Cardiovascular Drugs and Therapy 1991; 5 Suppl. © KI . . . . Academic Publishers, Boston. 3 7 3

Thrombolysis and

Antiplatelet agents

P178 rt-PA IN ACUTE MYOCARDIAL INFARCTION. EFFECTS ON MAJOR CARDIAC EVENTS AND EARLY MORBIDITY

David H. Roberts, William A. McCrea, Christopher M. Bellamy, David R. Ramsdale, Broadgreen Cardiothoracic Centre, Liverpool, United Kingdom

To assess potential benefits of rt-PA in addition to heparin (HEP) and aspirin (ASP) given early in acute myocardial infarction (MI), 61 pts were randomised double-blind after admission to either rt-PA 100 mgs IV over 3 hrs plus 1,000 U/hr HEP for 24 hrs plus 300 rags ASP daily (n=46) or HEP plus ASP only (n= 15). During the first 10 days, life threatening complications were less common in rt-PA pts (41% v 73%; P=0.04):

rt-PA Cont rt-PA Cont Death 3(7%) 2(13%) *Sustained VT I(2%) 3(13%) Non-fatal arrest 0 4(27%) *Pulmonary congestion 9(20%) 5(33%) Hypotension/ 2(4%) 3(20%) Pacing 1(2%) 2(13%) Inotropes (*requiring medical treatment)

However, coronary arteriography at 12 days (median) showed no difference in TIMI CLASS 0-1(35% v 27%) and 2-3(65% v 73%) between rt-PA and controls. At 3 months, more rt-PA patients were angina-free with greater activity ratings (71% v 39% ; P < 0.05). In conclusion, rt-PA early in MI may reduce life threatening complications within the first week after treatment as well as early morbidity but this benefit is not associated with improved coronary patency at or soon after hospital discharge.

P179 RANDOMIZED DOUBLE BLIND EVALUATION OF UROKINASE PRIOR TO CORONARY ANGIOPLASTY

P. Urban, B. Meier, V. Moles, F. de la Serna, AK. Pande, J. Favre, and PA. Dorsaz, Cardiology Center, University Hospital, CH-1211 Geneva 4, Switzerland

Early thrombus formation plays a crucial role in abrupt post angiopasty occlusion and may contribute to late restenosis, tn an ongoing double blind study we randomly assigned 136 consecutive patients to receive either placebo or urokinase 1,000.000 U as an iv bolus immediate[y prior to angioplasty in addition to 15-20,000 U heperin and aspirin. Main endpoints were major bleed, abrupt target lesion occlusion, myocardial infarction, need for emergency surgery, and death. Secondary endpoints were duration of femoral compression after sheath removal, puncture site hemgtoma, and fibrinogen levels after 5 and 24 hours, Results Placebo (n =66) Urokinase (n=70) Major bleed 0 0 Abrupt occlusion 3 (4%) 3 (3%) NS Myocardial infarct [Q wave] 2 (3%) [1 (2%)] 4 (6%) [0 (0%)l NS Emergent surgery 0 2 (3%) NS Death 0 0 Time to sheath removal (h) 9+7 9+7 NS Compression time (rain) 23+9 28+25 NS Hematoma + surgery 2 (3%) 0 (0%) NS Hematoma + transfusion 1 (2%) 1 (1%) NS Fibrinogen 24 h post-angioplasty(mg%) 384--+105 301+91 p<0,001 The administration of 1.000.000 U of iv urokinase prior to balloon coronary angioplasty appears safe and without clinical side effects despite & significant decrease of fibrinogen levels, There is no demonstrable beneficial effect on early post angioplasty complications for unselected patients. A possible effect on restenosis remains to be evaluated.

P180 Pooled Analysis of Pharmacokinetics of APSAC (Anisoylated Lys-Plasminogen Streptokinase Activator Complex) in Acute Myocardial Infarction Robin Fears, Ruth Standring. SmithKline Beecham Pharmaceuticals, Epsom, Surrey, U.K.

APSAC (anistreplase, Eminase) is a pro-enzyme whose rate of activation is determined by de-acylation. Plasma clearance half-life of total fibrinolytic activity was measured by a functional assay (fibrin-plate method) and published results have now been collated from 4 studies for 35 Acute Myocardial Infarction patients receiving the standard dose regimen (30U as a single intravenous injection in 2-5 minutes). The mean plasma clearance half-life was 80L--4 minutes, bioavailability being similar in male and female patients. Clearance half-life was unaffected by body weight (range 52-104 Kg) or by age of the patient (range 30-73 years). There was no association between pharmacokinetics and pretreatment antibody over a range of IgG up to 31.tg SK binding/ml serum (90th percentile) or pretreatment concentrations of o~z-antiplasmin and ct2-macroglobulin. The clinical findings confirm results obtained in experimental animals and substantiate the conclusion that the clearance of total circulating fibrinolytic activity after the administration of APSAC is controlled primarily by the rate of de-acylation. In consequence, the bioavailability of APSAC after a single injection is higher than the other standard thrombolytic agents. However, in clot lysis studies, in vitro, APSAC is found to be inhibited by e-aminocaproic acid and aprotinin so that atttidotes are available if it is ever desired to curtail the pharmacological action.

P181 DOES ASPIRIN INFLUENCE THE ONSET OF VENTRICULAR ARRHYTHMIAS IN MYOCARDIAL INFARCTION TREATED WITH THROMBOLYTIC THERAPY ? Viroinie Gressin, Yves Louvard, Michel Pezzano, Herv6 Lardoux, Gilles de Corbeil Hospital, CorbeiI-Essonnes, France.

Experimental studies have demonstrated that Aspirin (A) reduces reperfusion ventricular arrhythmias (VA). The purpose of this study was to evaluate the influence of A on VA during thrombolysis (T) for acute myocardial infarction. Forty consecutive Pts (age : 54 + 1,6 years, anterior infarction : 42,5 %) were treated intravenously with rtPA either alone (n = 23} or with a bolus of 250 mg of A (n = 17) within the first 6 hours (hrs) of onset of pain. Twenty four hr Hotter monitoring was started simultaneously with T and analysed on a Marquette 8000 computer. Premature ventricular complexes (PVCs), ventricular tachycardias (VT : _> 3 PVCs > 125 bpm) and accelerated idioventricular rhythms (AIVR : _> 3 PVCs < 125 bpm) were studied. The infarct-related artery patency (TIMI) was assessed by coronary angiography performed within 72 hr of onset of pain (26,7 + 2,52 hrs from pain, 60 % < 24 hrs). Nineteen Pts (83 %) treated with rtPA only and 17 Pts (100 %) treated with rtPA + A had a patent artery. Demographic data were similar in both groups. Reperfusion was achieved at the time of ST segment resolution. AlL Pts experienced VA without ventricular fibrillation.

rtPA (n = 19) rtPA + A In = 17) Number of PVCs Incidence of VG (%) Number of VT Incidence of AIVR (%) Number of AIVR

2944+1154 79

43+31 95

131 +55

2304 + 1358 65

5:~2 94

96+66 Mean + SEM, Mann-Whitney U test, p : NS for all comparisions

Intravenous A given with T for myocardial infarction seems to reduce the number of VT, but without reaching statistical significance. However, the variance ratio of VT between the 2 groups is highly significant (p < 0,001) suggesting a beneficial effect of A in Pts with a large number of VT.

Cardiovascular Drugs and Therapy 1991; 5 Suppl. 3 © Kluwer Academic Publishers, Boston.

P182 VI~i]~OJIAR ~ N~ DLST.~LE ,~NA:]NC]]~t~EE I~ATION ID ANGI~C O~LX~rICS

L .Oltrona ,P.A .Yerlini ,L. Ladelli,M. Sali,D.Grsaata ,M. Lombardo ,L.Campolo,

C.Be/li. DipartJmento Cardiologico DeC~,Osp.Niguarda,Milano,ltaly.

Ventricular arrhyt~(VA) were assessed in 25 pts with recent onset rest

angina(UA) at Holter monitoring in the first 72 h after hospitalization

sad at 15 day follow-up. Pts were randomized to receive in addition to conventional therapy either placebe(P1) or Streptokinase 1.5xlO61U in 60 min(~[b),or Streptdcinase 2.5xlO5Iu in 30 rain then lxlO5IU/h for 4&h(SKc). No antiarrhythmic drug was given. 24 pts had pramture ventricular ccm-

plexes(P~2) and 16 had episodes of vsatricular tachycardia(Vr) (me~):

P1 SKb SKc

h PVC TV WC TV WC 'IV 0-24 1 0 9 ~ 2 2.8..~2.0 1~.6j:59.3 7.1+5.9 935.8£4_52.4 29.1+1.5 24-48 25.I~.7_+1340.3~0.7 96.7:~1.8 0._3/0.1 L59.6!82.~ 1.5+2.6"

48-72 1127_+855 2.8~2.O 757.3~560 0.2_43.7 62.4~_31.7" 0.7_+0.4*

15 d 755.9~752 0.6!1.4 1550~1409 4.1+4.1 16.8~_12.5" 0.2_+0.4* *vsO-24 p 0.01

VA were not related to ejection fraction(FE) nor to severity of coronary disease(CAD) at lO-day angiography. In UA, VA are a frequent finding not

related to EF or severity of CAD. SKc se~m to reduce the number and se-

verity of VA during trentm~t sad at 15 days. 3heir prognostic sigrdfi-

cance has to be evaluated.

P183 EFFECT OF THROMBOLYTIC THERAPY ON LEFT VENTRICULAR FUNCTION AND gEOMETRY IN ONE YEAR FOLLOW-UP AFTER MYOCARDIAL INFARCTION ASSESSED 8Y SERIAL TWO-DIMENSIONAL ECHOCARDIOGRAPHY. S. Stawicki, J. Kochanowski, M. Jakubowska-Na3nigier, M. Niemczyk, g. Opolski, J. Stanislawska, T. Kraska. Dept. of CBrdiology, Medical Academy Warsaw, Poland.

The effects of thrombolysis on left ventricular /LV/ function and geometry were evaluated in 102 patients /pts/ with acute myocardial infarction /AMI/ by two-dimensional echocardiography performed before discharge and after one year follow-up. 64 pts were randomized to streptokinase /group I/ and 38 pts to heparin therapy /group II - cont- rol group/. In serial echocardiographic examination were assessed: left ventricular diastolic diameter /DD/, end- -diastolic volume /EDV/, wall motion score index /WMSI/, asynergic area /AA/, percent of dyskinetic segments /DS/ and LV thrombus. During examination in third week of AMI significant differences between both groups of pts showed: AA 27.4+20.4 vs 41.5+22.1 /p<O.02/, WMSI 1.44+0.50 vs 1.86+0.67 /p<O.02/ aGd DS 9 /14%/ vs 15 /39.5%/ /p<O.05/. In e~amination after one year significant differences were persisted.

The data indicate that thrombolytic therapy improves LV function in patients with AMI, reducing the extent of regional wall motion abnormalities. The beneficial effects persist up to one year.

374

P184 PROGNOSTIC SIGNIFICANCE OF AN EARLY PEAK PLASMA CK-MB AFTER STREPTOKINASE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION O.Stanistawska, 8.Opolski, K.Stomka, M.Niemczyk, A.gdrecki, W.Tadeusiak, T.Kraska, Oept. o f Cardiology, Medical Academy Medical Cent. of Postgraduate Education, Warsaw, Poland

Aithough an early peak in plasma CK-MB in acute myocar- dial infarction /AMI/ after thrombolytic therapy may indi- cate spontaneous reperfusion, yet its prognostic signifi- cance remains unknow. Among streptokinase treated patients with AMI we compare 59 pts with early CK-M8 peak /~15h/ after onset of symptoms to 45 pts with late CK-MB peak/>15h/

Early Late P Age /years/ 51.4 57.0 NS Reinfarction 4 /6.8%/ 3 /7.0%/ NS Ventr. fibrill. /<48h/ 5 /8.5%/ 2 /4.75%/ NS Complex ventr, arrhythmia 6 /10.3%/ ii /26.2%/ NS

/at 21st day/ In-hospital mortality l /1.7%/ i /2.5%/ NS New MI /follow-up av.18mo/ 4 /6.9%/ 2 /4.8%/ NS Unstable angina /av.18mo/ 8 /13.8%/ 2 /4.8%/ NS

An early peak CK-M8 in AMI after Streptokinase therapy has not prognostic significance in hospital period.

During follow-up period early peak of CK-MB is a pro- bably positive risk factor unstable angina and new MI.

P185 EFFECTS OF INHIBITORS OF THROMBOXANE A2 SYNTHETASE IN

PATIENTS WITH UNSTABLE ANGINA PECTORIS.

S.Be~iani, F.Gr~oo, G. Msttioli, Oardiolo~Univ~sityofModena, It~ky.

Several studies have documented release of arachidonic acid metabolite thromboxane ~ (TXA2) in the coronary venous blood of patients (pts) with unstable angina (UA) and have implicated TXA2 in vasoconstruction and in vivo platelet

aggregation. In order to investigate if selective TXA2

inhibitors (TXA2I) influence the clinical course of UA. we

enrolled 120 pts of both sexes with UA of which 58 were treated without ant±thrombotic therapy (CT) and 62 with

drugs TXA2I (Picotamide 300 mg. t.i.d, or Trapidil i00 mg. t.i.d.). Pts were monitored monthly up to 6 months. AMI and cardiovascular death (CD) were the primary end-points. The

results are shown in the table.

CT = 58 TXA2I = 62 Risk reduct, p value AMI 7 (12.0%) 3 (4.8%) 60 % N.S. CD 7 (12.0%) 1 (1.6%) 86 % N.S. TOTAL EVENTS 14 (24.0%) 4 (6.4%) 73 % p < 0.05

These data suggest the activation of platelets in pts with UA ahd the role of TXA2I to improve the prognosis in these pts.

P186 CELLUIAR F~L-31~NISM~ OF PROSTAGEANDIN E 2 ACTION

A.Runikhin, T.Krasnikova, G.Arabidze, V.Minchuna, M.Menshikov, P.Avdonin, Z.Gabbasov, A.Kravchenko, All- Union Cardiology Research Center, Moscow, USSR

A course of treatn~nt with Prostaglandin E 2 (I~2) iv infusions decreased blood pressure (BP) in 31 patients (pts) with severe essential hypertension (E~). To investi- gate cellular ~hani~s of PGE 2 action, mononuclear lym- phocyte B2-adrenoreceptor (62-AR) state, adenylate cyclase (AC) activity, Ca 2+ entry into platelets, and platelet ag- gregation, induced by 0,1~m ADP, were measured. 7 pts showed BP decrease only during the infusions. 24 pts had sustained effect: their BP dropped by 18-24% during PGE 2 infusions and remained low for at least 14 days af~d~ In 2 weeks after PGE 2 infusions, these pts showed 8 fold increase of initially low ly~ohocyte B2-AR affinity to ea- techolamines accc~panied with I, 5 fold decrease of ini- tially high B2-AR density and 2-3 fold increase of l-iso- proterenoljGpp(NH~, and forskolin capacity to activate AC. No reliable changes of these indices were noted in pts who had no sustained PGE 2 effect. PGE 2 infusions caused 2-3 fold decrease of ADP, platelet activating factor, end vaso- pressin induced Ca 2+ entry into platelets. PGE 2 normalized platelet aggregation which initially was 5 fold increased. Thus PGE 2 caused conversion of desensitizatio~ of B2-AR-AC + system and inhibition of receptor-mediated Ca ~ entry into cells.

P187 INDOMETHACIN AUGMENTS ANGIOTENSIN If-INDUCED ANTINATRIURESIS AND RENAL VASOCONSTRICTION IN MAN,

3G Motwani, AD Struthers, Dept. of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee.

We have studied in man the suggestion from experimental animal models that vasodilator prostaglandins (PGs) are important in counter-balancing the renal vasoconstrictor effects of renin-angiotensin system activation. 8 young adult male volunteers underwent overhydration on 4 separate mornings. Indornethacin (IND) 100mg or placebo (PL) was given at 10pm the night before and at Sam on the study day. After equilibration ei ther PL or angiotensin II (ANG II) lng/kg/min was infused. Effective renal plasma flow (ERPF) and glomerular f i l t ra t ion rate (GFR) were measured in ml/min as clearance of para-aminohippuric acid and inulin respectively. In comparison with PL (mean change±SEM, MANOVA), IND alone had no significant effects, ANG II alone reduced both sodium excretion (ENa, l~mol/min) (°2,4±0°3) and ERPF (-$1±16), both p<0.005, but not GFR. IND and ANG II together profoundly reduced ENa (-4.1±0.t~)and ERPF (-375±15) and in addition produced a fall in GFR (-30±2), all p<0.0005. Thus, non-steroidal ant i - inf lammatory drug therapy may be part icular ly deleterious in the presence of high circulating ANG lI levels, for example in chronic heart failure, where vasodilator PGs may play an important role in maintaining GFR by reducing afferent ar ter iolar constriction.

Cardiovascular Drugs and Therapy 1991; 5 Suppl. 3 © Kluwer Academic Publishers, Boston.

P188 EFFICACY AND SAFETY OF LOW-DOSE SUBCUTANEOUS HEPARIN IN PATIENTS WITH UNSTABLE ANGINA

D.Melina,G.Melina,lstituto Patologia Medica,Universit~ Cat tol ica del S.Cuore,Roma,ltalia

Before hospital discharge,50 consecutive male patients (P)admitted for unstable angina,were randomized for a 12- month study to conventlonal treatment(beta-blockers,nitra tes,calcium-antagonists) or conventional treatment plus subcutaneous Heparin(SH) 12.500 U1/die.The 2 groups of 25 P were similar for age,risk factors,cl inical data,hospita lization duration and hospital treatment,the only d i f fe - rence being SH treatment after discharge.All P were fo l lo wed for 12 months,and underwent an outpatient v i s i t every 4 months including:complete laboratory examinations,echo- cardiogram,standard and dynamic ECG.

In P treated with SH for 12 months we noted a s ign i f i - cantly lower incidence of myocardial infarct ion,refracto- ry angina,silent ischemia and ventricular arrhythmias.No adverse effects were observed.

375

P191 STREPTOKINASE (SK) PLUS DESMOPRESIN (DDAVP):FIBRINOLYTIC EFFECTS IN DOGS. R.Altman,E.Gurfinkel,B.Mautner,J.Rouvier,A. Scazziota,E.Cabrera Fisher and M.Benzazon,CEMEBl and Fundaci6n Favaloro,Libertador 2200,Buenos Aires,Argentina. The synergistic effect of SK and DDAVP in 12 non a- nesthetized dogs was studied. Each animal was trea ted with SK 2500 or 3750 U/Kg and DDAVP 6 or 8 ug at weekly intervals.drugs were given alone or toge- ther.Blood samples were collected before and 15, 30,60 and 120 min after infusion.No significant changes in hemogram,factor Vor VIII,a decrease of platelet count and fibrinogen were observed bet- ween groups. Euglobulin lysis time (ELT) was per- formed by 2 methods:ELTl was assayed by recalcifi- cation of whole Euglobulin fraction from dogs plas ma;ELT2 was assayed using human fibrin clot and t~ Euglobulin fraction obtained from the treated dog 's plasma. SK 2500 U/Kg plus DDAVP 6 ug produced a shortness in the ELT2 in relationship to the value obtained by each drug alone. Fibrinogen/fibrin de- gradation products increased in relationship to the shortness of ELT2.We conclude that SK and the tissue plasminogen activator released by DDAVP produced a synergistic activation of fibrinolysis in dogs.

P189 1 2 C 1 ~ (Iv L~ZF.tUtUX'a.t~ V'S ~ ]~1 PBK'v]gI~D!I)~ FaMK.Y

ltlY0E~I~IAL ]/~IFARCTII]N

TubsrO M, Mattioli G*, Cappello C*, Natale E, Gersrdi P~, Ricci R,

Milazzotto F - ~ Care Unit,S.Canillo Hospital and ~ of

Cardiology,tbi~ity of M0dena (Italy)

To co.pare defibrotide (D) vs heparin (H) efficacy in maintaining co-

ronary reperfbsicn after urokinase (U) d-~rapy (2 M IU iv over 12 hours

(h), we sDxiied 137 ~tive patients (p) with acute nlyocardial in-

farcticn (AMI),r~ 811coated after U eid~er to D (day 0:3.6 g iv

over 12 h; dsys 1-6:800 m£ rid iv; dsys 7-10:zK30 mg tid ira) or to H

(day 0:l(X30 IU/h x 12 h iv; days i-i0:5000 IU tid sc). 125 p had a com-

plete C~ curve and 106 p had ooron~ 6~giography (CA) on days 7-10.

Indirect evidence of reperfusion (enzyme peak earlier then 16 h) was

~ t in 64% p (D) vs 52% (H): ancng these p, 21/31 (6~) bad a patent

infarct related artery (IRA) at CA, vs 14/29 (49~) (H); in p wid~out ear-

ly er~ peak, IRA was patent in 10/17 (59%) (D) vs 11/28 (:3~T/o) (H).

All d%ese difTerences are not statistically significant, even if a clear

trend in favoar of D is sho~q. Overall, IPA was patent in 63~p (D) vs

(H) (p=O.06). These data demcr~trate that D is equal if not more effective than H

in achieving reperfusicn and preventing re~is in AMI.

P192 STREPTOKINASE DOES NOT AFFECT HUMAN NEUTROPHIL OXIDATIVE BURST OR CHEMOTAXIS

P. R. Hansen. A. Kharazmi. Dpt. of Medicine B, and Dpt. of Clinical Microbiology, Rigshospitalet, University of Copenhagen, DK

Neutrophils (PMN) accumulate in the myocardium during reperfusion after ischemic injury, and may contribute to tissue damage. We assessed the effects of streptokinase (SK) on PMN function.

Purified PMN were preincubated with various concentrations of SK and chemotaxis and chemiluminescence was determined following stimulation with opsonized zymosan (Z) or N-formyl-Meth-Leu-Phe (FMLP).

At SK concentrations encompassing therapeuticlevels, the chemilumi- nescence response of PMN to Z or FMLP was unchanged, and chemotaxis was unaffected. Furthermore, PMN chemiluminescence and chemotaxis were comparable to control values in 5 patients with myocardial infarction before and after the infusion of SK (1,5 MIO IU in 1 hour).

The results indicate that SK does not influence PMN function, and we conclude that modulation of PMN function is not contributory to the beneficial effect of SK in myocardial infarction.

P190 RELATIVE CONTRIBUTION OF IONIZED CALCIUM AND THROMBIN GENERATION IN THE MEDIATION OF AGONIST-INDUCED PLATELET AGGREGATION

D, Hoppensteadt, J. McConnell, J. Fareed, Loyola University Medical Center, Maywood, IL USA

To study the role of ionized calcium and thrombln generation in platelet aggregation, citrated (Cit) (3.2 mM), heparinized (Hep) (6.7 pM), and hirudinized (Hir) (1.5 pM) platelet rich plasma (PRP) were prepared (n-20). Agonists included collagen (0.8 #g/ml), arachidonic acid (300 #g/ml), ADP (2.5 #M), epinephrine (I0 #g/ml) and thrombin (0.5 u/ml). Aggregation profiles were analyzed for maximum % aggregation and slope. Ex- cept with epinephrine, agonist-lnduced responses were comparable in the three systems. Ionized calcium levels were identical (= i pM) in the platelet poor plasma of non-Cit systems. Response to thrombin was observed only in Cit PRP. With epinephrine, Hir PRP demonstrated a markedly diminished response which suggests possible alpha receptor modulation. Comparable responses to other agonists between Hit and Hep PRP suggest a minimal role of thrombln in mediating agonist-induced platelet activation. This data suggests a limited role of specific thrombln inhibitors such as hirudin in the regulation of platelet activation.