“Come effettuare la terapia anticoagulante nello STEMI e nel...

“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?



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


• EPARINA NON FRAZIONATA

RISULTATI DELLO STUDIO GUSTO IN ENG J MED 1993


• EPARINA NON FRAZIONATA


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%


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

- 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

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

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

Take home messages





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

“Come effettuare la terapia anticoagulante nello STEMI e nel...

Documents

Transcript of “Come effettuare la terapia anticoagulante nello STEMI e nel...