The

new england journal

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medicine

n engl j med

349;8

www.nejm.org august

21, 2003

798

editorials

Primary Angioplasty for Acute Myocardial Infarction — Is It Worth the Wait?

Alice K. Jacobs, M.D.

Nearly two decades after clinical trials establishedthat fibrinolytic therapy for acute myocardial infarc-tion preserves left ventricular function and reducesmortality, there is evidence that mechanical reper-fusion therapy is superior in reducing the rates ofdeath, reinfarction, intracranial bleeding, reocclu-sion of the infarct-related artery, and recurrent is-chemia. Initially introduced as an alternative to fi-brinolytic therapy (to circumvent contraindicationsto its use and the risk of intracranial bleeding), pri-mary percutaneous coronary intervention is now in-creasingly recognized as the reperfusion therapy ofchoice. The ability to restore robust coronary flowpromptly in more than 90 percent of patients andthe nearly linear relation between patency of the in-farct-related artery at 90 minutes after the initiationof reperfusion therapy and in-hospital mortalityrates lend credibility to the momentum behind pri-mary percutaneous coronary intervention for pa-tients with myocardial infarction associated withST-segment elevation. In fact, a quantitative review

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of 23 randomized trials in which primary percuta-neous coronary intervention was compared with fi-brinolytic therapy revealed that the former was su-perior in reducing the short-term rates of death(7 percent, vs. 9 percent with fibrinolytic therapy;P<0.001), nonfatal reinfarction (3 percent vs. 7 per-cent; P<0.0001), stroke (1 percent vs. 2 percent;P=0.0004), and the combined end point of death,nonfatal reinfarction, and stroke (8 percent vs. 14percent; P<0.001).

Nevertheless, fibrinolytic therapy remains themainstay of reperfusion treatment around the globebecause it is more widely available than coronary an-gioplasty. Even in the United States, the majority of

hospitals do not have angioplasty capabilities, andin many that do, nearly 50 percent of the patientswith myocardial infarction associated with ST-seg-ment elevation are treated with fibrinolytic agents.The widespread unavailability of primary percuta-neous coronary intervention appears to negate thesuperiority of this strategy as compared with fibri-nolysis. It also raises the obvious question of wheth-er primary percutaneous coronary intervention per-formed after a patient is transferred to a facilitywhere it is available will still be superior to fibrino-lytic therapy administered at the referral hospital.Given the inherent delay before transfer and therisks associated with transportation during acutemyocardial infarction, the answer is not intuitive.

Five randomized trials have attempted to addressthis question. The Danish Multicenter RandomizedStudy on Fibrinolytic Therapy versus Acute Coro-nary Angioplasty in Acute Myocardial Infarction(DANAMI-2), reported in this issue of the

Journal,

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is noteworthy for its randomized design, its practi-cal approach to a critical question, and its carefulconsideration of the time between the onset ofsymptoms (in addition to arrival at the hospital) andreperfusion in its comparisons of strategies andtreatment centers. Among patients at referral hos-pitals who were randomly assigned to be transferredto another center for primary angioplasty or to re-ceive fibrinolytic therapy on site, the primary endpoint (a composite of death, reinfarction, or dis-abling stroke at 30 days) was reached in 8.5 percentof the patients in the former group, as comparedwith 14.2 percent of those in the fibrinolytic-therapygroup (P=0.002), and the difference was driven bya reduction in the rate of reinfarction in the angio-

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n engl j med

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editorials

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plasty group (1.6 percent, vs. 6.3 percent in the fi-brinolytic-therapy group). Of note, 96 percent of thepatients were transferred from the referral hospitalto an angioplasty center within two hours after ran-domization. In fact, an analysis of all five trials

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thatcompared transfer for primary percutaneous coro-nary intervention with on-site fibrinolytic therapyrevealed that despite the delay necessary for thetransfer (43 minutes on average), primary percuta-neous coronary intervention was associated withsignificant reductions in the rates of death, nonfa-tal reinfarction, and total stroke. Overall, untowardevents during the transfer were infrequent (a mor-tality of 0.5 percent in one study and a rate of ven-tricular arrhythmias of 0.7 to 1.4 percent).

These provocative data raise the question of theimportance of the time to reperfusion in patientsundergoing primary angioplasty. Although the timedependency of catheter-based reperfusion may beless than that for fibrinolytic therapy, particularlyin the case of patients presenting more than threehours after the onset of symptoms, several studieshave shown that the interval between arrival at thehospital and inflation of the balloon catheter andrestoration of flow to the infarct-related artery (the“door-to-balloon time”) is directly related to in-hos-pital mortality. Indeed, a door-to-balloon time ofless than 90 to 120 minutes has been associated withimproved in-hospital survival. It is noteworthy thatin the DANAMI-2 study, conducted in Denmark, themedian interhospital transfer time was 32 minutes,and the median interval between arrival at the firsthospital and the initiation of the transfer was 50minutes.

2

Moreover, in the Czech Republic, wherethe Primary Angioplasty in Patients Transferredfrom General Community Hospitals to SpecializedPTCA Units with or without Emergency Thromboly-sis (PRAGUE-2)

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trial was undertaken, the time be-tween randomization and balloon-catheter inflationwas only 97 minutes.

In contrast, a U.S. report, from the National Reg-istry of Myocardial Infarction 4,

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revealed a mediandoor-to-balloon time of 185 minutes for patientstransferred to centers capable of percutaneous cor-onary intervention and a door-to-balloon time ofless than 90 minutes in only 3.0 percent of patients.Currently, in the United States, patients with acutemyocardial infarction who are admitted to hospitalsand who are in need of transfer to tertiary centersmust wait for the next available emergency vehicle,whereas a prompt response can be triggered by pub-

lic activation of emergency medical systems. More-over, helicopter transportation is not completely re-liable because weather conditions must be takeninto account.

Given the practical and logistic issues currentlyassociated with transport of patients during acutemyocardial infarction in this country, an integratedapproach to reperfusion therapy is critically impor-tant (Fig. 1).

2

For patients with myocardial infarc-tion associated with ST-segment elevation whopresent to hospitals without facilities for angioplas-ty within 2 to 3 hours after the onset of symptoms,fibrinolytic therapy should be considered and ad-ministered within 30 minutes after arrival (“door-to-needle time”). Transfer to a center capable of per-forming angioplasty should be strongly consideredwhen fibrinolytic therapy is contraindicated or un-successful, when cardiogenic shock ensues, whenthe transfer delay will be less than 60 minutes, or

Figure 1. Suggested Triage of Patients with Myocardial Infarction and ST-Segment Elevation.

The solid arrows represent existing triage to the nearest receiving hospital, and the dashed arrow the ideal triage to a designated center of excellence for the treatment of acute myocardial infarction. The additional time necessary for transport would be negated by the availability of an experienced team per-forming primary percutaneous coronary intervention with a door-to-balloon time of less than 60 minutes. Adapted from Armstrong et al.

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Capable of percutaneous coronaryintervention

Primary angioplastyGoal: door-to-balloon time <90 min

Interhospital transfer

TransportGoal: <30 min

Receiving hospital

Not capable of percutaneouscoronary intervention

FibrinolysisGoal: Door-to-needle time <30 min

Acute myocardialinfarction center capableof percutaneous coronary

intervention

Goal: Door-to-ballon time <60 min

30 min 30 min

Consider:Risk of lysisDelay in transferTime from onset of symptoms

Onset of symptomsof acute myocardial

infarction

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when more than 3 hours has elapsed since symp-toms began. Data available to date reveal that thetwo reperfusion strategies become equivalent withrespect to death as the difference between the door-to-needle time and the door-to-balloon time ap-proaches 60 minutes and with respect to the com-posite end point of death, reinfarction, or strokeafter a delay of 90 minutes.

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Furthermore, both theComparison of Primary Angioplasty and Prehospi-tal Thrombolysis in the Acute Phase of MyocardialInfarction (CAPTIM) trial

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and the PRAGUE-2 trialshowed that primary percutaneous coronary inter-vention is superior to fibrinolysis when the durationof symptoms is two to three hours or more but notwhen the duration of symptoms is less than twohours.

Nevertheless, now is the time for evidence-based therapy to dictate optimal patient care. Nowis the time to discard the practice of transporting pa-tients with acute myocardial infarction to the near-est hospital and to transport them preferentially tocenters of excellence for primary percutaneous cor-onary intervention (Fig. 1). This practice will fosterthe availability of highly experienced angioplastyteams that can perform primary percutaneous cor-onary intervention with minimal delay. The modelfor this type of care exists in the emergency systemcomprising regional centers of excellence for trau-ma victims. Moreover, now is the time for tertiaryhospitals capable of performing primary angioplas-ty to offer it 24 hours a day, seven days a week.

Certainly, we need to continue to promote pub-lic education about the warning signs of myocardialinfarction and to promote the immediate activationof emergency medical systems when symptoms dooccur (50 percent of patients with acute myocardialinfarction transport themselves to the hospital) inthe effort to minimize the delay in the provision oftreatment (with a goal of 30 minutes between theonset of symptoms and the start of reperfusion ther-apy). We also need to determine whether primaryangioplasty performed immediately after arrival atangioplasty-treatment centers is superior to thatperformed after transfer from referral hospitals —a finding that might compel community hospitalsthat do not currently perform angioplasty proce-

dures to begin to offer this reperfusion strategy.Clearly, we must continue to evaluate optimal phar-macologic and mechanical reperfusion strategiesthat may combine the advantages of both. Fibrinoly-sis before hospital arrival and facilitated percuta-neous coronary intervention (combination therapywith reduced-dose fibrinolytic agents and glyco-protein IIb/IIIa platelet inhibitors before transferfor angioplasty) hold promise, although the latterstrategy may be associated with an increased riskof bleeding.

When available and performed by experiencedoperators at high-volume centers, primary percuta-neous coronary intervention saves 20 lives and re-sults in 60 fewer events for every 1000 patientstreated. This suggests that primary percutaneouscoronary intervention is indeed worth the wait.However, as in Denmark and the Czech Republic,we must strive to minimize the wait by implement-ing systems that allow rapid transfer between hos-pitals and that ultimately will allow direct transportfrom the home or other off-site location to the near-est center of excellence for primary coronary angio-plasty.

From the Cardiology Section, Department of Medicine, BostonUniversity Medical Center, Boston.

1.

Keeley EC, Boura JA, Grines CL. Primary angioplasty versus in-travenous thrombolytic therapy for acute myocardial infarction: aquantitative review of 23 randomised trials. Lancet 2003;361:13-20.

2.

Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison ofcoronary angioplasty with fibrinolytic therapy in acute myocardialinfarction. N Engl J Med 2003;349:733-42.

3.

Zijlstra F. Angioplasty vs thrombolysis for acute myocardial in-farction: a quantitative overview of the effects of interhospital trans-portation. Eur Heart J 2003;24:21-3.

4.

Widimsky P, Budesinsky T, Vorac D, et al. Long distance trans-port for primary angioplasty vs immediate thrombolysis in acutemyocardial infarction: final results of the randomized national mul-ticentre trial — PRAGUE-2. Eur Heart J 2003;24:94-104.

5.

NRMI 4 Investigators. The National Registry of Myocardial In-farction 4 quarterly data report. South San Francisco, Calif.: Genen-tech, March 2003.

6.

Armstrong PW, Collen D, Antman E. Fibrinolysis for acute myo-cardial infarction: the future is here and now. Circulation 2003;107:2533-7.

7.

Nallamothu BK, Bates ER. Percutaneous coronary interventionversus fibrinolytic therapy in acute myocardial infarction: is timing(almost) everything? Am J Cardiol (in press).

8.

Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angio-plasty versus prehospital fibrinolysis in acute myocardial infarction:a randomised study. Lancet 2002;360:825-9.

Copyright © 2003 Massachusetts Medical Society.

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