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Resuscitation 81 (2010) 1505–1508

Contents lists available at ScienceDirect

Resuscitation

journa l homepage: www.e lsev ier .com/ locate / resusc i ta t ion

linical paper

rimary percutaneous coronary intervention and thrombolysis improve survivaln patients with ST-elevation myocardial infarction and pre-hospitalesuscitation�,��

liver Koetha,c, Ralf Zahna,c, Timm Bauera,c, Claus Juengerb,c, Anselm Kai Gitta,b,c,ochen Sengesb,c, Uwe Zeymera,b,∗,c

Herzzentrum Ludwigshafen, Department of Cardiology, Ludwigshafen, GermanyInstitut für Herzinfarktforschung Ludwigshafen an der Universität Heidelberg, Ludwigshafen, Germany

r t i c l e i n f o

rticle history:eceived 17 December 2009eceived in revised form 18 May 2010ccepted 11 June 2010

eywords:rimary percutaneous coronaryntervention

a b s t r a c t

Background: Patients with ST-elevation myocardial infarction (STEMI) surviving pre-hospital resuscita-tion represent a selected subgroup of patients with a very high adverse event rate. Only few data on theoutcome of primary percutaneous coronary intervention (primary PCI) and thrombolysis in such patientsare available.Methods: We analysed the Maximal Individual Therapy of Acute Myocardial Infarction (MITRA) Plusregistry. 1529 survivors of pre-hospital resuscitation with STEMI were included. 593 (38.8%) of thosepatients did not receive early reperfusion therapy, 793 (51.9%) patients received thrombolysis and 143(9.4%) patients received primary PCI. Hospital mortality in patients receiving primary PCI or thrombolysis

hrombolysisT-elevation myocardial infarctionesuscitationardiac arrest

was adjusted for confounding factors with a propensity score analysis.Results: Primary PCI as well as thrombolysis in survivors of pre-hospital resuscitation with STEMI wereassociated with a significant reduction of hospital mortality (OR: 0.29, 95% CI 0.17–0.50; and 0.74, 95%CI 0.54–0.99, respectively), while primary PCI was superior compared to thrombolysis (OR 0.50, 95% CI0.30–0.84).Conclusion: Reperfusion therapy improves mortality of patients with STEMI surviving pre-hospital resus-

CI see

citation, while primary P

. Introduction

In patients with ST-elevation myocardial infarction (STEMI)arly reperfusion therapy is the cornerstone of guideline recom-ended therapy and is therefore recommended by the European

ociety of Cardiology,1 the American College of Cardiology andhe American Heart Association.2 Patients with STEMI survivingre-hospital resuscitation represent a selected subgroup with aery high adverse event rate. Only few data on the outcome of

� A Spanish translated version of the summary of this article appears as Appendixn the final online version at doi:10.1016/j.resuscitation.2010.06.018.�� Results from the Maximal Individual Therapy in Acute Myocardial Infarction-lus (MITRA Plus) Registry.∗ Corresponding author at: Klinikum Ludwigshafen, Department of Cardiology,remserstr. 79, 67063 Ludwigshafen, Germany. Tel.: +49 621 503 4000;

ax: +49 621 503 4002.E-mail addresses: koetho@kiliu.de (O. Koeth), uwe.zeymer@t-online.de

U. Zeymer).c For the Maximal Individual Therapy in Acute Myocardial Infarction Plus (MITRA

lus) study group.

300-9572/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.resuscitation.2010.06.018

ms to be more effective than thrombolysis.© 2010 Elsevier Ireland Ltd. All rights reserved.

primary percutaneous coronary intervention (primary PCI) andthrombolysis in survivors of pre-hospital resuscitation are avail-able. In addition, the available data are usually obtained from smallsample size populations.3,4 In summary the role of early reperfu-sion therapy in patients surviving pre-hospital cardiopulmonaryresuscitation has not been fully explored. The aim of this study wasto investigate current use and clinical benefit of primary PCI andthrombolysis in those patients.

2. Methods

The MITRA Plus registry is a German prospective, multi-center,observational data pool of current treatment of AMI. From 1992to 2002, 36,665 consecutive patients with STEMI were includedin the MITRA Plus registry. The MITRA Plus registry consists of4 consecutive sub-registries that have been previously described:

60 min Myocardial Infarction Project (60 min MIP),5 Maximal Indi-vidual Therapy in Acute Myocardial Infarction (MITRA),6 theMyocardial Infarction Registry (MIR)7 and the Acute Coronary Syn-dromes (ACOS) registry.8 All consecutive patients with STEMI wereincluded in the MITRA Plus registry. The present investigation is an

1506 O. Koeth et al. / Resuscitation 81 (2010) 1505–1508

Table 1Baseline characteristics.

Baseline characteristics No reperfusion therapy n = 593 Thrombolysis (±PCI) n = 793 Primary PCI n = 143 p-Value

Age (years) 70.1 (61.7–77.7) 61.7 (50.8–71.2) 60.9 (50.4–71.7) <0.0001Female gender 34.0% 25.7% 23.9% <0.01Diabetes mellitus 22.1% 15.4% 13.3% <0.01Hypercholesterolemiaa 19.0% 33.3% 27.5% 0.09Smoker 17.7% 42.7% 35.3% <0.01Hypertension 30.4% 23.2% 25.9% <0.05Renal insufficiency 7.6% 2.5% 2.8% <0.0001Prior myocardial infarction 23.1% 14.9% 13.3% <0.001Prior stroke 2.0% 0.0% 2.1% <0.001Anterior myocardial infarction 56.2% 60.2% 58.7% 0.36ECG on admission not diagnostic for STEMI 35.5% 15.7% 14.5% <0.0001Cardiogenic shock 35.4% 28.9% 36.4% <0.05Killip class >2 9.6% 4.3% 2.8% <0.0001Process variables

a edica

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Pre-hospital delay >3 h 57.4%Door-to-balloon-time (in min) –Door-to-needle-time (in min) –

LDL cholesterol >130 mg/dl and/or history of hypercholesterolemia and/or actual m

nalysis of consecutive patients with STEMI <12 h, who survivedre-hospital resuscitation. Pre-hospital resuscitation was defineds defibrillation or chest compression before hospital admission.atients were recruited after been admitted to the emergencyoom or to the intensive care unit, where the MITRA Plus registryas started. 217 German hospitals, mainly community hospitals,articipated in the MITRA Plus registry. Most of the participatingentres were high-volume cardiology centres with high exper-ise in performing clinical trials in acute myocardial infarction.

ost of the centres were university hospitals or were organizedn the network of the “Arbeitsgemeinschaft Leitender Kardiolo-ischer Krankenhausärzte (ALKK)”, which has high expertise toardiovascular clinical trials in Germany. STEMI was diagnosed inhe presence of the two following criteria: (1) persistent anginaectoris for ≥20 min and ST-segment elevation of ≥1 mm in ≥2tandard leads or ≥2 mm in ≥2 contiguous pre-cordial leads, or2) persistent angina pectoris for ≥20 min and the presence of aeft bundle branch block. The final diagnosis of STEMI was basedn pre-hospital and in-hospital documented ECGs. ST-elevationyocardial infarction was later confirmed by an increase in cardiac

nzymes to more than twice the upper limit of normal. Pre-hospitalelay was defined as the time delay between onset of symptomsnd hospital admission and was measured in minutes. Mortality,on-fatal re-infarction and non-fatal stroke were defined as majordverse cardiac and cerebrovascular events (MACCE). Data con-erning the early intra-hospital period (first 48 h) were collectedsing a record form within the first 2–3 days at the intensive carenit. Clinical events after the initial period until hospital dischargeere registered on a separate record form. A follow-up was per-

ormed after 14 months. However, the 14-month follow-up wasot conducted by all participating hospitals and therefore the 14-onth data of approximately 60% of the patients are not known.

ll data sheets were sent to the central data centre (Institut fürerzinfarktforschung Ludwigshafen) for uniform monitoring, reg-

stration and data processing. Absolute numbers and percentagesere computed to describe the patient population. Categorical

ariables were compared using Chi-square or Fisher’s exact test.

able 2cute medical treatment (<48 h).

Acute medicaltreatment

No reperfusiontherapy n = 593

Thrombo(±PCI) n

Aspirin 67.1% 83.3%Statins 19.7% 46.6%Beta-blockers 25.0% 45.9%ACE-inhibitors 24.4% 34.3%

30.2% 28.1% <0.0001170 (90.0–470.0) 70 (45.0–120.0) n.c.

30 (15.0–60.0) – n.c.

tion for hypercholesterolemia.

Control for potential confounders was attempted by constructing apropensity score model using logistic regression. For the propensityscore analysis the following variables were included: age, gender,Killip class >2, cardiogenic shock, prior stroke, prior myocardialinfarction, renal insufficiency, ECG on admission not diagnostic forSTEMI, hypertension, diabetes mellitus, pre-hospital delay >3 h andacute medication. The patients were divided into quintiles definedby their probabilities (propensity scores). Balance of the covari-ables across the two groups was achieved after adjustment forthe propensity score. The balance was tested statistically by linearregression for continuous variables and logistic regression for thedichotomous variables. The propensity score quintiles were thenadded to the final logistic regression model. p-Values <0.05 wereconsidered significant. All p-values are results of two-tailed tests.

3. Results

From 1992 to 2002, 36,665 consecutive patients with STEMIwere enrolled into the MITRA Plus registry. For the present analy-sis, we included 1529 survivors of pre-hospital resuscitation anddivided them into three groups: 593 (38.8%) of those patientsreceived no early reperfusion therapy, 793 (51.9%) received throm-bolysis (with/or without PCI) and 143 (9.4%) received primaryPCI within 24 h. Baseline characteristics and acute adjunctivemedication of the three groups are shown in Tables 1 and 2.The baseline characteristics differed markedly. Patients receivingearly reperfusion therapy were younger, less often female andhad less often concomitant diseases compared to patients notreceiving early reperfusion therapy. Patients receiving reperfusiontherapy had less often a pre-hospital delay of more than 3 h. In-hospital mortality, non-fatal stroke and the combined endpoint(hospital mortality/re-infarction/stroke) were lower in survivors

receiving thrombolysis compared to patients not receiving reper-fusion therapy (Table 3). After adjustment for baseline variablesin the propensity score analysis, thrombolysis remained superiorconcerning hospital mortality (Table 4). C-statistic for propen-sity score models was 0.81. Survivors receiving primary PCI had

lysis= 793

Primary PCIn = 143

p-Value

97.2% <0.000160.8% <0.000152.5% <0.000145.4% <0.0001

O. Koeth et al. / Resuscitation 81 (2010) 1505–1508 1507

Table 3Clinical events (univariate).

Clinical events No reperfusiontherapy n = 593

Thrombolysis(±PCI) n = 793

Primary PCI n = 143 p-Value

Hospital mortality 58.2% (345/593) 36.3% (288/793) 20.3% (29/143) <0.0001

4

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Non-fatal re-infarction 2.4% (6/248)Non-fatal stroke 13.7% (34/248)Hospital mortality/re-infarction/stroke 64.9% (385/593)

lower hospital mortality and a lower combined endpoint com-ared to patients not receiving reperfusion therapy (Table 4). Afterdjustment for baseline variables in the propensity score anal-sis (C-statistic = 0.86), primary PCI remained superior in termsf hospital mortality (Table 4). Comparison of primary PCI withhrombolysis (Table 4) showed similar results. Primary PCI wasssociated with a lower hospital mortality and a lower combinedndpoint. This was sill true after adjusting for confounding vari-bles with the propensity score analysis (Table 4). The C-statisticor propensity score models in this analysis was 0.68. Mortalityithin 14 months after discharge was higher in patients not receiv-

ng reperfusion therapy compared to patients receiving primary PCIr thrombolysis within 24 h (20.0% vs. 11.4%; p < 0.05).

. Discussion

In our study 4% of the patients with STEMI survived pre-hospitalesuscitation. Until now only few data in patients with STEMI andre-hospital resuscitation are available. Gorjup et al.9 observedhat 5.7% of the patients with STEMI admitted to either catheter-sation laboratory or intensive care unit survived pre-hospitalesuscitation. A recent study reveals that 10–21% of patients withTEMI need defibrillation and cardiopulmonary resuscitation.10

bout 40% of patients with STEMI surviving pre-hospital resus-itation received in our study no reperfusion therapy. However,rimary PCI as well as thrombolysis was associated with a signif-

cant reduction of hospital mortality in survivors of pre-hospitalesuscitation with STEMI. In numerous studies thrombolysis andrimary PCI have already demonstrated to reduce infarct size andortality in patients with STEMI11–13 without cardiac arrest. There-

ore both therapies are recommended by the European Societyf Cardiology,1 the American College of Cardiology and Americaneart Association.2 In 1992 cardiopulmonary resuscitation was a

trict contraindication for fibrinolysis due to an increased risk ofleeding complications. In addition, primary percutaneous coro-ary intervention was not established in clinical practice in 1992.his may explain the high number of patients not receiving reper-usion therapy after resuscitation in our study. However, since992 guidelines for resuscitation have been updated several times.he current ERC Guidelines for Resuscitation 200514 advise that

hrombolytic therapy should be considered, when cardiac arrests thought to be due to proven or suspected pulmonary embolus.n addition, thrombolysis should be considered in adult cardiacrrest on a case by case basis following initial failure of standardesuscitation in patients in whom an acute thrombotic aetiology

able 4ropensity score analyses.

Propensity score analyses Thrombolysis (±PCI) n = 793 No rep

Hospital mortality 36.3% 58.2%Primary PCI n = 143 No rep

Hospital mortality 20.3% 58.2%Primary PCI n = 143 Throm

Hospital mortality 20.3% 36.3%

3.8% (19/505) 2.6% (3/114) 0.576.3% (32/505) 7.0% (8/114) <0.012.7% (339/793) 28.0% (40/143) <0.0001

for the arrest is suspected. When thrombolytic agents have beengiven, CPR should be performed for up to 60–90 min. In the Euro-pean guidelines successful resuscitation is no contraindication tofibrinolytic therapy, but fibrinolytic therapy should not be givento patients refractory to resuscitation. Safety of thrombolytic ther-apy in patients with previous cardiopulmonary resuscitation hasalready been demonstrated by several studies.10,15,16 Moreover, Liet al.3 performed a meta-analysis and pooled the results of 8 studiesevaluating the effect of thrombolysis in cardiopulmonary resusci-tation. In this meta-analysis, thrombolysis in patients treated withcardiopulmonary resuscitation was associated with a significantlyimproved rate of return of spontaneous circulation, a 24-h sur-vival rate, survival to discharge and long-term neurologic functionin patients treated with cardiopulmonary resuscitation (p < 0.01).However, patients receiving thrombolysis had a higher risk ofsevere bleeding (p < 0.01). Furthermore, Böttiger et al.17 showedthat after initially unsuccessful out-of-hospital CPR, thrombolytictherapy combined with heparin is safe and might improve patientoutcome. Ruiz-Bailén et al.18 showed that the administration ofthrombolysis to patients with AMI who require resuscitation is effi-cacious in reducing mortality, with no increase in haemorrhagiccomplications. The TROICA Trial Investigators and the EuropeanResuscitation Council Study Group19 presented conflicting results.In the TROICA trial thrombolysis in patients with out-of-hospitalcardiac arrest did not improve 30-day survival, return of spon-taneous circulation, hospital admission, 24-h survival, survival tohospital discharge and neurologic outcome compared to placebo.In our study thrombolysis was (compared to the no reperfusiontherapy-group) associated with a reduction in-hospital mortality.This was still true after adjusting for confounding variables with thepropensity score analysis. Data about major bleedings are not avail-able in our registry. However, thrombolysis was associated witha lower rate of non-fatal stroke. Fischer et al.20 already reporteda potential additional effect of fibrinolysis in the prevention ofmicrothrombi in the brain in patients with cardiac arrest. Never-theless, mechanical reperfusion may be the preferred option.

Only few data concerning primary PCI in survivors of pre-hospital resuscitation are available. Spaulding et al.4 performed astudy in which 84 consecutive survivors of out-of-hospital cardiacarrest with presumed cardiac cause underwent immediate coro-

nary angiography. In 37 patients, angioplasty was attempted andin 28 of these TIMI flow grade 3 was achieved. In-hospital mortalitywas 62%. Spaulding et al. demonstrated that successful angioplastyin survivors of out-of-hospital cardiac arrest is an independent pre-dictor of survival (OR, 5.2; 95% CI: 1.1–24.5). In addition Garot et

erfusion therapy n = 593 Odds ratio 95% Confidenceinterval

0.74 0.54–0.99erfusion therapy n = 593

0.29 0.17–0.50bolysis (±PCI) n = 793

0.50 0.30–0.84

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l.21 showed that a shorter interval between the onset of cardiacrrest and return of spontaneous circulation .(odds ratio, 0.91; 95%I: 0.87–0.96) is a predictor of 6-month survival in resuscitatedatients after cardiac arrest complicating acute myocardial infarc-ion. In our study primary PCI was (compared to the no reperfusionherapy-group) associated with a reduction in-hospital mortality.his was still true after adjusting for confounding variables withhe propensity score analysis. Nevertheless, in our study only 9.4%f survivors of pre-hospital resuscitation received primary PCI. Inatients with STEMI without pre-hospital resuscitation, primaryCI seems to be the therapy of first choice. As already described, the.9% absolute reduction in hemorrhagic stroke and the 1.0% abso-

ute reduction in total stroke are established benefits of primaryCI. In addition, primary PCI seems to be superior to thrombolyticherapy to reduce overall short-term death.13 In our study primaryCI was associated with an adjusted lower mortality compared tohrombolytic therapy. Therefore, primary PCI seems to be moreffective than thrombolytic therapy for survivors of pre-hospitalesuscitation with STEMI. Efforts should be made to establish a net-ork between hospitals with and without angioplasty facilities to

mprove hospital and transportation logistics to keep the time lossrom admission to primary PCI as short as possible. However, if pri-

ary PCI cannot be performed within 3 h, thrombolysis is still aalid option.

. Limitations

Some limitations of our study must be stressed as follows: (1)everity of the neurologic deficit was not measured. (2) Treatmentas left to the discretion of the physicians. This could result in

election bias, which cannot be fully eliminated by the propensitynalysis. (3) Data about major bleedings are not available in our reg-stry. (4) No information is available about the initial heart rhythm.5) Patients were recruited after been admitted to the emergencyoom or to the intensive care unit. Therefore, data about patientsho died already in the pre-hospital phase are not available. (6) TheITRA Plus registry was performed between 1992 and 2002. Ther-

peutic hypothermia after cardiopulmonary resuscitation has noteen introduced until 2002. Therefore none of our patients receivedherapeutic hypothermia. In addition, clopidogrel and primary per-utaneous coronary intervention have been implemented in dailylinical practice between 1992 and 2002. This explains the low usef clopidogrel and primary percutaneous coronary intervention inur study.

. Conclusion

Primary PCI and thrombolytic therapy in survivors of pre-ospital resuscitation with STEMI are both associated with aeduction of hospital mortality. However, primary PCI seems toe more effective than thrombolytic therapy for survivors of pre-

ospital resuscitation with STEMI.

onflict of interest statement

None to declare.

2

81 (2010) 1505–1508

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