Inpharma 1371 - 25 Jan 2003

ASSENT 3 PLUS: prehospital thrombolytics beneficial– Raewyn Poole –

Prehospital treatment with the thrombolytic tenecteplase [‘Metalyse’, ‘TNKase’] plus either enoxaparin sodium[‘Lovenox’] or unfractionated heparin (UFH) is as effective as inhospital treatment in reducing ischaemic eventsin patients following acute ST elevation myocardial infarction (MI), according to results from the ASSENT(ASsessment of the Safety and Efficacy of New Thrombolytic regimens) 3 PLUS study. These data, presented in alatebreaker session at the 75th Annual Scientific Sessions of the American Heart Association (AHA) [Chicago, US;November 2002] indicated that administration of thrombolytic therapy prior to hospital admission reducedtreatment delay by an average of 45 minutes, compared with inhospital treatment, and had comparable efficacyand tolerability. The combination of tenecteplase/enoxaparin was more effective than tenecteplase/UFH inpatients aged < 75 years. Tenecteplase/enoxaparin also showed a trend towards superiority in the overallpatient population, although this was offset by a higher mortality rate due to intracranial haemorrhage inpatients aged > 75 years.

that this was over 1 hour for about half of the patients inStudy designthe study.ASSENT 3 PLUS was a randomised, open-label,

parallel-group phase IIIb study involving 1639 patients Differences between heparinsat 88 centres in Europe and North America.1* Patients Initiation of thrombolytic therapy in the ambulancewho had ST-elevation and chest pain < 6 hours after the setting was generally as well tolerated as inhospitalonset of symptoms were randomised to receive treatment. An intention-to-treat analysis showed thattenecteplase plus enoxaparin, or tenecteplase plus the incidences of primary and secondary endpointweight-adjusted doses of UFH, in the ambulance events in the tenecteplase/enoxaparin and tenecteplase/setting.** UFH groups were comparable [see table]. However, a

ASSENT 3 PLUS, the largest ever trial of lytic therapy in significant reduction in the incidence of primary efficacythe treatment of MI in the prehospital setting, is a endpoint events was observed with tenecteplase/satellite of the ASSENT 3 trial, in which inhospital enoxaparin, compared with tenecteplase/UFH, intreatment with similar thrombolytic regimens was patients aged < 75 years; tenecteplase/enoxaparin alsoevaluated.† Originally intended as a feasibility study, a showed a trend towards superiority in the overall patientsuperiority hypothesis was added to the ASSENT 3 PLUS population. Furthermore, a meta-analysis of data fromdesign after the success of ASSENT 3. Data from the two ASSENT 3 and ASSENT 3 PLUS also showed thattreatment groups in ASSENT 3 PLUS were also tenecteplase/enoxaparin was more effective thancompared with results from 4038 patients in the original tenecteplase/UFH with respect to the primary endpoint.ASSENT 3 study, although direct comparison was not However, the greater efficacy of tenecteplase/possible as assessment of Killip class was not possible in enoxaparin, compared with tenecteplase/UFH inthe ambulance setting. reducing the rates of reinfarction and myocardial

The endpoints of ASSENT 3 PLUS were the same as ischaemia in the overall patient population, was offsetthose of ASSENT 3; the primary composite endpoint was by significant increases in the incidences of intracranialthe 30-day mortality rate, inhospital reinfarction, or haemorrhage and stroke, which resulted in a higherinhospital refractory ischaemia. ASSENT 3 PLUS also mortality rate (61 vs 49 deaths). Thus, no significantevaluated the combined safety and efficacy endpoint of difference was observed between tenecteplase/30-day mortality, and reinfarction, refractory ischaemia, enoxaparin and tenecteplase/UFH with respect to theintracranial haemorrhage and major bleeding in the primary composite endpoint of ASSENT 3 PLUS.hospital setting. Another major objective of the study

Caution needed in elderlywas to evaluate the time to treatment after the onset ofA subgroup analysis revealed that the highersymptoms.

incidence of intracranial haemorrhage in tenecteplase/Reduced treatment delay enoxaparin, compared with tenecteplase/UFH,

Administration of thrombolytic therapy in the recipients was only evident in patients aged > 75 years,ambulance setting reduced treatment delay by 40–45 and particularly in elderly women. High rates ofminutes, compared with inhospital treatment. Patients intracranial haemorrhage were also seen in patients withcalled the hospital a median of 1 hour after the onset of low bodyweight and those with hypertension, and theresymptoms, and the median time for the ambulance to was a slight increase in the incidence of intracranialreach the patient was 15 minutes; another 30–40 haemorrhage in elderly men. "The excess of [intracranialminutes elapsed before initiation of tenecteplase haemorrhage] in the [enoxaparin] group was only seen intherapy. In comparison, tenecteplase was initiated a patients above 75 years of age and also explained themedian of 160 minutes after symptom onset in ASSENT numerically higher mortality in that group", said the3. Almost 50% of patients in ASSENT 3 PLUS received researchers. A higher incidence of major bleeding (othertreatment within the first 2 hours of symptom onset, than intracranial haemorrhage) was also observed incompared with approximately 30% in ASSENT 3. tenecteplase/enoxaparin, compared with tenecteplase/

"In this trial we have been able to treat nearly half of all UFH, recipients, particularly among elderly women.patients within two hours", said Dr Lars Wallentin from There was a significant interaction between enoxaparinthe University Hospital of Uppsala, Sweden, who sodium use and the risk of bleeding in elderly patients (ppresented the results at the AHA meeting. "However, < 0.05).there is still a problem as to how long the patient takes to A trend toward an increased incidence of bleeding intelephone the emergency services", he remarked, adding elderly patients and women was observed in

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ASSENT 3 PLUS: prehospital thrombolytics beneficial – continuedtenecteplase/UFH recipients, although it was not as administration of thrombolytics has comparable safetyobvious as with tenecteplase/enoxaparin, said Dr and efficacy to inhospital treatment. Previous studiesWallentin. However, the proportion of elderly women have shown that a reduction in mortality rates ofwas slightly higher in the tenecteplase/enoxaparin, approximately 20% could be achieved with prehospital,compared with tenecteplase/UFH, group, he noted. compared with inhospital, initiation of thrombolytic

The higher incidence of intracranial haemorrhage in therapy, remarked Dr Faxon.elderly patients may have been due to reducedbodyweight and impaired renal function, compared with Table. Outcomes in patients with myocardialyounger patients, said Dr Wallentin. He went on to say infarction (MI) who received prehospitalthat this effect may be ameliorated with the use of lower thrombolytic therapydoses of enoxaparin in elderly patients. Dose-finding for

Tenecteplaseelderly patients treated with enoxaparin will beaddressed in the ExTRACT-TIMI 25 study.‡ + enoxaparin + unfractionated

sodium heparinComparison with inhospital treatment

Incidence of endpoint event (% of patients):"ASSENT-3+ shows that pre-hospital thrombolysisprimary efficacy 14.2 17.4†with UFH plus [tenecteplase] is as safe and efficacious as

endpoint*when given in-hospital. Taking into account theprimary efficacy 11.2 15.2‡reduction of ischemic events, the ease of administration endpoint* in

and the absence of monitoring, the combination of patients aged <75 years[enoxaparin sodium and tenecteplase] emerges as a veryprimary efficacy 18.3 20.3promising treatment", said Dr Wallentin, who noted that

and safetyfurther trials using reduced dosages for patients agedendpoint**over 75 years were warranted.mortality at 30 7.21 5.48A trend towards a greater incidence of intracranial days

haemorrhage in enoxaparin recipients was also inhospital MI 3.55 5.85‡observed in ASSENT 3, although it was not statistically inhospital 4.4 6.46†significant. It was important to note that ASSENT 3 PLUS refractoryinvolved a greater number of elderly patients and ischaemiawomen and that it included patients who had called for stroke 2.93 1.34‡an ambulance; this differed from the normal population inhospital 2.2 0.97‡

intracranialwith MI, in which some patients walked into thehaemorrhagehospital, said Dr David Faxon from the University of

* 30-day mortality, inhospital MI or inhospital refractory ischaemiaChicago, US.** 30-day mortality, inhospital MI, inhospital refractory ischaemia,Importance of early treatment inhospital intracranial haemorrhage or inhospital major bleeding

It is widely accepted that early treatment improves † 0.05 < p < 0.1 vs tenecteplase + enoxaparin sodiumoutcome in patients experiencing MI. "Early treatment ‡ p < 0.05 vs tenecteplase + enoxaparin sodiumhas the ability to reduce morbidity as well as mortality.Patients who are treated early have greater salvage of

* This study was sponsored by Boehringer-Ingelheim and Aventis.myocardial muscle. They will be able to resume more** Enoxaparin sodium was given as an IV bolus of 30mg followed bynormal lives than patients treated late, who have lostSC doses of 1 mg/kg every 12 hours for 7 days or until discharge fromsubstantial amounts of heart muscle", commented hospital; UFH was given as an IV bolus of 60 IU/kg then an infusion of

Professor Frans Van de Werf from University Hospital 12 IU/kg/h, with a target Activated Partial Thromboplastin Time of50–70 seconds.Gasthuisberg, Leuven, Belgium.

However, it is not always possible for patients to † See Inpharma 1303: 17, 1 Sep 2002;800817975undergo angioplasty immediately upon admission to ‡ The ExTRACT-TIMI 25 study will compare enoxaparin sodium and

UFH in patients undergoing thrombolysis following MI; thehospital; therefore, fibrinolytics were the number onerandomised, double-blind, double-dummy study will involvetreatment for MI, said Dr Wallentin. Newer agents, suchapproximately 21 000 patients at 1250 centres worldwide. Patientsas tenecteplase, that can be administered by a single IV aged > 75 years will receive reduced doses of enoxaparin sodium.

injection as opposed to an infusion facilitate prehospital1. Wallentin L, et al. Assessment of the safety and efficacy of a new thrombolytictreatment in the ambulance, which may improve regimen in the pre-hospital setting (ASSENT III Plus). 75th Scientific Sessions

outcomes due to the reduced treatment delay. of the American Heart Association Late Breaker : (oral presentation), 17 Nov2002.The results of ASSENT 3 PLUS have the potential to

800888674change current treatment practice for patients with MI,as they have demonstrated that prehospital

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