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Long-term treatment with piroximone in patients with chronic heart failure
Inrernurronal
Journal
of Cardiologbs,
29 (1990) 195-204
195
Elsevier
CARD10 01140
Long-term
treatment Gert
’ F~rsrDepartment
of Medium.
with piroximone heart failure
Baumann Klinikum
‘, Klaus
Ningel
in patients
‘, and Gabrielle
Rechts der tsar, Umuersity of Munich. Strashourg
Munich.
’
F. R. G.; .’ Merrell Dou’ Research
Instlrute.
France
(Received 25 January 1990: revision accepted
Baumann. G., Ningel, K., Cremer, G. Long-term failure. Int J Cardiol 1990;29:195-204.
Cremer
with chronic
treatment
18 May 1990)
with piroximone
in patients
with chronic
heart
The safety and efficacy of long-term oral piroximone therapy was assessed in 12 patients with chronic heart failure. Of these 12 patients, two died suddenly, and a further two were withdrawn because of worsening heart failure within 6 months while 8 completed the l-year follow-up period. In 7 of these 8 patients, clinical evaluations showed sustained benefit, as demonstrated by significant increases in exercise tolerance. The remaining patient experienced a recurrence of severe heart failure at the end of follow-up. Twenty-four hour ambulatory electrocardiograms were compared in 9 patients before and during piroximone therapy. Aggravation of existing arrhythmias was observed in 3 patients, an amelioration in one with no change in the remaining 5. In the 5 patients in whom the hemodynamic effects of a single oral dose of 25 mg of piroximone were studied, the first dose resulted in a 20% increase in mean cardiac index and a 30% decrease in mean pulmonary capillary wedge pressure. This responsiveness to single-dose administration was maintained after l-year follow-up. Likewise, comparison of the hemodynamic effects of four intravenous doses of piroximone revealed no significant difference in the response (n = 7), although the effects tended to be less marked at the end of follow-up. The present results suggesting that piroximone is effective and safe as adjunctive therapy in the management of patients with chronic heart failure will need to be confirmed in longer controlled trials. Key words:
Chronic
heart failure;
Inotropic
agent;
Introduction The primary underlying defect in the clinical syndrome of heart failure is an impairment of myocardial contractility which leads to a reduc-
Correspondence to: PD Dr. Gert Baumann, I. Med. Klinik und Poliklinik Rechts der Isar, Technische Universitlt Miinchen. Ismaningerstrasse 22. 8000 Miinchen, F.R.G.
0167-5273/90/$03.50
‘i’ 1990 Elsevier Science
Publishers
Long-term
therapy
tion in cardiac output with consequent systemic arterial and venous vasoconstriction [1,2]. By increasing cardiac contractility, positive inotropic agents act on the primary defect of heart failure. In addition to the stimulation of myocardial contractility, effective therapy of heart failure is also directed at reducing vasoconstriction which promotes the vicious cycle of further reductions in cardiac output and subsequent elevations in systemic vascular resistance. For many years, cardiac
B.V. (Biomedical
Division)
196
glycosides have been the only agents available for this purpose, but their modest inotropic activity along with their narrow therapeutic to toxic ratio [3] has stimulated the search for newer improved therapeutic agents. Piroximone is a novel cardiotonic agent which combines positive inotropic and vasodilatory properties [4,5]. It is believed to exert its main pharmacological action by selectively inhibiting type III phosphodiesterase, an isoenzyme specific for cyclic adenosine monophosphate degradation [6]. Piroximone has been shown to produce striking hemodynamic improvement, when given acutely to patients with heart failure [7-91, but little is known about its long-term efficacy in the treatment of chronic heart failure [lO,ll]. Recently, a single-blind oral dose-finding study has been undertaken to identify the effective and safe dose-range for repeated oral administration. At the end of the study, the patients were given the opportunity of continuing treatment with oral piroximone. The present report describes the experience with long-term oral piroximone in 12 patients with heart failure, 8 of whom were followed up for a period of 12 months.
Methods Patients The study group consisted of 12 patients who had responded to oral piroximone 25 mg four times per day for 4 weeks with satisfactory symptomatic and functional improvement, in a preceding oral dose-finding study. There were 9 men and 3 women and their age range was 42 to 71 years (mean = 60 years). The etiology of heart failure was coronary artery disease in 3 and idiopathic dilated cardiomyopathy in 9 patients. At initiation of oral piroximone therapy prior to the oral dosefinding study, 11 patients had been in New York Heart Association functional class III and 1 in class II. With the exception of maintenance digitalis, diuretic and antiarrhythmic drugs, all cardioactive agents had been discontinued prior to starting oral piroximone treatment. The dosage of digitalis, diuretic and antiarrhythmic therapy was kept constant throughout the study. All patients
gave informed written consent and the investigational protocol and consent form were approved by the Ethics Committee of the Technical University of Munich. Study protocol The study consisted of three parts all of which used open study designs: (a) long-term follow-up with repeated dose administration (n = 12); (b) hemodynamic assessment of the responsiveness to a single oral dose of 25 mg, undertaken before and after long-term treatment (n = 5); and (c) hemodynamic assessment of the responsiveness to four incremental intravenous doses of piroximone, undertaken before and after long-term treatment (n = 7). Long-term follow-up Patients were followed on an outpatient basis and attended the clinic at regular intervals for clinical assessment and provision of further study medication. In all patients, long-term piroximone therapy was commenced at 25 mg four times per day as this dose had been found, during the preceding oral dose-finding study, to produce a more than 30% increase in exercise tolerance. Sequential clinical evaluations included clinical examination, assessment of New York Heart Association class [12], 12-lead electrocardiogram, assessment of exercise capacity, and laboratory safety tests. Patients were also questioned as to subjective symptoms and feelings such as overall vitality, dyspnea and fatigue which were graded according to a scale ranging from 0 to 3. Symptom-limited graded exercise was performed on a treadmill according to a modified Naughton exercise protocol consisting of consecutive 4 min stages. In addition, a posteroanterior chest radiography was obtained prior to and after 6 months of oral treatment. The cardiothoracic ratio was determined as the transverse diameter of the heart over the internal diameter of the chest multiplied by 100. A 24-h ambulatory electrocardiogram was recorded with the use of a portable electrocardiographic tape monitor prior to long-term treatment and twice during long-term follow-up (after = 3 and = 6 months).
197
TABLE
1
Twenty-four-hour ambulatory electrocardiogram variability in ventricular arrhythmias (13-14)
> IO-fold increase
in frequency
of simple ventricular
criteria
for
extrasys-
tales or > IO-fold increase arrhythmias
in
frequency
> IO-fold decrease in frequency
of
complex
of simple ventricular
ventricular
extrasys-
to1es or > IO-fold decrease arrhythmias
in
frequency
of
complex
ventricular
Rhythm and minimum and maximum heart rate were examined. Arrhythmia analysis included quantification of supraventricular and ventricular extrasystoles and tabulation of the number of couplets, triplets and runs of ventricular extrasystoles (defined as greater or equal to four consecutive extrasystoles). For the purpose of this study, simple ventricular extrasystoles were defined as unifocal or plurifocal single ventricular extrasystoles. Complex ventricular arrhythmias were defined as the sum of couplets, triplets or runs of ventricular extrasystoles. Ventricular 24-h arrhythmia profiles at entry and during piroximone therapy were compared for each patient in order to define improvement or deterioration according to the criteria defined by Velebit and Morgenroth (Table 1). Hemodynamic
assessment
The hemodynamic effects of a single oral dose of 25 mg of piroximone were studied in 5 patients prior to starting oral therapy and at the end of the l-year long-term follow-up. On the morning of the hemodynamic investigation, food, digitalis and diuretics were withheld. A flow-directed balloontipped thermodilution catheter (7F Edwards Instruments) had been introduced at least 12 hours prior to the study. Systolic, diastolic and mean pulmonary artery pressure and right atria1 pressure were measured. In all patients, pulmonary
capillary wedge pressure was taken as pulmonary artery diastolic pressure. Systemic blood pressure was obtained according to the Riva Rocci method using a cuff sphygmomanometer. Heart rate was monitored continuously by means of a telemetered electrocardiogram. Cardiac output was measured in triplicate by the thermodilution technique (Edwards Laboratories Computer 9.205) and mean values were taken. Cardiac output was corrected for body surface area and tabulated as cardiac index. The following variables were calculated by conventional means: stroke volume index. systemic vascular resistance and pulmonary vascular resistance. After determination of control hemodynamic parameters, patients were given a single oral dose of 25 mg of piroximone and hemodynamic measurements were repeated 30 and 60 min after dosing. On the day preceding the final hemodynamic assessment. the two last piroximone doses were omitted to exclude any carryover effect resulting from previous dosing. Hemodynamic piroximone
responsiveness
to
intravenous
The hemodynamic responses to intravenous piroximone were assessed in 7 patients prior to starting oral therapy and at the end of the l-year follow-up. After determination of baseline hemodynamics, piroximone (8. 16. 24 and 32 pg/kg per minute) was administered by intravenous infusion for 15 min at each of the four infusion rates. Hemodynamic measurements were repeated 10 min after increase in dose. The final hemodynamic assessment was undertaken on the second day following administration of the last oral dose. Statistical
analysis
Long-term follow-up Due to the variable times at which follow-up visits occurred in the course of follow-up. it was decided to select visits corresponding to = 1.5, 3. 6 and 12 months for analysis. Parametric variables were analyzed using a multivariate analysis of variance with repeated measures. If the overall analysis indicated statisti-
198
cal significance (P < 0.05). individual comparisons were made. The experimentwise type I error rate was adjusted using the Bonferroni’s method for contrasts. Non-parametric variables were analyzed using the Friedman two-way ANOVA. If the results attained statistical significance, comparisons were made using the Wilcoxon matchedpairs signed-ranks test. Although the results of the initial oral dose-finding study will be reported elsewhere, some data (entry and initial treatment with 25 mg four times per day for 4 weeks) have been included in the present paper to allow a comprehensive evaluation of long-term treatment. Hemodynamic
assessment
Hemodynamic baseline parameters prior to oral dosing and after a l-year long-term treatment were compared using a paired t-test. The hemodynamic effects of a single oral dose (25 mg) were analyzed using repeated measures MANOVA where the main effects examined were Pre-Post (prior to oral dosing versus l-year follow-up) and Time (0.30 and 60 min post-dosing). Multiple comparisons were made if the main effect(s) attained statistical significance. Hemodynamic piroximone
responsiveness
to
intravenous
The hemodynamic effects of four incremental intravenous doses of piroximone after chronic therapy were compared with the data prior to oral dosing using repeated measures ANOVA with main effects on Pre-Post (prior to oral dosing versus l-year follow-up) and Dose (8, 16, 24 and 32 pg/kg per minute). Results Of the 12 patients, 2 patients died suddenly at home after 1 and 3 months of long-term therapy, respectively. Two other patients were withdrawn from the study after three and six months, respectively, because of clinical deterioration and decreased exercise tolerance. The remaining 8 patients completed the l-year follow-up period. All patients were considered for safety and efficacy
evaluation of piroximone while statistical analysis was conducted on follow-up data of 9 patients for the first 6 months and 8 for the l-year period. Adverse reactions Sudden death occurred in two patients but the relation to piroximone administration remains unclear. since both patients were known to have had frequent ventricular arrhythmias prior to enrollment into the study and for which both were receiving antiarrhythmic therapy. In the remaining patients, tolerability of piroximone was good. Unwanted effects recorded as possibly related to piroximone were atria1 flutter (2 X ), abdominal discomfort (1 x ), itching (2 x ), allergic exanthema (1 X ). a feeling of depression (1 x ) and peripheral polyneuritis (1 X ). No clinically relevant changes in laboratory parameters that could be attributed to piroximone were identified. Transitory elevations in liver enzymes occurred in 4 patients but were thought to be induced by hepatic congestion rather than by piroximone administration. Clinical signs and symptoms Long-term administration of piroximone was associated with no significant change in body weight, systemic blood pressure or heart rate nor was there any change in electrocardiographic intervals. Cardiothoracic ratios were not consistently altered. Analysis of the patient questionnaire revealed that during follow-up there was sustained symptomatic improvement as shown by improved (P < scores for ” vitality” (P < 0.01). “dyspnea” 0.01) and “fatigue” (P -c0.05) compared to predrug values. At 6 months follow-up (n = 9), New York Heart Association class was improved in 6 patients. deteriorated in 2 and unchanged in the remaining one compared to pretreatment. At lyear follow-up (n = 8) there was improvement in 7, with no change in the remaining one. Twenty-four-hour (Tables 2 and 3)
ambulatory
electrocardiograms
During follow-up, there was no significant change in maximum or minimum heart rate com-
199
TABLE
2
Twenty-four-hour ambulatory electrocardiogram; ventricular extrasystoles per 24 h (n = 9)
simple
Patient No.
Initial study
Long-term
follow-up
Placebo Run-in
Piroximone 25 mg four times per day
Piroximone 3 months
25 mg four times per day 6 months
I 2 4 5 8 10 11 12 13
372 1200 6000 1464 12 1608 1092 660 18
1080 240 2400 360 0 1872 1920 1200 48
NR NR 960 715 48 6480 1320 6480 48
4 992 936 720 600 24 5 880 NR 936 96
tients (Nos. 1, 2 and 12) one of whom (No. 1) also showed a ten-fold increase in the frequency of simple ventricular extrasystoles, while a ten-fold decrease in the frequency of complex ventricular arrhythmias occurred in one patient (No. 4) during long-term follow-up. Exercise
capacity
Of the 9 patients completing the first 6 months of follow-up, one (No. 7) was no longer able to perform exercise testing at the end of this period.
MINUTES 30
NR = not recorded.
pared to pre-drug values. The daily frequency of supraventricular and simple ventricular extrasystoles was not significantly altered and there was no significant change in the frequency of couplets, triplets and runs of ventricular extrasystoles. No patient exhibited sustained ventricular tachycardia (defined as ventricular tachycardia lasting for more than 30 seconds). When applying strict criteria for deterioration or improvement as defined in Table 1, a ten-fold increase in the frequency of complex ventricular arrhythmias was observed in three pa-
tot
MINUTES 30:
TABLE
3
Twenty-four-hour ambulatory electrocardiogram; ventricular arrhythmias per 24 h (n = 9)
complex
25
PO -
Patient No.
1 2 4 5 8 10 11 12 13
Initial study
Long-term
Placebo Run-in
Piroximone 25 mg four times per day
Piroximone 3 months
8 2 41 5 1 7 62 0 0
18 NR 1 14 1 80 28 53 1
0 0 114 37 1 29 8 2 0
NR = not recorded.
follow-up 25 mg four times per day 6 months 229 11 10 5 0 278 NR 5 0
15
j
10
5
0 :
Fig. 1. Mean (SD) exercise time during the initial study and on long-term therapy with piroximone (25 mg four times per day) in 8 patients during the first 6 months of follow-up (above) and in 7 during the l-year follow-up period (below). * * P i 0.01compared to entry.
200
Hemodynamic piroximone
while the remaining 8 showed sustained improvement in exercise tolerance (Fig. 1). When considering the 8 patients who underwent all exercise tests, the mean exercise duration was increased from 8.5 f 4.7 min at entry to 16.5 & 4.5 (P < 0.01) at the end of the 6-month observation period. At l-year follow-up, another patient (No. 10) was no longer able to undergo exercise testing, while the improvement was maintained in the remaining 7 (Fig. 1). Hemodynamic
responses to a single oral dose of 25
Following the first oral dose of 25 mg piroximone, heart rate, systolic and diastolic blood pressure remained unchanged. Cardiac index increased from 3.0 to 3.6 l/mm per m* and stroke volume index from 40 to 47 ml/m2 (Fig. 2). There was a decrease in systolic pulmonary artery pressure from 34 to 30 mm Hg, pulmonary capillary pressure from 15 to 11 mm Hg and right atria1 pressure from 4 to 2 mm Hg, while systemic vascular resistance decreased from 1281 to 1085 dynes. s. cmP5 (Fig. 3). At l-year follow-up, baseline hemodynamic parameters were not significantly different from pre-drug values and there was no significant change in the responsiveness to a single oral dose of 25 mg.
,l/min/m*
PRE
intravenous
Discussion Irrespective of its etiological basis, heart disease often leads to heart failure, a physiopathological state defined as the inability of the heart to pump + III 1
YEAR
ml/m 50T
r
to
Comparison of baseline hemodynamic parameters in the 7 patients who underwent repeated intravenous assessment revealed no significant interval worsening of cardiac function for the group as a whole, as shown by the similarity of the mean ( + SD) cardiac indices (pre: 3.0 f 0.7 versus post: 3.0 + 0.4 l/min per m*) and mean pulmonary capillary wedge pressures (pre: 15 + 7 versus post: 16 * 10 mm Hg) (Fig. 4). When considering individual patient data, 5 patients exhibited an improvement in baseline hemodynamics, while the remaining two showed hemodynamic deterioration. Comparison of the hemodynamic effects of four incremental intravenous doses of piroximone revealed no statistically significant differences for the overall effect but the hemodynamic responses tended to be less marked at follow-up compared to prior to chronic treatment and at same, but not all dose levels, the differences reached statistical significance (Figs. 4 and 5).
mg
*
responsiveness
2
SW
g
30
Minutes Fig. 2. Mean hemodynamic
effects of a single oral dose of 25 mg of piroximone on cardiac index (CI) and stroke volume index (SW) before and after chronic treatment with piroximone. n = 5.
20’
,. mmHg
SPAP
25
i..
___.~__
(I
__
1
_
60
30
PCWP
mmHg ” T
i
,. 1 ~__~_~_~~~~~~~~~~~__
.J
80
0
Minutes
Minutes
SVR mmHg 5r
RAP
dynes ,300 T
set
cm-5
Fig. 3. Mean hemodynamic effects of a single oral dose of 25 mg of piroximone on systolic pulmonary artery pressure (SPAP). pulmonary capillary wedge pressure (PCWP), right atria1 pressure (RAP) and systemic vascular resistance (SVR) before and after chronic treatment with piroximone. n = 5.
blood at a rate commensurate to the requirements of the metabolizing tissues. In chronic heart failure, there is a progressive impairment of myocardial contractility. As a result, cardiac output and oxygen delivery to the peripheral tissues are compromised, though cardiac function may be partially restored by compensatory mechanisms. Patients with chronic heart failure are most symptomatic during physical activity, when they experi-
ence breathlessness, fatigue or both. This decrease in exercise tolerance is used by the practicing physician to grade the severity of heart failure, to follow its clinical course and to determine the efficacy of new therapeutic agents. The aims of the present study were two-fold: (I) to provide the opportunity for long-term therapy to patients who had responded to oral piroximone, in a preceding oral dose-finding study,
202
a sllminlm2
I
1
Fig. 4. Mean hemodynamic (SVI), systolic pulmonary
SVI ,, ml/m2
effects of four incremental intravenous doses of piroximone on cardiac index (CI), stroke artery pressure (SPAP) and pulmonary capillary wedge pressure (PCWP) before and treatment with piroximone. n = 7.
with satisfactory symptomatic and functional improvement; and (2) to gather information on the efficacy and safety of long-term piroximone therapy. Early clinical improvement, as reflected by a significant increase in exercise tolerance, an amelioration in New York Heart Association functional classification and an improved sense of well being with a lesser degree of fatigue and dyspnea had been observed in 12 (out of 13) patients at the end of 4 weeks treatment with oral piroximone 25 mg four times per day. All of the 12 patients were considered for long-term therapy and followed up for a period of up to 12 months. During this period, 2 patients died, and a further 2 experienced worsening of heart failure within 6
volume index after chronic
months after starting oral piroximone therapy, while 8 completed the l-year follow-up. In 7 of these 8 patients, clinical evaluations showed sustained benefit as demonstrated by significant increases in exercise tolerance along with symptomatic improvement over the entire observation period. The remaining patient experienced recrudescence of symptoms towards the end of follow-up and was no longer able to undergo final exercise testing. There has been concern that inotropic agents by stimulating the failing myocardium may accelerate the progression of the underlying heart disease. In the subgroup of patients (n = 7) who underwent repeated hemodynamic investigation
203
dynes
set
cm-5
Fig. 5. Mean hemodynamic effects of four incremental intravenous doses of piroximone on right atria1 pressure (RAP). sy,stemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) before and after chronic treatment with piroximone. n = 7.
there was no significant worsening of cardiac function at l-year follow-up as shown by similar baseline hemodynamics. Although the possibility that piroximone might have had a deleterious effect in the 2 patients with hemodynamic deterioration cannot be excluded, it should be kept in mind that worsening of cardiac function due to disease progression is commonly seen in heart failure and is. therefore, not necessarily related to drug administration. However, the subgroup of patients followed for 1 year were self-selected by the fact that they had responded favorably and “survived”. Therefore, the possibility of enhanced myocardial damage cannot be excluded based on the present study results. Another concern that has been raised with inotropic agents is that they may induce or aggravate cardiac arrhythmias. The mechanism of action of piroximone appears to be related, at least in part, to phosphodiesterase type III inhibition with a consequent rise in intracellular cyclic adenosine monophosphate resulting in improved calcium handling. In addition to the increased energy requirements caused by enhanced myocar-
dial contractility, the increased cellular level of cyclic adenosine monophosphate can also be arrhythmogenic f15.161. In the present study. sudden death probably related to malignant arrhythmias occurred in 2 patients. Analysis of 24-h ambulatory electrocardiograms revealed no significant arrhythmia increases in the group as a whole (n = 9). but if the individual patient data are considered, arrhythmia increases were sufficient in 3 patients to qualify as proarrhythmogenic while one patient displayed an antiarrhythmic response. The relationship between sudden death. arrhythmia deterioration and piroximone therapy remains unclear. The question whether piroximone has arrhythmogenic properties cannot be resolved by the present data since the small sample size and the lack of a parallel control group compromises the evaluation of these effects which, equally, could have been caused by the natural course of underlying heart disease. At initial hemodynamic assessment, administration of a single oral dose of 25 mg of piroximone to a subset of patients (n = 5) resulted in hemodynamic improvement characterized by a
204
20% increase in mean cardiac index and a 30% decrease in mean pulmonary capillary wedge pressure. This hemodynamic response, though less pronounced than with intravenous piroximone, was felt adequate to improve cardiac function in the patients studied, all of whom presented with moderate to severe heart failure. Readministration of a single oral dose of 25 mg, at final hemodynamic assessment, led to similar effects indicating that the patients had retained the responsiveness to the circulatory effects of piroximone during continuous therapy. When comparing the hemodynamic responses to intravenous piroximone before and after chronic therapy, there was no significant difference in the overall effect, but the responses tended to be less marked at follow-up and at some, but not all dose levels, the differences reached statistical significance. However, even if the hemodynamic responses tended to be less, administration of intravenous piroximone at final assessment still resulted in major hemodynamic improvement. The present results suggest that larger controlled trials with piroximone as adjunctive therapy in the management of patients with chronic heart failure are needed.
Acknowledgments We gratefully acknowledge the secretarial of Carine Dott and Eliane Sturm.
help
References 1 Weber KT. New hope for the failing heart. Am J Med 1982;72:665-671. 2 Cohn JN, Mashiro I, Levine TB, Mehta J. Role of vasoconstrictor mechanisms in the control of left ventricular performance of the normal and damaged heart. Am J Cardiol 1979;44:1019-1022. 3 Doherty JE, Kane JJ. Clinical pharmacology of digitalis glycosides. Am Rev Med 1975;26:159-179. 4 Dage RC, Roebel LE. Cheng HC, Woodward JK. Cardio-
vascular properties of a new cardiotonic agent, MDL 19.205. J Cardiovasc Pharmacol 1984;6:35-42. 5 Roebel LE. Dage RC. Cheng HC, Woodward JK. In vitro and in viva assessment of the cardiovascular effects of the cardiotonic drug MDL 19.205. J Cardiovasc Pharmacol 1984;6:43-49. 6 Kariya T, Wille LJ, Dage RC. Studies on the mechanism of the cardiotonic activity of MDL 19.205: effects on several biochemical systems. J Cardiovasc Pharmacol 1984:6:5055. 7 Petein M, Levine TB. Cohn JN. Hemodynamic effects of a new inotropic agent, piroximone (MDL 19.205) in patients with chronic heart failure. J Am Co11 Cardiol 1984:4:364371. 8 Arbogast R. Brandt C, Fincker JL, Schechter PJ. Acute hemodynamic effects of piroximone (MDL 19.205) in patients with moderate congestive heart faiIure:comparison with sodium nitroprusside. J Cardiovasc Pharamcol 1986;8:82-89. 9 Massie BM. Cornyn J. Topic N, Loge D, Podolin RA. Combined hemodynamic and scintigraphic assessment of piroximone (MDL 19.205) and comparison with dobutamine and nitroprusside. Am J Cardiol 1987:60:647-653. 10 Petein M. Levine TB, Cohn JN. Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19.205) in patients with congestive heart failure. Circulation 1986;73 (suppl 111):230-236. 11 Weber KT, Janicki JS. Jain MC. Piroximone (MDL 19.205) in the treatment of unstable and stable chronic heart failure. Am Heart J 1987:87:805-812. 12 Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 6th ed Boston: Little, Brown, 1964:1-23. 13 Velebit V, Podrid P, Lown B, Cohen B, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs Circulation 1982;65:886-894. 14 Morgenroth J, Michelson EL, Horowitz LN, Josephson ME. Pearlman AS, Dunkman WB. Limitations of routine long-term electrocardiographic monitoring assess ventricular ectopic frequency. Circulation 1978;58:408-414. 15 Lubbe WF, Podzuweit T, Daries PS, Opie LH. The role of cyclic adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest 1978;61:1260-1269. 16 Podzuweit T, Lubbe WF. Opie LH. Cyclic adenosine monophosphate. ventricular fibrillation and antiarrhythmic drugs. Lancet 1976;1:341-342.
Journal
of Cardiologbs,
29 (1990) 195-204
195
Elsevier
CARD10 01140
Long-term
treatment Gert
’ F~rsrDepartment
of Medium.
with piroximone heart failure
Baumann Klinikum
‘, Klaus
Ningel
in patients
‘, and Gabrielle
Rechts der tsar, Umuersity of Munich. Strashourg
Munich.
’
F. R. G.; .’ Merrell Dou’ Research
Instlrute.
France
(Received 25 January 1990: revision accepted
Baumann. G., Ningel, K., Cremer, G. Long-term failure. Int J Cardiol 1990;29:195-204.
Cremer
with chronic
treatment
18 May 1990)
with piroximone
in patients
with chronic
heart
The safety and efficacy of long-term oral piroximone therapy was assessed in 12 patients with chronic heart failure. Of these 12 patients, two died suddenly, and a further two were withdrawn because of worsening heart failure within 6 months while 8 completed the l-year follow-up period. In 7 of these 8 patients, clinical evaluations showed sustained benefit, as demonstrated by significant increases in exercise tolerance. The remaining patient experienced a recurrence of severe heart failure at the end of follow-up. Twenty-four hour ambulatory electrocardiograms were compared in 9 patients before and during piroximone therapy. Aggravation of existing arrhythmias was observed in 3 patients, an amelioration in one with no change in the remaining 5. In the 5 patients in whom the hemodynamic effects of a single oral dose of 25 mg of piroximone were studied, the first dose resulted in a 20% increase in mean cardiac index and a 30% decrease in mean pulmonary capillary wedge pressure. This responsiveness to single-dose administration was maintained after l-year follow-up. Likewise, comparison of the hemodynamic effects of four intravenous doses of piroximone revealed no significant difference in the response (n = 7), although the effects tended to be less marked at the end of follow-up. The present results suggesting that piroximone is effective and safe as adjunctive therapy in the management of patients with chronic heart failure will need to be confirmed in longer controlled trials. Key words:
Chronic
heart failure;
Inotropic
agent;
Introduction The primary underlying defect in the clinical syndrome of heart failure is an impairment of myocardial contractility which leads to a reduc-
Correspondence to: PD Dr. Gert Baumann, I. Med. Klinik und Poliklinik Rechts der Isar, Technische Universitlt Miinchen. Ismaningerstrasse 22. 8000 Miinchen, F.R.G.
0167-5273/90/$03.50
‘i’ 1990 Elsevier Science
Publishers
Long-term
therapy
tion in cardiac output with consequent systemic arterial and venous vasoconstriction [1,2]. By increasing cardiac contractility, positive inotropic agents act on the primary defect of heart failure. In addition to the stimulation of myocardial contractility, effective therapy of heart failure is also directed at reducing vasoconstriction which promotes the vicious cycle of further reductions in cardiac output and subsequent elevations in systemic vascular resistance. For many years, cardiac
B.V. (Biomedical
Division)
196
glycosides have been the only agents available for this purpose, but their modest inotropic activity along with their narrow therapeutic to toxic ratio [3] has stimulated the search for newer improved therapeutic agents. Piroximone is a novel cardiotonic agent which combines positive inotropic and vasodilatory properties [4,5]. It is believed to exert its main pharmacological action by selectively inhibiting type III phosphodiesterase, an isoenzyme specific for cyclic adenosine monophosphate degradation [6]. Piroximone has been shown to produce striking hemodynamic improvement, when given acutely to patients with heart failure [7-91, but little is known about its long-term efficacy in the treatment of chronic heart failure [lO,ll]. Recently, a single-blind oral dose-finding study has been undertaken to identify the effective and safe dose-range for repeated oral administration. At the end of the study, the patients were given the opportunity of continuing treatment with oral piroximone. The present report describes the experience with long-term oral piroximone in 12 patients with heart failure, 8 of whom were followed up for a period of 12 months.
Methods Patients The study group consisted of 12 patients who had responded to oral piroximone 25 mg four times per day for 4 weeks with satisfactory symptomatic and functional improvement, in a preceding oral dose-finding study. There were 9 men and 3 women and their age range was 42 to 71 years (mean = 60 years). The etiology of heart failure was coronary artery disease in 3 and idiopathic dilated cardiomyopathy in 9 patients. At initiation of oral piroximone therapy prior to the oral dosefinding study, 11 patients had been in New York Heart Association functional class III and 1 in class II. With the exception of maintenance digitalis, diuretic and antiarrhythmic drugs, all cardioactive agents had been discontinued prior to starting oral piroximone treatment. The dosage of digitalis, diuretic and antiarrhythmic therapy was kept constant throughout the study. All patients
gave informed written consent and the investigational protocol and consent form were approved by the Ethics Committee of the Technical University of Munich. Study protocol The study consisted of three parts all of which used open study designs: (a) long-term follow-up with repeated dose administration (n = 12); (b) hemodynamic assessment of the responsiveness to a single oral dose of 25 mg, undertaken before and after long-term treatment (n = 5); and (c) hemodynamic assessment of the responsiveness to four incremental intravenous doses of piroximone, undertaken before and after long-term treatment (n = 7). Long-term follow-up Patients were followed on an outpatient basis and attended the clinic at regular intervals for clinical assessment and provision of further study medication. In all patients, long-term piroximone therapy was commenced at 25 mg four times per day as this dose had been found, during the preceding oral dose-finding study, to produce a more than 30% increase in exercise tolerance. Sequential clinical evaluations included clinical examination, assessment of New York Heart Association class [12], 12-lead electrocardiogram, assessment of exercise capacity, and laboratory safety tests. Patients were also questioned as to subjective symptoms and feelings such as overall vitality, dyspnea and fatigue which were graded according to a scale ranging from 0 to 3. Symptom-limited graded exercise was performed on a treadmill according to a modified Naughton exercise protocol consisting of consecutive 4 min stages. In addition, a posteroanterior chest radiography was obtained prior to and after 6 months of oral treatment. The cardiothoracic ratio was determined as the transverse diameter of the heart over the internal diameter of the chest multiplied by 100. A 24-h ambulatory electrocardiogram was recorded with the use of a portable electrocardiographic tape monitor prior to long-term treatment and twice during long-term follow-up (after = 3 and = 6 months).
197
TABLE
1
Twenty-four-hour ambulatory electrocardiogram variability in ventricular arrhythmias (13-14)
> IO-fold increase
in frequency
of simple ventricular
criteria
for
extrasys-
tales or > IO-fold increase arrhythmias
in
frequency
> IO-fold decrease in frequency
of
complex
of simple ventricular
ventricular
extrasys-
to1es or > IO-fold decrease arrhythmias
in
frequency
of
complex
ventricular
Rhythm and minimum and maximum heart rate were examined. Arrhythmia analysis included quantification of supraventricular and ventricular extrasystoles and tabulation of the number of couplets, triplets and runs of ventricular extrasystoles (defined as greater or equal to four consecutive extrasystoles). For the purpose of this study, simple ventricular extrasystoles were defined as unifocal or plurifocal single ventricular extrasystoles. Complex ventricular arrhythmias were defined as the sum of couplets, triplets or runs of ventricular extrasystoles. Ventricular 24-h arrhythmia profiles at entry and during piroximone therapy were compared for each patient in order to define improvement or deterioration according to the criteria defined by Velebit and Morgenroth (Table 1). Hemodynamic
assessment
The hemodynamic effects of a single oral dose of 25 mg of piroximone were studied in 5 patients prior to starting oral therapy and at the end of the l-year long-term follow-up. On the morning of the hemodynamic investigation, food, digitalis and diuretics were withheld. A flow-directed balloontipped thermodilution catheter (7F Edwards Instruments) had been introduced at least 12 hours prior to the study. Systolic, diastolic and mean pulmonary artery pressure and right atria1 pressure were measured. In all patients, pulmonary
capillary wedge pressure was taken as pulmonary artery diastolic pressure. Systemic blood pressure was obtained according to the Riva Rocci method using a cuff sphygmomanometer. Heart rate was monitored continuously by means of a telemetered electrocardiogram. Cardiac output was measured in triplicate by the thermodilution technique (Edwards Laboratories Computer 9.205) and mean values were taken. Cardiac output was corrected for body surface area and tabulated as cardiac index. The following variables were calculated by conventional means: stroke volume index. systemic vascular resistance and pulmonary vascular resistance. After determination of control hemodynamic parameters, patients were given a single oral dose of 25 mg of piroximone and hemodynamic measurements were repeated 30 and 60 min after dosing. On the day preceding the final hemodynamic assessment. the two last piroximone doses were omitted to exclude any carryover effect resulting from previous dosing. Hemodynamic piroximone
responsiveness
to
intravenous
The hemodynamic responses to intravenous piroximone were assessed in 7 patients prior to starting oral therapy and at the end of the l-year follow-up. After determination of baseline hemodynamics, piroximone (8. 16. 24 and 32 pg/kg per minute) was administered by intravenous infusion for 15 min at each of the four infusion rates. Hemodynamic measurements were repeated 10 min after increase in dose. The final hemodynamic assessment was undertaken on the second day following administration of the last oral dose. Statistical
analysis
Long-term follow-up Due to the variable times at which follow-up visits occurred in the course of follow-up. it was decided to select visits corresponding to = 1.5, 3. 6 and 12 months for analysis. Parametric variables were analyzed using a multivariate analysis of variance with repeated measures. If the overall analysis indicated statisti-
198
cal significance (P < 0.05). individual comparisons were made. The experimentwise type I error rate was adjusted using the Bonferroni’s method for contrasts. Non-parametric variables were analyzed using the Friedman two-way ANOVA. If the results attained statistical significance, comparisons were made using the Wilcoxon matchedpairs signed-ranks test. Although the results of the initial oral dose-finding study will be reported elsewhere, some data (entry and initial treatment with 25 mg four times per day for 4 weeks) have been included in the present paper to allow a comprehensive evaluation of long-term treatment. Hemodynamic
assessment
Hemodynamic baseline parameters prior to oral dosing and after a l-year long-term treatment were compared using a paired t-test. The hemodynamic effects of a single oral dose (25 mg) were analyzed using repeated measures MANOVA where the main effects examined were Pre-Post (prior to oral dosing versus l-year follow-up) and Time (0.30 and 60 min post-dosing). Multiple comparisons were made if the main effect(s) attained statistical significance. Hemodynamic piroximone
responsiveness
to
intravenous
The hemodynamic effects of four incremental intravenous doses of piroximone after chronic therapy were compared with the data prior to oral dosing using repeated measures ANOVA with main effects on Pre-Post (prior to oral dosing versus l-year follow-up) and Dose (8, 16, 24 and 32 pg/kg per minute). Results Of the 12 patients, 2 patients died suddenly at home after 1 and 3 months of long-term therapy, respectively. Two other patients were withdrawn from the study after three and six months, respectively, because of clinical deterioration and decreased exercise tolerance. The remaining 8 patients completed the l-year follow-up period. All patients were considered for safety and efficacy
evaluation of piroximone while statistical analysis was conducted on follow-up data of 9 patients for the first 6 months and 8 for the l-year period. Adverse reactions Sudden death occurred in two patients but the relation to piroximone administration remains unclear. since both patients were known to have had frequent ventricular arrhythmias prior to enrollment into the study and for which both were receiving antiarrhythmic therapy. In the remaining patients, tolerability of piroximone was good. Unwanted effects recorded as possibly related to piroximone were atria1 flutter (2 X ), abdominal discomfort (1 x ), itching (2 x ), allergic exanthema (1 X ). a feeling of depression (1 x ) and peripheral polyneuritis (1 X ). No clinically relevant changes in laboratory parameters that could be attributed to piroximone were identified. Transitory elevations in liver enzymes occurred in 4 patients but were thought to be induced by hepatic congestion rather than by piroximone administration. Clinical signs and symptoms Long-term administration of piroximone was associated with no significant change in body weight, systemic blood pressure or heart rate nor was there any change in electrocardiographic intervals. Cardiothoracic ratios were not consistently altered. Analysis of the patient questionnaire revealed that during follow-up there was sustained symptomatic improvement as shown by improved (P < scores for ” vitality” (P < 0.01). “dyspnea” 0.01) and “fatigue” (P -c0.05) compared to predrug values. At 6 months follow-up (n = 9), New York Heart Association class was improved in 6 patients. deteriorated in 2 and unchanged in the remaining one compared to pretreatment. At lyear follow-up (n = 8) there was improvement in 7, with no change in the remaining one. Twenty-four-hour (Tables 2 and 3)
ambulatory
electrocardiograms
During follow-up, there was no significant change in maximum or minimum heart rate com-
199
TABLE
2
Twenty-four-hour ambulatory electrocardiogram; ventricular extrasystoles per 24 h (n = 9)
simple
Patient No.
Initial study
Long-term
follow-up
Placebo Run-in
Piroximone 25 mg four times per day
Piroximone 3 months
25 mg four times per day 6 months
I 2 4 5 8 10 11 12 13
372 1200 6000 1464 12 1608 1092 660 18
1080 240 2400 360 0 1872 1920 1200 48
NR NR 960 715 48 6480 1320 6480 48
4 992 936 720 600 24 5 880 NR 936 96
tients (Nos. 1, 2 and 12) one of whom (No. 1) also showed a ten-fold increase in the frequency of simple ventricular extrasystoles, while a ten-fold decrease in the frequency of complex ventricular arrhythmias occurred in one patient (No. 4) during long-term follow-up. Exercise
capacity
Of the 9 patients completing the first 6 months of follow-up, one (No. 7) was no longer able to perform exercise testing at the end of this period.
MINUTES 30
NR = not recorded.
pared to pre-drug values. The daily frequency of supraventricular and simple ventricular extrasystoles was not significantly altered and there was no significant change in the frequency of couplets, triplets and runs of ventricular extrasystoles. No patient exhibited sustained ventricular tachycardia (defined as ventricular tachycardia lasting for more than 30 seconds). When applying strict criteria for deterioration or improvement as defined in Table 1, a ten-fold increase in the frequency of complex ventricular arrhythmias was observed in three pa-
tot
MINUTES 30:
TABLE
3
Twenty-four-hour ambulatory electrocardiogram; ventricular arrhythmias per 24 h (n = 9)
complex
25
PO -
Patient No.
1 2 4 5 8 10 11 12 13
Initial study
Long-term
Placebo Run-in
Piroximone 25 mg four times per day
Piroximone 3 months
8 2 41 5 1 7 62 0 0
18 NR 1 14 1 80 28 53 1
0 0 114 37 1 29 8 2 0
NR = not recorded.
follow-up 25 mg four times per day 6 months 229 11 10 5 0 278 NR 5 0
15
j
10
5
0 :
Fig. 1. Mean (SD) exercise time during the initial study and on long-term therapy with piroximone (25 mg four times per day) in 8 patients during the first 6 months of follow-up (above) and in 7 during the l-year follow-up period (below). * * P i 0.01compared to entry.
200
Hemodynamic piroximone
while the remaining 8 showed sustained improvement in exercise tolerance (Fig. 1). When considering the 8 patients who underwent all exercise tests, the mean exercise duration was increased from 8.5 f 4.7 min at entry to 16.5 & 4.5 (P < 0.01) at the end of the 6-month observation period. At l-year follow-up, another patient (No. 10) was no longer able to undergo exercise testing, while the improvement was maintained in the remaining 7 (Fig. 1). Hemodynamic
responses to a single oral dose of 25
Following the first oral dose of 25 mg piroximone, heart rate, systolic and diastolic blood pressure remained unchanged. Cardiac index increased from 3.0 to 3.6 l/mm per m* and stroke volume index from 40 to 47 ml/m2 (Fig. 2). There was a decrease in systolic pulmonary artery pressure from 34 to 30 mm Hg, pulmonary capillary pressure from 15 to 11 mm Hg and right atria1 pressure from 4 to 2 mm Hg, while systemic vascular resistance decreased from 1281 to 1085 dynes. s. cmP5 (Fig. 3). At l-year follow-up, baseline hemodynamic parameters were not significantly different from pre-drug values and there was no significant change in the responsiveness to a single oral dose of 25 mg.
,l/min/m*
PRE
intravenous
Discussion Irrespective of its etiological basis, heart disease often leads to heart failure, a physiopathological state defined as the inability of the heart to pump + III 1
YEAR
ml/m 50T
r
to
Comparison of baseline hemodynamic parameters in the 7 patients who underwent repeated intravenous assessment revealed no significant interval worsening of cardiac function for the group as a whole, as shown by the similarity of the mean ( + SD) cardiac indices (pre: 3.0 f 0.7 versus post: 3.0 + 0.4 l/min per m*) and mean pulmonary capillary wedge pressures (pre: 15 + 7 versus post: 16 * 10 mm Hg) (Fig. 4). When considering individual patient data, 5 patients exhibited an improvement in baseline hemodynamics, while the remaining two showed hemodynamic deterioration. Comparison of the hemodynamic effects of four incremental intravenous doses of piroximone revealed no statistically significant differences for the overall effect but the hemodynamic responses tended to be less marked at follow-up compared to prior to chronic treatment and at same, but not all dose levels, the differences reached statistical significance (Figs. 4 and 5).
mg
*
responsiveness
2
SW
g
30
Minutes Fig. 2. Mean hemodynamic
effects of a single oral dose of 25 mg of piroximone on cardiac index (CI) and stroke volume index (SW) before and after chronic treatment with piroximone. n = 5.
20’
,. mmHg
SPAP
25
i..
___.~__
(I
__
1
_
60
30
PCWP
mmHg ” T
i
,. 1 ~__~_~_~~~~~~~~~~~__
.J
80
0
Minutes
Minutes
SVR mmHg 5r
RAP
dynes ,300 T
set
cm-5
Fig. 3. Mean hemodynamic effects of a single oral dose of 25 mg of piroximone on systolic pulmonary artery pressure (SPAP). pulmonary capillary wedge pressure (PCWP), right atria1 pressure (RAP) and systemic vascular resistance (SVR) before and after chronic treatment with piroximone. n = 5.
blood at a rate commensurate to the requirements of the metabolizing tissues. In chronic heart failure, there is a progressive impairment of myocardial contractility. As a result, cardiac output and oxygen delivery to the peripheral tissues are compromised, though cardiac function may be partially restored by compensatory mechanisms. Patients with chronic heart failure are most symptomatic during physical activity, when they experi-
ence breathlessness, fatigue or both. This decrease in exercise tolerance is used by the practicing physician to grade the severity of heart failure, to follow its clinical course and to determine the efficacy of new therapeutic agents. The aims of the present study were two-fold: (I) to provide the opportunity for long-term therapy to patients who had responded to oral piroximone, in a preceding oral dose-finding study,
202
a sllminlm2
I
1
Fig. 4. Mean hemodynamic (SVI), systolic pulmonary
SVI ,, ml/m2
effects of four incremental intravenous doses of piroximone on cardiac index (CI), stroke artery pressure (SPAP) and pulmonary capillary wedge pressure (PCWP) before and treatment with piroximone. n = 7.
with satisfactory symptomatic and functional improvement; and (2) to gather information on the efficacy and safety of long-term piroximone therapy. Early clinical improvement, as reflected by a significant increase in exercise tolerance, an amelioration in New York Heart Association functional classification and an improved sense of well being with a lesser degree of fatigue and dyspnea had been observed in 12 (out of 13) patients at the end of 4 weeks treatment with oral piroximone 25 mg four times per day. All of the 12 patients were considered for long-term therapy and followed up for a period of up to 12 months. During this period, 2 patients died, and a further 2 experienced worsening of heart failure within 6
volume index after chronic
months after starting oral piroximone therapy, while 8 completed the l-year follow-up. In 7 of these 8 patients, clinical evaluations showed sustained benefit as demonstrated by significant increases in exercise tolerance along with symptomatic improvement over the entire observation period. The remaining patient experienced recrudescence of symptoms towards the end of follow-up and was no longer able to undergo final exercise testing. There has been concern that inotropic agents by stimulating the failing myocardium may accelerate the progression of the underlying heart disease. In the subgroup of patients (n = 7) who underwent repeated hemodynamic investigation
203
dynes
set
cm-5
Fig. 5. Mean hemodynamic effects of four incremental intravenous doses of piroximone on right atria1 pressure (RAP). sy,stemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) before and after chronic treatment with piroximone. n = 7.
there was no significant worsening of cardiac function at l-year follow-up as shown by similar baseline hemodynamics. Although the possibility that piroximone might have had a deleterious effect in the 2 patients with hemodynamic deterioration cannot be excluded, it should be kept in mind that worsening of cardiac function due to disease progression is commonly seen in heart failure and is. therefore, not necessarily related to drug administration. However, the subgroup of patients followed for 1 year were self-selected by the fact that they had responded favorably and “survived”. Therefore, the possibility of enhanced myocardial damage cannot be excluded based on the present study results. Another concern that has been raised with inotropic agents is that they may induce or aggravate cardiac arrhythmias. The mechanism of action of piroximone appears to be related, at least in part, to phosphodiesterase type III inhibition with a consequent rise in intracellular cyclic adenosine monophosphate resulting in improved calcium handling. In addition to the increased energy requirements caused by enhanced myocar-
dial contractility, the increased cellular level of cyclic adenosine monophosphate can also be arrhythmogenic f15.161. In the present study. sudden death probably related to malignant arrhythmias occurred in 2 patients. Analysis of 24-h ambulatory electrocardiograms revealed no significant arrhythmia increases in the group as a whole (n = 9). but if the individual patient data are considered, arrhythmia increases were sufficient in 3 patients to qualify as proarrhythmogenic while one patient displayed an antiarrhythmic response. The relationship between sudden death. arrhythmia deterioration and piroximone therapy remains unclear. The question whether piroximone has arrhythmogenic properties cannot be resolved by the present data since the small sample size and the lack of a parallel control group compromises the evaluation of these effects which, equally, could have been caused by the natural course of underlying heart disease. At initial hemodynamic assessment, administration of a single oral dose of 25 mg of piroximone to a subset of patients (n = 5) resulted in hemodynamic improvement characterized by a
204
20% increase in mean cardiac index and a 30% decrease in mean pulmonary capillary wedge pressure. This hemodynamic response, though less pronounced than with intravenous piroximone, was felt adequate to improve cardiac function in the patients studied, all of whom presented with moderate to severe heart failure. Readministration of a single oral dose of 25 mg, at final hemodynamic assessment, led to similar effects indicating that the patients had retained the responsiveness to the circulatory effects of piroximone during continuous therapy. When comparing the hemodynamic responses to intravenous piroximone before and after chronic therapy, there was no significant difference in the overall effect, but the responses tended to be less marked at follow-up and at some, but not all dose levels, the differences reached statistical significance. However, even if the hemodynamic responses tended to be less, administration of intravenous piroximone at final assessment still resulted in major hemodynamic improvement. The present results suggest that larger controlled trials with piroximone as adjunctive therapy in the management of patients with chronic heart failure are needed.
Acknowledgments We gratefully acknowledge the secretarial of Carine Dott and Eliane Sturm.
help
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vascular properties of a new cardiotonic agent, MDL 19.205. J Cardiovasc Pharmacol 1984;6:35-42. 5 Roebel LE. Dage RC. Cheng HC, Woodward JK. In vitro and in viva assessment of the cardiovascular effects of the cardiotonic drug MDL 19.205. J Cardiovasc Pharmacol 1984;6:43-49. 6 Kariya T, Wille LJ, Dage RC. Studies on the mechanism of the cardiotonic activity of MDL 19.205: effects on several biochemical systems. J Cardiovasc Pharmacol 1984:6:5055. 7 Petein M, Levine TB. Cohn JN. Hemodynamic effects of a new inotropic agent, piroximone (MDL 19.205) in patients with chronic heart failure. J Am Co11 Cardiol 1984:4:364371. 8 Arbogast R. Brandt C, Fincker JL, Schechter PJ. Acute hemodynamic effects of piroximone (MDL 19.205) in patients with moderate congestive heart faiIure:comparison with sodium nitroprusside. J Cardiovasc Pharamcol 1986;8:82-89. 9 Massie BM. Cornyn J. Topic N, Loge D, Podolin RA. Combined hemodynamic and scintigraphic assessment of piroximone (MDL 19.205) and comparison with dobutamine and nitroprusside. Am J Cardiol 1987:60:647-653. 10 Petein M. Levine TB, Cohn JN. Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19.205) in patients with congestive heart failure. Circulation 1986;73 (suppl 111):230-236. 11 Weber KT, Janicki JS. Jain MC. Piroximone (MDL 19.205) in the treatment of unstable and stable chronic heart failure. Am Heart J 1987:87:805-812. 12 Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 6th ed Boston: Little, Brown, 1964:1-23. 13 Velebit V, Podrid P, Lown B, Cohen B, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs Circulation 1982;65:886-894. 14 Morgenroth J, Michelson EL, Horowitz LN, Josephson ME. Pearlman AS, Dunkman WB. Limitations of routine long-term electrocardiographic monitoring assess ventricular ectopic frequency. Circulation 1978;58:408-414. 15 Lubbe WF, Podzuweit T, Daries PS, Opie LH. The role of cyclic adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest 1978;61:1260-1269. 16 Podzuweit T, Lubbe WF. Opie LH. Cyclic adenosine monophosphate. ventricular fibrillation and antiarrhythmic drugs. Lancet 1976;1:341-342.