EBQ:Major Cardiology Trials

Aspirin in MI

• 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

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

CURE

• 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

• 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

• 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

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

ATACS

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

• 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

• 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

• 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

• 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

• 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

• 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

Authors

Daniel Ostermayer