Long-term vasodilator treatment with flosequinan does not lead to hemodynamic tolerance or neurohormonal activation in severe heart failure

Journal of Cardiac Failure Vol. 1 No. 2 1995

,:,.'

Long-term Vasodilator Treatment With Flosequinan Does Not Lead to Hemodynamic Tolerance or Neurohormonal Activation in Severe Heart Failure G. L O U I S

BARTELS,

MAXIME

R LOOK,

MD, WILLEM

J. R E M M E ,

MD, PhD,

M S c , D I C K A. C. M . K R U I J S S E N ,

MD

R o t t e r d a m , The N e t h e r l a n d s

Abstract: Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohol~lonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 _+ 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 + 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of fiosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenualed during long-term treatment, flosequinan induces sustained arterial dilatation and imprmes cardiac pump function without activation of circulating neurohormones. Key words: f osequinan, vasodilatation, neurohormones, plasma level.

During the last decade, heart failure has become a major clinical problem, due to its ever increasing incidence and significant morbidity and mortality rates. _Although recent pharmacologic developments 1,2 (ie, angiotensin-converting enzyme [ACE] inhibition) have resulted in improvement, the effect of other approaches has not been uniformly positive. Vasodilator therapy, especially arteJial vasodilators

and, to a lesser extent, venodilators, is prone to hemodynamic tolerance during long-term therapy. Although this may significantly affect their clinical efficacy, possibly as a result of reflex vasoconstriction due to neurohormonal activation, unloading of the heart via vasodilatation is still considered potentially beneficial in heart failure, and the search for vasodilator therapy continues. >8 Flosequinan, a quinilone derivative, is a direct-acting, balanced-type vasodilator. At clinically effective plasma concentrations, it presumably reduces the turnover of inositol phosphates, thereby modulating intracelhilar calcium kinetics. 9 In addition to its vasodilating properties, flosequinan exerts a dose-dependent cardiotonic effect in animal models. ~14 A moderate inotropic effect is also observed

From Zuiderziekenhuis and Sticares Cardiovascular Research Foundation, Rotterdam, The Netherlands.

Manuscript received February 7, 1994; revised manuscript received June 23, 1994; accepted June 30, 1994. Reprint requests: W. J. Rename, MD, PhD, SticaresCardiovascular Research Foundation, PO Box 52006, 3007 La Rotterdam, The Netherlands.

117

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Journalof Cardiac Failure Vol. 1 No. 2 March 1995

informed consent, 23 patients (19 men and 4 women; mean age, 65 years; range, 52-79 years) with stable, moderate to severe heart failure, New York Heart Association (NYHA) classification II-IV, due to either ischemic or idiopathic dilated cardiomyopathy, were enrolled in the study. Patients with symptoms of dyspnea and/or fatigue, a left ventricular ejection fraction _<40%, as measured by radionuclide angiography, and either a resting cardiac index less than 2.5 L/mirdm2 and/or a pulmonary wedge pressure greater than 15 mmHg at baseline were included. Patients with stenotic valvular heart disease, angina pectoffs, a myocardial infarction, cardiac bypass surgery or coronary angioplasty within 3 months before the study, a systolic blood pressure < 100 mmHg, and renal or hepatic dysfunction were excluded. Heart failure was caused by ischemic heart disease in 20 patients and by idiopathic dilated cardiomyopathy in 3 patients. At baseline, 5 patients were in NYHA class II, 13 in class Ill, and 5 in class IV. The average left ventricular ejection fraction, as measured by radionuclide angiography, was 21% (range, 6-37%). Preexisting heart failure therapy consisted of loop diuretics in 21 patients, additional potassium-sparing diuretics in 21, digitalis in 15, vasodilator therapy in 11, nitrates in 8, calcium antagonists in 3, and hydralazine in 1. Six patients received ACE inhibitors and one patient received low-dosage metoprolol. Demographic and clinical criteria are given in Table 1.

after a 100 mg oral dose in heart failure patientsY Flosequinan is rapidly absorbed with peak plasma levels within 2 hours after oral administration and has a 2.5hour plasma half-life. 16 In contrast, its major active metabolite (BTS 53554) has a plasma half-life of approximately 38 hours. 17Although this allows for once-daily use, high plasma levels of BTS 53554 may result, which have been identified with phosphodiesterase-inhibiting activity. 13'14 Elevated BTS 53554 plasma levels and, hence, the possibility that phosphodiesterase inhibition may occur, can be relevant in view of the adverse outcome in long-term control trials with flosequinan, such as the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) study.18 In patients with congestive heart failure, flosequinan spurs hemodynamic and clinical efficacy, both following acute and short-term oral administration. 19-22Whether its plasma levels and those of BTS 53554 are altered during long-term treatment and whether this correlates with late hemodynamic tolerance or neuroendocrine changes is less well knOwn, however. This study was designed to evaluate the long-term pharmacokinetic, hemodynamic, and neuroendocrine profile of flosequinan and BTS 53554 in patients with moderate to severe heart failure and how it is related to the effects of flosequinan on hemodynamics and circulating neurohormones. Materials a n d M e t h o d s Patient Characteristics

Instrumentation

After approval of the study protocol by the institutional ethical review board, and after patients gave written

After a 5-day prestudy period during which all vasodilator, ACE-inhibitor, and beta-blocking therapy

Table 1. Clinical and Hemodynamic Characteristics of the Patients at Baseline Patient No.

Age (years)

Sex

Etiology

Class

LVEF (%)

1

78

M

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17" 18" 19" 20* 21" 22* 23t

52 63 70 57 64 71 62 67 69 66 62 52 70 53 74 64 69 66 63 79 61 67

M M M M F M M M F M M M M M M M M M M F F M

IHD IHD IHD IHD IHD IHD IHD IHD DCM IHD IHD IHD IHD IHD DCM IHD IHD IHD IHD IHD IHD DCM IHD

III II III III IV III III III II III III IV III III II 1I III III IV III IV IV II

20 20 36 24 22 28 17 6 25 25 31 7 18 14 26 26 18 18 24 11 37 14 19

NYHA

PCWP (mmHg) 23 20 22 6 31 5 18 20 25 16 19 23 19 9 30 18 15 29 40 24 28 29 8

Cardiac Index (L/rninhnz) 1.23 2.33 1.20 1.91 1.32 1.75 2.07 2.30 1.49 1.96 2.26 2.05 2.53 1.07 1.35 1.98 2.56 1.20 1.19 1.63 1.40 2.83 1.88

Duration of Outpatient Phase (weeks) 30 38 26 24 17 18 14 14 19 13 13 8 7 10 9 14 12 9 4 23 4 7

*Patients who died of progressive heart failure. -~Patient who died of a ruptured abdominal aortic aneurysm. NYHA, New York Heart Association; LVEK left ventricular ejection fraction; PCWP, pulmonary wedge pressure; IHD, ischemic heart disease; DCM, dilated cardiomyopathy.

Long-term Effects of Flosequinan

•

Bartels et al.

119

was withdrawn, patients were hospitalized 4 days prior to hemodynamic evaluations and maintained on a 2 g sodium diet. Patients continued with digitalis and diuretics , which were administered in the evening, 15 hours prior to baseline measurements on consecutive study days. On the day preceding the study, patients were admitted to the coronary care unit. Approximately 16-18 hours before the study, a Swan-Ganz thermodilution catheter (Baxter Healthcare, Irvine, CA) was positioned in a pulmonary artery to record right atrial and pulmonary artery pressures and to measure cardiac output. The latter was assessed using a bedside cardiac output computer (Edwards Laboratories, Irvine, CA). Triplicate measurements with a variation of less than 10% were accepted. Arterial pressures were measured noninvasively with an automatic oscillometric blood pressure device (Dinamap, Critikon, Tampa, FL), One electrocardiographic lead was monitored continuously for heart rate measurements.

solid-phase extraction cartridge (Bond-Elut C 1 8 ) a n d injected into a high-pressure liquid chromatograph (column: Liehrosorb 10 gm RP8, mobile phase: water/methanol/acetonitrile [65/20/10] with a flow rate of 1.5 mL/min at 40°C). Flosequinan'and BTS 53554 were determined by ultraviolet detection (X = 254 ran). Peak height ratios were measured electronically and concentrations were obtained by reference to a previously derived calibration curve.

Hemodynamic Measurements and Calculated Variables

Study Protocol

The measured hemodynamic pararaeters included heart rate (HR, min~), mean arterial pressure (MAR mmHg), mean pulmonary artery pressure (MPAR mmHg), pulmonary wedge pressure (PCWR mmHg), mean right atrial pressure (RAE mmHg), and cardiac output (CO, L/rain). The pulmonary artery and right atrial pressures were measured at midrespiration to assure stable values. From the above-mentioned parameters, the following variables were calculated: cardiac index (CI, L/min/m 2) = CO/BSA, where BSA = body surface area (m 2) stroke volume index (SVI, mL/m 2) = CI/HR stroke work index (g • m/m 2) (MAP-PCWP) • SVI • 0.0136 systemic vascular resistance (dyne • s • cm -5) = (MAP-RAP) • 80/CO pulmonary vascular resistance (dyne, s • cm 4) = (MPAP-PCWP) • 80/CO

Neurohumoral Determinations Venous blood was collected for norepinephrine (nmol/L), epinephrine (nmol/L), aldosterone (nmol/L), and plasma renin activity (nmol/L/h). Determinations were carried out by using a radioenzymatic assay for norepinephrine (normal range, 0.6-2.5 nmol/L) and epinephrine (normal range, 0.05-0.3 nmol/E). 23Aldosterone (normal range, 0.08-0.69 nmol/L) an d plasma renin activity (normal range, 0.9-2.4 nmol/L/h) were determined by radioimmunoassay. 24,25

Plasma Drug Levels Flosequinan, its first derivative BTS 53554, and an internal standard (BTS 49037) were selectively eluted from a

Nuclear Angiography Resting left ventricular ejection fraction was determined by multigated bloodpool scanning, using an MDS A 2 computer program, after in vivo labeling with 740 MBq99mTc. Scanning was performed in a 350-40 ° left anterior oblique position with a 10 ° cranial tilt for optimal separation of the left and right ventricles.

During the study, patients were hospitalized twice for invasive hemodynamic studies, which were separated by an outpatient phase of 17 _+ 2 weeks during which patients were on chronic flosequinan treatment. Both hospitalizations were comparable in design and consisted of a 4-day stabilization phase, followed by a 3day period during which hemodynamic studies were carried out. Nuclear angiography was performed before instrumentation during both hospitalizations. On each study day, repetitive control hemodynamic measurements were carried out, 2.5 hours after a light breakfast, to achieve stable baseline values. Following control evaluations, patients received, in a single-blind fashion, 100 mg flosequinan on day 1, placebo on day 2, and 100 mg flosequinan on day 3. This order was chosen to evaluate a 48-hour period without active treatment after an oral dose of flosequinan, in view of the long plasma half-life of BTS 53554. On each study day, hemodynamic variables were reassessed at 30, 60, 90, 120, 180, and 240 minutes, and at 24 hours after drug administration. Venous blood sampling for the determination of flosequinan and BTS 53554 plasma levels was performed at baseline, at 30, 60, 120, and 180 minutes, and at 24 hours after drug administration, whereas blood samples for the assessment of neurohormonal variables were collected at baseline and at 2 and 24 hours after drug administration. Patients were allowed to eat immediately after the 4-hour hemodynamic assessment. After completion of the 24-hour measurement on study day 3, patients were discharged and continued with 100 mg flosequinan daily during the outpatient and second hospitalization phase. On the first study day of the second hospitalization (R-day 1), patients received 100 mg flosequinan, placebo on R-day 2, and 100 mg flosequinan on R-day 3. During this period, digitalis and diuretics were continued in unchanged dosages.

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Journal of Cardiac Failure Vol. 1 No. 2 March 1995

Statistical Analysis

Hemodynamic Effects of Flosequinan

Statistical analysis consisted of analysis of variance for repeated measurements using the mixed procedure of the SAS 6.08 statistical software (Cary, NC). A two-tailed P value <.05 was indicative of a significant difference.

Short-term Effects. Following the first dose of flosequinan, pulmonary wedge pressure decreased by 40% after 1 hour; this effect lasted for 4 hours. After the second administration of flosequinan on day 3, an almost equivalent reduction in pulmonary wedge pressure of 35% was observed (Fig. 1B). Right atrial pressure also decreased by 54% between 1 and 2 hours after the first dose, but remained decreased until baseline on day 3 without further ctaanges after readministration of flosequinan (Fig. !B). Comparable changes were observed in mean pulmonary artery pressure (Table 2). Flosequinan immediately reduced systemic vascular resistance by 24% at 2 hours after administration, and it remained decreased until baseline on day 3, with a further 15% reduction following repeat administration. Concomitantly, cardiac index increased by 27% on day 1 and remained' improved for 48 hours, with a further increase of 18% on day 3 (Fig. 1C). As flosequinan did .not affect heart rate, stroke volume index also increased on day 1 by 20%; however, this improvement was relatively shortlasting (4 hours). Similarly,. stroke work index increased by 28%. Flosequinan did not affect arterial pressures during the entire study period. No hemodynamic changes occurred on day 2 during placebo treatment. Long-term Effects. Daily treatment with 100 mg flosequinan resulted in significant reductions in systemic (21%) and pulmonary (38%) resistances and in mean pulmonary pressure (12%) at baseline on R-day 1. Moreover, the baseline heart rate and cardiac index increased by 14 and 20%, respectively. Other baseline values were not affected during long-term flosequinan administration (Table 3). Following readministration, changes in pulmonary wedge and right atrial pressures were clearly attenuated as compared to those observed during first-dose administration (Fig. 1B). Moreover, systemic resistance, cardiac index, stroke volume index, and stroke work index did not change further following administration of flosequinan during the second hospitalization, although on R-day 3, cardiac index increased temporarily by 9 % .

Results Seven patients died during the course of the study while on flosequinan. Progressive' heart failure was the cause of death in six patients. The seventh patient died of a ruptured abdominal a0rtic~aneurysm 7 weeks after initiation of the study. Sixteen patients completed the study. The 7 deceased patients were excluded from the analysis of the long-term effects of flosequinan; thus, the study results are based on the 16 patients who completed the investigation. Flosequinan was well tolerated by the patients; only two experienced a mild headache after the first two dosages, starting approximately 1 hour after drug administration and lasting for 6 hours.

Plasma Drug Levels Short-term Effects. Plasma flosequinan levels increased immediately following the first oral administration of 100 mg flosequinan, with a peak value of 1.9 _+ 0.2 mg/L at 60 minutes, followed by a progressive decline toward baseline at 24 hours (Fig. 1A). During repeat administration on day 3 a similar change occurred. In contrast, the level of BTS 53554 increased slowly throughout the first day, with a maximal level of 1.4 + 0.2 mg/L at 24 hours, stabilized on the second (placebo) day, and increased further level of 2.6 _+0.7 mg/L at 24 hours after repeated drug administration on day 3. Long-term Effects. Long-term administration of flosequinan did not affect changes in flosequinan plasma levels, which were similar to those observed during the first two administrations. In contrast, plasma levels of BTS 53554 were markedly increased during longterm treatment to a level of 5.8 +_ 1.0 mg/L at baseline on R-day 1. BTS 53554 remained at this level following readministration of flosequinan during the hospitalization phase.

Fig. 1. Graphic representations following oral administrationof 100 mg flosequinanfollowing the first dose (day 1), second dose after 48 hours (day 3), during long-term administration (R-day 1), and repeated administrationafter 48 hours (R-day 3) for (A) plasma drug levels of flosequinan and its major metabolite, BTS 53554, (B) changes in pulmonary wedge pressure (PCWP) and right atrial pressure (RAP), and (C) changes in systemic vascular resistance (SVR) and cardiac index (CI). Open circles: significant differencefrom control day 1. Closed circles: nonsignificant difference from control day 1. *P < .05 vs daily control Data are presented as mean -+ SEM.

Long-term Effects of Flosequinan

•

Bartels et al.

']

FLOSEQUINAN mg/I

m:TS $3554

! I

C A

2

24

Day 1

~

2

24

Day 3

8hort-terr~

hours post-drug

C

2 R-Day 1

j

i

24

C

2

24 R-Day 3

Long-term

i

PCWP mmHg

lo

RAP mmHg

' 2

'

C a

' 4 1 Day

I

SVR d's'cm"

.

" 24

' C

' 2

' 4 3 Day

' 24

,Short-term

.~

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hours post-drug

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R-Day 1 4

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Long-term

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121

122

Journal of Cardiac FailureVol. 1 No. 2 March 1995

Table 2. Hemodynamic Changes Following Short-term Treatment With Flosequinan ' Day 1 Control PCWP (mmHg) RAP (mmHg) MPAP (mmHg) PVR (dyne • s • cm-5) SVR (dyne • s • cm-5) MAP (mmHg) Healt rate (min-~) Cardiac index (L/min/m2) SVI (mL/m2) SWI (g • rrdm2)

Day 3

2 Hours

4 Hours

24 Hours

Control

2 Hours

4 Hours

24 Hours

19 + 2 6 -+ 1 29 -+ 3 279 _+29 2,118 + 126 90 _+3 72 _+5 1.8 _+0.1

12"? 4"~ 25't 240 1,597'? 87 76 2.3*?

14"? 3"? 23"t 198't 1,824"? 89 75 2.1"?

16 4*? 26'? 209't 1,828"~ 86 74 2.0*?

16 -+ 2 4 + 1' 25 + 3* 202 _+37* 1,820 + 109" 91 _+4 72 _+5 2.1 _+0.1"

10"? 3* 22* 199" 1,558'? 85 73 2.3*?

13" 3* 23* 74* 1,707" 89 75 2.2*

15 3* 25* 266 1,956" 89 76 1.9'

26 + 2 25 + 2

31*t 32't

29*? 31*t

28 26

31 + 2* 31 _+3*

34* 34*

33* 34*

31" 30*

Day 1 represents the first dose of 100 mg flosequinan, day 3 represents second dose of 100 mg flosequinan, and hours represent the hours that have elapsed since flosequinan was administered. MAP, mean arterial pressure; MPAP, mean pulmonary artery pressure; PCWP, pulmonary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SVI, stroke volume index; SVR, systemic vascular resistance; SWI, stroke work index. *P < .05 vs control day. t P < .05 vs daily control. Data are mean _+SEM.

Table 3. Hemodynamic Changes During Long-term Treatment With Flosequinan R-Day 1

PCWP (mmHg) RAP (mmHg) MPAP (mmHg) PVR (dyne • s • cm-s) SVR (dyne • s • cm 5) MAP (mmHg) Heart rate (rain-1) Cardiac index (L/min/m2) SVI (mL/m2) SWI (g • m/mz)

"

R-Day 3

Control

2 Hours

4 Hours

24 Hours

Control

2 Hours

4 Hours

24 Hours

18 + 3 6+1 25 + 3* 183 + 33* 1,676 + 96* 87 -+4 82 + 5* 2.2 _+0.1"

15"t 4'? 24* 196" 1,664" 85 81" 2.2*

16 3'? 25* 212" 1,761" 87 82* 2.0*

17 4*t 25* 173" 1,751" 87 77* 2.1"

18 + 3 4 _+1" 27 - 3* 183 + 27* 1,656 + 83* 85 -+4 78 -+ 5* 2.1 +_0.1"

14"t 3* 23't 172" 1,544" 85 80* 2.4't

15"t 4* 24* 192" 1,572" 86 .... 79* 2.4*

21 7 28 161" L786" 90 77* 2.1"

28 _+2 27 + 3

29 27

27 27

27 26

28 +_2 26 _+4

30 28

29 29

29 27

R-day 1 represents the last dose of 100 mg flosequinan following chronic daily administration, R-day 3 represents the dose of 100 mg flosequinan 48 hours after the last long-term dose, and hours represent the hours that have elapsed since flosequinan was administered. *P < .05 vs control day. t P < .05 vs daily control. Data are mean _+SEM. Abbreviations the same as in Table 2.

Nuclear Angiography Left ventricular ejection fraction remained unaltered during long-term treatment with flosequinan, with values o f 21 + 2 % p r i o r to t h e s t u d y a n d 23 + 3 % after t r e a t m e n t .

Neurohumoral Changes Short-term E f f e c t s . F o l l o w i n g the first t w o a d m i n i s t r a t i o n s o f f l o s e q u i n a n , n o s i g n i f i c a n t c h a n g e s in n o r e p i n e p h r i n e , renin, a n d a l d o s t e r o n e l e v e l s w e r e o b s e r v e d . O n l y e p i n e p h r i n e w a s r e d u c e d at b a s e l i n e o n d a y 3 as c o m p a r e d to b a s e l i n e o n d a y 1, b u t it d i d n o t c h a n g e f u r t h e r after r e a d m i n i s t r a t i o n o f f l o s e q u i n a n (Table 4). Long-term E f f e e t s . F o l l o w i n g l o n g - t e r m a d m i n i s t r a tion of flosequinan, baseline values of epinephrine, norepinephrine, aldosterone, and renin were comparable

w i t h t h o s e at b a s e l i n e o n d a y 1. R e a d m i n i s t r a t i o n o f f l o s e q u i n a n d i d n o t r e s u l t i n a n y c h a n g e (Table 5).

Discussion Flosequinan, a novel, balanced-type vasodilator, induces short-term beneficial hemodynamic and clinical effects i n p a t i e n t s w i t h h e a r t failure. 19-22 R e c e n t d a t a indicate that long-term flosequinan may be equally beneficial, at least in t e r m s o f c l i n i c a l e f f i c a c y (ie, e x e r c i s e tolerance). 26-29 A l t h o u g h t h e latter o b s e r v a t i o n s u g g e s t s p r e s e r v a t i o n o f the h e m o d y n a m i c p r o f i l e o f t h e d r u g in h e a r t failure patients, r e l a t i v e l y little is k n o w n o f t h e c a r d i o v a s c u l a r activity o f f l o s e q u i n a n after l o n g - t e r m t r e a t m e n t . A s a vasodilator, f l o s e q u i n a n m a y i n d u c e a secondary neurohormonal response, which could nega-

Long-term Effectsof Flosequinan •

Bartels et al.

123

Table 4, Short-term Neurohumoral Effects of Flosequinan Day 1 Control Norepinephrine (nmol/L) Epinephrine (nmol/L) Renin (nmol/L/h) Aldosterone (nmol/L)

3.8 0.8 7.4 1.1

_+.0.5 -~:0.3 _+. 1.8 *_:0.2

Day 3

2 Hours

24 Hours

3.4 0.4 7.1 0.8

3.4 0.4 8.7 0.8

Control 3.2 0.3 8.4 0.8

2 Hours

24 Hours

3.4 0.4 7.8 0.8

3.5 0.4 6.9 0.9

_+0.4 _+0.l* + 2.l + 0.2

Day 1 represents the first dose of 100 mg flosequinan, day 3 represents the second dose of 100 mg flosequinan, and hours represent the hours tha! have elapsed since flosequinan was administered. *P < .05 vs control day 1. Data are mean _+SEM.

Table 5. Long-term Neurohumoral Effects of Flosequinan R-Day 1 Control Norepinephrine (nmol/L) Epinephrine (nmol/L) Renin (nmol/L/hour) Aldosterone (nmol/L)

4.3 0.4 5.3 1.1

,+_0.8 :_~0.1 :~_0.9 _*0.2

R-Day 3

2 Hours

24 Hours

4.3 0.5 4.6 1.1

3.5 0.4 5.1 1.0

Control 3.4 0.4 6.1 0.9

+ 0.5 + 0.1 + 1.5 + 0.3

2 Hours

24 Hours

3.4 0.4 4.2 0.7

3.5 0.4 4.7 0.8

R-day 1 represents the last dose of 100 mg flosequinan following chronic daily administration, R-day 3 represents the dose of 100 mg ftosequ nan 48 hours after the last long-term dose, and hours represent the hours that have elapsed since flosequinan was administered. Data are mean _+SEM.

tively affect its long-term vasodilato; efficacy and mortality. Recently, the PROF1LE study was prematurely terminated because 100 mg flosequinan daily increased mortality by 3 5 % . TM The only positive results on survival are observed with agents that reduce the neurohormonal activation in heart failure. 1,2 Moreover, mortality is significantly related to neurohormonal activation. 3°,31 Whether flosequinan leads to neurohormonal activation after long-term treatment is not well known. The purpose of this study was to evaluate whether the acute hemodynamic effects of flosequinan in patients with moderate to severe heart failure are preserved and reproducible following long-term administration of the drug and whether circulating neurohormonal changes influence its cardiovascular profile after long-term administration. As 7 of the initial 23 study patients died between both hospitalizations, this study was conducted on the 16 remaining patients. Six of the deceased patients had severe heart failure, NYHA classification III or IV, with the exception of one patient who died from a ruptured abdominal aortic aneurysm. Apart from a tendency toward being in a severe heart failure class, this patient group did not discriminate from surviving patients in terms of hemodynamic variables, left ventricular ejection fraction, or duration of heart failure before entry into the study (Table 1). Although the deaths of six of the seven patients were assumed to be related to the severity of their underlying disease, detrimental effects of flosequinan, possibly related to its presumed phosphodiesterase-inhibiting properties, cannot be excluded.

Hemodynamic Effects of Flosequinan Following Short-term Administration In this study, flosequinan induced immediate, shortlasting, but reproducible reductions in mean pulmonary artery and left ventricular filling pressures. In contrast, it induced an immediate but persisting reduction in systemic vascular resistance and fight ventricular filling pressure and, concomitantly, led to sustained improvements in cardiac index, stroke volume index, and stroke work index. Placebo administration did not affect the cardiovascular changes following ftosequinan. These observations compare well with previous acute studies with flosequinan. 19

Hemodynamic Effects During Long-term Treatment Following long-term administration, the initial preload reduction following first-dose administration of flosequinan was attenuated. However, its arterial vasolidafing effects were preserved. The latter were accompanied by a sustained increase in cardiac output. In a short-term study, flosequinan, administered for 6 days reduced pulmonary wedge pressure and increased cardiac output 24 hours after the last dose. 22However, in that study, cardiac output was not affected by the initial administration of flosequinan. Only after repeated administration, when plasma levels of flosequinan's main metabolite had become elevated due to its prolonged plasma half-life, did cardiac output increase. A cumulative, systemic vaso-

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Journal of Cardiac Failure Vol. 1 No. 2 March 1995

dilating effect in patients with heart failure and abnormally increased systemic vascular resistance were also reported by Kessler et al.19 In contrast, Cavero et al. 32did not observe this augmentation of vasolidating effects of flosequinan after 6 weeks of treatment in heart failure patients in whom baseline systemic vascular resistance values were within the normal range.

may have resulted in sufficiently high levels of BTS 53554 to induce phosphodiesterase-inhibiting effects. Clearly, this is a hypothesis that needs further documentation. Whether the increased mortality rate in the PROFILE study is related to neuroendocrine activation is as yet unclear. However, the absence of neurohormonal stimulation in our study does not support this, at least not for the 4-5 months' duration of the study period.

Neurohumoral Effects Neither acute nor long-term administration of flosequinan resulted in neurohumoral activation. In contrast, there was a tendency toward a reduction in circulating epinephrine levels and renin plasma activity. Absence of neurohumoral activation during flosequinan administration up to 6 weeks has been reported previously,zl,29 Our study adds to the observation that after a longer treatment period, neurohormones also do not change. These findings are of particular interest since long-term administration of flosequinan resulted in a 14% increase in heart rate in our study. Moreover, Elborn et al. z8 and Massie et al. 33 reported the occurrence of tachycardia in patients with severe heart failure following long-term treatment with flosequinan. The question arises whether, in the absence of enhanced sympathetic activity, this effect may be due to a direct effect on the sinus node, possibly as a result of accumulating BTS 53554 levels and phosphodiesterase-inhibiting effects.

Clinical Outcome and Plasma Drug Levels The pharmacokinetics of flosequinan itself do not change during long-term administration. The plasma levels of flosequinan were perfectly reproducible, with peak values of approximately 2 rag/L, 1 hour after oral administration, following both first-dose and long-term administration. In contrast, the plasma levels of flosequinan's first and active metabolite, BTS 53554, followed a completely different pattern, with gradually increasing values, due to its long plasma half-life of 38 hours. During long-term administration of flosequinan, plasma levels of BTS 53554 reached high values of about 6 mg/L. At these high levels, the phosphodiesterase-inhibiting properties of flosequinan may become more relevant. 13'14Of interest, in the flosequinan-ACE inhibitor trial (FACET trial), a higher dose of flosequinan (150 mg/day) worsened clinical well being, whereas a lower dose significantly improved quality of life after 16 weeks of treatment. 33 An augmentation of phosphodiesterase-inhibiting effects during long-term therapy theoretically could have contributed to this differential effect and to the negative outcome of the PROFILE trial. TM In the latter study, mortality reportedly increased in treated patients, irrespective of clinical class or left ventricular ejection fraction, but related to the dose level of flosequinan, that is, 100 mg daily. In contrast, a significant effect on survival was absent in the low-dose (75 rag) group. Again, in this study, the higher dose of flosequinan

Limitations of the Study The invasive character of this study and the severity of complaints in these patients with moderate to severe heart failure make a long-term placebo arm not desirable because of ethical considerations. As a result, a certain placebo effect cannot be ruled out in this uncontrolled study.

Conclusion During long-term treatment with flosequinan, the plasma levels of flosequinan's first metabolite, BTS 53554, increased significantly. This does not result in later tolerance. In contrast, flosequinan induces a sustained systemic vasodilatation and a persistent improvement in cardiac pump function and cardiac work without activating circulating neurohormones. Furthermore, the initial reduction in left and right heart filling pressures is attenuated.

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