The Effect of Flosequinan in Patients with

Acute-Onset Complicating

Acute Myocardial Infarction

Adam SCHNEEWEISS, M.D.,1 Ronan D. WYNNE, M.D.,2 and

Alon MARMOR, M.D.3

SUMMARY

We studied the hemodynamic effect of a single dose of the new direct-

acting vasodilator, flosequinan, in 25 patients with severe acute-onset

heart failure complicating acute myocardial infarction, which was resist-

ant to high doses of diuretics, nitrates and dobutamine given intrave-

nously. Flosequinan was added to conventional therapy within 3.7•}

0.8 days of the infarction in the form of a single oral dose of 100mg.

Hemodynamic monitoring was performed every hour for 4 hours after the

administration, without any other drug being added. Flosequinan pro-

duced hemodynamic improvement in all patients. The effect peaked at

1 to 2 hours and remained at this level at 4 hours. Pulmonary capillary

wedge pressure decreased from 28.4•}4.5 to 17.8•}5.7mmHg and cardiac

output increased from 3.5•}0.3 to 4.0•}0.4L/min (p<0.05 for both).

Pulmonary arterial and pulmonary vascular resistances were also signifi-

cantly reduced. Heart rate was not significantly altered. Mean sys-

temic arterial pressure was slightly but not significantly reduced. Admin-

istration of flosequinan was not associated with symptomatic hypotension,

cardiac arrhythmias or other adverse events and the hemodynamic effect

was not related to the pre-treatment serum sodium concentration. We

conclude that flosequinan is effective in producing acute hemodynamic

improvement in patients with heart failure complicating acute myocardial

infarction which is resistant to conventional therapy. Flosequinan is

well tolerated in this group of patients and therefore further studies to

determine the duration of action of the drug in this condition are ap-

propriate.

Additional Indexing Words:

Flosequinan Heart failure

From the 1Geriatric Cardiology Research Foundation, Geneva, Tel-Aviv, 2Department of Clini- cal Pharmacology and Cardiovascular Studies, the Boots Company PLC, Nottingham, U.K., and

3 Cardiology Department, Zive Medical Center, Safed, Israel. Address for reprints: Adam Schneeweiss, M.D., Rossbachhohe 10, 6204 Taunusstein 4 (Seit- zenhahn), Fed. Rep. of Germany. Received for publication July 11, 1988.

Accepted February 21, 1989.

627 628 SCHNEEWEISS, WYNNE, AND MARMOR September Jpn. Heart 1989 J.

HE standard therapy in acute-onset heart failure complicating acute T myocardial infarction is a combination of diuretics and nitrates; on this there is general agreement. However, if this therapy fails, the other pharmacological alternatives are all controversial. The positive inotropic agents may increase the ischemic burden, expand the damaged myocardial zone and enhance arrhythmias. Angiotensin converting enzyme (ACE) inhibitors may cause hemodynamic deterioration, hypotension and impair- ment of renal function in a considerable portion of the patients.1),2) More- over, the standard recommendation is to stop or reduce the dose of diuretics for several days prior to initiation of these drugs. This is, of course, not practical in patients with acute myocardial infarction. The ƒ¿-adrenoreceptor blockers carry a risk of first dose hypotension. Even some calcium antago- nists can cause early hemodynamic deterioration in certain patients with chronic heart failure3) and the effect on mortality of their early administra- tion after myocardial infarction is yet unknown. Obviously there is a need for a new direct-acting vasodilator with a balanced venous and arterial ef- fect, for use in patients with heart failure resistant to conventional therapy, complicating acute myocardial infarction.

Flosequinan (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) is a newly synthesized balanced mixed arteriovenous vasodilator.4),5) It has been shown to produce hemodynamic and clinical improvement in patients with chronic congestive heart failure.6),7) The purpose of this communica- tion is to describe our experience with the use of single doses of flosequinan in resistant heart failure complicating acute myocardial infarction.

MATERIALS AND METHODS

Twenty-five patients with acute myocardial infarction were studied.

Their mean age was 66.6•}10.7 years. Twenty were males and 5 were fe- males. Five had anterior, 3 anterolateral, 6 anteroseptal, 3 inferolateral, 2 inferior, 1 both anterior and inferior and 5 non Q wave infarctions. They did not receive thrombolytic therapy. All developed severe heart failure with dyspnea at rest, pulmonary rales, and pulmonary congestion on chest x ray within (less than) 3 days of hospitalization. No hemodynamic or clinical improvement was achieved by intravenous furosemide (80-160mg), intrave- nous nitroglycerin, , or (5-10mg/h).

In 11 of the patients an attempt to add dobutamine, at titrated doses, produced no hemodynamic improvement or aggravated arrhythmias. All patients were hemodynamically monitored by a Swan-Ganz thermodilution catheter from the onset of heart failure and the above conventional ther- Vol. 30 No.5 FLOSEQUINAN IN HEART FAILURE 629

apeutic intraventions were made in the 24 hours prior to the administration of flosequinan.

When no hemodynamic and/or symptomatic improvement was achieved with conventional treatment, a single dose of flosequinan (100mg orally) was given, and hemodynamic monitoring was performed at 1, 2, 3 and 4 hours after the dose. The drug was given within 3.7•}0.8 days of the in- farction. No changes in doses of all other drugs were made in the 2 hours prior to administration of flosequinan or during the 4 hours of hemodynamic monitoring. No other drugs were given during this period.

A period of 4 hours was chosen for measurements because that was the earliest time after the dose at which another drug (such as an antiar- rhythmic drug or a diuretic) had to be given according to the clinical regimen determined before administration of flosequinan.

Pre-treatment evaluation on the day of flosequinan administration included physical examination, routine laboratory studies and chest x ray.

Heart rate and rhythm were monitored constantly. Eight patients had pre-existing ventricular arrhythmias which required treatment with quinidine (6 patients), disopyramide (1 patient) and/or lidocaine (2 pa- tients).

Data analysis:

The hemodynamic responses to flosequinan at 1, 2, 3 and 4 hours after administration of the drug were compared to the pre-treatment levels. Qual- itative and quantitative differences between any two measurements and between each measurement and the pre-treatment values were compared using the t-test for paired data. Group data are expressed as means•}SEM.

In addition, repeated-measures analysis of variance was used for repetitive measurements. The Student Newman-Keul's test was used for multiple comparisons.

RESULTS

Flosequinan was given within 3.7•}0.8 days of the acute infarction.

Hemodynamic improvement, including reductions in pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resis- tances were observed, associated with increases in cardiac output (Table I).

The changes peaked at 1 to 2 hours after drug administration and remained constant for the 4 hours of monitoring. The reduction in right atrial pres- sure and systemic vascular resistance did not reach statistical significance.

Heart rate was not significantly altered. Systemic arterial pressure was slightly but not significantly reduced (Table I). The rate-pressure 630 SCHNEEWEISS, WYNNE, AND MARMOR September Jpn. Heart 1989 J.

Fig.1. Changes in mean pulmonary artery pressure induced by flose- quinan. A significant reduction was found after 1 hour which remained stable during the follow-up period.

Fig.2. Changes in left ventricular filling pressure induced by flose- quinan. Significant reduction occurred 1 hour after drug administration, remaining stable for the next 3 hours. product was not significantly altered (Table II). Pre-treatment serum sodium concentration ranged from 130 to 145 mmol/L. There was no correlation between the hemodynamic effect and the serum sodium concentration. The addition of no other drug was required during the 4 hours of moni- toring. No patient died during the study period or in the subsequent 24 hours. Adverseeffects: The drug was well tolerated with no adverse effects observed. Flose- Vol. 30 No.5 FLOSEQUINAN IN HEART FAILURE 631

Fig.3. Changes in pulmonary vascular resistance induced by flose-

quinan. Significant reduction was observed beginning 1 hour after drug administration and behaving in a similar manner as mean PAP and capillary wedge pressure.

Fig.4. Changes induced by flosequinan in systemic vascular resistance. Although there was a trend towards a decrease in SVR, it did not reach statistical significance due to the high standard deviation. quinan did not induce cardiac arrhythmias in this group of patients and was safe in acute administration. A single case of sudden death 4 days after administration of a single 100mg dose of flosequinan was not considered to be treatment related.

DISCUSSION

This short-term study showed that a single oral dose of flosequinan can produce beneficial hemodynamic changes in patients with acute-onset heart 632 SCHNEEWEISS, WYNNE, AND MARMOR September Jpn. Heart 1989 J.

Fig.5. Changes induced by flosequinan in cardiac output. There was a slight but significant increase in cardiac output between 1 and 4 hours.

Table I. Hemodynamic Parameters Before and at Peak Effect of Flosequinan

HR=heart rate (beat/min); SAP=systolic arterial pressure (mmHg); DAP=diastolic arterial

pressure (mmHg); MAP=mean arterial pressure (mmHg); PCWP=pulmonary capillary wedge

pressure (mmHg); SPAP=systolic pulmonary artery pressure; DPAP=diastolic pulmonary artery pressure; MPAP=mean pulmonary artery pressure; RA=right atrial pressure (mmHg); CO= cardiac output (L/min); SVR=systemic vascular resistance (dynes•Esec•Ecm-5); PVR=pulmonary

vascular resistance (dynes•Esec•Ecm-5).

Table II. Changes in Double Product Vol. 35 No.5 FLOSEQUINAN IN HEART FAILURE 633 failure complicating acute myocardial infarction, which is resistant to high- dose conventional therapy. Of special note is the persistence of the effect throughout the period of the study and the lack of adverse effects. Flose- quinan is a new synthetic vasodilator with a balanced effect on the venous and arterial vascular beds. At present it is only available in the oral form, however, following this route of administration it is rapidly absorbed and has a duration of action of 24 hours or, in some cases, even 30 hours. Part of its effect is attributed to an active metabolite, BTS 53554,5) formed by S- oxidation.

The hemodynamic responses to flosequinan in our patients with acute myocardial infarction resemble those observed in previous studies of the effect of single-dose or long-term therapy in patients with chronic congestive heart failure. Kessler and Packer7) studied the effect of a single oral dose of flosequinan, 1.5mg/kg, added to digitalis and diuretics, in 10 patients with severe chronic congestive heart failure. One to 2 hours after administration, increases in the cardiac index from 1.82•}0.11 to 2.29•}0.13L/min/m2 (26%) and stroke volume index (27%) were observed. Left ventricular filling pres- sure was reduced from 28.7•}1.7 to 16.1•}1.4mmHg (44%), mean pulmonary artery pressure-by 31%, right atrial pressure-by 66%, systemic vascular resistance-by 28% and pulmonary vascular resistance-by 24%. All these changes were statistically significant and persisted for 24 hours. Heart rate

was not significantly altered.

Similar hemodynamic responses to a single dose were found by Remme

et al8) and in a group of 12 patients with chronic congestive heart failure

which we studied (unpublished data).

Kessler and Packer6) studied the effect of long-term treatment with

flosequinan, 100-150mg/day, for 8-12 weeks in 26 patients with chronic

congestive heart failure. The initial hemodynamic response was similar to that described above and it persisted throughout the study period, as demon-

strated by repeated catheterizations. The present study is, to the best of

our knowledge, the first attempt to investigate the hemodynamic effect and

safety of flosequinan in acute heart failure complicating myocardial infarc-

tion, using invasive techniques.

A possible disadvantage of flosequinan in the treatment of heart failure

complicating acute myocardial infarction is its long duration of action.

Otherwise, the drug has many advantages over most other vasodilators used

as third-step therapy in heart failure resistant to high doses of diuretics and

nitrates. One of the most important is the lack of first-dose hypotension.

Additionally, the response is not related to the serum sodium level, which

is likely to be depleted in a proportion of these patients. The rate-pressure 634 SCHNEEWEISS, WYNNE, AND MARMOR September Jpn. Heart1989 J. product was not altered in our patients indicating that flosequinan does not increase the myocardial oxygen demand. Of special importance is the decrease in pulmonary vascular resistance which in our study was greater (by percentage) than the decrease in systemic vascular resistance. Unloading of the right ventricle is now recognized as an important factor in treatment of heart failure. The absence of tachy- cardia and symptomatic hypotension are other important advantages over alternative therapies. This study indicated that flosequinan could be safely added to diuretics and other vasodilators, in the acute setting. It should be remembered, however, that the blood pressure of our patients averaged 136/80 and the results cannot be directly extrapolated to the use of flose- quinan in patients who are not normotensive. In summary, flosequinan was shown to produce hemodynamic improve- ment in patients with acute-onset heart failure complicating acute myocardial infarction. The drug was safe and well tolerated. Further studies are now appropriate, with larger number of patients and longer periods of hemo- dynamic monitoring.

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