Anti thrombotics in STEMI Journal review Dr Nithin P G

Antiplatelets in STEMI

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

Odds reduction: 23%, SD 4 2P< (11.8%) Placebo tablets Aspirin 804 (9.4%) Cumulative no. of vascular deaths Odds reduction: 25%, SD 4 2P< (12.0%) Placebo infusion SK 791 (9.2%) Days after randomization Placebo infusion and tablets SK and aspirin Combination therapy compared with matched combination placebo Cumulative no. of vascular deaths Days after randomization Odds reduction: 42%, SD 5 2P< (13.2%) 343 (8.0%) Months after randomization Placebotablets Aspirin Estimated % surviving Dr Nithin P G

0– Subtotal for 0–4 5–12 13–24 Subtotal for 5–24 Total for 0– Time of randomization (hours from pain onset) SK better Placebo better Aspirin better Placebo better Reinfarction Major bleed (transfused) Minor bleed (not transfused) Stroke (excluding TIA) Placebo infusion (n=8595) SK allocation Clinical event Placebo tablets (n=8600) SK (n=8592) Aspirin (n=8587) Both placebos (n=4300) SK and aspirin (n=4292) Aspirin allocationCombination 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 pts in comparisons of antiplatelet therapy versus control & 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/ 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

Clopidogrel COMMIT-CCS Lancet 2005; 366: 1607– pts 93% STEMI, 54% fibinolysis Aspirin 162mg + clopidogrel 75mg Mean treatment duration 14.9 days COMMIT-CCS Lancet 2005; 366: 1607– pts 93% STEMI, 54% fibinolysis Aspirin 162mg + clopidogrel 75mg Mean 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) 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. 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. Dr Nithin P G

Clopidogrel CLARITY-TIMI 28 NEJM 2005;352: pts receiving fibrinolytic therapy within 12 hrs of STEMI Aspirin [ mg,75 to 162 mg] + Clopidogrel [300 mg, 75 mg] CAG hrs Follow up for 30 days CLARITY-TIMI 28 NEJM 2005;352: pts receiving fibrinolytic therapy within 12 hrs of STEMI Aspirin [ mg,75 to 162 mg] + Clopidogrel [300 mg, 75 mg] CAG hrs Follow up for 30 days RESULTS Reduction in rate of an occluded infarct artery [21.7% to 15.0% {OR (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 days after enrollment 3.6% vs 6.2% (OR 0.54 [95% CI 0.35 to 0.85]; p0.008) RESULTS Reduction in rate of an occluded infarct artery [21.7% to 15.0% {OR (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 days after 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. 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

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: Dr Nithin P G

Clopidogrel Heart 2011;97:98e105 Preloading???- 600 mg vs 300mg Dr Nithin P G

Prasugrel TRITON TIMI 38 Lancet 2009; 373: 723– pts 3534 STEMI 1765 Clopi vs 1769 Prasugrel 2438 pPCI Aspirin within 24 hrs f/up for 14.5 months TRITON TIMI 38 Lancet 2009; 373: 723– pts 3534 STEMI 1765 Clopi vs 1769 Prasugrel 2438 pPCI Aspirin within 24 hrs f/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 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 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 CAUTION Age > 75 yrs Weight < 60 kg Previous h/o stroke or TIA Dr Nithin P G

Ticagrelor PLATO NEJM 2009;361: ,624 pts T-37.5% & C-38% STEMI f/up for 12 months PLATO NEJM 2009;361: ,624 pts T-37.5% & C-38% STEMI f/up for 12 months RESULTS Significantly reduced CV deaths, MI or stroke No increase in major bleeding but increase in non procedure-related bleeding 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 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 2011 ACCF/AHA/SCAI PCI Guidelines Dr Nithin P G

Gp IIbIIIa JAMA. 2005;293: 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 TRIAL N Engl J Med 2008;358: On TIME TRIAL Lancet 2008; 372: 537–46. [600 mg clopid.+ UFH] + Abciximab ; median ischemic time 4.5 hrs BRAVE-3 TRIAL N Engl J Med 2008;358: [600 mg clopid.+ UFH] + Abciximab ; median ischemic time 4.5 hrs BRAVE-3 TRIAL N Engl J Med 2008;358: Meta-regression analysis of 17 randomized trials- may be benfecial in high risk patients ??? European Heart Journal (2009) 30, 2705–271 Meta-regression analysis of 17 randomized trials- may be benfecial in high risk patients ??? European Heart Journal (2009) 30, 2705–271 Dr Nithin P G

Consensus CLASS IIa pPCI 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 III Upstream GPI infusion not proven beneficial 2011 ACCF/AHA/SCAI PCI Guidelines Dr Nithin P G

Anticoagulants in STEMI

Heparin Despite the use of UFH in STEMI for over 40 years, there is continued controversy regarding its role. Dr Nithin P G

LMWH Dr Nithin P G

LMWH Dr Nithin P G

Bivalirudin 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) Dr Nithin P G

Thank You

ISIS-2 Vascular mortality (%) at 35 days Odds reduction: 23%, SD 4 2P< (11.8%) Placebo tablets Aspirin 804 (9.4%) Dr Nithin P G

Aspirin dose after PCI ?? Insights from the PCI-CURE study European Heart Journal (2009) 30, 900– 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” Dr Nithin P G