287
Internationai Journal of Cardiology, 31 (1991) 287-294 0 1991 Elsevier Science Publishers B.V. 0167-5273/91/$03.50 ADONIS 016752739100139X
CARD10
01260
First dose hypotension J. Hasford
r, W.-D.
Bussmann
with enalapril and prazosin heart failure *, W. Delius
3, W. Koepcke
4, K. Lehmann
in congestive 5 and
E. Weber
6
’ Biometric Centrefor Therapeutic Studies, Munich; ’ Department of Cardiology, Johann Wolfgang Goethe- Universittit. Frankfurt; 3 Department of Cardiology and Pulmonology of the Sttidtische Krankenhaus Miinchen-Bogenhausen, Munich; 4 Institute for Medical Informatics, Statistics and Biomathematics, Ludwig-Maximilians-Universitat, Munich; ’ Clinical Research, Merck, Sharp & Dohme GmbH, Munich; 6 Department of Clinical Pharmacology of the Ruprecht-Karls-Universitdt, Heidelberg, F.R.G. (Received
Hasford enalapril
J, Bussmann W-D, Delius and prazosin in congestive
3 August
1990; revision accepted
27 January
1991)
W, Koepcke W, Lehmann K, Weber E. First dose hypotension heart failure. Int J Cardiol 1991;31:287-294.
with
Since the introduction of angiotensin converting enzyme inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the augiotensin converting enzyme inhibitor enalapril a multicenter, open, randomized, prazosin-controlled trial was designed comparing the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 mg prazosin. Subjects were 1210 inpatients with New York Heart Association functional class (I)/11 and III who were not adequately compensated with digitalis and/or diuretics. In the group receiving enalapril, 3 patients (0.5%) experienced severe hypotension on day 1 and 28 patients (4.7%) moderate hypotension. In those given prazosin, 15 patients (2.6%) experienced severe hypotension and 60 patients (10.3%) moderate hypotension. The difference is statistically significant (P Q 0.000012). All patients recovered. It was concluded that treatment of patients suffering from congestive heart failure New York Heart Association functional class (I)/11 or III with enalapril is comparably well tolerated. Key words: Angiotensin converting tive heart failure; Hypotension
enzyme
inhibitors;
Introduction Angiotensin converting enzyme inhibitors are established drugs for the treatment of patients with hypertension or congestive heart failure. Soon
Correspondence to: J. Hasford, M.D., Biometric Centre for Therapeutic Studies (BZT), Pettenkoferstr. 35, D-8000 Munich 2. F.R.G.
Enalapril;
Blocker,
a-receptor;
Prazosin;
Conges-
after these inhibitors were introduced into regimes using adjunctive treatment of patients with congestive heart failure, however, concern grew about their safety, as some investigators reported the occurrence of symptomatic hypotension, especially on the first day of treatment [l-4]. As a result, regulatory drug agencies in some countries strongly recommended that treatment of patients with congestive heart failure by means of inhibi-
tors of angiotensin converting enzyme should be initiated only in hospital. The literature, however, does not provide valid and reliable estimates of the incidence and severity of hypotension. largely because reports are based upon small or selected samples [lLlO]. To determine the incidence and severity of hypotension in a population of patients with congestive heart failure being treated with the angiotensin converting enzyme inhibitor enalapril, a randomized trial was designed to assess the safety of enalapril especially when given on the first day of treatment. It was compared with another widely used vasodilator. namely, prazosin.
Patients and Methods Male and female patients over 18 years of age who had congestive heart failure with the second and third classes of the New York Heart Association. and who were not adequately compensated with digitalis and/or diuretics, were eligible for enrollment in this trial. Exclusion criteria for the trial were: New York Heart Association functional class IV: confinement to bed; systolic blood < 90 mmHg; pretreatment with either pressure trial medication; and all labelled contraindications of prazosin and enalapril. Patients in this trial had either to be inpatients, or else were admitted to the hospital. The primary endpoint was incidence of symptomatic hypotension on the first day of treatment. Secondary endpoints were: type and incidence of adverse events not related to hypotension on the first day of treatment, and during the optional two week follow-up period: and the incidence of symptomatic hypotension during the period of follow-up. The severity of hypotension was classified according to the clinical symptomatology, as outlined below: mild: drop in systolic or diastolic blood pressure without symptoms; moderate: drop in systolic or diastolic blood pressure with moderate symptoms like dizziness, buzzing in the ear, headache or fatigue: severe: as above, but with severe symptoms like fainting, collapse, angina pectoris, heart fibrillation, myocardial infarction, stroke or renal failure. A special form, which included a checklist and
space for documentation of adverse events, was used for collection of data. To provide for uniform classification, unclear cases were assessed by two independent cardiologists (W.-D.B., W.D.) who were not aware of the treatment assignment. Prior to administration of medication, the history was taken and a general work-up done, which included relevant laboratory parameters. Pre-existent risk factors, co-medication (particularly pretreatment with diuretics), low blood pressure, severity of congestive heart failure, and concomitant disorders were carefully noted. The administration of diuretics had to be withheld, or to be substantially reduced, one to two days prior to the first administration of the trial medication. Further vasodilators were not allowed. Concomitant therapy with digitalis and treatments for accompanying diseases could be maintained unchanged. At 8 a.m. on the first day of therapy, patients were given l/2 tablet of the medication under study (equivalent to 2.5 mg enalapril or 0.5 mg prazosin). Twice prior to intake of medication, and hourly for 8 hours thereafter, blood pressure and pulse rate were taken on each patient while seated and after standing for 5 minutes. Blood pressure was always taken on the right arm. Examinations were done under in-hospital conditions in cardiology units. If no adverse events occurred on the first day, the dosage was gradually titrated. As a rule. the maintenance dosage for enalapril was 10 mg/day and for prazosin 4 mg/day. The trial was designed in randomized, multicentric, two armed, and open fashion. Randomization was done centrally by telephone. The required sample size was estimated with the assumptions: p, = 7.5%, pz = 15%. 5% drop-out rate, cx< 0.01. ,f3< 0.10. The result was a sample size of 600 patients per treatment group, which ensured a 95%) probability of observing at least once an adverse event with an incidence of 1 : 200 applications. Continuous variables were analyzed by ttests. and discrete data by the chi-square-test. Analysis for potentially prognostic factors was done by logistic regression. The data processing and all statistical analyses were done exclusively by the independent Biometric Centre for Therapeutic Studies, Munich (W.K., J.H.).
289
The trial was carried out in accordance declaration of Helsinki/Tokyo.
with the
TABLE
1
Baseline
data.
Results A total of 1210 patients were enrolled in the trial from 101 hospitals; 607 patients were allocated to enalapril and 603 patients to prazosin. Eight patients receiving enalaprii and 16 of those given prazosin did not receive any trial medication due to the sudden occurrence of serious diseases like cerebrovascular accident or lung edema; their own refusal; systolic blood pressure less than 90 mmHg; and sudden discharge from hospital. Four patients assigned to prazosin received enalapril; they experienced no adverse events and were excluded from further analyses. Exclusion criteria were not properly applied to 11 patients, (8 having enalapril and 3 prazosin) whose blood pressure could not be measured in an upright position for medical reasons. As the major purpose of this trial was the evaluation of the safety of the respective therapies, these 11 patients were not excluded. Thus, all patients who had received the randomly allocated therapy (599 enalapril, 583 prazosin) are included in this report. An analysis for structural homogeneity of groups did not reveal any relevant differences (Table 1) between patients in the groups receiving enalapril and prazosin. Fifty-four percent of the patients were male and mean age was 68.4 years. Of the patients, 3.7% were in class I of the New York Heart Association, 39.4% were in functional class II, while 56.9% fell within the third functional class. Digitalis was administered to 79.7% of the patients and 76.4% were treated with diuretics.
Enalapril (n = 599)
Prazosin (n ==583)
Sex (female) Body weight (kg) Age (years)
45.6% 73.5 k 14.1 69.0*11.4
46.9% 73.4 + 14.9 67.8+11.0
Severity of CHF NYHA I NYHA II NYHA III
4.3% 40.3% 55.4%
3.1% 38.4% 58.5%
Etiology of CHF Coronary heart disease Myocardial infarction Cardiomyopathy Hypertension
60.2% 26.0% 12.0% 43.7%
61.5% 26.2% 11.1% 38.7%
77.6% 75.1% 68.5
81.8% 77.7% 68.2
8.8% 27.1%
7.9% 28.8%
147*26/ 85 *14 143 f 27/ 85 +14
144+25/ 83 +13 141+ 26/ 83 *13
8Oi13 86+14
80&13 86+_14
Comedication Digitalis Diuretics Furosemide (mg mean dose) Concurrent disorders Renal failure Diabetes mellitus Blood pressure seated (mmHg) standing
(mmHg)
Heart rate (beats per min) seated standing Laboratory data Potassium (mmoI/l) Sodium (mmol/l) Creatinine (p mol/l) CHF = congestive
4.24 k 0.47 139.3 * 12.2 97.3 f 38.1
4.23 f 0.46 139.8 jz 9.2 97.3 k 32.7
heart failure.
Primary endpoint In those given enalapril, 3 patients (0.5% 95% confidence interval: 0.1-1.548) experienced severe hypotension on day 1 and 28 patients (4.7%, 95% confidence interval: 3.2-6.7%) moderate hypotension. In those taking prazosin, 15 patients (2.6%, 95% confidence interval: 1.5-4.2%) experienced severe hypotension and 60 patients (10.3.%, 95% confidence interval: 8.0-13.1%) moderate hypotension (Table 2). Results indicated that signifi-
cantly less symptomatic hypotension was observed in those patients treated with enalapril than in those treated with prazosin (P < 0.000012). The clinical characteristics of patients assessed as being severely hypotensive are presented in Table 3. Except in one case, systolic blood pressure dropped below 100 mmHg in the standing position in those patients with severe hypotension. The most common severe symptoms observed were collapse, fainting and angina pectoris. In 14 of 18 patients,
290 TABLE
2
Primary endpoint: incidence day one with either enalapril Symptomatic hypotension
Enalapril n B
none moderate severe xz = 22.61
568 28 3 DF=
* CI = confidence
TABLE
94.8 4.1 0.5 2
of symptomatic or prazosin. Prazosin n
8
95% CL
3.2-6.7 0.1 -1.5
508 60 15
87.1 10.3 2.6
8.0-13.1 1.5- 4.2
Secondary endpoints and further results
P < o.oooo12
In the group given enalapril, 508 patients were followed up for 8 days and 323 for 2 weeks. In
interval
3 of severe hypotension
No.
Age
Sex
3 m Prazosin 1 f 2 m
trial medication was discontinued. All patients recovered. The median time until recovery was 4 hours. Leg elevation was usually sufficient treatment. Dizziness, headache, tinnitus and nausea were the most commonly reported moderate symptoms.
on
958 CL
Case reports
Enalapril 1 m 2 f
hypotension
on day 1 Time after 1st application hrs. min
Blood pressure (sitting) ‘h th
Blood pressure (standing)
49 74
1 IO,‘80 140/80
80/5U 120,‘65
loo/75 130/70
60/20
3 1
51
110/60
75/50
110/60
75/50
6
68 65
I IO/70
1 lo/60 70/30-40
150/80 115/80
hS/-/-
135/70
t,
th
3 4
f f
59 70
175/105 140/65
(laying) 125,‘80 130/x0
170/l 10 145,‘60
5 6 7
m f r
64 87 75
120/60 130/75 140/70
80/40 95/80 11 O/60
110/80 130/80 140/70
x 9
f f
79 60
150/70 115/70
90/60 75/50
130/80 115/80
10 11 12 13
m f f m
54 85 65 68
I40/70 120/80 100/80 1 lo/no
115,‘80 90/60 90/80 85/60
130/80 115,‘80 100/75 110/80
60/ 80/60
14
f
63
140/90
115/65
145/95
X0 /60
15
f
60
130/80
110/70
130/9u
70/
HR = heart rate: t, = before 1st application
1 IO/75 70/40
i 20’ 4h 40’ lh 50’ 3h 30’ 6
80/70 80/-/-
of trial medication;
12 2 1 2h 50’ 2
Symptoms
Duration
Trial medication
Low-output syndrome Collapsed after standing for 5 min Angina pectoris
10h lh
Withdrawal Continuation
Fainting, vomtting Near-fainting, vertigo; had to lie down Angina pectorts Angina pectoris, bradycardia (HR 40) Pre-shock Pm-shock. vertigo Fainting. collapse vertigo, headache Collapse, fainting Collapse, nausea fatigue Pre-collapse Collapse. tachycardia Collapse Presyncopal symptoms, orthostatic complaints while seated, not able to stand up Collapse without loss of consciousness Collapse. tinnitus. weakness
t,, = when symptomatic
hypotension
2h
Withdrawal
_ lh
Withdrawal Withdrawal
2h 50’ lh
Continuation Continuation
2h Ih 5h
Withdrawal Withdrawal Withdrawal
_ 5h
Withdrawal Withdrawal
4h 4h 12h lh
Continuation Withdrawal Withdrawal Withdrawal
5h
Withdrawal
2h
Withdrawal
occurred.
291 TABLE 4 Symptoms of severe and moderate hypotension during the optional follow-up period of 14 days. Patients might have had more than one symptom. Enalapril (n=9) Severe Angina pectoris Moderate Dizziness Nausea Tinnitus Headache
Prazosin (n = 34) 0
8 0 0 1
31 7 4 3
reaction to enalapril and kept the medication unchanged at 2.5 mg/day. Thirty-four patients receiving prazosin, and 8 of those given enalapril, suffered from moderate and symptomatic hypotension (Table 4). Adverse events, which were not accompanied by hypotension, are shown in Table 5. While these adverse events occurred during treatment, it remained uncertain as to whether they were related to the drugs because of the difficulty in assessing causality in single cases. Therapy was discontinued due to a rise of plasma creatinine levels in 12 patients in each group.
Risk factors those receiving prazosin, 453 patients were followed for 8 days and 303 for 2 weeks. Differences in rates of follow-up were due to the higher number of patients with symptomatic hypotension and subsequent termination of treatment in those given prazosin. Doses of maintenance therapy per day in the period of follow-up were: for those receiving enalapril 2.5 mg (21.7%), 5 mg (27.2%), and 10 mg (30.4%) and for those receiving prazosin 0.5 mg (13.5%) 1.0 mg (16.1%), 2.0 mg (13.5%), 3.0 mg (10.3%) and 4.0 mg (14.2%). During the optional period of follow-up, a single case of severe hypotension was observed (Table 4). A patient taking enalapril suffered from a drop in blood pressure from 110/90 to 80/70 in a sitting position for 2 hours on the seventh day. This was accompanied by paroxysmal tachycardia and angina pectoris. Since this patient had a lo-year history of paroxysmal tachycardia, the physician did not regard this adverse event as an adverse
TABLE 5 Adverse events unaccompanied
by hypotension,
days l-15.
Adverse event
Enalapril
Prazosin
Rise of blood pressure Exanthema Intrahepatic cholestasis Dry cough Tachycardia Myocardial decompensation Peripheral muscle weakness Rise of plasma creatinine
1 2 0 1 0 0 0 12
0 1 1 0 1 1 1 12
Univariate analysis of the relevant baseline variables as possible risk factors for symptomatic hypotension resulted in a partly different pattern in the two groups. Age (> 70 years), systolic blood pressure (G 120 mmHg), diastolic blood pressure (< 80 mmHg) and antiasthmatics were statistically significant in those given enalapril; while age, systolic and diastolic blood pressure, nonsmoking, no coffee drinking, antiasthmatics and P-blockers were significant in the group receiving prazosin. The multivariate stepwise logistic regression identified with decreasing weight the following risk factors for symptomatic hypotension on the first day: treatment with prazosin, nonsmoker status, therapy with antiasthmatic and beta blocking drugs, diastolic blood pressure < 80 mmHg and age > 70 years. The logistic regression indicated antiasthmatic therapy, P-blocker therapy and a diastolic blood pressure < 80 mmHg to be risk factors for symptomatic hypotension with enalapril; and antiasthmatic therapy, B -blocker therapy, age over 70 years and diastolic blood pressure G 80 mmHg as risk factors with prazosin. Results concerning risk factors must be interpreted cautiously, as these analyses were exploratory and case numbers per risk factor class were low.
Discussion Our trial showed a statistically significant difference in the incidence of symptomatic hypotension in patients with congestive heart failure of New York Heart Association functional class
292
(I)/11 and III receiving either enalapril or prazosin. Asymptomatic ‘mild’ hypotension was left aside, as it is quite common in these patients and neither needs antidotal therapy nor provokes discontinuation of therapy [ll]. The trial used central randomization and, as there were very few dropouts, there is no reason to doubt the comparability of the two groups. A possible source of bias however. may have been the unblinded nature of the trial. It is probable that physicians were more vigilant towards patients treated with enalapril because this agent is officially required to be given as a first drug in hospital settings in Germany and, therefore, may have biased the physicians’ recognition of symptomatic hypotension. Blood pressure readings for the 8 hours after the first application of trial medication presented no evidence that there was an overestimate of symptomatic hypotension in the prazosin group. Systolic blood pressure was reduced by about 10 mmHg and diastolic by 5-7 mmHg from baseline in both groups. A maximum decrease in blood pressure was achieved within 2 to 3 hours with prazosin, whereas the maximum decrease in blood pressure took 4 to 5 hours with enalapril. The time lag between the first application of the trial medication and the occurrence of symptomatic hypotension differed between the groups accordingly. The mean interval was 2.3 f 1.7 hours in those given prazosin, and 3.7 f 1.8 hours in the group receiving enalapril. Of the patients treated with prazosin, 13.3% experienced a drop in systolic blood pressure to below 100 mmHg, whereas this occurred in 10.4% of the patients treated with enalapril. The relative frequency of 30%decrease in systolic blood pressure when measured in an upright position, was higher in prazosin-treated patients (9.6%) than in the enalapril-treated patients (6.9%). Heart rate remained virtually unchanged in the patients given prazosin. In the ones taking enalapril, there was a decrease of 2-3 beats per minute. The remarkably quicker drop in blood pressure and the higher incidence of 30%blood pressure reductions in upright position demonstrated in the patients treated with prazosin may explain the differences in symptomatic hypotensive episodes evidenced between enalapril and prazosin. There
is little doubt that the findings of the primary endpoint of this trial are valid. Evidence from the optional follow-up data is weaker, as there was a considerable but unequal number of drop-outs after the first application of the trial medications. The occurrence of adverse events was the single major reason for early terminations. The follow-up samples, therefore, cannot be considered comparable and the followup data may be biased in favour of prazosin. To date, similarly well-controlled, large trials with a safety variable as primary endpoint have not been reported. There are, however, several studies which have focused on efficacy parameters. These have reported the relative frequency of symptomatic hypotension on the first day of treatment with either enalapril [l-3,5-10,12] or prazosin [13-151. Four studies administrating 5 mg enalapril to patients mainly with New York Heart Association functional class II or III report that no first dose hypotension occurred [5-81. Di Carlo et al. using an initial dosage of 2.5 mg enalapril in 15 patients with congestive heart failure of New York Heart Association functional class III or IV report that 2 patients experienced first dose hypotension [l]. Three studies with patients with congestive heart failure New York Heart Association functional class II-IV report incidences of hypotension of 44% [9], 12% [2] and 7% [3]. The interpretation of the findings of two studies remains difficult as either the dosage of enalapril has not been exactly described [3] or the time point when hypotension occurred [9]. In the third study [2], the initial dosage of enalapril was 5 mg in two patients and 10 mg in the third patient, who experienced hypotension. The inclusion criteria, the dosage regimen and the patient monitoring of these studies are too non-uniform to allow a conclusive comparison to this trial. In addition, the sample size of these studies varies between 9 and 127 patients and is thus too small to estimate precisely the incidence of the rather rare occurrence of severe hypotension. This trial had a sample size of approximately 600 patients per group and, with its primary endpoint as symptomatic hypotension, generated a precise and reliable estimate of the frequency of symptomatic hypotension after initiation of treatment with enalapril
293
or prazosin in patients with congestive heart failure New York Heart Association functional class (I)/11 and III. Our trial did not provide clinically relevant risk factors for hypotension beside the treatment itself. There was no evidence (P < 0.74) to confirm the findings of Packer et al. [ll], suggesting that severe hyponatremia ( < 130 mEq/liter) is a very good predictor of symptomatic hypotension after therapy with angiotensin converting enzyme inhibitors. This prognostic factor was found in patients with New York Heart Association functional class IV treated with captopril, which acts faster than the prodrug enalapril [16]. Our findings, which are in accordance with results of the Consensus Study [17] question that hyponatremia is a risk factor with all angiotensin converting enzyme inhibitors. The Consensus Study reported symptomatic hypotension in 12% of 34 patients of New York Heart Association functional class IV after an initial dose of 5 mg enalapril [12]. Subsequent reduction of the initial dose to 2.5 mg decreased the relative frequency to 3%. This dose-response relationship indicates strongly that enalapril can cause hypotension in patients with congestive heart failure. Our data suggest however, that the risk of symptomatic hypotension in patients with congestive heart failure of New York Heart Association functional class (I)/11 or III when administering initially 2.5 mg enalapril is comparatively low.
8
9
10
11
12
13
Acknowledgement 14
This work was supported by a grant Merck, Sharp & Dohme, Munich, F.R.G.
from
References
15
1 DiCarlo
L, Chatterjee K, Parmley WW et al. Enalapril: a new angiotensin-converting enzyme inhibitor in chronic heart failure: acute and chronic hemodynamic evaluations. J Am Co11 Cardiol 1983;2:865-871. 2 Cleland JGF, Dargie HJ, McAlpine H et al. Severe hypotension after first dose of enalapril in heart failure. Br Med J 1985:291:1309-1312. 3 Gomez HJ. Cirillo VJ, Davies RO, Bolognese JA, Walker JF. Enalapril in congestive heart failure: acute and chronic
16
17
invasive hemodynamic evaluation. Int J Cardiol 1986:ll: 37-48. Black J, Hunt TL, Godley PJ. Initiation of Captopril Therapy: The first dose effect. J Clin Pharmacol 1986:26:539540. Sharpe DN, Murphy J, Coxon R, Hannan SF Enalapril in patients with chronic heart failure: a placebo-controlled, randomized. double-blind study. Circulation 1984;70:271278. Cleland JGF, Dargie HJ, Ball SG et al. Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state. Br Heart J 1985;54:305-312. Kromer EP, Riegger GAJ. Liebau G, Kochsiek K. Effectiveness of converting enzyme inhibition (enalapril) for mild congestive heart failure. Am J Cardiol 1986;57:459462. Enalapril Congestive Heart Failure Investigators. Long-term effects of enalapril in patients with congestive heart failure: a multicenter, placebo-controlled trial. Heart Failure 1987:3:102-107. Franciosa JA. Wilen MM, Jordan RA. Effects of enalapril. a new angiotensin-converting enzyme inhibitor, in a controlled trial in heart failure. J Am Co11 Cardiol 1985;5:101107. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986;315:847-853. Packer M. Medina N, Yushak M. Relation between serum sodium concentration and the hemodynamic and clinical response to converting enzyme inhibition with captopril in severe heart failure. J Am Co11 Cardiol 1984:3:1035-1043. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. Colucci WS, Wynne J, Holmann BL, Braunwald E. Longterm therapy of heart failure with prazosin: a randomized double blind trial. Am J Cardiol 1980;45:337-344. Packer M, Medina N, Yushak M. Comparative hemodynamic and clinical effects of long term treatment with prazosin and captopril for severe chronic congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1986;57:1323-1327. Markham RV, Carbett JR, Gilmore A. Pettinger WA, Firth BG. Efficacy of prazosin in the management of chronic congestive heart failure: a 6 month randomized, doubleblind, placebo-controlled study. Am J Cardiol 1983;51:1346-1352. Raia JJ. Barone JA, Byerly WG, Lacy CR. Angiotensinconverting enzyme inhibitors: a comparative review. DICP Ann Pharmacother 1990:24:506-525. Kjekshus J. Swedberg K. Tolerability of enalapril in congestive heart failure. Am J Cardiol 1988;62:67A-72A.
Internationai Journal of Cardiology, 31 (1991) 287-294 0 1991 Elsevier Science Publishers B.V. 0167-5273/91/$03.50 ADONIS 016752739100139X
CARD10
01260
First dose hypotension J. Hasford
r, W.-D.
Bussmann
with enalapril and prazosin heart failure *, W. Delius
3, W. Koepcke
4, K. Lehmann
in congestive 5 and
E. Weber
6
’ Biometric Centrefor Therapeutic Studies, Munich; ’ Department of Cardiology, Johann Wolfgang Goethe- Universittit. Frankfurt; 3 Department of Cardiology and Pulmonology of the Sttidtische Krankenhaus Miinchen-Bogenhausen, Munich; 4 Institute for Medical Informatics, Statistics and Biomathematics, Ludwig-Maximilians-Universitat, Munich; ’ Clinical Research, Merck, Sharp & Dohme GmbH, Munich; 6 Department of Clinical Pharmacology of the Ruprecht-Karls-Universitdt, Heidelberg, F.R.G. (Received
Hasford enalapril
J, Bussmann W-D, Delius and prazosin in congestive
3 August
1990; revision accepted
27 January
1991)
W, Koepcke W, Lehmann K, Weber E. First dose hypotension heart failure. Int J Cardiol 1991;31:287-294.
with
Since the introduction of angiotensin converting enzyme inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the augiotensin converting enzyme inhibitor enalapril a multicenter, open, randomized, prazosin-controlled trial was designed comparing the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 mg prazosin. Subjects were 1210 inpatients with New York Heart Association functional class (I)/11 and III who were not adequately compensated with digitalis and/or diuretics. In the group receiving enalapril, 3 patients (0.5%) experienced severe hypotension on day 1 and 28 patients (4.7%) moderate hypotension. In those given prazosin, 15 patients (2.6%) experienced severe hypotension and 60 patients (10.3%) moderate hypotension. The difference is statistically significant (P Q 0.000012). All patients recovered. It was concluded that treatment of patients suffering from congestive heart failure New York Heart Association functional class (I)/11 or III with enalapril is comparably well tolerated. Key words: Angiotensin converting tive heart failure; Hypotension
enzyme
inhibitors;
Introduction Angiotensin converting enzyme inhibitors are established drugs for the treatment of patients with hypertension or congestive heart failure. Soon
Correspondence to: J. Hasford, M.D., Biometric Centre for Therapeutic Studies (BZT), Pettenkoferstr. 35, D-8000 Munich 2. F.R.G.
Enalapril;
Blocker,
a-receptor;
Prazosin;
Conges-
after these inhibitors were introduced into regimes using adjunctive treatment of patients with congestive heart failure, however, concern grew about their safety, as some investigators reported the occurrence of symptomatic hypotension, especially on the first day of treatment [l-4]. As a result, regulatory drug agencies in some countries strongly recommended that treatment of patients with congestive heart failure by means of inhibi-
tors of angiotensin converting enzyme should be initiated only in hospital. The literature, however, does not provide valid and reliable estimates of the incidence and severity of hypotension. largely because reports are based upon small or selected samples [lLlO]. To determine the incidence and severity of hypotension in a population of patients with congestive heart failure being treated with the angiotensin converting enzyme inhibitor enalapril, a randomized trial was designed to assess the safety of enalapril especially when given on the first day of treatment. It was compared with another widely used vasodilator. namely, prazosin.
Patients and Methods Male and female patients over 18 years of age who had congestive heart failure with the second and third classes of the New York Heart Association. and who were not adequately compensated with digitalis and/or diuretics, were eligible for enrollment in this trial. Exclusion criteria for the trial were: New York Heart Association functional class IV: confinement to bed; systolic blood < 90 mmHg; pretreatment with either pressure trial medication; and all labelled contraindications of prazosin and enalapril. Patients in this trial had either to be inpatients, or else were admitted to the hospital. The primary endpoint was incidence of symptomatic hypotension on the first day of treatment. Secondary endpoints were: type and incidence of adverse events not related to hypotension on the first day of treatment, and during the optional two week follow-up period: and the incidence of symptomatic hypotension during the period of follow-up. The severity of hypotension was classified according to the clinical symptomatology, as outlined below: mild: drop in systolic or diastolic blood pressure without symptoms; moderate: drop in systolic or diastolic blood pressure with moderate symptoms like dizziness, buzzing in the ear, headache or fatigue: severe: as above, but with severe symptoms like fainting, collapse, angina pectoris, heart fibrillation, myocardial infarction, stroke or renal failure. A special form, which included a checklist and
space for documentation of adverse events, was used for collection of data. To provide for uniform classification, unclear cases were assessed by two independent cardiologists (W.-D.B., W.D.) who were not aware of the treatment assignment. Prior to administration of medication, the history was taken and a general work-up done, which included relevant laboratory parameters. Pre-existent risk factors, co-medication (particularly pretreatment with diuretics), low blood pressure, severity of congestive heart failure, and concomitant disorders were carefully noted. The administration of diuretics had to be withheld, or to be substantially reduced, one to two days prior to the first administration of the trial medication. Further vasodilators were not allowed. Concomitant therapy with digitalis and treatments for accompanying diseases could be maintained unchanged. At 8 a.m. on the first day of therapy, patients were given l/2 tablet of the medication under study (equivalent to 2.5 mg enalapril or 0.5 mg prazosin). Twice prior to intake of medication, and hourly for 8 hours thereafter, blood pressure and pulse rate were taken on each patient while seated and after standing for 5 minutes. Blood pressure was always taken on the right arm. Examinations were done under in-hospital conditions in cardiology units. If no adverse events occurred on the first day, the dosage was gradually titrated. As a rule. the maintenance dosage for enalapril was 10 mg/day and for prazosin 4 mg/day. The trial was designed in randomized, multicentric, two armed, and open fashion. Randomization was done centrally by telephone. The required sample size was estimated with the assumptions: p, = 7.5%, pz = 15%. 5% drop-out rate, cx< 0.01. ,f3< 0.10. The result was a sample size of 600 patients per treatment group, which ensured a 95%) probability of observing at least once an adverse event with an incidence of 1 : 200 applications. Continuous variables were analyzed by ttests. and discrete data by the chi-square-test. Analysis for potentially prognostic factors was done by logistic regression. The data processing and all statistical analyses were done exclusively by the independent Biometric Centre for Therapeutic Studies, Munich (W.K., J.H.).
289
The trial was carried out in accordance declaration of Helsinki/Tokyo.
with the
TABLE
1
Baseline
data.
Results A total of 1210 patients were enrolled in the trial from 101 hospitals; 607 patients were allocated to enalapril and 603 patients to prazosin. Eight patients receiving enalaprii and 16 of those given prazosin did not receive any trial medication due to the sudden occurrence of serious diseases like cerebrovascular accident or lung edema; their own refusal; systolic blood pressure less than 90 mmHg; and sudden discharge from hospital. Four patients assigned to prazosin received enalapril; they experienced no adverse events and were excluded from further analyses. Exclusion criteria were not properly applied to 11 patients, (8 having enalapril and 3 prazosin) whose blood pressure could not be measured in an upright position for medical reasons. As the major purpose of this trial was the evaluation of the safety of the respective therapies, these 11 patients were not excluded. Thus, all patients who had received the randomly allocated therapy (599 enalapril, 583 prazosin) are included in this report. An analysis for structural homogeneity of groups did not reveal any relevant differences (Table 1) between patients in the groups receiving enalapril and prazosin. Fifty-four percent of the patients were male and mean age was 68.4 years. Of the patients, 3.7% were in class I of the New York Heart Association, 39.4% were in functional class II, while 56.9% fell within the third functional class. Digitalis was administered to 79.7% of the patients and 76.4% were treated with diuretics.
Enalapril (n = 599)
Prazosin (n ==583)
Sex (female) Body weight (kg) Age (years)
45.6% 73.5 k 14.1 69.0*11.4
46.9% 73.4 + 14.9 67.8+11.0
Severity of CHF NYHA I NYHA II NYHA III
4.3% 40.3% 55.4%
3.1% 38.4% 58.5%
Etiology of CHF Coronary heart disease Myocardial infarction Cardiomyopathy Hypertension
60.2% 26.0% 12.0% 43.7%
61.5% 26.2% 11.1% 38.7%
77.6% 75.1% 68.5
81.8% 77.7% 68.2
8.8% 27.1%
7.9% 28.8%
147*26/ 85 *14 143 f 27/ 85 +14
144+25/ 83 +13 141+ 26/ 83 *13
8Oi13 86+14
80&13 86+_14
Comedication Digitalis Diuretics Furosemide (mg mean dose) Concurrent disorders Renal failure Diabetes mellitus Blood pressure seated (mmHg) standing
(mmHg)
Heart rate (beats per min) seated standing Laboratory data Potassium (mmoI/l) Sodium (mmol/l) Creatinine (p mol/l) CHF = congestive
4.24 k 0.47 139.3 * 12.2 97.3 f 38.1
4.23 f 0.46 139.8 jz 9.2 97.3 k 32.7
heart failure.
Primary endpoint In those given enalapril, 3 patients (0.5% 95% confidence interval: 0.1-1.548) experienced severe hypotension on day 1 and 28 patients (4.7%, 95% confidence interval: 3.2-6.7%) moderate hypotension. In those taking prazosin, 15 patients (2.6%, 95% confidence interval: 1.5-4.2%) experienced severe hypotension and 60 patients (10.3.%, 95% confidence interval: 8.0-13.1%) moderate hypotension (Table 2). Results indicated that signifi-
cantly less symptomatic hypotension was observed in those patients treated with enalapril than in those treated with prazosin (P < 0.000012). The clinical characteristics of patients assessed as being severely hypotensive are presented in Table 3. Except in one case, systolic blood pressure dropped below 100 mmHg in the standing position in those patients with severe hypotension. The most common severe symptoms observed were collapse, fainting and angina pectoris. In 14 of 18 patients,
290 TABLE
2
Primary endpoint: incidence day one with either enalapril Symptomatic hypotension
Enalapril n B
none moderate severe xz = 22.61
568 28 3 DF=
* CI = confidence
TABLE
94.8 4.1 0.5 2
of symptomatic or prazosin. Prazosin n
8
95% CL
3.2-6.7 0.1 -1.5
508 60 15
87.1 10.3 2.6
8.0-13.1 1.5- 4.2
Secondary endpoints and further results
P < o.oooo12
In the group given enalapril, 508 patients were followed up for 8 days and 323 for 2 weeks. In
interval
3 of severe hypotension
No.
Age
Sex
3 m Prazosin 1 f 2 m
trial medication was discontinued. All patients recovered. The median time until recovery was 4 hours. Leg elevation was usually sufficient treatment. Dizziness, headache, tinnitus and nausea were the most commonly reported moderate symptoms.
on
958 CL
Case reports
Enalapril 1 m 2 f
hypotension
on day 1 Time after 1st application hrs. min
Blood pressure (sitting) ‘h th
Blood pressure (standing)
49 74
1 IO,‘80 140/80
80/5U 120,‘65
loo/75 130/70
60/20
3 1
51
110/60
75/50
110/60
75/50
6
68 65
I IO/70
1 lo/60 70/30-40
150/80 115/80
hS/-/-
135/70
t,
th
3 4
f f
59 70
175/105 140/65
(laying) 125,‘80 130/x0
170/l 10 145,‘60
5 6 7
m f r
64 87 75
120/60 130/75 140/70
80/40 95/80 11 O/60
110/80 130/80 140/70
x 9
f f
79 60
150/70 115/70
90/60 75/50
130/80 115/80
10 11 12 13
m f f m
54 85 65 68
I40/70 120/80 100/80 1 lo/no
115,‘80 90/60 90/80 85/60
130/80 115,‘80 100/75 110/80
60/ 80/60
14
f
63
140/90
115/65
145/95
X0 /60
15
f
60
130/80
110/70
130/9u
70/
HR = heart rate: t, = before 1st application
1 IO/75 70/40
i 20’ 4h 40’ lh 50’ 3h 30’ 6
80/70 80/-/-
of trial medication;
12 2 1 2h 50’ 2
Symptoms
Duration
Trial medication
Low-output syndrome Collapsed after standing for 5 min Angina pectoris
10h lh
Withdrawal Continuation
Fainting, vomtting Near-fainting, vertigo; had to lie down Angina pectorts Angina pectoris, bradycardia (HR 40) Pre-shock Pm-shock. vertigo Fainting. collapse vertigo, headache Collapse, fainting Collapse, nausea fatigue Pre-collapse Collapse. tachycardia Collapse Presyncopal symptoms, orthostatic complaints while seated, not able to stand up Collapse without loss of consciousness Collapse. tinnitus. weakness
t,, = when symptomatic
hypotension
2h
Withdrawal
_ lh
Withdrawal Withdrawal
2h 50’ lh
Continuation Continuation
2h Ih 5h
Withdrawal Withdrawal Withdrawal
_ 5h
Withdrawal Withdrawal
4h 4h 12h lh
Continuation Withdrawal Withdrawal Withdrawal
5h
Withdrawal
2h
Withdrawal
occurred.
291 TABLE 4 Symptoms of severe and moderate hypotension during the optional follow-up period of 14 days. Patients might have had more than one symptom. Enalapril (n=9) Severe Angina pectoris Moderate Dizziness Nausea Tinnitus Headache
Prazosin (n = 34) 0
8 0 0 1
31 7 4 3
reaction to enalapril and kept the medication unchanged at 2.5 mg/day. Thirty-four patients receiving prazosin, and 8 of those given enalapril, suffered from moderate and symptomatic hypotension (Table 4). Adverse events, which were not accompanied by hypotension, are shown in Table 5. While these adverse events occurred during treatment, it remained uncertain as to whether they were related to the drugs because of the difficulty in assessing causality in single cases. Therapy was discontinued due to a rise of plasma creatinine levels in 12 patients in each group.
Risk factors those receiving prazosin, 453 patients were followed for 8 days and 303 for 2 weeks. Differences in rates of follow-up were due to the higher number of patients with symptomatic hypotension and subsequent termination of treatment in those given prazosin. Doses of maintenance therapy per day in the period of follow-up were: for those receiving enalapril 2.5 mg (21.7%), 5 mg (27.2%), and 10 mg (30.4%) and for those receiving prazosin 0.5 mg (13.5%) 1.0 mg (16.1%), 2.0 mg (13.5%), 3.0 mg (10.3%) and 4.0 mg (14.2%). During the optional period of follow-up, a single case of severe hypotension was observed (Table 4). A patient taking enalapril suffered from a drop in blood pressure from 110/90 to 80/70 in a sitting position for 2 hours on the seventh day. This was accompanied by paroxysmal tachycardia and angina pectoris. Since this patient had a lo-year history of paroxysmal tachycardia, the physician did not regard this adverse event as an adverse
TABLE 5 Adverse events unaccompanied
by hypotension,
days l-15.
Adverse event
Enalapril
Prazosin
Rise of blood pressure Exanthema Intrahepatic cholestasis Dry cough Tachycardia Myocardial decompensation Peripheral muscle weakness Rise of plasma creatinine
1 2 0 1 0 0 0 12
0 1 1 0 1 1 1 12
Univariate analysis of the relevant baseline variables as possible risk factors for symptomatic hypotension resulted in a partly different pattern in the two groups. Age (> 70 years), systolic blood pressure (G 120 mmHg), diastolic blood pressure (< 80 mmHg) and antiasthmatics were statistically significant in those given enalapril; while age, systolic and diastolic blood pressure, nonsmoking, no coffee drinking, antiasthmatics and P-blockers were significant in the group receiving prazosin. The multivariate stepwise logistic regression identified with decreasing weight the following risk factors for symptomatic hypotension on the first day: treatment with prazosin, nonsmoker status, therapy with antiasthmatic and beta blocking drugs, diastolic blood pressure < 80 mmHg and age > 70 years. The logistic regression indicated antiasthmatic therapy, P-blocker therapy and a diastolic blood pressure < 80 mmHg to be risk factors for symptomatic hypotension with enalapril; and antiasthmatic therapy, B -blocker therapy, age over 70 years and diastolic blood pressure G 80 mmHg as risk factors with prazosin. Results concerning risk factors must be interpreted cautiously, as these analyses were exploratory and case numbers per risk factor class were low.
Discussion Our trial showed a statistically significant difference in the incidence of symptomatic hypotension in patients with congestive heart failure of New York Heart Association functional class
292
(I)/11 and III receiving either enalapril or prazosin. Asymptomatic ‘mild’ hypotension was left aside, as it is quite common in these patients and neither needs antidotal therapy nor provokes discontinuation of therapy [ll]. The trial used central randomization and, as there were very few dropouts, there is no reason to doubt the comparability of the two groups. A possible source of bias however. may have been the unblinded nature of the trial. It is probable that physicians were more vigilant towards patients treated with enalapril because this agent is officially required to be given as a first drug in hospital settings in Germany and, therefore, may have biased the physicians’ recognition of symptomatic hypotension. Blood pressure readings for the 8 hours after the first application of trial medication presented no evidence that there was an overestimate of symptomatic hypotension in the prazosin group. Systolic blood pressure was reduced by about 10 mmHg and diastolic by 5-7 mmHg from baseline in both groups. A maximum decrease in blood pressure was achieved within 2 to 3 hours with prazosin, whereas the maximum decrease in blood pressure took 4 to 5 hours with enalapril. The time lag between the first application of the trial medication and the occurrence of symptomatic hypotension differed between the groups accordingly. The mean interval was 2.3 f 1.7 hours in those given prazosin, and 3.7 f 1.8 hours in the group receiving enalapril. Of the patients treated with prazosin, 13.3% experienced a drop in systolic blood pressure to below 100 mmHg, whereas this occurred in 10.4% of the patients treated with enalapril. The relative frequency of 30%decrease in systolic blood pressure when measured in an upright position, was higher in prazosin-treated patients (9.6%) than in the enalapril-treated patients (6.9%). Heart rate remained virtually unchanged in the patients given prazosin. In the ones taking enalapril, there was a decrease of 2-3 beats per minute. The remarkably quicker drop in blood pressure and the higher incidence of 30%blood pressure reductions in upright position demonstrated in the patients treated with prazosin may explain the differences in symptomatic hypotensive episodes evidenced between enalapril and prazosin. There
is little doubt that the findings of the primary endpoint of this trial are valid. Evidence from the optional follow-up data is weaker, as there was a considerable but unequal number of drop-outs after the first application of the trial medications. The occurrence of adverse events was the single major reason for early terminations. The follow-up samples, therefore, cannot be considered comparable and the followup data may be biased in favour of prazosin. To date, similarly well-controlled, large trials with a safety variable as primary endpoint have not been reported. There are, however, several studies which have focused on efficacy parameters. These have reported the relative frequency of symptomatic hypotension on the first day of treatment with either enalapril [l-3,5-10,12] or prazosin [13-151. Four studies administrating 5 mg enalapril to patients mainly with New York Heart Association functional class II or III report that no first dose hypotension occurred [5-81. Di Carlo et al. using an initial dosage of 2.5 mg enalapril in 15 patients with congestive heart failure of New York Heart Association functional class III or IV report that 2 patients experienced first dose hypotension [l]. Three studies with patients with congestive heart failure New York Heart Association functional class II-IV report incidences of hypotension of 44% [9], 12% [2] and 7% [3]. The interpretation of the findings of two studies remains difficult as either the dosage of enalapril has not been exactly described [3] or the time point when hypotension occurred [9]. In the third study [2], the initial dosage of enalapril was 5 mg in two patients and 10 mg in the third patient, who experienced hypotension. The inclusion criteria, the dosage regimen and the patient monitoring of these studies are too non-uniform to allow a conclusive comparison to this trial. In addition, the sample size of these studies varies between 9 and 127 patients and is thus too small to estimate precisely the incidence of the rather rare occurrence of severe hypotension. This trial had a sample size of approximately 600 patients per group and, with its primary endpoint as symptomatic hypotension, generated a precise and reliable estimate of the frequency of symptomatic hypotension after initiation of treatment with enalapril
293
or prazosin in patients with congestive heart failure New York Heart Association functional class (I)/11 and III. Our trial did not provide clinically relevant risk factors for hypotension beside the treatment itself. There was no evidence (P < 0.74) to confirm the findings of Packer et al. [ll], suggesting that severe hyponatremia ( < 130 mEq/liter) is a very good predictor of symptomatic hypotension after therapy with angiotensin converting enzyme inhibitors. This prognostic factor was found in patients with New York Heart Association functional class IV treated with captopril, which acts faster than the prodrug enalapril [16]. Our findings, which are in accordance with results of the Consensus Study [17] question that hyponatremia is a risk factor with all angiotensin converting enzyme inhibitors. The Consensus Study reported symptomatic hypotension in 12% of 34 patients of New York Heart Association functional class IV after an initial dose of 5 mg enalapril [12]. Subsequent reduction of the initial dose to 2.5 mg decreased the relative frequency to 3%. This dose-response relationship indicates strongly that enalapril can cause hypotension in patients with congestive heart failure. Our data suggest however, that the risk of symptomatic hypotension in patients with congestive heart failure of New York Heart Association functional class (I)/11 or III when administering initially 2.5 mg enalapril is comparatively low.
8
9
10
11
12
13
Acknowledgement 14
This work was supported by a grant Merck, Sharp & Dohme, Munich, F.R.G.
from
References
15
1 DiCarlo
L, Chatterjee K, Parmley WW et al. Enalapril: a new angiotensin-converting enzyme inhibitor in chronic heart failure: acute and chronic hemodynamic evaluations. J Am Co11 Cardiol 1983;2:865-871. 2 Cleland JGF, Dargie HJ, McAlpine H et al. Severe hypotension after first dose of enalapril in heart failure. Br Med J 1985:291:1309-1312. 3 Gomez HJ. Cirillo VJ, Davies RO, Bolognese JA, Walker JF. Enalapril in congestive heart failure: acute and chronic
16
17
invasive hemodynamic evaluation. Int J Cardiol 1986:ll: 37-48. Black J, Hunt TL, Godley PJ. Initiation of Captopril Therapy: The first dose effect. J Clin Pharmacol 1986:26:539540. Sharpe DN, Murphy J, Coxon R, Hannan SF Enalapril in patients with chronic heart failure: a placebo-controlled, randomized. double-blind study. Circulation 1984;70:271278. Cleland JGF, Dargie HJ, Ball SG et al. Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state. Br Heart J 1985;54:305-312. Kromer EP, Riegger GAJ. Liebau G, Kochsiek K. Effectiveness of converting enzyme inhibition (enalapril) for mild congestive heart failure. Am J Cardiol 1986;57:459462. Enalapril Congestive Heart Failure Investigators. Long-term effects of enalapril in patients with congestive heart failure: a multicenter, placebo-controlled trial. Heart Failure 1987:3:102-107. Franciosa JA. Wilen MM, Jordan RA. Effects of enalapril. a new angiotensin-converting enzyme inhibitor, in a controlled trial in heart failure. J Am Co11 Cardiol 1985;5:101107. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986;315:847-853. Packer M. Medina N, Yushak M. Relation between serum sodium concentration and the hemodynamic and clinical response to converting enzyme inhibition with captopril in severe heart failure. J Am Co11 Cardiol 1984:3:1035-1043. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. Colucci WS, Wynne J, Holmann BL, Braunwald E. Longterm therapy of heart failure with prazosin: a randomized double blind trial. Am J Cardiol 1980;45:337-344. Packer M, Medina N, Yushak M. Comparative hemodynamic and clinical effects of long term treatment with prazosin and captopril for severe chronic congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1986;57:1323-1327. Markham RV, Carbett JR, Gilmore A. Pettinger WA, Firth BG. Efficacy of prazosin in the management of chronic congestive heart failure: a 6 month randomized, doubleblind, placebo-controlled study. Am J Cardiol 1983;51:1346-1352. Raia JJ. Barone JA, Byerly WG, Lacy CR. Angiotensinconverting enzyme inhibitors: a comparative review. DICP Ann Pharmacother 1990:24:506-525. Kjekshus J. Swedberg K. Tolerability of enalapril in congestive heart failure. Am J Cardiol 1988;62:67A-72A.
