Thrombolytics Improve Survival After Acute MI
Thrombolytic therapy administered within hours of the onset of an acute myocardial infarction (MI) reduces mortality compared with routine treatment alone. Although serious adverse effects can occur following thrombolytic treatment, their incidence is relatively low and can be reduced by carefully excluding patients with contraindications to these drugs.
The use of thrombolytics in acute MI is summarised in the Treatment Algorithm on page 8. Currently-available thrombolytic agents are compared in the Differential Features table.
Why Use Thrombolytics in Acute MI? Angiography shows that total coronary artery
obstruction occurs within 4 hours in 80 to 90% of patients with acute MI, and can be relieved by throm-bolytics. 11 ,12
Early arterial reperfusion leads to a smaller infarct size than that resulting from permanent occlusion. Ischaemic death progresses from the subendocardium to the endocardium over a 3- to 4-hour period 1, so early administration of thrombolytics is vital. Reperfusion of the affected artery at 90 minutes after symptom onset is associated with improved I-year survival compared with results when the artery remains occluded. 13
Mechanism of Action Thrombolytic agents are plasminogen activators.
They convert the proenzyme plasminogen to the active enzyme plasmin, which breaks down the fibrin clot at
the site of arterial obstruction. 14 This causes varying degrees of depletion of circulating fibrinogen, factor V and factor VIII and also affects platelet function. 1
Thrombolytic therapy actually increases mortality in the first day after treatment. 1S 16 However, beneficial effects on survival are greatest 3 to 5 weeks after treat-ment and persist over the following year. 17 , 18 Admini-stration of thrombolytics reduces overall mortality by 27%.1
Greater reductions in mortality occur in patients treated within 1 hour of symptom onset. 17
Treatment within 6 hours is preferred, but benefits have occurred in patients treated up to 12 hours after symptom onset. 1
Thrombolytic therapy has no beneficial effects on mortality for patients with ST segment depression or a normal ECG.l
The elderly derive significant benefit from throm-bolytic therapy. Some studies have shown greater mortality reductions in the elderly than in younger patients. IS
Survival rates are comparable between the different thrombolytics. 2,3,19
Addition of aspirin to streptokinase results in greater mortality reductions than streptokinase alone. 1S
Concomitant heparin administration does not appear to playa major role in reducing mortality. 1
. '. . .' .... - ~. f ~ .' ~. _ ',. J' ;.! . '9"'
Feature Streptokinase Urokinasea Alteplase (tPA) Anistreplase
Source Gp C Streptococci Recombinant, human Recombinant, human Gp C Strep.tococci, fetal kidney anisoylateO
Mode of action Activator complex Direct Direct Direct
Half-life (min) 18-23 14-20 3-4 70-120
Fibrin specificity x x ./ x
Antigenicity ./ x x ./
Blood viscosity Decreased Unknown Unchanged Decreased
Post-treatment fibrinogen levelsb
---------, ; j
Tr AI' h -. eatment gont m," , ~ _.J I Central cardiac chest pain I
suggesflve of MI
I ECG changes confirm MI? ~ No _ ...... 1 Elevated creatine kinase 1 Yes ~I levels? 1
Patient presented 6 to 12 ... " ... 1 Patient presented within I No hours after symptom onset 1 "'" "'-1 6 hours of symptom onset
+ , ECG suggests
evolving infarct? I Observe patient I r- No Yes ."
I Contralndicatlons present (see table 1) I Yes 1 No
"t I Risk: benefit ... assessment I For ... "
I Administer thrombolytic I Against t
I Observe for adverse effects I +
Yes I Streptokinase/anistreplase I ~
1 used for this MI?
Allergic reaction? I ... No I No ~ .4
~ Stop infusion for 15 minutes
Stop infusion I Hypotension? Lower patient's head Give antihistamines! Administer IV fluids corticoste roids
t No I BP normalised? ~
+ Yes .. I .. Restart infusion I ,r Urokinaselalteplase Yes
." No I I Yes Bleeding? I
Stop infusion Stop heparin and give
protamine if appropriate Give FFP, cryoprecipitate
or platelets as required
" ., " ... 1 I .. " ... Supportive care on CCU .. Abbreviations: CCU = coronary core unit; ECG = electrocardiogram; FFP = fresh frozen plasma; IV = intravenous.
Use of thrombolytic therapy in acute myocardial infarction (MI) 1-5 Copyright 1 993 Adis International Ltd
Vol 1, No.5; March 29, 1993 ISSN 1172-0360/93/0329-008/$1.00 Adis International Ltd
2. Patency Rates and Reoeelusion
Early patency rates are lowest for streptokinase and highest for rapidly administered alteplase (tPA). How-ever, patency rates between the different drugs tend to equalise later.
Arterial reocclusion doubles mortality compared with that in patients whose arteries which remain patent. 20 Although alteplase increases early patency rates, it has a higher rate of reocclusion (13%) compared with the other agents (8%). This may nullify any initial benefits.!
Combining alteplase with either streptokinase or urokinase gives a 90-minute patency rate of 77 to 85%, similar to alteplase alone, but only a 6% reocclusion rate.!
3. Rein/aretion About half of all patients with arterial reocclusion
experience another MI. Aspirin reduces the rate of reinfarction compared with placebo. Subcutaneous heparin may do so too, but the evidence is less convinc-ing.! However, the rate of reinfarction is higher after thrombolytic therapy than after placebo.2,3
Repeat thrombolytic therapy for reinfarction is often effective and appears to be safe.!
Tolerability Contraindications to and precautions with throm-
bolytic therapy are listed in table 1. Advanced age in itself is not a contraindication to thrombolytic therapy, as long as other contraindications have been ex-cluded.22 Management of complications is outlined in the Treatment Algorithm.
The most common complication of thrombolytic therapy is bleeding, the risk of which is increased by concomitant use of aspirin or heparin.l0 Bleeding attrib-uted to thrombolytics may occur in 5 to 20% of patients, approximately one-fifth of whom require transfusion.3,l9
Bleeding is usually the result of lysis of haemostatic plugs at sites of previous trauma or injury. Therefore, bleeding complications depend more on predisposing factors (see table 1) than the type of agent adminis-tered. 23 In the GISSI-2 trial, streptokinase caused more major bleeding than alteplase2, and was more likely to do so than alteplase or urokinase in several other stud-ies.23 However, no differences in rates of major bleed-ing between streptokinase, alteplase and anistreplase were reported in the ISIS-3 study.3
The overall incidence of stroke is the same with or without thrombolytic therapy. Although the risk of intracranial haemorrhage is greater after thrombolytic therapy, this is offset by a reduction in the incidence of embolic or ischaemic stroke. 2,3
However, intracranial haemorrhage has more devas-tating effects than strokes caused by ischaemia or embo-lism. Mortality is higher than with other strokes, and a large proportion of survivors are severely disabled.
Risk of intracranial haemorrhage is higher in women, the elderly and patients with hypertension.I,2
ISSN 1172-036019310329-0091$1.00 Adis International Ltd
- -Table 1. Contraindications to thrombolytic ther8py 1 ,21
All contra indications must be weighed against the potential benefits
Risk of bleeding Active internal bleeding Known intracranial damage/abnormality Recent major surgery, trauma or head injury (especially within 6 weeks) Recent CVA or TIA (especially within 6 months) Recent noncompressible arterial puncture within 14 days Symptoms of proven peptic ulceration within 3 months Known bleeding disorder Chronic liver disease with portal hypertension Dissecting aortic aneurysm Haemorrnagic pericarditis Pregnancy
Relative contraindications Uncontrolled severe hypertension (systolic BP > 175mm Hg or diastolic BP > 11 Omm Hg) Active menstruation or lactation Prolonged cardiopulmonary resuscitation Diabetic proliferative retinopathy Dental extraction within 14 days
Abbreviations: BP = blood P,ressure; CVA = cerebrovascular accident; TIA = transient ischaemic attock.
Stroke in general is more common with alteplase than streptokinase (excess rate of 4 in every 1000 treated patients), even when alteplase is used at recom-mended dosages (100mg over 3 hours). The incidence of intracranial haemorrhage is 3 times higher with alte-plase 150mg than 100mg. Direct comparisons have sh?wn that strokes are sig~ificantlr more common with amstreplase than streptokmase.22, 4-26
Streptokinase reduces systolic blood pressure (BP) by an average of 35mm Hg, a greater hypotensive effect being associated with faster rates of infusion. Vasopres-sor treatment is required in 7 to 10% of patients.! All thrombolytics have the potential to induce hypotension, but it is more common with streptokinase and anistreplase. 1 However, patients presenting with low BP or in shock fare no worse after streptokinase than those treated with alteplase. 2
Most people have circulating antibodies to strep-tokinase. Mild allergic reactions have been reported in 4.4% of treated patients compared with 0.9% of controls, but true anaphylaxis occurs in less than 0.5%.!5 Mild reacti