Effect of intravenous enalaprilat in moderate and severe systemic hypertension

Effect of Intravenous Enalaprilat in Moderate and Severe Systemic Hypertension

The antihypertensive effect and tolerability of enalaprilat, an intravenously administered angiotensin converting enzyme inhibitor, was studied in 65 patients with moderate or severe hypertension. In this randomized, double-blind study, enalaprilat was compared with placebo in 42 (22 enalaprilat, 20 placebo) moderate hypertensive (diastolic blood pressure [BP] 100 to 114 mm Hg) patients. It was compared with furosemide in 23 (12 enalaprilat, 11 furosemide) severe hypertensive (diastolic BP 115 to 130 mm Hg) patients. Enalaprilat (1.25 or 5.0 mg), placebo (5% dextrose) or furosemide (40 or 80 mg) was given every 6 hours intravenously up to 48 hours.

In the moderate hypertension stratum, the mean supine diastolic BP was significantly (p 50.01) reduced from baseline at all timepoints in the enalaprilat group. These diastolic BP reductions were significantly (p 50.01) greater in the enalaprilat group than the placebo at 1 to 24 hours (-12 vs -4 mm Hg), with 59% of the patients responding to enalaprilat compared with 30% of the patients responding to placebo. An even greater reduction (p 50.01) was seen at 25 to 48 hours (-14 vs -7 mm Hg, with 73% enalaprilat vs 58% placebo responders). Significant (p 50.01) reductions in mean, supine systolic BP were also seen at 1 to 24 hours (-22 vs -2 mm Hg) and 25 to 48 hours (-24 vs -8 mm Hg) during the 48 hours of the double-blind treatment phase in the enalaprilat group compared with placebo. In the severe hypertension stratum, significant (p 50.05) reductions were noted in the mean supine diastolic BP in the enalaprilat group compared with the furosemide group at 1 to 12 hours (-17 vs -8 mm Hg) with 36 versus 20% of the patients responding and at 13 to 24 hours (-17 vs -8 mm Hg) with 33 versus 11% of the patients responding. No significant difference in systolic BP was seen between enalaprilat and furosemide; however, both enalaprilat and furosemide significantly reduced mean supine systolic BP compared with baseline. Thus, enalaprilat is an ef- fective, well-tolerated agent for the treatment of moderate and severe systemic hypertension.

(Am J Cardiol 1988;62:1062-1067)

John Rutledge, MD, Carlos Ayers, MD, Robert Davidson, MD, Donald DiPette, MD, Gordon Guthrie, MD, Mary Fisher, PhD, Skai Schwartz, MA, and Ewa Rucinska, MD, PhD

nalapril is an oral angiotensin converting enzyme E inhibitor for the treatment of systemic hypertension; it is metabolized in the liver to the biologi-

cally active diacid, enalaprilat.’ Enalaprilat is the only currently marketed angiotensin converting enzyme inhibitor that can be given intravenously. Previous studies have found that intravenously administered enalaprilat lowers systolic and diastolic blood pressure (BP) in nor- mal subjects,2,3 in patients with accelerated hypertension and in patients with hypertensive crisis, including malignant hypertension.4J Intravenously administered angiotensin converting enzyme inhibitors have not been examined as first- or second-line therapy in the treatment of patients with moderate or severe hypertension. This study evaluated the efficacy and tolerability of par- enterally administered enalaprilat in such patients.

METHODS Patient selection: Male and female patients whose

supine diastolic BP was in the range of 100 to 130 mm Hg were entered into the study. Criteria for exclusion were secondary hypertension of any cause, pregnant and nursing women or women of child-bearing potential not using contraception, myocardial infarction in the last 3 months, presence of unstable angina pectoris, cerebral infarction or transient ischemic attack in the last year, hemodynamically significant valvular heart disease, serum potassium >5.5 mEq/liter or <3.5 mEq/liter, serum creatinine >2.5 mg/dl, proteinuria of 22+ on dip- stick or >500 mg/12 hrs, significant hepatic or hemato- logic disease or allergy to furosemide. The study was approved by the Human Subjects Review Committee at each of the participating institutions. Written informed consent was obtained from all patients.

Study design: This was a double-blind, 5-center study to evaluate the efficacy and tolerability of intravenous enalaprilat in the treatment of moderate (100 to 114 mm Hg) or severe (115 to 130 mm Hg) hypertensive patients. The strata were based on supine diastolic BP at baseline (Figures 1 and 2). The study consisted of baseline and double-blind treatment periods. Intrave- nous enalaprilat was compared with intravenous placebo (5% dextrose) in the group with moderate hyperten- From the University of California, Davis, School of Medicine, Division of Cardiovascular Medicine, Davis, California. This study was support- ed by a grant from Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania. Manuscript received February 17, 1988; revised manuscript received and accepted July 18, 1988.

Address for reprints: John C. Rutledge, MD, University of Califor- nia, Division of Cardiovascular Medicine, TB 172, Davis, California 95616.

1062 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

sion and compared with furosemide in the group with severe hypertension. Complete physical examinations, electrocardiograms and complete laboratory evaluations were performed during the baseline period and after 48 hours in the double-blind treatment period. Electrolytes, blood urea nitrogen and creatinine were also measured after 24 hours of the double-blind treatment period. Su- pine systolic and diastolic BP and pulse were recorded at set intervals throughout the baseline and double-blind treatment periods.

Baseline stabilization period: Patients who had an initial supine diastolic BP of 100 to 114 mm Hg, while receiving single or multiple antihypertensive drugs, were discontinued from the antihypertensive therapy and started on hydrochlorothiazide 50 mg. These patients were evaluated every 2 to 4 days for up to 2 weeks after discontinuation of previous drug therapy. Hydrochloro- thiazide was discontinued for at least 24 hours before randomization. Also, patients who were not receiving antihypertensive therapy were evaluated at 2- to 4-day intervals for 1 week. All patients with a supine diastolic BP of 100 to 114 mm Hg were admitted to the hospital and entered into the placebo-controlled study (moderate stratum). If supine diastolic BP was >_ 115 mm Hg during the baseline period, patients were immediately admitted to the hospital, observed for a 3- to 12-hour sta-

bilization period and entered into the furosemide-controlled study (severe stratum).

Double-blind treatment period: MODERATE STRATUM: After the baseline stabilization period, patients in the moderate stratum were randomized to receive either intravenous enalaprilat (Merck Sharp and Dohme Re- search Laboratories) 1.25 mg every 6 hours or intravenous placebo every 6 hours (Figure 1). Each dose of study medication was prepared in 5 ml of 5% dextrose and administered as an intravenous infusion over 1 mm- ute. BPS were measured at 5, lo,30 and 60 minutes and hourly after each dose of the study medication for a total of 48 hours. At 24 hours after entry into the double-blind treatment period, the response to therapy was evaluated. A responder (supine diastolic BP <95 mm Hg) was continued on the same study drug regimen for an additional 24 hours. A nonresponder had the dose of the study drug increased to enalaprilat 5 mg intravenously every 6 hours or matching placebo for an additional 24 hours and was ju8ged a responder if diastolic BP was <95 mm Hg.

SEVERE STRATUM: After the baseline stabilization period, patients in the severe stratum were randomized to receive either enalaprilat 1.25 mg intravenously every 6 hours or furosemide 40 mg intravenously every 6 hours (Figure 2). BP measurements were taken as in the mod-

FIGURE 1. Therapy flow sheet for the moderate hypertension strata.

FIGURE 2. Therapy ffow sheet for the severe strata. DBP = diastolic blood pressure.

Moderate Stratum (10&l 14 mmHg)

I.V. Placebo w-l x 4 I.V. Placebo Q6H x 4

2 Week Outpatient

Observation

-(Z!-12)H Inpatient NR Enaiaprilat 5.0 mg Q6H x 4

I

Enalaprilat 1.25 mg Q6H x 4 R Enalaprilat 1.25 mg Q6H x 4

Time -2 Weeks -(%12)H OH 6H 12H 16H 24H 46H

R = Responder (DBP 5 95 mmHg) NR = Nonresponder

- Severe Stratum (115130 mmHg) NR + Enalaprilat 1.25 mg Q6H x 4

Furosemide 40 mg’ Q6H x 4

R Furosemids 40 mg Q6H x 4 + /- Outpatient -(512)H Inpatient

Observation Stabilization NR + Furosamide 40 mg Q6H x 4

Enakqilat 1.25 mg’ C6H x 4

I R EMkprilat1.25mg~Hx4

lime -2 weeks -(512)H OH 6H 12H 1BH 24H 4[3H

R= Rewxier(DBPs 100mmHg) NR = tbwqxkr

‘-~D0~optionAv6ihbk. PaIientsb’@~~Du~NotExperisnce ~.Sl@EnbyWiRl-hvelheDcsedFurc6em&

alLeasta10mmHgReductxninDBPbylZH

m-dcclnthd mThalDosethrcugh4sHans. hmaaadtosomga~l~ to 5.0 mg

THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 15, 1988 1063

EFFECTS OF ENALAPRILAT

TABLE I Patient Demographics

Enalaprilat Placebo (n = 22) (n = 20)

Moderate statum Mean age (yrs) 49f 14 47+ 11 Sex (male:female) 7:15 l&6 Race (W:B:H) 16:5:1 1O:lO:O Duration of disease (yrs) 13+ 11 15% 13

Enalaprilat Furosemide (n = 12) (n = 11)

Severe stratum Mean age (yrs) 45*11 53f 15 Sex (male:female) 715 7:4 Race (W:B:H) 6:4:2 9:2:0 Duration of disease (yrs) 14&6 19f15

6 = black; H = Hispanic; W = white.

erate stratum. If the patient’s supine diastolic BP had not decreased by at least 10 mm Hg after 12 hours, the dose of the study drug was increased to enalaprilat 5 mg intravenously every 6 hours or furosemide 80 mg intravenously every 6 hours. After 24 hours, the patient’s response to the study medication was evaluated. Re- sponders (supine diastolic BP <lOO mm Hg) were continued on the same dose of the study medication for an additional 24 hours. Nonresponders had the alternative study drug added to the original study drug (enalaprilat 1.25 mg intravenously every 6 hours or furosemide 40 mg intravenously every 6 hours) and received both drugs for an additional 24 hours (Figure 2). Patients were withdrawn from the study if in the opinion of the investigator an increase or decrease in BP represented an unreasonable risk to the patient, and appropriate therapy was initiated.

Statistical analysis: All between-treatment comparisons were made by an analysis of variance that was blocked by investigator. Only changes from baseline were analyzed. Baseline was defined as the average of the last 2 preintravenous readings in the severe stratum, and as the average of the last 4 preintravenous readings in the moderate stratum. Within-treatment comparisons were made by Student’s t test for paired data. Unless stated, all tests were 2-sided with p = 0.05.

0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Hours)

1.25 mg

FIGURE 3. Moderate stratum, mean supine diastolic blood FIGURE 4. Moderate stratum, mean supine diastolic blood pressure (BP): doses 1 through 4. Diastolic BP (ordinate) is pressure (BP): doses 5 through 8. Diastolic BP (ordinate) is plotted against time (abscissa). Enalaprilat, n = 21; placebo, plotted against time (abscissa). Enalaprilat 1.29 mg, II = 10; n = 19. enalaprilat 5.0 mg, n = 9; placebo, n = 18.


RESULTS Sixty-five patients were enrolled into the study and

entered into the moderate (n = 42) or severe (n = 23) stratum. No significant difference was present in the patients assigned to each stratum and treatment group (Table I).

Results reported are only for the initial 8 doses of intravenous therapy. Any patient who received 8 doses of intravenous therapy was considered to have complet- ed the study. Seven patients received <8 doses (4 inade- quate therapeutic responses, 1 patient uncooperative and 2 protocol violations).

Six patients (4 enalaprilat, 2 placebo) in the moderate stratum and 4 patients (1 enalaprilat, 3 furosemide) in the severe stratum received hydrochlorothiazide during the baseline period. Hydrochlorothiazide was discontinued at least 24 hours before investigational drug was started in the moderate stratum and 12 hours before randomization in the severe stratum.

Blood pressure response: MODERATE STRATUM: In the moderate stratum changes in the mean supine diastolic BP in response to intravenous enalaprilat or intravenous placebo are shown in Figures 3 and 4. No statistically significant difference was noted in basal BP and pulse rate among the placebo and enalaprilat groups. In the moderate stratum, the supine diastolic BP readings were significantly (p lO.01) reduced from baseline by 5 minutes after the initial dose of intravenous enalaprilat and persisted with repeated doses every 6 hours for 48 hours. Figures 5 and 6 show the mean supine systolic BP readings for the 48-hour period. The reduction from baseline in supine systolic BP was significant (p 10.01) by 30 minutes after the initial dose of intravenous enalaprilat and was also seen in the nonresponder patients who received 5 mg of intravenous enalaprilat in the second 24-hour period. The placebo group failed to show consistently reduced supine systolic or diastolic BP readings from baseline over the 48-hour period. The mean supine diastolic BP reduction was significantly (p ~0.05) greater in the enalaprilat group than in the placebo group at 1 to 24 hours (Table II). An even greater reduction was seen at 25 to 48 hours for the enalaprilat 1.25 mg group, but not in the enalaprilat 5 mg group (patients not responding to enalaprilat 1.25 mg). Of

‘lo -&-Dose 5 ;-Dose 6 ;-Dose 7 ;-Dose 8

5 I

“E 100

E

d cd 90

,o . B Enalaprilat 1.25 mg

.P 80 . Enalaprilat 5 mg *

0 Placebo

701 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (Hours)

TABLE II Number of Responders in the Moderate and Severe Stratum After Receiving Intravenous Enalaprilat or Placebo or Furosemide

Moderate Stratum (baseline DBP = 100 to 114 mm Hg) Dose (w) No.

Enalaprilat 1.25 22 Enalaprilat 1.25 or 5.0 22 Placebo 20 Placebo 19

Severe stratum (baseline DBP = 115 to 130 mm Hg)

Doses Reduction”

l-4 12’ 5-8 14* l-4 4 5-8 7

Responders by DBPt No. %

13 59 16 73

7 30 11 58

Enalaprilat 1.25 12 l-2 17% 5 36 Enalaprilat 1.25 or 5.0 12 3-4 17s 4 33 Furosemide 40 10 l-2 8 2 20 Furosemide 40 or 80 9 3-4 8 1 11 Enalaprilat 1.25 or 5.0 6 5-8 21 5 83 Enalaprilat + Furosemide 12 5-8 22 8 67

* Reduction was the average of 1 to 48 hours. f Responder was defined in the protocol as a diastolic blood pressure of 295 m m Hg in the moderate stratum and _<lCO m m Hg in the severe StratUm. t $0.01; 5 50.05. p p DBP = diastolic blood pressure.

note, mean supine diastolic BP reductions after enalaprilat were significantly (p 50.05) greater than placebo throughout the dosing interval beginning 1 hour after the first dose, except at 2 hours after dose 2. Similarly, supine systolic BP decreased significantly (p lO.01) for the enalaprilat 1.25 mg group (1 to 48 hours).

SEVERE STRATUM: In the severe stratum changes in mean supine diastolic BP in response to intravenous enalaprilat and intravenous furosemide are shown in Fig- ure 7. No statistically significant difference was noted in basal BP and pulse rate among enalaprilat and furosemide groups. The mean supine diastolic BP was significantly (p 50.01) reduced from baseline by 10 minutes after the initial dose of intravenous enalaprilat. This reduction in mean supine diastolic BP in the intravenous enalaprilat group remained consistent with repeated doses; BP reduction was not sustained with repeated doses of intravenous furosemide. Because of the small sample sizes, the enalaprilat 1.25 mg and 5 mg groups were pooled (n = 12) as were the furosemide 40 and 80 mg groups (n = 11) for doses 3 and 4 (second 12-hour period on day 1). In general, differences in supine diastolic BP reductions were significant after doses 2 and 3; the mean supine diastolic BP in the enalaprilat group was significantly (p lO.05) less than the furosemide group at 1 to 12 and 13 to 24 hours (Table II).

Changes in mean supine systolic BP over the first 24 hours are shown in Figure 8. The mean l- to 1Zhour reduction in supine systolic BP was similar for the 2 groups (27 mm Hg for enalaprilat and 22 mm Hg for furosemide) (Table II). Mean reductions for the 2 groups in the 13- to 24-hour period tended to be slightly greater for the furosemide-treated group. The mean supine systolic BP reductions were not significantly differ- ent in the intravenous enalaprilat and furosemide groups over hours 1 to 24 and 25 to 48. Because of the small number of patients (n = 12) treated with enalaprilat plus furosemide, this group was not analyzed.

Responders: The number and percentage of responders are shown in Table II. A responder was defined as a patient with a reduction in supine diastolic

BP to <95 mm Hg in the moderate stratum and to <lOO mm Hg in the severe stratum. In the moderate stratum, enalaprilat produced 59% responders versus 30% responders among those receiving placebo on day 1 (doses 1 to 4) and 73% enalaprilat responders versus 58% placebo responders on day 2 (doses 5 to 8). In the severe stratum, enalaprilat produced 36 and 33% re-

I Dose 1 I-Dose 2 I-Dose 3 ;-Dose 4

B 170

i 160 a

m 2 150 0 2 . 140 Enalaprilat 1.25 mg

1301 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (Hours)

I

FIGURE 5. Moderate stratum, mean supine systolic blood pressure (BP): doses 1 through 4. Systolic BP (ordinate) is plotted against time (abscissa). Enalaprilat, n = 21; placebo, n = 19.

I 180 J-Dose 5 ;-Dose 6 ;-Dose 7 ;-Dose 8

B 170

E E

160

2 150

: 140 . z

Enalaprilat 1.25 mg

m 130 . Enalaprilat 5 mg

I 0 Placebo 12011,; I,;, ,;, I,

0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Hours)

FIGURE 6. Moderate stratum, mean supine systolic blood pressure (BP): doses 5 through 8. Systolic BP (ordinate) is plotted against time (abscissa). Enalaprilat, 1.26 mg, n = 10; enalaprilat 5.0 mg, n = 9; placebo, n = 18.

THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 15. 1988 1665

EFFECTS OF ENALAPRILAT

sponders on day 1 (doses 1 to 2 and 3 to 4) and 83% on day 2 (doses 5 to 8). Furosemide produced 20% and 11% responders for day 1 and 67% responders on day 2. As judged by the investigators in this study, more patients had a diastolic BP response to enalaprilat (1.25 or 5 mg) than to placebo in the moderate stratum (Table II). In the severe stratum, more patients had a diastolic BP response to enalaprilat (1.25 or 5 mg) than to furosemide (40 or 80 mg).

By random assignment to treatment groups, there were 9 blacks in the enalaprilat group (5 moderate, 4 severe), 10 blacks in the placebo group and 2 blacks in the furosemide group. Because of the small number of black patients, this subgroup was not statistically analyzed. In general, hypertensive blacks appeared to be nonresponders to intravenous enalaprilat and responders to intravenous placebo, particularly in the second 24- hour period.

Heart rate: In the moderate stratum the heart rate was reduced 4 beats/min in the enalaprilat group versus 1 beat/min in the placebo group in the first 24-hour period, During the second 24 hours, significant (p 10.05) reductions in heart rate were seen in the enalaprilat compared with the placebo group. The mean 25- to 48-hour reduction in heart rate of the enalaprilat group was 5 beats/min compared to no change in the placebo group. In the severe stratum during hours 1 to 12, the heart rate did not change in the furosemide group and decreased 4 beats/min in the enalaprilat group. During hours 13 to 24, a significant (p 10.01) increase in heart rate (6 beats/min) was noted in the furosemide group while a 2 beat/min decrease was seen in the enalaprilat group.

Safety: In the moderate stratum 6 of 22 (27%) enalaprilat patients and 4 of 20 (20%) placebo patients had 1 or more adverse experience. Adverse experiences noted with enalaprilat were headache (3), constipation (l), arthralgia (l), back pain (l), hemoptysis (1) and malar rash (1). No adverse experience was considered serious or severe by any investigator. The patient with a malar rash was withdrawn from the study; however, this patient had a history of rash before entering the study. All adverse experiences were considered “probably not” or “definitely not” drug related by the investigators. No

r 1

L

125 Dose 1 ;-Dose 2 ;-Dose 3 ;-Dose 4

B 120 f 1 I I I I I

115

2 110

g 105 i?T Enalaprilat 1.25 mg

100 A Furosemide 40 mg

95],,;, ,;, ,;, , ,

0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Hours)

FIGURE 7. Severe stratum, mean supine diastolic blood pressure (BP): doses 1 through 4. Diastolic BP (ordinate) is plotted against time (abscissa). Enalaprilat, n = 12; furosemide, n = 9.


significant differences were noted between enalaprilat and placebo in regard to laboratory parameters.

In the severe stratum, 3 of 12 (25%) patients in the enalaprilat and 3 of 11 (27%) patients in the furosemide group had at least 1 clinical adverse experience during the double-blind period of the study. Patients in the enalaprilat-treated group reported headache (2), insomnia (1) and constipation (1). No adverse experience was serious or severe. Two patients had hypotension: 1 who received furosemide and 1 who received furosemide fol- lowed by enalaprilat. A significant (p 10.01) increase from baseline in fasting serum glucose was noted in the furosemide-treated group (112 f 42 mg/dl baseline and 142 f 57 mg/dl poststudy). The enalaprilat group had a significantly (p 10.05) reduced serum sodium when compared with the furosemide group (with increased sodium) at 24 hours (143 f 2.3 vs 140 f 2.8 mEq/liter). However, these changes in laboratory parameters were not clinically significant.

DISCUSSION Parenteral enalaprilat is the only intravenous angio-

tensin converting inhibitor marketed for the treatment of hypertension. This study shows the efficacy and safety of intravenous enalaprilat (1.25 mg every 6 hours) in the treatment of 65 moderate or severe hypertensive patients. Intravenous enalaprilat is well tolerated and significantly lowers systolic and diastolic BP.

This study shows that enalaprilat acts rapidly. A BP decrease is seen within 5 to 10 minutes in hypertensive patients responding to intravenous enalaprilat, which is consistent with published reports of the onset of action of enalaprilat.4-6 The BP effect of a I1 mg dose of intravenous enalaprilat appears to peak at approximate- ly 4 hours after dosing.4Jj

Most patients who did not respond to a 1.25 mg dose of intravenous enalaprilat also did not respond to a 5.0 mg dose. In this study, no patient was randomized to an initial 5 mg dose of intravenous enalaprilat. Only nonresponders to the 1.25 mg dose were titrated to 5.0 mg of intravenous enalaprilat. In earlier reports, no further reduction in BP was seen with higher doses of intravenous enalaprilat, i.e., a 40 mg dose following a 10 mg dose of intravenous enalaprilat4 or repeated infusions of

2’0 YDose 1 ;-Dose 2 ;-Dose 3 ;-Dose 4

2 200 I

E 190 . ; I l Enalaprilat 1.25 I w

E A Furosemide 40 2

mg 180

I 0 2 4 6 8 10 12 150 1 ;

. , , , , ; , , ; , , ,

14 16 18 20 22 24 Time (Hours)

FIGURE 8. Severe stratum, mean supine diastolic blood pressure (BP): doses 1 through 4. Systolic BP (ordinate) is plotted against time (abscissa). Enalaprilat, II = 12; furosemide, n = 9.

5, 10, 20, 40 or 80 mg of intravenous enalaprilat6 in hypertensive patients. These results may indicate that doses of intravenous enalaprilat above 1.25 mg do not alter the magnitude of the antihypertensive effect.

In the moderate stratum, the explanation for the high percentage of placebo responders is unknown, but possibly relates to the antihypertensive effects of hospi- talization.This effect may take several days to manifest.

A reduction in heart rate has been seen in previous studies with parenteral enalaprilat.4*6 These reductions in pulse rate may be secondary to central or peripheral effects of angiotension converting enzyme inhibition on the sympathetic nervous system. The increase in heart rate seen with furosemide is most likely the consequence of intravascular volume depletion.

Racial differences in the response to enalaprilat were seen in this study. Blacks tended not to respond to enalaprilat, and this has been noted in a previous study with angiotensin converting enzyme inhibitors.7 The mecha- nism is not known, but may be related to blacks’ pre- dominantly low renin status.* When blacks were exclud- ed from analysis, greater reductions in systolic and diastolic BP were seen in both the moderate and severe groups.

Adverse experiences were not serious, not severe, not judged to be related to treatment and no more common in the enalaprilat group than in the placebo or furosemide groups. This is consistent with previously published reports.4,6 The only clinically significant adverse effect reported with the use of intravenous enalaprilat was hypotension. Although hypotension was not observed in the moderate or severe strata of patients treated with enalaprilat alone, hypotension was reported in 1 patient treated with furosemide alone and 1 patient treated with furosemide and enalaprilat. In patients treated with long-term, high doses of diuretics, or in patients with hypertension mediated by the renin angiotensin system, hypotension may result after the first

dose of intravenous enalaprilat. In patients receiving intravenous enalaprilat, no clinically significant change in laboratory parameters was noted.

Acknowledgment: We would like to acknowledge the significant contributions by these personnel at the study centers: University of California, Davis: Ezra A. Amsterdam, MD, Dennis Clark, DO, Doreen Arons, BS, and Sheila Enders, BS. University of Kentucky: Theodore A. Gotshen, MD, Sue Scheive, RN, Judy Hammond, RN, and June Robinette, RN. Allegheny General Hospital: Robert Evans, PharmD, and Mark Henzler, MD. University of Virginia: P. Kent Harmon, MD, and Paulette Kaplan, RN. University of Washing- ton: Stuart Bursten, MD, and Pamela Keeley, RN.

REFERENCES 1. Gross DM, Sweet CS, Ulm EH, Backhmd EP, Morris AA, Weitz D, Bohn DL, Wager HC, Vassil TC, Stone CA. Effect of N-[(S)-l-carboxy-3-phenylpropyll- L-ala-L-pro and its ethyl ester MK421 on angiotensin converting enzyme in vitro and angiotensin I pressor response in vitro. .I Pharmacol Exp Ther 1981;216;552- 557. 2. Till AE, Irvin JD, Hichens M, Lee RB, Davis RO, Swanson B, Vlasses PH. Pharmaccdynamics and disposition of intravenous MK-422, the diacid metabolite of enalapril maleate. Clin Pharmacol Ther 2982;31:275. 3. Ajaiji AA, Hockings N, Reid JL. Age and pharmacodynamics of angiotensin converting enzyme inhibitors enalapril and enalaprilat. Br J Clin Pharmacol 1986;21:349-357. 4. DiPette DJ, Ferraro JC, Evans RR, Martin M. Enalaprilat, an intravenous angiotensin converting enzyme inhibitor, in hypertensive crisis. Clin Phnrmacol The- 1985:3&l 99-204. 5. Strauss R, Garvas I, Vlahakos D, Garvas H. Enalaprilat in hypertensive emergencies. J Clin Pharmacol 1986:26:39-43. 6. Navis GJ, deJong PE, Danker AJM, vander Hem GK, deZeum D. Blood pressure response to enalaprilic acid in essential hypertension: dose-response and effect of pretreatment with furosemide. Eur J Clin Pharmacol 1985;29:9-15. 7. Chrysant SG, Danisa K, Dum DC, Smith WJ, Dillard BL, Frohlich ED. Racial differences in pressure volume and rain inter-relationships in essential hypertension. Hypertension 1979;1:136-141. 8. Kaplan NM, Kern DC, Holland OB, Kramer NJ, Higgins J, Gomez-Sanchez CE. The intravenous furosemide test: a simple way to evaluate renin responsive- ness. Ann Intern Med 1976;84:639-645. 9. Atlas SA, Case DB, Yu CY, Laragh JH. Hormonal and metabolic effects of angiotensin converting enzyme inhibitor. Am J Med 1984;77(suppl ZA):Z3-17.

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Effect of intravenous enalaprilat in moderate and severe systemic hypertension

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