EBQ:Major Cardiology Trials

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Aspirin in MI[1]

  • VA Patients
  • Primary end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms.
  • Multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina
  • At 12 weeks ASA group had 51% decrease in death & MI. 1

Aspirin or Sulfinpyrazone[2]

  • ASA with 51 % decrease in death or MI
  • ASA with 70% decrease in all cause mortality
  • No benefit w sulfinpyrazone.

CURE[3]

  • 12,562 pt in Randomized Controlled Trial with Unstale Angina or NSTEMI
  • Clopidogrel 300 mg loading dose followed by clopidogrel 75 mg daily for 3 to 12 months.
  • All patients were administered aspirin 75 to 325 mg daily.
  • Composite of CV mortality, non-fatal MI, or stroke with 9.3%(clopidogrel) vs 11.5(placebo)
  • Also less inpatient ischemia & revascularization, less thrombolitic or GP IIb/IIIa administration
  • Increased major and minor bleeding especially in CABG patients.

ESSENCE[4]

  • 3171 patients
  • Compared enoxaparin (1mq/kg BID) to Unfractionated Heparin (5000 U bolus then ptt to PTT 55-56) 48h-8d
  • 16.2% less death, MI, recurrent angina at 14 days and 19% less at 30 days
  • Only trends in MI and death. Only 46% of UFH group reached target PTT by 12-24h.
  • Major bleeding 6.5% (enoxaparin) vs 7.0% (UFH).

ESPIRIT[5]

  • Randomized controlled trial in which we assigned patients to aspirin (30—325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin
  • Primary composite outcome of death from all vascular causes, stroke, myocardial infarction, or major bleeding complications of (13%) patients on aspirin and dipyridamole and in (16%) on aspirin alone


FRAXIS[6]

  • Prolonged nadroparin treatment was associated with an increase in major bleeding events and equal short term efficacy

ATACS[7]

Two hundred fourteen patients were randomized to receive aspirin alone (162.5 mg daily) or a combination of aspirin plus anticoagulation

    • Aspirin 162.5 mg daily plus heparin (activated partial thromboplastin time, two times control) followed by aspirin 162.5 mg daily plus warfarin (international normalized ratio, 2 to 3)
  • Coumadin & ASA shows no long term benefit

OASIS-2[8]

  • 10,141 patients with unstable angina or suspected acute myocardial infarction without ST elevation
  • Double blind RCT to Heparin (5000 units bolus then 15 units kg) or hirudin (0.4 mg/kg bolus then 0.15 mg kg) for 72 hrs
  • Major bleeding requiring transfusion significantly increased with hirudin

OASIS-5 TRIAL[9]

  • Double-blinded multicenter RCT in 20,078 patients with UA/NSTEMI
  • Given Fondaparinux 2.5mg daily vs Enoxaparin 1mg/kg in patients receiving GP IIb/IIIa inhibitors
  • Primary endpoint was to determine whether fondaparinux was superior to enoxaparin in preventing major bleeding.
  • n patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding

OASIS-6[10]

  • 12,092 STEMI patients
  • Primary outcome: Death or recurrent MI
  • Randomization to control of Placebo or UFH based on the investigator's judgment vs fondaparinux
  • Potential morbidity benefit to Fondaparinux in STEMI over UFH in those not undergoing PCI

OASIS-7[11]

  • Randomized trial of 25,086 patients with an acute coronary syndrome referred for an invasive strategy
    • Double dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter)
    • Standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter)
      • Plus either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily).
  • No difference between high dose and low dose clopidogrel or asprin.

FRISC[12]

  • 1,506 patients with Unstable Anginat or NSTEMI given Dalteparin bid x 6d then QD x 35-45d.
  • 63% reduction in death or MI in first 6days.
  • 4-5 months after the end of treatment, there were no significant differences in the rates of death, new myocardial infarction, or revascularisation

GUSTO Trial[13]

  • Multi-center Randomized Placebo Controlled Trial
  • 7800 patients
    • randomly assigned placebo or
    • abciximab bolus and 24 h infusion or
    • abciximab bolus and 48 h infusion
    • all patients received aspirin and either unfractionated or low-molecular-weight heparin
  • No benefit in the abciximab groups

LIFE

Lancet 3/02

4yr f/u

->Losartan showed reduction of CV M&M vs atenolol in pts c HTN and LVH. Most of benefit in stroke reduction. Also c 25% reduction in development of DM.

GPIIb/IIIa


PRISM

NEJM 1998;338:1498

->Benefit c tirofiban in USA/NQWMI especially c TnI.

3232 pts c USA/NQWMI comparing tirofiban c heparin: @48h 3.8% vs 5.6% for death/MI/refractory angina. @ 30d 15.9 vs 17.1% nonsignificant. @30d death or MI 5.8 vs 7.1% p=0.11. Subgroup analysis showed greater benefit c elevated TnI.


PRISM-PLUS

NEJM 1998;338:1488

-> Tirofiban and UFH combo is beneficial in USA/NQWMI c or s PCI.

1915 pts c USA/NQWMI tirofiban, UFH, or combination for 48-108h. Tirofiban alone arm was dropped 2� excess mortality. Combo reduced death/MI/refractory angina @ 7d from 17.9 to 12.9% p=0.004. @30 d reduced by 22%. Death or MI by 43% @7d, 30% @ 30d, 22% @ 6m.

--In pts not undergoing PCI, significant benefit was only seen in HIGH risk pts


PURSUIT

NEJM 1998; 339:436

->Eptifibatide beneficial in USA/NSTEMI c or s PCI.

10948 pts c USA/NSQWMI c Eptifibatide in addition to standard tx. @ 30d death/MI 14.2% vs 15.7%. @ 96h 7.6 vs 9.1%.

?EPIC (JACC 1997; 30:149-56) 321 pts

->Abciximab bolus + infusion vs abciximab bolus c placements infusion vs placebo in high risk patients undergroinq PCI . Abciximab bolus and infusion reduced rate of MI' death, revascularization by 35% at 30d, 23% at 6m, 13% at 3years. Most of affect from reduction of repeat CABG/PCI . Higher rate of bleedinq.


TIMI 11B

Circ 1999;100:1602.

Compared enoxaparin (30mg IV then SC) c UFH. Study included outpt portion. Death or MI were 5.7 vs 6.9% at 14d and 7.9vs 8.9 % at 43d. Minor bleeding 9.1 vs 2.5%. Major bleeding 1.5 vs 1.0%.



Sources

  1. Lewis HD et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983 Aug 18;309(7):396-403
  2. Cairns J et al. Aspirin, Sulfinpyrazone, or Both in Unstable Angina — Results of a Canadian Multicenter Trial. N Engl J Med. 1985 Nov 28;313(22):1369-75
  3. Yusuf S, et al. "Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation". The New England Journal of Medicine. 2001. 345(7):494-502PDF
  4. Cohen M, et al. "A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease". The New England Journal of Medicine. 1997. 337(7):447-452 PDF
  5. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006 May 20;367(9523):1665-73PDF
  6. FRAX.I.S. Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAXiparine in Ischaemic Syndrome). Eur Heart J 1999;20:1553-1562
  7. Cohen M et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994 Jan;89(1):81-8 PDF
  8. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet. 1999 Feb 6;353(9151):429-38
  9. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial.J Am Coll Cardiol. 2009 Jul 28;54(5):468-76 PDF
  10. van Rees Vellinga T. et al. Efficacy and safety of fondaparinux in patients with ST-segment elevation myocardial infarction across the age spectrum. Results from the Organization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) trial.Am Heart J. 2010 Dec;160(6):1049-55PDF
  11. The CURRENT–OASIS 7 Investigator. Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes PDF
  12. Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group.Lancet. 1996 Mar 2;347(9001):561-8
  13. The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1915-1924PDF