Effect of Prehospital Thrombolysis on Aborting AcuteMyocardial Infarction

Evert J.P. Lamfers, MD, Ton E.H. Hooghoudt, MD, Astrid Uppelschoten, BSc,Pieter W.J. Stolwijk, MD, and Freek W.A. Verheugt, MD

To shorten the delay between coronary occlusionand thrombolytic treatment, we initiated a prehos-

pital thrombolysis program, working in close cooper-ation with our local general practitioners and ambu-lance service. We found that thrombolytic treatmentcould be instituted 63 minutes earlier than in hospital.Furthermore, 28% of patients in the prehospital groupwere treated within 1 hour of symptom onset, a speednot matched by any patient in the hospital group. After2 hours, these percentages became 65% and 25%,respectively.1 Although a lower mortality rate is ex-pected in patients who are treated earlier, this has beendifficult to prove statistically with randomized trials.2

Patients with an extensive acute myocardial infarctionand thus a high mortality tend to seek help earlier, areeasily diagnosed because of decisive electrocardio-graphic changes, and are thus favorable candidates forvery early (prehospital) thrombolysis. A high mortal-ity rate is thus found in the very early treated group,part of which would never have survived long enoughfor in-hospital thrombolysis. Indeed, the Global Uti-lization of Streptokinase and Tissue Plasminogen Ac-tivator for Occluded Coronary Arteries (GUSTO) trialconfirms a higher mortality in patients who are treatedvery early.3 We therefore evaluated our prehospitalthrombolysis program by comparing the number ofaborted myocardial infarcts against those of patientstreated in a nearby hospital without such a prehospitalprogram.

• • •Transtelephonic electrocardiograms from patients

with chest pain and the suspicion of acute myocardialinfarction by general practitioner or ambulance staff(duration of pain.30 minutes and,6 hours, notrelieved by sublingual nitroglycerin) were transmittedto the coronary care unit of 1 of our hospitals. Morethan 0.1-mV ST-segment elevation in 2 anatomicallycontiguous leads or.0.2 mV in leads V1 and V2confirmed the diagnosis of transmural myocardialischemia. A check list was used to assess contraindi-cations for thrombolytic therapy, following which 30mg of anistreplase was given intravenously, as well as160 mg of aspirin. A total of 227 patients were treatedin the prehospital setting. Their data were comparedretrospectively with those of 269 patients who under-went in-hospital thrombolytic therapy (1.5 million U

of intravenous streptokinase or 100 mg of intravenousrecombinant tissue plasminogen activator [rt-PA] andintravenous heparin) in the same period in a nearbyhospital not using a prehospital thrombolysis program(Hospital Rijnstate, Arnhem, The Netherlands). De-tails are given in Table I. The diagnosis of abortedmyocardial infarction was made for both groups: (1) ifthe combination of chest pain and transient electro-cardiographic changes suggested transmural ischemia;(2) if an increase in creatine kinase and its isoenzymewas,2 times the upper limit of normal; and (3) thecumulative ST-segment elevation and depression de-creased to,50% within 2 hours of treatment. AllST-segment shifts were measured by the same ob-server, using handheld calipers at 80 ms after theJ-point in all 12 leads.

In the prehospital group, 3 patients (1.3%) whounderwent thrombolytic therapy did not have an in-crease in cardiac enzymes, whereas, when viewedretrospectively, the history and electrocardiograms ofthese patients suggested no myocardial ischemia. Inthe hospital group, 3 patients (1%) also receivedthrombolytic therapy without justification. Our analy-sis excluded all these patients.

A total of 30 of the 224 patients (13%) of theprehospital group and 12 of the 266 (4%) in-hospitalgroup thus fullfilled the criteria for an aborted myo-cardial infarction (p,0.05, chi-square test).

Seven of the prehospital thrombolytic patients withaborted infarction were treated within 1 hour, but noneof the in-hospital thrombolytic patients achieved this.About half of the patients in both groups had 1-vesseldisease. Three of the prehospital treated patients and 2of the hospital-treated patients had no visible diseaseat angiography, although they had an extensive ST-segment shift in the acute phase, suggesting acuteanterior infarction and a hypokinetic segment at ven-triculography or echocardiography. None of the pa-tients of either group died during their stay in hospitalor before the follow-up at 12 months.

• • •Prehospital initiation of thrombolytic therapy

bodes well for patients with acute myocardial infarc-tion, but is fraught with medical, legal, and organiza-tional problems. Training of ambulance personnel andgeneral practitioners is time consuming, and manyhealth providers question whether the effort is worth-while. Our prehospital thrombolytic program has re-duced time to treatment by a median of 63 minutes,1

but has shown no mortality benefits (Table I), due tothe huge patient cohort and/or lengthy period betweenprehospital and hospital thrombolysis needed to detectany significant reduction in mortality.4 The GUSTO-Istudy (41,021 patients) found an increase in mortality

From the Departments of Cardiology, Canisius-Wilhelmina Hospital,Nijmegen; Hospital Rijnstate, Arnhem; and the Heartcenter, UniversityHospital, Nijmegen, The Netherlands. Dr. Lamfers’ address is: Depart-ment of Cardiology, Canisius-Wilhelmina Hospital, P.O. Box 9015,6500 GS Nijmegen, The Netherlands. Manuscript received February17, 1999; revised manuscript received and accepted May 26,1999.

928 ©1999 by Excerpta Medica, Inc. All rights reserved. 0002-9149/99/$–see front matterThe American Journal of Cardiology Vol. 84 October 15, 1999 PII S0002-9149(99)00468-3

as time to treatment increased, although patientstreated within 1 hour after symptom onset had a highermortality than those treated between 1 and 3 hours.3

Barbash et al,5 who compared early and late treatmentpatients, found more revascularization procedures inpatients in the early treated group, confirming the ideathat this group contains patients with a worse progno-sis. Furthermore, a patient with a large ST-segmentshift on the prehospital electrocardiogram, and thuswith a larger infarction, was easier to diagnose in theprehospital setting than a patient with only minimal

ST-segment changes who will thus be assessed andtreated in hospital. Also, the Grampian Region EarlyAnistreplase Trial (GREAT) showed that patients witha large infarct and a worse prognosis tend to seek helpearlier, thus confounding the mortality analysis ofprehospital thrombolytic trials.4 However, the meta-analysis of randomized prehospital thrombolytic trialsas performed by Boersma et al6 revealed a highlysignificant mortality reduction in favor of early treat-ment and thus of prehospital thrombolysis. Hence,comparison of patients without a randomization pro-cedure will result in a population with larger infarctsand a higher mortality rate in the prehospital situation,and renders mortality a dubious criterion. An alterna-tive parameter was therefore sought. In light of Rei-mers et al’s7 model of evolving myocardial infarction,we hypothesized that earlier thrombolytic treatmentmight result in a larger percentage of abortion ofmyocardial infarction.

Aborted myocardial infarctions have not previ-ously been suggested as an indicator for the efficacy ofprehospital thrombolysis, although most studies em-phasize the importance of very early thrombolytictreatment (Table II). The GREAT study found lessQ-wave infarctions in the prehospital group, whichcould indicate a greater number of aborted infarc-tions.4 Also, in a electrocardiograhic substudy, theGREAT authors found that the proportion of patientsshowing a reduction in ST elevation of.25% or even.50% between the home and hospital recordings wassignificantly greater in the early than in the late group.Although not mentioned, this is also suggestive ofabortion of myocardial infarction.8 In another study,a highly significant salvage of myocardium in pa-tients treated within 2 hours of onset of pain wasreported using technetium-99m sestamibi injectionsbefore thrombolysis and again at hospital discharge.9

By definition, patients with an aborted infarctiondo not have an increase in enzymes, just as do patientsinadvertently treated with thrombolysis. Retrospectiveanalysis of the electrocardiograms showed the samenumber of inadvertently treated patients in both pre-hospital and hospital groups. This compares well withthe 1% false-positive electrocardiograms mentioned inthe REPerfusion for Acute Infarction in Rotterdam(REPAIR) study,10 and the 1.1% reported in a studyexamining inadvertent thrombolytic therapy.11 Aftercorrection for these data, we found a significantlyhigher number of aborted infarctions in the prehospitalgroup than in the group receiving treatment in hospi-tal. This is probably due to the earlier time to treat-ment, because 7 of the 30 prehospital-treated patientswith aborted infarction had a time to treatment of,1hour. None of the 12 hospital-treated patients withaborted myocardial infarction were treated within 1hour. So, although infarction can be aborted by throm-bolytic treatment in a hospital setting, probably be-cause myocardial tissue is preserved by collateralblood flow before the artery is opened (stutteringinfarction), an infarction can also be aborted by givingvery early treatment, which in our experience is onlypossible via prehospital thrombolysis.

TABLE I Patient Characteristics

PrehospitalThrombolysis(n 5 227)

In-HospitalThrombolysis(n 5 269)

Age (mean) (yrs) 63 62Men 171 (75%) 192 (71%)Minutes to treatment 90* 155*Transmural ischemia

Anteroseptal 100 (44%) 120 (45%)Inferior 62 (28%) 76 (29%)Inferior 1 right ventricle 47 (21%) 60 (23%)Lateral 15 (7%) 10 (4%)

Inadvertently treated 3 3Aborted infarction 30 (13%)* 12 (4%)*Total ST-segment shift (mean) 1.9 mV 1.5 mVCoronary angiography 82 (36%) 99 (37%)

No visible disease 3 51-vessel 41 502-vessel 21 233-vessel 13 20

TreatmentConservative 160 (71%) 207 (77%)Angioplasty 46 (20%) 38 (14%)Bypass surgery 21 (9%) 24 (9%)

Mortality at 12 months 24 (11%) 26 (10%)

*p ,0.05 prehospital versus in-hospital thrombolysis.

TABLE II Aborted Infarction After Prehospital and In-HospitalThrombolysis

PrehospitalThrombolysis

(n 5 30)

In-HospitalThrombolysis

(n 5 12)

Age (mean) (yrs) 62 55Men 22 9Minutes to treatment 85* 165*Transmural ischemia

Anteroseptal 13 (43%) 9 (75%)Inferior 13 (43%) 2 (17%)Inferior 1 right ventricle 3 (10%) 1 (8%)Lateral 1 (3%) 0

Total ST-segment shift(mean mV)

1.2 0.9

Coronary angiographyNo visible disease 3 21-vessel 10 52-vessel 4 13-vessel 2 3

TreatmentConservative 17 3Angioplasty 9 6Bypass surgery 4 3

Mortality at 12 months 0 0

*p ,0.05 pre- versus in-hospital thrombolysis.

BRIEF REPORTS 929

In conclusion, very early (prehospital) throm-bolysis is associated with a threefold increase inabortion of myocardial infarction when comparedwith in-hospital treatment. Assessment of the num-ber of aborted myocardial infarctions may well bea better criterion than mortality for the efficacy ofearly thrombolysis, especially when small patientcohorts are studied.

Acknowledgment: We would like to thank thegeneral practitioners, ambulance personnel, and car-diologists of both hospitals in Nijmegen for their helpin making this study possible. Furthermore, they arevery grateful to both the cardiologists and Astrid Dek-ker of the Hospital Rijnstate in Arnhem, for theirgenerous help with examining the data of the in-hospital-treated patients.

1. Hooghoudt TEH, Lamfers EJP, Uppelschoten A, Verheugt FWA. Study oftime intervals in myocardial ischemic syndromes (STIMIS).Cardiologie1998;5:23–30.2. Theroux P. Coronary thrombolysis: prehospital use.Can J Cardiol1993;6:521–522.

3. The GUSTO Angiopgraphic Investigators. The effect of tissue plasminogenactivator, streptokinase or both on coronary-artery patency, ventricular function,and survival after acute myocardial infarction.N Engl J Med1993;329:1515–1522.4. Rawles J. Halving of mortality at 1 year by domiciliary thrombolysis in theGrampian Region Early Anistreplase Trial (GREAT).J Am Coll Cardiol1994;23:1–5.5. Barbash GI, Roth A, Hod H, Miller HI, Modan M, Rath S. Improved survivalbut not left ventricular function with early and prehospital treatment with tissueplasminogen activator in acute myocardial infarction.Am J Cardiol 1990;66:261–266.6. Boersma E, Maas ACP, Dekkers JW, Simoons ML. Early thrombolytictreatment in acute myocardial infarction: reappraisal of the Golden Hour.Lancet1996;348:771–775.7. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenom-enon of ischemic cell death. I. Myocardial infarction size vs duration of coronaryocclusion in dogs.Circulation 1977;56:786–794.8. Trent R, Adams J, Rawles J, on behalf of the GREAT Group. Electrocardio-graphic evidence of reperfusion occurring before hospital admission.Eur Heart J1994;15:895–897.9. Milavetz J, Giebel DW, Christian TF, Schwartz RS, Holmes DR, Gibbons RJ.Time to treatment and salvage in myocardial infarction.J Am Coll Cardiol1998;31:1246–1251.10. Grijseels EWM, Bouten MJM, Lenderink T, Deckers J, Hoes AW, HartmanJAM, Van der Does E, Simoons ML. Pre-hospital thrombolytic therapy witheither alteplase or streptokinase.Eur Heart J1995;16:1833–1838.11. Khoury NE, Borzak S, Gokli A, Havstad SL, Smith ST, Jones M. Inadvertentthrombolytic administration in patients without myocardial infarction: clinicalfeatures and outcome.Ann Emerg Med1996;28:289–293.

Frequency of Silent Myocardial Ischemia FollowingCoronary Stenting

Sekar Kathiresan, MD, Mark K. Jordan, MD, Giorgio Gimelli, MD,Julio Lopez-Cuellar, MD, Nassar Madhi, MD, and Ik-Kyung Jang, MD

S ilent myocardial ischemia, which occurs in up to50% of patients who present with acute coronary

syndromes, has been shown to be associated with poorprognosis.1–5 Even after a percutaneous transluminalballoon angioplasty, ischemia was still detected in22% of patients during the postprocedural period andhalf of them (11%) were silent.6 Coronary stenting hasbeen shown to be superior to balloon angioplasty forimmediate angiographic outcome and 6-month reste-nosis rate.7,8 It has also been shown that coronarystenting compared with balloon angioplasty almostcompletely corrects the underlying obstruction andrestores coronary flow reserve.9 However, no data areavailable on the incidence of silent ischemia aftercoronary stenting. A computerized 12-lead electrocar-diographic recording system was used to detect silentischemia in patients who presented with an acutecoronary syndrome and underwent successful coro-nary stenting.

• • •Thirty patients who underwent successful 1-vessel

coronary stenting after an acute coronary syndrome

presentation at the Massachusetts General Hospitalwere enrolled. We excluded patients with baselineelectrocardiographic changes that would precludeanalysis of silent ischemia (left bundle branch block,ventricular pacing, and severe left ventricular hyper-trophy with strain).

After obtaining informed consent, a baseline elec-trocardiogram was recorded before the procedure.During the first inflation, a 12-lead electrocardiogramwas recorded to use as a template. Shortly after theprocedure, continuous electrocardiographic recordingwas initiated using a 12-lead portable programmableST monitoring system (ELI 100/STM, Mortara Instru-ments, Milwaukee, Wisconsin).

At the end of the monitoring, patients were inter-viewed by one of the investigators regarding anginalsymptoms during the monitoring period. Ischemia wasdefined as either ST-segment deviation of at least 0.1mV from the baseline involving 2 contiguous leads,80 ms from the J point, and lasting for.30 seconds orsymmetric T-wave inversions of at least 0.3 mV. Aninterval of at least 2 minutes was required after theresolution of 1 episode for another episode to becounted as a discrete one. All patients were followeduntil the time of hospital discharge. Discrete variableswere compared using Fisher’s exact test. A p value,0.05 was considered significant.

The clinical characteristics of the 30 patients arelisted in Table I. Procedural success, as defined by

From the Department of Medicine and the Cardiology Division, Mas-sachusetts General Hospital, Harvard Medical School, Boston, Mas-sachusetts. Dr. Jang’s address is: Cardiology Division, Bulfinch 105,Massachusetts General Hospital, 55 Fruit Street, Boston, Massachu-setts 02114. E-mail: Jang.ik@mgh.harvard.edu. Manuscript receivedMarch 5, 1999; revised manuscript received May 26, 1999, andaccepted May 27.

930 ©1999 by Excerpta Medica, Inc. All rights reserved. 0002-9149/99/$–see front matterThe American Journal of Cardiology Vol. 84 October 15, 1999 PII S0002-9149(99)00469-5