Lisinopril for severe congestive heart failure

Lisinopril

for Severe

Congestive

Heart Failure

Barry F. Uretsky, MD, James A. Shaver, MD, Chang-seng Liang, MD, Devendra Amin, MD, Prediman K. Shah, MD, T. Barry Levine, MD, Paul Walinsky, MD, Thierry LeJemtel, MD, and Thomas Linnemaier, MD

Lisinopril, a new converting enzyme inhibitor, was studied hemodynamically in 55 patients. The response to 2.5,5and 10.mg doses showed significant increases in cardiac index and significant reductions in pulmonary artery wedge, right atrial, pulmonary arterial and systemic arterial pressures, as well as in systemic vascular resistance. Significant changes in most parameters were present at 24 hours. A dose-response relation for most parameters was noted. Over a 3-month period, 47 patients were followed up, with improvement in functionai capacity and symptomatic status. Metabolic parameters did not change over time, although 26% showed evidence of reversible renal dysfunction. Only 3 patients (6.4%) required discontinuation because of adverse effects. A subgroup of patients reassessed at 3 months demonstrated maintenance of hemodynamic effects. The present study demonstrates that (1) the hemodynamic effects of lisinopril are of relatively long duration; (2) within certain limits, a dose-response relation can be defined; and (3) the drug has an acceptable long-term tolerability profile. (Am J Cardiol 1989;63:8D-1lD)

From the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; University of Rochester School of Medicine, Rochester, New York; Cedars-Sinai Medical Center, Los Angeles, California; University of Minnesota, Minneapolis, Minnesota; Thomas Jefferson School of Medicine, Philadelphia, Pennsylvania; Albert Einstein College of Medicine, New York, New York; and St. Vincent’s Medical Center, Indianapolis, Indiana. Address for reprints: Barry F. Uretsky, MD, 3494 PresbyterianUniversity Hospital, DeSoto at O’Hara Streets, Pittsburgh, Pennsylvania 15213.

SD

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onverting enzyme inhibition has been clearly shown to be an effective method of improving hemodynamics in patients with severe congestive heart failure.1,2 Lisinopril, a lysine analog of enalaprilat (the active component of enalapril), has recently been approved for clinical use in hypertension. The present study was undertaken in patients with severe congestive heart failure to determine the hemodynamic response and duration of action of varying doses of this agent.

C

METHODS

Seven investigative centers participated in this study.3 All patients (46 men and 9 women, average age 59 years) were considered to have moderate to severe congestive heart failure. The patients continued medication with digoxin and diuretics up to the day of study, at which time diuretics were withheld. Right-sided cardiac catheterization and arterial cannulation were performed. Two hours after catheter insertion, baseline hemodynamic measurements were obtained in duplicate. Oral lisinopril was given as a 2.5, 5- or lo-mg dose. The dose was not known to the investigator or the patient. Hemodynamics were then measured every 2 hours for the first 12 hours and every 4 hours through the following 12 hours. The patients were followed for 12 weeks to determine the tolerability profile of this agent. Therapy was begun in all patients with 2.5 mg/day for chronic use and titrated to the optimal dose according to each investigator. Diuretics could be varied at the discretion of each investigator. In 4 centers, a second hemodynamic study at 12 weeks was urged to determine the long-term hemodynamic efficacy of this agent. We report the results from 1 center (University of Pittsburgh), in which most patients (10 of 13, or 77%) underwent the second study. Of the 3 patients not undergoing the late study, 2 had to discontinue therapy before 12 weeks because of adverse effects; the third patient refused to undergo the second assessment. The chronic hemodynamic effects would appear to be representative, therefore, since the 10 participants were not studied for clinical indications. The data were analyzed by the Fisher exact test, chisquare or rank-sum test for pairwise comparison when appropriate. Hemodynamic data used a nonlinear curvefitting technique to reduce bias in observed peak effectss4 Within-group changes used the sign-rank test. Betweengroup differences used rank analysis of variance. RESULTS

Seventeen patients received the 2.5-mg dose, 21 received the 5-mg dose and 17 received the lo-mg dose.

Using a 25% decrease in pulmonary capillary wedge pressure as a measure of efficacy, all 3 doses were effective; i.e., the 2.5-mg dose was effective in 53% of patients, the 5-mg dose was effective in 55%, and the IO-mg dose was effective in 64%. However, the IO-mg dose was signilicantly more effective (p <0.05) than either the 2.5- or 5mg dose in increasing cardiac output by 25%. Specifically, cardiac output increased by 25% or greater in only 14% of patients given the 2.5-mg dose and in only 18% of patients given the 5-mg dose, whereas over half the patients (53%) given the lo-mg dose showed such an increase. There were significant decreases in pulmonary artery wedge, pulmonary arterial, right atria1 and mean systemic arterial pressures, as well as an increase in cardiac output, over the 24-hour study period (Table I). Larger doses tended to provoke greater hemodynamic changes, particularly between 6 and 12 hours, and were significantly different between doses at several time points in several parameters (Table II). This relation (although far from exact) was particularly evident in the pulmonary artery wedge pressure, mean arterial pressure, cardiac index and systemic vascular resistance. In the 10 patients who underwent hemodynamic reassessment after 12 weeks of chronic lisinopril therapy, and who were given the same dose of the drug as they had received during the acute study, hemodynamic effects were maintained (Fig. 1). At 12 weeks, there were baseline improvements in several hemodynamic parameters,

1 TABLE

I Hemodynamic

Responses

to Varying

Oral Doses of Lislnoprll

PAW (mm Hg)

Cl (Ikters/min/m2)

(Dose b-%1) After Doslng

5

10

25

24f7 22 f 7 21h7” 21f6+ 20f5T 20f8’ 21 rt 6”

25f6 23*7t 20&5* 19f6+ 19&6+ 20h6t 20 f 47

24zk8 19* 11 16&t+ 15f9+ 16f9t 20&8t 20 f 10”

2.0 f 2.2 f 2.3f0.5* 2.2fO3” 2.3 f 2.1f0.3 2.1 f

baseline. t p <0 01 vs baseline Index. HR = heart rate, MAP = mean systemic rtght atrlal pressure, SVR = s stemlc vascular resistance Adapted from Am Heart J Y

dynamic (mm

0 7 0 3

0.3t 0.4

arterial

Parameters

Hg)

(Dose [mgl)

5

10

2.5

5

10

25

5

10

2 0 f 0.5 2.2 f 0 2t 2 2 f 0.4t 2.3fO3t 2 2 i 0 3 2.2fO3” 2 1 rkO.4

1.9zkO.5 2.2 f 0.3t 2.3f 0.3t 2.3zkOOt 2.2fO3t 20f05 2.2+0.5+

83f14 82 f 8 81 f 7 803~8 78f8 78f9 80f7

85f16 82f9” 81 f 10 %Ofll* 81 f 13 8Ozk6” 82 f 6

80~13 79*8 76f7 75f9” 75f7t 72f8t 75f8*

81fll 7858 75zkl2 76f9* 73+7t 74rt7t 73f8t

88k16 8358 78&8f 72+11+ 74&12+ 74dc7t 76fll+

82fll 75*11+ 66flOt 64fll+ 67&12+ 71 f8t 72f13+

pressure.

PA = mean pulmonary

to Varying

Doses

artery

pressure.

PAW = mean pulmonary

artery wedge pressure.

RA = mean

of Lisinoprll AMAP

(Dose [mgl)

-~

MAP (mm Hg)

(Dose [mgl)

ACI (Ilters/mtn/m2)

(Dose [mgl)

I------

HR (beats/mtn)

(Dose [WI)

2 5

APAW

particularly the pulmonary artery wedge and mean systemic arterial pressures, as well as systemic vascular resistance. These findings probably reflect the prolonged duration of the effect of lisinopril, which had last been given 24 to 28 hours before reassessment. Lisinopril was quite well tolerated, with only 3 (6.4%) patients being withdrawn because of major side effects (rash in 2 and lightheadedness in 1). In the remaining patients, there was only 1 episode of syncope or lightheadedness and 1 episode of taste disturbance. Two patients complained of cough, and 8 reported some type of gastrointestinal distress (2 each with abdominal pain, dyspepsia, nausea or vomiting). None of these complaints was severe enough to cause discontinuation of the drug. New York Heart Association classification improved at 12 weeks compared with baseline (p <0.05); 54% of patients were in class IV at baseline vs 17% at 12 weeks, and 46% of patients were in class III at baseline vs 68% at 12 weeks. The remainder were in class II. Furthermore, exercise time improved approximately 33% (+ 124 seconds) at 12 weeks (p <0.05) in patients (n = 27) who underwent this procedure. In addition, no significant metabolic or hematologic abnormalities were noted during the course of this study (Table III), although 26% of the subjects had either an increase in blood urea nitrogen of >I0 mg% from baseline or an absolute value >25 mg%, or an increase in creatinine levels of >0.2 mg% from baseline or an absolute value > 1.8 mg%.

(mm

Hg)

ASVR (dynes s ~rn-~) (Dose [mgl)

(Dose [mgl)

10

2.5

5

10

2.5

5

10

2.5

5

10

-50 -8 9* 43t -8 3 -5.6 -52

0.15 0 24 0.13 0.24 007 -0 02

0 18 0.22 0.26 0 17 0.19 0.10

030 0 36 0.41* 0.31 0.15 035

-3.0 -59 -5 1 -7.4 -64 -7.3

-5 7 -10 9* -16.35 -14.8 -12 8s -20.4

-8 1 -17 2” -la.%+ -1591 -11.8 -10 6

-141 -179 -196 -270 -141 -80

-197 -325* -435t -431 -3471 -256

-360 -6lOt -618t -496 -201 -434

The numbers I” each column represent the mean change for that parameter at that bme pant for each dose Standard deviations * p
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A SYMPOSIUM:

CONGESTIVE

HEART

FAILURE-ADVANCES

IN TREATMENT

100 90 OI z 80

/* ff ***

+

**

5

*** x**

5

-mm -* ,Iix@$G

70

40

* **

**

I

**

60

*

**

0 TIME

4

8 AFTER

12 16 20 LISINOPRILDOSING (hours 1

50

24

I

I

I

I

I

I

I

0

4

8

12

16

20

24

L-

TIME

AFTER

C

LISINOPRIL (hours)

DOSING

3.0 2000 _ “E

‘:

2.5

LO’

E 1800 Q iii 9 1600 z =. 23 1400

I

’ 0

4

I 8 AFTER

TIME 6

I

I

12 16 LISINOPRIL ( hours 1

I200

I

I 20 DOSING

0

24

D

4 TIME

8 AFTER

16 12 LISINOPRIL ( hours 1

20

24

DOSING

FIGURE 1. Acute and chronic hemodynamic responses to lisinopril in 10 patients who were taking the converting enzyme inhibitor for 12 weeks. At the chronic reassessment, the dose given was the same as that given initially. The average dose given was 6 f 3 mg. A, pulmonary artery wedge pressure (PAW); B, cardiac index (Cl); C, mean arterial pressure (MAP); D, systemic vascular resistance (SVR). So/id circles represent the initial study; open squares represent the 12-week reassessment. All levels of significance relate to the time point vs the respective baseline value. In addition to the significant levels shown in the figures, mean arterial pressure and systemic vascular resistance were significantly lower (p
TABLE Ill Laboratory Parameters Weeks of Lisinopril Therapy

at Baseline

and at 12

1 Parameter

Baseline

Serum Serum Blood Serum

138i3

136*3

3.9 f 0.5 25 f 14 1.3dzo.5

4.2 f 0.5 31 f 21 15f0.6

sodium (mEq/liter) potassium (mEq/liter) urea nitrogen (mg%) creatinlne (mg%)

12 Weeks

1

DISCUSSION

The observed hemodynamic effects of lisinopril were qualitatively similar to those seen with other converting enzyme inhibitors.1,2,5-9 There was a long duration of action of lisinopril that was at least 24 hours in duration for most hemodynamic parameters. A dose-response re100

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lation appeared to be present in most hemodynamic parameters. This fact implies that some difference in the degree of converting enzyme inhibition exists with different doses of lisinopril. The use of a higher dose (for instance, 20 mg) would have been necessary to determine whether a further hemodynamic improvement could have been effected, which would imply that the lo-mg dose did not totally inhibit the converting enzyme. However, on the basis of extensive previous work, once converting enzyme inhibition is complete, it is not likely that increasing the dose will effect further hemodynamic changes. In addition, the hemodynamic effects of lisinopril appear to be sustained, as has been seen with other converting enzyme inhibitors. In the subgroup of patients in whom long-term hemodynamics are reported, baseline hemodynamics were improved over those observed in the initial

study. This improvement probably represents a continued hemodynamic effect of lisinopril, which had last been given 24 to 28 hours before the chronic hemodynamic study. The tolerability profile of lisinopril was good, and the absence of neutropenia reassuring. Biochemical parameters did not change significantly, and the percentage of subjects in whom any degree of renal dysfunction developed was similar to that found in other studies of patients with severe heart failure.5 The improvement in New York Heart Association functional classification and exercise testing should be considered cautiously, because of the absence of a control group. However, the magnitude of improvement in exercise duration was very similar to that seen with both enalapril and captopril in previous, double-blind, controlled trials.bd9 CONCLUSION

Our data provide a rationale for the use of once-daily converting enzyme inhibition with lisinopril as a means to control patients with symptomatically severe heart failure. A prolonged hemodynamic effect has previously been considered to be a problem by some investigators5 Our data, both hemodynamic and clinical, suggest that a long duration of action is compatible with an excellent clinical response. The recent Cooperative North Scandinavian Enalapril Survival Study demonstrated that the converting enzyme inhibitor enalapril was effective in prolonging life in this group of patients. to It is reasonable to extrapolate from these findings that other converting enzyme inhibitors may have a similar effect in this set-

ting. An agent with a once-daily dosing, such as lisinopril, would tend to streamline the medical regimen of these patients, who so often are taking multiple drugs. Acknowledgment: We thank Rhonda Oliver for the preparation of this manuscript.

REFERENCES 1. Levine converting

TB, Franciosa JA, Cohn JN. Acute and long-term enzyme inhibttor, captopril m congestive heart

response to an oral famwe. Circulation

1980,62:35-41. 2. Todd PA, Heel RC. Enalaprtl

Drugs 1986;31.19&248. 3. Uretsky BF, Shaver JA, Liang C, Amin D, Shah PK, Levine TB, Wahnsky P, LeJemtel T, Lmnematcr T, Rush JE. Langendorfer A, Snapinn S Modulatton of hcmodynamic effects with a converting enzyme mhibitor acute hemodynamic dose-response relationshtp of the new angiotcnsm convertmg enzyme Inhibitor lismopril wtth observations on long-term chmcal, fnncttonal, and biochemical responses. Am Heart J 1988,116~480-488. 4. Marquardt DW. An algorithm for least-squares estnnatton of non-hnear parameters. J Sac Indust Appl Math 1963:11:431~441. 5. Packer M, Lee WH, Yushak M, Medina N. Compartson of captoprd and cnalaprtl m patients with severe chronic heart failure. New Engl J Med

1986,315:847-853. 6. Kramer BL, Massie BH, Topic N. Controlled trtal of captopril tn refractory chronic conrrestive heart failure. JACC 1983:2:755-766 7. Powers ER, Bonnerman KS, Stone J, R&on DS, Escalo EL, Kalischer A, Weiss MB, Scmcco RR, Cennon PJ. The effect of captopril on renal, coronary, and systemtc hemodynamics in patients wtth severe congestwe heart failure. Am Heart J 1982:104:1203~1210. 8. Sharpe DN, Murphy .I, Coxon R, Hannan SF. Enalapril in pattents with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circulation 1984;70:271-278. 9. Franciosa JA, Wilen MM, Jordan RA Effects of enalapnl, an angtolcnsionconverting enzyme inhtbitor, in a controlled trial in heart fatlure JACC 1985;5:101~107. 10. The CONSENSUS Trial Study Group. Effects of enalaprd on mortality m severe congestive heart failurc: results of the Cooperative North Scandinavian Enalapril Survwal Study (CONSENSUS). N Engl JMed 1987;316:1429-1435

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