Patient characteristics Intervention Comparison Length of follow-up

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1 ANTIPLATELET CHAPTER Aspirin compared with placebo Ref ID: 4158 Reference Antithrombotic TC. Collaborative meta-analysis randomised trials antiplatelet therapy for prevention death, myocardial infarction, and stroke in high risk patients (Structured abstract). BMJ. 2002; 324(7329): Ref ID: Study type/ Evidence level SR: 1+ Search: Medline, Embase, Derwent, Scisearch, Biosis, Cochrane Stroke and PVD disease groups, manual searches; contacted investigators to get patient data Note: only metaanalysis aspirin versus placebo in unstable angina population presented Number patients Total RCTs = 195 RCT (unstable angina population) = 12 N high risk patients ( occlusive arterial disease) = Subgrouped into previous MI (12 RCT) Acute MI (15 RCT) Previous stroke/tia (21 RCT) Acute stroke (7 Patient characteristics Intervention Comparison Length follow-up Inclusion: RCTs available in 1997 comparing an antiplatelet with a placebo control in patients considered to be at high risk vascular events because existing disease or previous occlusive event. Only trials with appropriate allocation concealment included and only difference between 2 arms was antiplatelet therapy. Oral antiplatelet trails eligible providing they were assessed for more than 1 day treatment. Exclusion: poor randomisation; confounding; large loss to follow-up; abandoned study; cross-over design; patients with dementia or occluded retinal veins Aspirin in unstable angina patients N= 2497 Placebo in unstable angina patients N= 2534 Range 6 days 18 months) in the unstable angina population Outcome measures Vascular event (defined as nonfatal MI, nonfatal stroke, or death from a vascular cause or death from an unknown cause) Source funding MRC, BHF, Imperial Cancer Research Fund, Stroke Association, Chest, Heart and Stroke Scotland, Edinburgh University

2 RCT) Other high risk (140 RCT) Effect Size Outcome RCTs Total N Antiplatelet (% events) Placebo (% events) RR (95% CI) vascular events (nonfatal MI, nonfatal stroke, or death from a 12 unstable angina (0.51, vascular cause or death from an unknown cause) population 0.71) % odds reduction (SE) 46 (7) Compared to those treated with placebo, people with unstable angina treated with antiplatelet agents (predominantly aspirin) had a significantly lower risk vascular events. Data for other high risk populations (acute MI, acute stroke, previous stroke, previous MI, etc) not presented here. CLOPIDOGREL Reference Chan AW, Moliterno DJ, Berger PB, Stone GW, DiBattiste PM, Yakubov SL et al. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year Study type Evidence level Post-hoc TARGET study 1 2+ Number patient s N= 4,809 Patient characteristics Intervention Comparison Length followup Inclusion criteria for this post-hoc: In all patients included by the study a loading dose 300 mg clopidogrel at least 2 to 6 h before the procedure was recommended. Alternatively, the same dose clopidogrel could be given just before the PCI procedure if it were performed immediately following diagnostic angiography. The timing clopidogrel administration was at the interventional cardiologists discretion. Clopidogrel pretreatment group Aspirin 2 + GP IIb/IIIa + heparin + Clopidogrel 3 N= 4,477 Placebo Aspirin + GP IIb/IIIa + heparin + Placebo N= 332 one year Outcome measures Primary endpoint: composite death, nonfatal MI, or urgent TVR within 30 days the index procedure Secondary endpoints: Primary outcome at six months and mortality at one year. Source funding Merck 1 This double-blind RCT enrolled 4,809 patients undergoing elective or urgent PCI-stent native coronary vessels or bypass grafts. Patients were randomized to receive a bolus and infusion either abciximab or tiriban. 2 All patients received 250 to 500 mg aspirin within 24 h before the procedure and 75 to 325 mg/day following the procedure. At the time procedure, heparin was administered to achieve an activated clotting time > 250 s.

3 survival: results from the Do Tiriban and ReoProGive Similar Efficacy Outcome Trial (TARGET).[see comment]. J Am Coll Cardiol 2003; 42(7): Ref ID: 255 Patients who received clopidogrel before either abciximab or tiriban was given were categorized into the clopidogrel pretreatment group. Otherwise, a 300-mg loading dose clopidogrel was to be given as early as possible after the procedure. Clopidogrel was continued for 30 days after PCI at a dose 75 mg daily. All patients were categorized according to whether they received pretreatment with clopidogrel or not. Baseline characteristics: Of the 4,809 patients enrolled, 4,477 (93.1%) were given clopidogrel before PCI. The two groups were similar regarding CV risk prile, the prevalence comorbidities, and indication for coronary revascularization. Compared with patients who did not receive clopidogrel before PCI, clopidogrel-pretreated patients were more likely to receive aspirin, beta-blockers, calcium-channel blockers, and lipid-lowering therapy before their procedures (see * below). Clopi pretreatment No Clopi Age Men 74% 72% LVEF >50% 73% 73% 30-50% 25 % 23% >30% 2 % 4% Previous MI 40% 37% Previous PCI 30% 27% Previous CABG 17% 13% Medications Randomized to abciximab 49.8% 54.2% ASA (within 24h) 97% 93% * ACEi 37% 32% B-blockers 66% 58% * Bleeding

4 Effect size CCB 32% 24% * Lipid-lowering 61% 49% * Nitrates 59% 59% Indication for PCI Q-wave MI 5% 5% Non-Q-wave MI 10% 9% Unstable angina 47% 51% Stable angina 37% 34% The primary composite end point death, MI, or urgent TVR at 30 days occurred in 10.4% patients without pretreatment and in 6.6% patients with clopidogrel pretreatment (p= 0.009). The benefit clopidogrel pretreatment was predominantly due to a reduction in MI (9.5% vs. 6%, p = 0.012) There was NS difference in the primary endpoint between patients who received pretreatment for 0 to 2 h and those who were pretreated for 2 to 6 h Compared with patients who did not receive clopidogrel until after PCI, those who were pretreated 0 to 6 h before the procedure had a 34% lower composite event rate (6.9% vs. 10.4%, p= 0.021) Compared with those who were pretreated for <6 h, patients who were clopidogrel-loaded for >6 h before PCI had a 29% lowering in 30-day events (6.9% vs. 4.9%, p= 0.045) Abciximab vs tiriban When given to patients randomized to tiriban therapy, clopidogrel pretreatment relatively reduced the 30-day event rate by 43%, from 12.8% to 7.3% (p = 0.017). Likewise, patients who were pretreated with clopidogrel and received abciximab had a 30% relative reduction in the composite event rate (from 8.4% to 5.9%, NS) compared with abciximab without clopidogrel pretreatment Bleeding There were not significant differences in the incidence major and minor bleeding, and frequency transfusion between those patients receiving clopidogrel pretreatment and those who did not receive it. 4. Reference Cuisset T, Frere C, Quilici J, Morange PE, Nait SL, Carvajal J et al. Benefit a 600-mg loading dose clopidogrel on platelet Study type Evidence level RCT 1+ Number patients N=292 Patient characteristics Intervention Comparison Length followup Inclusion criteria: Consecutive patients admitted for NSTE ACS to the Department Cardiology the Timone hospital between June 2004 and October 2005 were eligible for this trial if they had undergone successful coronary stenting. 300-mg Clopidogrel loading dose 5 N= mg Clopidogrel loading dose N= month 6 Outcome measures Composite CV endpoint: CV death, acute or subacute stent thrombosis, recurrent ACS, and stroke Source funding Public Hospital Marseill e. 4 Whereas the overall TARGET study showed a 26% relative risk reduction in primary end point with abciximab as compared with tiriban, the superiority abciximab was attenuated among patients who received clopidogrel pretreatment 5 KEY POINTS: Patients were randomly assigned to receive a 300mg or 600mg loading dose clopidogrel at least 12h before stenting. All patients received aspiring 160mg daily after a loading dose 250mg administered at least 12h before stenting. The PCI was performed within 48h after admission. For all patients, anticoagulation was begun before PCI in the ICU and performed with LMWH (enoxaparin) or UFH in patients over 75 years old or with renal insufficiency. 6 One month follow-up was completed in all patients

5 reactivity and clinical outcomes in patients with non-st-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48(7): Ref ID: 103 Exclusion criteria: history bleeding diathesis, persistent ST elevation ACS, HF class IV (NY Heart Association). PCI or CABG < 3months, contraindications to antiplatelet therapy, platelet count <100 g, creatinine clearance <25ml/min, and use glycoprotein IIb/IIIa before the procedure. Patient characteristics: A total 387 NSTE ACS patients who fulfilled the enrolment criteria were randomized to a 300-mg (N= 192) or 600-mg (N=195) loading dose clopidogrel. After coronary angiography, 95 patients who did not receive successful angioplasty were excluded from the study (72 were treated medically, 20 with elective bypass surgery and 3 with failed PCI). The demographic, clinical, and therapeutic parameters were similar in the 300-mg and 600-mg groups (NS differences. Baseline characteristics: 300mg 600mg Age: Men: 79% 73% BMI: Risk factors: Previous ACS 44% 45% Hypertension 58% 56% Diabetes 29% 33% Admission ECG ST segment changes 22% 25% Anticoagulation LMWH 65% 68% UFH 35% 32% Positive troponin I on admission 26% 21% Major bleeding: defined as intracranial bleeding or clinically overt bleeding associates with a decrease haemoglobin 5g/dl

6 LVEF 56% 55% Medications Statins 60% 61% B-Blockers 49% 42% Diuretics 16% 16% Effect size Loading dose Clopidogrel : 300mg vs 600mg CV outcomes Recurrent ischemic events occurred more frequently in the 300mg [18 (12%)] group than in the 600mg group [7 (5%)]. p=0.02. This difference was not affected by adjustment for potential confounders such as age, gender, CV risk factors, troponin elevation, ST-segment changes, LVEF, or tiriban use (p= 0.035) Distribution the CV events: 300 mg group 15 hospitalizations for recurrent ACS (2 acute stent thrombosis) 2 strokes 1 CV death Bleeding 600 mg group 6 hospitalizations for recurrent ACS (1 acute stent thrombosis) 1strokes No patient in either group had postprocedural major bleeding or required transfusions. Ref ID: 4178 Reference Study type/ Evidence level Number patients Patient characteristics Intervention Compari son Length follow-up Outcome measures Sourc e fundin g

7 Yong G, Rankin J, Ferguson L et al. Randomized trial comparing 600- with 300-mg loading dose clopidogrel in patients with non- ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: results the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial. American Heart Journal. 2009; 157(1): RCT 1+ Randomised Double blind ITT Overall drop out rate (Missing 6 month follow up): 7/256 = 2.7% 256 Inclusion criteria: NSTEACS (ischaemic symptoms lasting >=10 minutes without persistent ST elevation on ECG) and had at least one the following high risk features: ischaemic ECG changes (>=2 leads demonstrating ST depression >=0.5 mv, T- wave inversion >=2 mv, or transient ST elevation >=1mm), elevated cardiac troponin, or history coronary artery disease (previous MI, coronary revascularization, or positive stress test). Pts also had to be scheduled for coronary angiography no sooner than 2 hours after the study drug administration, with a view to performing PCI no later than midnight the following day. Exclusion criteria: treatment with abciximab, a thienopyridine, or dipyridamole within the previous 7 days; treatment with eptifibatide, tiriban, or nonsteroidal anti- 600 mg LD clopidogrel (All pts received an initial open label dose 300mg clopidogrel and then either a further 300mg clopidogrel or 300mg placebo blinded) 300 mg LD clopidogr el 6 months Primary: Post-PCI myonecrosis (defined as postprocedure troponin I > preprocedure troponin I and > 5X UL reference range (0.1 ng/ml) Secondary: Death MI Stroke Target vessel revascularizati on Hospitalization for recurrent ischemia to 6 months Unrest ricted educat ional grant from Sani - Aventi s

8 inflammatory drug within the previous 48 hours; inability to take aspirin or clopidogrel; and high risk bleeding Baseline and angiographic characteristics: 300mg 600mg (N=12 (N=13 4) 2) Age 64.2+/ / Male 65% 76.3% Elevat ed troponi n on presen tation Ischae mic ECG chang es Left vein diseas e Multive ssel 82.1% 81.1% 43.9% 40.9% 5.74% 9.85% 55.6% 52.3%

9 diseas e PCI 57.3% 52.3% Medica 32.3% 31.8% l manag ement CABG 10.4% 15.9% Mean delay between open label clopidogrel and study drug administration was 5.25 hrs (SD=6.10hrs). Mean time between study drug administration and angiography was 13.2 hrs (SD=14.4 hrs) and between study drug administration and PCI was 16.1 hrs (SD=10.9 hrs) Effect Size Primary outcome: Post-PCI myonecrosis Post-PCI myonecrosis occurred in 39.1% clopidogrel 300 mg group and in 39.1% clopidogrel 600 mg group (p=1.0) Clopidogrel 300mg (N=124) Clopidogrel 600mg (N=132) RR (95% CI) P value Clinical ischemic events at 6mths Death 2 (1.65%) 1 (0.78%) 2.13 (

10 23.19) MI 6 (4.96%) 11 (8.59%) 0.58 ( ) Stroke 0 1 (0.78%) 0.35 ( ) Target vessel 4 (3.31%) 3 (2.34%) 1.42 (0.32 revascularization 6.21) Hospitalization for 12 (9.91%) 11 (8.59%) 1.16 (0.53 recurrent ischemia Death / nonfatal MI / nonfatal stroke / hospitalizations for recurrent ischemia 2.53) 16 (!3.2%) 17 (13.3%) 1.00 ( ) Hemorrhage at 1 month TIMI major 3 (2.42%) 2 (1.52%) 1.60 ( ) TIMI major CABG related 1 (0.81%) 1 (0.76%) 1.06 ( ) TIMI major Non-CABG 2 (1.61%) 1 (0.76%) 2.12 (0.20 related 23.19) TIMI minor 3 (2.42%) 3 (2.27%) 1.06 ( ) Transfusion 5 (4.03%) 8 (6.06%) 0.67 ( ) Other adverse events at 1 month Rash 4 (3.39%) 7 (5.43%) 0.62 ( ) Thrombocytopenia 1 (0.81%) 1 (0.76%) 1.06( ) Reference Study type Number Patient characteristics Intervention Comparison Length Outcome measures Source

11 Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ et al. Benefits and risks the combination clopidogrel and aspirin in patients undergoing surgical revascularization for non-st-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110(10): Ref ID: 216 followup 3-12 months (mean 9 months) Eviden ce level Posthoc analysis CURE 1+ patients N= 12,562 N= 2,072 CABG N= 2,658 PCI N= 7,985 MEDICAL Inclusion criteria : Patients who presented with acute coronary syndromes without ST-segment elevation. Patients were eligible for the study if they had been hospitalized within 24 hours after the onset symptoms and had either electrocardiographic changes or an elevation in the serum level cardiac enzymes or markers at entry. Exclusion criteria: Patients with contraindications to antithrombotic or antiplatelet therapy, those who were at high risk for bleeding or severe heart failure, those who were taking oral anticoagulants, and those who had undergone coronary revascularization in the previous three months or had received intravenous glycoprotein IIb/IIIa receptor inhibitors in the previous three days were excluded. Clopidogrel 300mg loading dose CABG N= 1,011 PCI N= 1,313 Placebo CABG N= 1,061 PCI N= 1,345 Primary endpoint: Composite CV death, MI, or stroke Secondary endpoints: The above composite plus refractory ischemia 7. Bleeding complications, which were categorized as life-threatening, major (requiring the transfusion 2 or more units blood), or minor. funding Sani & BMS Baseline characteristics: Baseline characteristics among CABG patients assigned placebo and clopidogrel were well balanced link 7 It was defined as recurrence angina with new ECG changes despite optimal antianginal and antithrombotic therapy that required an emergent intervention or transfer for an intervention within 24 hours.

12 Effect size Patients undergoing CABG 8 The primary outcome occurred in 16.2% placebo-treated patients and 14.5% clopidogrel-treated patients (RR, 0.89; 95% CI, 0.71 to 1.11) undergoing CABG. However, this difference was not statistically significant Benefits were observed mainly before the procedure; 71 patients (6.7%) experienced a primary endpoint in the placebo group compared with 57 (5.6%) in the clopidogrel group (RR, 0.82; 95% CI, 0.58 to 1.16). After CABG surgery, similar numbers events occurred in the placebo and clopidogrel groups (112 vs. 103; RR, 0.97; 95% CI, 0.74 to 1.26). Patients undergoing PCI Clopidogrel was associated with a significant RR reduction in the primary endpoint in patients undergoing PCI. 126 clopidogrel-treated patients (9.6%) experienced the primary outcome, compared with 177 (13.2%) placebo-treated patients (RR, 0.72; 95% CI, 0.57 to 0.90; p< 0.004) PCI-CURE study 2001 Patients treated medically (no revascularization procedure) In this group, 10% patients treated with placebo experienced the primary endpoint compared with and 8.1% rate in the clopidogrel group. (RR 0.80; 95% CI 0.69 to 0.92; p< 0.003) CABG & Bleeding 9 Of patients who underwent CABG after randomization, 80 placebo patients (7.5%) and 97 clopidogrel patients (9.6%) experienced major bleeding (NS) Of these, 60 placebo patients (5.7%) and 71 clopidogrel patients (7.0%) fulfilled the CURE criteria for life-threatening bleeding (NS). Whereas no excess in any bleeding was observed for patients stopping clopidogrel for > 5 days before surgery, a nonsignificant excess in major bleeding was seen for those who continued the drug within 5 days surgery 10. Clopidogrel in patients undergoing CABG - Risk & benefits Risks and benefits overall may be considered by combining the primary end point and life-threatening or major bleeding. Overall, for the primary endpoint or life-threatening bleeding, the RR is 0.84 (95% CI, 0.76 to 0.93), very similar to those treated by medical therapy only (RR, 0.82; 95% CI, 0.72 to 0.95). Including major bleeding and refractory angina with the primary end point gives an RR 0.87 (95% CI, 0.79 to 0.96; p< 0.005). In those treated by any revascularization, the RR is 0.87 (NS). For those undergoing CABG, the corresponding RR is 0.98 (NS). 8 The median time from randomization to CABG was 25.5 days (interquartile range, 12 to 70.5 days). The time to CABG for those undergoing the procedure during the initial hospitalization (N= 1,013) was 12 days (interquartile range, 8 to 19 days) for the placebo group and 13 days (interquartile range, 8 to 21 days) for the clopidogrel group. For those undergoing later CABG (N= 1,057), the respective figures are 73 days (interquartile range, 36 to 129) for placebo and 67.5 days (interquartile range, 38 to 141 days) for clopidogrel. 9 For the entire study, major bleeding occurred in 169 placebo patients (2.7%) and 231 clopidogrel patients (3.7%; RR 1.38, 95% CI, 1.13 to 1.67; p< 0.001). However, the impact on life-threatening bleeding was not statistically significant: 112 placebo patients (1.8%) and 135 clopidogrel patients (2.2%; RR, 1.21; 95% CI, 0.95 to 1.56; p< 0.13). There was no excess when bleeding was classified according to TIMI major bleeding criteria.

13 Reference Lewis BS, Mehta SR, Fox KA, Halon DA, Zhao F, Peters RJ et al. Benefit clopidogrel according to timing percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. American Heart Journal 2005; 150(6): Ref ID: 154 Patient characteristics Intervention Comparison Length followup Study type Eviden ce level Posthoc study the CURE trial 1+ Number patients N= Inclusion criteria : patients included were 2, those hospitalized within 24 hours symptom onset with ischemic changes on ECG (non-stsegment elevation) or elevated cardiac enzymes or markers to at least twice the upper limit or normal. Pi 1. in 370 patients early (<48 hours) after randomization Median time from randomization to PCI = 1.0 days 2. in 1,360 later during hospitalization ( 48hours after randomization) Median time from randomization to PCI = 6.8 days 3. in 928 at a later point in time (after initial hospital discharge) Median time from randomization to PCI = 47.6 days Clopidogrel 300mg loading dose 12 N = 1,313 PCI < 48hours N= 178 PCI 48hours N= 643 PCI after discharge N=492 Placebo 13 ) N= 1,345 PCI < 48hours N= 192 PCI 48hours N= 717 PCI after discharge N= 436 Mean 9 months Outcome measures Primary endpoint: CV death and Non fatal MI Bleeding Source funding Sani & BMS Baseline characteristics: The 3 groups were similar in age, sex, prevalence diabetes mellitus, and systemic hypertension. Patients undergoing PCI early (< 48h) tended to have a lower prevalence previous MI (p= 0.098) and higher prevalence previous PCI (p= 0.068) reflecting common clinical practice. Patients had an admission diagnosis NSTEMI (as opposed to UA) more frequently (p=0.054). The median TIMI risk score was 10 Before CABG, 1928 (93.1%) the patients who proceeded to CABG stopped the study drug before CABG, and 66 (3.2%) continued the drug (data on timing was not available for 78 patients). Of the 1928 patients who stopped the study drug before CABG, 1451 (75.3%) restarted after CABG. The median time f the study drug before CABG was 17 days (interquartile range, 9 to 33) and the median time after CABG was 10 days (interquartile range, 6 to 25). 11 A subset 2,538 patients who underwent PCI during the CURE study period (N= 12,562) forms the basis the present report. 12 Followed by 75mg/d orally 13 Aspirin was administered at doses (75-325mg day) selected by the treating physician

14 identical in the 3 patient subsets, but the propensity to undergo PIC was higher in the early (< 48hours) patient subset (p> ) PCI included stent placement more frequently in patients undergoing PCI early or during initial hospitalization (p= 0.047). Open label thienopyridine use was higher in these 2 groups (p< ) but open label thienopyridine use before PCI was less frequent in patients undergoing earlier intervention. There was a greater use platelet glycoprotein IIb/IIa inhibitors in patients undergoing early PCI than those later during hospitalization, and use these drugs was less frequent when PCI was performed after initial hospital discharge. There was no difference in the distribution procedural and periprocedural variables within the groups, apart from a tendency to lesser use glycoprotein IIb/IIa inhibitors in patients treated with clopidogrel, especially in the inhospital PCI group.

15 Effect size Clopidogrel was associated with a lower incidence CV death/non fatal MI from the time randomization to end follow-up for the group as a whole (8.8% vs 12.6%, RR 0.69; 0.54 to 0.87 p= 0.002) There was also a consistent benefit with Clopidogrel across all 3 patient subsets by timing PCI (although NS statistical differences were reported in any group) * PCI < 48 hours 6.7% vs. 12.5%, RR 0.53, 95% CI 0.27 to 1.06 * PCI in-hospital group 8.7% vs. 11.9%, RR 0.72, 95% CI 0.51 to 1.01 * PCI post-discharge 9.8% vs. 13.8%, RR 0.70, 95% CI 0.48 to 1.02 In patients treated with clopidogrel, the absolute event rate (AER) was lower and relative risk reduction (RRR) was greater the earlier PCI was performed (NS) * PCI < 48 hours AER 6.7% RRR 47% * PCI in-hospital group AER 8.7% RRR 28% * PCI post-discharge AER 9.8% RRR 30% No clear relationship was found between the timing PCI and subsequent risk death or nonfatal MI in the placebo group * PCI < 48 hours 12.5% * PCI in-hospital group 11.9% * PCI post-discharge 13.8% Secondary endpoints: Mortality alone was low in all subgroups and not altered by administration clopidogrel (early PCI group 2.2% vs 3.6%, inhosptial PCI 2.3% vs 2.6%, post-discharge 2.6% vs 1.1%, all p= NS) MI alone was low in patients randomized to clopidogrel, particularly in the pre-pci period and particularly in patients undergoing early (0.6% vs 2.1%) or inhosptial (2.0% vs 4.0%) intervention. (all p= NS). After PCI, there was little difference in the rate MI by timing PCI. IIb/IIIa inhibitors: the rate CV death/nonfatal MI was higher in patients treated with IIb/IIIa inhibitors, both for the group as a whole (16.3% vs 9.0% p<0.0001)) and for those not treated with clopidogrel (placebo group) 18.8% vs 10.3% p< The findings were consistent in all groups, irrespective timing PCI. 14 Bleeding The rate major and life-threatening bleeds was identical in the 3 patients subsets irrespective treatment allocation. Reference Study Number Patient characteristics Intervention Comparison Length Outcome measures Source 14 This suggested that the low event rate in the early PCI patients was related to clopidogrel treatment rather than administration the glycoprotein IIb/IIIa inhibitors

16 Steinhubl SR, Berger PB, Brennan DM, Topol EJ. For the CREDO investigators. Optimal timing for the initiation pretreatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006; 47(5): Ref ID: 856 type Eviden ce level Post hoc analysis an double blind, multicen tre RCT 2+ patients N=1, from 99 centres in North America Inclusion criteria : Inclusion criteria: patients who had symptomatic coronary arteria disease with objective evidence ischaemia, were referred for PCI or thought to be at high likelihood for requiring PCI with either stent placement with or without conventional balloon angioplasty or another revascularization device; were at least 21 years old. Exclusion criteria: major exclusion criteria included contraindications to antithrombotic/antiplatelet therapy; greater than 50% stenosis the left main coronary artery; failed coronary intervention in the previous 2 weeks; coronary anatomy no amenable to stent placement; persistent ST elevation within 24 hours prior to randomization; planned staged interventional procedure; and administration the following medications prior to randomization: GpIIb-IIIa inhibitor within 7 days, clopidogrel within 10 days, or thrombolytics within 24 hours. Clopidogrel pretreatment < 15h 16 N= 645 Clopidogrel pretreatment 15h N= 202 Placebo N= 915 followup 28 days Primary endpoint: a composite death, MI, or Urgent Target Vessel Revascularization at 28 days Major bleeding (defined as intracranial bleeding or bleeding associated with a decrease in haemoglobin more than 5g/dl. funding Sani- Aventis and Bristol- Myers Squibb Baseline demographics in the 2 treatment groups were well matched, although there was less use statins and calcium channel blockers in the clopidogrel arm Baseline characteristics: Placebo Clopi<15h Clopi 15h Age BMI Men 70.7% 71.8% 70.3% 15 The present analysis includes only those 1,815 patients who underwent a PCI shortly after enrolment, during the index catheterization. The timing study drug was able to be analyzed in 1,762 these 1,815 patients, and they comprise the study population. 16 Patients were randomly assigned to receive a 300-mg clopidogrel loading dose or placebo 3 to 24 hours before PCI (at this stage all the patients also received 325mg aspirin) Thereafter, all patients received clopidogrel, 75mg/d, through day 28. from day 29 through 12 months patients in the loading-dose group received clopidogrel, 75mg/d, and those in the control group received placebo. Both groups continued to receive standard therapy including aspirin ( mg/d, at the discretion the investigator, until the end the 12-month treatment period. The present analysis is only the relationship between duration pre-treatment and outcome at 28 days.

17 Hypertension 69.3% 67.3% 68.3% Diabetes 25.7% 28.0% 27.7% Hyperlipidaemia 78.2% 76.2% 81.5% Previous MI 34.7% 32.8% 41.1% Previous PCI 29.9% 26.0% 28.2% Previous CABG 16.3% 16.3% 13.8% Indication for procedure: UA 53.6% 53.4% 47.0% Recent MI 13.5% 14.8% 16.3% SA 28.4% 26.0% 30.2% PCI success <50% residual stenosis 96.9% 96.3% 98.2% IIb/IIIa antagonist used 43.3% 49.8% 42.6%

18 Effect size The mean duration pre-treatment was 9.8 hours. The incidence the 28-day endpoint was similar in those patients randomized to the placebo arm and those randomized to the clopidogrel arm who had therapy initiated <15h before PCI. (8.3% vs. 7.8% respectively NS differences) The RR reduction in those pre-treated with clopidogrel from 15h compared with the placebo arm was 58.8% (p= 0.028). The incidence the endpoint in patients receiving clopidogrel 15h was 3.5% (for pre-treatment 15h versus placebo, p = 0.018; for for pre-treatment 15h versus < 15h, p= 0.033) a) This RR reduction associated with 15h clopidogrel pretreatment before PCI was unchanged when only those patients in the placebo (N= 206) and treatment (N= 202) arms who had been pre-treated 15h were compared (9.7% vs. 3.5%; RR reduction 66.6%, 95% CI (19.2 to 56.2%), p= b) When all pertinent baseline and procedural characteristics were evaluated in a multivariate analysis, clopidogrel pretreatment for 15h remained a significant predictor the 28-day endpoint (OR 0.72; p= 0.043) Among the patients randomized to placebo, no relationship was found between the duration pre-treatment and the occurrence the primary 28-day combined endpoint. On the other hand, patients randomized to receive a 300mg loading dose clopidogrel had a strong relation ship between the duration pretreatment and occurrence the primary endpoint. Unexpectedly, no separation between the placebo and treatment arm curves was seen until after 10 to 12h pre-treatment and this difference did not become statistically significant until after 15h pretreatment. 17 Bleeding The incidence major and minor bleeding at 28 days was not significantly different between the placebo arm, those patients pretreated <15h, and those patients pretreated 15h GLYCOPROTEIN IIB/IIIA INHIBITORS What is the efficacy and safety GpIIb/IIIa inhibitors (tiriban, eptifibatide and abciximab) in the medical management patients with UA or NSTEMI compared to other antiplatelets or placebo? What is the efficacy and safety GpIIb/IIIa inhibitors (tiriban, eptifibatide and abciximab) as adjunct therapy to patients with UA/ NSTEMI undergoing PCI compared to other antiplatelets or placebo? Reference Study type Eviden ce level Number patients Patient characteristics Intervention Comparison Outcome measures Source funding 17 The log odds the 28-day combine endpoint continued to decrease out to the maximal duration pretreatment in this study, 24h.

19 Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de WF et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a metaanalysis all major randomised clinical trials. Lancet 2002; 359(9302): Ref ID: 242 Metaanalysis 6 RCTs 1+ 31,402 patients in 41 countries. Inclusion/Exclusion criteria : Trials reported since 1990 with the following characteristics: randomisation patients with acute coronary syndromes without persistent ST segment elevation; comparison a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non recommendation early (<48 h) coronary revascularisation during study-drug infusion; and enrolment at least 1,000 patients. RCTs included: Six trials were identified that fulfilled the inclusion criteria: PRISM (tiriban), PRISM- PLUS (tiriban), PARAGON-A (Lamifiban), PURSUIT (Eptifibatide), PARAGON-B (Lamifiban), and GUSTO-IV ACS (Abciximab) GP IIb/IIIa inhibitor Placebo or control Primary endpoint: 5-day composite death or nonfatal MI ( note that MI was part the composite efficacy endpoint all trials, but the applied MI definitions were different, especially with regard to the required level increased CK or CK- MB concentrations. Still, given that heterogeneity in an endpoint definition will not lead to invalid results, the meta-analysis applied the trial-specific definition MI for practical reasons. There were also between-trial differences with regard to the definition major bleeding, which was the primary safety endpoint. Again the trial-specific definitions were retained) No industry funding Patients Characteristics at baseline There were no important differences in baseline characteristics between patients randomly assigned glycoprotein IIb/IIIa inhibitors (n=18,297) and those assigned placebo or control (n=13,105). The mean age the population was 64 years, 65% were men, and 76% had a history CV disease. 56% the patients presented with STsegment depression, 46% with raised CK- MB concentrations, and 80% with either one these features. 30-day composite death or nonfatal MI Bleeding Data analysis In the primary analysis, this meta-analysis intended to assess event rates at the end study-drug infusion. There were, however, important between-trial differences in the duration study-drug infusion as required per protocol, and analyses event rates at different points in time across the studies might have resulted in heterogeneous estimates treatment effect. Authors, therefore decided to assess early event rates 120 h (5 days) after randomisation, since study-drug infusion should have stopped at

20 that point in each trial. Events were further assessed at 30 days, since this point was the most common among trials. Authors assessed differences between glycoprotein IIb/IIIa inhibitors and placebo or control within each trial, and reported odds ratios and corresponding 95% CI.

21 Effect size Primary endpoint At 5 days: Glycoprotein IIb/IIIa inhibitors were associated with a highly significant 16% relative reduction in the odds death or myocardial infarction at 5 days after randomisation (p=0 0003). The absolute risk reduction with glycoprotein IIb/IIIa inhibitors was largely maintained until 30 days follow-up, but no additional risk reduction was seen between 5 and 30 days At 30 days: The relative risk reduction in the odds death or myocardial infarction at 30 days was 9% (p=0 015). See table below Meta-analysis (6 RCTs pooled) Outcome events at 5 days Glycoprotein IIb/IIIa (N=18 297) Control (N=13 105) Death or MI 1,042 (5.7%) 901 (6.9%) OR (95% CI) 0 84 (0.77 to 0.93) p for treatment effect p for homogeneity Outcome events at 30days Death or MI 1,980 (10.8%) 1,550 (11.8%) 0.91 (0.85 to 0.98) Death 631 (3.4%) 485 (3.7%) 0.91 (0.81, 1.03) Nonfatal MI 1349 (7.4%) 1065 (8.1%) 0.92 (0.85, 1.00) CABG or PCI 6862 (37.5%) 5103 (38.9%) 0.99 (0.94, 1.03) Major bleed 445 (2.4%) 180 (1.4%) 1.62 (1.36, 1.94) < NR Intracranial haemorrhage 16 (0.09%) 8 (0.06%) NR 0.40 NR Note: There was no statistical evidence heterogeneity in treatment effect among the separate trials at either time point (p=0 81 and p=0 34) Subgroup differences Treatment effects in subgroups patients The benefits glycoprotein IIb/IIIa inhibitors were consistent across various prognostically important subpopulations, including those grouped by age, status with regard to diabetes mellitus and history cardiac disease, and condition on admission. The treatment effect seemed larger in patients with ST segment depression than in those without, but the difference did not reach significance. Baseline cardiac troponin data were available in 69% the patients enrolled in PRISM, 6% in PRISM-PLUS, 4% in PURSUIT, 23% in PARAGON-B, and 91% in GUSTO-IV (in PRISM, these data were not strictly baseline values, but were obtained a median 8 h after randomisation). No cardiac troponin data were available in PARAGON-A. Thus, information on baseline cardiac troponins were available in a selected subset 11,059 patients (35% the entire population). Gender differences: A highly significant interaction with respect to cardiac events was seen between sex and allocated treatment. In men, glycoprotein IIb/IIIa inhibitors were associated with a 19% reduction in the odds 30-day death or myocardial infarction compared with placebo or control. By contrast, in women, the point estimate and 95% CI treatment effect were compatible with a risk increase.

22 The sex difference in treatment effect remained (p<0 0001) after adjustment for differences in baseline characteristics by multivariable regression analysis. (There were important differences between men and woman with regard to: age, DM, history MI, history heart failure, history coronary revascularization, ST-segment depression on admission and increased CK- MB concentrations on admission) This sex difference in treatment effect disappeared (p=0 44) if troponin status was added to the multivariable regression equation 18 analysis due to missing data) See table below: (but more than 65% patients were excluded from this All patients Glycoprotein IIb/IIIa Men Control Death or MI 1,242 (10.4%) 1,070 (12.6%) Patients with missing data on baseline cardiac troponin Death or MI 881 (11.6%) 825 (14.3%) Patients with data on baseline cardiac troponin Death or MI 361 (8.5%) 245 (9.0%) Patients with baseline cardiac troponin T or I <0 1 ug/l Death or MI 159 (7.6%) 100 (6.9%) Patients with baseline cardiac troponin T or I 0 1 ug/l Death or MI 202 (9.3%) 145 (11.3%) OR (95% CI) 0.81 (0.75 to 0.89) 0.78 (0.70 to 0.86) 0.93 (0.78 to 1.11) 1.10 (0.84 to 1.43) 0.82 (0.65 to 1.03) Glycoprotein IIb/IIIa Women Control 738 (11.5%) 480 (10.4%) 523 (13.3%) 350 (11.5%) 215 (8.6%) 130 (8.3%) 96 (6.2%) 53 (5.3%) 119 (12.7%) 77 (13.6%) OR (95% CI) 1.15 (1.01 to 1.30) 1.18 (1.02 to 1.36) 1.07 (0.85 to 1.35) 1.29 (0.91 to 1.83) 0.93 (0.68 to 1.28) p for heterogeneity Information on baseline cardiac troponins were available in a selected subset 11,059 patients (35% the entire population). PCI/CABG Glycoprotein IIb/IIIa inhibitors were associated with a significant reduction in death MI until PCI or 30-day follow-up, whichever came first (hazard ratio 0.92 [95% CI 0.86 to 0.99], p=0.030). A similar reduction in this composite endpoint by glycoprotein IIb/IIIa inhibitors was seen until the moment either a PCI or CABG procedure, if any (0.91 [0.84 to 0.99], p=0.027) NOTE: The authors this meta-analysis noted important differences between patients chosen to undergo early PCI and those not chosen. First, they showed that, compared with the placebo patients, significantly fewer patients assigned to the active treatment arms had undergone early PCI (14.9% versus 13.2%; p= 0.049). Among patients who did undergo early PCI, those treated 18 Reduction in the 30- day rate death or myocardial infarction by glycoprotein IIb/IIIa inhibitors was seen in men and women with positive baseline troponins, whereas no risk reduction was seen in patients with negative troponins, irrespective sex.

23 with placebo (compared with active treatment) experienced significantly more MIs before the procedure occurred (OR, 0.70; 95% CI, 0.55 to 0.89). For the subgroup patients who did not undergo an early PCI, the treatment difference was not statistically significant (OR, 0.95; 95% CI, 0.87 to 1.02). However, if all patients in the study were included, using the information during the medical management each patient, then the treatment difference was statistically significant (OR, 0.92; 95% CI, 0.86 to 0.99). Bleeding Glycoprotein IIb/IIIa inhibitors were associated with an increased risk major bleeding complications compared with placebo or control. 2.5% vs. 1.4% respectively OR 1.64; 95% CI, (1.36 to 1.97) p< Glycoprotein IIb/IIIa inhibitors were not associated with a significantly higher rate intracranial haemorrhage (p= 0.40), nor with an increased incidence total stroke. Note: Bleeding results were similar in patients treated with or without heparin JD Comments: This study In a nutshell:

24 At 30 days, a 9% reduction in the odds death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% [1,980/18,297] vs. 11.8% [1,550/13,105] events; odds ratio 0.91 [95% CI 0.84 to 0.98]; p=0.015). An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0.81 [0.75 to 0.89] but not in women (1.15 [1.01 to 1.30]). However, once patients were stratified according to troponin concentration, there was no evidence a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin. Study Limitations Internal validity & External validity: In the six trials under consideration, 12 different regimens were investigated (which included four different glycoprotein IIb/IIIa inhibitors), and the number patients allocated to either these strategies was relatively small, varying from 345 (PRISM-PLUS high-dose tiriban) to 4,722 (PURSUIT high-dose eptifibatide). Indeed, disappointing and divergent findings were seen in GUSTO- IV ACS with abciximab, with the point estimate treatment effect in the 48-h infusion group compatible with a 15% increased risk cardiac events. On these grounds, findings this metaanalysis should be interpreted in relation to the pharmacological properties the applied agents, and in relation to evidence that exists from other investigations. Clinical implications: Glycoprotein IIb/IIIa inhibitors reduce the occurrence death or myocardial infarction in patients with acute coronary syndromes who are not routinely scheduled for early revascularisation. The event reduction is clinically most meaningful in patients at high risk intracoronary thrombotic complications. In a cost-cautious environment, treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered early after admission in high-risk patients, and continued until a decision about whether to revascularise has been made. The authors suggest that combined early intensive therapy with aspirin, heparin, and a glycoprotein IIb/IIIa inhibitor, followed by long term oral therapy with a thienopyridine, might be appropriate and beneficial to the patient. Reference Rfi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Moliterno DJ et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient benefit related to the revascularization strategy. Eur Heart J 2002; 23(18): Study type Eviden ce level Metaanalysis six trials 1+ Number patients Patient characteristics Intervention Comparison Outcome measures Source funding 29,570 Inclusion/Exclusion criteria : Randomized, double-blind, placebo-controlled trials intravenous platelet glycoprotein IIb/IIIa antagonists evaluating the medical management acute coronary syndromes in the absence STsegment elevation RCTs included: 19 Six trials were identified that fulfilled the inclusion criteria: PRISM (tiriban), PRISM-PLUS (tiriban), PARAGON-A (Lamifiban), PURSUIT (Eptifibatide), PARAGON-B (Lamifiban), and GUSTO-IV ACS IIb/IIIa inhibitor Placebo or control Primary endpoint: Death, Death/ non fatal MI Bleeding not reported No Industry funding 19 In PRISMPLUS, the study arm not including heparin (n=345) was discontinued before completion the trials and was not included in this analysis. In PURSUIT, the protocol mandated the discontinuation the lower-dose arm eptifibatide after documentation an acceptable safety prile the higher dose in the interim analysis (N= 1,487), this arm was not included in this analysis. That provided this meta-analysis with a total 29,570 patients compared with the 31,402 included in the meta-analysis performed by Boersma et al.

25 Ref ID: 1880 (Abciximab) Patients Characteristics at baseline Among the 29,570 patients included, 6,337 (21%) underwent PCI, 2,249 (7.6%) had the PCI performed while receiving the GP IIb/IIIa inhibitor, and 20,054 received only medical therapy for their ACS. Data analysis The enzyme definitions MI were CK or CK-MB greater than the upper limit normal in PURSUIT; CK or CK-MB greater than twice the upper limit normal in PRISM, PRISM-PLUS, PARAGON A and PARAGON B; and CK-MB greater than three times the upper limit normal in GUSTO IV. In addition, PRISM-PLUS, PARAGON B, and PURSUIT defined MI post percutaneous intervention as CK or CK-MB greater than three times the upper limit normal.

26 Effect size Outcome Death or MI at 30 days Death or MI at 30 days Death or MI at 30 days Death or MI at 30 days Death or MI at 30 days Population All patients Patients undergoing PCI during index hospitalization Patients undergoing PCI while still receiving study drug Patients undergoing PCI after drug discontinuation Patients treated medically* N= Gp IIb/IIIa inhibitor Contr ol 29, % 11.5% 6,337 (21%) 2,249 (7.6%) 4,088 (13.8% ) 20,054 (67.8% ) 10.7% 12.7% 10.5% 13.6% 10.9% 12.3% 9.3% 9.7% OR (95% CI) 0.91 (0.85 to 0.99) 0.82 (0.71 to 0.96) 0.74 (0.57 to 0.96) 0.87 (0.72 to 1.06) 0.95 (0.86 to 1.04) p Overall, IIb/IIIa integrin blockade was associated with a reduction in death or non-fatal MI at 30 days, from 11.5% to 10.7% (OR 0.91, 95% CI 0.85 to 0.99; p=0.02). Patients undergoing PCI during index hospitalization sustained a greater reduction in death/mi (OR 0.82; 95% CI 0.71 to 0.96 ; p =0.01) than patients medically managed (odds ratio 0.95, NS).

27 Among patients undergoing PCI, the benefit was more pronounced if the procedure was performed during glycoprotein IIb/IIIa inhibitor infusion (OR 0.74; 95% CI 0.57 to 0.96; p =0 02), than if revascularization was performed after drug discontinuation (odds ratio 0.87, NS). Bleeding Not reported JD Comments: This study In a nutshell: Although not based on a prospectively defined hypothesis, the findings suggest a gradient benefit conferred by IIb/IIIa agents depending upon the revascularization strategy used. Accordingly, patients undergoing percutaneous coronary intervention while on platelet glycoprotein IIb/IIIa inhibitor derived a significant benefit, while patients undergoing revascularization after drug discontinuation demonstrated a moderate event reduction that did not reach statistically significance, and only a marginal benefit was observed among patients medically managed. Internal validity 1. Inherent to all meta-analyses, the included trials differed in design, MI-enzyme definition, inclusion criteria, therapeutic agents, regimens, and access to percutaneous revascularization, among others. 2. In the RCTs included (as in most the studies) the decision to perform a PCI or simply to manage the patient medically was not randomized, but instead was left to the discretion the treating physician. This is an important limitation sub-group analyses in this area, as the ischaemic event reduction associated with platelet glycoprotein IIb/IIIa inhibitors in patients undergoing PCI may have been influenced by selection bias 3. Conclusions from this meta-analysis overlooked the fact that all events occurring before the PCI were attributed to the PCI arm. Therefore, a large treatment benefit seen during the early hours treatment may have been erroneously attributed to the PCI group and not the medical therapy group to which they actually belonged. Clinical implications: While this analysis supports the concept that the benefit with IIb/IIIa agents is closely related to the revascularization procedure, part the ischaemic event reduction may have occurred prior to percutaneous intervention. Such upstream benefit has been described for CAPTURE, PURSUIT and PRISM PLUS. No conclusion can be drawn from this analysis on the use these drugs immediately prior to percutaneous intervention, as none the trials addressed such a strategy. The limited benefit glycoprotein IIb/IIIa inhibitors observed in this analysis among patients solely medically managed should not lead to the conclusion that these agents are indicated only in patients undergoing percutaneous coronary intervention. Reference Kastrati A, Mehilli J, Neumann FJ, Dotzer F, Ten B, Bollwein H et al. Abciximab in patients with acute coronary syndromes undergoing Study type Eviden ce level RCT double blind, multicen tre Number patients Patient characteristics Intervention Comparison Length followup N= 2,022 Inclusion criteria : The inclusion criteria were an episode angina (with an accelerating pattern or prolonged [ >20 minutes] or recurrent episodes at rest or with minimal effort) within the preceding 48 hours, accompanied by an ASA 500mg + clopidogrel 600mg (at least 2 hours before PCI) + Heparin + abciximab 20 ASA 500mg + clopidogrel 600mg (at least 2 hours before PCI) + Heparin + placebo 21 Outcome measures 30 days Primary endpoint: a composite death, MI, or urgent target vessel revascularization occurring within 30 days after randomization Source funding German Heart Insititute 20 abciximab 0.25 mg/kg body weight bolus, followed by a μg/kg per minute [maximum, 10 μg/min] infusion for 12 hours, plus heparin, 70 U/kg body weight

28 percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA: Journal the American Medical Association 2006; 295(13): Ref ID: elevated troponin T level (>0.03 μg/l) or a new finding ST-segment depression at least 0.1 mv or transient (<20 minutes) STsegment elevation at least 0.1 mv or new or presumed new bundle-branch block; significant angiographic lesions in a native coronary vessel or venous bypass graft amenable to and requiring a PCI; and written informed consent from the patient. Exclusion criteria: The exclusion criteria were an ST-segment elevation acute MI (STsegment 0.1 mv elevation in 2 contiguous ECG leads persisting for at least 20 minutes); haemodynamic instability; pericarditis; malignancies with life expectancy less than 1 year; increased risk bleeding (stroke within the previous 3 months, active bleeding or bleeding diathesis, recent trauma or major surgery in the last month, suspected aortic dissection); oral anticoagulation with a coumarin derivative within the previous 7 days; receipt a Gp IIb/IIIa inhibitor within the previous 14 days; systolic blood pressure greater than 180 mm Hg unresponsive to therapy; a haemoglobin level less than 100 g/l or hematocrit less than 34%, or platelet count less than 100 x 10 3 cells/μl or greater than 600 x 10 3 cells/μl; known allergy to the study medication; and pregnancy (present or suspected). N= 1,012 N= 1,010 Bleeding (rates inhospital major and minor bleeding) Note: The recommended strategy was an early PCI with stenting within 6 hours from establishment the diagnosis NSTE- ACS Post interventional therapy included 200mg aspirin indefinitely; 75 mg clopidogrel twice a day until discharge but for no longer than 3 days, followed by daily administration 75 mg for at least 6 months; as well as other cardiac 21 placebo bolus and infusion 12 hours, plus heparin bolus, 140 U/kg body weight