PREHOSPITAL THROMBOLYSIS-TIME IS MUSCLE AND MUSCLE IS TIME

Review Article

INTRODUCTION

Therapy of acute ST-elevation myocardial infarction(STEMI) has undergone dramatic improvements during thepast three decades, and in-hospital and 30-day mortalityrates have tremendously decreased from >15-20% in thepre-thrombolytic era to 8-10% using fibrin-non-specificagents, to 6-8% using fibrin-specific thrombolytic agents,and down to 4.5% by the use of primary percutaneouscoronary intervention (PPCI) in controlled trials byexperienced centres under optimal trial conditions. Time toreperfusion plays an important role for myocardial salvage,and the concept of the ‘golden hour’, i.e. the optimal timewindowfor initiation of treatment (within 1 h from the onsetof pain), appears now to be applicable to all patients,including those treated by pharmacological reperfusiontherapies (Fig.1).

A meta-analysis of 22 trials, including more than 50000patients, showed maximal effectiveness of thrombolytictherapy within the first hour of symptom onset (the goldenhour), whereas the benefit was reduced by nearly 50% in thesubsequent hour.[2]. An estimated 65, 37, 26 and 29 livesare saved per 1000 patients when treated with thrombolytictherapy within 0-1, 1-2, 2-3 and 3-6 hours respectively. Ifthe patients of AMI can be identified and treated very earlyafter the onset of symptoms, the infarction process canessentially be aborted.[3]At present, Pri.PCI is onlyavailable on an average for ~15–20% of patients sufferingfrom STEMI in the western world. In most regions in theworld in general, thrombolytic therapy is still the fastest andbest accessible reperfusion treatment for most patients

PREHOSPITAL THROMBOLYSIS-TIME IS MUSCLE AND MUSCLE IS TIME

SK Gupta and Amit K MalikDepartment of Cardiology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.

Correspondence to: Dr S K Gupta, Senior Consultant, Department of Cardiology, Indraprastha Apollo Hospitals,Sarita Vihar, New Delhi 110 076, India.

E-mail: drskgupta@hotmail.com

Although the medical and technological revolution in the last three decades has improved clinical outcome inpatients presentingwith acute STEMI, residual morbidity and mortality are still high. It is widely acknowledgedthat the key factor in the successful treatment of AMI is the time elapsed between the onset of symptoms andinitiation of therapy. The obvious step in the continuing effort to shorten time-to-treatment and thus to achievemaximal myocardial salvage is the use of prehospital thrombolysis. According to the mortality data, pre-hospital and also in-hospital thrombolysis has successrates comparable with Pri.PCI when initiated within thefirst 2–3 h after the onset of pain. Therefore, in these patients, thrombolytic therapy should not be withheld infavorof mechanical reperfusion if it cannot be offered within 90 min.

Key words: Myocardial infarction, Prehospital, Thrombolysis.

presenting with acute STEMI, as indicated in theinternational guidelines [4]. In addition, thrombolysis andPri.PCI are not mutually exclusive therapies, and attemptsat combining them are ongoing. Therefore, the mainquestions today are not whether percutaneous coronaryintervention (PCI) is superior to thrombolytic therapy, but(i) what kind of reperfusion therapy is immediatelyavailable, dependent on the local situation; (ii) how toreduce time from onset of symptoms to reperfusion; and(iii) whether the combinationof both strategies, immediatemedical reperfusion followed by PCI (‘facilitated PCI’),will further improve the therapy of STEMI.

PRE-HOSPITAL THROMBOLYSIS - CLINICALEVIDENCES

Pre-hospital initiation of thrombolytic therapy inSTEMI has led to an additional reduction of the delay time

Fig 1. Effect of time-to-treatment on 6-week mortality. Cannonet al [1].

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between 33 and 130 min, as demonstrated in three high-quality pre-hospital thrombolysis trials: the EMIP, MITI,and GREAT trials [5-7]. A meta-analysis of the sixrandomized trials comparing pre-hospital vs. in-hospitalthrombolyis, involving 6434 patients, demonstrated thattime-to-treatment was reduced by 58 min with pre-hospitaltherapy. This overall reduction in delay time was associatedwith a significant 1.7% absolute (17% relative) riskreduction of 30-day mortality, as shown by the three bestperformed pre-hospital thrombolysis trials (Fig. 2).

PCI often exceeds the optimal pre-intervention periodof 90 min [9] recommended in the recent guidelines [10].As shown in several trials, including the PRAGUE-2,STOPAMI-1 and -2, MITRA, MIR, and CAPTIM trials,[11-14] this is of special interest in patients with a shortduration of infarct symptoms (up to 3 h), because of thesimilar effectiveness of thrombolytic therapy whencompared with primaryPCI on mortality and infarct size inthose patients.

Comparison of prehospital fibrinolysis with transfer to ahospital for immediate PCI in the CAPTIM trial revealedno statistically significant between-treatment differenceregarding the composite primary end point (death, nonfatalreinfarction, and nonfatal disabling stroke within 30 days)or mortality, suggesting that PCI did not confer an event-free survival advantage. Among patients randomized <2 hafter symptom onset, there was a strong trend toward lower30-day mortality with prehospital fibrinolysis (2.2% vs.5.7%; p=0.058).

ABORTED INFARCTION - THE ULTIMATEMYOCARDIAL SALVAGE

The expression “aborted infarction” was first used to

describe the patients treated very early in the MyocardialInfarction and Triage Intervention (MITI) trial. It was foundthat 40% of all patients treated within 3 hours of onset ofsymptoms had no evidence of infarction as measured bythallium scan at 30 days follow-up. Minimal infarct size ofless than 10% was noted in additional 35% patients. Fewreports have focused on the impact of prehospitalthrombolysis on the incidence of aborted infarction [15,16].Aborted infarction was defined on the basis of ECG criteria(subsiding of cumulative ST segment elevation anddepression to <50% of the level at presentation), togetherwith a rise of creatine kinase less than twice the upper limitof normal. As expected, the median time-to-treatment wasshorter by approximately one hour in the prehospital groupcompared to in-hospital group (97 min v. 153 min, p<0.05).Prehospital thrombolysis was associated with a four-foldincrease of aborted infarction compared with in-hospitaltherapy (17.1% v. 4.5%, p<0.05). In comparison toestablished AMI, patients with aborted infarction had asignificantly lower 30-day (1.0% v. 9.2%, p<0.01) and 1-year mortality (2.2% v. 11.6%, p<0.01).

CHOICE OF AGENT FOR PREHOSPITALTHROMBOLYSIS

Various factors need to be considered regarding thechoice of agent for pre hospital thrombolytic therapy. Theseinclude ease of drug administration, its efficacy, potentialfor adverse reactions, cost, and storage. Streptokinase (firstgeneration thrombolytic agent) is not an ideal option for aparamedic-initiated pre hospital thrombolysis. It has to beadministered as an infusion and carries risk of allergicreactions and hypotension. Similarly, anistreplase(APSAC) though given as a bolus injection, has similarrisks of allergic reactions. Alteplase [tissue-type

Fig 2. Pre-hospital vs. in-hospital thrombolysis trials. Odds ratio for 30-day mortality. Only data from the three highest-qualitytrials are given. Adapted from Morrison, et al [8]

No. of Quality Odds ratio Favours pre-hospital Favours in hospitalStudy patients score (95 % CI) thrombolysis thrombolysis

MITI, 1993 360 0.91 0.69 (0.30-1.57)

EMIP, 1993 5469 0.85 0.86 (0.72-1.03)

GREAT 1991 311 0.78 0.56 (0.25-1.23)

Overall 6140 0.84 (0.70-0.99)

0.02 0.05 0.1 0.2 0.5 1 2 5 10

Odds ratio (95 % CI)

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plasminogen activator (t-PA), a second generationthrombolytic agent] has high safety and efficacy profile, butneed for administration as an infusion makes it lessattractive in the pre hospital setting.

New third generation thrombolytic agents which arepredominantly derivatives of alteplase include: reteplase(recombinant plasminogen activator, r-PA), tenecteplase(TNK-mutant of alteplase), and lanoteplase(novelplasminogen activator, n-PA) [17]. Reteplase has agreat potential for pre hospital administration. Theadvantages of this drug in the pre hospital treatment aremanifold. It is administered as a bolus injection. Since earlyreoccclusion of the infarct-related artery had been observedwith single bolus administration, it is currently given asdouble boluses of 10 U each, 30 min apart. The drug-dosingpattern is standard irrespective of the body weight of thepatient making its use simple in the pre hospital scenario[18]. Presently, it appears that reteplase may be consideredas the ‘drug of choice’ for pre hospital administration.Another thrombolytic agent, tenecteplase, has relative longplasma half-life that allows for a single bolus application.Lanoteplase has plasma half-life 10 times that of alteplaseand therefore can be administered as single bolus. Buthigher incidence of hemorrhagic stroke has been reportedwith this drug. Thus, the third generation thrombolytic

agents are likely to replace current thrombolytic therapyregime in near future.

COMPONENTS OF TIME DELAY INREPERFUSION THERAPY

Reasons for delay in the treatment of AMI bythrombolytic therapy include: patient delay, ambulanceresponse time, transportation to hospital, and door to needletime. Public awareness, comprehensive communityplanning and rapid diagnosis of AMI in the emergencydepartment may partly reduce the delay. However, the timedelay factor that is most vulnerable is the transportation timeto the hospital. This time can be unacceptably long in ruralor congested urban areas. A recent study from a tertiary carehospital of northern India showed that pre hospital delaywas the most important factor in delayed administration ofthrombolytic therapy. Only a third of the patients couldreach the hospital within two hours of onset of symptoms.Additional delay of one hour in administering the thrombo-lytics resulted in only a few patients actually receivingthrombolysis within the first two hours (Fig 3) [19].

CONCLUSION

Clinical trials data support the safety and efficacy of prehospital fibrinolysis in the treatment of STEMI. Based on

Fig 3. Options for Transportation of STEMI Patients and Initial Reperfusion Treatment Goals [2007 Focused Update of ACC/AHA Guidelines]

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the many studies showing the benefit of early initiation offibrinolytic therapy, the ACC/AHA STEMI guidelines statethat “it seems reasonable to expect that if fibrinolytictherapy could be started at the time of pre hospitalevaluation, a greater number of lives could be saved”. Thistreatment is feasible in locations where the fibrinolytic isadministered by paramedics (under the supervision of aphysician), general practitioners, or medical intensivists.Prehospital fibrinolysis may also decrease time to treatmentin other settings, including rural or congested urban areaswhere transportation times are long, as well as areas inwhich primary PCI facilities are not immediately availableor where time to mobilize the appropriate team may beexcessive.

The concept of pre hospital thrombolysis appearsparticularly relevant to India. The population ispredominantly rural and patients have to travel longdistances to avail medical facility. Even in the urban areastertiary care centers are few in number and travel time maybe long due to various factors including congestion.Although these circumstances seem to warrant an urgentneed for pre hospital thrombolysis program, it will requiretremendous infrastructure support. Nevertheless, futuredevelopments in this direction would be useful not only inachieving the maximum benefits of thrombolytic therapy toall patients of AMI but such networks will also serve asmodels of health care in the community.

REFERENCES

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19. Malhotra S, Gupta M, Chandra KK, et al. Prehospital delayin patients hospitalized with acute myocardial infarction inthe emergency unit of a North Indian tertiary care hospital.Indian Heart J 2003; 55: 349-353.

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