indicated by dots above and below arrows. p value for each trme perrod Indicates srgnrfrcance of difference In the mean between prazosrn- and atenolol-treated groups at that time period. Upper row of p val- ues refers to monotherapy and lower row refers to total treatment groups (wrth and without hy- drochlorothrazrde).

tions were mild and transient, and none necessitated withdrawal from therapy. During the initial phase of therapy, postural dizziness was observed in two of 12 patients treated with prazosin. Headache was the most frequently occurring side effect among patients treated with atenolol. Peripheral edema, seen equally in both groups, responded to diuretic therapy. No pa- tient reported impotence, which has been reported in other series after beta-blocker treatment by Burnett and Chanine[ 121.

Adverse effects occurred in neither total cholesterol levels nor in low-density lipoprotein cholesterol levels due to either prazosin or atenolol treatment, with or without hydrochlorothiazide. Plasma triglyceride lev- els increased in atenolol-treated patients, with no such finding obtained in the prazosin group. These results are consistent with previous literature reports [13,14] that the desirable effects of alpha-blocking agents on blood pressure control are unaccompanied by adverse effects on lipid patterns. This offers a strong rationale for the selection of the alpha-blocking agents as anti- hypertensive drugs of choice with regard to coronary heart disease risk management.

ACKNOWLEDGMENT We wish to acknowledge the expert secretarial as-

sistance of Mrs. Jutta Neumann.

REFERENCES 1. Cuche J-L, Kuchel 0, Barbeau A, LangloIs Y. Boucher R. Genest J Autonomic nervous system and benign essential hypertension I” man I Usual blood pressure, catechol am~nes, renln. and their lnterrelatlonshlps. Clrc Res 1974. 35 281-289 2. Lund-Johansen P: Haemodynamlcs in essential hyperterwon. Clan SCI 1980.59 343% 354s. 3. Stanaszek WF. Kellerman D, Brogden RN, Romanktewr JA Prarosin update A wew of its pharmacologIcal propertIes and therapeutic use in hypertension and congestive heart fallure. Drugs 1983, 25: 339-384 4. LundJohansen P. Ohm OJ: Haemodynamlc long-term effects of /_-receptor-blocklng agents in hypertension a comparison between alprenolol, atenolol metoprolol. and tlmo- 101. Clin Sc Mel Med 1976; 51: 481S-483s 5. Allaln CC, Poon LS, Chan CSG, Richmond W, Fu PC: Enzymatic determlnatlon of total serum cholesterol. Clan Chem 1974, 20: 470-475 6. Fossat P. Prenclpe L. Serum trlglycerldes determined color~metr~cally with an enzyme that produces hydrogen peroxide Cltn Chem 1982, 28: 2077-2080 7. Frledewald WT, Levy RI. Fredrickson DS: Estlmatlon of the concentration of low-density lipoprotein cholesterol in plasma, wIthout use of the preparative UltracentrIfuge. Clln Chem 1972; 18: 499-502 8. Frels ED: Antlhypertenstve agents. Prog Clan 5101 Res 1986; 214. 313-322. 9. Holland OB, GdmwSanchez C, FaIrchIld C, Kaplan NM Role of renin classlficatlon for dluretlc treatment of black hypertensive pattents Arch Intern Med 1979. 139 1365-1370 10. Pedersen EB Effect of sodium loading and exercise on renal hemodynamlcs and urinary sodturn excretion in young patients wth essential hypertension before and dung propranolol treatment Acta Med Stand 1977; 201, 365-373 11. Epstein M, Oster JR, Hollenberg NK fi-Blockers and the kidney, Impllcatlons for renal function and renin release The Physlologlst 1985, 28. 53-62. 12. Burnett WC, Chanlne RA. Sexual dysfunction as a compllcatlon of propranolol therapy in men Cardlovasc Med 1979, 4. 811-815 13. Leren P, Foss PO, Hjermann I, Helgeland A. Holme I, Lund-Larsen PG. Effect of pro- pranolol and prarow on blood lipids. The Oslo Study Lancet 1980; II 4-6 14. Lardinols CK, Neuman SL The effects of antIhypertensIve agents on serum lIpids and Ilpoprotelns. Arch Intern Med 1988; 148 1280-1288.

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