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. Currently­available 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 throm­bolytics. 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

Differential Features

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

Efficacy

1. Survival

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 treat­ment and persist over the following year. 17 , 18 Admini­stration 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 throm­bolytic 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

<20% '" 25% 30 to 40% 20 to 40%

Conventional IV dosage 1 .5 million U infused 3.0 million U infused 100mg infused over 90 30U bolus injected over over 60 min over 60 min min to 3hc 5 min

Cost/dosed $ $$$$$$$ $$$$$$$$ $$$$$$

a In the UK, urokinase is not licensed for the treatment of acute myocardial infarction b As a proportion of pretreatment levels. c Higher doses and more rapid infusion increase arterial patency rates7, whilst high doses and prolonged infusions cause greater

fiorinogen depletion and increased risk of bleeding.8,9 Body weight is also associated with bleeding when fixed doses are used. 8,10 Therefore/ a weight-adjusted rapid (90-minute) intusion of alteplase may be recommended. 1 However, in the UK, the recommended dosage ot alteplase is 100mg given over 3 hours.

d Estimated hospital cost per conventional dose relative to the cost of a conventional 1.5 million U dose of streptokinase (US market). Symbols: ./ = applicable; x = not applicable. Abbreviations: ICH = intracranial haemorrhage; IV = intravenous; U = units.

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---------, ; 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

Yes

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 Yes

."

~ 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

required? No

." No I I Yes

Bleeding? I

No .,r

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). How­ever, 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 convinc­ing.! 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 ex­cluded.22 Management of complications is outlined in the Treatment Algorithm.

1. Bleeding

The most common complication of thrombolytic therapy is bleeding, the risk of which is increased by concomitant use of aspirin or heparin.l0 Bleeding attrib­uted 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 adminis­tered. 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 stud­ies.23 However, no differences in rates of major bleed­ing between streptokinase, alteplase and anistreplase were reported in the ISIS-3 study.3

2. Stroke

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 devas­tating effects than strokes caused by ischaemia or embo­lism. 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

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- -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 recom­mended dosages (100mg over 3 hours). The incidence of intracranial haemorrhage is 3 times higher with alte­plase 150mg than 100mg. Direct comparisons have sh?wn that strokes are sig~ificantlr more common with amstreplase than streptokmase.22, 4-26

3. Hypotension

Streptokinase reduces systolic blood pressure (BP) by an average of 35mm Hg, a greater hypotensive effect being associated with faster rates of infusion. Vasopres­sor 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

4. Allergy

Most people have circulating antibodies to strep­tokinase. 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 reactions can usually be controlled with antihistamines or corticosteroids. 23 Prophylactic corticosteroids do not prevent allergic reactions and are not recommended. l

Following treatment with streptokinase or anistreplase, antibodies to streptokinase develop over the next 4 to 5 days. These antibodies have the potential to nullify the effect of readministered streptokinase or anistreplase, although this has not been proven. Levels remain elevated for a year in most patients, and for at least 4 years in about 50%.27

For the present, nonantigenic agents such as uroki­nase or alteplase should be used if readminstration of thrombolytics is required following streptokinase or anistreplase.23

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References 1. Granger CB, et al. Drugs 44: 293-325, 1992 2. GISSI. Lancet 336: 65-71,1990 3. ISIS-3 Collaborative Group. Lancet 339: 753-770,1992 4. Lew AS, et al. Circulation 72: 1321-1326, 1985 5. Yusuf S, et al. Circulation 82 (Suppl. II): II-117-II-134, 1990 6. Pindur G, et al. Thrombosis Research 67: 191-200, 1992 7. Topol EJ. J Am Coli Cardiol 145: 922-924, 1990 8. Bovill EG, et al. Ann Intern Med 115: 256-265,1991 9. Smalling RW, et al. J Am Coli CardiollS: 915-921, 1990

10. Califf RM, et al. Am J Cardiol69: 12A-20A, 1992 11. DeWood MA, et al. N Engl J Med 303: 897-902, 1980 12. Rentrop KP, et al. Clin Cardiol2: 92-105, 1979 13. Dalen JE, et al. Am J Cardiol62: 179-185, 1985 14. Sharma GVRK, et al. N Engl J Med 306: 1268-1276, 1982 15. ISIS-2 Collaborative Group. Lancet 2: 349-360, 1988 16. GISSI. Lancet 1: 397-402,1986 17. GISSI. Lancet I: 871-874,1987 18. AIMS Trial Study Group. Lancet 335: 427-431,1990 19. Anderson JL, et al. Circulation 83: 126-140, 1991 20. Ohman EM, et al. Circulation 82: 781-791 , 1990 21. Verstraete M. Circulation 82 (Suppl. II): II-96-II-109, 1990 22. Williamson BD, et al. Drugs & Aging 2: 461-468, 1992 23. Woo KS, White HD. Drug Safety 8: 19-29, 1993 24. Gore JM, et al. Circulation 83: 448-459, 1991 25. Maggioni AP, et al. BMJ 302: 1428-1431, 1991 26. Maggioni AP, et al. N Engl J Med 327: 1-6, 1992 27. Elliott JM, et al. Circulation 84 (Suppl. II): II-116, 1991 ......... Future Directions in Thrombolytic Therapy

Research into fibrin-specific thrombolytics contin­ues unabated, even though their potential survival bene­fits have not yet been realised with alteplase (see previous feature). Duteplase and saruplase are new fibrin-specific thrombolytics which are at an advanced stage of development. Both drugs have half-lives of around 6 to 8 minutes and have low antigenicity com­pared with streptokinase and anistreplase. 1

Duteplase Duteplase (Sumitomo) is a double-chain native tissue

plasminogen activator, closely related to the single­chain alteplase. It is awaiting registration in Japan.

After an acute myocardial infarction, duteplase improves arterial patency rates to a greater extent than urokinase. 2 Mortality rates with duteplase are similar to those of streptokinase and anistreplase, but inhospital reinfarction rates are lower than with streptokinase. 3

Following reinfarction, duteplase is as effective as alteplase in restoring patency and preserving left ventricular function. 4

Allergic reactions occur less frequently with dute­plase than streptokinase. Duteplase causes more strokes, but less hypotension, than streptokinase. 3

Bleeding risk with duteplase is associated with higher doses and longer duration of infusion.5

Saruplase Saruplase (Gruenenthal) is a single-chain prouroki­

nase, which is undergoing phase III clinical trials.

TSSN 1172·{)3/i0l93/()329·0011/JiI.OO © Adis International Ltd

Initial patency rates are better with saruplase than with streptokinase, but rates equalise 90 minutes post­dose. 6 Early clinical outcome also favours saruplase over streptokinase, but after 1 year, mortality and the incidence of recurrent cardiovascular events are simi­lar. 7 A combination of saruplase and urokinase is as effective as monotherapy with either saruplase or alte­plase. 8,9

Compared with alteplase, saruplase causes greater systemic activation of the fibrinolytic system. 10 How­ever, fewer bleeding complications occur with saruplase than streptokinase or urokinase. 11 This may be related to the fibrin-specificity of saruplase.

Despite its lack of antigenicity, allergic reactions, and hypotension, have been reported as frequently with saruplase as with streptokinase. 6

References 1. Granger CB, et al. Drugs 44: 293-325, 1992 2. Freeman MR, et al. Circulation 85: 150-157, 1992 3. ISIS-3 Collaborative Group. Lancet 339: 753-770,1992 4. Purvis JA, et al. Coron Art Dis 3: 713-720, 1992 5. Kalbfleisch J, et al. Am J Cardia I 69: 1120-1127, 1992 6. Darius H, Meyer 1. Cardiovas Rev Rep 12: 56-59, 1991 7. Diefenbach C, et al. Caron Art Dis 3: 925-931,1992 8. Kasper W, et al. J Am Call Cardia I 16: 733-738, 1990 9. Gulba D, et al. Circulation 83: 837-944, 1991

10. Belgian Saruplase Alteplase Trial Group. Caron Art Dis 2: 349-355, 1991

11. Ostermann H, et al. Eur Heart J 13: 1225-1232, 1992

Managing the Menopause and Beyond: Part 1

Hormonal changes at the menopause include decreased production of estrogen and progesterone. 1

Menopause alters the homeostasis of several body systems, resulting in both short and long term conse­quences. Short term menopausal symptoms include hot flushes, sweats, urogenital symptoms and psychologi­cal effects. While these can be distressing, they are relatively benign.

The 2 most important consequences of the meno­pause are osteoporosis and cardiovascular disease.

This first part of a 2-part series considers the avail­able therapies for osteoporosis prevention.

The second part of the series, to be published in the next issue, evaluates the overall role of hormone replacement therapy (HRT) in these women.

Osteoporosis Osteoporosis is a decrease in bone density that pre­

disposes to fractures. At menopause, estrogen defi­ciency produces an increase in bone resorption resulting in around 5% of the spinal trabecular bone being lost annually for 5 to 10 years. Subsequently, the rate of bone loss slows, but bone density continues to decline. 2

Osteoporotic fractures occur in around 50% of women, with the wrist, hip and spine being most com­monly involved. 80% of hip fractures are associated with osteoporosis. Femoral neck fracture has fatal con-

Vol. 1. No.5: March 29.1993