Clinical Science (1982) 63.443~445~ 443s Captopril: evaluation of low doses, twice-daily doses and the addition of diuretic for the treatment of mild to moderate hypertension VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP* ON ANTIHYPERTENSIVE AGENTS From the Cooperative Studies Program of the Veterans Administration Medical Research Service Summary 1. We randomized 475 men whose diastolic blood pressure was 92-109 mmHg to either placebo- or captopril-treated (37.5, 75 and 150 mg/day) groups for 7 weeks. 2. After 7 weeks, the placebo-treated patients were given hydrochlorothiazide (25 mg twice daily), as were two-thirds of each captopril- treated group, and they were observed for 7 additional weeks. 3. Captopril reduced blood pressure by 12.2 + O-8/9.4 f 0.4 mmHg at 7 weeks (n = 323) and captopril plus placebo by 10.3 f 1.9110.2 + 0.9 at 14 weeks (n = 83); placebo by 2.0 + l-7/3.4 + O-8 (n = 76); captopril plus hydro- chlorothiazide by 24.4 f 1.1/16.2 f O-6 (n = 173). The effect of low-dose captopril was similar to that of a high dose. The effect of twice-daily captopril appeared to be equal to that of * Study participants: (co-chairmen) B. J. Materson and E. D. Freis; (participating investigators) W. W. Neal, R. E. Borreson, J. T. Taguchi, B. Mukherji, H. M. Perry, K. C. Mezey, W. Flamenbaum and R. Hamburger; (nurses or physician assistants) B. Munze, P. Melly, R. Collins, M. Curry, P. Ulrich, R. Berry, M. Fitzgerald, A. Faiella and B. Gregory; (Biostatistical Center) S. Anderson. T. Tosch and J. Foregger; (Central Laboratory) W.`Flamenbaum and R. Hamburger; (Central Research Pharmacist) L. Young; (Operations Committee) W. M. Kirkendall, W. McF. Smith and C. M. Hawkins; (consultants) J. Alexander, J. Stritar and J. Meyer; (Cooperative Studies Program Central Administration) J. A. Hagans, P. Huang, W. G. Henderson and M. Sather. Correspondence: Dr Barry J. Materson, Miami Veterans Administration Medical Center, 1201 N.W. 16th Street, Miami, FL 33 125, U.S.A. / thrice-dailv treatment but monitoring studies are needed to confirm this. 4. Only 15 out of 384 (3.9%) of patients were dropped from the study because of adverse effects. 5. Low-dose captopril may be useful in patients with mild to moderate hypertension. Key words: captopril, hydrochlorothiazide. Introduction Captopril (SQ 14 225), an oral angiotensin converting enzyme inhibitor, was proposed as an ideal antihypertensive drug because it was tar- geted to a major humoral system responsible for sustaining elevated arterial pressure 111. Indeed, captopril was effective in lowering arterial press- ure even in patients who had low plasma renin activity and it was not associated with the adverse effects of the sympatholytic drugs 121. Unfortunately, captopril had adverse effects, including a rash, neutropenia and proteinuria. Its initial use, however, had been restricted to severely ill patients and patients with severe hypertension resistant to multiple drug com- binations. In general, very high doses (450 mg or more) of captopril were used 131. We designed this study on patients with mild, uncomplicated hypertension to determine whether captopril was effective as a hypotensive agent in doses much lower than had been used previously and to determine if lower effective doses were associated with fewer adverse effects. We also sought to determine the degree of hypotension induced by the addition of hydrochlorothiazide to captopril and to determine whether captopril could be administered twice rather than three times daily. 444s Low-dose captopril Methods We enrolled 722 ambulatory male veterans whose diastolic (Korotkoff phase V) blood press- ure was 92-109 mmHg and who met other quali- fying criteria. All patients gave fully informed, written consent before they were enrolled. The protocol had been approved by a central human studies committee and similar com- mittees at each of the seven participating centres. Patients were withdrawn from current medication for at least 2 weeks and then given a placebo capsule. Patients meeting the blood pressure entry criteria and compliance requirements (checked by count of pills remaining in a special blister pack) were randomized to taking a capsule which was identical in appearance with the placebo capsule but contained one of the follow- ing: placebo, captopril 12.5 mg, 25 mg, 37.5 mg or 50 mg. All of these medications were to be taken three times a day with the exception of captopril 37.5 mg, which was taken twice daily. The blind was preserved by placing a placebo as the mid-day dose on the blister pack. After 7 weeks (phase A), all patients were given a tablet that contained either hydrochlorothiazide (25. mg) or placebo and were instructed to take it twice daily. All patients previously given placebo instead of active captopril were given active hydrochlorothiazide so that no patients remained in the study on placebo alone beyond this point. All other patients receiving active captopril were randomized such that one-third of each dose group received placebo and two-thirds received active hydrochlorothiazide. The patients were followed for an additional 7 weeks (phase B), at which time they were either returned to placebo for 2 weeks or entered into a long-term trial of captopril. Appropriate tests of leucocytes, blood chemistry and urine protein excretion were made. Results Of the 722 men enrolled, 475 (65.8%) qualified for randomization; 399 completed phase A and 3 15 finished phase B. The data which follow have been derived from these patients. The racial distribution was 248 (52.2%) white, 222 (46.7%) black and 5 (1.1%) other. Their average age was 55.0 years and 58.4% of them had previously received treatment for hypertension. The blood pressure results are presented in Table 1. During phase A, all doses of captopril were equally effective in reducing blood pressure. The twice-daily performed as well as the thrice- daily dose and the percentage at goal (diastolic blood pressure less than 91 mmHg) was the same. During phase B, the 83 patients who were randomized to have placebo instead of active hydrochlorothiazide added to captopril main- tained approximately the same level of blood pressure as in phase A, except for an increase of systolic pressure in patients taking 12.5 mg thrice daily and a slight additional blood pressure reduction in patients taking 37.5 mg twice daily and 50 mg thrice daily. The 173 remaining captopril-treated patients who received hydro- chlorothiazide experienced a marked further reduction in both systolic and diastolic blood pressure. There was no difference in the response TABLE 1. Bloodpressure reduction achieved by captopril and captoprilplus hydrochlorothiazide Mean blood pressures are reported in mmHg f SE. Base, baseline; SBP, systolic blood pressure; DBP, diastolic blood pressure; Goal, goal blood pressure (<91 mmHg diastolic); HCTZ, hydrochlorothiazide; n = number in group. Captopd doses are recorded by mg given thrice daily (except 37.5 mg, which was given twice daily). PlX&G Phase A Phase B Captopril Captopril plus placebo Captopril plus hydrochlorothiazide 12.5 25 mg 37.5 50 mg 12.5 25 mg 37.5 50mg HCTZ 12.5 25 mg 37.5 50mg w w mg Tz w mg n 76 79 78 85 81 23 20 22 18 59 44 41 39 48 Base SBP 146.0 147.6 147.6 149.3 147.4 149.4 148.9 149.9 145.0 145.6 146.1 148.1 148.8 146.8 21.6 k1.7 k1.3 f1.5 k1.8 i3.1 f2.8 f3.6 k3.1 kl.8 1-2.4 k1.7 kl.9 22.3 -A SBP 2.0 9.9 11.6 13.7 13.3 3.1 11.6 13.1 14.7 11.6 23.3 26.5 25.8 22.5 21.7 il.7 k1.6 fl.7 f1.5 k2.4 23.7 k3.9 k4.9 kl.7 k2.6 k2.2 t2.6 fl.8 Base DBP 97.8 97.0 98.1 97.5 97.9 97.7 98.6 97.4 96.8 97.6 96.2 98.2 97.5 98.4 f0.5 -to.4 F0.5 f0.5 f0.5 f0.9 kO.8 io.9 +1.2 kO.6 -CO.6 kO.7 kO.7 to.7 -A DBP 3.4 8-6 9.2 9.5 10.3 8.3 8.2 12.6 11.9 8.2 16.6 15.5 14.5 17.6 f0.8 kO.9 +0.9 kO.9 f0.8 ?I.7 kl.7 f2.1 k2.0 k1.0 il.1 21.2 11.2 il.1 96 at goal 36.8 65.8 58.9 63.5 70.3 56.5 47.3 76.1 83.3 55.9 95.5 85.3 82.1 89.5 Veterans Administration Cooperative Study Group 445s of the two groups which received 75 mg of captopril per day. During phase A, white patients tended to respond to captopril better than black patients. Black patients responded better when hydro- chlorothiazide was added to placebo during phase B and the racial differences were abolished in the captopril-treated groups by the addition of the diuretic. During phase A, 2.6% of patients taking placebo and 3.1% taking captopril developed a rash. During phase B, 1.7% of the patients receiving the placebo plus hydrochlorothiazide, 3.6% of those receiving captopril plus placebo and 1.2% of those receiving captopril plus hydrochlorothiazide had a rash. The overall incidence of the development of a rash in the captopril-treated patients was 15 out of 384 (3.9%), of which five patients were receiving the 150 mg/day dose. Therefore the incidence in the low dose group was 2.4%. Eighteen patients were withdrawn from the trial owing to drug intolerance. These were evenly distributed across all of the groups. Two patients taking captopril 37.5 twice daily and 50 mg thrice daily were withdrawn on account of urticaria; three taking diuretic plus captopril 12.5, 25 and 50 mg thrice daily had a maculo- papular rash; two taking the diuretic plus 25 mg thrice-daily and 37.5 mg twice-daily captopril had loss of taste, which returned on dis- continuation of the drugs; two taking the diuretic plus captopril 12.5 and 25 mg thrice daily had nausea and vomiting. Proteinuria occurred in three patients. Urinary protein excretion rose in one patient taking captopril 12.5 mg thrice daily from a baseline value of 126 mg to 665 mg after 5 weeks of captopril treatment and returned to baseline after captopril had been discontinued. In another patient urinary protein excretion rose from a baseline level of over 453 mg/day to 1600 mg/day after 12 weeks of captopril 50 mg thrice daily. One patient who was randomized to placebo treatment excreted 800 mg/day and 1200 mg/day of protein 4 days later. He returned to normal within 1 month without intervention. Three patients were withdrawn owing to intoler- able hypotension; two were taking 50 mg of captopril thrice daily and one the diuretic and 25 mg of captopril thrice daily. One patient taking 37.5 mg of captopril twice daily complained of intolerable headaches. Two patients taking placebo were withdrawing owing to drug in- tolerance. One complained of weakness, dizziness and dry mouth after the first dose and refused to return. One complained of headache, impotence, dysuria and urinary frequency after 5 weeks of therapy. Discussion Captopril 50 mg thrice daily was included in this experimental design because it was then con- sidered to be the lowest effective dose. This study demonstrates clearly that captopril alone in lower doses (37.5 and 75 mg daily) reduces blood pressure in mildly hypertensive patients as well as captopril 150 mg daily. The expected enhancing effect of added diuretic was also clear. We believe that our data suggest that captopril can be administered twice rather than thrice daily, but definitive proof requires blood pressure monitor- ing experiments. Previous unpublished data have suggested that captopril would not be effective alone in black patients, but our study shows a good effect. Racial response was equalized by the addition of a diuretic. Withdrawals for adverse effects were very low and in the range we have experienced in previous studies of diuretics and /I-adrenoceptor-blocking agents. That is not to imply that effects such as rashes did not occur, but that discontinuation of the drug was usually unnecessary. It was also very difficult to be certain whether a rash was due to captopril or to the diuretic or to the combination. We believe that this short-term study demon- strates that the use of captopril in low doses may be extendable to the general population of hyper- tensive patients and might no longer need to be restricted to severe or resistant hypertensive patients. Acknowledgments This study was supported by a grant from the Squibb Institute for Medical Research. References Ill RUBIN, B., ANTONACCIO, M.J. & HOROWITZ, Z.P. (1978) Captopril (SQ 14.225) (D~3~mercapto-2~methylpropanoyl~l- proline), a novel orally active inhibitor of angiotensin-con- verting enzyme and anti-hypertensive agent. Progress in Cardiocascular Diseases, 21, 183-194. 121 GAVRAS. H.. BRUNNER, H.R., TURINI, G.A.. KERSHAW, G.R., TIFFT, C.P., CUTTELOD, S., CAVILAS, I., VUKOVICH, R.A. & MCKINSTRY, D.N. (1978) Anti-hypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14,225 in man. New England Journal oJMedicine, 229,991-995. 131 W&EBER, B., GAVRAS, I., BRUNNER, H.R. & GAVRAS, H. (198 I) Safety and efficacy of chronic therapy with captopril in hypertensive patients: an update. Journal of Clinical Pharmaco/ogy, 21,508-j 16.