Content Fibrinolytic agents Clinical studies Metalyse prescribing information STEMI networks Importance of time Treatment strategies amp guidelines Registries Take home points Importance of time ID: 774987
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Slide1
STEMI treatment
Role of fibrinolysis
Slide2Content
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide3Importance of time
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide4Management of acute MI and rationale for early reperfusion
‘TIME IS MUSCLE!’
Aims
Prevent death Limit extent of myocardial damageMinimise patient’s discomfort and distress
Strategy
Re-establish myocardial reperfusion before irreversible damage occurs:mechanically (PPCI, primary percutaneous coronary intervention)pharmacologically (induction of thrombolysis by thrombolytic agent)pharmaco-invasive (combination of pharmacological and mechanical intervention)
Steg et al.
Eur
Heart J
2012;33:2569-2619
.
AMI, acute myocardial infarction
Slide5Absolute benefit per 1,000
treated patients
Influence
of time-to-treatment on odds ratio
(or) of mortality
Treatment delay in hours
0
3
6
9
12
15
18
21
24
0
20
40
60
80
“Golden hour”: 65 lives are saved for every 1,000 patients treated when the treatment is initiated within the first hour of symptom onset!
Boersma
et al.
Lancet
1996;348:771-775.
Slide6Time
delay elements in thrombolysis
Rural
patients
receiving thrombolysisin hospital
Urban patients receiving thrombolysis in hospital
Rural patients receiving pre-hospital thrombolysis
On scene
Transfer
Door-to-needle-time
150
0
50
100
Thrombolysis
Thrombolysis
Thrombolysis
Call to on scene
MEDIAN TIMES IN MINUTES
Adapted from
Pedley
et al.
BMJ
2003;327:22-26.
Slide7Improving time to treatment
Foster strong communication among medical professionals involved in the treatment of AMI
Public education & AMI awareness
reduce symptom onset-to-call times
Medical professionals
reduce first medical contact (FMC)-to-treatment times
Facilitate pre-hospital diagnosis and thrombolysis or referral to a PCI-capable facility within guideline-specific timeframes
STEMI networks
Slide8Treatment strategies & guidelines
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide9Reperfusion treatments
Pharmacological reperfusionPre-hospital / in-hospital thrombolysis (PHT / IHT)
Pharmaco-invasive therapyThrombolysis followed by early angiography and mechanical intervention if indicated
Time is critical for STEMI management!Organised STEMI networks can be an invaluable asset in enabling STEMI patients to undergo coronary reperfusion in a timely manner
Mechanical
reperfusion
Primary percutaneous coronary intervention (PPCI)
Slide10Percutaneous coronary intervention (PCI)& primary PCI (PPCI)
Choi et al. Prehosp Emerg Care 2016;20:66-75.Sinnaeve & Van de Werf. Eur Heart J 2016;37:1041-1043.Keeley & Hillis. N Engl J Med 2007;356:47-54.
Stent in coronary artery
Stent
Guide
wire
Catheter
PPCI is the gold standard in STEMI care –
IF performed within 120 min of FMC
1,2
Timely PPCI is difficult to achieve in many regions, when patients do not present directly to a PCI-capable facility via EMS or arrival at a facility is delayed 1,2
PCI involves
revascularisation of the blocked coronary artery by mechanical meansUsing the femoral or radial artery as an access point, a catheter with a balloon (and often a stent) is passed through the occlusion3The balloon is then inflated to open up the vessel, and the stent is put in place to maintain the revascularisation3
EMS, emergency medical services
FMC,
first medical contact
PPCI, primary percutaneous coronary intervention
Slide11STEMI treatment guidelines
O’Gara et al. Circulation 2013;127:e362-e425. ESC Task Force. Eur Heart J 2018;39(2):119–177.
STEMI guidelines state that acute myocardial ischaemia (<12 h)
should be treated with reperfusion therapy1,2
Guidelines from the ACC/AHA
1 and ESC2 agree that:Primary PCI (PPCI) is the gold-standard of reperfusion treatment for STEMI if delivered ≤120 minutes of diagnosisWhere this is not possible, fibrinolysis should be performed with a fibrin-specific agent (tenecteplase, alteplase or reteplase) as soon as possible within 10 min from STEMI diagnosis, preferably pre-hospital, alongside adjunctive antiplatelet and anticoagulant therapies, and patients should be transferred to a PCI-capable centre for subsequent therapy
ACC/AHA, American College of Cardiology/American Heart Association
ESC, European Society of Cardiology
PPCI, primary percutaneous coronary intervention
Slide12ESC STEMI guidelines
2017:
reperfusion strategies
Adapted from ESC Task Force.
Eur Heart J
2018;
39(2):119–177
.
48 hours
12 hours
3 hours
0
hours
Recent STEMI
Evolved STEMI
Early phase of STEMI
Primary PCI
(if symptoms, haemodynamic instability, or arrhythmias)
Primary PCI
(asymptomatic stable patients)
Routine PCI
(asymptomatic stable patients)
Primary PCI
Fibrinolysis
(if PCI cannot be performed within 120 min from STEMI diagnosis)
I
A
I
A
Primary PCI
Fibrinolysis
(if PCI cannot be performed within 120 min from STEMI diagnosis)
I
A
I
A
I
C
IIa
B
III
A
Symptom onset
Slide13ESC STEMI guidelines
2017:
reperfusion strategies
Time to PCI centre
STEMI diagnosis (ECG)
24h
Time from diagnosis
≤2 h
>2h
Adapted from ESC
Task Force.
Eur Heart J
2018;
39(2):119–177
.
0
10 min
90 min
2 h
Primary PCI
Pharmacoinvasive
strategy*
Bolus fibrinolytic
Transfer to PCI centre
Reperfusion successful?
No
Rescue PCI
Routine PCI
Yes
60-90 min
≥120 min
Alert & immediate transfer to PCI centre
*If fibrinolysis is contraindicated, transfer to PCI centre regardless of time to PCI
m
ax. 10 min delay to administration
Slide14STEMI networks
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide15STEMI networks aims and guidelines
Huber et al. Eur Heart J 2014;35:1526-1532.O’Gara et al. Circulation 2013;127:e362-e425.ESC Task Force. Eur Heart J 2018;39(2):119–177.
The aim of a STEMI network is to ensure early recognition of STEMI, shorten time delays to treatment, and optimise outcomes
1
Network organisation recommendations from the ACC/AHA
2 and ESC3Single emergency telephone number Protocols for standardised care (diagnosis, therapy, transfer)Optimal pre-hospital care (ambulances equipped with ECGs and defibrillators, correct/prompt diagnosis, pre-activation of the cath lab, early initiation of thrombolysis if timely PPCI is not possible)Bypass non-PPCI capable hospitals to increase proportion of patients receiving timely PPCICardiology/intensive care specialist as network leaderInvolve healthcare authoritiesContinual quality improvement with prospective registries & regular meetings of involved parties
PPCI, primary percutaneous coronary intervention
Slide16STEMI network organisation
STEMI network components:
1,2Emergency Medical services (EMS)Franco-German model Physicians present both in ambulances and hospitalAnglo-American model Ambulances staffed with paramedics/emergency medical technician, supported via telemedicine/remote physicianNon-PCI-capable hospitalsHospitals with PCI facilities
STEMI networks are diversely organised, and can be country-wide, regional, or city based
Tubaro
et al. Acute Card Care 2011;13:56-67.Hamon M et al. EuroIntervention 2013 Mar;8(11):1242-1251.Figure adapted from ESC Task Force. Eur Heart J 2018;39(2):119–177.
Total ischaemic time
Patient delay
System delay
FMC: EMS
911
STEMI
diagnosis
FMC: Non-PCI centre
FMC: PCI centre
STEMI
diagnosis
Time to
PCI?
PPCI
PPCI
FT*
Reperfusion
(Wire crossing)
Reperfusion
(Lytic bolus)
Reperfusion
(Wire crossing)
≤120 min
>120 min
<90
min
<10
min
<60
min
Total ischaemic time
Patient delay
System delay
<10 min
<10 min
<10
min
EMS delay
*FT, fibrinolysis
FMC, first medical contact
Slide17European STEMI networks: two models
Vienna STEMI network1,2Central triage system started in 2003, organised by Vienna Ambulance System24/7 access to cath lab facilities with experienced interventionalistsGuaranteed through rotational system between tertiary centres: all centres available during the day & only two centres at night Fibrinolysis is a part of reperfusion strategy when patient transfer is delayed >90 mins Since initiation, the number of patients receiving timely PPCI has increased and the numbers receiving fibrinolysis have decreased (now only ∼3% of patients); marked decline in numbers receiving no reperfusion therapy
French Service d’Aide Médicale Urgente (SAMU) system2Nationwide system implemented in 1995, & monitored by FAST-MI STEMI registryOne SAMU medical response centre for each region, responsible for mobile intensive care unit (MICU) dispatch (1 physician, 1 nurse, & a driver (trained emergency medical technician) provide basic/advanced life support on-site &/or during transfer)MICU alerts medical centre ahead of arrival about medical status of the patient to allow direct admission & avoid treatment delayImplementation has improved outcomes, and increased reperfusion, mainly due to increased PPCIWhen PPCI is not possible, a pharmaco-invasive strategy is implemented
Huber et al
. Eur Heart J 2014;35:1526-1532.Danchin. JACC: Cardiovascular Interventions 2009;2:901-908.
Slide18STEMI networks around the world
Huber et al.
Eur Heart J 2014;35:1526-1532.
South Africa
Limited number of centres with PPCI facilities and long transfer times
Latin America
In Salvador, Bahia, Brazil, a regional STEMI alert team receives ECG from telemedicine centre and advises EMS to start
pharmaco-invasive treatment or immediate transfer for PPCI
Middle East
Wide disparity in STEMI care owing to geographical diversity
Australia
Well-organised STEMI networks in urban areas however long transfer times in rural areas
India, China, Russia
Only few STEMI networks in accordance with International guidelines
REVERSE-STEMI trial: in Shanghai physicians travel to outlying catheter laboratories instead of transporting patients
Slide19Huber et al. Eur Heart J 2014;35:1526-1532.ESC Task Force. Eur Heart J 2018;39(2):119–177Danchin. JACC Cardiovasc Interven 2009;2:901-908.
Future directions to improve STEMI management
Education campaign1Community organisation1Unique European-wide emergency telephone number1,2Automated external defibrillators (AEDs) in public places1Standardised written STEMI management protocols1*Ambulances (vehicles, helicopters, planes) equipped with defibrillators, 17-lead ECG, trained professionals capable of basic and advanced life support or initiation of FT in case of delays1,2ECG transmission/teleconsultation1-3Single number to activate catheterisation laboratory1,3Experienced cardiologist or intensive care specialist to lead the network124/7 accessible tertiary care centres1,2Increased use of radial access in STEMI patients referred for PPCI to reduce bleeding complications1,2
*Procedures and treatment should be agreed between network members and put in writing
Slide20Fibrinolytic agents
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide21Summary of rationale for pre-hospital thrombolysis (PHT) and pharmaco-invasive strategy
Not all medical centres are PPCI-capable1,2 &/or pre-hospital delays often prevent patients from receiving timely PPCI3,4
No specialist equipment required and PHT has been established as a safe and effective treatment for STEMI5
PHT reduces time to reperfusion and improves outcomes if PPCI is not possible within 2h6,7
Steg et al.
Eur
Heart J
2012;33:2569-2619. Pinto et al. Circulation 2006;114:2019-2025. Armstrong, Bowden. Ann Intern Med 2011;155:389-391. Armstrong et al. N Engl J Med 2013;368(15):1379-1387. O’Gara et al. J Am Coll Cardiol 2013;61:e78-e140. Morrison et al. JAMA 2000;283(20):2686–2692.Wallentin et al. Circulation 2003;108:135-142.Gershlick et al. N Engl J Med 2005;353:2758-2768.
Pharmaco-invasive strategy may achieve reperfusion directly; in case of thrombolysis failure, reperfusion can be achieved with subsequent rescue PCI8
Slide22Thrombolytics
Kunandian & Gibson. Cardiovasc Ther 2012;30:e81-e88. Chesebro et al. Circulation 1987;76:142-154.GUSTO investigators. N Engl J Med 1993;329:673-682.GUSTO III investigators. N Engl J Med 1997;337:1118-1123.Cannon CP et al. Circulation 1998;98:2805-2814. ASSENT-2 investigators. Lancet 1999; 354:716-722.
Streptokinase (and derivatives)Considered an inferior thrombolytic drug to tPA compounds as it is not given as a bolus and lacks fibrin specificity and antigenicity1
Alteplase (rt-PA)Recombinant form of human tissue plasminogen activator (tPA) with a 4-8 min plasma half-life.1 Improved outcomes in myocardial infarction treatment vs. streptokinase2,3
Reteplase (r-PA) Genetically modified rt-PA with longer half-life (13-16 min)1 and simplified administration. Failed to show clinical benefit over alteplase4
Tenecteplase
(TNK)
Longer plasma half-life
, highest fibrin
specificity, and resistance to plasminogen activator inhibitor-1 (PAI-1) vs rt-PA. Single bolus pharmacological reperfusion therapy, with equivalent efficacy and improved safety profile to alteplase
5,6
Slide23+
+
Fibrin-specific and non fibrin-specific
fibrinolyticsMode of action
Fibrin-specific (tPA, rt-PA, TNK)activate the conversion of fibrin-bound plasminogen to plasmin; associated with lower risk of bleeding than non fibrin-specific agents
Non fibrin-specific(streptokinase)act on free and fibrin-bound plasminogen and directly catalyses the production of fibrin from fibrinogen
Hilleman et al. Pharmacotherapy 2007;27(11):1558-1570.
Fibrin-bound plasminogen on the surface of the thrombus
Fibrin degradation products & clot dissolution
Fibrin
cleaves
Plasmin
+
activated by thrombin
Free plasminogen in the circulation
Fibrinogen
+
Slide24Thrombolytics: from infusion to single bolus
Application time (min)
From slow infusion to … single bolus
Infusion
Infusion 2
Bolus
tenecteplase
0
20
40
60
80
100
reteplase
alteplase*
streptokinase
From slow and
awkward infusion
to fast and easy
single bolus
* Alteplase “accelerated” administration regimen shown
Slide25Comparison alteplase-reteplase-tenecteplase
CharacteristicAlteplase (rt-PA)Reteplase (rPA)Tenecteplase (TNK-tPA)ImmunogenicityNoNoNoPlasminogen activationDirectDirectDirectFibrin specificity++++++Plasma half-life4-6 min18 min20 minDose15 mg bolus plus90 min infusionup to 85 mg10+10MU double bolus 30 min apart±0.5 mg/kg single bolus over approx. 10 secondsPAI-1 resistanceLowLow*80-fold higher than rt-PAGenetic alteration to native tPANo (recombinant version)YesYes
Adapted from Ross.
Clin
Cardiol
1999;22:165-171.
* Reteplase resistance described as “Comparable to Alteplase” in Nordt.
Heart
2003;89:1358-1362
.
Slide26The ideal thrombolytic agent1
Rapid acting
High efficacy in terms of both 60-90 minute vessel patency (TIMI grade flow)
Low incidence of adverse reactions, particularly bleeding and stroke
Easy to administer (bolus vs. infusion)
Good long-term effects on clinical outcome
Cost-effective
Simple, patient-tailored dosage regimen
Van de Werf.
Eur Heart J
1999;20:1452-1458
.
Low re-occlusion rate
Slide27Greater fibrin specificity
than alteplaseLonger plasma half-life than alteplase(20 minutes vs 4-6 minutes)Higher resistance to PAI-1 than alteplase
Tenecteplase: structure
1
‘Finger’
2
Growth Factor
3
‘Kringle 1
’
4
‘Kringle 2’
5
Protease
Metalyse®. Summary of Product Characteristics, 2014.
Slide28Weight-adapted dosage of
tenecteplase (TNK)
Metalyse®. Summary of Product Characteristics, 2014.
90 kg
80 – 89 kg
70 – 79 kg
60 – 69 kg
8 ml
<
60
kg
8,000
units pack
10,000units pack
6,000units pack
A pre-existing intravenous line may be used for administration of TNK in 0.9% sodium chloride solution only. TNK is incompatible with dextrose solution. No other medicinal product should be added to the injection solution.
Conversion: 1 ml = 5 mg = 1,000 units
The required dose should be administered as a single intravenous bolus over approximately 10 seconds
7 ml
6 ml
10 ml
9 ml
Slide29Metalyse® (tenecteplase) in brief1
The only single bolus thrombolytic commercially available
The only thrombolytic proven to be equivalent to rt-PA – regardless ofpatient subgroup2
Fast acting
Increased resistance to PAI-1 compared to
rt
-PA
Reduced risk of bleeding complications when used to treat STEMI2
Optimal efficacy through tailored, weight-adjusted dosing
Cannon et al.
Circulation
1998;98:2805
-
2814.
ASSENT-2 Investigators.
Lancet
1999;354:716-722.
Fast and easy to administer: administered over 5 – 10 seconds in a single dose
Slide30Clinical studies
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide31ASSENT trial series summary: ASSENT-2, ASSENT-3/ASSENT-3 PLUS, ASSENT-4 PCI
For more information on the ASSENT trials, please visit http://www.metalyse.com/studies or refer to the original publications.
ASSENT-2: Tenecteplase is equivalent to alteplase in the treatment of AMI with respect to: 30-day mortality1 and 1-year mortality outcomes2Combined outcomes for mortality and non-fatal stroke1Significantly fewer bleeding complications occurred with tenecteplase, reducing the need for blood transfusions.1
ASSENT-3/ASSENT-3 PLUS: Results support association between earlier treatment and improved 30-day mortality3,4Low-molecular-weight heparins (LMWHs), e.g. enoxaparin, were superior to unfractionated heparin (UFH) as concomitant anticoagulation4
ASSENT-4 PCI: Investigated whether full-dose tenecteplase administered prior to PCI (facilitated PCI) could mitigate negative effect of delay to PCI5Study was stopped prematurely due to higher mortality in facilitated PCI group vs. standard PCI5Facilitated PCI as performed in the trial was associated with more major adverse events than primary PCI alone and cannot be recommended5
ASSENT-2 Investigators.
Lancet
1999;354:716-722.
Sinnaeve et al.
Am Heart J
2003;146:27-32.
ASSENT-3 Investigators.
Lancet
2001;358:605-613.
Wallentin et al.
Circulation
2003;108:135-142.
ASSENT-4 PCI Investigators.
Lancet
2006;367:569–578.
Slide32FINESSE: Study design
Adapted from Ellis et al. Am Heart J 2004;147:e16 and Ellis et al. N Eng J Med 2008;358:2205-2217.
Acute MI patients with ST elevation or New LBBB, <6 hours of pain to qualifying ECG (n=2,452)
Randomised
Reteplase/ Abciximab
Facilitated PCI
Primary PCI
AbciximabFacilitated PCI
ASA, unfractionated heparin 40U/kg (max 3000U) or enoxaparin (0.5 mg/kg IV + 0.3 mg/kg SC) – Substudy only
Abciximab Bolus
Abciximab Placebo
Abciximab Bolus
Reteplase
5U X2 (X1 if age !75)
Placebo for Reteplase X2
Placebo for Reteplase X2
Abciximab Placebo
Abciximab Bolus
Abciximab Placebo
Transfer to Catheterisation Lab for Angiography
Immediate PCI, with abciximab Infusion
Primary Endpoint: Composite of death from all causes, ventricular fibrillation occurring more
than 48 hours after randomisation, cardiogenic shock, and congestive heart failure at 90 days
Slide33FINESSE: Kaplan-Meier curves for the primary endpoint at 90 days
PCI, percutaneous coronary interventionPPCI, primary PCI
Patients
with primary endpoint (%)
Days
30
60
90
0
10.7%
9.8%
10.5%
0
12
8
4
16
PPCI
Reteplase
/
Abciximab
PCI
Abciximab
PCI
Adapted from Ellis et al
. N Eng J Med
2008;358:2205-2217.
Slide34FINESSE: All-cause mortality at 1 year
Adapted from Ellis et al
. JACC
2009;2:909–916.
Slide35FINESSE: Conclusions
* based on modified TIMI risk score ≥3; with a symptom-to-randomisation time ≤4 h
Primary endpoint: similar between treatment groups
1
No facilitated PCI strategy provided clinical benefit vs. PPCI with in-lab abciximab
1
In high risk patients* presenting to a site without PCI capability, facilitated PCI with early administration of a combination of
abciximab
+ half-dose reteplase or abciximab alone may reduce 90-day clinical outcomes vs. abciximab given just before PCI3
Reteplase
/
abciximab facilitation, and abciximab facilitation, increased bleeding vs. in-lab administration of abciximab1
PPCI with in-lab
abciximab
provides better benefit-to-risk ratio vs. two facilitated strategies in STEMI patients who can undergo PCI within 4 h of 1st medical contact1
1-year follow-up survival data confirms overall lack of clinical benefit with either treatment regimens tested for non-high-risk patients
2
Combination-facilitated PCI significantly reduced 1-year mortality vs. PPCI
3
Ellis et al
. N
Eng
J Med
2008;358:2205–2217.
Ellis et al
. JACC
2009;2:909–916.
Herrmann et al
. JACC
2009;2:917–924.
Slide36DANAMI-2 (Danish acute myocardial infarction 2 study1)
1,572 patients with acute STEMI (symptoms present for ≥30 min but <12 h) randomly assigned to either:
treatment with primary PCI, or thrombolysis (accelerated treatment with intravenous alteplase)
Patients were enrolled at either:
1 of 24 referral hospitals (n=1,129), or
1 of 5 invasive-treatment centres (n=443)
Compared fibrinolysis within hospitals with transfer to invasive-treatment centres for PCI
Average distance between referring hospitals and invasive-treatment centres was 50 km
Study design
Primary endpoint: Composite of death from any cause, clinical evidence of
re-infarction or disabling stroke within 30 days of follow-up.
Andersen et al.
N Engl J Med
2003;349:733-742.
Slide37DANAMI-2: clinical outcome at 30 days & at long-term follow-up (median 7.8 years)
p=0.15
p<0.001
p=0.35
p<0.001
p=0.14
Adapted
from Nielsen et al.
Circulation
2010;121:1484-1491.
Slide38DANAMI-2: Conclusions
Clinical benefit of PPCI over fibrinolysis was seen at 30 days and at long-term follow-up, largely due to a reduction in the risk of re-infarctionIf transfer of patient to an invasive-treatment centre can be completed within 2 h, PPCI is superior to on-site fibrinolysis
Nielsen et al.
Circulation
2010;121:1484-1491.
Slide39Registries
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide40The importance of registries
Prospective registries are a vital component of a STEMI network, and facilitate monitoring of outcomes and subsequent improvements1
Data from prospective registries has led to changes in STEMI practice, for example:
Registry and post-hoc analyses suggested benefit of adding glycoprotein IIb/IIIa-inhibitors (GPIs) pre-hospital en route to the cath. lab, which is now utilised by some networks2-4
Huber et al.
Eur Heart J 2014;35:1526-153.Huber et al. Eur Heart J 2010;31:1708–171.Rakowski et al. Am Heart J 2007;153:360–365.Rakowski et al. Am Heart J 2009;158:569–575.
Here, the registries for the Vienna, Minneapolis, and French (SAMU) STEMI networks are presented
Slide41Vienna STEMI registry
Kalla et al. Circulation 2006;113:2398–2405.
In 2002, Vienna had one catheterisation laboratory which offered a 24-hour PPCI service on a routine basis (on-call) for patients with acute STEMI
This situation was profoundly reorganised by the implementation of:
Central triage for STEMI patients by the Viennese Ambulance System (VAS)A second catheterisation laboratory open at night (Monday to Friday) by use of a rotation principle between 4 non-academic hospitals (on weekends [Friday afternoon to Monday morning], only 1 catheterisation centre was active during this preliminary network)Pre-hospital or in-hospital TT if acute PPCI was unlikely to be offered within the recommended time intervals
Slide42Vienna STEMI registry: Changes in reperfusion strategies
50
34
16
13.4
60
26.7
Adapted from Kalla et al.
Circulation
2006;113:2398–2405.
Slide43Vienna
STEMI
registry: Time to treatment
Influence of time to treatment on in-hospital mortality
Treatment strategies vs. time to treatment
Hours from onset of pain
Adapted from
Kalla
et al.
Circulation 2006;113:2398–2405.
Slide44Vienna STEMI registry: Conclusions
Adapted from Kalla et al. Circulation 2006;113:2398–2405.
Implementation of guideline-recommended STEMI treatment improved clinical outcomesPPCI and TT showed comparable mortality rates when initiated within 2-3 h of onset; PPCI showed improved mortality when initiated >3 and <12 h of acute STEMI
Slide45Minneapolis STEMI registry
Larson et al. Eur Heart J 2012;33:1232-1240.
In rural settings, direct transfer of patients STEMI patients for PCI is often subject to prolonged delays
This prospective study, conducted in Minneapolis, assessed the safety and efficacy of a
pharmaco
-invasive reperfusion strategy with half-dose fibrinolytic and direct transfer for immediate PCI compared with PPCI
Slide46Minneapolis STEMI registry
STEMI <24 hours
(n=2,634)
Zone 1 hospital
<60 miles
Zone 2 hospital
≥60 miles
ASA 325 mg, clopidogrel 600 mg, UFH 60 U/kg IV loading dose (max 4000 U) then 12 U/kg IV infusion (max 1000 U/h), beta blocker (unless contra-indicated)
PPCI
(n=600)
PPCI
(n=1,163)
Ph-INV*
(n=32)
Ph-INV*(n=660)
PPCI(n=179)
PPCI(n=1,763)
PPCI(n=692)
PCI hospital
Ph-INV, pharmaco-invasive (half-dose thrombolytic then transfer for immediate PCI); PPCI, primary percutaneous coronary intervention;
STEMI, ST-elevation myocardial infarction; UFH, unfractionated heparin
Larson et al.
Eur Heart J
2012;33:1232-1240.
A
B
C
D
E
Slide47Minneapolis STEMI registry: group A (PPCI) vs group D (Ph-INV)
Ph-INV, pharmaco-invasive; PPCI, primary percutaneous coronary interventionLarson et al. Eur Heart J 2012;33:1232-1240.
p
=0.76
p
=0.67
p=0.87
p=0.48
Rapid transfer to a PCI-capable facility in combination with standardised protocols and an integrated transfer system has the same outcome for patients as does presenting directly to a PCI-capable facility.
Slide48French registries of acute STEMI & NSTEMI(FAST-MI)
Puymirat et al. JAMA 2012;308:998-1006.
FAST-MI 2005 and 2010 and their earlier counterparts, USIK 1995 and USIC 2000, included data from a total of 6,707 STEMI patients
These 4 registries were one-month, nationwide surveys
Aim: to provide cardiologists and health authorities with national and regional data on acute MI management and outcomes every 5 years
Slide49Characteristics of STEMI patients in the 4 French national registries
Puymirat
et al. JAMA 2012;308:998-1006.
MEN
WOMEN
p
<0.001
p
<0.001
% of patients
% of patients
1995 (n=1536)
2000 (n=1844)
2005 (n=1611)
2010 (n=1716)
p
for
trend
%
change
1995
to
2010
Age (
mean
), y
66.2
64.5
64.0
63.3
<0.001
-2.9
Slide50Characteristics of STEMI patients in the 4 French national registries
p
=0.006
p
=0.001
p
<0.001
p
<0.001
p<0.001
p<0.001
p<0.001
p<0.001
MI: myocardial infarction; TIA: transient ischaemic attackPuymirat et al. JAMA 2012;308:998-1006.
%
%
Slide51Management of STEMI patients in the 4 French national registries (median time delay)
Puymirat et al. JAMA 2012;308:998-1006.
p
<0.001
Minutes
Slide52Management of STEMI patients in the 4 French national registries (reperfusion therapy)
Puymirat et al. JAMA 2012;308:998-1006.
p
<0.001
-25.3%
change
1995 to 2010
-23.6% change1995 to 2010
48.9% change1995 to 2010
%
%
%
%
%
%
%
%
Slide53Changes in 30-day mortality according to use & type of reperfusion therapy
Puymirat et al. JAMA 2012;308:998-1006.
The adjusted odds ratios comparing 1995 with 2010 are 0.47 (95% CI, 0.32-0.70) for those who received no perfusion, 0.29 (95% CI, 0.11-0.76) for those who received fibrinolysis treatment, and 0.29 (95% CI, 0.15-0.58) for those who received percutaneous coronary intervention. Error bars indicate 95% CIs.
Slide54Cumulative 6-month mortality in patients with STEMI by year of FAST-MI survey1FAST-MI data indicated that in patients with STEMI, 6-month mortality after acute myocardial infarction decreased considerably over the past 20 years.1
Improving treatments and STEMI care has a huge impact on mortality over the years
Puymirat et al. Circulation 2017;136(20):1908-1919.
Permission granted by Copyright Clearance Centre’s Copyright © 2018
Puymirat
et al. Circulation 2017;136(20):1908-1919.
19952000200520102015
STEMI
Slide55FAST-MI update
FAST-MI data supports current recommendation of performing coronary angiogram within 3–24 h after successful fibrinolysis when timely PPCI is unavailable
France’s well-established emergency medical system often includes physicians, which contributes to high pre-hospital fibrinolysis rate and early treatment initiation
PCI-related delay might have contributed to the
favourable
outcomes observed in the fibrinolysis group
ElGuindy
. Glob Cardiol Sci Pract 2014;2014(2):56-60.
Difficult to emulate in many countries/regions
Slide56Take home points
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide57Take home points
STEMI is a time-critical medical emergency: clinical outcomes improve with reduced time to reperfusion. Every effort should be made to reduce ischaemic time.
Implementation of STEMI networks is guideline-recommended and has been shown in studies and registries to reduce delays in reperfusion strategies and improve clinical outcomes.
PPCI is considered the gold-standard of care if performed ≤2 h of FMC (first medical contact).
A pharmaco-invasive strategy is recommended whenever PPCI cannot be performed within recommended timelines (<120 min), and may be followed by transfer for angiography and mechanical intervention if indicated.
Slide58Metalyse® prescribing information
Fibrinolytic agents
Clinical studies
Metalyse
®
prescribing information
STEMI networks
Importance of time
Treatment strategies & guidelines
Registries
Take home points
Slide59Summary of product characteristics
This is the SPC as approved for
Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK.
For product use, please check the local SPC of the country you live in.
1. NAME OF THE MEDICINAL PRODUCT
Metalyse
®
Powder and solvent for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 vial contains:
6,000
units
(30 mg)
tenecteplase
or
8,000
units
(40 mg)
tenecteplase
or
10,000
units
(50 mg)
tenecteplase
, respectively.
1 prefilled syringe contains:
6 ml
water
for
injections
or
8 ml
water
for
injections
or
10 ml
water
for
injections
, respectively.
The reconstituted solution contains 1,000 units (5 mg)
tenecteplase
per ml.
Potency of
tenecteplase
is expressed in units (U) by using a reference standard which is specific for
tenecteplase
and is not comparable with units used for other thrombolytic agents.
Tenecteplase
is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell line by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
The powder is white to off-white. The reconstituted preparation is a clear and
colourless
to slightly yellow solution.
4. CLINICAL PARTICULARS
4.1
Therapeutic
indications
:
Metalyse
is indicated in adults for the thrombolytic treatment of suspected myocardial infarction with persistent ST elevation or recent left Bundle Branch Block within 6 hours after the onset of acute myocardial infarction (AMI) symptoms.
Slide60This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.2 Posology and method of administration Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to monitor that use.Treatment with Metalyse should be initiated as soon as possible after onset of symptoms. Metalyse should be administered on the basis of body weight, with a maximum dose of 10,000 units (50 mg tenecteplase). The volume required to administer the correct dose can be calculated from the following scheme:
Patients’ body weight category(kg)Tenecteplase(U)Tenecteplase(mg)Corresponding volume of reconstituted solution(ml)< 606,000306≥ 60 to < 707,000357≥ 70 to < 808,000408≥ 80 to < 909,000459≥ 9010,0005010For details see section 6.6: Special precautions for disposal and other handling
The required dose should be administered as a single intravenous bolus over approximately 10 seconds.A pre-existing intravenous line may be used for administration of Metalyse in 0.9% sodium chloride solution only. Metalyse is incompatible with dextrose solution.No other medicinal product should be added to the injection solution.Paediatric populationMetalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and efficacy.Adjunctive therapyAntithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered according to the current relevant treatment guidelines for the management of patients with ST-elevation myocardial infarction.Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical studies with Metalyse.Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment unless it is contraindicated.
Summary
of
product
characteristics
Slide61This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.3 ContraindicationsMetalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening) reaction to any of the constituents (i.e. tenecteplase or any excipient) or gentamicin (a trace residue from the manufacturing process). If treatment with Metalyse is nevertheless considered to be necessary, facilities for resuscitation should be immediately available in case of need. Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is associated with a higher risk of bleeding: Significant bleeding disorder either at present or within the past 6 monthsPatients with current concomitant oral anticoagulant therapy (INR > 1.3)Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)Known haemorrhagic diathesisSevere uncontrolled hypertensionMajor surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current AMI)Recent trauma to the head or craniumProlonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeksAcute pericarditis and/or subacute bacterial endocarditisAcute pancreatitisSevere hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitisActive peptic ulcerationArterial aneurysm and known arterial/venous malformationNeoplasm with increased bleeding riskAny known history of haemorrhagic stroke or stroke of unknown originKnown history of ischaemic stroke or transient ischaemic attack in the preceding 6 monthsDementia4.4 Special warnings and precautions for use Bleeding: The most common complication encountered during Metalyse therapy is bleeding. The concomitant use of heparin anticoagulation may contribute to bleeding. As fibrin is lysed during Metalyse therapy, bleeding from recent puncture site may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cut down sites and needle puncture sites). The use of rigid catheters as well as intramuscular injections and non-essential handling of the patient should be avoided during treatment with Metalyse.Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival bleeding were observed.
Summary
of
product
characteristics
Slide62This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration should be terminated immediately. Administration of protamine should be considered if heparin has been administered within 4 hours before the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. In the following conditions, the risk of Metalyse therapy may be increased and should be weighed against the anticipated benefits:Systolic blood pressure > 160 mm HgCerebrovascular diseaseRecent gastrointestinal or genitourinary bleeding (within the past 10 days)High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillationAny known recent (within the past 2 days) intramuscular injectionAdvanced age, i.e. over 75 yearsLow body weight < 60 kgArrhythmiasCoronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator) be available when Metalyse is administered.GPIIb/IIIa antagonistsConcomitant use of GPIIb/IIIa antagonists increases bleeding risk. Hypersensitivity/Re-administrationNo sustained antibody formation to the tenecteplase molecule has been observed after treatment.However, there is no systematic experience with re-administration of Metalyse. Caution is needed when administering Metalyse to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients, or to gentamicin (a residue from the manufacturing process). If an anaphylactoid reaction occurs, the injection should be discontinued immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2- antiplasmin.Primary Percutaneous Coronary Intervention (PCI)If primary PCI is scheduled according to the current relevant treatment guidelines, Metalyse as administered in the ASSENT-4 PCI study (see section 5.1) should not be given.Paediatric populationMetalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and efficacy.
Summary of product characteristics
Slide63This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.5 Interaction with other medicinal products and other forms of interactionNo formal interaction studies with Metalyse and medicinal products commonly administered in patients with AMI have been performed. However, the analysis of data from more than 12,000 patients treated during phase I, II and III did not reveal any clinically relevant interactions with medicinal products commonly used in patients with AMI and concomitantly used with Metalyse.Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine, clopidogrel, LMWH) may increase the risk of bleeding prior to, during or after Metalyse therapy. Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.4.6 Fertility, pregnancy and lactationPregnancyThere is a limited amount of data from the use of Metalyse in pregnant women. Nonclinical data performed with tenecteplase have shown bleeding with secondary mortality of dams due to the known pharmacological activity of the active substance and in a few cases abortion and resorption of the foetus occurred (effects only have been observed with repeated dose administration). Tenecteplase is not considered to be teratogenic (please see section 5.3).LactationIt is not known if tenecteplase is excreted into breast milk. Breast milk should be discarded within the first 24 hours after thrombolytic therapy.FertilityNo preclinical fertility studies were performed for tenecteplase. In the preclinical repeat-dose toxicity studies conducted with tenecteplase, histopathology did not reveal any findings regarding the male reproductive organs.4.7 Effects on ability to drive and use machinesNot relevant.4.8 Undesirable effectsHaemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of haemorrhage is predominantly superficial at the injection site. Ecchymoses are observed commonly but usually do not require any specific action. Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Summary
of
product
characteristics
Slide64This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Table 1 displays the frequency of adverse reactions (part 1).
Summary of product characteristics
System Organ Class
Adverse Reaction
Immune system disorders
Rare
Anaphylactoid reaction (including rash, urticaria, bronchospasm, laryngeal oedema)
Nervous system disorders
Uncommon
Intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation stroke, intracranial haematoma, subarachnoid haemorrhage) including associated symptoms as somnolence, aphasia, hemiparesis, convulsion aphylactoid reaction (including rash, urticaria,
bronchospasm, laryngeal oedema)
Eye disorders
Uncommon
Eye haemorrhage
Cardiac disorders
Uncommon
Reperfusion arrhythmias (such as asystole, accelerated
idioventricular arrhythmia, arrhythmia, extrasystoles, atrial fibrillation, atrioventricular first degree to atrioventricular block complete, bradycardia, tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia) occur in close temporal relationship to treatment with tenecteplase. Reperfusion arrhythmias may lead to cardiac arrest, can be life threatening and may require the use of conventional antiarrhythmic therapies.
Rare
Pericardial haemorrhage
Slide65This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Table 1 displays the frequency of adverse reactions (part 2).
Summary of product characteristics
System Organ Class
Adverse Reaction
Vascular disorders
Very common
Haemorrhage
Rare
Embolism (thrombotic embolization)
Respiratory, thoracic and mediastinal disorders
Common
Epistaxis
Rare
Pulmonary haemorrhage
Gastrointestinal disorders
Common
Gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage)
Uncommon
Retroperitoneal haemorrhage (such as retroperitoneal haematoma)
Not known
Nausea, vomiting
Skin and subcutaneous tissue disorders
Common
Ecchymosis
Renal and urinary disorders
Common
Urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)
Slide66This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Table 1 displays the frequency of adverse reactions (part 3).As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and/or thrombolytic administration:very common (>1/10): hypotension, heart rate and rhythm disorders, angina pectoriscommon (>1/100, <1/10): recurrent ischaemia, cardiac failure, myocardial infarction, cardiogenic shock, pericarditis, pulmonary oedemauncommon (>1/1,000, <1/100): cardiac arrest, mitral valve incompetence, pericardial effusion, venous thrombosis, cardiac tamponade, myocardial rupturerare (>1/10,000, <1/1,000): pulmonary embolism These cardiovascular events can be life-threatening and may lead to death.4.9 OverdoseIn the event of overdose there may be an increased risk of bleeding. In case of severe prolonged bleeding substitution therapy may be considered (plasma, platelets), see also section 4.4.
Summary of product characteristics
System Organ Class
Adverse Reaction
General disorders and administration site conditions
Common
Injection site haemorrhage, puncture site haemorrhage
Investigations
Rare
Blood pressure decreased
Not known
Body temperature increased
Injury, poisoning and procedural complications
Not known
Fat embolism, which may lead to corresponding consequences in the organs concerned
Slide67This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic groupAntithrombotic agents, ATC code: B01A D11Mechanism of actionTenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.Pharmacodynamic effectsAfter administration of tenecteplase dose dependent consumption of α2-antiplasmin (the fluid-phase inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been observed. This observation is consistent with the intended effect of plasminogen activation. In comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and plasminogen levels. No clinically relevant antibody formation was detected at 30 days.Clinical effectsPatency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a single intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects experiencing an AMI on a dose related basis.A large scale mortality trial (ASSENT II) in approx. 17,000 patients showed that tenecteplase is therapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days, upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associated with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.Coronary patency and limited clinical outcome data showed that AMI patients have been successfully treated later than 6 hours after symptom onset.The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU unfractionated heparin administered prior to primary Percutaneous Coronary Intervention (PCI) to be performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the group receiving the exploratory regimen of tenecteplase followed by routine immediate PCI: 18.6% (151/810) compared to 13.4% (110/819) in the PCI only group, p=0.0045. This significant difference between the groups for the primary endpoint at 90 days was already present in-hospital and at 30 days.
Summary
of
product
characteristics
Slide68This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Numerically all of the components of the clinical composite endpoint were in favour of the PCI only regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target vessel revascularisation were significantly increased in the group pre-treated with tenecteplase: reinfarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4% p=0.0041. The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial haemorrhage: 1% vs. 0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4% p=0.3118; minor bleeds: 25.3% vs. 19.0% p= 0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873; abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.5.2 Pharmacokinetic properties Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen.Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t- PA, resulting in a prolonged half-life. Data on tissue distribution and elimination were obtained in studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase distributed was the liver. It is not known whether and to what extent tenecteplase binds to plasma proteins in humans.After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction, tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of tenecteplase clearance in the therapeutic dose range. The initial, dominant half life is 24 ± 5.5 (mean +/-SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129 ± 87 min, and plasma clearance is 119 ± 49 ml/min.Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this can be explained by the generally lower body weight of women.The effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans is not known. There is no specific experience to guide the adjustment to tenecteplase dose in patients with hepatic and severe renal insufficiency. However, based on animal data it is not expected that renal dysfunction will affect the pharmacokinetics.5.3 Preclinical safety data Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity studies in rats and dogs confirmed these above-mentioned observations, but the study duration was limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in anaphylaxis.Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by changes of ECG, but these occurred at exposures that were considerably higher than the clinical exposure.With regard to the indication and the single dose administration in humans, reproductive toxicity testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose.Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and genotoxicity and carcinogenicity testing were not necessary.No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous administration of the final formulation of tenecteplase.
Summary
of
product
characteristics
Slide69This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder for solution: L-arginine Phosphoric acid, Polysorbate 20 Solvent: Water for injections 6.2 Incompatibilities Metalyse is incompatible with dextrose infusion solutions. 6.3 Shelf life Shelf life as packaged for sale2 yearsReconstituted solutionChemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at 30°C.From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C.6.4 Special precautions for storage Do not store above 30°C. Keep the container in the outer carton.For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container 20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder for solution for injection.10 ml plastic syringe pre-filled with 6 ml of water for injections for reconstitution.Sterile vial adapter.Sterile needle for single use.
Summary
of
product
characteristics
Slide70This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.6 Special precautions for disposal and other handling Metalyse should be reconstituted by adding the complete volume of water for injections from the prefilled syringe to the vial containing the powder for injection.1. Ensure that the appropriate vial size is chosen according to the body weight of the patient.2. Check that the cap of the vial is still intact.3. Remove the flip-off cap from the vial.4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial adapter and penetrate the vial stopper in the middle with the spike of the vial adapter.5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid foaming.6. Reconstitute by swirling gently.7. The reconstituted preparation results in a colourless to pale yellow, clear solution. Only clear solution without particles should be used.8. Directly before the solution will be administered, invert the vial with the syringe still attached, so that the syringe is below the vial.9. Transfer the appropriate volume of reconstituted solution of Metalyse into the syringe, based on the patient’s weight.10. Disconnect the syringe from the vial adapter.11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be administered in a line containing dextrose.12. Any unused solution should be discarded.Alternatively the reconstitution can be performed with the included needle.7. MARKETING AUTHORISATION HOLDERBoehringer Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany
Summary of product characteristics
Patients‘
body
weight
category
(kg)
Volume of
reconstituted
solution (ml)
Tenecteplase
(U)
Tenecteplase
(mg)
<60
6
6,000
30
≥ 60 to < 70
7
7,000
35
≥ 70 to < 80
8
8,000
40
≥ 80 to < 90
9
9,000
45
≥ 90
10
10,000
50
Slide71Published byBoehringer Ingelheim International GmbHwww.metalyse.comRealisationinfill healthcarecommunicationwww.infill.com
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