Editorial

Reperfusion of the occluded infarct-related artery isthe primary goal of initial therapy of acute myocardialinfarction (MI). Restoration of antegrade blood flowresults in myocardial salvage, improved left ventricularfunction, and survival.1 Both thrombolytic therapy andprimary percutaneous transluminal coronary angio-plasty (PTCA) are well established as means to achievingan open infarct-related artery,2-9 but the issue of whichis best for a patient with an evolving infarction is contro-versial. Use of thrombolytic therapy is supported bynumerous multicenter trials, whereas the data for pri-mary PTCA are from relatively small trials comparingangioplasty and thrombolytic therapy.

Many studies have shown that intravenous throm-bolytic therapy is effective in restoring antegrade flow,improving left ventricular function and reducing mortal-ity rate.2-5 There are also data that demonstrate a survivalbenefit with thrombolytic therapy without significantimprovement in left ventricular function.10,11 The extentof improvement in ventricular function does notaccount for the disproportionate reduction in mortalityrate associated with this treatment.Thus thrombolytictherapy appears to result in a greater survival benefitthan accounted for by the improvement in left ventricu-lar function it confers.

Thrombolytic therapy, however, fails to lyse the occlu-sive thrombus in 25% of patients, and severe residualcoronary stenoses or reduction in flow rate are oftenpresent in those patients in whom it is successful.12-14

Often patients have contraindications to receiving athrombolytic agent, and treatment appears less effectivein older patients and in older clots in which 90-minutereperfusion rates are less at 6 hours or more.1 Becauseof these limitations and the higher rates of recurrentischemia, reocclusion, and intracranial bleeding, primaryPTCA has been used by many cardiologists as the prefer-ential means of reperfusion in MI.15 Studies of primaryPTCA show higher patency rates, smaller enzymaticinfarct size, shorter lengths of hospital stay, and reducedrates of mortality, reinfarction, and stroke comparedwith thrombolytic therapy.6,7,15

A recent meta-analysis combined the data for mortality,stroke, and reinfarction from 10 randomized trials com-

paring primary PTCA with intravenous thrombolytictherapy.16 Mortality rate at 30 days or less, rates of deathor reinfarction, and strokes were all significantlydecreased with PTCA.This difference was less notable intrials of accelerated tissue plasminogen activator than intrials of streptokinase.These clinical outcomes representthe sum of the beneficial effects of reperfusion and thedeleterious effects of reperfusion injury.

Because no single comparative study has been largeenough to quantitate precisely the difference betweenPTCA and thrombolytic therapy, the relative benefits ofthe 2 strategies remain unknown. Observations suggestthat the mortality rate difference found may be relatedto factors other than differences in reperfusion. Indeed,some studies suggest that less than half of the deaths areattributable to differences in reperfusion.3 Anotherstudy showed identical ejection fraction but a signifi-cantly lower mortality rate after PTCA compared withtherapy with tissue plasminogen activator.6

The apparent difference between the clinical outcomesobtained with PTCA and thrombolysis in acute MI may berelated to such factors as higher rates of early patencyand achievement of Thrombolysis in Myocardial Infarc-tion grade 3 flow with PTCA,or direct detrimental effectsof thrombolytic therapy on the myocardium,whichundermines its effect on coronary reperfusion.Higherrates of early patency are supported by the findings ofone study that showed that both patency and ejectionfraction were significantly better after PTCA com-pared with streptokinase.7 Detrimental effects on themyocardium, including hemorrhagic transformation,pro-coagulant activities, inflammation,and depressed left ven-tricular function,have all been previously described.17

Hemorrhagic transformation is usually within the cen-tral region of necrosis, where ischemia disrupted theintegrity of the microvasculature, especially if treatmentis delayed or if the infarct is transmural.Thus a hemor-rhagic infarct has been reported to be the hallmark ofthrombolytic therapy.18,19 Histologically, the hemor-rhagic zones found in autopsied patients treated withthrombolysis consist of coagulative necrosis.20 Post-mortem observations describe striking differencesbetween hearts of patients who have received throm-bolytic therapy, PTCA, or a combination of both asreperfusion therapy for acute MI.The findings ofmyocardial and intraplaque hemorrhage are found morefrequently in those treated with thrombolytic therapy,either alone or in combination with PTCA, but not inthose treated with primary PTCA.21 By contrast, afterprimary PTCA, infarcts are anemic.

Infarct size: Thrombolysis versus PTCAEllen C. Keeley, MD, and W. Douglas Weaver, MD, FACC Detroit, Mich

From Cardiovascular Medicine, Henry Ford Health System.Reprint requests: W. Douglas Weaver, MD, Cardiovascular Medicine, Henry FordHealth System, 2799 W Grand Blvd, Detroit, MI 48202-2689.Am Heart J 1999;137:1007-9.0002-8703/99/$8.00 + 0 4/1/93852

See related article on page 1169.

Extensive neutrophil aggregation and inflammationcaused by thrombolytic therapy promote myocardialinjury, whereas depletion of the reservoir of plasmino-gen in serum reduces clot lysability and therefore theefficacy of these agents.17 Procoagulant activities havebeen described and are thought to be the cause of coro-nary reocclusion.17 Left ventricular dysfunction has alsobeen described after treatment of acute MI.11,22 A studyinvolving an open-chest dog model demonstrated thatinduction of a systemic lytic state resulted in immediateechocardiographic and early histologic alterations char-acteristic of reperfusion injury and was associated withimpaired functional recovery of the myocardium.23 Sucheffects were not observed with direct recanalization ofthrombotic occlusions by mechanical interventions.

In this issue of the Journal, Ottervanger et al24 presentdata that address the question of whether PTCA confersany benefit over thrombolytic therapy in treating acuteMI.This group has previously demonstrated the abilityto achieve excellent outcomes with primary PTCA inthe treatment of acute MI.25 In this study, they evalu-ated 401 patients with acute MI treated with primaryPTCA or thrombolytic therapy (streptokinase). Infarctsize was estimated by measurement of serial levels oflactate dehydrogenase and predischarge radionuclideestimation of left ventricular ejection fraction.Theyreport a higher rate of early patency and establishmentof Thrombolysis in Myocardial Infarction grade 3 flowwith the use of primary PTCA compared with throm-bolytic therapy. Patients treated with primary PTCA hadlower cumulative enzyme release, lower in-hospitalmortality rates, and higher ejection fraction on dis-charge. Interestingly, even patients with an open infarct-related vessel after successful thrombolysis had a lowerejection fraction and greater enzyme release comparedwith those treated with PTCA.

The authors acknowledge several limitations.Theexact time of reperfusion after thrombolytic therapy isunknown, and the increased lactate dehydrogenase lev-els may have originated from other organs, such as theliver. Despite these limitations, this article underlines animportant difference in the short-term clinical outcomesof patients treated with PTCA and thrombolytic therapyfor acute MI.Whether these short-term differences trans-late into long-term differences in morbidity and mortal-ity rates is a critical issue that remains to be determined.

These findings raise an important mechanistic ques-tion: In the presence of an open infarct-related artery,why do patients treated with thrombolytic therapy havelarger infarct sizes and depressed left ventricular functioncompared with those treated with primary angioplasty?The authors hypothesize that either the induction of asystemic lytic state generates an injurious milieu thatexerts adverse effects on the reperfused myocardium,orPTCA results in a more rapid and complete restoration ofantegrade flow, thus salvaging more myocardium.

Despite the many trials of reperfusion therapy andnumerous studies comparing these 2 strategies,ourunderstanding of the optimal method for reperfusionremains incomplete.Future studies should investigatewhether there is a thrombolytic plateau for patency, themicrovascular factors affecting flow rate,and the compos-ite changes that occur during and after successful reperfu-sion that may influence long-term clinical outcome.

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10. Granger CB, White HD, Bates ER, Ohman EM, Califf RM. A pooledanalysis of coronary arterial patency and left ventricular functionafter intravenous thrombolysis for acute myocardial infarction. Am JCardiol 1994;74:1220-8.

11. Harrison JK, Califf RM, Woodlief LH, Kereiakes D, George BS, StackRS, et al. Systolic left ventricular function after reperfusion therapy foracute myocardial infarction. Analysis of determinants of improvement.The TAMI Study Group. Circulation 1993;87:1531-41.

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17. Gurewich V, Muller J. Is coronary thrombolysis associated with sideeffects that significantly compromise clinical benefits? Am J Cardiol1991;77:756-8.

18. Yasuno M, Endo S, Takahashi M, Ishida M, Saito Y, Suzuki K, et al.Angiographic and pathologic evidence of hemorrhage into themyocardium after coronary reperfusion. Angiology 1984;35:797-801.

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23. Ohnishi Y, Butterfield MC, Saffitz JE, Sobel BE, Corr PB, GoldsteinJA. Deleterious effects of a systemic lytic state on reperfusedmyocardium. Minimization of reperfusion injury and enhancedrecovery of myocardial function by direct angioplasty. Circulation1995;92:500-10.

24. Ottevanger JP, Liem A, de Boer M-J, et al. Limitation of myocardialinfarct size after primary angioplasty: is a higher patency the onlymechanism? Am Heart J 1999;137:1169-72.

25. Suryapranata H, van’t Hof AW, Hoorntje JC, de Boer MJ, Zijlstra F.Randomized comparison of coronary stenting with balloon angio-plasty in selected patients with acute myocardial infarction. Circula-tion 1998;97:2502-5.

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