- Email: [email protected]
Long-term effects of a once-a-day versus twice-a-day regimen of enalapril for congestive heart failure
Gary S. Francis, MD, and Ewa J. Rucinska, MD, PhD, for the Enalagril Congestive Heart Failure Investigators *
hough an abundance of short-term clinical trials s evaluated the use of enalapril in congestive failure (CHF), there has been a paucity of egarding the long-term effects of this angio-converting enzyme inhibitor. Moreover, a questron has arisen as to whether a once- or twicedaily dosing schedule is preferable. To address these issues, a multicenter trial was conducted with the objective of obtaining long-term (48 weeks) experience with enalapril in 142 patients with CHF. A subgroup of patients (n = 88) were randomized to receive enafapril in a dosing schedule of either 20 mg once daily or 10 mg twice daily. Of the overall group, 96 patients completed the 48 weeks of follow-up. Improvement in New York Heart Association functional class, exercise duration and left ventricular ejection fraction was observed. Improvein clinical status was seen in 68% of all nts, whereas conditions in 5% worsened with pril therapy. The most frequent adverse experiences were dizziness and hypotension. There were no obvious differences between the effects of - and twice-daily dosing regimens, with 26 mg/day and 2.5 to 15 mg/day being o about 70 and 30% of patients, respectivepril appears to provide well-tu~erated an
*Investigators in the Enalapril listed m the Appendix.
Congestive
Heart
Failure
study
are
From the Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania, and the Veterans Administration Medical Center, Minneapolis, Minnesota. Address for reprints Ewa J. Rucinska, MD, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
nalapril maleate is a potent, long-acting angionsin-converting enzyme inhibitor that has recentbeen shown in the Cooperative North Scandinavian Enalapril Survival Study’ to improve survival in patients with advanced congestive heart failure (CHF).’ The agent has been shown to produce acute hemodynamic benefits in patients with CHF.2m5 Controlled trials of enalapril in patients with CHF have demonstrated sustained clinical and hemodynamic improvement,6-10 as well as a significant trend toward improved exercise tolerance.“-‘” However, most of these have been relatively short-term studies (512 weeks). There has been little information on the long-term use of enalapril in patients with CHF. Consequently, a multicenter trial was undertaken to evaluate long-term (48 weeks) experience with enalapril in patients with CHF. To determine the proper dosing regimen for this long-acting angiotensin-converting enzyme inhibitor, a subgroup of patients was randomized in a double-blind fashion to receive either 20 mg once daily or 10 mg twice daily. E-i-HODS Patients:
Men and women, aged 21 to 80 years, with clinical evidence of symptomatic CHF were eligible for the study. In all, 142 patients (108 men and 34 women) entered the trial, 96 of whom were treated for a minimum of 48 weeks (Table I). The average age was 63 years, and the mean duration of CHF before entering the trial was 3.1 years. The preponderance of patients had underlying ischemic heart disease (58%) or dilated cardiomyopathy (32%). Most patients (63%) were in New York Heart Association (NYHA) functional class III, whereas only a small number (7%) were in class IV. Mean ejection fraction for the entire group was 32%. Nearly all patients were already receiving therapy with diuretics (94%) and digitalis (78%); 42% were taking nitrates, 18% calcium antagonists and 8% other vasodilator drugs. The patients were studied at 18 centers in the United States and Puer” to a: During a 2-week baseline period, each patient’s clinical status was stabilized. Each patient underwent a complete clinical evaluation, including NYHA functional classification, routine blood work, urinalysis, electrocardiography, chest x-ray with cardiothoracic ratio, and assessment of left ventricular ejection fraction by gated blood pool scan. A modified Naughton treadmill
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
21, 1989
A SYMPOSIUM:
TABLE
CONGESTIVE
I Patient
HEART
Characteristics
Label
IN TREATMENT
exercise test’j was performed twice during the baseline period to assessexercise time and to insure reproducibility of measured exercise tolerance. Of the total 142 patients, 54 entered the open-label arm of the long-term (4%week) study. Patients were allowed to take concomitant therapy for CHF. Enalapril therapy was started at a dose of 5 mg twice daily and increased to 10 mg twice daily after 2 weeks of treatment (Fig. 1). Patients were followed every 2 weeks for the first 3 months and monthly thereafter. Those patients in whom symptomatic hypotension developed on day 1 of therapy returned to the clinic the following day and received 2.5 mg of enalapril. The other 88 patients entered a double-blind, randomized arm of the study to compare once- and twice-daily treatment regimens. Group I received two 5-mg tablets of enalapril each morning and a placebo tablet each evening; group II received one 5-mg tablet of enalapril plus 1
at Baseline
Sex (no.) Male Female Total Mean age (years) Etiology (no.) lschemrc Cardiomyopathy Other Mean duration of congestive heart failure (years) Mean ejectron fraction (% f standard deviation) New York Heart Assocratron (no.) Class II Class Ill Class IV Unknown Mean
Open
FAILURE-ADVANCES
108 34 142 63 f 10 (range
36 to 82)
83 46 13 3.1 f 3.2 (range 32f
0.83 to 14)
16
33 90 10 9 2.82
Study n=54
Baseline
,
Double-Blind
5 mg BID Enalapril
Once
,
vs Twice
10 m9 BID Enalapril
Daily
I
-
FIGURE 1. Design of 46week enalapril study. A total of 142 patients entered the clinical trial; BB participated in a doubleblind, randomized arm to compare a once(QD) to a twice-daily (BID) dosing regimen.
Study
n=88 10 mg BID Enalapril
5 mg BID Enalapril
10 mg in AM
20
Enalapril
2
mg in AM Enalapril
4
48 WEEKS
4 n
:
o
i
l
a P
c G 0
Total Qroup, N = Double-Blind BID, Double-Blind QD, Open Label BID,
97 N = 29 N = 33 N = 35
3L
i.
I
i k 2
2
____----
p%
---A----
.‘-‘d.
----__
a
-0-
I
i Baseline
I
!
I
16
32
48
WEEK
1SD
-- _______
‘-1
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
63
FIGURE 2. Mean New York Heart Association functional status before and after enalapril therapy. There was a substantial improvement in New York Heart Association functional status by 16 weeks, which persisted at 46 weeks. There was no important difference between the effects of once- (QD) vs twice-daily (BID) dosing of enalapril.
placebo tablet each morning and 1 5-mg tablet each evening. At the end of the first 2 weeks, the enalapril dose was doubled (group I received 20 mg in the morning and group II received 10 mg twice daily). The double-blind dosing schedule was continued for 3 months. After week 12, placebo was discontinued and all patients continued their treatment on the previous regimen (once or twice daily) in an open fashion. NYHA functional class was estimated at weeks 16, 32 and 48. Exercise duration was measured at weeks 4, 16,32 and 48. Eeft ventricular ejection fraction was measured at week 48, or sooner if the patient.did not complete the long-term protocol, All evaluations were made according to an all-patients-treated analysis, which requires inclusion of any patient who has at least 1 baseline and 1 on-treatment value for any variable being analyzed. Thus, the number of patients analyzed for a particular variable does not depend on the number of patients completing the trial, but on the availability of data during the trial, and therefore it may vary from 1 variable to another. Statistical significance was assessed by the chi-square test.
more than 70% of patients. All within-group changes in NYHA cardiac status were significant, but there was no difference between the double-blind subgroups. Exercise duration: Figure 3 shows the mean exercise tolerance for all groups before and during enalapril therapy. After 4 weeks, all groups showed similar improvement beyond control levels; this improvement was sustained for 48 weeks. The average improvement in exercise duration for all patients (n = 129) was 107.6 seconds (p
TOLERABILITY
OF ENALAPRIL
effect: After the initial
dose of enalapril, patients’ blood pressures were recorded for at least 6 hours. Decreases in blood pressure after the initial lo-mg doses (once-a-day regimen) were slightly larger than afFirst-dose
TABLE Enalapril
ESULTS Symptomatic response: The 48-week trial was completed by 96 of 142 patients (68%). Only 10 of 142 (7%) were noncompliant or were lost to follow-up. Treatment in 1 patient was unsuccessful, 10 patients were withdrawn because of adverse experiences, and 15 patients died during the study. Table II indicates changes in measured clinical parameters, and Figure 2 shows the mean NYHA status before and during enalapril. The once- and twice-daily regimens were equally effective, and the improvement was sustained over 48 weeks. There was a dramatic improvement in NYHA cardiac status for patients in all groups. In the all-patients-treated analysis, 85 patients (68%) had functional improvement, whereas only 6 (5%) worsened. Of the patients who completed 48 weeks of therapy, conditions in 69 (81%) improved, compared with 3 (4%) in whom conditions worsened. In particular, dyspnea on effort, paroxysmal nocturnal dyspnea, fatigue, pitting edema and rales were all alleviated in
II Improvements Therapy
in ClInical
Parameters Pabents
After
wtth Symptoms Improvement
Parameter
At Baselrne (no.)*
No.
%
Dyspnea on effort Dyspnea at rest PND PNC Fatrgue Nocturia Lung rales Edema Jugular vern drstensron Thrrd heart sound NYHA cardtac status
132 71 74 65 127 106 50 57 46 61 125
102 52 58 46 93 63 44 44 26 14 85
77 73 7% 71 73 59 88 77 57 23 68
*A patrent was evaluated for any given vamble d he had a valid value at both baseline and dwng treatment NYHA = New York Heart Assoclatlon. PNC = paroxysmal nocturnal cough; PND = paroxysmal nocturnal dyspnea
1
A _________-
ean change in exercise duration (modified Naughton protocol) during enalapril therapy. The overall improvement in exercise duration was 107.6 seconds (p
----A.----
-____
--------A----
-------------*
======! e
m Total Group, o Double-Blind e Double-Blrnd A Open I
I
0
4
I
I
I
I
I
I
I
Label
N-129 BID. Nm4( 1 QD, N-40 BID.
/I
I
32
16
48
WEEK
THE AMERICAN
JOURNAL
OF CARDIOLOGY
M=49
i
FEBRUARY
21.
1989
A SYMPOSIUM:
140
CONGESTIVE
HEART
FAILURE-ADVANCES
IN TREATMENT
-
VI =
loo-
: DlaStOllC 60
TK?.Xtf7lellt - _____ ---
60
I 0
I
I 1
05
I 15
2
I 25
1 3
I 35
_______ I 4
I 45
----, 5
-5 ---IO
, 55
mg (N = 99) mg (N = 34)
, 6
HOUR
FIGURE 4. Mean supine systolic and diastolic blood pressure by initial dose recorded over a period of 6 hours. The decreases of systolic blood pressure afler the initial lo-mg doses were slightly larger than after the 5-mg doses, but the difference was small. There was virtually no difference in diastolic blood pressure reductions after the lo- and S-mg doses.
TABLE Ill Adverse Clinical Experiences Reported Among 142 Patients Receiving
Most Frequently Enalapnl Therapy
Adverse
No.
%
12 12 10 6 5
8 8 7 4 4
Experience
Asymptomatlc
hypotenslon
Dlzzlness Orthostatlc hypotenslon Weakness/fatigue Cough
ter the 5-mg doses, but the difference was small (Fig. 4). In 2 patients, the dose was reduced from 5 to 2.5 mg. Adverse experiences: Overall, 15 deaths and 24 serious adverse experiences occurred during the study. In 10 patients, treatment was discontinued because of serious adverse experiences. In the other 14 patients who experienced serious adverse reactions, therapy either continued without interruption or was restarted with enalapril after a short interruption. The most frequent adverse experiences (Table III) were dizziness and hypotension. In 5 patients, enalapril was withdrawn because of hypotension or dizziness. Overall, enalapril was well tolerated. DISCUSSION
This trial was particularly useful because long-term (48-week) follow-up data were obtained, and the onceand twice-daily dosing regimens could be compared. Long-term studies with converting enzyme inhibitor drugs for CHF are rarely performed.l,14,16 Such studies are important because they allow observations to be made over the course of many months, thereby ensuring information about whether efficacy is sustained or diminished with time. Moreover, long-term trials allow for a more accurate assessment of adverse clinical experiences. In this open-label trial, 96 of 142 patients (68%) were treated with enalapril over 48 weeks. Improvement in NYHA functional status and exercise duration was sustained and ejection fraction increased by an average of 3%, while 20D
THE AMERICAN
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63
adverse clinical experiences were rare. Although the results must be viewed with caution because the study lacked a control, nevertheless, these observations are consistent with those of short-term placebo-controlled trials. These data suggest that in patients with chronic CHF, improvement from enalapril can be sustained over a long follow-up period. The improvement in ejection fraction, although small, is also consistent with large, placebo-controlled trials using other vasodilators, which were previously shown to improve survival in patients with CHF.17 More rigorously controlled long-term clinical trials comparing enalapril with hydralazine and isosorbide dinitrate (Veterans Administration Vasodilator Heart Failure Trial [V-HeFT II]) and with placebo (Studies of Left Ventricular Dysfunction [SOLVDI-Treatment) are currently underway. This study was the first to investigate the use of oncevs twice-daily dosing of enalapril for CHF. Dosing information is particularly valuable when planning therapeutic strategy. Enalapril is a long-acting prodrug that undergoes desterification in the liver to its active form, enalaprilat. This biotransformation accounts for the smooth onset and partially also for the long duration of action of the parent compound. Current practice is to prescribe enalapril twice daily. Data from this open-labeled trial indicate no apparent difference between once- and twicedaily dosing of enalapril in patients with CHF. The target dose of 20 mg/day appeared to be well tolerated by most patients; however, the possibility of maintaining the beneficial effects of enalapril with lower doses was not fully explored in this study. CONCLUSIONS
Enalapril appears to be a well-tolerated and effective adjunctive therapy to digitalis and diuretics in patients with established CHF. There are no obvious differences in the effects of a once- vs twice-daily dosing regimen, with an average daily dose of 20 mg being optimal. Decreasing the dose of diuretic in the face of hypotension, with careful readjustment of chronic diuretic therapy thereafter, is essential for prevention of symptomatic hypotension and deterioration of renal function.‘* Acknowledgment: We wish to thank for their significant contribution to the completion and evaluation of this study: Phyllis Denny, Barbara A. Price, RN, Elizabeth A. Reilly, Steven M. Snappin, MD, James P. Whipple and Shu-Jane Tan.
REFERENCES 1. CONSENSUS Study Trial Group. Effect of enalaprd on mortahty in severe congestwe heart failure. Results of the CONSENSUS Trial (Cooperative North Scandinavian Enalapril Survival Study) N Engl J A4ed 1987916.1429-1435. 2. Dunkman WB, Wilen M, Franciosa JA. Enalapril (MK 421), a new angiotensin convertmg enzyme inhibltor. Acute and chronic effects in heart failure. Chwr 1983;84.539-545. 3. Cody RJ. Clmical and hemodynamic experience with enalaprll in congestive heart failure. Am J Cardiol 1985;55suppl.36A-4OA. 4. Fitzpatrick D, Nicholls MG, &ram H. Espiner EA. Hemodynamic. hormonal and electrolyte effects of enalapril in heart failure Br Heart J 198330~163-169.
5. Levme TB, Ohvarl MT, Garberg V, Sharkey SW, Cohn JN. Hemodynamx and clinical response to enalapril, a long-acting converting enzyme inlnbitor m patients wth congestive heart failure Circulatrorr 2984;69.54&553. 6. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized. double-blind study Circulation 1984:70.271-278. 7. McGrath BP, Arnolda L, Mathews PG, Jackson B, Jennmgs G, Klat H. Johnston CI. Controlled trial of enalaprd m congestwe heart failure. Br Heart J 1985:54:405-414. 6. Cody RJ, Covit AB, Schaer CL, Laragh JH. Evaluatmn of a long-acting converting enzyme mhibitor (enalaprd) for the treatment of congestive heart fallwe. JACC 19X3:1:1 154-l 159 9. DiCarlo L, Chatterjee K, Parmley WW, Swedberg K, Atherton B, Curran D. Cucci M. Enalapril: a new angiotensin convertmg enzyme inhibitor m chrome cardiac fadure: acute and chronic hemodynamic evaluations. JACC 1983;2:865871. 10. Gomez HJ, Clrillo VJ, Davies RO. Enalapril m congestive heart failure: acute and chronic invasive hemodynamic evaluation. Inl J Car&l 1986;11.37-4X 11. Cleland JGF, Dargle HJ, Ball SG, Gdlin 6, Hodsman GP, Morton JJ, East BW, Robertson I, Ford I, Robertson JIS Effects of enalapril in heart failure: a double-bhnd study of effects on exercise performance, renal function, hormones, and metabohc state. Br Heart J 1985;5:305-312 12. Francmsa JA, Wile” MM, Jordan RA. Effects of enalapril, a new anglotensm converting enzyme inlxbitor, in a controlled trial m heart fadwe J,4CC 198S;5~101-107. 13. Creager MA, Massie BM, Faxon DP, Friedman SD, Kramer BL, Weiner DA, Ryan TJ, Topic N, Melidowan CD. Acute and long-term effects of cnalapril on the cardiovascular response to exercise and exercise tolerance m patients with congestwe heart failure JACC 1985:6:163-l 70. 14. Enalaprd Congestive Heart Fadure Investigators. Long-term effects of enalapril in patients with congestive heart failure. a multicenter, placebo-controlled trial. Heart Failure 1987,3:102-107 15. Patterson JA, Naughton J, Pletras RJ, Gunnar RM. Treadmill exercise m assessment of the functmnal capacity of patients with cardiac disease. Am J Cardiol 1972;30:757-762 16. Captopril MultIcenter Research Group. A placebo-controlled trial of captopril in refractory chrome congestive heart failure. JACC 1983;2,755-763.
17. Cohn JN, Archibald DG, Ziesche S, Francmsa JA, Harston WE, Trlatani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR. Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortahty in chrome congestive heart failure Results of a Veterans Adnumstralion Cooperatwe Study N Engl J Med 1986;314:1547-
1552. 16. Packer M. Lee WH, Medma N, Yushak M, Kessier PD. Functmnal insufficiency during long-term captopril and enalapril in severe chronic failure. Ann Intern Med 1987:106.346-354,
renal heart
APPENDIX
The Enalapril Congestive Heart Failure Investigators are as follows: Lofty Basta, MD (Tulsa, Oklahoma); Barry Beller, MD (San Antonio, Texas); Alan Dauer, MD (Whittier, California); William J. Hamilton, MD (St. Louis, Missouri); James C. Laidlaw, MD (Winchester, Virginia); Thomas J. Linnemeier, MD (Indianapolis, Indiana); Frank A. McGrew, MD (Memphis, Tennessee); John H. Morledge, MD (Madison, Wisconsin); Carl Oshrain, MD (Rochester, New York); L. Kent Smith, MD (Phoenix, Arizona); James Burke, MD (Philadelphia, Pennsylvania); Gary Francis, MD (Minneapolis, Minnesota); Manuel Martinez-Maldonado, MD (San Juan, Puerto Rico); John A. McChesney, MD (Daly City, California); Douglas C. Morris, MD (Atlanta, Georgia); James Price, MD (Santa Rosa, California); Hillel S. Ribner, MD (Chicago, Illinois); Vivienne E. Smith, MD (Farmington, Connecticut); and Peter Schulman, MD (Farmington, Connecticut).
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
21, 1989
hough an abundance of short-term clinical trials s evaluated the use of enalapril in congestive failure (CHF), there has been a paucity of egarding the long-term effects of this angio-converting enzyme inhibitor. Moreover, a questron has arisen as to whether a once- or twicedaily dosing schedule is preferable. To address these issues, a multicenter trial was conducted with the objective of obtaining long-term (48 weeks) experience with enalapril in 142 patients with CHF. A subgroup of patients (n = 88) were randomized to receive enafapril in a dosing schedule of either 20 mg once daily or 10 mg twice daily. Of the overall group, 96 patients completed the 48 weeks of follow-up. Improvement in New York Heart Association functional class, exercise duration and left ventricular ejection fraction was observed. Improvein clinical status was seen in 68% of all nts, whereas conditions in 5% worsened with pril therapy. The most frequent adverse experiences were dizziness and hypotension. There were no obvious differences between the effects of - and twice-daily dosing regimens, with 26 mg/day and 2.5 to 15 mg/day being o about 70 and 30% of patients, respectivepril appears to provide well-tu~erated an
*Investigators in the Enalapril listed m the Appendix.
Congestive
Heart
Failure
study
are
From the Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania, and the Veterans Administration Medical Center, Minneapolis, Minnesota. Address for reprints Ewa J. Rucinska, MD, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
nalapril maleate is a potent, long-acting angionsin-converting enzyme inhibitor that has recentbeen shown in the Cooperative North Scandinavian Enalapril Survival Study’ to improve survival in patients with advanced congestive heart failure (CHF).’ The agent has been shown to produce acute hemodynamic benefits in patients with CHF.2m5 Controlled trials of enalapril in patients with CHF have demonstrated sustained clinical and hemodynamic improvement,6-10 as well as a significant trend toward improved exercise tolerance.“-‘” However, most of these have been relatively short-term studies (512 weeks). There has been little information on the long-term use of enalapril in patients with CHF. Consequently, a multicenter trial was undertaken to evaluate long-term (48 weeks) experience with enalapril in patients with CHF. To determine the proper dosing regimen for this long-acting angiotensin-converting enzyme inhibitor, a subgroup of patients was randomized in a double-blind fashion to receive either 20 mg once daily or 10 mg twice daily. E-i-HODS Patients:
Men and women, aged 21 to 80 years, with clinical evidence of symptomatic CHF were eligible for the study. In all, 142 patients (108 men and 34 women) entered the trial, 96 of whom were treated for a minimum of 48 weeks (Table I). The average age was 63 years, and the mean duration of CHF before entering the trial was 3.1 years. The preponderance of patients had underlying ischemic heart disease (58%) or dilated cardiomyopathy (32%). Most patients (63%) were in New York Heart Association (NYHA) functional class III, whereas only a small number (7%) were in class IV. Mean ejection fraction for the entire group was 32%. Nearly all patients were already receiving therapy with diuretics (94%) and digitalis (78%); 42% were taking nitrates, 18% calcium antagonists and 8% other vasodilator drugs. The patients were studied at 18 centers in the United States and Puer” to a: During a 2-week baseline period, each patient’s clinical status was stabilized. Each patient underwent a complete clinical evaluation, including NYHA functional classification, routine blood work, urinalysis, electrocardiography, chest x-ray with cardiothoracic ratio, and assessment of left ventricular ejection fraction by gated blood pool scan. A modified Naughton treadmill
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
21, 1989
A SYMPOSIUM:
TABLE
CONGESTIVE
I Patient
HEART
Characteristics
Label
IN TREATMENT
exercise test’j was performed twice during the baseline period to assessexercise time and to insure reproducibility of measured exercise tolerance. Of the total 142 patients, 54 entered the open-label arm of the long-term (4%week) study. Patients were allowed to take concomitant therapy for CHF. Enalapril therapy was started at a dose of 5 mg twice daily and increased to 10 mg twice daily after 2 weeks of treatment (Fig. 1). Patients were followed every 2 weeks for the first 3 months and monthly thereafter. Those patients in whom symptomatic hypotension developed on day 1 of therapy returned to the clinic the following day and received 2.5 mg of enalapril. The other 88 patients entered a double-blind, randomized arm of the study to compare once- and twice-daily treatment regimens. Group I received two 5-mg tablets of enalapril each morning and a placebo tablet each evening; group II received one 5-mg tablet of enalapril plus 1
at Baseline
Sex (no.) Male Female Total Mean age (years) Etiology (no.) lschemrc Cardiomyopathy Other Mean duration of congestive heart failure (years) Mean ejectron fraction (% f standard deviation) New York Heart Assocratron (no.) Class II Class Ill Class IV Unknown Mean
Open
FAILURE-ADVANCES
108 34 142 63 f 10 (range
36 to 82)
83 46 13 3.1 f 3.2 (range 32f
0.83 to 14)
16
33 90 10 9 2.82
Study n=54
Baseline
,
Double-Blind
5 mg BID Enalapril
Once
,
vs Twice
10 m9 BID Enalapril
Daily
I
-
FIGURE 1. Design of 46week enalapril study. A total of 142 patients entered the clinical trial; BB participated in a doubleblind, randomized arm to compare a once(QD) to a twice-daily (BID) dosing regimen.
Study
n=88 10 mg BID Enalapril
5 mg BID Enalapril
10 mg in AM
20
Enalapril
2
mg in AM Enalapril
4
48 WEEKS
4 n
:
o
i
l
a P
c G 0
Total Qroup, N = Double-Blind BID, Double-Blind QD, Open Label BID,
97 N = 29 N = 33 N = 35
3L
i.
I
i k 2
2
____----
p%
---A----
.‘-‘d.
----__
a
-0-
I
i Baseline
I
!
I
16
32
48
WEEK
1SD
-- _______
‘-1
THE AMERICAN
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OF CARDIOLOGY
VOLUME
63
FIGURE 2. Mean New York Heart Association functional status before and after enalapril therapy. There was a substantial improvement in New York Heart Association functional status by 16 weeks, which persisted at 46 weeks. There was no important difference between the effects of once- (QD) vs twice-daily (BID) dosing of enalapril.
placebo tablet each morning and 1 5-mg tablet each evening. At the end of the first 2 weeks, the enalapril dose was doubled (group I received 20 mg in the morning and group II received 10 mg twice daily). The double-blind dosing schedule was continued for 3 months. After week 12, placebo was discontinued and all patients continued their treatment on the previous regimen (once or twice daily) in an open fashion. NYHA functional class was estimated at weeks 16, 32 and 48. Exercise duration was measured at weeks 4, 16,32 and 48. Eeft ventricular ejection fraction was measured at week 48, or sooner if the patient.did not complete the long-term protocol, All evaluations were made according to an all-patients-treated analysis, which requires inclusion of any patient who has at least 1 baseline and 1 on-treatment value for any variable being analyzed. Thus, the number of patients analyzed for a particular variable does not depend on the number of patients completing the trial, but on the availability of data during the trial, and therefore it may vary from 1 variable to another. Statistical significance was assessed by the chi-square test.
more than 70% of patients. All within-group changes in NYHA cardiac status were significant, but there was no difference between the double-blind subgroups. Exercise duration: Figure 3 shows the mean exercise tolerance for all groups before and during enalapril therapy. After 4 weeks, all groups showed similar improvement beyond control levels; this improvement was sustained for 48 weeks. The average improvement in exercise duration for all patients (n = 129) was 107.6 seconds (p
TOLERABILITY
OF ENALAPRIL
effect: After the initial
dose of enalapril, patients’ blood pressures were recorded for at least 6 hours. Decreases in blood pressure after the initial lo-mg doses (once-a-day regimen) were slightly larger than afFirst-dose
TABLE Enalapril
ESULTS Symptomatic response: The 48-week trial was completed by 96 of 142 patients (68%). Only 10 of 142 (7%) were noncompliant or were lost to follow-up. Treatment in 1 patient was unsuccessful, 10 patients were withdrawn because of adverse experiences, and 15 patients died during the study. Table II indicates changes in measured clinical parameters, and Figure 2 shows the mean NYHA status before and during enalapril. The once- and twice-daily regimens were equally effective, and the improvement was sustained over 48 weeks. There was a dramatic improvement in NYHA cardiac status for patients in all groups. In the all-patients-treated analysis, 85 patients (68%) had functional improvement, whereas only 6 (5%) worsened. Of the patients who completed 48 weeks of therapy, conditions in 69 (81%) improved, compared with 3 (4%) in whom conditions worsened. In particular, dyspnea on effort, paroxysmal nocturnal dyspnea, fatigue, pitting edema and rales were all alleviated in
II Improvements Therapy
in ClInical
Parameters Pabents
After
wtth Symptoms Improvement
Parameter
At Baselrne (no.)*
No.
%
Dyspnea on effort Dyspnea at rest PND PNC Fatrgue Nocturia Lung rales Edema Jugular vern drstensron Thrrd heart sound NYHA cardtac status
132 71 74 65 127 106 50 57 46 61 125
102 52 58 46 93 63 44 44 26 14 85
77 73 7% 71 73 59 88 77 57 23 68
*A patrent was evaluated for any given vamble d he had a valid value at both baseline and dwng treatment NYHA = New York Heart Assoclatlon. PNC = paroxysmal nocturnal cough; PND = paroxysmal nocturnal dyspnea
1
A _________-
ean change in exercise duration (modified Naughton protocol) during enalapril therapy. The overall improvement in exercise duration was 107.6 seconds (p
----A.----
-____
--------A----
-------------*
======! e
m Total Group, o Double-Blind e Double-Blrnd A Open I
I
0
4
I
I
I
I
I
I
I
Label
N-129 BID. Nm4( 1 QD, N-40 BID.
/I
I
32
16
48
WEEK
THE AMERICAN
JOURNAL
OF CARDIOLOGY
M=49
i
FEBRUARY
21.
1989
A SYMPOSIUM:
140
CONGESTIVE
HEART
FAILURE-ADVANCES
IN TREATMENT
-
VI =
loo-
: DlaStOllC 60
TK?.Xtf7lellt - _____ ---
60
I 0
I
I 1
05
I 15
2
I 25
1 3
I 35
_______ I 4
I 45
----, 5
-5 ---IO
, 55
mg (N = 99) mg (N = 34)
, 6
HOUR
FIGURE 4. Mean supine systolic and diastolic blood pressure by initial dose recorded over a period of 6 hours. The decreases of systolic blood pressure afler the initial lo-mg doses were slightly larger than after the 5-mg doses, but the difference was small. There was virtually no difference in diastolic blood pressure reductions after the lo- and S-mg doses.
TABLE Ill Adverse Clinical Experiences Reported Among 142 Patients Receiving
Most Frequently Enalapnl Therapy
Adverse
No.
%
12 12 10 6 5
8 8 7 4 4
Experience
Asymptomatlc
hypotenslon
Dlzzlness Orthostatlc hypotenslon Weakness/fatigue Cough
ter the 5-mg doses, but the difference was small (Fig. 4). In 2 patients, the dose was reduced from 5 to 2.5 mg. Adverse experiences: Overall, 15 deaths and 24 serious adverse experiences occurred during the study. In 10 patients, treatment was discontinued because of serious adverse experiences. In the other 14 patients who experienced serious adverse reactions, therapy either continued without interruption or was restarted with enalapril after a short interruption. The most frequent adverse experiences (Table III) were dizziness and hypotension. In 5 patients, enalapril was withdrawn because of hypotension or dizziness. Overall, enalapril was well tolerated. DISCUSSION
This trial was particularly useful because long-term (48-week) follow-up data were obtained, and the onceand twice-daily dosing regimens could be compared. Long-term studies with converting enzyme inhibitor drugs for CHF are rarely performed.l,14,16 Such studies are important because they allow observations to be made over the course of many months, thereby ensuring information about whether efficacy is sustained or diminished with time. Moreover, long-term trials allow for a more accurate assessment of adverse clinical experiences. In this open-label trial, 96 of 142 patients (68%) were treated with enalapril over 48 weeks. Improvement in NYHA functional status and exercise duration was sustained and ejection fraction increased by an average of 3%, while 20D
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adverse clinical experiences were rare. Although the results must be viewed with caution because the study lacked a control, nevertheless, these observations are consistent with those of short-term placebo-controlled trials. These data suggest that in patients with chronic CHF, improvement from enalapril can be sustained over a long follow-up period. The improvement in ejection fraction, although small, is also consistent with large, placebo-controlled trials using other vasodilators, which were previously shown to improve survival in patients with CHF.17 More rigorously controlled long-term clinical trials comparing enalapril with hydralazine and isosorbide dinitrate (Veterans Administration Vasodilator Heart Failure Trial [V-HeFT II]) and with placebo (Studies of Left Ventricular Dysfunction [SOLVDI-Treatment) are currently underway. This study was the first to investigate the use of oncevs twice-daily dosing of enalapril for CHF. Dosing information is particularly valuable when planning therapeutic strategy. Enalapril is a long-acting prodrug that undergoes desterification in the liver to its active form, enalaprilat. This biotransformation accounts for the smooth onset and partially also for the long duration of action of the parent compound. Current practice is to prescribe enalapril twice daily. Data from this open-labeled trial indicate no apparent difference between once- and twicedaily dosing of enalapril in patients with CHF. The target dose of 20 mg/day appeared to be well tolerated by most patients; however, the possibility of maintaining the beneficial effects of enalapril with lower doses was not fully explored in this study. CONCLUSIONS
Enalapril appears to be a well-tolerated and effective adjunctive therapy to digitalis and diuretics in patients with established CHF. There are no obvious differences in the effects of a once- vs twice-daily dosing regimen, with an average daily dose of 20 mg being optimal. Decreasing the dose of diuretic in the face of hypotension, with careful readjustment of chronic diuretic therapy thereafter, is essential for prevention of symptomatic hypotension and deterioration of renal function.‘* Acknowledgment: We wish to thank for their significant contribution to the completion and evaluation of this study: Phyllis Denny, Barbara A. Price, RN, Elizabeth A. Reilly, Steven M. Snappin, MD, James P. Whipple and Shu-Jane Tan.
REFERENCES 1. CONSENSUS Study Trial Group. Effect of enalaprd on mortahty in severe congestwe heart failure. Results of the CONSENSUS Trial (Cooperative North Scandinavian Enalapril Survival Study) N Engl J A4ed 1987916.1429-1435. 2. Dunkman WB, Wilen M, Franciosa JA. Enalapril (MK 421), a new angiotensin convertmg enzyme inhibltor. Acute and chronic effects in heart failure. Chwr 1983;84.539-545. 3. Cody RJ. Clmical and hemodynamic experience with enalaprll in congestive heart failure. Am J Cardiol 1985;55suppl.36A-4OA. 4. Fitzpatrick D, Nicholls MG, &ram H. Espiner EA. Hemodynamic. hormonal and electrolyte effects of enalapril in heart failure Br Heart J 198330~163-169.
5. Levme TB, Ohvarl MT, Garberg V, Sharkey SW, Cohn JN. Hemodynamx and clinical response to enalapril, a long-acting converting enzyme inlnbitor m patients wth congestive heart failure Circulatrorr 2984;69.54&553. 6. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized. double-blind study Circulation 1984:70.271-278. 7. McGrath BP, Arnolda L, Mathews PG, Jackson B, Jennmgs G, Klat H. Johnston CI. Controlled trial of enalaprd m congestwe heart failure. Br Heart J 1985:54:405-414. 6. Cody RJ, Covit AB, Schaer CL, Laragh JH. Evaluatmn of a long-acting converting enzyme mhibitor (enalaprd) for the treatment of congestive heart fallwe. JACC 19X3:1:1 154-l 159 9. DiCarlo L, Chatterjee K, Parmley WW, Swedberg K, Atherton B, Curran D. Cucci M. Enalapril: a new angiotensin convertmg enzyme inhibitor m chrome cardiac fadure: acute and chronic hemodynamic evaluations. JACC 1983;2:865871. 10. Gomez HJ, Clrillo VJ, Davies RO. Enalapril m congestive heart failure: acute and chronic invasive hemodynamic evaluation. Inl J Car&l 1986;11.37-4X 11. Cleland JGF, Dargle HJ, Ball SG, Gdlin 6, Hodsman GP, Morton JJ, East BW, Robertson I, Ford I, Robertson JIS Effects of enalapril in heart failure: a double-bhnd study of effects on exercise performance, renal function, hormones, and metabohc state. Br Heart J 1985;5:305-312 12. Francmsa JA, Wile” MM, Jordan RA. Effects of enalapril, a new anglotensm converting enzyme inlxbitor, in a controlled trial m heart fadwe J,4CC 198S;5~101-107. 13. Creager MA, Massie BM, Faxon DP, Friedman SD, Kramer BL, Weiner DA, Ryan TJ, Topic N, Melidowan CD. Acute and long-term effects of cnalapril on the cardiovascular response to exercise and exercise tolerance m patients with congestwe heart failure JACC 1985:6:163-l 70. 14. Enalaprd Congestive Heart Fadure Investigators. Long-term effects of enalapril in patients with congestive heart failure. a multicenter, placebo-controlled trial. Heart Failure 1987,3:102-107 15. Patterson JA, Naughton J, Pletras RJ, Gunnar RM. Treadmill exercise m assessment of the functmnal capacity of patients with cardiac disease. Am J Cardiol 1972;30:757-762 16. Captopril MultIcenter Research Group. A placebo-controlled trial of captopril in refractory chrome congestive heart failure. JACC 1983;2,755-763.
17. Cohn JN, Archibald DG, Ziesche S, Francmsa JA, Harston WE, Trlatani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR. Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortahty in chrome congestive heart failure Results of a Veterans Adnumstralion Cooperatwe Study N Engl J Med 1986;314:1547-
1552. 16. Packer M. Lee WH, Medma N, Yushak M, Kessier PD. Functmnal insufficiency during long-term captopril and enalapril in severe chronic failure. Ann Intern Med 1987:106.346-354,
renal heart
APPENDIX
The Enalapril Congestive Heart Failure Investigators are as follows: Lofty Basta, MD (Tulsa, Oklahoma); Barry Beller, MD (San Antonio, Texas); Alan Dauer, MD (Whittier, California); William J. Hamilton, MD (St. Louis, Missouri); James C. Laidlaw, MD (Winchester, Virginia); Thomas J. Linnemeier, MD (Indianapolis, Indiana); Frank A. McGrew, MD (Memphis, Tennessee); John H. Morledge, MD (Madison, Wisconsin); Carl Oshrain, MD (Rochester, New York); L. Kent Smith, MD (Phoenix, Arizona); James Burke, MD (Philadelphia, Pennsylvania); Gary Francis, MD (Minneapolis, Minnesota); Manuel Martinez-Maldonado, MD (San Juan, Puerto Rico); John A. McChesney, MD (Daly City, California); Douglas C. Morris, MD (Atlanta, Georgia); James Price, MD (Santa Rosa, California); Hillel S. Ribner, MD (Chicago, Illinois); Vivienne E. Smith, MD (Farmington, Connecticut); and Peter Schulman, MD (Farmington, Connecticut).
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