Doxazosin in the treatment of mild or moderate essential hypertension: An echocardiographic study Sixteen patients with mild or moderate essential hypertension received 1 to 8 mg/day of doxazosin (mean daily dose, 2.7 mg). Blood pressure reduction (supine and standing) was highly significant (p < O-001), and no significant changes in heart rate were observed. A significant reduction (p < 0.01) in left ventricular mass was seen without a change in left ventricular systolic function. All side effects were mild, and only one patient withdrew from the study. (AM HEART J 1991;121:352-6.)

Jose Luis Corral, MD, Nora C. Lopez, MD, Angello Pecorelli, MD, Luis A. Rincon, MD, and Vilma D. Teran Muracay, Venezuela

Doxazosin is a quinazoline derivative, chemically related to prazosin, which acts on postsynaptic (YIreceptors and lowers blood pressure by reducing the peripheral vascular resistance. No reflex tachycardia is observed. ‘,’ Doxazosin has a more gradual and prolonged action than does prazosin and has the advantage of once-daily administration.3 Several studies have also shown that doxazosin has a favorable effect on lipid metabolism, lowering total cholesterol and triglyceride levels and increasing high-density lipoprotein (HDL) cholesterol and the HDL/total cholesterol ratio.4-’ Many antihypertensive agents, such as P-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, centrally acting compounds, and al-inhibitors, can produce a reduction in left ventricular mass (LVM) in patients with hypertension8‘11; hydralazine and minoxidil do not have this effect,12 and doxazosin has yet to be studied. A reduction in LVM without a change in left ventricular function is advantageous, because this may avoid the progression to left ventricular failure. Indeed, left ventricular hypertrophy is an independent risk factor for coronary artery disease13 and is related to the development of ventricular arrhythmias and sudden death. This study evaluated the antihypertensive efficacy and safety of doxazosin in patients with mild or moderate essential hypertension. Echocardiography was carried out at the start and conclusion of the From

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Jo& Luis Corral, MD, Unidad de Hipertensi6n de Maracay, E&ado Aragua, Venezuela.

Arterial,

study to evaluate any changes that occurred in LVM and left ventricular systolic function. METHODS Patients. Sixteen patients with mild or moderate essential hypertension took part in the trial. Patients were included if standing diastolic blood pressure (DBP) was 95 to 115 mm Hg. The criteria for exclusion were prior myocardial infarction, heart failure, renal failure, diabetes mellitus, cerebrovascular injury, hypertensive retinopathy grade III to IV (Keith-Wagener classification), pregnancy, potential blood donors, and those patients without an adequate echocardiographic window. Protocol. The study design is summarized in Fig. 1. After an initial 2-week drug-free period, patients received placebo, once daily, for 2 weeks. Blood pressure and heart rate were measured after 5 and 10 minutes of rest (supine blood pressure) and after 1 and 3 minutes of standing. Patients were evaluated biweekly, and the mean of two visits during the placebo period was taken as the baseline value. Patients were allowed to receive active drug if mean standing DBP was 95 to 115 mm Hg. At the end of the placebo period, blood samples were taken for hematology, blood urea nitrogen, creatinine, fasting glucose, total cholesterol, triglycerides, uric acid, total and fractionated bilirubin, total protein, albumin, globulin, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase, and serum electrolytes. An echocardiographic assessment was also carried out. M-mode echocardiography. Patients were placed in a 30-degree left lateral supine position, and the transducer was placed in the fourth left intercostal space, with the ultrasonic beam immediately below the mitral valve. The ejection fraction, velocity of circumferential fiber shortening, and LVM were estimated according to the formulas were evalugiven in the Appendix. 14-16 Echocardiograms ated independently by two investigators.

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Echocardiography Drugfree period

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Weeks Fig.

1. Study

Treatment with doxazosin. After the initial echocardiographic assessment, treatment with doxazosin was initiated at 1 mg/day. The dose of doxazosin was sequentially increased, if required, to 2, 4, and 8 mg/day until standing DBP was 190 mm Hg. Blood pressure and heart rate were evaluated every 2 weeks, 3 hours after administration. Patients were treated with doxazosin for 12 weeks, and at the end of the study blood pressure, heart rate, LVM, left ventricular function, and laboratory measurements were reassessed. Side effects were recorded at each visit. Statistical analysis. Changes in blood pressure, heart rate, and laboratory variables were assessed with the Student t test for paired data. Wilcoxon’s nonparametric test was used for the echocardiographic analysis. RESULTS Patient profile. Of the 16 patients who began the study, 13 were available for final assessment; one patient was withdrawn from the study because of side effects, and two did not comply with the treatment regimen. Patient characteristics of the efficacy-evaluable patients are given in Table I. Changes in LVM. In the eight patients in whom the ventricular walls could be adequately visualized echocardiographically, a significant reduction in LVM was seen after 12 weeks of treatment with doxazosin (Fig. 2). The mean LVM was reduced from 131.4 gm/m2 (baseline) to 122.4 gm/m2 (final) of body surface area. No significant changes in left ventricular function (ejection fraction and velocity of circumferential fiber shortening) were observed (Table II). Blood pressure. Doxazosin reduced supine systolic blood pressure/DBP from 155.2/101.6 (baseline) to 142.9/88.1 mm Hg (week 16). Standing systolic blood pressure/DBP was reduced from 154.2/102.3 to 136.4/ 87.8 mm Hg. All changes were significant atp < 0.001 (Fig. 3). No significant changes in heart rate were observed. The final mean daily dose of doxazosin was 2.7 mg. All patients with mild hypertension (DBP 90 to 104 mm Hg) had their blood pressure controlled (DBP F 90 mm Hg) with doxazosin monotherapy. One of

design: Summary.

Table

I. Patient

characteristics*

No. of patients Mild hypertension (DBP 90 to 104 mm Hg) Moderate hypertension (DBP 105 to 114 mm Hg) Evidence of LVHt Mean age (yr) Mean duration of hypertension

13 (8 men,

5 women)

10 3 2 39.1 4.2

(Yr)

LVH.

Left ventricular hypertrophy. *Three patients were withdrawn from the study: (1) a women, aged 27 years, with no evidence of LVH and moderate hypertension 01’0.6 years duration; (2) a woman, aged 39 years, with no evidence of LVH and mild hypertension of 7 years’ duration: and (3) a man. aged 35 years. with no evidence of LVH and moderate hypertension of 11 years’ duration. Patient No. 2 was withdrawn from the study because of side effects, and patients 1 and 3 did not comply with the treatment regimen. tLVH as determined by ECG.

the three patients with moderate hypertension (DBP 105 to 114 mm Hg) was controlled by doxazosin. Laboratory variables. Transaminase and alkaline phosphatase levels increased without exceeding normal values, and the levels of triglycerides decreased. None of the changes observed reached statistical significance. Side effects. Of the 16 patients studied, one experienced mild somnolence at the beginning of treatment, which disappeared with continued treatment; one patient suffered mild dizziness, which disappeared when the dose of doxazosin was reduced; and one patient was withdrawn from therapy because of palpitations, nausea, and vomiting. DISCUSSION

Doxazosin administered once daily produced a significant decrease in blood pressure in patients with mild or moderate essential hypertension. Very few, mild side effects were observed. No significant changes were found in heart rate or laboratory test values. Doxazosin has been documented to increase

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LVM (g/m*)

Baseline (End placebo) Fig.

2. Effect

of doxazosin

Table II. Changes in left ventricular systolic function (ejection fraction and velocity of circumferential fiber shortening) in eight patients treated with doxazosin Initial

Velocity of circumferential shortening (cirisec) Ejection fraction ( pi ) cirfscc.

Circumferences

fiber

1.09 61.3

Final 1.14 60.2

p value NS NS

per second.

HDL cholesterol and thus help reduce the risk of coronary heart disease.6 In this study, although HDL cholesterol was not measured, no potentially adverse changes were observed in plasma cholesterol or triglyceride levels. In the eight patients in whom a high-quality echocardiographic recording of the left ventricle was obtained, a significant reduction in LVM was seen after 12 weeks of treatment with doxazosin. No changes in left ventricular systolic function were observed. In two patients LVM was reduced from a low initial value. One patient was a woman whose LVM was reduced from 110 gm/m2 (borderline figure in women, between normal mass and left ventricular hypertrophy)17 to 95 gm/m2. The other example was a young man whose LVM was reduced from 83 to 75 gm/m’. Rowlands et al. lo found a similar reduction in ventricular mass in patients treated for hypertension who did not demonstrate echocardiographic criteria of left ventricular hypertrophy. This suggested that

on LVM

Final (12 weeks’ doxazosin) of eight patients.

hypertensive patients could have evidence of left ventricular hypertrophy even though echocardiographic parameters were still within the normal range. Frohlich18 emphasized the importance of assessing all changes in ventricular dimension rather than setting fixed limits between normal mass and left ventricular hypertrophy, and he stressed that LVM should be considered as a continuous variable. Drugs with different mechanisms of action, such as p-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, and centrally acting agents, can produce a similar reduction in ventricular mass.*-l1 With doxazosin and prazosin, the regression of cardiac hypertrophy could be related not only to the drop in left ventricular afterload, but also to the preservation of the feedback that controls the norepinephrine release mechanism at the level of cardiac sympathetic nerve terminals.lg In previous studies with prazosin,20 left ventricular function improved, which was attributed to normal or slightly depressed systolic function in these patients before therapy. In this study patients had normal initial ventricular function, and no changes in either ejection fraction or velocity of circumferential fiber shortening were observed. Devereux”’ has demonstrated that an echocardiographic LVM index (LVM divided by the body surface area in m2) >125 gm/m2 is a good predictor of cardiovascular morbidity and an even stronger predictor of cardiovascular mortality. Doxazosin is an

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Standing

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-4 Change in BP (mm Hg) and HR @pm)

-6 -8 -10 -12 -14 -16 -18 -20

Fig. 3. Mean changes doxazosin. *p < 0.001, systolic blood pressure.

SBP

in blood pressure Student t Test for

DBP and paired

heart data

effective and well-tolerated antihypertensive agent that produces a reduction in LVM. Thus, doxazosin could prevent left ventricular failure and may reduce the risk of coronary artery disease, ventricular arrhythmia, and sudden death.

REFERENCES

1. Alabaster VA, Davey MJ. The alphal-adrenoceptor antagonist profile of doxazosin: preclinical pharmacology. Br J Clin Pharmacol 1986;21(suppl 1):9S-17s. 2. Singleton W, Saxton CA, Hernandez J,Prichard BN. Postjunctional selectivity of alpha-blockade with prazosin, trimazosin and UK 33274 in man. ,J Cardiovasc Pharmacol 1982;4:S14551. 3. Vincent J, Elliott HL, Meredith PA, Reid JL. Doxazosin and alphal-adrenoceptor antagonist; pharmacokinetics and concentration-effect relationship in man. Br J Clin Pharmacol 1983;15:719-25. 4. Hayduk K. Efficacy and safety of doxazosin in hypertension therapy. Am J Cardiol 1987;59:36G-9G. 5. Rosenthal J. A multicenter trial of doxazosin in West Germany. Am J Cardiol 1987;59:40G-5G. 6. Pool JL. Plasma lipid lowering effects of doxazosin a new selective alpha1 adrenergic inhibitor for systemic hypertension. Am J Cardiol 1987;59:46G-50G. 7. Torvik D, Madsbu HP. An open one-year comparison of doxazosin and prazosin for mild to moderate essential hypertension. Am J Cardiol 1987;593680-72G.

HR rate

SBP resulting

from

(n = 13). BP, Blood

DBP 12 weeks pressure;

HR of

treatment rate;

HR, heart

with SRP,

8. Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa. Am J Cardiol 1982;49:795-801. 9. Rowlands DB, Glover DR. Stallard TJ, Littler WA. Control of blood pressure and reduction of echocardiographically assessed left ventricular mass with once-daily timolol. Br J Clin Pharmacol 1982;14:89-95. 10. Rowlands DB, Glover DR, Ireland MA, et al. Assessment of left ventricular mass and its response to antihypertensive treatment. Lancet 1982;1:467-70. 11. Dunn FG, Oigman W, Ventura HO, Messerli F, Kobrin I, Frohlich ED. Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. Am J Cardiol 1984;53:105-8. 12. Devereux RV, Savage DD, Sach I, Laragh JH. Effect of blood pressure control on left ventricular hypertrophy and function in hypertension. Circulation 1980;62(suppl 11):11-X6. 13. Levy D. Left ventricular hypertrophy. Epidemiological insights from the Framingham Heart Study. Drugs 1988;(suppl 5):1-5. 14. Salcedo EE. Krzystof C, Tarazi RC. Left ventricular mass and wall thickness in hypertension. Am d Cardiol 1979;44:936-40. 15. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 1977;55:613-8. 16. Teichholdz LE. Kreulen T, Herman AV, Gorlin R. Problems in echocardiographic volume determinations: echocardiograpic angiographic correlations in the presence or absenrr of asynergy. Am J Cardiol 1976:37:7-l 1. 17. Devereux RB. Detection of left ventricular hypertrophy II? M-mode echocardiography. Hypertension 1987:9(suppl Z):ll19.

Corral et al.

American

18. Frohlich ED. Future direction in the use of echocardiography. Hypertension 1987;9(suppl. 2):11-77. 19. Davey M. Mechanisms of alpha blockade for blood pressure control. Am J Cardiol 1987;59(14):18G-28G. 20. Corral JL, Rincon LA, Lopez NC, Pecorelli AM, Rivas LA. Estudio cruzado y evaluation ecocardiografica de Prazosin, Propranolol e Hidroclorotiazida en hipertension arterial leve y moderada. AVFT 1985;4:395-403. 21. Devereux RB. Importance of left ventricular mass as a predictor of cardiovascular morbidity in hypertension. Am J Hypertens 1989;2:650-4. APPENDIX

Formulas used in the calculation of LVM and left ventricular systolic function (ejection fraction and velocity of

January 1991 Heart Journat

circumferential fiber shortening) are as follows: LVM = (DLVd + ST + PWT)” - (DLVd)” X 1.05; where DLVd = dimensions of left ventricle at end of diastole, ST = septum thickness and PWT = posterior wall thickness. Normal value = 110 gm/m2 of body surface (women); 134 gm/m2 of body surface (men). EF = (EDV-ESV)/EDV X 100; where EF = ejection fraction, EDV = end-diastolic volume, and ESV = endsystolic volume. Normal value = 53 5’ to 77 r;‘. Vcf = (DLVd-DLVs)/(DLVd X ET); where Vcf = velocity of circumferential fiber shortening, DLVs = dimensions of left ventricle at end of systole and ET = ejection time. Normal value = 0.88 to 1.65 circumferences/set.

Echocardiographic assessment of doxazosin on left ventricular mass in patients with essential hypertension A single daily dose of doxarosin taken during a 12-week period produced a significant reduction in blood pressure and left ventricular mass index in patients with mild or moderate hypertension. The systolic shortening coefficient was also increased and a trend in the improvement of ejection fraction, rate of circumferential fiber shortening, systolic contraction time, and preejective/ ejective ratio was observed. No change in heart rate was recorded and no patients had side effects. The serum lipid profile was modified favorably, particularly with regard to the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio. By producing a reduction in blood pressure and left ventricular mass while favorably modifying the serum lipid profile, doxazosin produced a beneficial change in the overall coronary heart disease risk profile. (AM HEART J lgg1;121:356-61.)

Pedro Monsalve, MD, Omaira Vera, MD, Frank Perez Acufia, MD, Omar Medina, MD, Kasmir Ostojich, MD, Berardo Lopez, MD, Nidia Torres, Vicenta Lugo de France, MD, Ricardo Fonseca, MD, and Francisco Fragachan, MD, MSc Caracas, Venezuela

In 1974 Sen et al.’ demonstrated regression of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats. However, the regression could be achieved only with some antihypertensive drugs and not others of equal antihypertensive efficacy.2 Sub-

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sequent experiments confirmed the regression of LVH, with no correlation between the hypertrophic regression and a reduction in blood pressure level3 In other studies it was found that centrally acting antihypertensive drugs, such as cr-methyldopa and clonidine, did induce LVH regression, whereas vasodilators of the hydralazine type did not.4 This suggests that LVH regression does not depend exclusively on a reduction of high blood pressure but could also be modulated by several neurohumoral factors.5T 6 Doxazosin is a new quinazoline derivative with an-