Effect of Captopril Injection in Patients With Moderate to Severe Hypertension Y. Lacourciere, M. Lebel, W. F. Graney, C. A. Forchette, and A. J. Block
The effect of intravenous captopril was studied in 24 white patients who had moderate to severe hypertension. Patients received incremental doses of 1 to 10 mg delivered at 10 min intervals over 50 to 80 min. Blood pressure (BP) was lowered within 5 to 10 min after the initial dose was administered and continued to decline, reaching a maximum response after 20 min (2 to 4 mg). At this time group mean BP fell from 175 ± 3/111 ± 1 to 166 ± 3 / 97 ± 2 mm Hg (P < 0.01). Additional dose increments to an average cumulative dose of 40 mg did not increase the initial effect. No adverse side effects or symptomatic hypotension occurred in any subject. There was a significant correlation be-
A
ngiotensin-converting enzyme inhibitors are recognized as effective when given orally in the treatment of patients with hypertension and congestive heart failure. Recently, the use of captopril, administered intravenously, has been suggested for the treatment of patients with severe cardiac failure and may provide a continuation of therapy during emergency treatment or when parenteral therapy is indicated. While the effects of intravenous captopril have been studied in normotensive subjects, there are presently no data available on its effects in hypertensive patients. 12
tween diastolic BP decreases observed in response to intravenous captopril and subsequent long-term oral captopril therapy. The addition of hydrochlorothiazide increased the proportion of patients reaching normotension. We conclude that small intravenous bolus injections of captopril appear to be effective rapidly and are well tolerated in moderate to severe essential hypertension. Shortterm intravenous administration seems to predict the response to chronic oral captopril therapy. Am J Hypertens 1990;3:769-774 KEY WORDS: Intravenous captopril, moderate to severe essential hypertension.
The present study was designed to evaluate the efficacy and safety of captopril administered in incremental intravenous doses in patients with moderate to severe essential hypertension. Furthermore, it was set up to evaluate the conversion from parenteral to oral therapy in these patients and to verify whether the long term response can be predicted from the acute administration.
3,4
5
From the Department of Medecine, Universite Laval, Quebec, Canada (YL, ML), and E.R. Squibb & Sons, Inc., Princeton, New Jersey (WFG, CAF, AJB). A preliminary report of this work was presented at the annual meeting of the American Society of Hypertension in New York, New York, May, 1987. Address correspondence and reprint requests to Dr. Yves Lacourciere, Hypertension Research Unit, Centre Hospitalier de l'Universite Laval, 2705 Boulevard Laurier, Ste-Foy, Quebec, Canada, G1V 4G2.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
PATIENTS AND METHODS Twenty-four white patients, 12 women and 11 men, aged 41 to 70 years (mean age, 55 years), with a diagnosis of essential hypertension (mean duration 11.2 years), were entered in this open label study performed in the hypertension clinic of the hospital. In all patients, secondary causes of hypertension were ruled out by thorough clinical and biological investigations. Twentythree of the 24 patients were receiving treatment but were poorly controlled with a combination of up to three different drugs not including converting enzyme inhibitors. Our hypertensive patient population included sub-
jects in whom a seated diastolic blood pressure equal to or greater than 105 mm Hg was documented. Exclusion criteria included cerebral or myocardial in farction within the last six months, insulin dependent diabetes, congestive heart failure, serious allergy, his tory of drug hypersensitivity, collagen disease and women of childbearing potential. Antihypertensive medication was tapered if necessary and withdrawn 2 to 7 days prior to enrollment. The study was approved by the local ethics committee and all subjects signed an informed consent form before starting the study. Each patient underwent a complete physical exami nation and investigation including standard hematol ogy, biochemistry determinations, urinalysis, chest x-ray and 12-lead electrocardiography (ECG) per formed prior to treatment. Continuous ECG monitoring was initiated prior to and during the period of treatment with captopril injections. With patients in the supine position, blood pressure and heart rate were monitored every 5 min by a Dinamap 845XT automated recorder (Critikon, Tampa, FL). Blood pressure and heart rate recording began at rest 20 min before the start of capto pril dosing. Left ventricular ejection fraction, obtained from an equilibrium radionuclide ventriculography, was determined before and after intravenous adminis tration of captopril. Laboratory tests and ECG were re peated the day after the acute treatment. Captopril was provided in a 1 mL sterile solution at a concentration of 25 m g / m L to be diluted with sterile water for injection USP prior to injection. Incremental doses of captopril were administered intravenously over 1 min periods at 10 min intervals. Patients were randomly assigned to receive an initial dose of either 1.0 or 2.0 mg. Subse quent doses were administered in response to the pre ceding one, and were gradually increased at 5 and 10 mg to reach a maximum of 51 mg of captopril given intravenously over the course of 50 to 80 min. Blood pressure and heart rate measurements were continued for 2 hours after the first dose. Patients were then ob served at the clinic for an additional 2 h period. Follow ing completion of captopril injections, patients were converted to oral captopril for a period of 12 weeks. Conversion to oral therapy began with a dosage of ei ther 12.5 or 25 mg thrice daily started within 12 h of intravenous therapy. The initial dose was based on the total dose of captopril administered intravenously. When the injected dose was less than 16 mg, the initial dose was 12.5 mg. The initial dose was 25 mg in patients who received more than 16 mg of captopril by injection. These low oral doses were chosen because it is now generally accepted that a dose of 25 to 50 mg captopril three times a day is adequate to control blood pressure in most hypertensive patients. Patients were seen 24 h after the first oral dose of captopril and then followed every two weeks. Adjustments were made in captopril dosage to a maximum of 50 mg thrice daily and 50 mg 1,6,7
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
hydrochlorothiazide (HCTZ) daily was added to the treatment regimen in an attempt to maintain a diastolic pressure of less than 90 mm Hg. Blood pressure was measured after 15 min of rest in the supine position with a Dinamap 845 XT automated recorder and was defined as the mean of three readings. Statistical Analysis Data are reported as mean ± SEM. Statistical evaluation of the blood pressure and heart rate results was performed with a one-way analy sis of variance for repeated measures followed by Dun can's multiple range test. Correlation coefficients were calculated by the least-squares method. The level of significance was Ρ < .05. RESULTS Patients received incremental intravenous captopril doses reaching 15 to 51 mg (mean 40 mg) over 50 to 80 min according to blood pressure. As illustrated in Figure 1, intravenous therapy at an average cumulative dose of 2 to 4 mg resulted in a reduction of mean supine blood pressure for the group from 1 7 3 ± 3 / l l l ± l t o l 6 6 ± 3 / 9 7 ± 2 mm Hg (P < .01), within 20 min of treatment. Blood pressure was lowered within 5 to 10 min after the initial dose was administered and continue to decline, reaching maximum response at 20 min. Individual patient responses to subsequent dosages were variable with respect to magnitude and direction, the overall effect being one of no change between 30 and 90 min despite dose increments. The cumulative dose for individual mean maximum response ranged from 1 to 8 mg (mean 4.5). The effectiveness of captopril injection therapy based upon the individual patient's response 10 min after re ceiving the last dose of captopril injection (Table 1) was categorized according to the following criteria: 1) Full 180-
χ Β
1
6
0
Η
Ε
-
140Η
ο-ο
Systolic Diastolic
(Λ
ω
120Η
Ό Ο Ο
00
100-
80
" Τ —ι— "Ί
Time (min.) - 2 0 -10 Ο 10 20 Dose (mg). 1-2 2-4 5
π— 30 10
40 50 60 17 26 35
70 40
80 90 40
FIGURE 1. Average systolic and diastolic blood pressures be fore and after intravenous bolus injections of captopril (average cumulative dose).
TABLE 1. INDIVIDUAL BP RESPONSES AFTER INTRAVENOUS INJECTION OF CAPTOPRIL Dose information
Post effect*
Cumulative dose at mean maximum response (mg)
170/101 157/101 168/88 165/92 153/100 176/88 145/107 132/97 142/93 152/106 136/88 183/105 152/82 150/89 171/104 187/124 203/100 156/97 198/110 172/103 167/94 121/94 171/103 158/85
6 5 2 6 4 4 3 4 4 6 3 6 1 2 6 6 5 5 6 2 6 8 5 6
Blood pressure Subject number
Baseline BP(mm Hg)
Maximum response (mm Hg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
168/110 148/108 200/106 191/115 180/106 162/109 159/116 160/120 172/106 161/111 172/106 155/120 165/118 161/106 168/107 211/126 207/117 184/109 190/112 170/108 178/109 171/116 174/108 190/112
170/96 153/97 167/77 169/103 181/93 173/86 161/94 149/100 154/94 162/104 139/92 175/100 147/85 157/85 156/104 186/109 210/104 168/101 187/100 166/87 172/110 163/108 148/91 166/101
Total dose (mg)
Time of last dose (min)
Response categoryt
41 50 25 28 39 29 48 39 44 50 38 50 16 24 31 51 50 50 41 15 50 48 50 46
60 80 70 60 60 50 80 70 70 70 60 60 50 60 50 70 70 70 60 60 70 60 75 80
Ρ Ρ F F Ρ F Ρ F F Ρ F F F F Ν Ν F F Ν Ρ F F Ρ F
* 10 minutes after last dose. f F = Full Ρ = Partial
N = No
response.
response characterized by a reduction of diastolic blood pressure (DBP) of at least 10% from pretreatment value, 2) partial response by a reduction of DBP of at least 5%, and 3) no response by a reduction of DBP less than 5 % from pretreatment value. These categories were de signed in an attempt to identify the patients who were acutely sensitive to inhibition of angiotensin-converting enzyme. By these criteria, 14 patients had a full re sponse, with 6 patients (25%) exhibiting an acute reduc tion in DBP to 90 mm Hg or less (Table 2). Seven pa-
tients responsed with a reduction of DBP between 5 and 10%, which met the criteria for a partial response. Three patients failed to respond to a dose regimen of 31, 41 and 51 mg of captopril administered over 50, 60 or 70 min time period, respectively. None of the patients ex perienced hypotension (Table 1). Captopril did not af fect heart rate, which was 79 ± 3 beats/min at time 0 and 74 ± 2 beats/min 90 min later. Reduction in blood pressure was attained without any significant changes in ECG during the protocol and the day after.
TABLE 2. BP REDUCTION ACHIEVED BY INTRAVENOUS AND ORAL CAPTOPRIL
Baseline BP Systolic BP (mm Hg) Diastolic BP (mm Hg) Patients reaching normotension (DBP < 90 mm Hg)
173 ± 3 111 ± 11
10 Min after last injection
Oral captopril 24 h
Oral captopril 4 weeks
Captopril + hydrochlorothiazide 12 weeks
162 ± 4* 98 ± 2* 5/24(21%)
154 ± 1 * 96 ± 3* 4/22(18%)
157 ± 3* 96 ± 2* 6/22(27%)
153 ± 3* 92 ± 2* 11/22(50%)
Compared with baseline: * Ρ < .01. Captopril:
25 mg thrice daily (n = 2), 50 mg thrice daily (n = 20). Captopril + hydroclorothiazide
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
(n = 16).
Left ventricular ejection fraction was not significantly modified by intravenous captopril treatment. Mean left ventricular ejection fraction prior to and following ad ministration of captopril injection was 72 ± 2 % and 74 ± 2 % , respectively. There were no reports of adverse drug experiences while patients were receiving intrave nous therapy. However, one patient developed tran sient elevation of creatinine phosphokinase and serum creatinine following therapy. Twenty-two of the 24 patients continued with longterm oral captopril treatment administered thrice daily at an initial dosage of 12.5 mg in one patient and 25 mg in 21 patients. Captopril was then increased to 25 mg thrice daily in 2 patients and to 50 mg thrice daily in 20 patients. For 16 patients 50 mg hydrochlorothiazide daily was added to the regimen. The transition to oral therapy was uneventful. The comparative effects of acute and oral captopril after 24 h and 4 and 12 weeks are shown in Table 2. Both systolic and diastolic pressures were reduced sig nificantly (P < .01) 10 min after the last dose of capto pril injection. The overall response did not change after 24 h and 4 weeks of oral captopril monotherapy. Figure 2 illustrated the relationship between the blood pressure responses observed with intravenous and oral captopril. For individual subjects there were no significant corre lations r = 0.17, (P < .4) between the acute and longterm systolic blood pressure (SBP) reduction. However there was a significant positive correlation r = 0.5, (P < .02) between the DBP decrease observed in response to intravenous and oral therapies. After 12 weeks of oral therapy with captopril and hydrochlorothiazide, 5 0 % of the patients reached normotension (DBP < 90 mm Hg) compared to 27% with captopril monotherapy (Table 2).
20-
o Systolic (r=o.i7) • Diastolic (r«0.5)
Q_ _
ω]Έ c ο. φ ο
-20-Ι
i f
- °-
0
V·· • 8
3
-40-50-40
ι
'
r ι 0 20 Chronic BP response to 4 weeks of captopril P.O. (mm Hg) 1
Inhibition of the renin-angiotensin system by blockade of angiotensin-converting enzyme (ACE) with paren teral teprotide and enalaprilat or with oral captopril has been effective in lowering blood pressure (BP) both in severe hypertension and in hypertensive crisis. " Our results with intravenous captopril, further support these observations. Intravenous therapy resulted in a signifi cant BP decrease within 20 min of treatment (Figure 1). Moreover, when looking at the individual response 10 min after the last captopril injection, 14 patients had a full response with a normalization in 5 of them. The greater response rate observed in this study compared to those obtained with teprotide and enalaprilat ' could be related to our hypertensive population as captopril was administered only to white patients with moderate to severe hypertension. It has previously been noted that blacks with hypertension have lower plasma renin ac tivity, particularly if the hypertension is not in an accel erated or malignant phase. Therefore, black patients with an equally elevated blood pressure may be less likely to respond to angiotensin-converting enzyme in hibitors. One study found that the percentage of black patients in whom blood pressure became normal after treatment with a low dose of captopril was only 2 0 % , as compared with 6 0 % of whites. In this study, captopril was administered at doses well above those shown to produce ACE inhibition. Al though the acute BP reduction after captopril or enala prilat is predominantly secondary to inhibition of an giotensin II formation, other mechanisms have been suggested. These mechanisms involve the sympathetic nervous system, kinins and prostaglandins. Continued administration of captopril to an average cumulative dose of 40 mg over 80 min did not enhance the early response. These findings concur with the re sults obtained by Dipette et al in which no further BP reduction was observed following incremental intrave nous doses of enalaprilat in patients with severe and malignant hypertension. Thus intravenous captopril appears to be effective as initial doses of 1 and 2 mg were sufficient to lower the BP within 5 and 10 min. Moreover, the overall maximum response seen at 20 min was obtained with a cumulative dose of 2 to 4 mg. The cumulative dose (Table 1) at individual mean maxi mum response ranged from 1 to 8 mg (mean 4.5). Twenty-two of the 24 patients were converted to long-term oral therapy with captopril alone or in combi nation with hydrochlorothiazide. Continued therapy with oral captopril over 4 weeks produced an increase in the number of responders without affecting the overall blood pressure reduction (Table 2). In this study the acute antihypertensive response to intravenous capto pril was a good predictor of the diastolic blood pressure reduction obtained with long-term oral therapy (Figure 8
8 9
12
13
14
15
9
10H
•10-
DISCUSSION
1
1
-20
1 40
FIGURE 2. Relationship between the acute blood pressure (BP) response to intravenous captopril and the BP response to chronic oral captopril therapy.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
11
2). A sustained effect of captopril has also been de scribed by many authors in patients with various form of severe hypertension. While most patients in an early study have required an increase in medication from initial doses other studies have shown a sus tained reduction of BP despite a reduction in the total daily dose of captopril. Bidiville et a l did not find such a correlation between the acute response to intra venous enalaprilat and the long-term efficacy of enalapril. This difference in comparison with our findings may be due to differences in subject selection since our patients had moderate or severe hypertension. In this study, with the addition of hydrochlorothiazide there was an additional decrease in blood pressure and a sig nificantly greater proportion of patients reaching nor motension, which is in agreement with previous data. The efficacy and safety of both intravenous captopril and enalaprilat suggest that ACE inhibitors offer a valuable alternative to other parenteral drugs for the treatment of hypertension when the oral route is to be avoided (eg, in the perioperative period). As both intravenous enalaprilat and captopril result in a signifi cant BP decrease within minutes, patient response can immediately be discerned and the nonresponding pa tient can quickly be changed to an alternate therapy. The absence of hypotension and of other acute serious side-effects may make it possible to use these inhibitors even outside an intensive care unit and without the in vasive arterial pressure monitoring. Since angiotensinconverting enzyme inhibitors may preferentially pre serve blood flow to vital organs such as brain, heart and kidney, they offer a distinct advantage over other drugs, particularly direct vasodilatators. In summary, this small study indicates that a low dose of intravenous captopril given as a bolus injection can rapidly lower BP in patients with moderate to severe hypertension. No further blood pressure reduction was observed following incremental doses. The absence of hypotension and apparent adverse effects suggest that intravenous captopril at low dosage may be an alterna tive to other parenteral or sublingual antihypertensive drugs when the oral route is to be avoided. The acute diastolic BP response to intravenous injection can pre dict the chronic effect of captopril administered orally in patients with moderate to severe hypertension. 16-19
20
21,22
nous captopril treatment in patients with severe cardiac failure. Br Heart J 1986;55:187-190. 4.
Boyd O, Pohl JEF: Intravenous captopril for cardiac fail ure. Lancet 1986;i:1041-1042.
5.
Nussberger J, Waeber G, Bidiville J, et al: Pharmacody namic and humoral effects of single intravenous doses of captopril in normal subjects. Clin Exp Hypertens 1987;A9(2& 3):345-349.
6.
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Captopril: evaluation of low doses twice daily and the addition of a diuretic for the treatment of mild to moderate hypertension. Clin Sci 1982;63(suppl 8):4435-4455.
7.
Williams G: Converting enzyme inhibitors in the treat ment of hypertension. Ν Engl J Med 1988;319:15171525.
8.
Tifft CP, Gavras H, Kershaw GR, et al: Converting en zyme inhibition in hypertensive emergencies. Ann In tern Med 1979;90:43-47.
9.
Dipette JR, Ferraro JC, Evans RR, Martin M: Enalaprilat, an intravenous antiotensin-converting enzyme inhibi tor, in hypertensive crises. Clin Pharmacol Ther 1988;38:199-204.
10.
Saragoca MA, Homsi E, Ribeiro A, et al: Hemodynamic mechanism of blood pressure response to captopril in human malignant hypertension. Hypertension 1983; 5(suppl 1):153-158. Biollaz J, Waeber B, Brunner HR: Hypertensive crisis treatment with orally administered captopril. Eur J Clin Pharmacol 1983;25:245-259.
23
21,24
8
11. 12.
Chrysant SG, Danisak, Dem DC, et al: Racial differences in pressure, volume and renin interrelationship in essen tial hypertension. Hypertension 1979;1:136-141.
13.
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Racial difference in response to low dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol 1982;14:9751015.
14.
Reyes AJ, Leary WP, Acosta-Barrios TN: Once-daily ad ministration of captopril and hypotensive effects. J Car diovasc Pharm 1985;7(suppl 1):516-519.
15.
Johnston CI, Jackson B, Cubela R, Arnold L: Mechanism for hypertensive action of angiotensin converting en zyme inhibitors. Clin Exp Hypertens 1984;A142:551561.
16.
Brunner HR, Gavras H, Waeber Β et al: Oral angiotensin converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med 1979;90:19-23.
17.
Case DB, Atlas SA, Marion RE, Laragh JH: Long-term efficacy of captopril in renovascular hypertension. Am J Cardiol 1982;49:1440-1446.
1. Edwards CRW, Padfield PL: Angiotensin converting en zyme inhibitors: past, present and bright future. Lancet 1985;1:30-34.
18.
Ferguson RR, Vlasses PH, Koplin JR, Captopril in severe treatment-resistant hypertension. Am Heart J 1980; 99:579-585.
2.
19.
Havelka HJ, Boerlin A, Studer P, et al: Long term experi ence with captopril in severe hypertension. Br J Clin Pharmacol 1982;14:71S-76S.
20.
Johns DW, Baker KM, Ayers CR, et al: Acute and chronic effect of captopril in hypertensive patients. Hyperten sion 1980;2:567-575.
8,25,26
REFERENCES
3.
The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: re sults of the Cooperative with Scandinavian Enalapril Survival Study (CONSENSUS). Ν Engl J Med 1987;316:1429-1435. Rademaker M, Shaw TRD, Williams BC, et al: Intrave
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
21.
Karlberg BE, Asplund J, Wettre S, Ohman KP: Long term experience of captopril in the treatment of primary hy pertension. Br J Clin Pharmacol 1982;14:133S-137S.
24.
Weinberger MH: Comparison of captopril and hydro chlorothiazide alone or in combination in mild to moder ate hypertension. Br J Clin Pharmacol 1982;14:127-131.
22.
Mimran A, Jover B: Maintenance of the antihypertensive efficacy of captopril despite consistent reduction in daily dosage. Br J Clin Pharmacol 1982;14:81S-85S.
25.
Gavras H, Liany CS, Brunner HR: Redistribution of re gional blood flow after inhibition of the angiotensinconverting enzyme. Circ Res 1978;43(suppl 1):159 -162.
23.
Bidiville J, Nussberger J, Waeber G, et al: Individual re sponses to converting enzyme inhibitors and calcium an tagonists. Hypertension 1988;11(2):166-172.
26.
Barry DI, Lassen Ν A: Cerebral blood flow in hyperten sion and effects of antihypertensive drugs. J Hypertens 1984;2(suppl 3):519-526.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
The effect of intravenous captopril was studied in 24 white patients who had moderate to severe hypertension. Patients received incremental doses of 1 to 10 mg delivered at 10 min intervals over 50 to 80 min. Blood pressure (BP) was lowered within 5 to 10 min after the initial dose was administered and continued to decline, reaching a maximum response after 20 min (2 to 4 mg). At this time group mean BP fell from 175 ± 3/111 ± 1 to 166 ± 3 / 97 ± 2 mm Hg (P < 0.01). Additional dose increments to an average cumulative dose of 40 mg did not increase the initial effect. No adverse side effects or symptomatic hypotension occurred in any subject. There was a significant correlation be-
A
ngiotensin-converting enzyme inhibitors are recognized as effective when given orally in the treatment of patients with hypertension and congestive heart failure. Recently, the use of captopril, administered intravenously, has been suggested for the treatment of patients with severe cardiac failure and may provide a continuation of therapy during emergency treatment or when parenteral therapy is indicated. While the effects of intravenous captopril have been studied in normotensive subjects, there are presently no data available on its effects in hypertensive patients. 12
tween diastolic BP decreases observed in response to intravenous captopril and subsequent long-term oral captopril therapy. The addition of hydrochlorothiazide increased the proportion of patients reaching normotension. We conclude that small intravenous bolus injections of captopril appear to be effective rapidly and are well tolerated in moderate to severe essential hypertension. Shortterm intravenous administration seems to predict the response to chronic oral captopril therapy. Am J Hypertens 1990;3:769-774 KEY WORDS: Intravenous captopril, moderate to severe essential hypertension.
The present study was designed to evaluate the efficacy and safety of captopril administered in incremental intravenous doses in patients with moderate to severe essential hypertension. Furthermore, it was set up to evaluate the conversion from parenteral to oral therapy in these patients and to verify whether the long term response can be predicted from the acute administration.
3,4
5
From the Department of Medecine, Universite Laval, Quebec, Canada (YL, ML), and E.R. Squibb & Sons, Inc., Princeton, New Jersey (WFG, CAF, AJB). A preliminary report of this work was presented at the annual meeting of the American Society of Hypertension in New York, New York, May, 1987. Address correspondence and reprint requests to Dr. Yves Lacourciere, Hypertension Research Unit, Centre Hospitalier de l'Universite Laval, 2705 Boulevard Laurier, Ste-Foy, Quebec, Canada, G1V 4G2.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
PATIENTS AND METHODS Twenty-four white patients, 12 women and 11 men, aged 41 to 70 years (mean age, 55 years), with a diagnosis of essential hypertension (mean duration 11.2 years), were entered in this open label study performed in the hypertension clinic of the hospital. In all patients, secondary causes of hypertension were ruled out by thorough clinical and biological investigations. Twentythree of the 24 patients were receiving treatment but were poorly controlled with a combination of up to three different drugs not including converting enzyme inhibitors. Our hypertensive patient population included sub-
jects in whom a seated diastolic blood pressure equal to or greater than 105 mm Hg was documented. Exclusion criteria included cerebral or myocardial in farction within the last six months, insulin dependent diabetes, congestive heart failure, serious allergy, his tory of drug hypersensitivity, collagen disease and women of childbearing potential. Antihypertensive medication was tapered if necessary and withdrawn 2 to 7 days prior to enrollment. The study was approved by the local ethics committee and all subjects signed an informed consent form before starting the study. Each patient underwent a complete physical exami nation and investigation including standard hematol ogy, biochemistry determinations, urinalysis, chest x-ray and 12-lead electrocardiography (ECG) per formed prior to treatment. Continuous ECG monitoring was initiated prior to and during the period of treatment with captopril injections. With patients in the supine position, blood pressure and heart rate were monitored every 5 min by a Dinamap 845XT automated recorder (Critikon, Tampa, FL). Blood pressure and heart rate recording began at rest 20 min before the start of capto pril dosing. Left ventricular ejection fraction, obtained from an equilibrium radionuclide ventriculography, was determined before and after intravenous adminis tration of captopril. Laboratory tests and ECG were re peated the day after the acute treatment. Captopril was provided in a 1 mL sterile solution at a concentration of 25 m g / m L to be diluted with sterile water for injection USP prior to injection. Incremental doses of captopril were administered intravenously over 1 min periods at 10 min intervals. Patients were randomly assigned to receive an initial dose of either 1.0 or 2.0 mg. Subse quent doses were administered in response to the pre ceding one, and were gradually increased at 5 and 10 mg to reach a maximum of 51 mg of captopril given intravenously over the course of 50 to 80 min. Blood pressure and heart rate measurements were continued for 2 hours after the first dose. Patients were then ob served at the clinic for an additional 2 h period. Follow ing completion of captopril injections, patients were converted to oral captopril for a period of 12 weeks. Conversion to oral therapy began with a dosage of ei ther 12.5 or 25 mg thrice daily started within 12 h of intravenous therapy. The initial dose was based on the total dose of captopril administered intravenously. When the injected dose was less than 16 mg, the initial dose was 12.5 mg. The initial dose was 25 mg in patients who received more than 16 mg of captopril by injection. These low oral doses were chosen because it is now generally accepted that a dose of 25 to 50 mg captopril three times a day is adequate to control blood pressure in most hypertensive patients. Patients were seen 24 h after the first oral dose of captopril and then followed every two weeks. Adjustments were made in captopril dosage to a maximum of 50 mg thrice daily and 50 mg 1,6,7
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
hydrochlorothiazide (HCTZ) daily was added to the treatment regimen in an attempt to maintain a diastolic pressure of less than 90 mm Hg. Blood pressure was measured after 15 min of rest in the supine position with a Dinamap 845 XT automated recorder and was defined as the mean of three readings. Statistical Analysis Data are reported as mean ± SEM. Statistical evaluation of the blood pressure and heart rate results was performed with a one-way analy sis of variance for repeated measures followed by Dun can's multiple range test. Correlation coefficients were calculated by the least-squares method. The level of significance was Ρ < .05. RESULTS Patients received incremental intravenous captopril doses reaching 15 to 51 mg (mean 40 mg) over 50 to 80 min according to blood pressure. As illustrated in Figure 1, intravenous therapy at an average cumulative dose of 2 to 4 mg resulted in a reduction of mean supine blood pressure for the group from 1 7 3 ± 3 / l l l ± l t o l 6 6 ± 3 / 9 7 ± 2 mm Hg (P < .01), within 20 min of treatment. Blood pressure was lowered within 5 to 10 min after the initial dose was administered and continue to decline, reaching maximum response at 20 min. Individual patient responses to subsequent dosages were variable with respect to magnitude and direction, the overall effect being one of no change between 30 and 90 min despite dose increments. The cumulative dose for individual mean maximum response ranged from 1 to 8 mg (mean 4.5). The effectiveness of captopril injection therapy based upon the individual patient's response 10 min after re ceiving the last dose of captopril injection (Table 1) was categorized according to the following criteria: 1) Full 180-
χ Β
1
6
0
Η
Ε
-
140Η
ο-ο
Systolic Diastolic
(Λ
ω
120Η
Ό Ο Ο
00
100-
80
" Τ —ι— "Ί
Time (min.) - 2 0 -10 Ο 10 20 Dose (mg). 1-2 2-4 5
π— 30 10
40 50 60 17 26 35
70 40
80 90 40
FIGURE 1. Average systolic and diastolic blood pressures be fore and after intravenous bolus injections of captopril (average cumulative dose).
TABLE 1. INDIVIDUAL BP RESPONSES AFTER INTRAVENOUS INJECTION OF CAPTOPRIL Dose information
Post effect*
Cumulative dose at mean maximum response (mg)
170/101 157/101 168/88 165/92 153/100 176/88 145/107 132/97 142/93 152/106 136/88 183/105 152/82 150/89 171/104 187/124 203/100 156/97 198/110 172/103 167/94 121/94 171/103 158/85
6 5 2 6 4 4 3 4 4 6 3 6 1 2 6 6 5 5 6 2 6 8 5 6
Blood pressure Subject number
Baseline BP(mm Hg)
Maximum response (mm Hg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
168/110 148/108 200/106 191/115 180/106 162/109 159/116 160/120 172/106 161/111 172/106 155/120 165/118 161/106 168/107 211/126 207/117 184/109 190/112 170/108 178/109 171/116 174/108 190/112
170/96 153/97 167/77 169/103 181/93 173/86 161/94 149/100 154/94 162/104 139/92 175/100 147/85 157/85 156/104 186/109 210/104 168/101 187/100 166/87 172/110 163/108 148/91 166/101
Total dose (mg)
Time of last dose (min)
Response categoryt
41 50 25 28 39 29 48 39 44 50 38 50 16 24 31 51 50 50 41 15 50 48 50 46
60 80 70 60 60 50 80 70 70 70 60 60 50 60 50 70 70 70 60 60 70 60 75 80
Ρ Ρ F F Ρ F Ρ F F Ρ F F F F Ν Ν F F Ν Ρ F F Ρ F
* 10 minutes after last dose. f F = Full Ρ = Partial
N = No
response.
response characterized by a reduction of diastolic blood pressure (DBP) of at least 10% from pretreatment value, 2) partial response by a reduction of DBP of at least 5%, and 3) no response by a reduction of DBP less than 5 % from pretreatment value. These categories were de signed in an attempt to identify the patients who were acutely sensitive to inhibition of angiotensin-converting enzyme. By these criteria, 14 patients had a full re sponse, with 6 patients (25%) exhibiting an acute reduc tion in DBP to 90 mm Hg or less (Table 2). Seven pa-
tients responsed with a reduction of DBP between 5 and 10%, which met the criteria for a partial response. Three patients failed to respond to a dose regimen of 31, 41 and 51 mg of captopril administered over 50, 60 or 70 min time period, respectively. None of the patients ex perienced hypotension (Table 1). Captopril did not af fect heart rate, which was 79 ± 3 beats/min at time 0 and 74 ± 2 beats/min 90 min later. Reduction in blood pressure was attained without any significant changes in ECG during the protocol and the day after.
TABLE 2. BP REDUCTION ACHIEVED BY INTRAVENOUS AND ORAL CAPTOPRIL
Baseline BP Systolic BP (mm Hg) Diastolic BP (mm Hg) Patients reaching normotension (DBP < 90 mm Hg)
173 ± 3 111 ± 11
10 Min after last injection
Oral captopril 24 h
Oral captopril 4 weeks
Captopril + hydrochlorothiazide 12 weeks
162 ± 4* 98 ± 2* 5/24(21%)
154 ± 1 * 96 ± 3* 4/22(18%)
157 ± 3* 96 ± 2* 6/22(27%)
153 ± 3* 92 ± 2* 11/22(50%)
Compared with baseline: * Ρ < .01. Captopril:
25 mg thrice daily (n = 2), 50 mg thrice daily (n = 20). Captopril + hydroclorothiazide
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
(n = 16).
Left ventricular ejection fraction was not significantly modified by intravenous captopril treatment. Mean left ventricular ejection fraction prior to and following ad ministration of captopril injection was 72 ± 2 % and 74 ± 2 % , respectively. There were no reports of adverse drug experiences while patients were receiving intrave nous therapy. However, one patient developed tran sient elevation of creatinine phosphokinase and serum creatinine following therapy. Twenty-two of the 24 patients continued with longterm oral captopril treatment administered thrice daily at an initial dosage of 12.5 mg in one patient and 25 mg in 21 patients. Captopril was then increased to 25 mg thrice daily in 2 patients and to 50 mg thrice daily in 20 patients. For 16 patients 50 mg hydrochlorothiazide daily was added to the regimen. The transition to oral therapy was uneventful. The comparative effects of acute and oral captopril after 24 h and 4 and 12 weeks are shown in Table 2. Both systolic and diastolic pressures were reduced sig nificantly (P < .01) 10 min after the last dose of capto pril injection. The overall response did not change after 24 h and 4 weeks of oral captopril monotherapy. Figure 2 illustrated the relationship between the blood pressure responses observed with intravenous and oral captopril. For individual subjects there were no significant corre lations r = 0.17, (P < .4) between the acute and longterm systolic blood pressure (SBP) reduction. However there was a significant positive correlation r = 0.5, (P < .02) between the DBP decrease observed in response to intravenous and oral therapies. After 12 weeks of oral therapy with captopril and hydrochlorothiazide, 5 0 % of the patients reached normotension (DBP < 90 mm Hg) compared to 27% with captopril monotherapy (Table 2).
20-
o Systolic (r=o.i7) • Diastolic (r«0.5)
Q_ _
ω]Έ c ο. φ ο
-20-Ι
i f
- °-
0
V·· • 8
3
-40-50-40
ι
'
r ι 0 20 Chronic BP response to 4 weeks of captopril P.O. (mm Hg) 1
Inhibition of the renin-angiotensin system by blockade of angiotensin-converting enzyme (ACE) with paren teral teprotide and enalaprilat or with oral captopril has been effective in lowering blood pressure (BP) both in severe hypertension and in hypertensive crisis. " Our results with intravenous captopril, further support these observations. Intravenous therapy resulted in a signifi cant BP decrease within 20 min of treatment (Figure 1). Moreover, when looking at the individual response 10 min after the last captopril injection, 14 patients had a full response with a normalization in 5 of them. The greater response rate observed in this study compared to those obtained with teprotide and enalaprilat ' could be related to our hypertensive population as captopril was administered only to white patients with moderate to severe hypertension. It has previously been noted that blacks with hypertension have lower plasma renin ac tivity, particularly if the hypertension is not in an accel erated or malignant phase. Therefore, black patients with an equally elevated blood pressure may be less likely to respond to angiotensin-converting enzyme in hibitors. One study found that the percentage of black patients in whom blood pressure became normal after treatment with a low dose of captopril was only 2 0 % , as compared with 6 0 % of whites. In this study, captopril was administered at doses well above those shown to produce ACE inhibition. Al though the acute BP reduction after captopril or enala prilat is predominantly secondary to inhibition of an giotensin II formation, other mechanisms have been suggested. These mechanisms involve the sympathetic nervous system, kinins and prostaglandins. Continued administration of captopril to an average cumulative dose of 40 mg over 80 min did not enhance the early response. These findings concur with the re sults obtained by Dipette et al in which no further BP reduction was observed following incremental intrave nous doses of enalaprilat in patients with severe and malignant hypertension. Thus intravenous captopril appears to be effective as initial doses of 1 and 2 mg were sufficient to lower the BP within 5 and 10 min. Moreover, the overall maximum response seen at 20 min was obtained with a cumulative dose of 2 to 4 mg. The cumulative dose (Table 1) at individual mean maxi mum response ranged from 1 to 8 mg (mean 4.5). Twenty-two of the 24 patients were converted to long-term oral therapy with captopril alone or in combi nation with hydrochlorothiazide. Continued therapy with oral captopril over 4 weeks produced an increase in the number of responders without affecting the overall blood pressure reduction (Table 2). In this study the acute antihypertensive response to intravenous capto pril was a good predictor of the diastolic blood pressure reduction obtained with long-term oral therapy (Figure 8
8 9
12
13
14
15
9
10H
•10-
DISCUSSION
1
1
-20
1 40
FIGURE 2. Relationship between the acute blood pressure (BP) response to intravenous captopril and the BP response to chronic oral captopril therapy.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
11
2). A sustained effect of captopril has also been de scribed by many authors in patients with various form of severe hypertension. While most patients in an early study have required an increase in medication from initial doses other studies have shown a sus tained reduction of BP despite a reduction in the total daily dose of captopril. Bidiville et a l did not find such a correlation between the acute response to intra venous enalaprilat and the long-term efficacy of enalapril. This difference in comparison with our findings may be due to differences in subject selection since our patients had moderate or severe hypertension. In this study, with the addition of hydrochlorothiazide there was an additional decrease in blood pressure and a sig nificantly greater proportion of patients reaching nor motension, which is in agreement with previous data. The efficacy and safety of both intravenous captopril and enalaprilat suggest that ACE inhibitors offer a valuable alternative to other parenteral drugs for the treatment of hypertension when the oral route is to be avoided (eg, in the perioperative period). As both intravenous enalaprilat and captopril result in a signifi cant BP decrease within minutes, patient response can immediately be discerned and the nonresponding pa tient can quickly be changed to an alternate therapy. The absence of hypotension and of other acute serious side-effects may make it possible to use these inhibitors even outside an intensive care unit and without the in vasive arterial pressure monitoring. Since angiotensinconverting enzyme inhibitors may preferentially pre serve blood flow to vital organs such as brain, heart and kidney, they offer a distinct advantage over other drugs, particularly direct vasodilatators. In summary, this small study indicates that a low dose of intravenous captopril given as a bolus injection can rapidly lower BP in patients with moderate to severe hypertension. No further blood pressure reduction was observed following incremental doses. The absence of hypotension and apparent adverse effects suggest that intravenous captopril at low dosage may be an alterna tive to other parenteral or sublingual antihypertensive drugs when the oral route is to be avoided. The acute diastolic BP response to intravenous injection can pre dict the chronic effect of captopril administered orally in patients with moderate to severe hypertension. 16-19
20
21,22
nous captopril treatment in patients with severe cardiac failure. Br Heart J 1986;55:187-190. 4.
Boyd O, Pohl JEF: Intravenous captopril for cardiac fail ure. Lancet 1986;i:1041-1042.
5.
Nussberger J, Waeber G, Bidiville J, et al: Pharmacody namic and humoral effects of single intravenous doses of captopril in normal subjects. Clin Exp Hypertens 1987;A9(2& 3):345-349.
6.
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Captopril: evaluation of low doses twice daily and the addition of a diuretic for the treatment of mild to moderate hypertension. Clin Sci 1982;63(suppl 8):4435-4455.
7.
Williams G: Converting enzyme inhibitors in the treat ment of hypertension. Ν Engl J Med 1988;319:15171525.
8.
Tifft CP, Gavras H, Kershaw GR, et al: Converting en zyme inhibition in hypertensive emergencies. Ann In tern Med 1979;90:43-47.
9.
Dipette JR, Ferraro JC, Evans RR, Martin M: Enalaprilat, an intravenous antiotensin-converting enzyme inhibi tor, in hypertensive crises. Clin Pharmacol Ther 1988;38:199-204.
10.
Saragoca MA, Homsi E, Ribeiro A, et al: Hemodynamic mechanism of blood pressure response to captopril in human malignant hypertension. Hypertension 1983; 5(suppl 1):153-158. Biollaz J, Waeber B, Brunner HR: Hypertensive crisis treatment with orally administered captopril. Eur J Clin Pharmacol 1983;25:245-259.
23
21,24
8
11. 12.
Chrysant SG, Danisak, Dem DC, et al: Racial differences in pressure, volume and renin interrelationship in essen tial hypertension. Hypertension 1979;1:136-141.
13.
Veterans Administration Cooperative Study Group on Antihypertensive Agents: Racial difference in response to low dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol 1982;14:9751015.
14.
Reyes AJ, Leary WP, Acosta-Barrios TN: Once-daily ad ministration of captopril and hypotensive effects. J Car diovasc Pharm 1985;7(suppl 1):516-519.
15.
Johnston CI, Jackson B, Cubela R, Arnold L: Mechanism for hypertensive action of angiotensin converting en zyme inhibitors. Clin Exp Hypertens 1984;A142:551561.
16.
Brunner HR, Gavras H, Waeber Β et al: Oral angiotensin converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med 1979;90:19-23.
17.
Case DB, Atlas SA, Marion RE, Laragh JH: Long-term efficacy of captopril in renovascular hypertension. Am J Cardiol 1982;49:1440-1446.
1. Edwards CRW, Padfield PL: Angiotensin converting en zyme inhibitors: past, present and bright future. Lancet 1985;1:30-34.
18.
Ferguson RR, Vlasses PH, Koplin JR, Captopril in severe treatment-resistant hypertension. Am Heart J 1980; 99:579-585.
2.
19.
Havelka HJ, Boerlin A, Studer P, et al: Long term experi ence with captopril in severe hypertension. Br J Clin Pharmacol 1982;14:71S-76S.
20.
Johns DW, Baker KM, Ayers CR, et al: Acute and chronic effect of captopril in hypertensive patients. Hyperten sion 1980;2:567-575.
8,25,26
REFERENCES
3.
The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: re sults of the Cooperative with Scandinavian Enalapril Survival Study (CONSENSUS). Ν Engl J Med 1987;316:1429-1435. Rademaker M, Shaw TRD, Williams BC, et al: Intrave
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
21.
Karlberg BE, Asplund J, Wettre S, Ohman KP: Long term experience of captopril in the treatment of primary hy pertension. Br J Clin Pharmacol 1982;14:133S-137S.
24.
Weinberger MH: Comparison of captopril and hydro chlorothiazide alone or in combination in mild to moder ate hypertension. Br J Clin Pharmacol 1982;14:127-131.
22.
Mimran A, Jover B: Maintenance of the antihypertensive efficacy of captopril despite consistent reduction in daily dosage. Br J Clin Pharmacol 1982;14:81S-85S.
25.
Gavras H, Liany CS, Brunner HR: Redistribution of re gional blood flow after inhibition of the angiotensinconverting enzyme. Circ Res 1978;43(suppl 1):159 -162.
23.
Bidiville J, Nussberger J, Waeber G, et al: Individual re sponses to converting enzyme inhibitors and calcium an tagonists. Hypertension 1988;11(2):166-172.
26.
Barry DI, Lassen Ν A: Cerebral blood flow in hyperten sion and effects of antihypertensive drugs. J Hypertens 1984;2(suppl 3):519-526.
Downloaded from https://academic.oup.com/ajh/article-abstract/3/10_Pt_1/769/182165 by Washington University, Law School Library user on 05 March 2018
