Comparison of Lisinopril Versus Digoxin for Congestive Heart Failure During Maintenance Diuretic Therapy Johan Herlitz, MD, PhD, on behalf of the Lisinopril-Digoxin
lisinopril5-20 mg once daily was compared with diioxin 0.l25-0.375 mg once daily in a doubleblind, randomized, parallel-group study hwolving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades IHII) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, diioxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistiilly significant (p = 0.1343). After 12 weeks, diioxin and liiinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of diioxin compared with the baseline value was not significant but that for liiinopril was (p = 0.0027). 7he diirence between treatments approached statistiil signiicame (p = 0.0613). There was no difference between liiinopril and diioxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic bkuxl pressure were consistently lower in the lisinopril group througliout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both llsinopril and diioxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for diioxln). Withdrawals from treatment were of a similar frequency for both treatments. lt is concluded that liiinopril may be a useful alternative to digitalis
in patients with heart failure who remain symptomatic on diuretic therapy. (Am J Cardiol1992370:64C-9OC)
F
or some years, angiotensin-converting enzyme (ACE) inhibitors have been recognized as being effective in the management of congestive heart failure (CHF) when added to previous therapy with optimum doses of digitalis and diuretics.‘J Currently, there is increasing interest in the possibility that ACE inhibitors may be used earlier in the treatment of CHF.3 However, in order to replace traditional first-line therapy of CHF, ACE inhibitors must be established to be superior to, or at least as effective as, the current first-line agents, digitalis or diuretics. Digitalis has a narrow therapeutic ratio and there is a consequent risk of digitalis toxicity especially in the elderly.4 Several studies have compared digitalis and ACE inhibitors in the treatment of mild heart failure.5-10 The studies concerning the short-acting ACE inhibitor captopril have shown comparable or slightly greater exercise capacity with the ACE inhibitor than with digitalis.5-8 Single studies comparing enalapril versus digoxin and lisinopril versus digoxin indicate similar results.9J0 The principal aim of this study was to compare the effects of the long-acting ACE inhibitor lisinopril with the effects of digoxin on exercise capacity in patients with mild-to-moderate CHF who were already receiving optimum doses of diuretics. A secondary aim was to examine the effects of lisinopril and digoxin on the spectrum of arrhythmias seen in patients with mild-to-moderate CHF.
METHODS Patients:
From the Division of Cardiology, Sahlgrenska Hospital, Gothenburg, Sweden. Address for reprints: Johan Herlitz, MD, Division of Cardiology, Sahlgrenska Hospital, S-41345 Gothenburg, Sweden.
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Study Group
Following informed consent patients were recruited for this study at 21 centers in 5 countries: Denmark (2) Sweden (12) Spain (3) United Kingdom (1) Austria (3). Male or female OCTOBER
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patients >21 years old with the clinical signs and symptoms of CHF of New York Heart Association (NYHA) grades II and III were considered eligible for entry into the study. The diagnosis of CHF was based on clinical signs and symptoms supported by the use of chest radiograph, radioisotope scan or echocardiography. Criteria for inclusion were age > 21 years, either sex, clinical signs and symptoms of CHF, NYHA grade II or III, cardiothoracic ratio > 0.5 or ejection fraction 160 mm Hg; right heart failure; fixed rate cardiac pacemaker fitted; atria1 fibrillation or other arrhythmias requiring therapy; history of liver, blood, or endocrine disorders; clinically important renal disorder and abnormal serum potassium; history of drug or alcohol abuse; and hypersensitivity or other contraindications to ACE inhibitors or digoxin. All patients were maintained on stable doses of diuretics. The study was conducted in accordance with the Declaration of Helsinki, and local ethical committee approval was obtained. Study design: Lisinopril and digoxin were compared using a double-blind, parallel-group, randomized, multicenter study design, which is depicted in Figure 1. A double-dummy technique was used to maintain blindness. The study incorporated a baseline period of lo-14 days, during which time the diuretic dosage was optimized in the absence of vasodilator therapy. Patients were then randomized to either lisinopril or digoxin for 12 weeks. At randomization, all patients received a test dose of lisinopril (2.5 mg). Symptoms reported or experi-
enced by the patients were fully documented. Those randomized to lisinopril thereafter received lisinopril 5 mg once daily for 2 weeks initially. Those patients randomized to receive digoxin received 0.125 mg once daily for 2 weeks initially. If, after 2 weeks of the randomized treatment, there was evidence of clinical improvement, the patient continued on that dosage. An increase in the dosage of study medication was considered after 2 weeks of randomized treatment, and again after a further 2 weeks of randomized treatment. The dose was increased if, in the opinion of the investigator, there was evidence of a need for an additional effect and provided that the following 2 safety conditions were met: standing systolic blood pressure was 290 mm Hg and there were no symptoms of hypotension (syncope, faintness, orthostatic effects, dizziness) on the current dose. When an increase in the dosage of study medication was indicated, lisinopril dosage was first increased to 10 mg once daily and finally to a maximum of 20 mg once daily. The dosage of lisinopril was reduced at any relevant visit if the patient exhibited symptomatic hypotension or any other adverse event. An increase in the dosage of digoxin to 0.250 mg once daily was considered after 2 weeks of randomized treatment if there was need for further efficacy and the previously mentioned safety conditions were met. If, after a further 2 weeks of treatment, the dosage of digoxin warranted an increase, the dosage was increased to a maximum of 0.375 mg once daily. This dosage of digoxin was not considered appropriate for patients aged >65 years or those weighing < 50 kg. As a consequence, these patients were not given the highest dose of digoxin or lisinopril permitted in the protocol, i.e., no more than 0.250 mg of digoxin. If a side effect appeared that was believed to be attributable to overdosage of digoxin, the dose could not be reduced, but rather the patient was withdrawn from the study,
LISINOPRIL I Smgod
FIGURE 1. Schematic representation of the study design and dose titration schedule. od = once daily.
1
Optimization of diuretic
5-10mgod
1
5-2Omgod
1
5-20mgod
Concurrent therapy: Diuretics
10.14days
1 0.1’25-0.250mg od 1 0,125.0.375mg od 1 0.12%0.375mg od
2
4
6
12
DIGOXIN
A SYMPOSIUM:
HEART
FAILURE
MANAGEMENT
8=
without breaking the double-blinded nature of the treatment. Concurrent medication: During the randomized phase of the study, the aim was to maintain patients on the same or similar regimen of diuretics as they received during the baseline period. However, the diuretic dose could be adjusted during the randomized treatment phase if needed, based on the clinical assessment. The morning dose of diuretic was withheld on the day the patient received the test dose of lisinopril and potassium-sparing diuretics were not permitted during the study. If a patient developed hypokalemia, potassium supplements were administered with monitoring of serum levels. Chronic nitrate therapy, when used, was kept constant, and additional sublingual nitroglycerin was permitted as required. No other drugs known to affect preload or afterload were allowed. A complete physical exClinical assessment: amination of each patient was conducted at the time of entry into the study. An abbreviated symptom review and physical examination was performed at randomization and at the end of 12 weeks of randomized treatment. Exercise testing was performed using an electrically braked bicycle ergometer, and followed a schedule with continuous incremental work loads. All patients underwent a bicycle exercise test on 2 separate occasions during the placebo run-in, prior to entry into the randomized treatment phase of the study. The first exercise test served as a familiarization procedure for the patient. The second exercise test enabled the duration of exercise to be determined. If the duration of the 2 exercise tests differed by more than 2 minutes, a third test was required before proceeding to randomization. Exercise tests were also carried out after 6 and 12 weeks of randomized treatment. Patients undertook each exercise test at the same time of day (preferably in the morning), and medication was delayed on the day of the exercise test until measurements were complete. Blood pressure was measured at each clinical visit on the same arm, using a mercury sphygmomanometer. Heart rate was measured on each visit by palpation of the radial pulse over a 30-second period. Recordings of blood pressure and heart rate were made after the patient had been standing for 2 minutes. Classification of the patient according to the NYHA criteria was done by the same observer at the end of the placebo run-in period and again after 12 weeks of randomized treatment. Holter monitoring was performed for a 24-hour period during placebo run-in and during the last week of randomized treatment using a 2-channel 86c
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Holter monitor. Analysis of all the 24-hour tapes was performed electronically by Hertford Medical (Hertford, UK). Only data from patients with at least 8 hours of monitoring for the run-in and end of treatment examinations were summarized and analyzed. Blood samples were obtained at entry to the study and after 12 weeks of randomized treatment for hematology and biochemical assessments. Blood samples were taken after 2, 4, and 6 weeks of randomized treatment for biochemical assessment only. Full blood count and an estimation of urea, sodium, potassium and creatinine were carried out. Reports of side effects were elicited at each visit after the start of the placebo run-in period using a nonleading question, and the nature and severity of any symptoms reported were noted. Patients were asked to bring any unused tablets with them at each visit to assess compliance. Patients with evidence of tablet consumption < 50% or > 150% of the prescribed dose were considered to have deviated from the study protocol. Statistical analysis: It was calculated that 172 patients (86 per group) would be required to detect a mean difference between treatments in exercise duration of 60 seconds. This calculation was made at the 5% level of significance, with 90% power and using a standard deviation of 120 seconds. To allow for withdrawals from the study, it was intended that 250 patients (125 per group) would take part in the study. Analysis of covariance was used to compare lisinopril and digoxin for the change in exercise duration from the run-in visit to treatment week 6 and the change from the run-in visit to that at treatment week 12. The results reported below are based on an analysis of data from patients for whom complete data were available both at run-in and after 12 weeks of treatment (completers analysis). The analyses have been reported with respect to the comparison between lisinopril and digoxin using the t-test. The proportion of patients in each treatment group with a reduction in the hourly rate of ventricular ectopic counts after 12 weeks of treatment was compared between lisinopril and digoxin using Fisher’s exact test. The proportion of patients with adverse reactions and the proportion who withdrew due to adverse reactions were compared between lisinopril and digoxin using Fisher’s exact test. Because these analyses were concerned with treatment safety, all randomized patients were included in this analysis. OCTOBER
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TABLE I Demographic Variables of the Study Population Randomized to Either Lisinopril or Digoxin Therapy* Lisinopril
Digoxin
No. patients Females (%) Males (%)
107 31 (29)
102 19 (19)
Mean age (yr)
63 k 10
76 (71)
Age range (yr) Body weight (kg)
38-82 73.7
Etiology of heart failure? (%) lschemic heart disease Cardiomyopathy Valvular heart disease Hypertension Other Exercise capacity (seconds) All patients at entry Prior to randomization
83 (81) 62?
11
35-94
2 11.6
76.5
+- 13.3
66
69
22
25
17
8
10
12
2
4
445
+- 138
463
IF 141
446
-+ 128
468
-+ 140
*Data are presented as mean f standard deviation. ‘tSome patients had more than 1 cantributingfactorfor
heart failure.
RESULTS A total of 217 patients entered the study. Of these, 8 patients withdrew during the run-in period. After the run-in period, 107 patients were randomized to receive lisinopril and 102 patients were randomized to receive digoxin. The demographic data for the 2 randomized groups of patients are shown in Table I. Duration of exercise at the entry and run-in visits was found to be higher for the patients randomized to receive digoxin than for the patients randomized to lisinopril. As a guide, significance tests were carried out to compare the treatment groups at entry and run-in. Neither of these tests was significant at the 20% level (p > 0.2). During active treatment, the proportions of patients on low (5 mg), medium (10 mg), and high (20 mg) daily doses of lisinopril were 33, 44, and 23%, respectively. The corresponding proportions for the patients in the digoxin-treated group were 29, 44, and 27%, respectively. Thus, any imbalance between the 2 groups with regard to baseline exercise capacity does not appear to be reflected in any change in the relative proportions of the drug dosages used. The effects of lisinopril and digoxin treatments on exercise duration after 6 and 12 weeks of treatment are shown in Figure 2. After 6 weeks of treatment there was a significant improvement in mean exercise duration from run-in, for both the digoxin and lisinopril treatment groups. Digoxin treatment increased exercise duration by 18 seconds (p = 0.015) and lisinopril treatment increased exercise duration by 32 seconds (p = 0.0007). The
TMLE II Proportion of Patients with Changes in Exercise Capacity and NYHA Grading after 12 Weeks of Treatment Lisinopril or Digoxin Compared with Baseline
Exercise capacity Increased No change Decreased Before treatment NYHA grade II NYHA grade Ill After treatment NYHA grade I NYHA
grade
Lisinopril (%)
Digoxin (%)
66
56
9
II
NYHA grade III NYHA grade IV Change with treatment Improvement No change Deterioration
with
9
25
35
76 23
75 25
5 82
6 81
12
13
1
17
16
78 5
81 2
NYHA = New York Heart Association.
difference between the mean improvements on each of the treatments was small. Similarly, 12 weeks of randomized treatment with lisinopril or digoxin improved exercise capacity compared with their respective run-in values. Digoxin treatment increased exercise capacity by 29 seconds, and lisinopril treatment improved exercise capacity by 51 seconds compared with exercise capacity at baseline. This effect with digoxin was not statistically significant, but that for lisinopril was (p = 0.0027). Mean treatment difference at 12 weeks was 27 seconds. However, this difference did not reach significance (p = 0.081). After 12 weeks of treatment, 66% of patients improved their exercise time on lisinopril treatment compared with 56% on digoxin (Table II). The percentages of patients who showed decreased exercise capacity
I 5401 +-+
0
Weeks
6
12
on Lisinopril
” = 82
0
6
12
Weeks on Digoxin n = 82
FIGURE 2. The effect of llslnoprll or dlgoxln on exerclss capacity at the end of the run-In period and after 6 and 12 weeks oftreatment. Data see presented as mean -C standard devhtlon. There were 82 patients in each group. A SYMPOSIUM:
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TABLE III Effect of 12 Weeks of Treatment Digoxin on Arrhythmic Activity
with Lisinopril
Lisinopril (n = 78)
Digoxin (n = 70)
Patients with > 5 VEC/min (%) At end run-in After 12 weeks of treatment
10.2 6.4
12.8 10.0
Patients showing Decrease No change Increase
59 0 41
46 0 54
Patients with couplets (%) At end run-in After 12 weeks of treatment
69.2 68.0
65.7 55.7
Patients showing Decrease No change Increase
45 21 35
39 26 36
Patients with nonsustained VT (%) At end run-in After 12 weeks of treatment
35.9 23.1
31.4 25.7
Patients showing Decrease No change Increase
31 56 13
27 53 20
Arrhythmic Ventricular
ectopic
Activity
(59%), and 32 of 70 patients (46%) who received digoxin had a reduction in the hourly rate of ventricular ectopic counts from run-in to treatment week 12. There was no significant difference between lisinopril and digoxin for these proportions. Blood pressure: Blood pressure was unaffected by digoxin treatment. At the end of the run-in period, blood pressure was 133 + 18/82 * 9 mm Hg, and after 12 weeks of treatment, it was 135 or: 19/82 of: 9 mm Hg. Heart rate was similarly unaffected, decreasing from 83 * 12 beats/min at the end of the run-in period to 80 + 13 beats/min after 12 weeks of treatment with digoxin. On lisinopril treatment, blood pressure fell slightly but not significantly from 132 + 20/81 -+ 12 mm Hg at the end of the run-in period to 127 + 20/79 rt 11 mm Hg after 12 weeks of treatment. Heart rate was unchanged (82 ? 13 beats/min at run-in compared with 81 2 13 beats/min after 12 weeks of lisinopril treatment). NYHA grading: The proportion of patients with the different grades of heart failure before and after treatment with either lisinopril or digoxin is shown in Table II together with the proportion of patients on each treatment in whom changes in NYHA grade were seen. No differences were observed between treatments. Symptoms and signs of CHF: The percentage of patients in whom particular symptoms of heart failure were present at run-in and after 12 weeks of randomized treatment is shown in Figure 3. For the most part, the 2 treatments were indistinguishable, except possibly for edema, where a higher proportion of patients treated with digoxin (13%) appeared to experience a loss of the symptom,
or
(VECs)
counts
change
(%)
Couplets
Nonsustained
change
ventricular
(%)
tachycardia
change
(VT)
(%)
n = number of patients in analysis.
after 12 weeks of lisinopril or digoxin treatment were 25% and 35%, respectively. 24-Hour electrocardiographic monitoring: The proportion of patients who exhibited ventricular ectopic counts, couplets, and nonsustained ventricular tachycardia both before and after treatment with lisinopril or digoxin together with the percentage of patients in whom the frequency of arrhythmias changed on treatment are summarized in Table III. Of 78 patients who received lisinopril, 46 % 0 Paroxysmal Nocturnal Dyspnea Rales
Edema
Third Heart Sound
;
Orthopnea
Lisinopril
Jugular Venous Distension
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run-in
m
Lisinopril
0
Digoxin
run-in
m
Digoxin
12 weeks
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RGURE 3. Percentage of patients wRh symptoms of heart failure present at run-in and after l3 weeks of randomlzod treatment wtth llsinoprll and diioxln. The bars represent the percentage of patients In each treatment group In whom this sign or symptom was present at run-In and after l3 weeks of treatment. In the Ibinoprfl-treated group the percentage of patients with paroxysmal noctural dyspnea Increased after I2 weeks of treatment compared with the end run-In assessment.
TABLEV Incidence Weeks of Treatment
TABLE IV Adverse Events Reported in > 1% of Patients Randomized to Either Lisinopril or Digoxin Lisinopril (n = 107)
Death Cough Nausea Dizziness Fatigue Dyspnea Myocardial infarction Vertlgo Cardiac arrhythmias Hypotension Chest pain
Lisinopril (n = 107)
Digoxin (n = 102) %
n
1 12 3 4 2
0.9 11.2 2.8 3.7
3
2.9
1
1.0
3
2.8
6 4 3 1
5.9 3.9 2.9 1.0
n
of Deaths and Adverse Events During with Lisinopril or Digoxin
1.9
%
3
2.8
1
1.0
3
2.8
1
1.0
1
0.9
2
2.0
3
2.8
0
0.0
3
2.8
0
0.0
compared with a smaller number (4%) on lisinopril treatment. Adverse events: Adverse reactions were reported for 30 of 107 patients (28%) who received lisinopril and for 30 of 102 patients (29.4%) who received digoxin (Table IV). The most frequent adverse events reported for digoxin were nausea, dizziness, fatigue, and death. The pattern was different in the lisinopril group, with cough, dizziness, nausea, dyspnea, vertigo, myocardial infarction, hypotension, and chest pain being reported as the most frequent adverse events. One patient died during lisinopril treatment due to myocardial infarction and there were 3 deaths in the digoxin-treated group (due to myocardial infarction in 2 patients and sudden death in 1 patient). Withdrawals from therapy due to adverse reactions occurred for 9 out of 107 patients (8.4%) who received lisinopril and for 11 of 102 patients (10.7%) who received digoxin. Side effects leading to withdrawal are listed in Table V. There was no significant difference between lisinopril and digoxin with regard to the proportion of patients who withdrew due to adverse reactions. One patient withdrew from the study because of deterioration in the disease, and one patient failed to attend for evaluation in the digoxin group. Two patients in the lisinopril-treated group and two patients in the digoxin group withdrew from the study after randomization for reasons other than adverse reactions.
DISCUSSION
There was a small imbalance in the 2 treatment groups at randomization with regard to baseline exercise duration. However, it appears that this did
n Death Withdrawals Adverse events Leading to withdrawal Not leading to withdrawal
12
Digoxin (n = 102)
%
n
1
0.9
3
% 2.9
12
11.2
18
17.6
9 20
8.4
11
18.7
16
10.7 15.7
not interfere with the conduct of the study or with the overall conclusions of it. There was also a slight imbalance with regard to the proportion of men in the digoxin group (81%) compared with the lisinopril group (71%). This difference was not significant but a slightly higher proportion of men in the digoxin group might have contributed somewhat to the better run-in exercise time in the digoxin group. When added to background treatment with diuretics, the effect of 12 weeks of treatment with lisinopril or digoxin on exercise capacity were not significantly different. Both treatments improved exercise capacity after 6 weeks of treatment with respect to baseline but no significant difference between treatments was found. Thus, this study demonstrates a similar effect on exercise duration for both the ACE inhibitor and digoxin. In this regard this study is consistent with the majority of those previously reporting on comparisons of other ACE inhibitors and digoxin,5-9 and with a smaller, earlier study in which lisinopril and digoxin were compared.1° The data presented in Figure 2 suggest little improvement in exercise capacity was achieved with digoxin between weeks 6 and 12, perhaps implying that its initial effects may not be sustained. Exercise duration on digoxin was not significantly different after 12 weeks of treatment compared with the baseline value. Doubts have been expressed regarding the long-term efficacy of digoxin in heart failure and its value has been doubted in the presence of sinus rhythm. Although it now appears to be effective in the presence of good sinus function, its role is much clearer in the presence of atria1 fibrillation4 In this study, both lisinopril and digoxin treatment produced an improvement in exercise capacity in a similar proportion of patients and both treatments were also similar with regard to their effect on the global NYHA grading of patients. The addition of lisinopril or digoxin to baseline treatment with diuretics produced a reduction in the ectopic activity exhibited by some patients, but A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
8m
there was no significant difference between treatments for the hourly rates of ventricular ectopic counts, couplets, and nonsustained ventricular tachycardia after 12 weeks of treatment. Blood pressure did not decline significantly and heart rate was not affected by either of the 2 study treatments. These latter observations have been made previously for lisinopril (see Zannad et al and Bach and Zardini, elsewhere in this symposium), and it is reassuring that the ACE inhibitor treatment was not associated with a marked decrease in blood pressure. There was a more marked reporting of cough as a side effect to lisinopril in this study compared with other studies, in which lisinopril was compared to other ACE inhibitors (see Zannad et al and Bach and Zardini). This may suggest that cough may go relatively unrecognized during treatment with an ACE inhibitor, and its presence in the population is more clearly recognized when a non-ACE inhibitor comparator is used in the study. The design of the study, necessitating the withdrawal of any patient suspected of a side effect attributable to digoxin overdose rather than dose reduction, may have resulted in the withdrawal of some lisinopril-treated patients.
CONCLUSION The results of this study indicate that when added to diuretic treatment both lisinopril and digoxin improved exercise duration after 12 weeks of treatment with no significant difference between treatments. When compared with baseline values, there was a significant increase with lisinopril but not with digoxin. Both drugs can be safely added to diuretics in patients with mild to moderate heart failure. Lisinopril seems to be a useful alternative to digoxin in this clinical situation.
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APPENDIX Members of the study group were as follows. Sweden: J. Herlitz, B. Karlson (Goteborg); K. Boman, L. Wikstrom (Skelleftea); P-O Bengtsson, M. Freitag (Karlskrona); A. Rindner (Skene); J.E. Frisell (Ludvika); K-A Svensson (Ljungby); J. Jonsson, C. Nemeczek, (Varberg); B. Ritter, H. Wingman (Ostersund); S. Hansen, S. Ekdahl, (Eksjo); P. Lantz, J. Landelius (Uppsala); P. Srnedgard (Sk&de); D. Ursing, U. Ahremark (Angelholm). Denmark: S.L. Rasmussen, R. Videbaek (Hvidovre); E. Vigholt (Aarhus). Austria: H. Mayr, J. Bergler-Klein (Vienna); W. Klein, J. Dusleag (Graz). Spain: L.M. Elbal, C. Saenza de la Calzada (Madrid); F. Algarra (Valencia). United Kingdom: R. Wray (Hastings). REFERENCES 1. Ryden L. When and how to use angiotensti-converting enqme inhibition in congestive heart failure. Am J Cardiol1988;62:7SA-8OA. 2. Riegger AJG. ACE inhibitors in congestive heart failure. Caniiology 1989; 76(suppl2):42-49. 3.McMurray J, Lang CC, Maclean DD, McDevitt DG, Struthers AD. A survey of current use of angiotensin converting enzyme inhibitors by Scottish physicians in the treatment of chronic cardiac failure. SC& Med .I 1989;34:425427. 4. Lewis RP. Digitalis: A drug that refuses to die. Crit Care Med
i99O;lS:SSs13. 5. AIicandri C, Fariello R, Boni E, Zanineli A, Muiesan G. Comparison of captopril and digoxin in mild to moderate heart failure. Postgmd A4ed J 1986; 62(suppl 1):17@175. 6. Captopri-Digoxin Multicentre Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JM1988;259(suppl4):539-544. 7. Heck I, Miiller HM, Esser H, Liideritz B. CaptopriI versus dig&n in der behandhmg der leichten bis mittelschweren Herzinsuflizienz. D?.K!I Med Wochenschr 1989;114:695-699. 6. Mantes Orbe PM, Ormaetxe JM, Martinez JD, Rodriguez E, Ruiz de Azua E, Iriarte MM. Fun&n ventricular derecha y tolerancia al esfuerzo en 10s pacientes con insuficiencia cardiaca congestiva cr6nica. Estudio cruzado a doble ciego. Rev Esp Cardiol 1990;43:137-141. 9. Beaune J for Enalapril Versus Digoxin French Multicentre Study Group. Comparison of enalapril versus digoxin for congestive heart failure. Am J Cardiol1989;63:22D-2SD. 10. Galinier M, Bounhoure J-P. Efficacy and tolerance of lisinopril versus digoxin in congestive heart failure. In: Nicholls MG, ed. A Focus on the Clinical Effects on a Long-Acting ACE Inhibitor/Heart Failure. New York: Raven Press, 1990:23-30.
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lisinopril5-20 mg once daily was compared with diioxin 0.l25-0.375 mg once daily in a doubleblind, randomized, parallel-group study hwolving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades IHII) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, diioxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistiilly significant (p = 0.1343). After 12 weeks, diioxin and liiinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of diioxin compared with the baseline value was not significant but that for liiinopril was (p = 0.0027). 7he diirence between treatments approached statistiil signiicame (p = 0.0613). There was no difference between liiinopril and diioxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic bkuxl pressure were consistently lower in the lisinopril group througliout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both llsinopril and diioxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for diioxln). Withdrawals from treatment were of a similar frequency for both treatments. lt is concluded that liiinopril may be a useful alternative to digitalis
in patients with heart failure who remain symptomatic on diuretic therapy. (Am J Cardiol1992370:64C-9OC)
F
or some years, angiotensin-converting enzyme (ACE) inhibitors have been recognized as being effective in the management of congestive heart failure (CHF) when added to previous therapy with optimum doses of digitalis and diuretics.‘J Currently, there is increasing interest in the possibility that ACE inhibitors may be used earlier in the treatment of CHF.3 However, in order to replace traditional first-line therapy of CHF, ACE inhibitors must be established to be superior to, or at least as effective as, the current first-line agents, digitalis or diuretics. Digitalis has a narrow therapeutic ratio and there is a consequent risk of digitalis toxicity especially in the elderly.4 Several studies have compared digitalis and ACE inhibitors in the treatment of mild heart failure.5-10 The studies concerning the short-acting ACE inhibitor captopril have shown comparable or slightly greater exercise capacity with the ACE inhibitor than with digitalis.5-8 Single studies comparing enalapril versus digoxin and lisinopril versus digoxin indicate similar results.9J0 The principal aim of this study was to compare the effects of the long-acting ACE inhibitor lisinopril with the effects of digoxin on exercise capacity in patients with mild-to-moderate CHF who were already receiving optimum doses of diuretics. A secondary aim was to examine the effects of lisinopril and digoxin on the spectrum of arrhythmias seen in patients with mild-to-moderate CHF.
METHODS Patients:
From the Division of Cardiology, Sahlgrenska Hospital, Gothenburg, Sweden. Address for reprints: Johan Herlitz, MD, Division of Cardiology, Sahlgrenska Hospital, S-41345 Gothenburg, Sweden.
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Study Group
Following informed consent patients were recruited for this study at 21 centers in 5 countries: Denmark (2) Sweden (12) Spain (3) United Kingdom (1) Austria (3). Male or female OCTOBER
8, 1992
patients >21 years old with the clinical signs and symptoms of CHF of New York Heart Association (NYHA) grades II and III were considered eligible for entry into the study. The diagnosis of CHF was based on clinical signs and symptoms supported by the use of chest radiograph, radioisotope scan or echocardiography. Criteria for inclusion were age > 21 years, either sex, clinical signs and symptoms of CHF, NYHA grade II or III, cardiothoracic ratio > 0.5 or ejection fraction 160 mm Hg; right heart failure; fixed rate cardiac pacemaker fitted; atria1 fibrillation or other arrhythmias requiring therapy; history of liver, blood, or endocrine disorders; clinically important renal disorder and abnormal serum potassium; history of drug or alcohol abuse; and hypersensitivity or other contraindications to ACE inhibitors or digoxin. All patients were maintained on stable doses of diuretics. The study was conducted in accordance with the Declaration of Helsinki, and local ethical committee approval was obtained. Study design: Lisinopril and digoxin were compared using a double-blind, parallel-group, randomized, multicenter study design, which is depicted in Figure 1. A double-dummy technique was used to maintain blindness. The study incorporated a baseline period of lo-14 days, during which time the diuretic dosage was optimized in the absence of vasodilator therapy. Patients were then randomized to either lisinopril or digoxin for 12 weeks. At randomization, all patients received a test dose of lisinopril (2.5 mg). Symptoms reported or experi-
enced by the patients were fully documented. Those randomized to lisinopril thereafter received lisinopril 5 mg once daily for 2 weeks initially. Those patients randomized to receive digoxin received 0.125 mg once daily for 2 weeks initially. If, after 2 weeks of the randomized treatment, there was evidence of clinical improvement, the patient continued on that dosage. An increase in the dosage of study medication was considered after 2 weeks of randomized treatment, and again after a further 2 weeks of randomized treatment. The dose was increased if, in the opinion of the investigator, there was evidence of a need for an additional effect and provided that the following 2 safety conditions were met: standing systolic blood pressure was 290 mm Hg and there were no symptoms of hypotension (syncope, faintness, orthostatic effects, dizziness) on the current dose. When an increase in the dosage of study medication was indicated, lisinopril dosage was first increased to 10 mg once daily and finally to a maximum of 20 mg once daily. The dosage of lisinopril was reduced at any relevant visit if the patient exhibited symptomatic hypotension or any other adverse event. An increase in the dosage of digoxin to 0.250 mg once daily was considered after 2 weeks of randomized treatment if there was need for further efficacy and the previously mentioned safety conditions were met. If, after a further 2 weeks of treatment, the dosage of digoxin warranted an increase, the dosage was increased to a maximum of 0.375 mg once daily. This dosage of digoxin was not considered appropriate for patients aged >65 years or those weighing < 50 kg. As a consequence, these patients were not given the highest dose of digoxin or lisinopril permitted in the protocol, i.e., no more than 0.250 mg of digoxin. If a side effect appeared that was believed to be attributable to overdosage of digoxin, the dose could not be reduced, but rather the patient was withdrawn from the study,
LISINOPRIL I Smgod
FIGURE 1. Schematic representation of the study design and dose titration schedule. od = once daily.
1
Optimization of diuretic
5-10mgod
1
5-2Omgod
1
5-20mgod
Concurrent therapy: Diuretics
10.14days
1 0.1’25-0.250mg od 1 0,125.0.375mg od 1 0.12%0.375mg od
2
4
6
12
DIGOXIN
A SYMPOSIUM:
HEART
FAILURE
MANAGEMENT
8=
without breaking the double-blinded nature of the treatment. Concurrent medication: During the randomized phase of the study, the aim was to maintain patients on the same or similar regimen of diuretics as they received during the baseline period. However, the diuretic dose could be adjusted during the randomized treatment phase if needed, based on the clinical assessment. The morning dose of diuretic was withheld on the day the patient received the test dose of lisinopril and potassium-sparing diuretics were not permitted during the study. If a patient developed hypokalemia, potassium supplements were administered with monitoring of serum levels. Chronic nitrate therapy, when used, was kept constant, and additional sublingual nitroglycerin was permitted as required. No other drugs known to affect preload or afterload were allowed. A complete physical exClinical assessment: amination of each patient was conducted at the time of entry into the study. An abbreviated symptom review and physical examination was performed at randomization and at the end of 12 weeks of randomized treatment. Exercise testing was performed using an electrically braked bicycle ergometer, and followed a schedule with continuous incremental work loads. All patients underwent a bicycle exercise test on 2 separate occasions during the placebo run-in, prior to entry into the randomized treatment phase of the study. The first exercise test served as a familiarization procedure for the patient. The second exercise test enabled the duration of exercise to be determined. If the duration of the 2 exercise tests differed by more than 2 minutes, a third test was required before proceeding to randomization. Exercise tests were also carried out after 6 and 12 weeks of randomized treatment. Patients undertook each exercise test at the same time of day (preferably in the morning), and medication was delayed on the day of the exercise test until measurements were complete. Blood pressure was measured at each clinical visit on the same arm, using a mercury sphygmomanometer. Heart rate was measured on each visit by palpation of the radial pulse over a 30-second period. Recordings of blood pressure and heart rate were made after the patient had been standing for 2 minutes. Classification of the patient according to the NYHA criteria was done by the same observer at the end of the placebo run-in period and again after 12 weeks of randomized treatment. Holter monitoring was performed for a 24-hour period during placebo run-in and during the last week of randomized treatment using a 2-channel 86c
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Holter monitor. Analysis of all the 24-hour tapes was performed electronically by Hertford Medical (Hertford, UK). Only data from patients with at least 8 hours of monitoring for the run-in and end of treatment examinations were summarized and analyzed. Blood samples were obtained at entry to the study and after 12 weeks of randomized treatment for hematology and biochemical assessments. Blood samples were taken after 2, 4, and 6 weeks of randomized treatment for biochemical assessment only. Full blood count and an estimation of urea, sodium, potassium and creatinine were carried out. Reports of side effects were elicited at each visit after the start of the placebo run-in period using a nonleading question, and the nature and severity of any symptoms reported were noted. Patients were asked to bring any unused tablets with them at each visit to assess compliance. Patients with evidence of tablet consumption < 50% or > 150% of the prescribed dose were considered to have deviated from the study protocol. Statistical analysis: It was calculated that 172 patients (86 per group) would be required to detect a mean difference between treatments in exercise duration of 60 seconds. This calculation was made at the 5% level of significance, with 90% power and using a standard deviation of 120 seconds. To allow for withdrawals from the study, it was intended that 250 patients (125 per group) would take part in the study. Analysis of covariance was used to compare lisinopril and digoxin for the change in exercise duration from the run-in visit to treatment week 6 and the change from the run-in visit to that at treatment week 12. The results reported below are based on an analysis of data from patients for whom complete data were available both at run-in and after 12 weeks of treatment (completers analysis). The analyses have been reported with respect to the comparison between lisinopril and digoxin using the t-test. The proportion of patients in each treatment group with a reduction in the hourly rate of ventricular ectopic counts after 12 weeks of treatment was compared between lisinopril and digoxin using Fisher’s exact test. The proportion of patients with adverse reactions and the proportion who withdrew due to adverse reactions were compared between lisinopril and digoxin using Fisher’s exact test. Because these analyses were concerned with treatment safety, all randomized patients were included in this analysis. OCTOBER
8, 1992
TABLE I Demographic Variables of the Study Population Randomized to Either Lisinopril or Digoxin Therapy* Lisinopril
Digoxin
No. patients Females (%) Males (%)
107 31 (29)
102 19 (19)
Mean age (yr)
63 k 10
76 (71)
Age range (yr) Body weight (kg)
38-82 73.7
Etiology of heart failure? (%) lschemic heart disease Cardiomyopathy Valvular heart disease Hypertension Other Exercise capacity (seconds) All patients at entry Prior to randomization
83 (81) 62?
11
35-94
2 11.6
76.5
+- 13.3
66
69
22
25
17
8
10
12
2
4
445
+- 138
463
IF 141
446
-+ 128
468
-+ 140
*Data are presented as mean f standard deviation. ‘tSome patients had more than 1 cantributingfactorfor
heart failure.
RESULTS A total of 217 patients entered the study. Of these, 8 patients withdrew during the run-in period. After the run-in period, 107 patients were randomized to receive lisinopril and 102 patients were randomized to receive digoxin. The demographic data for the 2 randomized groups of patients are shown in Table I. Duration of exercise at the entry and run-in visits was found to be higher for the patients randomized to receive digoxin than for the patients randomized to lisinopril. As a guide, significance tests were carried out to compare the treatment groups at entry and run-in. Neither of these tests was significant at the 20% level (p > 0.2). During active treatment, the proportions of patients on low (5 mg), medium (10 mg), and high (20 mg) daily doses of lisinopril were 33, 44, and 23%, respectively. The corresponding proportions for the patients in the digoxin-treated group were 29, 44, and 27%, respectively. Thus, any imbalance between the 2 groups with regard to baseline exercise capacity does not appear to be reflected in any change in the relative proportions of the drug dosages used. The effects of lisinopril and digoxin treatments on exercise duration after 6 and 12 weeks of treatment are shown in Figure 2. After 6 weeks of treatment there was a significant improvement in mean exercise duration from run-in, for both the digoxin and lisinopril treatment groups. Digoxin treatment increased exercise duration by 18 seconds (p = 0.015) and lisinopril treatment increased exercise duration by 32 seconds (p = 0.0007). The
TMLE II Proportion of Patients with Changes in Exercise Capacity and NYHA Grading after 12 Weeks of Treatment Lisinopril or Digoxin Compared with Baseline
Exercise capacity Increased No change Decreased Before treatment NYHA grade II NYHA grade Ill After treatment NYHA grade I NYHA
grade
Lisinopril (%)
Digoxin (%)
66
56
9
II
NYHA grade III NYHA grade IV Change with treatment Improvement No change Deterioration
with
9
25
35
76 23
75 25
5 82
6 81
12
13
1
17
16
78 5
81 2
NYHA = New York Heart Association.
difference between the mean improvements on each of the treatments was small. Similarly, 12 weeks of randomized treatment with lisinopril or digoxin improved exercise capacity compared with their respective run-in values. Digoxin treatment increased exercise capacity by 29 seconds, and lisinopril treatment improved exercise capacity by 51 seconds compared with exercise capacity at baseline. This effect with digoxin was not statistically significant, but that for lisinopril was (p = 0.0027). Mean treatment difference at 12 weeks was 27 seconds. However, this difference did not reach significance (p = 0.081). After 12 weeks of treatment, 66% of patients improved their exercise time on lisinopril treatment compared with 56% on digoxin (Table II). The percentages of patients who showed decreased exercise capacity
I 5401 +-+
0
Weeks
6
12
on Lisinopril
” = 82
0
6
12
Weeks on Digoxin n = 82
FIGURE 2. The effect of llslnoprll or dlgoxln on exerclss capacity at the end of the run-In period and after 6 and 12 weeks oftreatment. Data see presented as mean -C standard devhtlon. There were 82 patients in each group. A SYMPOSIUM:
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MANAGEMENT
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TABLE III Effect of 12 Weeks of Treatment Digoxin on Arrhythmic Activity
with Lisinopril
Lisinopril (n = 78)
Digoxin (n = 70)
Patients with > 5 VEC/min (%) At end run-in After 12 weeks of treatment
10.2 6.4
12.8 10.0
Patients showing Decrease No change Increase
59 0 41
46 0 54
Patients with couplets (%) At end run-in After 12 weeks of treatment
69.2 68.0
65.7 55.7
Patients showing Decrease No change Increase
45 21 35
39 26 36
Patients with nonsustained VT (%) At end run-in After 12 weeks of treatment
35.9 23.1
31.4 25.7
Patients showing Decrease No change Increase
31 56 13
27 53 20
Arrhythmic Ventricular
ectopic
Activity
(59%), and 32 of 70 patients (46%) who received digoxin had a reduction in the hourly rate of ventricular ectopic counts from run-in to treatment week 12. There was no significant difference between lisinopril and digoxin for these proportions. Blood pressure: Blood pressure was unaffected by digoxin treatment. At the end of the run-in period, blood pressure was 133 + 18/82 * 9 mm Hg, and after 12 weeks of treatment, it was 135 or: 19/82 of: 9 mm Hg. Heart rate was similarly unaffected, decreasing from 83 * 12 beats/min at the end of the run-in period to 80 + 13 beats/min after 12 weeks of treatment with digoxin. On lisinopril treatment, blood pressure fell slightly but not significantly from 132 + 20/81 -+ 12 mm Hg at the end of the run-in period to 127 + 20/79 rt 11 mm Hg after 12 weeks of treatment. Heart rate was unchanged (82 ? 13 beats/min at run-in compared with 81 2 13 beats/min after 12 weeks of lisinopril treatment). NYHA grading: The proportion of patients with the different grades of heart failure before and after treatment with either lisinopril or digoxin is shown in Table II together with the proportion of patients on each treatment in whom changes in NYHA grade were seen. No differences were observed between treatments. Symptoms and signs of CHF: The percentage of patients in whom particular symptoms of heart failure were present at run-in and after 12 weeks of randomized treatment is shown in Figure 3. For the most part, the 2 treatments were indistinguishable, except possibly for edema, where a higher proportion of patients treated with digoxin (13%) appeared to experience a loss of the symptom,
or
(VECs)
counts
change
(%)
Couplets
Nonsustained
change
ventricular
(%)
tachycardia
change
(VT)
(%)
n = number of patients in analysis.
after 12 weeks of lisinopril or digoxin treatment were 25% and 35%, respectively. 24-Hour electrocardiographic monitoring: The proportion of patients who exhibited ventricular ectopic counts, couplets, and nonsustained ventricular tachycardia both before and after treatment with lisinopril or digoxin together with the percentage of patients in whom the frequency of arrhythmias changed on treatment are summarized in Table III. Of 78 patients who received lisinopril, 46 % 0 Paroxysmal Nocturnal Dyspnea Rales
Edema
Third Heart Sound
;
Orthopnea
Lisinopril
Jugular Venous Distension
8%
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run-in
m
Lisinopril
0
Digoxin
run-in
m
Digoxin
12 weeks
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RGURE 3. Percentage of patients wRh symptoms of heart failure present at run-in and after l3 weeks of randomlzod treatment wtth llsinoprll and diioxln. The bars represent the percentage of patients In each treatment group In whom this sign or symptom was present at run-In and after l3 weeks of treatment. In the Ibinoprfl-treated group the percentage of patients with paroxysmal noctural dyspnea Increased after I2 weeks of treatment compared with the end run-In assessment.
TABLEV Incidence Weeks of Treatment
TABLE IV Adverse Events Reported in > 1% of Patients Randomized to Either Lisinopril or Digoxin Lisinopril (n = 107)
Death Cough Nausea Dizziness Fatigue Dyspnea Myocardial infarction Vertlgo Cardiac arrhythmias Hypotension Chest pain
Lisinopril (n = 107)
Digoxin (n = 102) %
n
1 12 3 4 2
0.9 11.2 2.8 3.7
3
2.9
1
1.0
3
2.8
6 4 3 1
5.9 3.9 2.9 1.0
n
of Deaths and Adverse Events During with Lisinopril or Digoxin
1.9
%
3
2.8
1
1.0
3
2.8
1
1.0
1
0.9
2
2.0
3
2.8
0
0.0
3
2.8
0
0.0
compared with a smaller number (4%) on lisinopril treatment. Adverse events: Adverse reactions were reported for 30 of 107 patients (28%) who received lisinopril and for 30 of 102 patients (29.4%) who received digoxin (Table IV). The most frequent adverse events reported for digoxin were nausea, dizziness, fatigue, and death. The pattern was different in the lisinopril group, with cough, dizziness, nausea, dyspnea, vertigo, myocardial infarction, hypotension, and chest pain being reported as the most frequent adverse events. One patient died during lisinopril treatment due to myocardial infarction and there were 3 deaths in the digoxin-treated group (due to myocardial infarction in 2 patients and sudden death in 1 patient). Withdrawals from therapy due to adverse reactions occurred for 9 out of 107 patients (8.4%) who received lisinopril and for 11 of 102 patients (10.7%) who received digoxin. Side effects leading to withdrawal are listed in Table V. There was no significant difference between lisinopril and digoxin with regard to the proportion of patients who withdrew due to adverse reactions. One patient withdrew from the study because of deterioration in the disease, and one patient failed to attend for evaluation in the digoxin group. Two patients in the lisinopril-treated group and two patients in the digoxin group withdrew from the study after randomization for reasons other than adverse reactions.
DISCUSSION
There was a small imbalance in the 2 treatment groups at randomization with regard to baseline exercise duration. However, it appears that this did
n Death Withdrawals Adverse events Leading to withdrawal Not leading to withdrawal
12
Digoxin (n = 102)
%
n
1
0.9
3
% 2.9
12
11.2
18
17.6
9 20
8.4
11
18.7
16
10.7 15.7
not interfere with the conduct of the study or with the overall conclusions of it. There was also a slight imbalance with regard to the proportion of men in the digoxin group (81%) compared with the lisinopril group (71%). This difference was not significant but a slightly higher proportion of men in the digoxin group might have contributed somewhat to the better run-in exercise time in the digoxin group. When added to background treatment with diuretics, the effect of 12 weeks of treatment with lisinopril or digoxin on exercise capacity were not significantly different. Both treatments improved exercise capacity after 6 weeks of treatment with respect to baseline but no significant difference between treatments was found. Thus, this study demonstrates a similar effect on exercise duration for both the ACE inhibitor and digoxin. In this regard this study is consistent with the majority of those previously reporting on comparisons of other ACE inhibitors and digoxin,5-9 and with a smaller, earlier study in which lisinopril and digoxin were compared.1° The data presented in Figure 2 suggest little improvement in exercise capacity was achieved with digoxin between weeks 6 and 12, perhaps implying that its initial effects may not be sustained. Exercise duration on digoxin was not significantly different after 12 weeks of treatment compared with the baseline value. Doubts have been expressed regarding the long-term efficacy of digoxin in heart failure and its value has been doubted in the presence of sinus rhythm. Although it now appears to be effective in the presence of good sinus function, its role is much clearer in the presence of atria1 fibrillation4 In this study, both lisinopril and digoxin treatment produced an improvement in exercise capacity in a similar proportion of patients and both treatments were also similar with regard to their effect on the global NYHA grading of patients. The addition of lisinopril or digoxin to baseline treatment with diuretics produced a reduction in the ectopic activity exhibited by some patients, but A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
8m
there was no significant difference between treatments for the hourly rates of ventricular ectopic counts, couplets, and nonsustained ventricular tachycardia after 12 weeks of treatment. Blood pressure did not decline significantly and heart rate was not affected by either of the 2 study treatments. These latter observations have been made previously for lisinopril (see Zannad et al and Bach and Zardini, elsewhere in this symposium), and it is reassuring that the ACE inhibitor treatment was not associated with a marked decrease in blood pressure. There was a more marked reporting of cough as a side effect to lisinopril in this study compared with other studies, in which lisinopril was compared to other ACE inhibitors (see Zannad et al and Bach and Zardini). This may suggest that cough may go relatively unrecognized during treatment with an ACE inhibitor, and its presence in the population is more clearly recognized when a non-ACE inhibitor comparator is used in the study. The design of the study, necessitating the withdrawal of any patient suspected of a side effect attributable to digoxin overdose rather than dose reduction, may have resulted in the withdrawal of some lisinopril-treated patients.
CONCLUSION The results of this study indicate that when added to diuretic treatment both lisinopril and digoxin improved exercise duration after 12 weeks of treatment with no significant difference between treatments. When compared with baseline values, there was a significant increase with lisinopril but not with digoxin. Both drugs can be safely added to diuretics in patients with mild to moderate heart failure. Lisinopril seems to be a useful alternative to digoxin in this clinical situation.
9oc
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APPENDIX Members of the study group were as follows. Sweden: J. Herlitz, B. Karlson (Goteborg); K. Boman, L. Wikstrom (Skelleftea); P-O Bengtsson, M. Freitag (Karlskrona); A. Rindner (Skene); J.E. Frisell (Ludvika); K-A Svensson (Ljungby); J. Jonsson, C. Nemeczek, (Varberg); B. Ritter, H. Wingman (Ostersund); S. Hansen, S. Ekdahl, (Eksjo); P. Lantz, J. Landelius (Uppsala); P. Srnedgard (Sk&de); D. Ursing, U. Ahremark (Angelholm). Denmark: S.L. Rasmussen, R. Videbaek (Hvidovre); E. Vigholt (Aarhus). Austria: H. Mayr, J. Bergler-Klein (Vienna); W. Klein, J. Dusleag (Graz). Spain: L.M. Elbal, C. Saenza de la Calzada (Madrid); F. Algarra (Valencia). United Kingdom: R. Wray (Hastings). REFERENCES 1. Ryden L. When and how to use angiotensti-converting enqme inhibition in congestive heart failure. Am J Cardiol1988;62:7SA-8OA. 2. Riegger AJG. ACE inhibitors in congestive heart failure. Caniiology 1989; 76(suppl2):42-49. 3.McMurray J, Lang CC, Maclean DD, McDevitt DG, Struthers AD. A survey of current use of angiotensin converting enzyme inhibitors by Scottish physicians in the treatment of chronic cardiac failure. SC& Med .I 1989;34:425427. 4. Lewis RP. Digitalis: A drug that refuses to die. Crit Care Med
i99O;lS:SSs13. 5. AIicandri C, Fariello R, Boni E, Zanineli A, Muiesan G. Comparison of captopril and digoxin in mild to moderate heart failure. Postgmd A4ed J 1986; 62(suppl 1):17@175. 6. Captopri-Digoxin Multicentre Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JM1988;259(suppl4):539-544. 7. Heck I, Miiller HM, Esser H, Liideritz B. CaptopriI versus dig&n in der behandhmg der leichten bis mittelschweren Herzinsuflizienz. D?.K!I Med Wochenschr 1989;114:695-699. 6. Mantes Orbe PM, Ormaetxe JM, Martinez JD, Rodriguez E, Ruiz de Azua E, Iriarte MM. Fun&n ventricular derecha y tolerancia al esfuerzo en 10s pacientes con insuficiencia cardiaca congestiva cr6nica. Estudio cruzado a doble ciego. Rev Esp Cardiol 1990;43:137-141. 9. Beaune J for Enalapril Versus Digoxin French Multicentre Study Group. Comparison of enalapril versus digoxin for congestive heart failure. Am J Cardiol1989;63:22D-2SD. 10. Galinier M, Bounhoure J-P. Efficacy and tolerance of lisinopril versus digoxin in congestive heart failure. In: Nicholls MG, ed. A Focus on the Clinical Effects on a Long-Acting ACE Inhibitor/Heart Failure. New York: Raven Press, 1990:23-30.
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