“Come effettuare la terapia
anticoagulante nello STEMI enel NSTEMI”
“Come effettuare la terapia
anticoagulante nello STEMI enel NSTEMI”
Dr.ssa Lidia RossiResponsabile S.S.V.D. UTICAOU Maggiore della CaritàNovara
Dr.ssa Lidia RossiResponsabile S.S.V.D. UTICAOU Maggiore della CaritàNovara
AspirinaClopidogrelAnti GPIIb IIIa
UFHEnoxaparina
AspirinaClopidogrelAnti GPIIb IIIa
UFHEnoxaparina
AspirinaClopidogrelPrasugrelTicagrelorAnti GPIIb IIIa
UFHEnoxaparinaFundaparinuxBivalirudina…..NAO
AspirinaClopidogrelPrasugrelTicagrelorAnti GPIIb IIIa
UFHEnoxaparinaFundaparinuxBivalirudina…..NAO
ANNO 2007ANNO 2007 ANNO 2013ANNO 2013
• In quale contesto clinico ?
• In quale strategia?
• In quale contesto clinico ?
• In quale strategia?
ESC STEMI GUIDELINES 2012
TERAPIA ANTICOAGULANTE E FIBRINOLISITERAPIA ANTICOAGULANTE E FIBRINOLISI
TERAPIA ANTICOAGULANTE E PPCITERAPIA ANTICOAGULANTE E PPCI
Raccomandadazioni delle Linee Guida ESC 2012per la scelta della terapia riperfusiva dell’IMA
Raccomandadazioni delle Linee Guida ESC 2012per la scelta della terapia riperfusiva dell’IMA
STEMISTEMI
Angioplastica PrimariaAngioplastica Primaria TrombolisiTrombolisi
E’ indicata in tutti i pazienti con dolore da meno di 12 ore e con una elevazione del tratto ST o di un (presunto) nuovo
BBS, deve essere effettuata da un team esperto
E’ indicata in tutti i pazienti con dolore da meno di 12 ore e con una elevazione del tratto ST o di un (presunto) nuovo
BBS, deve essere effettuata da un team esperto
Va iniziata il più precomentepossibile in assenza di
controindicazioni e se una angioplastica primaria non può
essere effettuata da un team esperto
Va iniziata il più precomentepossibile in assenza di
controindicazioni e se una angioplastica primaria non può
essere effettuata da un team esperto
Livello di evidenza IA Livello di evidenza IAEuropean Heart Journal 2012
TERAPIA ANTICOAGULANTE E FIBRINOLISI
• EPARINA NON FRAZIONATAEFFICACIA ENF NEL RIDURRE LA MORTALITA’ DEI PAZ CON STEMICOLLINS BMJ 1996
RISULTATI DELLO STUDIO GUSTO IN ENG J MED 1993
69° congresso SIEC –roma 2008
TERAPIA ANTICOAGULANTE E FIBRINOLISI
• EPARINA NON FRAZIONATA
RISULTATI DELLO STUDIO GUSTO IN ENG J MED 1993
69° congresso SIEC –roma 2008
• EPARINA NON FRAZIONATA
69° congresso SIEC –roma 2008
ASSENT 3: Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding
Days to Death or Reinfarction or Refractory Ischemia or ICH or MDays to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleedingajor Bleeding
Prob
abili
ty (%
)Pr
obab
ility
(%)
00
22
44
66
88
1010
1414
1212
1616
1818
2020
55 1010 1515 2020 2525 3030
UnfractionatedUnfractionatedHeparinHeparin
AbciximabAbciximab
EnoxaparinEnoxaparin
LogLog--rank test: rank test: PP=0.0062=0.0062
00
13.8%14.2%
17.0%
TERAPIA ANTICOAGULANTE E FIBRINOLISI
ENOXAPARINA
“In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative
anticoagulant treatment when given in combination with tenecteplase”.
ExTRACT-TIMI 25: Background
• In STEMI patients, prolonged infusion of UFH has not been shown to prevent reocclusion following angiographically successful fibrinolytic therapy– Therefore, current recommendations limit duration of infusion to
48 hours
• LMWH vs UFH provides a reliable level of anticoagulation without the need for therapeutic monitoring and with relatively greater proximal inhibition of the coagulation cascade
• ExTRACT-TIMI 25 compared LMWH (enoxaparin) and UFH as adjunctive therapy for fibrinolysis in STEMI– Enoxaparin was administered for duration of hospitalization and
dosed according to age and renal function
• In STEMI patients, prolonged infusion of UFH has not been shown to prevent reocclusion following angiographically successful fibrinolytic therapy– Therefore, current recommendations limit duration of infusion to
48 hours
• LMWH vs UFH provides a reliable level of anticoagulation without the need for therapeutic monitoring and with relatively greater proximal inhibition of the coagulation cascade
• ExTRACT-TIMI 25 compared LMWH (enoxaparin) and UFH as adjunctive therapy for fibrinolysis in STEMI– Enoxaparin was administered for duration of hospitalization and
dosed according to age and renal function
Antman EM et al. N Engl J Med. 2006;354:1477-88.Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT- TIMI 25ExTRACT- TIMI 25
TIMI major bleeding at 30 days stratified by age cut-off of 75 yearsTIMI major bleeding at 30 days stratified by age cut-off of 75 years
Enoxaparin 30 mg IV bolus, 1.0 mg/kg sc q12h*
median 7 daysEnoxaparin
*Aged ≥75 yr: no IV bolus, 0.75 mg/kg sc q12h; CrCl
Impact of enoxaparin on key outcomes
• In patients with STEMI treated with fibrinolytic therapy, the modified (reduced) dosing regimen of ENOX in patients > 75 years appears to have been helpful in reducing themagnitude of the relative increase in major bleeding,including the intracranial haemorrhage that has been observed in this age group in previous trials.
• The similar ARD and NNT in the elderly and young patients suggest that the reduced ENOX dose in the elderly did not compromise its efficacy in preventing death or MI.
• Thus, the ENOX strategy as implemented in ExTRACT-TIMI 25 is preferred to the standard UFH strategy in both younger and older STEMI patients treated with fibrinolysis.
OASIS-6 Randomized Trial
JAMA. 2006;295(13):1519-1530.
JAMA. 2006;295(13):1519-1530.
OASIS-6 Randomized Trial
OASIS – 6 Trial: Conclusions
• The benefit of Fondaparinux was confined to patients in Stratum 1 where placebo or no antithrombin was administered
• Fondaparinux was not superior to active control UFH
• Fondaparinux was associated with a hazard in those patients who underwent PCI including guiding catheter thrombosis
•• The benefit of The benefit of FondaparinuxFondaparinux was confined was confined to patients in Stratum 1 where placebo or no to patients in Stratum 1 where placebo or no antithrombin was administeredantithrombin was administered
•• FondaparinuxFondaparinux was not superior to active was not superior to active control UFHcontrol UFH
•• FondaparinuxFondaparinux was associated with a hazard was associated with a hazard in those patients who underwent PCI in those patients who underwent PCI including guiding catheter thrombosisincluding guiding catheter thrombosis
Presented at ACC 2006Presented at ACC 2006
12.1
8.3
5.5
9.2
4.9 5.4
0
5
10
15
20
Net adverse clinical events
Major bleeding (non CABG)
MACE
30 d
ay e
vent
rate
s (%
)
Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)
Diff = Diff = 0.0% [-1.6, 1.5]RR = 0.99RR = 0.99 [0.76, 1.30]
PPsupsup = 0.95= 0.95
Primary Endpoints at 30 Days
Diff = Diff = -3.3% [-5.0, -1.6]RR = RR = 0.60 [0.46, 0.77]
PPNINI ≤≤ 0.00010.0001PPsupsup ≤≤ 0.00010.0001
Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]
PPNINI ≤≤ 0.00010.0001PPsupsup = 0.005= 0.005
1° endpoint 1° endpoint Major 2° endpoint
Stone GW et al. NEJM 2008;358:2218-30
HORIZONS-AMIHORIZONS-AMI
00
22
44
66
88
1010
1212
1414
1616
1818
2020
00 11 22 33 44 55 66 77 88 99 1010 1111 121200
22
44
66
88
1010
1212
1414
1616
1818
2020
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
*MACE or major bleeding (non CABG)
Number at riskNumber at riskBivalirudinBivalirudin alonealoneHeparin+GPIIb/IIIaHeparin+GPIIb/IIIa
18001800 15591559 15141514 14831483 1343134318021802 14991499 14591459 14271427 12811281
Time in Months
18.3%
15.7%
Diff [95%CI] = -2.6% [-5.1, -0.1]
HR [95%CI] = 0.84 [0.71, 0.98]
P=0.03
1-Year Net Adverse Clinical Events*
NA
CE
(%)
Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802))
Mehran R, TCT 2008
00
22
44
66
88
1010
1212
1414
1616
1818
2020
00 11 22 33 44 55 66 77 88 99 1010 1111 121200
22
44
66
88
1010
1212
1414
1616
1818
2020
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
*MACE or major bleeding (non CABG)
Number at riskNumber at riskBivalirudinBivalirudin alonealoneHeparin+GPIIb/IIIaHeparin+GPIIb/IIIa
18001800 15591559 15141514 14831483 1343134318021802 14991499 14591459 14271427 12811281
Time in Months
18.3%
15.7%
Diff [95%CI] = -2.6% [-5.1, -0.1]
HR [95%CI] = 0.84 [0.71, 0.98]
P=0.03
1-Year Net Adverse Clinical Events*
NA
CE
(%)
Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802))
Mehran R, TCT 2008
1-year analysis of the HORIZONS-AMI trial shows that in patients withSTEMI undergoing PPCI, procedural anticoagulation with bivalirudin
alone seemed to reduce haemorrhagic complications, late reinfarctionand early and late cardiac and all-cause mortality compared with UFH
plus the routine use of a GPI.
Conclusions• In this large scale, prospective, randomized trial of pts with
STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:
– A significant 16% reduction in the 1-year rate of composite net adverse clinical events
– A significant 39% reduction in the 1-year rate of major bleeding
– Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year
• In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:
– A significant 16% reduction in the 1-year rate of composite net adverse clinical events
– A significant 39% reduction in the 1-year rate of major bleeding
– Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year
Mehran R, TCT 2008
Clinical Implications
• HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival
– Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies
• HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival
– Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies
Mehran R, TCT 2008
3-year MACE Components*UFH + GPI(N=1802)
Bivalirudin
(N=1800)HR [95%CI] P Value
Number needed to treat
Death 7.7%7.7% 5.9%5.9% 0.75 (0.58,0.97) 0.03 54-- CardiacCardiac 5.1%5.1% 2.9%2.9% 0.56 (0.40,0.80) 0.001 45
-- Non cardiacNon cardiac 2.8%2.8% 3.1%3.1% 0.62Reinfarction 8.2%8.2% 6.2%6.2% 0.76 (0.59,0.92) 0.04 52
-- QQ--wavewave 3.8%3.8% 3.4%3.4% 0.61
-- Non QNon Q--wavewave 4.9%4.9% 3.2%3.2% 0.009 58Death or reinfarction 14.5%14.5% 11.3%11.3% 0.72 (0.58,0.91) 0.005 31
Ischemic TVR 12.1%12.1% 14.2%14.2% 0.06Stroke 2.0%2.0% 1.7%1.7% 0.50
*Kaplan-Meier estimates, CEC adjudicated
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke
Conclusions: Pharmacology Randomization
• In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in:– A significant 36% reduction in major bleeding and a significant
24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke
– A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)
• In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in:– A significant 36% reduction in major bleeding and a significant
24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke
– A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-year analysis of the HORIZONS-AMI trial shows that in patients withSTEMI undergoing PPCI, procedural anticoagulation with bivalirudinalone seemed compared to heparin plus GPI resulted in:
• 36% reduction in major bleeding
• significant 24% reduction in reinfarction
• significant 44% reduction in cardiac mortality
• 25% reduction in all-cause mortality
• non significantly different rates of stent thrombosis, TVR and stroke
1-year analysis of theHORIZONS-AMI trial
shows that in high-risk patients with STEMI undergoing primary PCI, procedural
anticoagulation with bivalirudinalone seemed to reduce haemorrhagiccomplications,late reinfarction, and earlyand late cardiac and all-cause mortality
compared with unfractionated heparin plus the routine use of a GPI.
1-year analysis of theHORIZONS-AMI trial
shows that in high-risk patients with STEMI undergoing primary PCI, procedural
anticoagulation with bivalirudinalone seemed to reduce haemorrhagiccomplications,late reinfarction, and earlyand late cardiac and all-cause mortality
compared with unfractionated heparin plus the routine use of a GPI.
ATOLL trial
ATOLL trial
- Intravenous enoxaparin compared withunfractionated heparin did not significantly reduce theATOLL primary endpoint; however, significance waspresent in patients consistently treated with the studydrug. - Intravenous enoxaparin did reduce secondaryendpoints of adverse ischaemic events without asignificant difference in bleeding endpoints comparedwith unfractionated heparin. > net clinical benefit was improved with enoxaparin in
patients undergoing primary PCI.
- Intravenous enoxaparin compared withunfractionated heparin did not significantlyreduce the ATOLL primary endpoint; however, significance was present in patientsconsistently treated with the study drug.
- Intravenous enoxaparin did reduce secondaryendpoints of adverse ischaemic events withouta significant difference in bleeding endpointscompared with unfractionated heparin.
> net clinical benefit was improved withenoxaparin in patients undergoing primary PCI.
- Intravenous enoxaparin compared withunfractionated heparin did not significantlyreduce the ATOLL primary endpoint; however, significance was present in patientsconsistently treated with the study drug.
- Intravenous enoxaparin did reduce secondaryendpoints of adverse ischaemic events withouta significant difference in bleeding endpointscompared with unfractionated heparin.
> net clinical benefit was improved withenoxaparin in patients undergoing primary PCI.
Anticoagulants in NSTEMI-ACS
Indirect inhibitors of coagulationIndirect thrombin inhibitors: UFH
LMWHsIndirect factor Xa inhibitors: LMWHs
fondaparinuxDirect inhibitors of coagulation
Direct factor Xa inhibitors: apixaban, rivaroxaban, otamixaban
Direct thrombin inhibitors (DTIs): bivalirudin, dabigatran
OASIS 5OASIS 5
N Engl J Med 2006; 354, 1464-76
Fondaparinux is similar to enoxaparin in the short termin preventing ischemic events among patients with
acute coronary syndromes without ST-segment elevation,but it is associated with substantially less bleeding, substantially less bleeding,
that translates into lower longthat translates into lower long--term mortality and term mortality and morbiditymorbidity.
Fondaparinux at a dose of 2.5 mg daily issimilar to enoxaparin in the short term in preventing ischemic events among patientswith acute coronary syndromes without ST-segment elevation, but it is associated withsubstantially less bleeding an effect thattranslates into lower long-term mortalityand morbidity.
> fondaparinux is an attractive option as ananticoagulant in the short-term care of patients with acute coronary syndromes.
The FUTURA/OASIS-8 RandomizedTrial
The FUTURA/OASIS-8 RandomizedTrial
The FUTURA/OASIS-8 RandomizedTrial
Low-dose compared with ACTguided standard-dose heparin did not reduce peri-PCI bleedingand vascular access site complications.
Catheter thromboses are rare when usingunfractionated heparin for PCI in patients withnon–ST-segment elevation acute coronary syndromes treated with fondaparinux.
Therefore, patients with acute coronary syndromes treated with fondaparinux and undergoing PCI should receive the guideline-recommended ACT-guided standard dose of unfractionated heparin.
Low-dose compared with ACTguided standard-dose heparin did not reduce peri-PCI bleedingand vascular access site complications.
Catheter thromboses are rare when usingunfractionated heparin for PCI in patients withnon–ST-segment elevation acute coronary syndromes treated with fondaparinux.
Therefore, patients with acute coronary syndromes treated with fondaparinux and undergoing PCI should receive the guideline-recommended ACT-guided standard dose of unfractionated heparin.
SYNERGY Randomized Trial
SYNERGY Randomized Trial
SYNERGY Randomized Trial
In high-risk patients with ACS treatedwith an early invasive strategy withfrequent use of antithrombin therapyprior to enrollment and postrandomizationcrossovers, enoxaparin is not inferior tounfractionated heparin.
Enoxaparin carries a modest increase in bleeding and is likely superior whenstarted as initial first-line therapywithout changing to alternative agents
In high-risk patients with ACS treatedwith an early invasive strategy withfrequent use of antithrombin therapyprior to enrollment and postrandomizationcrossovers, enoxaparin is not inferior tounfractionated heparin.
Enoxaparin carries a modest increase in bleeding and is likely superior whenstarted as initial first-line therapywithout changing to alternative agents
0 1 2
Upp
er b
ound
ary
non-
infe
riorit
y
11.7%10.1% 0.86 (0.77-0.97) 0.02Net clinical outcome
Ischemic composite
Major bleeding
7.3%7.8% 1.08 (0.93-1.24) 0.32
5.7%3.0% 0.53 (0.43-0.65)
JACC 2010; 55: 1416
• In quale contesto clinico ?
• In quale strategia?
• In quale contesto clinico ?
• In quale strategia?
Take home messages
• In quale contesto clinico ?
• In quale strategia?
• In quale contesto clinico ?
• In quale strategia?
STEMI :
FIBRINOLISI > ENOXAPARINA
PPCI > BIVALIRUDINA
NSTEMI:
URGENT / EARLY INVASIVE > BIVALIRUDINA / UFHNON URGENT > FUNDAPARINUX
TERAPIA CONSERVATIVA:ENOXAPARINA / FUNDAPARINUX
Take home messages 2
A quale paziente ?
Ndrepepa G, et al. JACC 2008
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