Patient characteristics Intervention Comparison Length of followup

Transcription

1 ANTICOAGULANT CHAPTER Low Molecular Weight Heparins compared with Unfractionated Heparin Ref ID: 1903 Reference Antman EM, McCabe CH, Gurfinkel EP et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-qwave myocardial infarction. Results the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999; 100(15): Study type/ Evidence level RCT: centres across 10 countries in North America, South America and Europe ITT Double Blind Number patients Total 3910 Enoxaparin: 1953 UFH: 1957 Dropouts in the acute phase not reported. 60.6% UFH and 60.4% LMWH went on to outpatient phase. 344 CABG, 349 withdrew consent and 168 for adverse event (bleeding) Patient characteristics Intervention Comparison Length followup Inclusions: All patients to have ischaemic discomfort >= 5mins at rest within 24hrs before randomisation. At start trials patients eligible if had either a history coronary artery disease, ST deviation or elevated serum cardiac markers. After 10 months, inclusion criteria modified to focus on higher risk patients requiring that all patients have either ST deviation or positive serum cardiac markers. Exclusions: planned revascularisation within 24 hours, a treatable cause angina, an evolving Q wave MI, history CABG surgery within 2 months or PTCA within 6 months, UFH > 24hrs before enrolment, history HIT and contraindications to anticoagulation. Baseline population characteristics: NS differences between groups UFH Enoxaparin Age 66 (57-65 (56-73) 72) Male 1256 (64.2%) 1276 (65.3%) St-segment 533(27.2) 515 (26.4) elevation (%) St-segment depression 1081 (55.2) 1069 (54.37) LMWH (enoxaparin) in acute phase (initial 30mg intravenous bolus followed by injections 1.0mg/kg every 12 hrs) and outpatient phase (injections every 2hrs 40mg for patients weighing <65kg and 60mg for those weighing >=65kg) + aspirin ( mg/d) + placebo to mimic UFH UFH for >=3 days (bolus 70U/kg and an initial infusion 15 U kg -1 h -1 ) + aspirin ( mg/d) + placebo to mimic LMWH 72 hrs, 8 days, 14 days 43 days Outcome measures Primary: death, MI or urgent revascularization Major haemorrhage in first 72 hrs [also gives same outcome at 43 days this is not reported here] Source funding Grant from Rhone-Polenc Rorer (Collegeville, Pa) the manufacturers Lovenox (enoxaparin)

2 (%) T wave inversion (%) Time from qualifying discomfort to first dose study medication (hours) IV UFH <= 24 hrs before randomisation (%) Unstable angina (%) Non-Q-wave MI (%) 852 (43.5) 11.0 (5.9,18.9) 676 (34.5 ) 794(40.7) 10.9 (5.8,18.5) 653 (33.4) 1136 (58) 1153 (59) 676 (34.5) 658 (33.7)

3 Effect size Median duration acute phase therapy: 3.0 (2.99,3.98) days UFH and 4.6 (2.97,6.59) days in LMWH (enoxaparin). Time point End Point UFH ( N=1957) LMWH enoxaparin (N=1953) Risk reduction (%) OR ( 95% CI) 48hours Death 6 (0.3) 11 (0.6) ( ) MI 38 (1.9) 26 (1.3) ( ) Urgent revascularization 103 (5.3) 79 (4.0) ( ) Death/MI 42 (2.1) 33 (1.7) ( ) Death./ MI / revascularization 142 (7.3) 108 (5.5) ( ) days Death 41 (2.1) 34 (1.7) ( ) MI 93 (4.8) 66 (3.4) ( ) Urgent revascularization 190 (9.7) 167 (8.6) ( ) Death/MI 115 (5.9) 90 (4.6) ( ) Death./ MI / revascularization 284 (14.5) 242 (12.4) ( ) days Death 55 (2.8) 43 (2.2) ( ) MI 105 (5.4) 83 (4.2) ( ) Urgent revascularization 217 (11.1) 187 (9.6) ( ) Death/MI 135 (6.9) 111 (5.7) ( ) Death./ MI / revascularization 326 (16.7) 277 (14.2) ( ) Bleeding Time point End Point UFH ( N=1936) LMWH p enoxaparin (N=1938) 72 hours Major haemorrhage 14 (0.7) 16 (0.8) Minor haemorrhage 45 (2.3) 99 (5.1) < days Major haemorrhage 19 (1.0) 29 (1.5) Minor haemorrhage 48 (2.5) 176 (9.1) <0.001 p Ref ID: 1905 Reference Blazing MA, de Lemos JA, Study type/ Evidence level RCT:1+ Number patients Total: 3987 Patient characteristics Intervention Comparison Length followup Inclusion: Pts who presented within 24 hours after onset ischaemic symptoms at rest were eligible LMWH enoxaparin Weight adjusted UFH 48hrs, 7 days Outcome measures Composite all cause death, Source funding Merck

4 White HD et al. Safety and efficacy enoxaparin vs unfractionated heparin in patients with non-stsegment elevation acute coronary syndromes who receive tiriban and aspirin: a randomized controlled trial. JAMA. 2004; 292(1): [A-Z Trial] 340 sites in 41 countries (mainly Europe + US) Open label ITT LMWH : 2026 UFH: 1961 for enrolment, provided symptoms lasted at least 10 minutes and were associated with 0.5mm ST segment depression or higher, transient ST elevation, or elevated cardiac markers. Exclusion: nonischaemic pain, shock, medical conditions precluding use study drug, ongoing use lipid lowering therapy, total cholesterol higher than 250 mg/dl and serum creatinine higher than 2mg/dL Baseline population characteristics: NS difference between the groups. LMWH (N=2026) Age (median) 61 (52-69) Sex (male) 1445 (71.4%) Prior cardiovascular history Angina 1176 (58.2%) MI 360 (17.8%) Coronary 185 revascularization (9.1%) Coronary artery 95 bypass graft (4.7%) surgery Percutaneous 86 intervention (4.2%) Stent 51 Prior medication Angiotensinconverting enzyme inhibitor (2.5%) 497 (24.6%) UFH P (N=1961) 61 (53-69) (71.2%) (55.2%) (18.3%) 191 (9.8%) (5.4%) (4.4%) (2.2%) (25.5%).51 Beta blocker (1mg/kg every 12 hours) + tiriban (bolus 10mg/kg over 3mins followed by a maintenance infusion 0.1mg/kg per min for a minimum 48hours and a max 120 hours) + aspirin (initial dose mg/d, followed by a daily dose mg/d) titrated to achieve an activated partial thromboplastin time seconds. + tiriban (bolus 10mg/kg over 3mins followed by a maintenance infusion 0.1mg/kg per min for a minimum 48hours and a max 120 hours) + aspirin (initial dose mg/d, followed by a daily dose mg/d) 30 days new MI or refractory ischaemia within 7 days tiriban initiation, urgent coronary revascularization and documented multiple clinical myocardial ischaemic events.

5 (50%) (51.2%) Nitrate (68.3%) (67.6%) Diuretic (15.5%) (15.8%) Long-term (41%).95 aspirin (40.9%) UFH before (38.5).44 randomisation (37.3%) LMWH before randomisation 693 (34.3%) 688 (34.2%).95 Effect Size Median duration drug use was 49.1 hrs for LMWH and 48.2 hrs for UFH LMWH UFH Major bleeding ( combined) 18/1940 (0.9%) 8/1965 (0.4%) Any bleeding ( combined) 59/1940 (3%) 44/1965 (2.2%) combined = investigator + independent assessor Outcomes at 7 days: End point LMWH ( N=2026) UFH ( N=1961) Hazard Ratio (95% CI) p Death 23/2024 (1.1%) 17/1957 (0.9%) 1.26 ( ).47 MI 73/1998 (3.6%) 86/1938 (4.4%) 0.82( ).23 Refractory Ischemia 81/1997 (4.1%) 95/1937 (4.9%) 0.82 ( ).19 Urgent revascularization 103/1992 (5.1%) 101/1926 (5.2%) 0.98 ( ).89 Documented multiple clinical 22/1985 (1.1%) 37/1927 (1.9%) 0.58 ( ).04 myocardial ischemic events Composite 255/2006 (12.7%) 275/1937 (14.2%) 0.89 ( ).16 Ref ID: 1902 Reference Cohen M, Demers C, Gurfinkel EP et Study type/ Evidence level Number patients RCT: 1+ Total = 3171 LMWH=1067 Inclusion: men or non pregnant women at least 18 years old with recent onset angina at rest lasting at least 10 mins and occurring within 24 1mg enoxaparin per kg body weight UFH intravenous bolus (usually 48hrs, 14 days, Outcome measures Composite death, MI or Source funding Patient characteristics Intervention Comparison Length followup Rhone- Poulenc Rorer

6 al. A comparison low-molecularweight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997; 337(7): [ESSENCE trial] 176 centres in the US, Canada, South America and Europe (total 10 countries) Double blind ITT UFH=1564 hours before randomization. In addition, patients were required to have evidence underlying ischemic heart disease as manifested by one these theree criteria: 1) a new ST segment depression at least 1.0 mv, a transient STsegment elevation, or T-wave changes in at least two contiguous leads; 2) a documented previous MI or revascularization procedure; 3) results noninvasive or invasive testing suggesting ischemic heart disease. Exclusion: left bundle branch block or pacemaker, persistent ST segment elevation, angina with an established precipitating cause (e.g. heart failure or tachydysrhythmia), contraindications to anticoagulation or creatinine clearance less then 30mL per minute. UFH (N=1564) LMWH (N=1607) Age (mean) Sex (male) 1033 (66.1%) 1079 (67.1%) Electrocardiographic changes 894 (57.2%) 897 (55.8%) ST segment elevation 113 (7.2%) 114 (7.1%) ST segment depression 388 (24.8%) 358 (22.3%) T wave inversion 601 (38.4%) 623 (38.8%) subcutaneously every 12 hours + placebo bolus (mimic for UFH) oral aspirin daily 5000 units) followed by continuous infusion at a dose adjusted according to the activated partialthromboplastin time. + subcutaneous placebo injections (mimic for LMWH) oral aspirin daily 30 days recurrent angina Corporation Effect Size The assigned therapy was initiated within 12 hours randomization in 96% patients. The median duration treatment for both trail therapies was 2.6 days. Time point End Point UFH (N=1564) LMWH (N=1607) Risk reduction OR ( 95% CI) P value 48hrs Composite triple 115 (7.4%) 99 (62%) ( ) 0.18 Death 7 (0.4% 8 (0.5%) ( ) 0.83 MI 14 (0.9%) 11 (0.7%) ( ) 0.5 Recurrent angina 99 (6.3%) 83 (5.2%) ( )

7 14 days Composite triple 309 (19.8%) 266 (16.6%) ( ) 0.02 Death 36 (2.3%) 36 (2.2%) ( ) 0.92 MI 70 (4.5%) 51 (3.2%) ( ) 0.06 Recurrent angina 243 (15.5%) 207 (12.9%) ( ) days Composite triple 364 (23.3%) 318 (19.8%) ( ) 0.02 Death 57 (3.6%) 4.7 (2.9%) ( ) 0.25 MI 81 (5.2%) 62 (3.9%) ( Recurrent angina 281 (18%) 252 (15.7%) ( ) 0.08 Hemorrhagic and serious adverse events at day 30 UFH LMWH P value Hemorrhage Major 107 (7%) 102 (6.5%) 0.57 Minor 110 (7.2%) 188 (11.9%) <0.001 Stroke 7 (0.5%) 7 (0.4%) Hemorrhagic 1 (0.1%) 0 Nonhemorrhagic 6 (0.4%) 7 (0.4%) Transient ischemic attack 8 (0.5%) 1 (0.1%) Drop in platelet count >50% from baseline 56 (3.7%) 39 (2.5%) 0.08 Ref ID: 1906 Reference Cohen M, Theroux P, Borzak S et al. Randomized double-blind safety study enoxaparin versus unfractionated heparin in patients with non-st-segment elevation acute Study type/ Evidence level RCT: international centres Double blind Powered for bleeding, not ischemic end points Number patients Total = 525 LMWH = 210 UFH = 315 Patient characteristics Intervention Comparison Length followup Inclusion: Pts at higher risk for ischemic events and had UA/NSTEMI. Prolonged (>=20mins) or repetitive episodes angina at rest or minimal effort within previous 24 hours and either evidence by means ECG myocardial ischemia or abnormal cardiac markers. Electrocardiographic changes included new ST-segment depression, transient elevation >=1mm or T-wave inversions (in>=3 leads). Abnormal cardiac enzymes are defined as a creatinine kinase myocardial band isoenzyme (CK-MB) or Enoxaparin 1.0mg/kg subcutaneous injection every 12 hours ASA daily + tiriban (loading infusion 0.4 µg/kg/min for 30mins, UFH loading bolus 5000, maintenance 1000 U/hr adjusted to therapeutic aptt ASA daily + tiriban 30 days Outcome measures Bleeding, MI, death, refractory ischemia requiring urgent hospitalization, rehospitalization due to UA. Source funding Merck

8 coronary syndromes treated with tiriban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tiriban and Enoxaparin. Am Heart J. 2002; 144(3): troponin level greater than the upper limit normal or CK level equal to or greater than twice the upper limit normal. Patients who were already receiving IV UFH or open label enoxaparin were eligible for the trial. Exclusion: STEMI within 48 hrs; contraindication to anticoagulants; history thrombocytopenia; allergy or intolerance to ASA, UFH or tiriban; need for immediate invasive therapy; serum creatinine level >2.0mg/dL or platelet count <150,000/mm 3. maintenance 0.1 µg/kg/min for minimum 47.5 horus hrs) +placebo to mimic UFH (loading infusion 0.4 µg/kg/min for 30mins, maintenance 0.1 µg/kg/min for minimum 47.5 horus hrs) + placebo to mimic LMWH LMWH (n=210) UFH (N=315) Age (mean) / / Sex (male) 141 (67.1%) 207 (65.7%) Presenting diagnosis Unstable angina 110 (52.4%) 143 (45.4%) Postinfarction 7 (3.3%) 19 (6%) angina pectoris Non ST segment 93 (44.3%) 153 (48.6%) elevation MI Prior therapies Aspirin 197 (93.8%) 301 (95.6%) UFH 89 (42.4%) 134 (42.5%) LMWH 40 (19%) 55 (17.5%)

9 Effect Size Mean infusion duration for UFH was 58.1hrs and 60.6hrs for LMWH Primary outcome : bleeding UFH LMWH OR (95% CI) Patients with any bleeding event 72/210 (34.3%) 172/315 (54.6%) TIMI major 2 1 TIMI minor 7 7 TIMI loss no site 1 3 All TIMI 10 (4.8%) 11 (3.5%) 1.4 ( ) UFH ( N=210) Enoxoparin (n=315) Risk ratio (95% CI) p MI 15 (7.1%) 21 (6.7%) 1.06 ( ).86 Periprocedural MI 5 (2.4%) 12 (3.8%) 0.63 ( ).46 Non periprocedural MI 10 (4.8%) 9 (2.9%) 1.66 ( Death 4 (1.9%) 8 (2.5%) 0.76 ( ).77 Refractory ischemia 9 (4.3%) 2 (0.6%) 7.17 ( ).01 requiring urgent intervention Rehospitalization due to UA 15 (7.1%) 5 (1.6%) 4.44 ( ).002 Ref ID: 947 Reference Ferguson JJ, Califf RM, Antman E. Study type/ Evidence level Number patients RCT:1+ N= excluded Patient characteristics Intervention Comparison Length followup Inclusion: pts with ischemic symptoms lasting at least 10 minutes occurring within 24 hours enrolment and at least 2 the Enoxaparin subcutaneously 1mg/kg every 12 UFHintravenous bolus and 30 days Outcome measures Primary: composite all cause death or Source funding Aventis

10 Enoxaparin vs unfractionated heparin in highrisk patients with non-st-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results the SYNERGY randomized trial. Journal the American Medical Association. 2004; 292(1): centres in 12 countries Powered Open label ITT for randomisation error LMWH = 4993 UFH=4985 following: age 60 or older, troponin or creatine kinase elevation above the upper limit normal, or ST-segment changes on ECG. Patients already on antithrombin therapy as part routine were eligible. 75% patients already received UFH or LMWH prior to randomisation. Inclusion criteria: LMWH UFH Age >=60 and elevated cardiac biomarkers Age >= 60 and ECG changes Elevated cardiac biomarkers and ECG changes Age >=60 elevated biomarkers and ECG changes (n=4828) 996 (20.6%) 768 (15.9%) 925 (19.2%) 2139 (44.3%) (n=4830) 952 (19.7%) 767 (15.9%) 936 (19.4%) 2175 (45%) Exclusion: known or suspected pregnancy, contraindications to UFH or LMWH recent (<48hrs) or planned spinal or epidural anaesthesia or puncture, PCI or thrombolytic therapy within the preceding 24 hours, increased risk bleeding due to recent stroke or surgery, elevated international normalised ratio (>1.5), past or present bleeding disorder, or creatine clearance less than 30mL/min. hrs + daily aspirin ( mg) or if allergic to aspirin, 75mg/d clopidogrel U/kg (max 5000 U) and initial infusion U/kg per hour (max 1000 U/h initially) with a goal activated partial thromboplastin time times the institutional upper limit normal or seconds. + daily aspirin (62 325mg) or if allergic to aspirin, 75mg/d clopidogrel non fatal MI at 30 days Secondary: composite death or non fatal MI at 14 days and composite all cause mortality, non fatal MI, stroke, or recurrent ischemia requiring vascularization; and individual components this composite at 14 and 30 days. Primary safety endpoint: major bleeding and stroke LMWH (N=4993) UFH (N=4985) Age 68 (61-75) 68 (61-75) (median) Sex 1692 (34%) 1684

11 (female) (33.8%) Effect Size In hospital procedures through 30 days Procedures LMWH (n=4993) UFH (n=4985) Diagnostic coronary angiography 4600 (92.1%) 4588 (92%) Median time to angiography (h) 21.7 ( ) 21.5 ( ) PCI 2323 (46.5%) 2364 (47.4%) Median time to PCI (h) 22.7 ( ) 22.5 ( ) CABG 965 (19.3%) 899 (18%) Median time to CABG (h) 91.4 ( ) 89.1 ( ) Concomitant medications during hospitalization LMWH (n=4993) UFH (n=4985) Aspirin 4751 (95.2%) 4723 (94.7%) Beta blocker 4312 (86.4%) 4283 (85.9%) ACE inhibitor 3185 (63.8%) 3100 (62.2%) Statin 3453 (69.2%) 3490 (70%) Clopidogrel 3119 (62.5%) 3154 (63.3%) Angiotensin receptor blocker 276 (5.5%) 327(6.6%) Glycoprotein IIb/IIIa inhibitor Any 2819 (56.5%) 2898 (58.2%) Preenrollment 1030/2800 (36.8%) 1020/2884 (35.4%) Post- enrollment 911/2800 (32.5%) 956/2884 (33.2%) Before/After catheterization or PCI 859/2800 (30.7%) 908/2884 (31.5%) Primary outcomes at 30 days, 14 days and 48hrs LMWH (n=4993) UFH (n=4985) Hazard Ratio ( 95% CI) P value 30 days Death or MI 696 (14%) 722 (14.5%) 0.96 ( ).40 Death 160 (3.2%) 153 (3.1%) 1.04 ( ).71 MI 580 (11.7%) 627 (12.7%) 0.92 ( ) days Death or MI 639 (12.8%) 668 (13.4%) 0.95 ( ).38 Death 120(2.4%) 118 (2.4%) 1.01 ( ).91 MI 554 (11.2%) 586 (11.8%) 0.94 ( ) hours Death or MI 284 (5.7%) 323 (6.5%) -.10 Death 21 (0.4%) 26 (0.52%) -.46 MI 268 (5.4%) 301 (6.0%) -.15

12 In-hospital bleeding LMWH UFH P value GUSTO severe 136/4993 (2.7%) 109/4983 (2.2%) 0.08 TIMI major 453/4993 (9.1%) 379/4984 (7.6%) TIMI CABG related 338/4993 (6.8%) 295/4984 (5.9%) 0.8 TIMI non-cabg related 119/4993 (2.4%) 87/4984 (1.8%) 0.3 TIMI minor 611/4885(12.5%) 603/4888 (12.3%) 0.80 Decrease in hemoglobin and/or hematocrit* 743/4874 (15.2%) 611/4882 (12.5%) <0.001 Any transfusion 850/4993 (17%) 796/4985 (16%) 0.16 Lowest platelet count X10 3 /µl >= /4675 (94%) 4424/4697 (94.2%) >50 to < /4675 (5.3) 250/4697 (5.3%) >20 to <=50 22/4675 (0.5%) 16/4697 (0.3%) 0.67 <=20 10/40675 (0.2%) 7/4697 (0.1%) * at least a 5-g/dL decrease in hemoglobin or at least a 15% decrease in hematocrit not associated with an overt bleeding event Ref ID: 11 Reference Goodman SG, Fitchett D, Armstrong PW et al. Randomized evaluation the safety and efficacy enoxaparin versus unfractionated heparin in highrisk patients with non-stsegment elevation acute Study type/ Evidence level RCT:1+ 50 centres in Canada Randomised Allocation concealment Open label Number patients Total = 746 LMWH=380 UFH=366 Patient characteristics Intervention Comparison Length followup Inclusion: 18+, hospitalized with ischemic chest discomfort >= 10 minutes duration occurring at rest and <= 24 hours before enrolment. Patients also required to have 1) ST-segment depression >=0.1 mv or transient /st-segment elevation >=0.1 mv in >=2 contiguous ECG leads; and/or 2) elevation troponin I or T >=3 times the upper reference limit, or creatinine kinase (CK)-MB higher then normal. Excluded: 1) cardiovascular: left bundle branch block; ischemia due to an established precipitating cause; cardiogenic shock; scheduled or recent revascularization. 2) bleeding risk: bp >200 LMWH (1mg/kg subcutaneously every 12 hrs for 48hrs) + eptifibatide (180 µg/kg bolus followed by a 2.0µg kg -1 min -1 infusion for 48 hrs) + oral aspirin ( >=160mg initially followed by 80 UFH (70 U/kg intravenous bolus followed by 15 U kg -1 h -1 continuous infusion, titrated to an activated partial thromboplastin time 1.5 to 2 times control for 48 hours. + eptifibatide 48hrs, 96hrs, 30 days Outcome measures Bleeding, death, MI. Source funding Canadian Heart research centre, key pharmaceuticals and millennium pharmaceuticals. Enoxaparin provided by Aventis

13 coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003; 107(2): [INTERACT trial] mm HG systolic or >110 mmhg diastolic; hemoglobin <11 g/dl for men or >9 g/dl for women, thrombocytopenia; ulcerative gastrointestinal disease in the last 6 months; history cerebral haemorrhage or known intracerebral vascular disease; non hemorrhagic stroke in previous month; eye, spine or central nervous system surgery in previous 2 months; major surgery, organ biopsy, puncture non compressible vessel in previous 2 weeks; or known or suspected pregnancy. 3) prior or concomitant therapy: treatment with abciximab in previous 14 days or with tiriban or eptifibatide in previous 7 days; allergy or contraindication to aspirin or study drugs; oral anticoagulation treatment in previous 5 days or INR >1.2; fibrinolysis in previous 24 hours; or treatment with investigational agents in previous 30 days. 4) General: renal failure, liver disease; or inability to commence ST-segment monitoring <= 8 hours after randomisation. Initially pts excluded if taken LMWH or UFH <=24 hours before enrolment, changed to <= 12 hrs. Baseline population characteristics were similarly distributed. 325 mg daily) (180 µg/kg bolus followed by a 2.0µg kg - 1 min -1 infusion for 48 hrs) + oral aspirin ( >=160mg initially followed by mg daily) LMWH (N=380) Age (median) 64 (54,72) Sex (female) 121 (31.8%) Time onset 4.4 symptoms (2.8,7.7) to randomisation (hours) UFH (N=366) 64 (54,73) 112 (30.6%) 4.4 (2.8,6.7)

14 Transient ST elevation ST depression CK-MB and/or troponin elevation 24 (6.4%) 63 (16.8%) 311 (81.8%) 24 (6.7%) 54 (15.0%) 312 (85.3%) Treatment and procedures LMWH (N=380) Concomitant medications Aspirin 364 Intravenous Beta blockers Oral Beta blockers Calcium channel blockers Angiotensinconverting enzyme inhibitor Intravenous nitrate (95.8%) 63 (16.6%) 322 (84.7%) 37 (9.7%) 213 (56.1%) 146 (38.4%) Oral nitrate 181 (47.6%) Median time 100 to (65,164) angiography (hrs) UFH (n=366) 350 (95.6%) 52 (14.2%) 290 (79.2%) 44 (12%) 206 (56.3%) 129 (35.3%) 215 (58.7%) 101 (60,168) p

15 Median time to PCI (hrs) Median time to CABG (hrs) 132 (76, 232) 326 (188, 462) 109 (60, 232) 304 (157,456) Effect Size Bleeding LMWH (N=380) UFH (N=366) p Major bleeding Non CABG related 48h 4 (1.1%) 14 (3.8%) h 7 (1.8%) 17 (4.6%) day 11 (2.9%) 21 (5.7%) All 48h 4 (1.1%) 16 (4.4%) h 8 (2.1%) 20 (5.5%) day 20 (5.3%) 32 (8.7%) Transfusions 16 (4.2%) 19 (5.2%) 0.53 CABG related 4 (1.1%) 7 (1.9%) 0.33 Minor bleeding 48h 102 (26.8%) 67 (18.3%) h 115 (30.3%) 76 (20.8%) day 121 (31.8%) 89 (24.3%) 0.22 LMWH (N=380) UFH (N=366) p Death or (re)mi 19 (5.0%) 33 (9%) MI peri-vascularization 2 (0.5%) 7 (1.9%) 0.1 Death, (re) MI or RA with ECG 34 (9%) 46 (12.6%) 0.11 changes Death, (re) MI or RA requiring urgent 53 (14%) 59 (16.1%) 0.41 revascularization Death 9 (2.4%) 15 (4.1%) 0.18 (Re) MI 15 (4%) 21 (5.8%) 0.25 RA with ECG changes 7 (1.8%) 15 (4.1%) RA requiring urgent revascularization 28 (7.4%) 20 (5.5%) 0.29 Ref ID: 1908 Reference Study Number Patient characteristics Intervention Comparison Length Outcome Source

16 Klein W, Buchwald A, Hillis SE et al. Comparison low-molecularweight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation. 1997; 96(1): type/ Evidence level RCT: centres in 9 countries Open label Powered ITT patients Total: 1499 UFH: 731 LMWH: randomised but not treated 166 in LMWH and 184 in UFH withdrew during the acute phase Inclusion: patients that satisfied the clinical criteria for unstable coronary artery disease according to a modified Braunwald classification. Admission had to have been within 72 hours last episode chest pain and an ECG on admission had to show either 1 or both the following abnormalities on at least two adjacent leads: temporary or persistent STsegment depression >=0.1 mv and or temporary or persistent t-wave inversion >= 0.1 mv below baseline without corresponding Q waves. Exclusions: newly developed Q waves; left bundle-branch block on ECG; an indication for thrombolytic therapy; a pacemaker; known primary myocardial disease, septic endocarditis, pericarditis, or aortic valvular disease haemodynamic significance; any known defect hemostasis; ongoing treatment with oral anticoagulants or heparin; diastolic bp >120mmHg or systolic <90mmHg; fever with temp >-39; hemoglobin <125 g/l male or <110 if female; known renal or liver insufficiency; a history cerebrovascular events, peptic ulcer, or gastrointestinal bleeding within 3 months admission; surgery any type within one week; malignancy or other diseases with unfavourable prognosis; know hypersensitivity to aspirin, UFH or LMWH; patients with planned CABG or PTCA within 3 weeks admission, pregnant women. LMWH (dalteparin) administered twice daily subcutaneously + aspirin ( mg/d) UFH administered first by intravenous infusion ( for >=48 hours and then subcutaneous injection + aspirin ( mg/d) measures followup 6 days Composite outcome, death or MI, MI, Death, Revascularisation. funding Pharmacia & Upjohn UFH LMWH (N=731) (N=751) Median age 65 (25-89) 65 (29-92)

17 Effect Size Results are for phase one trial only Male: female 66:34 63:37 T-wave 42% 40% inversion St-segment 32% 34% depression Medication on entry (%): Aspirin Beta blocker Ca channel blocker Nitrate Diuretic Digitalis ACE inhibitor Outcomes at 6 days Outcomes at 6 days LMWH (N=751) UFH ( n=731) Relative Risk 95% CI p Composite outcome % (n) 9.3 (69) 7.6 (55) Death or MI % (n) 3.9 (29) 3.6 (26) MI % (n) 2.6 (19) 3.2 (23) Death % (n) 1.5 (11) 0.4 (3) Revascularization % (n) 4.8 (36) 5.3 (39) Adverse events UFH LMWH Major bleeding % (n) 1.0 (7) 1.1 (8) Minor bleeding % (n) 3.3 (24) 3.1 (23) Thrombocytopenia % (n) 0.7 (5) 0.3 (2) Allergic reaction % (n) 0.8 (6) 0.4 (3) Ref ID: 3401 Reference Murphy SA, Gibson CM, Study type/ Evidence level SR: 1+ Number patients 6 RCTs in NSTEMI: Patient characteristics Intervention Comparison Length followup Inclusion: RCTs comparing enoxaparin with UFH in people with either NSTEMI or Outcome measures Enoxaparin UFH 30 days All cause death, death Source funding Not stated

18 Morrow DA et al. Efficacy and safety the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J. 2007; 28(17): Ref ID: 3401 Searched pubmed, hand search Also contacted investigators to confirm data and provide missing data ESSENCE TIMI IIB ACUTE II INTERACT A to Z SYNERGY Total: 21,945 STEMI. Note: Only NSTEMI meta-analysis reported here. Effect Size Outcome RCTs OR (95% CI) P value Heterogeneity? (p value) Death or nonfatal MI (0.81, 0.996) Not reported Death, nonfatal MI, or nonfatal major bleed (0.86, 1.09) NS NS p=0.132 death (0.83, 1.18) NS Not reported Nonfatal MI (0.79, 0.96) Not reported Major bleed (0.84, 1.54) NS Not reported + MI, and major bleeding Ref ID: 3400 Reference Petersen JL, Mahaffey KW, Hasselblad V et al. Efficacy and bleeding complications Study type/ Evidence level SR:1- No discussion search strategy No discussion study quality Number patients Total: 21,946 LMWH: 11,100 Patient characteristics Intervention Comparison Length follow-up Outcome measures Non-ST segment elevation ACS Enoxaparin UFH 30 days All cause death, death + MI, transfusion and major bleeding Source funding Aventis

19 among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non- ST-Segment elevation acute coronary syndromes: a systematic overview.[see comment]. [Review] [24 refs]. JAMA. 2004; 292(1): UFH: 10,845 Effect Size Baseline Characteristics ESSENCE TIMI IIb ACUTE II INTERACT A to Z SYNERGY Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Number Age (median) Sex (Female) ECG changes Biomarker positive 65 (56-73) 65 (56-65 (56-73) 66 ( (11.7) (54-72) 64 (54-61 (52-69) 61 (53-68 (61-75) 68 (61-73) 72) (12.9) 73) 69) 75) 32.9% 33.9% 34.9% 35.8% 34.3% 32.9% 31.8% 30.6% 28.6% 28.8% 34% 33.8% 55.8% 57.2% 82.5% 83.1% NA NA 23.2% 21.7% 70.3% 71.9% 78.2% 79.1% NA NA 37.8% 39.6% 59.4% 58.1% 81.8% 85.3% 80.3% 79.7% 84.1% 84.1% Use medication and procedures ESSENCE TIMI IIb ACUTE II INTERACT A to Z SYNERGY Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Enoxaparin UFH Number PCI 14.7% 18.7% 17.7% 19% 28.2% 31.4% 27.1% 30.3% 30% 30.6% 46.2% 47.4% CABG surgery 12.3% 13.7% 6% 7% 15.6% 19% 12.6% 12.3% 8.8% 10.1% 19.3% 18.0% Aspirin 65% 66% 83.2% 84.4% 96.2% 95.7% 95.8% 95.6% 98.9% 98.4% 95.2% 94.7% Thienopyridine 2.6% 2.4% 1.5% 1.3% 7.9% 7.6% 16.3% 15.3% NA NA 66% 66.8% Glycoprotein NA NA NA NA 100% 100% 100% 100% 100% 100% 56.5% 58.1%

20 IIb/IIIa inhibitor Beta blocker 68.6% 69.3% 73.6% 71.6% 76.2% 75.2% 84.7% 79.2% 84.9% 83.7% 86.4% 85.9% ACE inhibitor NA NA 27.2% 24.5% 21% 23.8% 56.1% 56.3% 43.1% 44.1% 63.8% 62.2% Statin NA NA 25.7% 23.5% 42.9% 43.8% 50.3% 51.4% NA NA 69.2% 70% Outcomes (intention to treat population) Death at 30 days: N=6 trials (enoxaparin: 329/11100 UFH: 325/10845) OR: 1.00 (95% CI: ) Death or MI at 30 days: N= 6 trials (enoxaparin: 1116/11099 UFH: 1192/10847) OR: 0.91 (95% CI: ) Major bleeding up to 7 days after randomization: N = 4 trials (enoxaparin: 381/8044 UFH: 386/8606) OR: 1.04 (95% CI: ) FONDAPARINUX Fondaparinux compared with enoxaparin Ref ID: 1856 Reference Yusuf S, Mehta SR, Chrolavicius S et al. Comparison fondaparinux and enoxaparin in acute coronary syndromes. New England Journal Medicine. 2006; 354(14): Ref ID: 1856 Study type/ Evidence level RCT countries ITT Double blind Randomised Allocation concealment Powered Low dropout at 9 days Number patients N total = N fondaparinux = N enoxaparin = Dropouts (at 9 days): 0.07% fondaparinux 0.04% enoxaparin. No detail for dropouts at 30 days Patient characteristics Intervention Comparison Length followup Inclusions: OASIS-5 RCT: people randomised within 24 hours symptom onset if they met 2/3 criteria: age 60 years; elevated troponin/ck- MB; ischaemic ECG changes (note that people < 60 years old subsequently randomised providing they had both ECG changes and biomarker elevation) Exclusions: contraindications to LMWH, recent hemorrhagic stroke, indications for anticoagulation other than an ACS, serum creatinine 3mg/dl Baseline population characteristics: NS differences between groups Fondaparinux (2.5 mg/day; s.c.) N = PCI subgroup Fondaparinux N= 3135 Protocol: people randomised to fondaparinux + placebo (enoxaparin) or enoxaparin + placebo (fondaparinux). Fondaparinux given until hospital discharge or for up enoxaparin (1mg/kg; twice daily; s.c) N= PCI subgroup enoxaparin N= 3104 Protocol: as for intervention 9 days, 30 days, 180 days Outcome measures 1 outcome: death, MI, or refractory ischemia at 9 days 1 safety outcome: Major bleeding at 9 days 2 outcome: death, MI, or refractory Source funding Sani- Aventis, Organon, GSK

21 enox fond Age, yr Male (%) ST-segment depression mm (%) UA (%) Suspected MI (%) Previous MI (%) Previous CABG/PCI (%) Aspirin after randomisation (%) Clopidogrel or ticlopidine after randomisation (%) UFH after randomisation (%) PCI after randomisation (%) CABG after randomisation (%) Characteristics those undergoing PCI within first 8 days randomisation Enox (N=3104) Fond (N=3135) Concomitant UFH (%) Concomitant thienopyridines (%) Concomitant GP IIb/IIIa inhibitors (%) to 8 days. Enoxaparin given for 2-8 days or until patient was stable. Standard treatment given in addition. PCI subgroup: Clopidogrel and aspirin was recommended at least 6 hours before PCI. People in the enoxaparin group received no additional anticoagulant if they had received enoxaparin < 6 hours before PCI. If the last sc enoxaparin injection was > 6 h before PCI, UFH was added at 0.02 ml/kg if no GP IIb/IIIa was used or at ml/kg if a GB IIb/IIIa was administered. For people undergoing PCI who had received fondaparinux < 6 hours before the PCI, another 2.5 mg fondaparinux was given (if there was no GP IIb/IIIa used). For people undergoing PCI who had received ischemia at 30 days death or MI at 30 days major bleeding at 30 days

22 fondaparinux < 6 hours before the PCI and had also received GP IIb/IIIa, no additional fondaparinux was given. In those who had received their last fondaparinux > 6 hours before the PCI, another 5.0 mg fondaparinux was added (without a GB IIb/IIIa) or 2.5 mg fondaparinux was added if they received a GB IIb/IIIa inhibitor). Effect size Mean duration treatment was similar in the 2 groups (5.4 and 5.2 days ; fondaparinux vs enoxaparin) Outcome Enoxaparin Fondaparinux Hazard Ratio (95% P value (N=10021) (N=10057) CI) 1 death, MI, or refractory ischemia at 9 days 5.7 % 5.8% 1.01 ( ) NS noninferiority 1 Major bleeding at 9 days 4.1 % 2.2% 0.52 ( ) < superiority 2 death, MI, or refractory ischemia, or major bleeding at 9 9.0% 7.3% 0.81 ( ) <0.001 superiority days 2 death, MI, or refractory ischemia at 30 days 8.6 % 8.0 % 0.93 ( ) NS 0.13 superiority - NS 2 Major bleeding at 30 days 5.0 % 3.1 % 0.62 ( ) < superiority 2 death, MI, refractory ischemia, or major bleeding at % 10.2 % 0.82 ( ) < superiority days 2 death at 30 days 3.5% 2.9% 0.83 ( ) 0.02 superiority At 9 days: NS differences in risk between the enoxaparin and fondaparinux for: Death or MI Death MI Refractory ischaemia Stroke

23 At 30 days: NS differences in risk between the enoxaparin and fondaparinux for: Death or MI [HR 0.90 (0.81, 1.01)] MI [HR 0.94 (0.82, 1.08)] Refractory ischaemia [HR 0.99 (0.82, 1.19)] Stroke [HR 0.77 (0.57, 1.05)] Subgroup analysis: major bleeding at 9 days consistently lower in fondaparinux compared with enoxaparin in all groups assessed; regardless whether UFH was administered before randomisation or not. PCI population: Among those undergoing PCI within the first 8 days randomisation (N= 3104 enoxaparin and N= 3135 fondaparinux): Outcome Enoxaparin (N=3104) Fondaparinux (N=3135 Hazard Ratio (95% CI) P value 1 death, MI, or refractory ischemia at 9 days 8.6% 9.3% Not reported NS 1 Major bleeding at 9 days 5.1 % 2.3% 0.45 ( ) 2 death, MI, stroke, or major bleeding at 9 days 10.3% 8.2% 0.79 ( ) any procedural complication, major bleeding, death, MI, or stroke at 9 days 20.6 % 16.6 % 0.81 ( ) < death, MI, or refractory ischemia at 30 days 9.6% 10.4% Not reported NS 2 Major bleeding at 30 days 5.4 % 2.8 % 0.51 ( ) 2 death, MI, stroke, or major bleeding at 30 days 11.7 % 9.5 % 0.81 ( ) At 9 days in those undergoing PCI: NS differences in risk between the enoxaparin and fondaparinux groups for: Death MI Death, MI, or stroke Stroke At 30 days in those undergoing PCI: NS differences in risk between the enoxaparin and fondaparinux groups for: Death MI Death, MI, or stroke Stroke Notes: authors suggest fondaparinux as an alternative to enoxaparin as it reduces bleeding. Increased bleeding with enoxaparin may be due to a dose that is too high, despite recommendations to use this dose

24 Ref ID: 9 Reference Mehta SR, Granger CB, Eikelboom JW et al. Efficacy and safety fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol. 2007; 50(18): Ref ID: 9 Study type/ Evidence level RCT countries ITT Double blind Randomised Allocation concealment Powered No detail on dropouts in PCI group Number patients N undergoing PCl within 8 days = 6238 N fondaparinux +PCI = 3134 N enoxaparin + PCI = 3104 Dropouts in PCI groups: not stated Patient characteristics Intervention Comparison Length followup Inclusions: people undergoing PCI in the OASIS-5 RCT: randomised within 24 hours symptom onset if they met 2/3 criteria: age 60 years; elevated troponin/ck-mb; ischaemic ECG changes (note that people < 60 years old subsequently randomised providing they had both ECG changes and biomarker elevation). Exclusions: contraindications to LMWH, recent hemorrhagic stroke, indications for anticoagulation other than an ACS, serum creatinine 3mg/dl Baseline population characteristics those undergoing PCI within first 8 days randomisation: NS differences between groups Enox (N=3104) Fond (N=3134) Age, yrs Female (%) ST-segment depression 1 mm (%) ST-segment elevation > 2 mm (%) ASA after randomisation (%) Clopidogrel after randomisation (%) Fondaparinux (2.5 mg/day; s.c.) PCI subgroup Fondaparinux N= 3134 N= 1412 fondaparinux had an early PCI within 24 h randomisation Protocol: people randomised to fondaparinux + placebo (enoxaparin) or enoxaparin + placebo (fondaparinux). Fondaparinux given until hospital discharge or for up to 8 days. Enoxaparin given for 2-8 days or until patient was stable. Standard treatment given in addition. PCI subgroup: Clopidogrel and aspirin was enoxaparin (1mg/kg; twice daily; s.c) PCI subgroup enoxaparin N= 3104 N=1420 enoxaparin had an early PCI within 24 h randomisation Protocol: as for intervention 9 days, 30 days, 180 days Outcome measures 1 outcome: death, MI, or stroke at 9 days 1 safety outcome: Major bleeding at 9 days (defined as overt bleeding that was either fatal, intracranial, retroperitoneal, intraocular, decrease Hb> 3.0 g/dl or requiring transfusion 2 U RBC. 2 outcome: death, MI, or stroke at 30 days death or MI at 30 days major bleeding at 30 days Source funding Sani- Aventis, Organon, GSK

25 Clopidogrel 6h before PCI (%) GP IIa/IIIb inhibitor after randomisation (%) Intracoronary stents performed Drug-eluting stents performed recommended at least 6 hours before PCI. Blinded treatments continued during PCI. People in the enoxaparin group received no additional anticoagulant if they had received enoxaparin < 6 hours before PCI. If the last sc enoxaparin injection was > 6 h before PCI, UFH was added at 0.02 ml/kg if no GP IIb/IIIa was used or at ml/kg if a GP IIb/IIIa was administered. For people undergoing PCI who had received fondaparinux < 6 hours before the PCI, another 2.5 mg fondaparinux was given (if there was no GP IIb/IIIa used). For people undergoing PCI who had received fondaparinux < 6 hours before the

26 PCI and had also received GP IIb/IIIa, no additional fondaparinux was given. In those who had received their last fondaparinux > 6 hours before the PCI, another 5.0 mg fondaparinux was added (without a GP IIb/IIIa) or 2.5 mg fondaparinux was added if they received a GP IIb/IIIa inhibitor). Effect size Fondaparinux/placebo given for mean 2.4 days before PCI. Enoxaparin/placebo given for a mean 2.6 days before PCI. Protocol amendment: Data was collected on open-label addition UFH prior to PCI in both trial arms in the last 1758 people undergoing PCI. Total PCI population: Among those undergoing PCI within the first 8 days randomisation Outcome Fondaparinux Enoxaparin (N=3104) Hazard Ratio P value (N=3134) (95% CI) 1 death, MI, or stroke at 9 days 6.3% 6.2% 1.03 ( ) 0.79 NS 1 Major bleeding at 9 days 2.4% 5.1 % 0.46 ( ) < death, MI, stroke, or major bleeding at 9 days 8.2% 10.4% 0.78 ( ) 0.004

27 2 death, MI, or stroke at 30 days 7.4% 7.4% 1.00 ( ) 0.99 NS 2 Major bleeding at 30 days 2.9 % 5.4 % 0.52 ( ) < death, MI, stroke, or major bleeding at 30 days 9.5 % 11.8 % 0.80 ( ) Not reported At 9 days in those undergoing PCI: NS differences in risk between the enoxaparin and fondaparinux groups for: Death MI Stroke At 30 days in those undergoing PCI: NS differences in risk between the enoxaparin and fondaparinux groups for: Death [HR 0.94 (0.67, 1.34)] MI [HR 1.04 (0.84, 1.29)] Stroke [HR 0.76 (0.41, 1.44)] Fondaparinux was superior to enoxaparin for reducing major bleeds whether the study drugs were restarted after PCI procedure (HR 0.42, p< )or not restarted (HR 0.55, p< ). In people undergoing early PCI within 24 h randomisation: At 9 days in those undergoing early PCI within 24 h randomisation: NS differences in risk between the enoxaparin and fondaparinux groups for: Death MI Stroke Outcome in those with early PCI (within 24-h Fondaparinux Enoxaparin (N=1420) Hazard Ratio (95% P value randomisation) (N=1414) CI) 1 death, MI, or stroke at 9 days 5.3% 5.4% 0.98 ( ) 0.89 NS 1 Major bleeding at 9 days 2.3% 4.9 % 0.48 ( ) death, MI, stroke, or major bleeding at 9 days 7.3% 9.5% 0.76 ( ) Effect addition other anticoagulants/antiplatelets: Major bleeds at 30 days Fondaparinux + GP Enoxaparin + GP Hazard Ratio (95% P value IIb/IIIa at least 6 hours before/during PCI (N=1198) IIb/IIIa at least 6 hours before/during PCI (N=1263) CI) 4.0% 6.6 % 0.56 ( ) 0.02 Fondaparinux without GP IIb/IIIa at least 6 hours Enoxaparin without GP IIb/IIIa at least 6 hours before/during Hazard Ratio (95% CI) P value

28 before/duringpci PCI (N=1842) (N=1874) 2.0% 4.7% 0.43 ( ) < Fondaparinux + Enoxaparin + Hazard Ratio (95% P value clopidogrel at least 6 hours before PCI (N=912) clopidogrel at least 6 hours before PCI (N=923) CI) 1.8% 3.8% 0.45 ( ) Fondaparinux without Enoxaparin without Hazard Ratio (95% P value clopidogrel at least 6 hours before PCI (N=2060) clopidogrel at least 6 hours before PCI (N=2086) CI) 1.4% 3.4% 0.52 ( ) < During PCI, Fondaparinux was superior to enoxaparin in decreasing major bleeds at 30 days with or without pre-treatment with clopidogrel or GP IIb/IIIa inhibitors. Addition UFH to enoxaparin group undergoing PCI If PCI was performed > 6 h after the last injection enoxaparin, UFH was added to the enoxaparin group, but NOT the fondaparinux group. Fondaparinux significantly reduced major bleeding 48 h post-pci compared with enoxaparin alone [RR 0.42 (95% CI ), p<0.0001] or compared with enoxaparin + UFH [RR 0.39 (95% CI ), p<0.0001]. Effect open-label UFH: N=1758 Open label UFH given before PCI to N=75 fondaparinux (mean dose 47 IU/kg) and N=80 enoxaparin (mean dose 37 IU/kg). NS differences in risk between the enoxaparin + UFH versus fondaparinux + UFH groups for: 30 day death/mi/stroke/major bleed [HR 0.38 (0.14, 1.07)] 30 day death/mi/stroke [HR 0.52 (0.13, 2.06)] 30 day major bleed [HR 0.22 (0.05, 1.03)] In those who did not receive open label UFH before PCI, Catheter thrombus occurred in 1.1% fondaparinux and 0.5% enoxaparin [HR 2.30 ( )-NS]. Notes: authors suggest fondaparinux as an alternative to enoxaparin as it reduces bleeding. Note that the numbers people receiving UFH in both enox and fond groups were small (N<100) BIVALIRUDIN REF ID: 1864 Reference Study type Number Patient characteristics Intervention Comparison Length Outcome measures Source

29 Stone GW, McLaurin BT, Cox DA et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006; 355(21): Ref ID: 1864 Evidence level RCT, open label, multicentre trial 1+ patients N= 13,819 Inclusion criteria : ACUITY trial: Patients aged 18 years or older with symptoms unstable angina lasting for 10 min or more within the preceding 24 h were deemed to be eligible for enrolment if one or more the following criteria were met: new ST-segment depression or transient elevation 1mm or more; raised troponin I, T, or creatine kinase MB isozyme; known coronary artery disease; or all four other unstable angina risk criteria as defined by the TIMI study group. Exclusion criteria: Exclusion criteria included acute ST-segment elevation MI or shock; bleeding diathesis or major bleeding episode within 2 weeks; thrombocytopenia; calculated creatinine clearance less than 30 ml per min; recent administration abciximab, warfarin, fondaparinux, fibrinolytic agents, bivalirudin, or two or more doses low molecular mass heparin; and allergy to study drugs or iodinated contrast that could not be adequately premedicated. Note: Aspirin ( mg orally or mg intravenously) administered daily during hospitalisation, followed by 75 to 325 mg daily after discharge. Initial timing and dosing clopidogrel were left to investigator discretion although a loading dose 300mg or more was required no later than 2 h after PCI. Baseline characteristics: Baseline characteristics were well balanced among study groups. Heparin (unfractionated or enoxaparin) plus GPIIb/IIIa inhibitors N= 4,603 Unfractionated heparin was administered as an intravenous bolus 60 IU/kg plus infusion 12IU/kg per hour to target an activated partial thromboplastin time s before angiography and an activated clotting time s during PCI. Enoxaparin 1mg/kg twice daily delivered subcutaneously was administered before angiography, with an additional 0.3 mg/kg or 0.75 mg/kg intravenous bolus given before PCI if the most recent subcutaneous dose had been given more than 8 or 16 hours earlier, respectively. Bivalirudin plus GPIIb/IIIa inhibitors N= 4,604 bivalirudin alone, N=4,612 Bivalirudin was initiated with an intravenous bolus 0.1 mg/kg and an infusion 0.25 mg//kg per hour. An additional intravenous bolus 0.5 mg/kg was administered before PCI, and the infusion was increased to 1.75 mg/kg per hour. followup 30 days Primary endpoints: Composite ischaemia (death, MI or unplanned revascularisation). Major bleeding (not related to CABG surgery). Net clinical outcomes (composite ischaemia or major bleeding). Other outcomes: Minor bleeding All major bleeding Bleeding according to the TIMI scale (major and minor) funding Medicines Co. and Nycomed Heparin + GPIIa/IIIb Bivalirudin + GPIIa/IIIb Bivalirudin alone

30 Age Male 70.6% 69.9% 69.3% Baseline STsegment deviation 1 mm 35.2% 35.4% 34.3% Elevation troponin levels Aspirin before angiography or PCI: Clopidogrel before angiography or PCI: ASA taken regularly after hospital discharge through 30 days Thienopyridine taken regularly after hospital discharge through 30 days Beta-blocker taken regularly after hospital discharge through 30 days ACE or ARB taken regularly after hospital discharge through 30 days Statin taken regularly after hospital discharge through 30 days 58.3% 57.2% 59.2% 98.0% 97.8% 97.9% 62.3% 64.2% 63.9% 92.7% % 68.6% 68.6% 76.2% 77.2% % %

31 Effect size Angiography was performed during initial hospitalisation in 99% patients (median 19.6 h after admission). 56% underwent PCI, 11% underwent CABG, 33% medical therapy. NSTEMI 59% UA 41% Heparin (unfractionated or enoxaparin) plus GPIIb/IIIa inhibitors VERSUS Bivalirudin plus GPIIb/IIIa inhibitors Primary endpoints: Composite ischaemia (death, MI or unplanned revascularisation) The proportion individuals with composite ischaemia outcomes at 30 days was not significantly different in those who received bivalirudin plus GPIIb/IIIa inhibitors compared with those who received heparin plus GPIIb/IIIa inhibitors: 356 (7.7%) patients vs 334 (7.3%) patients, (relative risk [RR], 1.07; 95% CI, 0.92 to 1.23; p= 0.39). Major bleeding (not related to CABG) The proportion individuals with major bleeding by 30 days was not significantly different in those who received bivalirudin plus GPIIb/IIIa inhibitors compared with those who received heparin plus GPIIb/IIIa inhibitors: 243 (5.3%) patients vs 262 (5.7%) patients, (RR, 0.93; 95% CI, 0.78 to 1.10; p= 0.38). Net clinical outcomes (composite ischaemia or major bleeding) The proportion individuals with net clinical outcomes at 30 days were not significantly different in those who received bivalirudin plus GPIIb/IIIa inhibitors compared with those who received heparin plus GPIIb/IIIa inhibitors: 541 (11.8%) patients vs 538 (11.7%) patients, (RR, 1.01; 95% CI, 0.90 to 1.12; p= 0.93). All major bleeding: Reported in 512 patients (11.1%) assigned to bivalirudin plus GPIIb/IIIa inhibitors vs 543 patients (11.8%) assigned to heparin plus GPIIb/IIIa inhibitors (p=0.31-ns). Minor bleeding: Reported in 1001 patients (21.7%) assigned to bivalirudin plus GPIIb/IIIa inhibitors vs 993 patients (21.6%) assigned to heparin plus GPIIb/IIIa inhibitors (p=0.84-ns). Bleeding according to the TIMI scale: Major TIMI bleeding was reported in 76 patients (1.7%) assigned bivalirudin plus GPIIb/IIIa inhibitors vs 86 patients (1.9%) assigned to heparin plus GPIIb/IIIa inhibitors (p=0.43-ns) and to minor TIMI bleeding was reported in 281 patients (6.1%) assigned to bivalirudin plus GPIIb/IIIa inhibitors vs 295 patients (6.4%) assigned to heparin plus GPIIb/IIIa inhibitors (p=0.54-ns) Heparin (unfractionated or enoxaparin) plus GPIIb/IIIa inhibitors VERSUS Bivalirudin alone Outcome Heparin (unfractionated or enoxaparin) plus GPIIb/IIIa inhibitors Bivalirudin alone RR (95% CI) p-value Composite ischaemia (death, MI or unplanned revascularisation) 7.3% 7.8% 1.08 ( ) NS Net clinical outcomes (composite ischaemia or major bleeding) 11.7% 10.1% 0.86 ( ) Major bleeding (not related to CABG) 5.7% 3.0% 0.53 ( ) <0.001 ALL Major bleeding 11.8% 9.1% Not reported <0.001 Minor bleeding (not related to CABG) 21.6% 12.8% Not reported <0.001 Note: There was no significant difference between treatment groups for any the components the primary endpoints. SV Comments: This study In a nutshell: In patients with ACS who were undergoing invasive treatment with GP IIb/IIIa inhibitors, bivalirudin was associated with rates ischemia and bleeding that were similar to those with heparin.