ACS TrialsɸapplACSt8CH00CH00CH00CH00CH01CH01vCH01$$CH01(CH0206CH025]CH02;CH02@CH02F CH02KCH03RWCH04V,CH04\8CH04aCH05gCH05lCH06q7CH06yCH06[CH06SCH063CH07CHEKCHSTCHST7CHSTYCHSTCHSTCHSTCHSTCHSTMBARMBARTalt:TaltTbmpcodecodecode;dataǿpreftAIBtAIN̔tFRM̠tFRMLtFRMtFRMtFRMxtSTRӢtSTRөtSTRtverאVA Cooperative Aspirin in Unstable Angina Study NEJM 1983; 309:396-403 1266 men with unstable angina randomized to aspirin vs placebo. INCLUSION Men with chest pain suggestive of unstable angina with evidence of CAD (by history, ECG, or previous angiogram/ETT) and absence of baseline myocardial infarction on admission by ECG or enzymes. EXCLUSION Class IV congestive heart failure Secondary cause of UA Contraindications to aspirin or anticoagulants Previous aspirin ingestion MI within 6 weeks CABG within 12 weeks METHODS Patients were recruited within 48 hrs of admission, and treatment begun within 51 hours of admission. Patients randomly assigned to 324 mg aspirin daily vs placebo for 12 weeks. FOLLOW-UP 12 weeks OUTCOMES Death or MI over 12 weeks RESULTS Death or MI was significantly lower in aspirin group (5.0% vs 10.1%, p=0.0005) Frequency of acute MI (3.5% vs 7.8%), nonfatal MI (3.4% vs 6.9%) significantly lower in aspirin group Freqency of death trended toward being lower in aspirin group (1.6% vs 3.3%, p=0.054) Benefit persisted to 1 year follow-up: mean mortality rate in significantly lower in aspirin group vs placebo group (5.5% vs 9.6%, p=0.008). CONCLUSION This study shows clear benefit of aspirin in unstable angina, persisting long after discontinuation of medication Canadian Multicenter Aspirin Trial NEJM 1985; 313:1369-75 555 patients with UA/NSTEMI randomized to high-dose aspirin, sulfinpyrazone, both, or neither. 20-25% with ECG changes, 45-50% with rest pain. INCLUSION: CCU patients with unstable angina with crescendo pattern or prolonged pain at rest. EXCLUSION Age > 70 Acute myocardial infarction upon presentation Infarction within 12 weeks Contraindications to study drugs Normal coronary angiogram during study METHODS Patients enrolled within 8 days after admission. Patients randomized to aspirin 325 mg four times a day, sulfinpyrazone 200 mg four times a day, both, or placebo. Patients were followed for up to 2 years, mean follow-up of 18 months. OUTCOMES Primary outcome was combined cardiac death/nonfatal MI RESULTS 61% underwent catheterization during study period. 19% of those who underwent catheterization had minimal disease and were removed from study. Overall, 28% were withdrawn from study, either by physician or by patient. By efficacy analysis, primary outcome of cardiac death/nonfatal MI was significantly reduced in groups given aspirin (8.6% vs 17%, p=0.008) for 50% risk reduction. Secondary outcome of cardiac death alone also significantly reduced in aspirin group by 70.6%, p=0.004. By intention-to-treat analysis (i.e. including those who were eventually withdrawn from study), risk reduction of primary outcome for aspirin was 30% (p=0.07), and risk reductions for cardiac death and death from any case were significantly reduced in groups initially assigned to aspirin (RR 56%, p=0.009 for cardiac death alone, RR 43%, p=0.035 for death from all causes) There was no significant benefit of sulfinpyrazone and no interaction with aspirin. CONCLUSIONS Aspirin was beneficial in UA/NSTEMI. High doses of aspirin (1300 mg qd) probably was esponsible for high rate of withdrawal from trial. Montreal Heart study. NEJM 1988;319:1105-1111. 479 pts with unstable angina randomized to receive aspirin, heparin or both INCLUSION: Accelerating pattern of chest pain for >/= 20 minutes, within 24 hours. CK < 2x normal ECG changes compatible with ischemia, or confirmatory diagnosis by at least 2 cardiologists. EXCLUSION: Chronic aspirin, Warfarin, or other anticoagulants or antiplatelet meds PCI within 6 mos Contraindications to asa or heparin CABG within 12 months or scheduled surgery Age > 75 Precipitating cause METHODS: Patients were randomized in a 2x2 factorial design to 650 mg aspirin, then 325 bid, heparin 5000 U + 1000 U/hr to target PTT 1.5-2.0 x normal, both or double-placebo for a mean of 6 days PRIMARY ENDPOINT: Death, MI or refractory angina Follow up: 3 months. RESULTS: Primary: Relative Risk (p value) vs placebo Ref Angina MI Death ASA 0.67(0.217) 0.29(0.012) -- Heparin 0.31(0.002) 0.06(<0.001) -- ASA + Heparin 0.40(0.011) 0.12(0.001) -- Number of fatal events too low to calculate differences Secondary: Bleeding increased two-fold (p=0.09) with heparin, and with aspirin-heparin combination. RISC trial (Research in Instability in Coronary Artery disease) Lancet 1990;336:827-830. 796 patients with UA/NSTEMI randomized to one of four arms: aspirin and heparin, aspirin and placebo heparin, placebo aspirin and heparin, or placebo INCLUSION: Men, less than 70 years of age. Symptoms suggestive of unstable CAD EXCLUSION: Acute QWMI Depressed EF from previous MI or non-ischemic heart disease Valvular heart disease CABG LBBB Concurrent anticoagulation or aspirin use Increased risk of bleeding Aspirin allergy METHODS: Universal oral metoporolol 100-200mg per day Patients were randomized to: Aspirin 75 mg + Heparin 10,000units q6h x 24hours, then 7500q6h x 4 days Aspirin 75 mg + placebo heparin Placebo + Heparin as above Placebo + placebo Aspirin was continued for up to one year Heparin was continued for 5 total days while in hospital FOLLOW-UP: Planned follow-up was 12 months. Trial was terminated prematurely after results of ISIS-2 PRIMARY ENDPOINT: MI or death at each time interval RESULTS: Primary: Aspirin and Heparin: 1.4% Aspirin and placebo: 3.7% Placebo and Heparin: 5.5% Placebo and placebo: 6.0% At 5 days: Aspirin decreased risk by 57% At 30 days: decreased risk by 69% At 3 months: decreased risk by 64% Heparin: No effect on event rate, though the group treated with combination of aspirin and heparin had the lowest event rate of all groups. TAKE HOME POINTS: 1. Aspirin decreased death or MI in patients with unstable coronary syndromes 2. Difference in event rate was evident as early as five days into randomization. 3. Side effects of low dose (75 mg) aspirin was very rare CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Events (NEJM 2001;345: 494-502) 12662 patients with unstable angina or non-ST elevation MI randomized to get ASA plus clopidogrel vs. ASA INCLUSION: 60yrs or older ACS within 24hrs EXCLUSION: contraindication to antithrombotic rx ST elevation high bleeding or CHF risk oral anticoagulation IIb/IIIa inhibitor within 3 days METHOD: Patients received either clopidogrel (Plavix) 300mg loading dose, then 75 mg po qd for up to one year, or placebo. PRIMARY ENDPOINTS: composite: vascular death, MI, or stroke. FOLLOW UP: 3-12 mos. Mean 9 mos. RESULTS: Primary composite endpoint to follow-up: 9.3% for clopidogrel vs. 11.4% for placebo, a 20% relative risk reduction, p<0.001. At 24 hours, there was a reduction in CV death, MI, stroke or refractory ischemia: 1.4% for clopidogrel vs. 2.1% for placebo, a 34% relative risk reduction p=0.002. Major bleeds: 3.7% vs. 2.7%, p=0.001 TAKE HOME POINTS: 1. Plavix decreases CV death, MI or stroke by 20% 2. Benefits present across all subgroups, including low- and high-risk patients. 3. Benefits occurred within few hours and persisted out to one year PCI-CURE: Percutaneous Coronary Intervention - Clopidogrel in Unstable Angina to Prevent Recurrent Events Lancet 2001; 358: 527-33. 2658 pts with UA/NSTEMI undergoing PCI, who had been randomized to receive clopidogrel versus placebo in addition to aspirin in the CURE trial. INCLUSION: 60 yrs or older ACS symptoms within 24 hours (EKG changes and/or positive enzymes) EXCLUSION: ST elevation > 1mm Contraindication to antiplatelet or antithrombotic High bleeding risk Oral anticoagulants METHODS: Randomized, placebo controlled, double blinded. Of the 12562 pts in CURE trial, 2658 (21%) had PCI Pts were pretreated with Plavix (or placebo) for a mean of 6 days prior to PCI, then followed for endpoints for duration of follow-up. Patients in both arms were given open-label thienopyridine for 30 days post PCI if stent was deployed, then returned to blinded study drug. ENDPOINTS: Primary: Composite of death, MI, Urgent revascularization within 30 days. RESULTS: Primary: Plavix 4.5%, Placebo 6.4%, p=0.03 Secondary: CV Death or MI from PCI to 30 days was 2.9% vs. 4.4%, p=0.047, CV death or MI from randomization to follow-up, 8.8% vs. 12.6%, OR=0.69, p=0.002 TAKE-HOME POINTS: 1. Plavix significantly decreased event rates in patients with ACS undergoing PCI when pretreated for a mean of 6 days. 2. Event rate curves separate early post PCI and continue to separate through follow up. 3. Major bleeding rate similar between the groups. CAPRIE: Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events Lancet 1996; 348: 1329-1339 19185 patients with atherosclerotic vascular disease (stroke, MI, PVD) randomized to clopidogrel vs ASA. INCLUSION History of vascular disease Ischemic stroke < 6 months Myocardial infarction < 35 days Symptomatic peripheral artery disease EXCLUSION Age < 21 Cerebral deficit leading to pt being bedridden/demented CEA after stroke Uncontrolled HTN Contraindication to study drug (renal/hepatic insufficiency, bleeding diathesis, thrombocytopenia) Planned long term oral anticoagulant Thrombolytic within 48 hrs METHODS Randomized to ASA 325 mg qd or clopidogrel 75 mg qd Treated for 1- 3 years (mean duration of follow-up was 1.9 years) ENDPOINTS Primary endpoint was vascular death, MI or ischemic stroke. RESULTS Primary endpoint significantly lower in clopidogrel group vs ASA group (5.32% vs 5.83%, p=0.043), for RRR = 8.7%. MI reduced by 19.2%, vascular death by 7.6%. Significantly fewer side effects in clopidogrel group (GI hemorrhage was 2.0% vs. 2.7% for aspirin, p<0.05). CONCLUSION Significant benefit to clopidogrel over aspirin with less GI bleeding . CLASSICS: Clopidogrel Aspirin Stent International Cooperative Study Circulation 2000;102:624-629. 1020 patients undergoing stenting randomized to receive clopidogrel with or without a loading doses versus Ticlopidine INCLUSION: Planned or unplanned stenting Single vessel disease, lumen > 2.8mm <10% residual stenosis No angiographic evidence of thrombus or dissection within treated vessel TIMI 3 flow in treated vessel CPK< 2x ULN EXCLUSION: Vein Grafts Primary angioplasty for ST elevation MI Use of oral anticoagulants IIb/IIIa inhibitor use for procedure Thrombolytic therapy Allergy or intolerance to study meds METHODS: Patients were randomized to one of three groups: 1) Ticlopidine 250 mg po bid x 28 days; 2) Clopidogrel 300 mg for day one, then 75 mg po qd x 27 days (Load). 3) Clopidogrel 75 mg po qd x 28 days (No load). FOLLOW-UP: Patients were followed for 28 days. PRIMARY ENDPOINT: Major peripheral or bleeding complications (false aneurysms, need for surgical repair of puncture site, blood transfusions (>/= 2 units), intracranial hemorrhage, retroperitoneal hemorrhage, overt bleeding with loss of 3g/dl of Hgb. Neutropenia, defined as neutrophil count < 1.5 x 109/L. Thrombocytopenia defined as platelet count < 100 x 109/L. Early discontinuation of study drug due to non-cardiac adverse event (including non-cardiac death). RESULTS: Primary Composite: Clopidogrel with loading dose 2.9% vs. Clopidogrel without loading dose 6.3% vs. Ticlopidine 9.1%. Clopidogrel combined = 4.6%, which is a 50% relative risk reduction from 9.1% with ticlopidine, p=0.005) Major cardiac event rates were similar between the groups. TAKE-HOME POINTS: There were fewer study drug side-effects and discontinuations with clopidogrel than ticlopidine, which translates into more patients completing a course of important anti-platelet therapy. Efficacy appeared similar between the two agents PRISM (Platelet Receptor Inhibition For Ischemic Syndrome Management) (NEJM 1998;338:1498-505) 3232 patients with UA/NSTEMI randomized to tirofiban or heparin for 48 hrs in addition to aspirin 70% ECG changes, 24% with NSTEMI INCLUSION: Ischemic chest pain within 24 hrs with either ECG changes, elevated enzymes, h/o CAD) EXCLUSION: Bleeding or platelet disorder, thrombocytopenia Cr > 2.5 History of GI bleeding H/o CVA or TIA within past year Major surgical procedure in past month Active peptic ulceration in past 3 months METHODS: ASA for all Randomized in double-blind fashion to tirofiban 0.6 mcg/kg/min for 30 min, then 0.15 mcg/kg/min x 48hrs vs. heparin 5000 u bolus plus 1000u/hr x 48 hrs, Angiography and revascularization discouraged in first 48 hrs. PRIMARY ENDPOINTS: Composite of death, MI, refractory ischemia @ 48hrs FOLLOW UP: 30 days RESULTS: Composite endpoint @ 48hrs 3.8% vs 5.6% (p=0.01) Refractory ischemia @ 48hrs 3.5% vs 5.3% (p=0.01) Composite endpoint @ 30 days 15.9 vs 17.1 (p=0.34) Death @ 30 days 2.3% vs 3.6% (p=0.02) No significant difference in bleeding SUMMARY Tirofiban plus ASA better than heparin plus ASA at 48hrs without early invasive strategy in patients with USA/NQWMI. Benefit for those with medical management as well as those with revascularization. PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) NEJM.1998;338:1488-97 1915 patients with UA/NSTEMI on ASA randomized to tirofiban, heparin, or both More than 90% with ECG changes, 45% with NQWMI 90% with angiography during hospitalization, 30% PCI, 23.3% CABG INCLUSION: Anginal chest pain in past 12 hrs and: 1. ECG changes 2. Elevated enzymes EXCLUSION Active or high risk of bleeding Platelet d/o, thrombocytopenia (<150,000) Stroke within1 yr. PCI within 6 mo. CABG within 1mo. Angina for identifiable reason Cr > 2.5 METHODS: ASA for all. Randomized in double-blind fashion to one of 3 arms 1. Tirofiban alone*: 0.6mcg/kg/min x 30min, then 0.15mcg/kg/min 2. Tirofiban 0.4mcg/kg/min x 30min, then 0.1 mcg/kg/min plus IV heparin 3. IV heparin alone Infusion for minimum 48 hrs (mean 71 hours) Interventions were postponed until after this period unless refractory angina, new MI. Tirofiban continued 12-24hrs after procedure *Tirofiban alone group stopped early due to excess mortality at 7 days PRIMARY ENDPOINT Death, MI, or refractory ischemia at 7 days. RESULTS: Composite endpoint @ 7 days 17.9% vs 12.9% (p=0.004) MI @ 7 days 7% vs 3.9% (p=0.006) RI @ 7 days 12.7% vs 9.3% (p=0.02) All subgroups benefited Benefit occurred early (within 48 hours) and persisted Composite endpoint @ 30 days 22.3% vs 18.5% (p=0.03) Composite endpoint @ 6 mo 32.1% vs 27.7% (p=0.02) SUMMARY: Early and persistent benefit to tirofiban plus heparin vs heparin alone Benefit was seen in patients treated with PTCA, CABG or medical therapy PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) (NEJM 1998;339:436-443) 10, 948 patients with UA/NSTEMI randomized to eptifibatide vs. placebo, in addition to standard heparin & ASA 45% with NSTEMI. 90% with ECG changes 59-60% underwent cath, 24% PCI, 13% CABG INCLUSION CP within 24 hours with ECG changes or CK-MB elevation EXCLUSION Persistent ST-elevation Active bleeding or h/o bleeding diathesis GI or GU bleeding within 30 days Ischemic stroke within 30 days Any history of hemorrhagic stroke Renal failure METHODS All patients received aspirin, and heparin was recommended (5000u then 1000u/hr) Randomized to eptifibatide bolus 180 mcg/kg, then 2.0 mcg/kg/min x 72 hours or placebo PRIMARY ENDPOINTS Death or Nonfatal MI @ 30 days RESULTS Death or Nonfatal MI @ 30 days 14.2% vs 15.7% (p=0.04) Death or Nonfatal MI @ 96 hrs 7.6% vs 9.1% (p=0.01) Benefits achieved by 4 days, and maintained at 30 days. For those who underwent PTCA within 72 hrs, 31% reduction in composite endpoint @ 30 days. Nonsignificant benefit for those who did not. Increased bleeding in eptifibatide group SUMMARY Significant reduction in death or MI with the IIb/IIIa inhibition seen at 30 days, with suggestion of greater benefit in those who underwent PTCA GUSTO IV-ACS (Global Use of Strategies to Open Occluded Coronary Arteries) (Lancet.357:1915-24) 7800 pts with UA/NSTEMI randomized to abciximab x 24h, or abciximab x 48h or placebo INCLUSION: Chest pain > 5mins within last 24 hours > 0.5mm ST segment depression OR + TnT/TnI EXCLUSION: ischemia from other causes ST elevation or new LBBB PCI < 14d planned PCI/CABG in 30 d active bleeding or bleeding disorder recent trauma or surgery GI/GU bleeding <6 weeks intracranial neoplasm/aneurysm stroke < 2y or with residual defect oral anticoagulation Plts <100k PRIMARY ENDPOINT death or MI at 30 days FOLLOW-UP: 30 days RESULTS: Primary: Placebo: 8.0%, Abciximab x 24h 8.2%, Abciximab x 48h: 9.1% (P=NS) No difference with (+) troponin, and no benefits seen across any subgroups. Death rate higher in first 48 hours with either 24 hour or 48 hour infusions 0.3% vs. 0.7% vs. 0.9% (OR 2.3 p=0.048, and 2.9 p=0.007 respectively for 24 and 48 hours versus placebo). TAKE HOME POINTS: Abciximab for ACS did not confer an advantage for patients not undergoing PCI and is therefore contraindicated Trial included a low risk group given entry criteria of pain for only 5 minutes, but even Troponin (+) patients did not demonstrate an advantage. Mortality was actually higher for patients receiving Abciximab therapy in first 48 hours. CAPTURE (c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina) Lancet 1997;349:1429-1435 1265 patients with refractory unstable angina randomized to abciximab or placebo before PTCA. INCLUSION Refractory UA defined as chest pain at rest with ECG changes within 48h despite therapy with heparin/nitrates. All had undergone angiography and had culprit lesion suitable for PTCA. EXCLUSION Recent MI Features mandating immediate intervention LM or bypass graft disease Bleeding risk factors, such as recent surgery GI / GU bleeding in past 6 weeks Stroke within 2 years Thrombolytics Bleeding disorder, thrombocytopenia METHODS Pts were enrolled within 24 hrs of angiography after which PTCA was planned after 18-24 hours of abciximab vs placebo. All received aspirin, IV nitrates, IV heparin. Patients randomly assigned to abciximab (0.25mg/kg bolus and 10mcg/min infusion) or placebo for 24 hours pre- and up to 1 hr post-PTCA. ENDPOINTS Primary endpoint was death/MI/urgent revascularization at 30 days RESULTS Trial discontinued after 3rd interim analysis, after 1266 patients enrolled. Primary endpoint @ 30 days was significantly lower in abciximab group vs placebo (11.3% vs 15.9%, p=0.012). Difference mainly due to difference in MI. No difference in death/MI/revasc at 6 months (30.8% for placebo, 31% for abciximab) Major bleeding more common in abciximab group vs placebo (3.8% vs 1.9%, p=0.043) CONCLUSION 29% lower rate of primary endpoint @ 30 days, with 50% reduction in MI. IIb/IIIa Meta-Analysis Lancet 2002;359189-198. Meta-analysis of 6 large randomized trials (patient n=31,402) of UA/NSTEMI with various IIb/IIIa inhibitors versus placebo or control INCLUSION: Trials with > 1000 patients of ACS reported since 1990 Randomization of patients with ACS to IIb/IIIa or placebo or control Trials were: PRISM, PRISM-PLUS, PARAGON-A, PARAGON-B, PURSUIT, GUSTO IV-ACS EXCLUSION: No other specific exclusions. METHODS: Trials generally involved standard therapy with aspirin and heparin, and added IIb/IIa inhibitors or placebo, administered as bolus and infusion, for 2-5 days. Meta-analysis of all endpoints using initial trial definitions PRIMARY ENDPOINT: Death or MI at 30 days. RESULTS: Primary: IIb/IIIa 10.8% vs. placebo 11.8% OR 0.91, p=0.015. At 5 days: 5.7% vs. 6.9% OR 0.84, p=0.0003 Benefits were seen across important subgroups such as age, diabetics, and prior cardiac history. Greater benefit in troponin + patients. No benefit is apparent when patients do not have a positive troponin. IIb/IIIa inhibitors increased bleeding events with an odds ratio of 1.62 No increased rate of intracranial hemorrhage or stroke. TAKE-HOME POINTS: IIb/IIIa inhibitors decreased rate of death or MI by a relative 9% (absolute 1%) compared with control. This effect was seen at 5 days, and persisted (though did not increase) by 30 days. Dosing regimens varied in these trials, and a class-effect across clinical situations cannot be interpreted. Final comment by authors suggests that high-risk patients receive upfront IIb/IIIa inhibitors until a decision about revascularization has been made. Heparin Meta-Analysis JAMA 1996; 276: 811-815 Heparin in Unstable Angina, meta analysis INCLUSION CRITERIA: Pts had either Unstable angina or NQWMI Pts were either given heparin and aspirin or aspirin alone EXCLUSION CRITERIA: Standard bleeding risks. METHODS: Medline search, Jan/66 to Sep/95 Heparin was given to target PTT 1.5-2 x normal, for duration 2-7 days Aspirin in doses 75-325mg daily, indefinitely Data was extracted via linear regression analyses, with RRs and CIs, PRIMARY ENDPOINT: MI or death between 2-12 weeks across the studies RESULTS: Primary Endpoint: asa + heparin : 7.9% vs. asa alone 10.4 % RR 0.67, p=0.06 Rec Ischemic Pain 17.3% vs. 22.6% RR 0.68, p=0.08 Bleeding: 1.5% vs. 0.4% RR 1.89, p=0.68 CONCLUSIONS: 1. Heparin created an overall trend towards decreasing death or MI in a meta-analysis of 6 small trials, however it did so without true statistical significance. 2. Heparin also created trends towards increased rates of major bleed FRISC (Fragmin Research in Instability in Coronary Artery Disease) Lancet 1996347:561-568. 1506 patients with UA/NSTEMI randomized to receive subcutaneous dalteparin or placebo in addition to aspirin. INCLUSION: Men age > 40 years Women > 1 year past menopause Chest pain within last 72 hours (newly developed or increased or rest during the previous 2 months) EXCLUSION: Increased risk of bleeding: Creatinine > 200umol/L New LBBB or Pacemaker Primary myocardial disease Aortic valve disease PTCA or CABG within 3 months METHODS: aspirin 300mg x1, then 75 per day Acute Phase (5-8 days): Patients were randomized to receive dalteparin 150U/kg q12, but the dose was changed to 120 IU/kg q12 after initial high bleeding rate vs. placebo. During the Outpatient Phase (35-45 days): Patients received dalteparin 7500IU q12h vs. placebo as per original randomization assignment FOLLOW-UP: In-house x 5 days 40-50 days PRIMARY ENDPOINT: Death, MI at 6 days RESULTS: Primary endpoint at 6 days: Dalteparin: 1.8% vs. Placebo: 4.8% RR 0.37 CI 0.20-0.68 p<0.001 At 40 days, the benefit was persistent with dalteparin, but was limited to non-smokers. At 150 days, the benefit was reduced to a trend. Compliance was equal and good for both groups. No difference was seen in major bleeding. There was an increase in minor bleeding. TAKE-HOME POINTS: 1. Dalteparin decreased the rate of death or MI at 6 days, a benefit maintained at 40 days, but lost at 150 days. 2. There was a rebound effect noted at the time of dose reduction to once daily. ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave Coronary Events) N Engl J Med. 1997;337:447-52. 3171 pts with UA/NSTEMI randomized to receive subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in addition to standard therapy. INCLUSION: Ischemic pain > 10 minutes, within 24 hours ECG changes, Previous MI, or Positive non-invasive test. EXCLUSION: LBBB or pacemaker Treatable precipitant cause of UA Contraindication to anticoagulation Creatinine clearance < 30ml/min METHODS: All patients received aspirin 100-325 mg Patients were randomized to enoxaparin 1mg/kg subcutaneous q12 hours for 48hours to 8 days (+ placebo infusion) or IV UFH to target PTT 55-85 (+ placebo subcutaneous injection) FOLLOW-UP 30 days. PRIMARY ENDPOINT: Combined triple endpoint of death, MI, recurrent angina RESULTS: Primary: Enoxaparin: 16.6% vs. UFH 19.8% OR 0.80, p=0.019. At 30 days: 19.8% vs. 23.3% OR 0.81, p=0.02 TAKE-HOME POINTS: Enoxaparin given 1mg/kg by subcutaneous injection decreased cardiac events for patients with ACS. TIMI 11b trial gave initial intravenous dose, and included higher risk patients, but benefit was still seen in ESSENCE. ESSENCE trial is in contrast to FRIC trial (asa + dalteparin vs asa alone in ACS), but enoxaparin has a better Xa:IIa activity level ratio than dalteparin. Similar relative risk reduction in each endpoint. TIMI 11B (Thrombolysis in Myocardial Infarction 11B) Circulation 1999;100:1593-1601 3910 patients with UA/NSTEMI randomized to receive unfractionated heparin versus the low-molecular weight heparin enoxaparin in addition to aspirin INCLUSION: Ischemic discomfort at rest lasting at least 5 minutes within 24 hours ST segment deviation, or elevated cardiac markers Or, For initial part of trial, Hx of CAD EXCLUSION: Planned revascularization within 24 hours Treatable cause of angina History of CABG within 2 months or PTCA within 6 months History of heparin-associated thrombocytopenia Contraindications to anticoagulation METHODS: Aspirin 100-325 mg po qd Randomized in double-blind fashion to Enoxaparin 30mg iv bolus dose, followed by 1mg/kg sq q12 hours or Unfractionated heparin 70u/kg bolus followed by 15u/kg infusion to target PTT 1.5-2.5 x normal, for 3-8 days. After acute phase of hospital stay, pts were continued on either treatment enoxaparin, or placebo for a total of 43 days. PRIMARY ENDPOINTS: Death, MI, or urgent revascularization at 8 days and 43 days FOLLOW-UP: 43 days RESULTS (Enoxaparin vs. UFH): Primary: 8 days: 12.4% vs 14.5%, OR 0.83, p=0.048. 43 days: 17.3% vs. 19.7%, OR 0.85, p=0.048 Major Bleed: 1.5% vs. 1.0%, p=NS TAKE HOME POINTS: 1. Enoxaparin is superior to unfractionated heparin in preventing events in pts with ACS. 2. Benefit was seen across all groups, but greatest benefit in higher risk patients 3. Advantage to enoxaparin was seen within 8 hours of randomization. OASIS-2 (Organisation to Assess Strategies for Ischemic Syndromes) Lancet 1999;353:429-438. 10,141 patients with UA/NSTEMI randomized to receive lepirudin or heparin in addition to standard aspirin therapy. INCLUSION: Ischemic chest pain within 12 hours (new, worsening or with minimum exertion) ECG evidence of ischemia or previous objective evidence of CAD Abnormal ECG required in all pts < 60 yrs old EXCLUSION: Hx of stroke in last year Creatinine > 2.0 Chronic anticoagulation PTCA within 6 months METHODS: Standard aspirin 80-325 mg daily Randomized to heparin 5000 bolus + 15U/kg infusion + placebo Or Hirudin 0.4mg/kg bolus + 0.15mg/kg infusion + placebo Target PTT 60-100s PRIMARY ENDPOINT: cardiovascular death or new MI at 7 days. FOLLOW-UP: Patients were kept in hospital for 7 days, and monitored for 35. RESULTS: Primary endpoint at 7 days: lepirudin 3.6% vs. heparin 4.2% RR 0.84, p=0.08. At 72 hours: 2.0% vs. 2.6%, RR 0.76 p=0.039 At 35 days: 6.8% vs. 7.7% RR 0.68 p=0.06 Major Bleeding: 1.2% vs. 0.7% RR 1.73 p=0.01 No differences in hemorrhagic strokes. TAKE-HOME POINTS: 1. Lepirudin (hirudin) tended to decrease death and MI when combined with aspirin for patients with ACS, but not statistically significant. GUSTO IIb (The Global Use of Strategies to Open Occluded Coronary Arteries) NEJM 1996;335:775-782 12142 patients with ACS randomized to 72 hours of hirudin vs heparin 1/3 with ST elevation INCLUSION Chest discomfort within 12 hrs with ECG changes (ST elevation, depression, T wave inversion) EXCLUSION Active bleeding H/o Stroke Contraindication to heparin, hirudin Cr > 2.0 METHODS All on ASA, beta-blocker, etc Patients with ST elevation were eligible for thrombolytic (tPA or streptokinase) Randomized to recombinant hirudin, desirudin (0.1mg/kg bolus then 0.1mg/kg/hr) or heparin (5000u bolus then 1000u/hr). APTT adjusted to 60-85s. ENDPOINT Primary endpoint was death/MI at 30 days. RESULTS Primary endpoint not significantly different between hirudin vs heparin (8.9% vs 9.8%, p=0.058). No significance achieved in STE or NSTE groups. Composite death/MI @ 24 hours significantly lower in hirudin group (1.3% vs 2.1%, p=0.001) Significantly higher rates of moderate bleeding & transfuion in hiruden vs heparin. CONSLUSION Marginal benefit at 30 days from hirudin at cost of more bleeding. Only benefit was early (24 & 48 hrs) and that dissipated over time. TIMI IIIb Circulation 1994;89:1545-1556 1473 patients with UA/NSTEMI randomized by 2 x 2 design to 1) TPA vs placebo, and 2) early invasive vs early conservative strategies. 74% with ECG changes, 32% with NQWMI INCLUSION CP at rest c/w ischemic pain, between 5 min to 6 hrs, within 24 hrs of presentation Also, must have objective evidence of ischemic heart dz 1. New ECG changes in 2 adjacent leads 2. Documented CAD (by previous angiogram, nuclear study) EXCLUSION Treatable/reversible cause of angina MI within previous 21 days Cath within 30 days PTCA within 6 months Prior CABG Pulmonary edema at enrollment SBP >180 or DBP>100 Contraindication to thrombolytic / heparin LBBB Coexisting severe illness Woman of child-bearing potential Oral anticoagulants METHODS All received conventional medical therapy (ASA, heparin, metoprolol, diltiazem, nitrates) 1. One part of study was TPA (0.8 mg/kg of tPA, max 80mg) or placebo. 2. Other part was Early invasive strategy (cath/angiogram within 48 hrs and PTCA/CABG, if feasible) or early conservative strategy (medical therapy, with cath only if medical therapy failed, which was defined as ischemic discomfort with ECG changes or unsatisfactory result on predischarge ETT thallium before stage II of modified Bruce protocol) 98% of early invasive underwent cath, 64% of conservative strategy underwent cath. PRIMARY ENDPOINT For tPA/placebo comparison, primary endpoint was death/MI/failure of initial therapy at 6 weeks. For invasive/conservative comparison, primary endpoint was death/MI/unsatisfactory ETT at 6 week visit. RESULTS For tPA vs placebo, no difference in primary endpoint at 6 weeks. Early invasive vs early conservative Primary endpoint 16.2% in invasive, 18.1% in conservative (not significant). This difference remained nonsignificant at 1 year of followup. Secondary endpoints (LOS, rate of rehospitalization,# of antianginal meds) significantly lower in invasive strategy CONCLUSIONS No benefit to thrombolytic therapy for UA/NSTEMI No difference in mortality/morbidity in invasive vs conservative strategy, and either may be carried out safely, but invasive strategy results in shorter hospital stay and fewer rehospitalizations. VANQWISH (Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital) NEJM 1998;338:1785-92 920 patients with NQWMI randomized to invasive or conservative management. 75-80% had LM or multivessel disease INCLUSION CK-MB 1.5x above upper limits of normal, no Q waves on ECG. EXCLUSION Serious coexisting conditions High risk ischemic complications (persistent ischemia despite intensive medical therapy or severe heart failure despite medical therapy) METHODS All received ASA, diltiazem, plus other meds as needed. Mean followup of 23 months. 1) Early invasive routing coronary angiography soon after randomization and underwent PTCA or CABG at discretion of investigator 2) Early conservative angiography reserved only for patients with postinfarction angina with ECG changes or > 2 mm ST-segment depression or positive thallium ETT 96% underwent cath in invasive strategy, 48% in conservative strategy 44% vs 33% underwent revascularization PRIMARY ENDPOINT Death or MI to follow-up RESULTS Death/MI tended to be higher, but not significantly through follow-up. However, mortality was significantly higher in invasive strategy at discharge, 1 month, and 1 year. Peri-CABG mortality was high in the invasive group over 12% CONCLUSIONS Invasive strategy was not beneficial in this study. Potential reasons are the low rate of revascularization achieved in the invasive group. MATE (Medicine versus Angiography in Thrombolytic Exclusion) JACC 1998;32596-605. 201 patients with ACS randomized to routine angiography vs. conservative management INCLUSION: Acute chest pain syndrome within 24 hours Ineligible for thrombolysis because of symptoms lasting longer than 6 hours, or lack of diagnostic ECG changes EXCLUSION: Symptoms lasting longer than 6 hours Increased bleeding or stroke risk Absolute contraindication to cardiac catheterization METHODS: Aspirin 325mg, IV Heparin, metoprolol Randomization to conservative arm for monitoring or transfer to the catheterization laboratory as soon as possible from the emergency department, and definitely within 24 hours, and interventional therapy as indicated. FOLLOW-UP: Index hospitalization, then for 12-52 months, mean 21 PRIMARY ENDPOINT: Death, MI or Recurrent ischemia RESULTS: Primary: Triage angiography 13% vs. Conservative 34% RR 0.55, p= 0.0002. No differences in death or MI, mean length of stay, rate of late revascularization, recurrent MI, mortality, azotemia, stroke, vascular complications. Small increase in transfusion rate in the triage angiography group TAKE-HOME POINTS: No difference in death or MI from early invasive approach, but lower rate of recurrent ischemia FRISC II (FRagmin and Fast Revascularisation during InStability in Coronary artery disease ) Lancet 1999;354:708-715 2457 patients with UA/NSTEMI randomized to early invasive strategy or non-invasive strategy and short vs. long-term dalteparin (LMWH). INCLUSION Symptoms of ischemia at rest or increasing pattern within 48h with evidence of ischemia by ECG or enzymes. EXCLUSION Elevated risk of bleeding PTCA within 6 months Awaiting coronary revascularization Other severe or acute cardiac, renal, hepatic disease Age > 75 METHODS 2 x 2 factorial design for and invasive vs conservative, dalteparin vs placebo post discharge x 3 months, All started on ASA, beta-blocker, and dalteparin 120 IU/kg sq bid (max 10000) subcutaneously twice daily for 5 days or until procedure. Then, pts randomized to dalteparin or placebo x 3 months, and to invasive vs. conservative strategy. Invasive group underwent angiogram within 7 days of randomization with revascularization as needed (98% underwent cath) Non-invasive group rx with medical therapy, and underwent cath in pt with refractory ischemia or severe ischemia on pre-discharge ETT. (10% underwent cath in-hospital) ENDPOINTS Primary endpoint was death/MI at 6 months. RESULTS Significantly less death/MI in invasive group (9.4%) vs non-invasive (12.1%) at 6 mo. Significantly lower CCS angina score/antianginal meds for invasive group than noninvasive. Significantly lower readmission rate for invasive group than noninvasive. Morality was significantly reduced at 1 year.( Lancet. 2000;356:9-16.) No significant difference for long-term dalteparin vs placebo at 6 months. CONLUSIONS Invasive strategy was beneficial compared with a conservative strategy. Differences between this and other studies may involve aggressive antithrombotic regimen with LMWH, availability of stents, and low mortality rate for revascularization, especially CABG. Conservative strategy was very conservative, which probably contributed to difference between the groups. TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with Invasive or Conservative Strategy TIMI 18) NEJM 2001;344:1879-87 Early conservative vs. early invasive management of ACS 2220 patients with UA/NSTEMI treated with aspirin, heparin, and tirofiban, randomized to early invasive or early conservative strategy INCLUSION: Unstable angina for >20mins within 24 hrs, at rest or with minimal exertion and accelerating pattern Either ECG changes, positive cardiac markers or history of CAD EXCLUSION: Elev bleeding risk LBBB or Paced rhythm Secondary angina PTCA < 6mos CABG < 6 mos Cardiogenic Shock METHODS: All patients received aspirin 325 mg daily, IV heparin and tirofiban 0.4mcg/kg/min x 30 min followed by 0.1 mcg/kg/min Randomized to invasive: cath routinely within 4-48 hours or conservative: only to cath if med failure (recurrent angina with ECG changes or requiring rehospitalization, positive stress test) PRIMARY ENDPOINT: Death, MI, or rehospitalization for ACS at 6 months RESULTS: Primary endpoint: Inv: 15.9% vs. Cons: 19.4%, OR=0.78, p=0.025 Greater benefit if + troponin, ST changes or TIMI risk score > 3 TAKE-HOME POINTS: 1. Early invasive strategy better, especially for pts with +troponin, ST changes or TIMI risk score > 3 2. Use of IIb/IIIa inhibitor eliminated early hazard or invasive strategy seen in 4 prior trials, thus Upstream IIb/IIIa inhibition was integral part of strategy MIRACL Trial (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) JAMA 2001;285:1711-1718. 3086 conservatively-managed patients with UA/NSTEMI randomized to receive Atorvastatin 80mg daily or placebo INCLUSION: Chest pain for greater than 15 minutes at rest or with minimal exertion within 24 hours preceding admission, and a change from a previous pattern of angina. New or dynamic S-T or T-wave changes, or new wall motion abnormality, or positive non-invasive test Troponin or CKMB < 2 x ULN for Unstable angina, or > 2 x ULN for NQWMI. EXCLUSION: serum cholesterol > 270 QWMI < 4 weeks ago CABG < 3 months ago PCI < 6 months ago LBBB or Paced rhythm Lipid lowering drugs other than niacin at doses < 500mg daily Vitamin E unless at doses of < 400IU daily Liver dysfunction (ALT > 2x ULN) IDDM METHODS: Randomization of patients with ACS within 24-96 hours of presentation to high dose Atorvastatin (80mg) or matching placebo, in addition to standard therapy. FOLLOW-UP: 4 months PRIMARY ENDPOINT: Combined endpoint of death, MI, cardiac arrest with resuscitation, or recurrent symptomatic ischemia with objective evidence requiring emergency hospitalization RESULTS: Primary: Atorvastatin: 14.8% vs. Placebo: 17.4%, p=0.048 Recurrent ischemic events with objective evidence were decreased with Atorvastatin, RR 0.74, p=0.02, but no difference in death, MI, or cardiac arrest. Stroke was decreased in the atorvastatin group (RR 0.41, p=0.02). TAKE-HOME POINTS: 1. Atorvastatin decreased the rate of the quadruple endpoint by 16%. 2. No difference in death or MI 3. Lipid levels were decreased by ~40% with atorvastatin, but findings were not coupled to degree of lipid-lowering. 4. Very few side effects: 3% developed increase in LFTS 3x > normal, no cases of rhabdomyolysis were observed. 5. This study provides rationale for initiating high-dose atorvastatin therapy at onset of ACS, rather than waiting for the post-event period. AspirinClopidogrelIIb/IIIa inhibitorsHeparinLMWHDirect thrombin inhibitorsInvasive vs ConservativeStatinsVA MulticenterCanadian MulticenterMontreal HeartRISCCURE PCI-CURECAPRIE CLASSICSPRISM PRISM-PLUS PURSUIT GUSTO IV-ACS CAPTURE Meta-analysisMeta-analysisFRISCESSENCETIMI 11BOASIS II GUSTO IIb TIMI IIIBVANQWISH MATEFRISC IITACTICS-TIMI 18MIRACLY/ RBDZAfOptionsDisclaimerAboutY/ d5M3 tDA'C'SOptionsDisclaimerAboutEditCopySelect AllUnsupported DeviceThis program requires PalmOS 2.0 or greaterOKOut of MemoryThere is not enough memory to load this trialOK((@??x>|<<xxp pP!NP@P@@@@G@G@Oq!xx8<<>|x?(( hP / @//@@ //? jC@ZA+@(@:4@rppp ?p44@8([W@ ?/ /@@// @ ((7s nR% q` oP`o  o90 ?pUVP P `lP`__ __U_/_/ PP_` _U un`i?p o oP`o ` qnR% 7s(((222222222222ؾھ۾ܾھھھ۾ؾ222222222222(( ?<NVHHnHnHnNOO J@g<NO4p`b n<*(8(6Cga?/?aPJCgaf?/?aP.PJCga?/?a/././.NO LN^NuNVH80.B@gnHnBg/OJ@gA/?<A/NOO BHnBB<NO>OJ@gAj/?<Au/NOO R ( -@re6 .g p-@`$gr`g p-@`r-A R .న c2BHnBB<NO>OJ@gA/?<A/NOO Hn?ONONO g ?</aJ$nN^NuNV/v֎Hx/NO/NOO Jf,Hn/BNOO Jf//-aPJf/NOX nf&.N^NuNVJnfaJ@g `aa6` <`pN^NuNV/ / &nE g0/aXJg$ Sg/ /a4@` g ?</a(B@$n&nN^NuNV/ / &nE g0/aXJg$ Sg/ /a @` g ?</aB@$n&nN^NuNV/ / &nE g0/aXJg$ Sg/ /af@` g ?</a NB@$n&nN^NuNV nBN^NuNV/ / &n$Sg $j/a~Xf0. g/ af$n&nN^NuNVH0&n6. (. S`$H jgPfg!D`$Hx a40!DBf&`%HL N^NuNV n0. ". P` hgPf/(/NON^NuNVH0&nBg/~.NOs&'C?<L/NO?/NOO 'H&+?<M/NO?/NOO 'H</+NO/+NO7@BCO |܎Cc(<Bg?/+NOB'?/+NOORCke<Bg/+NOA/Bg/+NOBg/&.$nN^NuChecklistEntryForm already instantiatedNV/ EJgA/?<*A/NOO Hxa/a$$nN^NuNVpN^NuNV/ $nHnHnHn/*NOO0.2.4A@e4.SA??Bg?./*NO$nN^Nu NVH0&n$n B0Y@ @bA Ѐ00N||||\|||||||||||j||>|||||||||>NOs&'C?</NO?/NOO 'H&+?</NO?/NOO 'HBg/NV .g/NON^NuNV .fp/NON^NuNVH8:.(. 6.EƕG0I4ʹc [?/?NPbL8N^NuNVH8:.(. 6.GxI4E8˹d b?/?NPeL8N^NuNVH8G6E8I8˹c ZNbLN^NuNVH8GI8E8˹d bNeLN^NuNVH8EA$vI`/NO!$XRC?/>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>3>>>>>>>>>>>>>3qq>>>>>>>>>>>>>>>q3>>>>>>>>>>>>>>>q3>>>>>>>>>>>>>>>3qE3q>>>>>>>>>>>>>>>>>Eq3>>>>>>>>>>>>>>>q33>>>>>>>>>>>>>>3qq>>>>>>>>>>>>>>>>>Eq3>>>>>>>>>>>>>q3>>>>>>>>>>>>>>>>3qE>>>>3q>>>>>>>>>>>3>>>>>EE>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>ACS Trials n ACS Trials in Your Palm'Kanwar P. Singh, M.D.' Ashvin N. Pande, M.D.' ,Christopher P. Cannon, M.D.A@        AsL b 1234567890123456789012345678901234567890L}@           }MO N  b 1234567890123456789012345678901234567890}}  2 b About Cardiac Checklistpp' Version 1.0.0. March 11, 2002' * Dismiss2x \t Disclaimerx}}y' * DismissTrialsThis program was developed and edited by Christopher P. Cannon, M.D., Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School. The summaries were written by Kanwar P. Singh, M.D. and Ashvin N. Pande, M.D., and edited by Dr. Cannon. The software was developed by PDA Verticals Corporation. This program was supported by an unrestricted educational grant from Bristol-Myers Squibb. Program copyright 2002, Kanwar P. Singh, M.D., Ashvin N. Pande, M.D., and Christopher P. Cannon, M.D. Software copyright 2002, PDA Verticals Corporation. All rights reserved.This program was developed as a clinical aid to provide physicians with trial data to assisting for treating patients with unstable angina and non-ST elevation myocardial infarction. However, in all cases, clinical judgment should be used when utilizing the information found in this program. Please refer to prescribing information listed for a complete list of contraindications for the selected medications.1.0.0