acute myocardial infarction lancet 2003

8/14/2019 Acute Myocardial Infarction Lancet 2003

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For personal use. Only reproduce with permission from The Lancet Publishing Group.

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IntroductionDuring the past decades, major improvements have beenachieved in management of patients with acute myocardialinfarction. The introduction of coronary care units in the1960s, pharmacological reperfusion therapy in the 1980s,and the widespread application of catheter-basedinterventions in the 1990s have contributed to a strikingfall in in-hospital mortality rates. 16 Additionally, chronictreatment with aspirin, blockers, angiotensin-convertingenzyme (ACE) inhibitors, and statins have contributed toimproved long-term prognosis in survivors of the acutephase of this disorder. 710 Despite these developments,myocardial infarction remains a major event, from aclinical, psychological, and social point of view. First, alarge number of asymptomatic individuals are at seriousrisk of developing a first heart attack because of theirgenetic predisposition, smoking behaviour, unhealthydietary habits, or physical inactivity. Second, evidence isemerging that medical practice does not adequatelyimplement preventive actions in asymptomatic high-riskindividuals and patients with established coronarydisease, 11 and thus they remain at substantial risk of (recurrent) disease and death. Third, about a third of patients with evolving myocardial infarction die before theyreach hospital to receive any effective treatment. 12 Finally,the improved survival of acute coronary syndromes hasresulted in a growing population of patients with chronicconditions, 13 which is amplified by the ageing of the generalpopulation. Thus, myocardial infarction remains animportant health problem, and merits continued attentionfrom basic and clinical researchers, epidemiologists, andpractising physicians. We review the current knowledgeabout acute myocardial infarction and discuss issues aboutthe pathophysiology, diagnosis, epidemiology, treatment,and prevention of this disorder. We concentrate on themost prominent recent developments.

Lancet 2003; 361: 84758

Erasmus University Medical Center and Thoraxcenter, Departmentof Cardiology, Rotterdam, Netherlands (E Boersma PhD ,N Mercado MD, D Poldermans MD, M Gardien MD, J Vos MD,Prof M L Simoons MD)

Correspondence to: Eric Boersma, Erasmus Medical Center andThoraxcenter, Department of Cardiology, Room H543,3015 GD Rotterdam, Netherlands(e-mail: [email protected])

PathophysiologyThe term myocardial infarction is thought to reflect deathof cardiac myocytes due to prolonged ischaemia. 14 Assuch, myocardial infarction is an acute coronary syndromethat can occur during the natural course of coronaryatherosclerosis (figure 1). 15,16 Progression of atherosclerosis is triggered and enhanced by severalfactors, which can cause mediating diseases or directlyaffect the arterial wall. In advanced stages of the diseaseprocess, atherosclerotic plaques develop. Initially, normallumen cross-sectional area will be preserved, sincecoronary arteries undergo compensatory outwardremodelling in relation to plaque area. 17 Development of the disease might therefore be clinically silent for years. Inthe long run, however, stenoses become functionallyimportant, and coronary artery disease becomessymptomatic.

Fissuring and disruption of atherosclerotic plaques cantake place at any time during this chronic process,initiating intraluminal thrombosis. 18 These eventsgenerally arise in angiographically non-significantstenoses. Intraluminal thrombi, superimposed on theruptured plaque, can cause total occlusion of theepicardial coronary artery, so that the coronary blood flowis interrupted and delivery of nutrients to the myocardiumis blocked. This situation might be further complicated bycoronary vasoconstriction and thrombi micro-embolisation. If a coronary occlusion persists for longerthan 30 min, irreversible damage to the myocardiumie,myocardial infarction, might occur. 19 Long-term coronary

Acute myocardial infarction

Eric Boersma, Nestor Mercado, Don Poldermans, Martin Gardien, Jeroen Vos, Maarten L Simoons

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THE LANCET Vol 361 March 8, 2003 www.thelancet.com 847

Acute myocardial infarction is a common disease with serious consequences in mortality, morbidity, and cost to thesociety. Coronary atherosclerosis plays a pivotal part as the underlying substrate in many patients. In addition, a newdefinition of myocardial infarction has recently been introduced that has major implications from the epidemiological,societal, and patient points of view. The advent of coronary-care units and the results of randomised clinical trials onreperfusion therapy, lytic or percutaneous coronary intervention, and chronic medical treatment with variouspharmacological agents have substantially changed the therapeutic approach, decreased in-hospital mortality, andimproved the long-term outlook in survivors of the acute phase. New treatments will continue to emerge, but thegreatest challenge will be to effectively implement preventive actions in all high-risk individuals and to expand deliveryof acute treatment in a timely fashion for all eligible patients.

Search strategy and selection criteria

We identified 20 047 reports by a computerised search of Medline that were published in the English language betweenJan 1, 1990, and Jan 18, 2003, with myocardial infarction asmajor topic, and aetiology, pathophysiology, epidemiology,diagnosis, therapy, or prevention as secondary topics. Of these, we reviewed the abstracts of 5231 reports labelled asclinical trials, meta-analysis, review, or practice guidelines.Relevant papers (n=592) were selected, and the contentexamined. The corresponding bibliographies were manually searched, specifically focusing on in-hospital treatment andrecent developments. Additionally, we searched the scientificsessions abstracts in Circulation , the Journal of the American

College of Cardiology , and the European Heart Journalpublished between 1996 and 2002.


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occlusion results in a progressive increase of the infarctsize. After about 6 h of continuous occlusion the entirejeopardised area becomes necrotic. Loss of functionalmyocardium results in reduced left-ventricular function,which can affect the patients quality of life, and generallycauses premature death.

Atherosclerosis and inflammationThe development, disruption, and subsequent progressionof atherosclerotic lesions is a chronic inflammatoryprocess. 20,21 Established risk factors (panel 1), such asraised plasma low density lipoprotein cholesterol,decreased high density lipoprotein cholesterol, smoking,high blood pressure, and increased glucoseconcentrations, 22 all stimulatevia several pathwaystheentry and activation of inflammatory cells into the arterialwall. Monocytes, which turn into activated macrophages,and lymphocytes are the main inflammatory cells enteringthe arterial subendothelium. These cells are rich sources of cytokines and growth factors, which induce and amplifyfurther damage. Continuing inflammatory processes resultin atherosclerotic lesions composed of a core of lipid andnecrotic tissue, covered by a fibrous capsule, which areprone to rupture.

Emerging risk factors for coronary heart diseaseThe recognition that myocardial infarction often affectspatients without established risk factors, and theknowledge that atherosclerosis is mainly an inflammatoryprocess, has stimulated research on serum markers of inflammation as potential indicators of atherothrombosis.Several investigations have shown a positive relationbetween increased concentrations of C-reactive protein,serum amyloid A, interleukin-6, fibrinogen,homocysteine, lipoprotein A, and pregnancy-associatedplasma protein A and the risk of acute coronary events. 2328

Chronic infection is also an emerging risk marker in thiscontext, although data sometimes conflict. 2932

The origin of coronary heart disease has an importantgenetic component. Insights into differences of geneticregulation of inflammatory processes between otherwisesimilar individuals might help to understand why somepeople develop the disease and others do not. Preliminarydata suggest a relation between gene polymorphisms of tumour necrosis factors, transforming growth factors,interleukin 1, CD14, and adhesion proteins, and the riskof coronary disease. 33

Research has also focused on thrombotic markers,showing an association between tissue-type plasminogen

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848 THE LANCET Vol 361 March 8, 2003 www.thelancet.com

Birth

Genetic dispositionFamily history Environment

Lifestyle

Periodic screeningCardiovascular disease

risk evaluation

Preclinical

StageDetection/

classification

Death

Diabetes mellitusHypertensionDyslipidaemia

Periodic screeningCardiovascular disease

risk evaluationNon-invasive imaging

Clinical, mediating diseases

Peripheral artery diseaseCoronary artery diseaseCerebrovascular disease

Cardiovascular diseaserisk evaluation

Non-invasive imagingStress test

Coronary angiography

Clinical chronic

Stroke TIAAortic aneurysm

Critical limb ischaemiaMyocardial infarction

Cardiovascular diseaserisk evaluation

Echo/Thallium/MRICoronary angiograpy

Clinical acute

Heart failureSevere disability

Echo/Thallium/MRICoronary angiograpy

Clinical endstage

Primary prevention

Treatment

Primary preventionMedical treatment

Secondary preventionMedical treatment

PCI/CABG

Acute treatmentSecondary prevention

Medical treatmentPCI/CABG

Tertiary preventionMedical treatmentHeart transplant

Figure 1: Natural course of atherosclerosisCVD= cardiovascular disease. PCI=percutaneous coronary interventions. CABG=coronary artery bypass graft. TIA=transient ischaemic attack.


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activator, plasminogen activator inhibitor, and the risk of coronary events. 34 Altogether, promising results have beenachieved to identify possible risk markers of acute coronarydisease. However, the cause of atherosclerosis is multi-factorial, and whether these new markers add to the pre-dictive value of established risk factors remains to be seen.

The search for the vulnerable lesionMacrophage-rich lesions, covered by a thin fibrous cap areunlikely to withstand the stress caused by the pulsatilepressure of the blood flow. Intravascular ultrasoundelastography is a promising technique to identify thesevulnerable lesions, based on the notion that soft materialwill deform more than hard material when force is appliedto the tissue. The strain is determined by the ultrasoundsignal (figure 2). This technique is being assessed forintravascular purposes, and applied to study humanarteries in vivo. 35 Investigation of temperature changes atthe coronary lesion with an intravascular thermographycatheter and high-resolution MRI techniques are otherdeveloping options to unmask the vulnerable lesion. 36,37

Definitions, diagnosis, and epidemiologyAccording to WHOs definition, a myocardial infarctionoccurs if at least two of three criteria are fulfilled: typicalischaemic chest pain; raised concentrations of creatinekinase-MB in serum; and typical electrocardiographicfindings, including development of pathological Q-waves. 38

Creatine kinase-MB, however, is not a sensitive marker of myocardial necrosis. Therefore, application of the WHOdefinition in clinical practice results in several patientserroneously diagnosed with non-myocardial infarction,since actually irreversible myocardial damage hadoccurred. Indeed, for purposes of epidemiologicalresearch, the WHO definition aimed for high specificity.However, for purposes of risk stratification and subsequenttreatment, a sensitive detection of cardiac injury is needed.Assays are available for much more sensitive detection of (minimum) myocardial damage, including assays for thecardiac troponins T and I, which are also highly specific(figure 3). 39 These developments formed the basis of arevised definition of myocardial infarction as recentlyproposed by the European Society of Cardiology (ESC)and the American College of Cardiology (ACC)(panel 2). 14

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Panel 1: Established and emerging cardiovascularrisk factors

Established risk factors EvidenceRaised plasma low density lipoproteincholesterolDecreased plasma high density

lipoprotein cholesterolSmoking High blood pressure Increased plasma glucose concentrations Physical inactivity Obesity Advanced age Emerging risk factorsInflammatory markersC-reactive protein Interleukins Serum amyloid A Pregnancy-associated plasma protein A ?Chronic infection ( Chlamydophila pneumoniae , ?Helicobacter pylori , etc)

Procoagulant markersHomocysteine Tissue plasminogen activator Plasminogen activator inhibitor Lipoprotein A Process markersFibrinogen D-dimer ?Coronary artery calcification ?Genetic factorsTumour necrosis factors ?Transforming growth factors ?Interleukin 1 ?CD14 ?Adhesion molecules ?

=clear evidence, and modification of the risk factor decreases therisk of cardiovascular disease; =clear evidence, but less clearwhether modification of the risk factor decreases the risk of cardiovascular disease; ? risk factor under scrutiny.

Figure 2: Intravascular echogram (A) and elastogram (B) of adiseased human femoral artery with the correspondinghistology: picro-Sirius red with polarised light microscopy (C),anti -actin (D), and antibody to CD68 (E)

The echogram shows an eccentric plaque from 60 to 330. Theelastogram reveals high strain in the plaque between 60 and 120,whereas low strain values were in the remaining plaque area (bothcompared with the non-diseased part of the vessel). The histology revealsa fatty plaque region between 60 and 120 (absence of collagen [C] andsmooth muscle cells [D]) with inflammation (rich on macrophages [E]) anda fibrous composition in the remaining part (rich on collagen [C] andsmooth muscle cells [D]).

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0 1 2 3Time after onset of acute myocardial infarction (days)

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Release of myoglobin or creatine kinase-MB isoformsCardiac troponinCreatine kinase-MBCardiac troponin after angina

Upper reference limitAcute myocardial infarction limit

Figure 3: Timing of release of cardiac serum markers after

acute ischaemic myocardial infarctionData are plotted on a relative scale, where 1 is the acute myocardial cut-off concentration. Reproduced with permission from Wu and colleagues. 28


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ESC/ACC definition of myocardial infarctionThe ESC/ACC definition fits with the patients clinicalcourse. Patients do not present with overt myocardialinfarction, but with acute chest pain suggestive of acutecoronary pathology, characterised by presence or absence

of ST-segment elevation, and by presence or absence of biochemical markers of myocardial injury (figure 4). 40 Anacute thrombotic obstruction of a major epicardialcoronary artery is most likely in patients presenting withST-segment elevation. Most of these patients finallydevelop myocardial infarction, although imminentmyocardial injury can be avoided by early reperfusion. 41

Myocardial infarction had also occurred in patientspresenting without ST-elevation in whom raisedconcentrations of biochemical markers indicateirreversible cell damage. Until recently, many of thesepatients were diagnosed as having unstable angina. Inpatients undergoing percutaneous coronary interventions,procedural related enzyme leaks are indicative of celldeath due to myocardial ischaemia. Therefore, theESC/ACC definition indicates that such patients shouldbe regarded as having myocardial infarction.

Application of the ESC/ACC definition has majorimplications for clinical and epidemiological research,individual patient care, and society. The ESC/ACCcommittee that advised on the new definition thereforerecommended that information be provided about thecircumstances in which the infarction had occurred, theresidual left ventricular function, the extent and severity of coronary artery lesions, and the development of thedisease over the recent past. 14

Critics of the proposed new definition have questionedthe clinical importance of minor myocardial damage,especially in coronary interventions. 42 A practicalobjection against application of this new definition is thatavailable assays for troponin detection do not have thesensitivity to adequately detect small increases. 43 Finally,the ESC/ACC definition is thought to be inappropriate

for general diagnostic use, since it does not cover earlyand fatal cases. 42

Decreasing death ratesDeath rates from coronary heart diseasesand amongthese, ischaemic heart diseaseshave decreased in mostdeveloped countries (eg, figure 5). 44,45 Results from theWHO MONICA project 46 suggest that the decreasingnumber of coronary events is the major determinant of this decline, whereas improved coronary care andsecondary prevention were associated with decreasedevent rates. 47 The decline in deaths due to coronary heartdisease runs parallel with increasing numbers of patientswith chronic conditions. 13 Consequently, prevalence of coronary heart disease in developed countries is still

increasing. Furthermore, deaths from coronary andischaemic heart disease have increased, and are stillincreasing, in most eastern European countries (Hungaryand Romania are presented as examples in figure 5), andin many developing countries. Elements with a role in thisregional variation include epidemiological transitions,such as fewer deaths from infectious diseases, changes inlife-style and environmental risk markers, and intrinsicdifferences in genetic profile between populations. 48 Theprevalence of risk factors varies greatly betweengeographical regions and ethnic groups. However, riskfactors for myocardial infarction seem to have similar riskirrespective of geographical region or ethnic origin. 49

In-hospital treatmentSince myocardial infarction was shown to be caused by anacute intracoronary thrombotic occlusion, treatmentstrategies have been introduced that aim at rapid,complete, and lasting restoration of coronary bloodcirculation. Physicians can now choose from differentpharmacological reperfusion regimens based onthrombolytic, antiplatelet, and anticoagulant agents. Insome hospitals, catheter-based interventions are alsoavailable.

Pharmacological lysisGISSI-1 50 and ISIS-2 51 are the major landmark studies of thrombolytic therapy, by showing a 26% reduction in30-day mortality in patients given streptokinase comparedwith placebo. 52 Streptokinase still is the most frequentlyused thrombolytic agent. However, since the results of theGUSTO-1 trial 53 showed a further mortality reduction byaccelerated or front-loaded alteplase (100 mg infusionover 90 min, with over half of the dose within 30 min)over streptokinase, front-loaded alteplase became the goldstandard for pharmacological reperfusion therapy.GUSTO-1 54 is also important because an angiographicsubstudy showed an association between the patency of the initially occluded coronary artery and outcome.

During the 1990s several wild-type alteplase mutantswere developed with less high-affinity fibrin capacity, alonger half-life, and therefore a greater thrombolyticpotency. In phase 2 trials, 55,56 the bolus injection of reteplase and lanoteplase was associated with more rapidand complete vessel patency than front-loaded alteplase.However, similar patency rates were achieved withtenecteplase when compared with front-loaded alteplase. 57

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Panel 2: European Society of Cardiology/AmericanCollege of Cardiology definition of myocardialinfarction

Any of the following criteria satisfy diagnosis of an acute,evolving or recent myocardial infarction1) Typical rise and gradual fall (troponin) or more rapid rise

and fall (creatine kinase-MB) of biochemical markers of myocardial necrosis with at least one of the following:a) Ischaemic symptomsb) Development of pathological Q-waves on electrocardiogramc) Electrocardiogram changes indicative of myocardial

ischaemia (ST-segment elevation or depression)d) Coronary artery intervention (eg, coronary angioplasty)

2) Pathological findings of an acute myocardial infarction

Troponinpositive

Entry

Workingdiagnosis Acute coronary syndrome

Electro-cardiogram

Bio-chemistry

Creatinekinase MB

Troponinnegative

Finaldiagnosis

Acute myocardialinfarction Unstable angina

ST elevation No ST elevation

Chest pain

Figure 4: Acute coronary syndrome terminologyReproduced with permission from Hamm and colleagues. 40


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1985Ischaemic heart diseases

1990 1995 2000 1985Myocardial infarction

1990 1995 2000 1985Other ischaemic heart diseases

1990 1995 2000

RomaniaFranceNetherlandsFinlandUK Hungary Czech Republic

Figure 5: Standardised ischaemic heart diseases mortality in selected European countries(Left) Mortality associated with ICD-9 codes 410414 or ICD-10 codes I20I25. (Middle) Mortality associated with ICD-9 codes 410411 or ICD-10 codesI21I23. (Right) Mortality associated with ICD-9 codes 412414 or ICD-10 codes I24I25.

0 05 10 15 20 25

Exp better Ctrl better

Intracranial

haemorrhage

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Exp better

Myocardial

reinfarction *

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Exp better Ctrl better

Death

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GUSTO-1

GUSTO-3COBALTASSENT-2InTIME-2Combined

GUSTO-5ASSENT-3

ASSENT-3

Combined

Meta(1)

Meta(2)

Meta(3)

Meta(4)

HERO-2Combined

Experimental treatment

Front-loaded alteplase

ReteplaseDouble bolus alteplaseTenecteplaseLanetoplaseBolus plasminogen activator

Reteplase and abciximabTenecteplase and abciximab

Alteplase and enoxaparin

Bolus plasminogen activatorand abciximabLytic and direct thrombin inhibitors

Primary percutaneouscoronary interventionPrimary stenting

Primary percutaneouscoronary interventionand abciximab

Streptokinase and tenecteplaseLytic and direct thrombin inhibitors

Control treatment

Streptokinase

Front-loaded alteplaseFront-loaded alteplaseFront-loaded alteplaseFront-loaded alteplaseFront-loaded alteplase

ReteplaseTenecteplase

Alteplase and unfractionated heparin

Bolus plasminogen activator

Lytic and unfractionated heparin

Lytic

Primary balloon angioplasty

Primary percutaneouscoronary intervention

Streptokinase and unfractionated heparinLytic and unfractionated heparin

Ctrl better

Figure 6: Relative treatment effect associated with several acute treatment modalities in patients presenting withST-elevation acute coronary syndromesMeta(1) includes data from reference 60. Meta(2) includes data from reference 4. Meta(3) includes data from reference 61. Meta(4) includes data from

references 6266. Data are odds ratios and 95% CIs. *Data for myocardial reinfarction as a single endpoint were not available for meta(3); in this casethe figure presents odds ratios for the composite of death or myocardial reinfarction. Intracranial haemorrhage was not reported in meta(1)data werederived from the HERO-1, HIT-4, TIMI9b, and GUSTO2b trials that were included in this meta-analysis.


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Subsequently, large phase 3 mortality trials 58 showed nosuperiority with reteplase and equivalent results withtenecteplase and lanoteplase when compared withalteplase. In a meta-analysis, 59 use of bolus thrombolytic

agents was associated with increased incidence of intracranial haemorrhage. However, this increased riskwas not evident in patients given tenecteplase or reteplaseas compared with front-loaded alteplase (figure 6). 67

Furthermore, the intensity of antithrombin treatmentseems to be a confounding factor. 67 Altogether, theintroduction of bolus thrombolytic agents did not result ina net clinical benefit. Yet, the major advantage is thatthrombolytic agents are now available with a similarefficacy and safety profile as front-loaded alteplase, buteasier to administer.

Antiplatelet treatmentAdequate vessel patency does not guarantee perfusion onmyocardial tissue. 68,69 Thrombolytic treatment has threeimportant caveats in this respect. First, the occludingthrombus might fall apart in smaller parts as a result of treatment, causing distal microembolisation. Second,treatment with a thrombolytic agent only resolves thefibrin-rich red part of the thrombus (and therefore canbetter be named fibrinolytic therapy), whereas the platelet-rich white part remains largely untouched (figure 7).Finally, fibrinolysis generates raised concentrations of freethrombin, and activates platelet aggregation, which mightcause a further worsening of the microcirculation. Toovercome these caveats, pharmacological reperfusionstrategies were developed to combine fibrinolytictreatment with aggressive anti-platelet therapy.

Antiplatelet treatment has been used in patients withmyocardial infarction for many years by means of aspirinadministration. The ISIS-2 study 51 provided evidence forthe benefits of starting aspirin early after the onset of suspected infarction. Aspirin, however, is a weakantiplatelet agent, since it inhibits only one of thepathways leading to platelet aggregation (figure 7). Thefinal common pathway in this process is formed byactivation of the platelet glycoprotein IIb/IIIa receptor.Therefore, inhibitors of the platelet glycoprotein IIb/IIIaare more potent agents than aspirin. Results of phase 2trials 7073 of myocardial infarction with ST-elevationshowed that combined fibrinolytic therapy andglycoprotein IIb/IIIa inhibitors achieved more completereperfusion than did fibrinolytic therapy alone.Additionally, shorter time periods to ST-segmentresolution were recorded, indicating improved earlyreperfusion in the myocardial tissue. 74,75 In GUSTO-5, 76

combined treatment with reduced dose reteplase and

abciximab was not associated with a lower 30-daymortality compared with full-dose reteplase alone(figure 6, table). Myocardial reinfarction was significantlyreduced, but this endpoint did not translate into amortality reduction beyond the 30 days. 77 Combinationtherapy was associated with increased frequency of majorbleeding complications, especially in elderly patients. The

results of the ASSENT-3 trial,78

which comparedtenecteplase plus abciximab with tenecteplase alone, fitwell with GUSTO-5: no effect on mortality, significantlyreduced composite endpoint that included myocardialinfarction, and increased risk of major bleedingcomplications.

Antithrombin therapy Release of thrombin from the thrombus, as a result of fibrinolysis, contributes to a procoagulant state (figure 7).Thus, fibrinolytic and antiplatelet therapy could becombined with anticoagulant or antithrombin therapy.GISSI-2 79 and ISIS-3 80 investigated the efficacy of subcutaneous heparin in addition to streptokinase andaspirin. The investigators recorded a non-significant

reduction in 30-day death and myocardial reinfarction inpatients given heparin compared with placebo. Bycontrast, major or severe bleeding complicationsincreased. In GUSTO-1 no major differences wererecorded between subcutaneous and intravenous heparinamong patients on streptokinase. In view of these data,neither subcutaneous nor intravenous heparin probablyadds much to the outcome in patients given streptokinaseand aspirin. This opinion, however, is not commonlyshared, 81 and unfractionated heparin is frequently used inpatients with myocardial infarction who are givenstreptokinase. Apart from that, intravenous heparin as acomponent of the GUSTO-1 front-loaded alteplaseregimen is widely accepted, although front-loadedalteplase without intravenous heparin has not beenextensively studied.

Unfractionated heparin is an indirect thrombininhibitor, since it requires the presence of antithrombinIII. Direct thrombin inhibitors such as hirudin andbivalirudin (formerly known as hirulog), do not need thisenzyme to be present, and therefore have a higherantagonistic potency. In a meta-analysis on patientspresenting with ST-segment elevation, use of directthrombin inhibitors was associated with a significantreduction in 30-day death or myocardial reinfarctioncompared with unfractionated heparin. 60 Death rates werenot affected by direct thrombin inhibitors. Similar datawere recorded in the HERO-2 trial, 82 which comparedbivalirudin and unfractionated heparin in patientspresenting with ST-elevation who were givenstreptokinase. Use of direct thrombin inhibitors was notassociated with an increase in the frequency of majorbleeding complications.

Similar to direct thrombin inhibitors, low molecularweight heparin has better pharmacological properties thanunfractionated heparin, which offer advantages for its usein clinical practice. Results of phase 2 trials 83,84 indicate atrend toward better angiographic patency, improved ST-segment resolution, and fewer rates of reocclusionassociated with enoxaparin compared with unfractionatedheparin, as an adjunctive to streptokinase or front-loadedalteplase. In the ASSENT-3 trial, in which tenecteplasewas used, patients randomly allocated to receiveenoxaparin were significantly less likely to die or to have amyocardial reinfarction within 30 days than were those onunfractionated heparin (figure 6). Because of its ease of administration, tenecteplase plus enoxaparin seems to be

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Thrombin

Collagen

Factor XaGlycoprotein

IIb/IIIa receptor

FibrinFibrinogen

Platelet cascade

Coagulation cascade

white

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TXA2

ADP

Heparin, low molecular weight heparin, hirudin, bivalirudin

(hirulog), warfarin

ThrombinProthrombin

Aspirin

Ticlopidine,clopidogrel

Figure 7: The platelet and coagulation cascade that results in(intracoronary) thrombus formation


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Experiment Control Effect *

GUSTO-1Procedure Front-loaded alteplase, aspirin, infusion Streptokinase, aspirin, subcutaneous

unfractionated heparin or infusion unfractionated heparinunfractionated heparin

Patients 10 396 20 251 Death63% 73% 103 fewerMyocardial infarction .. .. ..Stroke 16% 13% 21 moreIntracranial haemorrhage 07% 05% 21 more

GUSTO-3, COBALT, ASSENT-2, and InTIME-2Procedure Reteplase, double bolus alteplase, lanoteplase Front-loaded alteplase, aspirin, infusion

or tenecteplase, aspirin, infusion unfractionated unfractionated heparinheparin

Patients 32 222 22 015Death 70% 67% 22 moreMyocardial infarction 44% 43% 13 fewerStroke 18% 16% 11 moreIntracranial haemorrhage 10% 08% 21 more

GUSTO-5, and ASSENT-3Procedure Reteplase or tenecteplase (both reduced dose), Reteplase or tenecteplase, aspirin,

aspirin, abciximab, infusion unfractionated heparin infusion unfractionatedheparin

Patients 10 345 10 298

Death 58% 59% 13 fewerMyocardial infarction 23% 36% 142 fewerStroke 11% 10% 11 moreIntracranial haemorrhage 07% 07% 01 equal

Meta-analysis , and HERO-2Procedure Streptokinase or front-loaded alteplase, aspirin, Streptokinase or front-loaded alteplase,

hirudin or bivalirudin (hirulog) aspirin, infusion unfractionated heparinPatients 13 664 13 356Death 83% 84% 13 fewerMyocardial infarction 27% 35% 82 fewerStroke 12% 10% 31 moreIntracranial haemorrhage 05% 04% 11 more

ASSENT-3Procedure Tenecteplase, aspirin, enoxaparin Tenecteplase, aspirin, infusion

unfractionated heparinPatients 2040 2038Death 53% 60% 67 fewer

Myocardial infarction 27% 42% 166 fewerStroke 16% 15% 14 moreIntracranial haemorrhage 09% 09% 03 equal

Meta-analysis Procedure Primary PCI (balloon angioplasty or stenting) LyticPatients 3872 3867Death 69% 93% 236 fewerMyocardial infarction 24% 68% 445 fewerStroke 09% 20% 113 fewerIntracranial haemorrhage 005% 11% 113 fewer

Meta-analysisProcedure Primary stenting Primary balloon angioplasty Patients 2050 2070Death 37% 36% 16 moreMyocardial infarction 21% 29% 85 fewerStroke .. .. ..

Intracranial haemorrhage .. .. ..Meta-analysisProcedure Primary PCI (balloon angioplasty or stenting) Primary PCI (balloon angioplasty or

and abciximab stenting)Patients 1747 1719Death 21% 30% 95 fewerMyocardial infarction 10% 14% 44 fewerStroke 02% 02% 02 equalIntracranial haemorrhage 0 0 Equal

PCI=percutaneous coronary intervention. Most commonly used doses of the drugs described above: Aspirin, 150325 mg orally. Abciximab, 025 mg/kg bolus+0125 mg/kg/min infusion (max 10 mg/kg/min). Subcutaneous unfractionated heparin, 12500 U twice daily. Infusion unfractionated heparin (infusion), 40005000 Uweight adjusted bolus+8001200 U/h weight adjusted infusion. Hirudin, 01 mg/kg bolus+01 mg/kg/h infusion; Bivalirudin, 025 mg/kg bolus+05 mg/kg/hinfusion during the first 12 h+025 mg/kg/h infusion during the next 36 h. Streptokinase, 15 MU over 60 min. front-loaded alteplase, 15 mg bolus+075 mg/kginfusion (max 50 mg) over 30 min+050 mg/kg infusion (max 35 mg) over 60 min. Tenecteplase, 3050 mg weight adjusted bolus. Reteplase, two 10 U boluses,30 min apart. Lanoteplase, 120 KU/kg bolus. *Effect per 1000 patients assigned experimental treatment. Includes data presented in reference 60. Includes datapresented in reference 4. Includes data presented in reference 61. Includes data presented in references 6266.

Main efficacy and safety results of major clincal trials and meta-analyses of different reperfusion strategies in patients presentingwith ST-elevation acute coronary syndromes


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an attractive alternative reperfusion regimen that warrantsfurther investigation.

Percutaneous coronary interventionsResults of randomised trials 3,4 have shown better clinicaloutcomes in those receiving mechanical reperfusion thanin those receiving pharmacological reperfusion. A meta-

analysis4

of 23 randomised trials showed a 27%reduction in short-term mortality in favour of primaryangioplasty compared with lytic therapy (figure 6). Thereduction in risk was less pronounced in fibrin-specifictrials (20% risk reduction) than in streptokinase trials(47% risk reduction), with statistical evidence of heterogeneity between these two groups of trials. Primaryballoon angioplasty was also associated with asignificantly lower incidence of myocardial reinfarction,stroke, and intracranial haemorrhage compared withpharmacological reperfusion (figure 6). This initialbenefit was maintained during long-term follow-up. 85

Overall, the results of primary angioplasty obtained inearly trials were mainly achieved because of experiencedoperators (>75 cases per year), high-volume centres

(>200 cases per year), with door-to-balloon times of lessthan 90 min. 86 However, after careful training, primarypercutaneous coronary interventions can be donesuccessfully at community hospitals without on-sitecardiac surgery backup, as reported in the C-PORTstudy. 87 Five other studies 8892 have assessed the potentialbenefit of a transfer for primary percutaneous coronaryintervention over fibrinolytic treatment in acutemyocardial infarction. Whether these results could beapplied and translated into daily practice remainsunclear, but practice guidelines have already changedafter the release of these new data. In 1999, theACC/AHA guidelines recommended primarypercutaneous coronary intervention as an alternativetreatment to fibrinolytic therapy. 86 4 years later, theEuropean Society of Cardiology (ESC) guidelinesregarded primary percutaneous coronary intervention asthe preferred therapeutic option when it can be donewithin 90 min after first medical contact. 93

No significant difference in mortality was recordedbetween primary coronary stenting and balloonangioplasty, but primary stenting was associated with anon-significant trend for reduction in the frequency of myocardial reinfarction and a significant reduction intarget vessel revascularisation. 61 Thus, coronary stenting isa safe alternative that augments the angiographic andclinical results of primary balloon angioplasty.

Use of glycoprotein IIb/IIIa inhibitors in patients withST-elevation myocardial infarction undergoingpercutaneous interventions inhibits platelet aggregation atthe site of plaque rupture and balloon-induced orstenting-induced injury, potentially improving the clinicaloutcome. In five randomised trials 6266 comparing primaryballoon angioplasty or stenting with or without abciximab,a non-significant trend for reduction in mortality andmyocardial reinfarction was noted with use of glycoprotein IIb/IIIa inhibitors, which is compatible withthe benefit of glycoprotein IIb/IIIa use as seen in otherstudies of percutaneous coronary intervention. 94,95

Time to treatmentTime from symptom onset to treatment is one of the mostimportant determinants of the success of pharmacologicalreperfusion therapy. 96 Results of several investigationshave shown that initiation of fibrinolytic treatment at thepatients home, before admission, reduces treatment delayby about an hour. 97 Two meta-analyses 98,99 of all

randomised trials comparing prehospital and inhospitalfibrinolysis have shown a significant mortality reductionby the prehospital treatment strategy. Prehospitalfibrinolysis also seems to be associated with a three-foldincrease in abortion of myocardial infarction comparedwith in-hospital treatment. 41 The safety of prehospitalfibrinolysis is strongly dependent on a correct diagnosis in

the prehospital setting. To confirm ongoing myocardialinfarction, a standard 12-lead electrocardiogram isneeded, which can either be transmitted via a telephoneconnection for interpretation by skilled cardiologists, orinterpreted on-site by specifically designed computerprograms. Both approaches are associated with similarlylow false-positive rates. 100,101

Primary angioplasty is associated with an increasedtreatment delay compared with fibrinolytic therapy, buthow much extra angioplasty-related treatment delaywould nullify its benefits is unclear. In a largeobservational study 102 of patients treated by primaryangioplasty, increased mortality rates were recorded oncethe door-to-balloon time exceeded 2 h. Data fromrandomised trials 103 indicated that primary angioplasty and

fibrinolytic therapy yielded equivalent mortalityreductions if the angioplasty is delayed by 50 min. Inother investigations, 88 however, primary angioplasty wasassociated with a significant reduction in major cardiacendpoints over fibrinolysis even after long delays intreatment. Analyses are hampered by the fact that only afew patients undergoing primary angioplasty are treatedwithin 2 h from onset of symptoms. 104,105

Prevention and long-term treatmentIt is important to stratify patients according to the risk of further coronary events after acute myocardial infarction,and to take measures to prevent them. In high-riskpatients, coronary interventions should be considered. 106

In general, however, effort should be devoted to actionsthat aim to change unhealthy life-styles, and provideindividualised advice on smoking, diet, weight control,and exercise. 22 For long-term medical management, thevalue of aspirin, blockers, and ACE inhibitors has beenshown beyond all reasonable doubt. Weaker conclusionscan be drawn about long-term treatment with statins andanticoagulants.

AspirinThe available evidence for long-term antiplatelettreatment in patients who have had a myocardialinfarction is mostly derived from a meta-analysis of 25trials of antiplatelet therapy in secondary prevention of cardiovascular disease. This meta-analysis included tenpostinfarction trials of antiplatelet therapy that showed asignificant reduction in total vascular mortality, non-fatalreinfarction, non-fatal stroke and important vascularevents, a composite endpoint that included total vascularmortality, non-fatal reinfarction, and non-fatal stroke. 107

There is no general consensus about the optimumduration of treatment in secondary prevention, butindirect data suggest that aspirin should be continuedindefinitely after infarction.

blockersUse of intravenous blockers in patients in the acutephase immediately after myocardial infarction withoutobvious clinical contraindications could be consideredwhen there is tachycardia (in the absence of heart failure),hypertension, or chest pain unresponsive to opioids.Short-term treatment in the acute phase seems to be of nobenefit in reducing mortality and morbidity unless

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blockade is continued long term. 8 Moreover, data fromlong-term trials 108 suggest that blockers should becontinued indefinitely in all patients who have recoveredfrom an acute myocardial infarction.

ACE-inhibitorsBased on several clinical studies, and provided that there

are no major contraindications for their use, ACE-inhibitors should be initiated in the early phase afterhaemodynamic stabilisation. 109 These studies have shownthat ACE-inhibitors reduce rates of reinfarction, and exerta favourable effect on ventricular remodelling that isusually accompanied by a decrease in development of congestive heart failure, which in turn is translated into areduction in mortality. The efficacy is probably of greatestvalue in patients who are at high risk, such as elderlypeople, those with Killip class II or greater, andasymptomatic patients with depressed left ventricularfunction. If treatment is well tolerated, it should becontinued indefinitely. 9

Statins

Data from two observational studies 110,111 have shown thatsurvivors of acute coronary syndromes who weredischarged on statin treatment had a reduced mortality at6 months and 1 year. In the MIRACL study, 10 patientswith an acute coronary syndrome were randomlyallocated to atorvastatin or placebo. Mortality reductionwas not significant. However, statin treatment wasassociated with a significant reduction in the compositeendpoint of death, non-fatal myocardial reinfarction,cardiac arrest with resuscitation, or recurrentsymptomatic myocardial ischaemia. If statins arewithdrawn after admission for an acute coronarysyndrome, death and non-fatal reinfarction increasecompared with patients who continue to receive them,and tended to be higher compared with patients whonever received it. 112

Anticoagulant treatmentOral anticoagulant agents could also be used in the longterm, although most of the clinical trials with these agentswere undertaken before widespread use of aspirin. 113

Several clinical trials could not show a reduction in eventsby combined aspirin and low-intensity oral anticoagulanttreatment. 113,114 However, in two clinical trials, 115,116

combined aspirin and more intensive oral anticoagulationtherapy (INR>2) was associated with significantly lowerfrequency of death, myocardial reinfarction, and strokethan was aspirin alone, although at the cost of an increasein non-fatal bleeding complications.

Future directionsWith the understanding on development of coronaryatherosclerosis as an inflammatory disease, future researchshould concentrate on development and wideimplementation of new approaches that will allowscreening for serum markers of chronic low-grade vascularwall inflammation, and clinical imaging of the vulnerableplaque that will discriminate among patients who are atan increased risk for plaque rupture and infarction.However, front-line research towards new risk markersof coronary atherosclerosis should not divert ourattention from what is already known. Data is emergingthat we are failing to modify traditional risk factors. Inthe recent EUROASPIRE surveys 11 of coronary riskfactors across several European countries in 199596and 19992000, risk factor modification was notsuccessful. Smoking prevalence increased from 19% to

21%, obesity from 25% to 33%, and diabetes from 18%to 22%. Prevalence of hypertension andhypercholesterolaemia was still as high as 54% and 59%,respectively. This was considered as a collective failureof medical practice to achieve the substantial potentialamong patients with coronary heart disease to reduce therisk of recurrent disease and death. 11

A similar situation appears with regard to acutetreatment. On the one hand, reperfusion therapycontinues to evolve, and adjunctive therapies withadenosine and super-saturated aqueous oxygen toreduce reperfusion injury are promising, as is inductionof moderate systemic hypothermia. 117119 Newdevelopments in this respect also include investigationstowards the effectiveness and safety of low-molecularweight heparins (enoxaparin), antiXa agents(pentasaccharides), glucose insulin potassium infusion,and ADP inhibitors (clopidogrel). On the other hand,treatment strategies proven to be effective, such asreperfusion therapy, are still largely underused. This wasevident in two recent surveys. In GRACE 120 up to a thirdof eligible patients presenting with ST-segment elevation

myocardial infarction within 12 h of symptom onset didnot receive reperfusion therapy. Similarly, in the EuroHeart Survey 6 of acute coronary syndromes, only half thepatients enrolled with ST-segment elevation receivedreperfusion therapy. And finally, despite compellingevidence about the importance of very early reperfusiontherapy, the time from symptom onset to treatment of 27 h, as recorded in clinical trials in the beginning of the1990s (GUSTO-1), has remained unchanged. 121123

ContributorsE Boersma was responsible for the concept and applied methods.E Boersma and N Mercado drafted the report. D Poldermans,M Gardien, J Vos, and M L Simoons were responsible for critical revisionof the report.

Conflict of interest statementNone declared.

AcknowledgmentsNo industrial or non-industrial grant was obtained for this seminar.

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acute myocardial infarction lancet 2003

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