sign in sign up
<<
Home , Phenindione

Maltese Medical Journal 12 Volume II l ssae II 1)0(91

RECENf ADVANCES IN CARDIOVASCULAR MEDICINES THROMBOLYTICS

Marise Gatt, Herbert Felice, Dean Harron

INTRODUCTION Plasmin is formed from the inactive inhibit'> the oction of . It also plasminogen by the action of thmmbin increases the negativity of blood vessel Thrombolytic therapy represents a major in the presence of pla<;minogcn octivators walls and helps prevent thrombus advance in reducing mortality following ,md activator inhibitors (PAl-I). The formation (due to it'> structure). Also myocardial infarction. Phannacist<; must lysis of fibrin by plasmin is held in check included in this group of parenteral be aware of the principles and problems by alpha 2 ,mtipla<;min. anticoagulants are epoprostenol of and the large studies ( anti platelet activity) and conducted in hospital and now in the , an enzymatic principle derived community. from the venom of the Malaysian pit­ viper. HEMOSTASIS INTRI NS IC With regards to before relca<;e When a small vessel is cut and damaged Inac tiv e XII from the liver into the blood stream, the the injury initiates a series of events that Vitcunin K-depcndent coagulation factors 1Colla g en EXTRINSIC leads to the formation of a clOL The initial Acti ve (prothrombin, VII, IX and X) are converted event is constriction of the vessel, followed XII Tis sue to a functional group by the addition of an by the formation of a platelet plug. The ~ thrombo pla s tin extra C<1fboxyVgroup to a glutamic acid Inactive AcXtivl e platelets adhere to exposed collagen and XII ~ l residuc. In the presence of warfarin, the liberate serotonin and adenosine ~ coagulation factors arc released from the Inac t i v e Acti ve A c tive Inac t ive diphosphate (ADP); this attracts other IX I X VII V II liver in their unconverted form and hence platelets etc. This is formed into a ~~ Inac tive p latele ts Acti v e Inactive inhibit coagulation. Other oral defInitive clot by fibrin, which involves a X X X include phenindione and cascade of reactions (Fig. I ). Potential v c,'· protcunine sulphate. Although this latter 1p la telets clotting inside vessels and the breaking Fib rinoge n compowld is normally used to counteract down of clots so formed are controlled by Pr o t hrombin ---+- Th r ombin -+! overdose, when in excess, it has a number of limiting reactions; Fibrin an effect. (loose) XIII! (1) Formation from octivated of The platelet-aggregation inhibiting effects F ibrin an (antithrombin Ill) and CO A GU L A TlO N CA S CADE (tight) of a<;pirin result from its ability to acetylate the removal of some activated clotting and irreversibly inhibit platelet factors from the airculation by the liver; cyc1ooxygenase, thereby reducing the formation of thromboxone A2. Its effects (2) A2 which promotes on thc synthesis of prostacyclin is less platelet aggregation and hence clotting, is marked at low doses (1). Also in this in dynamic equilibrium with the group is . simultaneous formation of prostacyclin Figure 1 Scherrultic diagram of the coagulation which inhibits aggregation; and {".l1scatie (adapted from Guyen 1951). M. GATr, B. I'IIARM. sr LUKE'S IIOSprrAL, C'MANGIA (3) The fIbrinolytic system that limit') DRUGS WHICH INHIBIT H. FELICE, M.D, LIC. SI'EC. CARDIOl.. clotting. CLOTTING AND/OR sr LUKE'S /lOsprrAL. C'MANGIA BREAKDOWN THROMBII D.W.G. IIARRON, BSC, I'h.D, M.R.I'.S.G.B, The octive component of the fIbrinolytic M.I'.S.N.L, A.C.I'.I'. system is plasmin which lyses fIbrin and Heparin is a potent anti-coagulant, DEPARTMENT OF 771ERAPEUTICS AND fibrinogen with the formation of normally found in the body, which acts PHARMACOLOCY THE QUEEN'S UNlVFJ?SrrY OF BElFAST degradation products which in inhibit by preventing the octivation of factor IX turn NOR77!ERN IRELAND thrombin. and by activating a platelet factor that Maltese Medical Journal 14 Volume IT Issue IT '90(91

effects. The aim of theTaIXutic is the selective activation of plasminogen PLASMINOGEN associated with fibrin, while sparing the plasminogen in the surrounding blood

I A RG I 56 0 (i.e. fibrin specificity). This occurs with

F i b r in the natural plasminogen activators of I' 1" 0 UK UK PlaslTlln ~ Dea c y Ja tio n blood, t-P A and pro-UK. However if infused at high doses which are necessary IV AL I 561 ~ F ibri n ,-t P A for effective thrombolysis in patients with coronary thrombosis, non-specific plasminogen activation takes place(2).

STREPTOKINASE

PLASMIN This is a bacterial protein (from cultures of Group C beta- haemolytic streptococci) that reacts on a one-to-{)ne basis with human plasminogen forming a Figure 2 Activation oJ plasminogen to plasmin (adapted from Sherry /988). -plasminogen complex Pla<;ll1inogen activators (sce list below) The compounds act indirectly/directly to which activates the fibrinolytic act by converting the inert pro-enzyme activate pla<;minogen (2); this involves mechanism. As streptokinase is a foreign plasminogen, into its protcolytically active splitting of the arg560-val561 band in protein it is antigenic. fonn plasmin. plasminogen, which exposes the enzyme centre of plasmin (Fig.2). Apsac (Anisoylatcd derivative of the Lys­ This laocr group of drugs is now widely Plasmin is a non-specific proteolytic plasminogen streptokinase) used ,L<; thrombolytic therapy following enzyme which derives its fibrinolytic acute myocardial infarction. The rationale prop;rties by the binding of pla<;minogen This is a complex of human lys­ is that reperfusion will retard myocardial to fibrin during clotting and also by the pla<;minogen and streptokinase in which necrosis, reduce infarct size and possibly binding of endogenous t-PA to fibrin in a para-anisoyl group has been added to maintain ventricular function and hence close proximity to plasminogen following the catalytic centre of the enzyme complex enhance patient survival. Other uses may its release locally from endothelial cells. (Figure 3). include · pulmonary embolus, dcep vein A<; a result, plasmin fonnation is facilitated thrombosis, p;ripheral arterial thrombosis on the fibrin surface and is indep;ndent of In aqucous media, including blood, the and local instillation into occluded shunts, the various mechanisms governing and anisoyl group is removed by hydrolytic e.g. in renal dialysis patients or restoring regulating pla,minogen activation in the deacylation. The kringles on the complex potency in occluded central venous systemic circulation (2). are the molecular elements which bind to catheters.

THROMBOLYI'IC AGENTS AND CATALYTIC CENTRE THEIR MECHANISMS OFACTION

There are now 6 agents being used or evaluated for the lysis of thrombi following myocardial infarction. These are ­

(a) Indirect acting

(I) Streptokinase (SK). CO (2) Anisoylatcd pla<;minogen ­ streptokinase activator complex M . W.131 .000 D I (APSAC). 9 CONTROLLED RELEASE (b) Directly acting ! I N BLOODSTREAM p-ANISOYL GROUP (3) (UK). ~ AND IN CLOT (4) Recombinant single stranded OCH3 tissue-type plasminogen Figure 3 Sclwmatic represenlation oJ the rrIDlemlar structure oJ APSAC (Permi~~ion Jrom Beecham). activator (r t-PA, one chain). (5) Recombinant prourokinase The hallmark of physiological fibrinolysis the fibrin that holds together the thrombus. (r pro UK or r scu-PK). is its specificity, by contrdst therap;utic This binding capacity is increase6 170 (6) Recombinant double stranded thrombolysis, even by the newer times by using the lys71 plasminogen tissue-type plasminogen activators, is accompanied by non-specific rather than the glu-fonn which circulates activator (rt-PA, 2 chain). proteolysis which may have untoward in the bloodstream (Figure 4) - (fibrin 1 Maltese Medical Journal 15 Volume IT Issue IT '90191

The clinical evaluation of thrombolytics in AMI has been marked by a nwnbcr of BLOOD THROMBUS major well conducted placebo controlled APSAC trials. ~ STREPTOKINASE Iys- PLASM I NOGEN - S T REPT(lK I NASI' (lys-Plg- SK) ISIS-2 (Second International Study of / Infarct Survival) (3). In this study, 17,187 Iys -PLASMINOGEN patients entering 417 hospitals up to 24 glu-PLASMINOCEN (FIBRIN-BOUND)'" hours (median 5 hours) after the onset of CG acute myocardial infarction were randomised with a placebo control, ~ between ­

g lu- PLASM I N (1) a I-hour i.v. infusion of 1.5 million , V / units of streptokinase (SK), FIBRIN ENHANCEM ENT (2) one month of 160 mglday enteric coated (ASA), (3) both active treatments (SK and ASA), (4) neither. Figure 4· Calalylic efficiency of APSAC. (Permi.~\'ion from Beecham). enhancement factor). The value of the physiological conditions. It has been The results indicated that both SK and para-anisoyl group is that it protects the suggested a<; having a different mechanism ASA alone produced a significant catalytic centre of the enzyme and acts as of action than t-PA, in that it is thought reduction in 5 week vascular mortality. a possible pro- drug for its fibrolytic that pro-urokinase only activates lys­ activity. Advantages of this include a plasminogen (the type bound to fibrin) SK 791/8592 (9.2%) vs gradual onset on action following a 4-5 and not glu-plasminogen (the plasma placebo 1029/8595 min injection and hence possibly avoiding form) and this is the basis for its clot (12.0%) (25% reduction) hypotension. It also prolongs APSACs sensItIvIty. It is being produced ASA 804/8587 (9.4%) vs duration of action. Antigenicity occurs-­ -commercially by recombinant DNA placebo 1016/8600 with APSAC. technology by transfer of the cyclic DNA (11.8%) (23% reduction) from a hwnan tumour source to a non­ SK + ASA 343/4292 (8.0%) vs neither UROKINASE hwnan cell line. As with urokinase and 568/4300 (13.2%) rt-PA it is not antigenic. (42% reduction) This is the first of the naturally occurring and direct plasminogen activators (can COMPARISONS BETWEEN There was evidence of benefit from each stimulate plasmin formation without first THROMBOLYTIC AGENTS agent even for patients treated late after forming an activator complex). Currently pain onset Adverse effects associated it is being produced by growing hwnan Plasminogen activation in the plasma, with SK were an excess of bleeds requiring foetal kidney cells in tissue culture. (It is and the 'fibrin- enhancement' of its effect transfusion (0.5% vs 0.2%) and of not antigenic). associated with the thrombus platelets confirmed cerebral haemorrhage (0.1% and endothelial cells varies between vs 0.0%) but with fewer other strokes rt-PA drugs (Table 1), although as stated (0.6% vs 0.8%). earlier at therapeutic thrombolytic Tissue is released doses differentiation disappears. Aspirin significantly reduced non-fatal under physiological conditions from Pharmaceutical aRd pharmacokinetic reinfarction (1.0% vs 2.0%) and non-fatal various tissue cells. The preparation of differences are shown in Table 2. They strokes (0.3% vs 0.6%) and wa<; not this highly clot selective type of activator indicate that tl/2 plasma elimination half associated with any significant increase has utilized recombinant DNA lives range from 90 min for APSAC, with in cerebral haemorrhage or in bleeds technology. Its preparation has involved a very short infusion of 5 min compared requiring transfusion. An excess of non­ the transfer of genetic material from a t­ with a 5 min tl/2 for rt-PA; an infusion of fatal reinfarction was reported with SK PA producing cell line (originally a 180 mins is required for its therapeutic when used alone, but not in combination melanoma) to a Chinese hamster ovarian effect The clinical profIles demonstration with ASA. Those given both had cell line. rt-PA is not antigenic. reperfusion in 65-70% of patients if treated significantly fewer reinfarctions (1.8% in three hours with re--occlusion occurring vs 2.9%) and strokes (0.6% vs. 1.0%). r-pro-UROKINASE in 10--20% of patients (Table 3). The differences in va<;eular and all cause mortality produced by SK and ASA This is a highly clot selective single chain CLINICAL EVALUATION OF remained significant over the 15 month urokinase, which, like t-PA is released THROMBOLYTICS IN AcurE follow-up. from various tissue cells under MYOCARDIAL INFARCTIO(AMl) Maltese Medical JoumaI 17 Volume IT Issue IT '9Of91

TABl.E 1 Plasminogen activation of thrombolytics

PLASMINOGEN ACTIVATION OF THROMBOLYTICS

Sk APSA Uk rt-PA rpro-Uk

Plasma 4 4 3 2 2 Fibrin 1 1 2 3 4 Platelet - - - 2 - Erdothelial cell - - - 2 -

(1- 4 indicated inaeasing ocIwity)

TABLE 2 Pharmaceutic and phannacokinetic profile of thrombolytics.

PHARMACEUTIC AND PHARMACOKINETIC PROFILE OF THROMBOLlYlCS Sk APSAC Uk rt-PA

Dosage by I.V. 1.5 million 30 units 2 million 100 gm adminisrtation units units (58 million units)

Infusion time(min) 30-60 5 20-90 180 Plasma elimination half-life (min) 23 90 16 5 Heparin infusion received 0 0 0 Yes Cost (MIMS JAN 1990) £85 £495 £198 £816

TABLE 3 Clinical profile of thromboiytics.

CLINICAL PROFILE OF THROMBOLYTICS Sk APSAC Uk rt-PA rPRO-UK

Reperfusion% (patients treated within 3 hrs) 65 68 66 70 67

Time to Reperfusion (min) 45+- 45+- 45+- 45+- 45+­

Bleeding complications following invasive prodedures Yes Yes Yes Yes Yes

Re-occlusion% 15+- 10+- 10+- 20+- ­ Maltcsc Medical Journal 18 Volume II Issue IT '90(91

Other major studies with streptokinase include Gruppo Italiano per 10 studio delta weighed linear regression streptochinase nell'infarto miocardico­ Gissi (4,5) (11,806 patients). ISAM (6) %= -9.5 *DOT+ 93.0 p=0.0001 (1,741 patients); Kennedy et al (7) (368 80 patients) and White et al (8). The results • of these trials arc summarized in Table 4. 70 1 • • r TISSUE PLASMINOGEN I 60 • ACTIVATOR (rtPA) ed in Malta in March, 1989. The Maltese Medical Journal 19 Volume IT Issue II "90(91

TABLE 4 Major placebo conlrol/eLi clinical trials with inlravenous thrombolytic therapy in acute myocardial infarction.

Major placebo controlleld clinical trials with intravenous thrombolytic therapy in aOJte myocardial infarction - Study Patient AdjunctiveTherapy Major Bleeding(%) Neurological Event Rate (%) Early Mortality Rate (%) Number Aspirin Heparin Plaoebo Act'rve Defin~ion Plaoebo Active En~int Placebo Act'rve

A. Streptokinase ------~- - - . ------,.._------­ GISSI (4) (5) 11 ,806 14% 21 % ? 0.3 Stroke 0.9 1.1 21d 13.0 10.7 0.0002 SK-CVA 0.2 ISAM (6) 1,741 + + ? 0.8 ICB 0 0.5 21d 7.1 6.3 NS WWASH (7) 368 ? + (0.7) (13) ICB 0 0.5 14d 9.7 6.3 NS N.ZEALAND (8) 219 + + 0 1 ICB 0 0 30d 12.9 2'.5 0.012 ISIS-2 (3) 17,187 +/- - 0.2 0.6 Stroke 0.9 0.8 35d 11.7 8.9 0.0001 SK-ICB 0.1-0.2

B. rt-PA .------­ ECSG (19) 721 + + 1.9 3.7 Stroke 0.5 2.0 14d 5.7 2.8 0.053 ICB ? 1.4 < < ASSET (10) 5,111 - +(24hr) 0.4 1.4 Stroke 1.0 1.1 30d 9.8 7.2 0'(XXl2

C. APSAC ------_._ ------_ .. __._------.-- -­ AIMS (12) 1,004 ? + ? ? Stroke 1.0 0.4 3)d 12.2 6.4 0.0016

Abbreviations: *ICB: intracerebral bleedi~ ; CVA: cerebrovasrular accident; SK-CVA: associated with streptokinase therapy; Sk-ICB: ICB associated with SK therapy; rt-PA ICB: ICB associated with rt-PA therapy. Collen and Gold (9)

TABLE 5 ASSEr mortality in excluded patient,. TABLE 6 In.hospital complication other than strokes.

Reason % Exdusion % Dead rt-PA Placebo n % n %

durauon symptoms > 5 hrs 73.5 10.6 Recurrent MI 97 (3.9) 111 (4.5) age > 75 yrs 8.3 26.2 VentriOJlar arrhythmias (day 1) 149 (5.8) 107 (4.3) recent haemorhage, ulcer Ventricular fibrillation 94 (3.7) 120 (4.8) bleeding diathesis 5.9 12.1 Asystole 100 (3.9) 124 (5.0) other serious disease 5.4 13.5 Pulmonary embolism 11 (0.4) 15 (0 .6) refused consent 4.3 8.0 Other embolism 12 (0.4) 19 (0.8) receiving warfarin 4.2 10 .0 Cardiogenic shock (3.8) 131 (5.2) emergency CPR 4.1 28 .7 96 recent stroke, trauma or surgery 3.6 14.3 Heart failure 453 (17.9) 466 (18.6) lives away 3.6 7.4 high systolic BP 2.2 3.8 proliferative retinopathy 1.5 18.5 Hampton (17) pregnancy 0.3 3.6 _._-- -- Hampton (17)

TABLE 7 Cost per administration of thrombolytic agent.

THROMBOLYTIC AGENT COST PER ADMINISTARTION IN LM*

Streptokinase 33 Urokinase 158 APSAC 275 rt-PA 453 ------* Source: last tender for SK & UK Mims Jan. 1990 for APSAC & rt-PA Maltese Medical Journal 20 Volume IT Issue II '90[91

Thrombolytic agent used then was UrOkinase in administered in a dose of l.5 WNDON, IRC 1F£IINlCAL SERVICES LID, 1989. Streptokinase. million unit'> over 30 - 40 minutes in the same way as Streptokinase with the 10. WILCOX R.G, VON DER UPPE G., OL<;SON e.G., According to the policy (19) adopted by exception of corticosteriods which are JENSSEN G., SKENE AM., HAMPTON JE. TRIAL OF the Department of Medicine, St Luke's not required with Urokinase. TISSUE PLASMINOGEN ACTIVATOR (RT-PA) FOR Hospital, the indications for using MORTAUIY REDUCTON IN ACUTE MYOCARDIAL thrombolytic therapy in AMI are as INFARCTION: THE ANGW-SCANDINAVIAN STUDY Although the Medical Department is well OF EARLY mROMBOLYSIS (ASSFl). LANCET, 1988; 2, follows:­ aware of the other thrombolytic agent,> 525-530. now on the market, ego APSAC and rt­ - Age: < 65 years (the age limit is only a P A, and the possible advantages they ll. VAN DE WOlF F., ARNOW AER. INTRAVToNOUS guideline, the decision is at the offer, the cost involved must also be TISSUE PLASMINOGEN ACTIVATOR AND SfLE OF discretion of the admitting consultant) considered (fable 7). INFARCT, LEFT VEfVfRIUCLAR FUNcrrON, AND SURVIVAL IN ACUTE MYOCARDlAL INFARCl70N. - Diagnosis: (a) typical chest pain > 30 REFERENCES BRMEDJ., 1988; 297, 1374-1379. minutes 12. AlMS TRIAL STUDY GROUP. EFFECT OF (b) ECG: ST> Imm in 2 or more limb 1. PEDERSON AK, FmGERAW, GA DOSE fNTRAVFNOUS APSAC ON MORTALITY AFIFJI ACU1E leads REUl1ED KINEl7CS OF ASPIRIN. NEW FNGUMED., MYOCARDlAL INFARCTION: PREUMINARY REPORT > 2mm in 2 or more precordial leads 1984; 311, J206-I211. OF A PLACEBO-COfVfROLLED CUNICAL TRIAL. LANCET, 1988; 1, 545- 549. - Time factor: treatment must be initiated 2. SHERRY S. ACU1E MYOCARDIAL INF ARC110N: COMPARISON OF DlFFEREfVf THROMBOLY71C within six hours of onset of the pain. 13. VERSlRAFrE M., BERNARD R., BORY M. F:J AL. AGFNrS. CURRFNf OPINION IN CARDIOLOGY, 1988; RANDOMIZED TRIAL OF INTRAVENOUS 3, 480491. - Negative test to nitrates: no RECOMBINANT TISSUE-TYPE PLASMINOGEN ACINATVR VERSUS INTRAVFNOUS STREPTOKINASE modification of ST elevation five 3. ISIS-2 (SECOND INTERNATIONAL STUDY OF IN ACU1E MYOCARDIAL INFARCTION. LANCET; 1985; minutes after the administration of INFARCT SURVIVAL) COllABORATIVE GROUP. 1, 842-847. sublingual GlN. RANDOMIZED TRIAL OF IfVfRAVENOUS STRFFT'OKINASE, ORAL ASPIRIN, B011I OR NFIlHFJI 14. CHESEBRO 1., KNA7TERUD G., BRAUNWALD E. AMONG 17,187 CASES OF SUSPECTED ACUTE To date (April 1990), a total of about 150 CORRESPONDF.NCE SECllON. NENGUMED., 1987; MYOCARDIAL INFARCDON. ISIS-2, LANCFr, 1988; 2, patients suffering from AMI were treated 319, 1544. with Streptokinase. Urokinase has been 349-360. recently made available in St Luke's 15. WHl1E HD_, RIVERS J.T., NORRlS RM. ET AL IS 4. GRUPPO ITALlANO PER W STUDIO DEUA Hospital. The use of Urokinase in the RT-PA OR STREPTOKINASE SUPERIOR FOR STREPTOCHlNASI NEU'INFARTO MIOCARDICO treatment of AMI is being restricted to PRESERVATlO OF LEFT VEfVfRlCULAR FUNCTION (GISSl). AFTER MYOCARDIAL INFARCTION? those patients who suffer a further AMI EFFECTIVENESS OF lNlRAVENOUS mROMBOLY77C CIRCULATION, 1989, 9IN PRESS). after 8 days to within 6 months following TREATMFNT IN ACU'lE MYOCARDIAL INF ARCflON. the previous one. At prcsent,it is estimated LANCET, 1986; 1, 397402. that about 12 patients will benefit from 16. MAGNANI B. AND mE PLASMINOGFN ACTIVATOR ITAUAN MULTICENTER STUDY (PAlMS) GROUP. 5. ROVElll F., DE VITA C., FFJlUGUO, GA., ET AL the use of Urokinase per year. COMPARISON OF IfVfRAVENOUS RECOMBINAtvr GISs/ TRIAL: EARLY RESULTS AND LATE FOLWW SINGLE CHAIN HUMAN TlSSUE-IYPE PLASMINOGEN UP. JAM. COLL. CARDIOL., 1987; 10, 33B-39B. Streptokinase is administered in a dose of ACTIVATOR (RT-PA) Wlm INTRAVENOUS 1.5 million units over 45 minutes in 60mls STREPTOKINASE IN ACUTE MYAOCARDIAL 6. mE lSAM STUDY GROUP. A PROSPEClTVE TRIAL of 5% dextrose. It is used in conjunction INFARCTION. J.AM.COU. CARDIOL., 1989, (IN OF IfVfRAVENOUS STREPTOKINASE IN ACUTE with other therapy as follows:­ PRESS). MYOCARDIAL INFARCl10N (ISAM). MORTALITY, MORIBlDITY AND INFARCl' SIZE AT 21 DAYS. 17. HAMPTON JE. mE ANGW-SCANDINAVIAN - Hydrocortisone 200mg IV NENGLJMED., 1986; 314, 1465-1471. STUDY OF EARLY mROMBOLYSIS. (FO~ mE ASSET STUDY GROUP). IN: mROMBOLYSIS. mE DAWN OF - +/- Lignocaine lOOmg IV bolus 7. KFNNEDY J.w., MARTIN GY., DAVID K.B., ET AL. A NEW ERA? SYMPOSIUM 25126 JANUARY, 1989, THE WESTERN WASHINGTON INTRAVENOUS ROYAL COLLEGE OF PHYSICIANS, WNDON, IBC STREPTOKINASE IN ACUTE MYOCARDIAL - +/-B Blockers (early) TECHNICAL SERVICES LID. INFRACTION RANDOMfZED TRIAL. CIRCULATION, 1988; 77, 345-352. - Heparin 1000 uniWhour, started one to 18. BOISSEL JP. PRE-HOSPITAL mROMBOLYS/S: A two hours after the end of Streptokinase CHAUENGE? 8. WHl1E II.D., NORRlS RM., BROWN. MA., ET AL infusion. It is continued for six days, IN: mROMBOLYSIS. WE DAWN OF A NEW ERA? EFFECT OF INTRAVENOUS STREPTOKINASE ON SYMPOSIUM, 25126 JANUARY, 1989, ROYAL COllEGE the dose being adjusted to keep APIT LEFT VENTRICULAR FUNCTION AND EARLY OF PHYSICIANS, WNDON, IBC 1ECIINICAL SERVICES at l.5 - 2 x normal value. SURVIVAL AFTER ACU1E MYOCARDIAL INFRACDON. LTD. NENGLJMED., 1987; 317, 850-855. - Aspirin 75mg daily 19. HOSPITAL CIRCULAR (1989). If reinfarction occurs within seven days 9. COUEN D. AND GOW ilK. NEW DEVFI.DPMFNrS mROMBOLYI7C mERAPY IN mE 1RFATMFNr OF ON mROMBOLY77C 11IERAPY. IN: mROMBOLYSIS. of the use of Streptokinase, it may be used ACU1E MYOCARDIAL INFARCTION. DEPARTMENT mE DAWN OF A NEW ERA? SYMPOSIUM 25126 again together with a high dose of OF MEDICINE, ST LUKE'S HOSPITAL, MALTA. corticosterOids. JANUARY 1989, ROYAL COLLEGE OF PHYSICIANS, The copyright of this article belongs to the Editorial Board of the Malta Medical Journal. The Malta Medical Journal’s rights in respect of this work are as defined by the Copyright Act (Chapter 415) of the Laws of Malta or as modified by any successive legislation.

Users may access this full-text article and can make use of the information contained in accordance with the Copyright Act provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holder.

This article has been reproduced with the authorization of the editor of the Malta Medical Journal (Ref. No 000001)