anti thrombotics in stemi

Anti thrombotics in STEMI

Journal review

Dr Nithin P G

Antiplatelets in STEMI

Dr Nithin P G

Aspirin

ISIS-2: Second International Study of Infarct Survival Lancet 1988;ii:349–60

• Design: Multicenter, multinational, randomized, double-blind, placebo-controlled

• Patients: 17,187 patients with suspected MI in previous 24h; patients with history of stroke or GI hemorrhage/ulcer were excluded

• Follow up and primary endpoint: Median 15 months follow up. Primary endpoint vascular mortality 35 days

• Treatment

Patients randomized to one of four groups• SK (1.5 million U over 60 min) and aspirin (160 mg/day for 1 month)• SK (1.5 million U over 60 min) and placebo matching aspirin• Placebo matching SK and aspirin (160 mg/day for 1 month)• Placebo matching SK and placebo matching aspirin

Dr Nithin P G

0 7 14 21 28 3550

600

400

200

800

1000

Odds reduction: 23%, SD 4 2P<0.00001

1016(11.8%)

Placebo tablets

Aspirin

804(9.4%)

Cumulativeno. of

vasculardeaths

0 7 14 21 28 3550

600

400

200

800

1000


1029(12.0%)

Placebo infusion

SK

791(9.2%)

Days after randomization

Placebo infusion and tablets SK and aspirin

Combination therapy compared withmatched combination placebo

Cumulativeno. of

vasculardeaths

Days after randomization

0 7 14 21 28 35

0

400

300

200

100

500

600

Odds reduction: 42%, SD 5

2P<0.00001

568 (13.2%)

343 (8.0%)

Months after randomization

0 12 2470

100

95

90

85

80

Placebo tablets

Aspirin

Est

imate

d %

surv

ivin

g

Dr Nithin P G

0–1 2 3 4 Subtotal for 0–4

5–12 13–24 Subtotal for 5–24

Total for 0–24

0.5 1.0 1.5 0.5 1.0 1.5

Time of randomization(hours from pain onset)

SKbetter

Placebobetter

Aspirinbetter

Placebobetter

Reinfarction

Major bleed (transfused)

Minor bleed (not transfused)

Stroke (excluding TIA)

202

18

81

67

238

46

297

61

284

33

163

81

156

31

215

47

123

11

33

45

77

24

167

25

Placeboinfusion(n=8595)

SK allocation

Clinicalevent

Placebotablets

(n=8600)

SK

(n=8592)

Aspirin

(n=8587)

Bothplacebos(n=4300)

SK andaspirin

(n=4292)

Aspirin allocation Combination therapy

Dr Nithin P G

Aspirin

Compared with placebo in the ISIS-2 trial, up to 1 month of

aspirin 162 mg daily after suspected acute MI prevented about

40 deaths, nonfatal reinfarctions, or strokes per 1000 patients

treated (and these early benefits persisted for at least 10 years).

BMJ 1998; 316: 1337–43

Dr Nithin P G

Aspirin

Antithrombotic Trialists' Collaboration [ATC] Metanalysis BMJ 2002;324:71–86

• Randomised trials of an antiplatelet regimen versus control or one antiplatelet regimen versus another in high risk pts (with acute or previous vascular disease or some other predisposing condition) [Results available before September 1997]

• 287 studies involving 135 000 pts in comparisons of antiplatelet therapy versus control & 77 000 in comparisons of different antiplatelet regimens.

Dr Nithin P G

1 month of aspirin therapy 38 fewer vascular events /1000 treated pts• Non fatal MI 13 fewer/1000• Vascular deaths 23 fewer/1000• Non fatal stroke 2 fewer/1000

Only 1-2 addl major bleed/1000

Dr Nithin P G

Aspirin- consensus

• A daily dose of aspirin (initial dose of 162 to 325 mg orally; maintenance dose of 75 to 162 mg) should be given indefinitely after STEMI to all patients without a true aspirin allergy. Class I (Level of Evidence: A)

[STEMI guidelines -AHA,ESC]• Although no specific trials available comparing to placebo, all patients

undergoing PCI also given aspirin loading– Patients already taking daily aspirin therapy should take 81 mg to

325 mg before PCI Class I (Level of Evidence: B)– Patients not on aspirin therapy should be given nonenteric aspirin 325 mg before PCI.

Class I(Level of Evidence: B)– After PCI, use of aspirin should be continued indefinitely Class I (Level of Evidence: A)

2011 ACCF/AHA/SCAI PCI Guidelines• After PCI, it is reasonable to use aspirin 81 mg per day in preference to higher

maintenance doses . CLASS IIa (Level of Evidence: B)

2011 ACCF/AHA/SCAI PCI Guidelines

Dr Nithin P G

Dr Nithin P G

Clopidogrel

COMMIT-CCS Lancet 2005; 366: 1607–21

45 852 pts93% STEMI, 54% fibinolysis

Aspirin 162mg + clopidogrel 75mgMean treatment duration 14.9 days

RESULTS•Composite end point [death, reinfarction, or stroke] was reduced from 10.1% to 9.2% (OR 0.91 [95% CI 0.86 to 0.97]; p0.002)•All-cause mortality was reduced from 8.1% to 7.5% (OR 0.93 [95% CI 0.87 to 0.99]; p0.03; NNT167)

•Adding clopidogrel 75 mg daily to aspirin in acute MI prevents about another 10 deaths, reinfarctions, or strokes per 1000 pts treated for about 2 weeks.

•Compared with no antiplatelet treatment, combination of clopidogrel + aspirin prevents an average of about 50 major vascular events per 1000 treated for just a few weeks soon after the onset of acute MI.

Clopidogrel

CLARITY-TIMI 28 NEJM 2005;352:1179-89.

• 3491 pts receiving fibrinolytic therapy within 12 hrs of STEMI

• Aspirin [150-325 mg ,75 to 162 mg] + Clopidogrel [300 mg, 75 mg]

• CAG- 48-192 hrs• Follow up for 30 days

RESULTS•Reduction in rate of an occluded infarct artery [21.7% to 15.0% {OR- 0.64 (95% CI 0.53 to 0.76)}]; p<0.001•Reduction in mortality by preventing infarct-related reocclusion rather than by facilitating early reperfusion. •No increase in TIMI major bleed, [safety of clopidogrel 300 mg)•Clopidogrel arm undergoing PCI- composite end point of CV death, r/c MI, or stroke from PCI to 30 daysafter enrollment 3.6% vs 6.2% (OR 0.54 [95% CI 0.35 to 0.85]; p0.008)

•COMMIT-CCS-2 and CLARITY-TIMI 28 trials provided evidence for benefit of adding clopidogrel to aspirin in patients undergoing fibrinolytic therapy, CLARITY-TIMI supported clopidogrel use in PCI

•The COMMIT-CCS-2 trial also supported the use of clopidogrel in patients who were not receiving reperfusion therapy.

Dr Nithin P G

Dr Nithin P G

Clopidogrel

“…pretreatment with clopidogrel in addition to aspirin in patients with ACS undergoing PCI is beneficial in reducing major ischaemic events up to 30 days after PCI. Longer-term administration of clopidogrel therapy for a mean period of 8 months after PCI was associated with a reduction in cardiovascular death or myocardial infarction at the end of follow-up.” PCI-CURE study Lancet 2001; 358: 527–33

JAMA. 2005;294:1224-1232

Dr Nithin P G

Clopidogrel

Heart 2011;97:98e105

Preloading???- 600 mg vs 300mg

Dr Nithin P G

PrasugrelTRITON TIMI 38

Lancet 2009; 373: 723–3113608 pts

3534 STEMI1765 Clopi vs 1769 Prasugrel

2438 pPCIAspirin within 24 hrsf/up for 14.5 months

RESULTS•2.2 % abs & 19% relative reduction of

end points [9.9% vs 12.1% Clop]• Reduction in non fatal MI

• More bleeding • No difference in non MI mortality

STEMI•CV mortality, MI, stroke, TVR reduced

• Less stent thrombosis• Effect lasts atleast 15 months

CAUTION• Age > 75 yrs• Weight < 60 kg

• Previous h/o stroke or TIA

Dr Nithin P G

Ticagrelor

PLATO NEJM 2009;361:1045-5718,624 pts

T-37.5% & C-38% STEMIf/up for 12 months

RESULTS•Significantly reduced CV deaths, MI or stroke •No increase in major bleeding but increase in non procedure-related bleeding

CAUTION• Dyspnea, Bradycardia

• High maintenance dose of aspirin interferes with action

Dr Nithin P G

Other antiplatelets-consensus

Non PCI

• Clopidogrel 75 mg per day orally should be added to aspirin in

patients with STEMI regardless of whether they undergo

reperfusion with fibrinolytic therapy or do not receive

reperfusion therapy. Class I (Level of Evidence: A) 2007 AHA STEMI Guidelines

Dr Nithin P G

Other antiplatelets-consensus

For PCI• Loading of-

– Clopidogrel 600 mg (ACS and non-ACS patients) Class I (Level of Evidence: B)– Prasugrel 60 mg (ACS patients) Class I (Level of Evidence: B)– Ticagrelor 180 mg (ACS patients) Class I (Level of Evidence: B)

[The loading dose of clopidogrel for PCI after fibrinolytic therapy =300 mg within 24 hours and 600 mg after 24 hours. Cass I (Level of Evidence: C)]

• Duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows:– BMS or DES for ACS at least 12 months.[Options include clopidogrel 75 mg daily,

prasugrel 10 mg daily, and ticagrelor 90 mg twice daily] Class I(Level of Evidence: B)– DES for a non-ACS indication clopidogrel 75 mg daily at least 12 months Class I

(Level of Evidence: B)– BMS for a non-ACS indication clopidogrel for a minimum of 1 month and ideally up to

12 months ( if at increased risk of bleeding; then it should be given for a minimum of 2 weeks) Class I (Levelof Evidence: B


Dr Nithin P G

Gp IIbIIIa

JAMA. 2005;293:1759-1765

Adjunctive abciximab-significant reduc. in 30-day reinfarction in all STEMI but, significant reduc. in short- and long-term mortality only pPCI

Abciximab -higher risk of major bleeding complications esp fibrinolytic therapy.

Dr Nithin P G

FINESSE TRIALN Engl J Med 2008;358:2205-17

On TIME TRIALLancet 2008; 372: 537–46.

[600 mg clopid.+ UFH] + Abciximab ; median ischemic time 4.5 hrsBRAVE-3 TRIALN Engl J Med 2008;358:2205-17

Meta-regression analysisof 17 randomized trials- may be benfecial in high risk patients ??? European Heart Journal (2009) 30, 2705–271

Dr Nithin P G

Consensus

CLASS IIapPCI treated with UFH, it is reasonable to administer a GPI (abciximab,

double-bolus eptifibatide, or high-bolus dose tirofiban), whether or not patients were pretreated with clopidogrel. (not pretreated with clopidogrel, Level of

Evidence: A; for pretreated with clopidogrel, Level of Evidence: C)

CLASS IIIUpstream GPI infusion not proven beneficial


Anticoagulants in STEMI

Dr Nithin P G

Heparin• Despite the use of UFH in STEMI for over 40 years, there is

continued controversy regarding its role.

Trial Design/ Comparisons CommentsMetanalysis of aspirin, UFH & Fibrinolytic therapyNEJM 1997;336:847-60

ISIS-3 and GISSI-2 [only small mort. benefit for s/c heparin] 68000 pts

5 lives saved/1000 pts treated with UFH + STK

GUSTO-I trialNEJM 1993;329:673-82

20 000 pts STK/tPA + [IV vs S/C UFH]

No sign. diff. observed in death, reinfarction, or non h’gic strokes Patency rate (5-7 d)- IV UFH [88% vs 2%] Reinfarction- S/C UFH (3.4% vs 4.0%)5yr follow up demonstrated similar survival rates for STK + UFH cf tPA

SCATI trial Lancet1989;ii:1826

2000-IU bolus UFH followed by 12 500 U s/c BD vs placebo.

Reduction in mortality & stroke. UFH may be given in patients with high risk of embolism

Dr Nithin P G

LMWHTrial Design Comments

AMI-SKEuropean Heart Journal (2002) 23, 1282–1290

STK + [IV bolus + S/C enox]496 patients

Enox- improved STR at 180 mins and higher rates of IRA patency at 8 d

ASSENT 3 trialLancet 2001;358:605-13

TNK + UFH 48 hrs or enoxaparin (bolus + S/C for duration of hospital stay)

Enox better at 30 day CE but increased bleeding especially in elderly >75 yrs. At 1 yr no significant difference.

ExTRACT-TIMI 25NEJM 2006;354:1477–88

20 506 patients(48 countries) within 6 hrs of STEMI and for whom fibrinolytic therapy was planned. 2d UFH vs 7d Enox

Enox superior to UFH, but increased risk of bleeding. Can support anticoag. in pts undergoing PCI

LMWHTrial Design Comments

FINESSE Trial substudyJ. Am. Coll. Cardiol. Intv. 2010; 3; 203-212

Subgroup analysis of enox vs UFH

Enox-better CE at 30 days & reduction of 90 d mortality, non major bleed also less

ATOLL trialLancet 2001;358:605-13

pPCI 1:1 open labelled trial enox 0.5 mg/kg bolus vs UFH

Enox- 30-day incidence of death, MI complication, procedure failure, or major bleeding same. [composite of death, r/c ACS, or urgent revasc. reduced]

Oasis 6 trialJAMA. 2006;295:1519-1530

Fondaparinux vs UFH in STEMI

Fondaparinux superior to UFH in fibrinolytic and non fibrinolytic pts. No diff in PCI group increased incidence of catheter thrombosis.

Dr Nithin P G

Dr Nithin P G

Bivalirudin

Trial Design CommentsHERO-2 TrialLancet 2001; 358: 1855–63

STK+ IV Bivalirudin or IV UFH17 073 patients

Bivalirudin reduced reinfarction No mortality benefit

HORIZONS AMI TrialNEJM 2008;358:2218-301 yr follow upLancet 2009;374:1149-59

3602 patients; pPCI UFH +GPI or Bivalirudin alone

Bivalirudin- reduced 30d major bleeding and NACE but increased incidence of acute stent thrombosis [Clopi. 300 vs 600 mg]. At 1 yr MACE similar but all cause mortality and cardiac mortality reduced

Dr Nithin P G

Consensus

Non PCI

• IV UFH in pts undergoing reperfusion therapy with alteplase, reteplase, or tenecteplase with dosing as follows: bolus of 60 U/kg (maximum 4000 U) followed by an infusion of 12 U/kg/hr (maximum 1000 U) initially adjusted to maintain aPTT at 1.5 to 2.0 times control (approx. 50 to 70 seconds). (Level of Evidence: C)

• IV UFH in pts treated with nonselective fibrinolytic agents (streptokinase, anistreplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, atrial fibrillation (AF), previous embolus, or known LV thrombus). (Level of Evidence: B)

Dr Nithin P G

Consensus

Class IIa

It is reasonable for patients with STEMI who do not undergo reperfusion

therapy to be treated with anticoagulant therapy (non-UFH regimen) for

the duration of the index hospitalization, up to 8 days. (Level of Evidence:

B) Convenient strategies that can be used include those with LMWH

(Level of Evidence: C) or fondaparinux (Level of Evidence: B)

Dr Nithin P G

Consensus

Patients undergoing PCI:• For prior treatment with UFH, administer additional boluses of UFH as

needed, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C)

• For prior treatment with enoxaparin, if the last subcutaneous dose was administered at least 8 to 12 hours earlier, an IV (intravenous) dose of 0.3 mg/kg of enoxaparin should be given; if the last subcutaneous dose was administered within the prior 8 hours, no additional enoxaparin should be given. (Level of Evidence: B)

• For prior treatment with fondaparinux, administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C)

• Bivalirudin is useful as a supportive measure for primary PCI with or without prior treatment with UFH (Level of Evidence: B)

Thank You

Dr Nithin P G

ISIS-2

Aspirin PlaceboSK 8.0 10.4

Placebo 10.7 13.2

Vascular mortality (%) at 35 days

0 7 14 21 28 3550

600

400

200

800

1000


1016(11.8%)

Placebo tablets

Aspirin

804(9.4%)

Dr Nithin P G

Aspirin dose after PCI ??

Insights from the PCI-CURE studyEuropean Heart Journal (2009) 30, 900–907

• 2658 patients with acute coronary syndromes undergoing PCI• Stratified into three aspirin dose groups 200 mg (high, n = 1064), 101–199

mg (moderate, n = 538), and 100 mg (low, n = 1056)• Efficacy- the moderate- (7.4%) and high-dose groups (8.6%) had similar

rates of cardiovascular death, myocardial infarction, or stroke compared with the low-dose group(7.1%)

• Major bleeding- was increased with high dose aspirin [3.9, 1.5, and 1.9% in the high-, moderate-, and low-dose groups; hazard ratio (HR) of high vs. low dose 2.05 (95% CI 1.20–3.50, P ¼ 0.009]

“ Low-dose aspirin appeared to be as effective as higher doses in preventing ischaemic events but was also associated with a lower rate of major bleeding”

anti thrombotics in stemi

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