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6 BivaliRudin for Acute Myocardial Infarction versus
7 heparin and GPI plus Heparin Trial (BRIGHT)
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9 Study Protocol
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13 Version：V1.03 14 Version date：2012-04-09
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19 Statement: any information regarding to this trial is prohibited to be disclosed to any other
20 party beyond the scope specified in this protocol without prior written consent of sponsor.
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21 Protocol Synopsis
BivaliRudin for Acute Myocardial Infarction versus heparin and Title of study GPI plus Heparin Trial （BRIGHT）
Sponsor General Hospital of Shenyang Military Region Principal investigator Yaling Han Primary study center General Hospital of Shenyang Military Region Study centers Approximately 82 centers in China First patient in：August, 2012 Time frame of study Last patient in：December, 2013 To investigate safety and efficacy of bivalirudin for patients with Objectives AMI undergoing primary PCI. Prospective, multicenter, randomized, open-label, active Study design controlled study. Study medication Bivalirudin Control medications (1) Heparin; (2) heparin plus tirofiban Patients were randomly assigned to receive bivalirudin alone, heparin alone, or heparin plus tirofiban in a 1:1:1 ratio. (1) Bivalirudin alone arm：Bivalirudin was given before coronary angiography in the catheterization laboratory, initialized with a bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/hr during the PCI procedure and for at least 30 minutes but no more than 4 hours after procedure. Following this mandatory infusion, a reduced dose infusion (0.2 mg/kg/hr) for up to 20 hours could be administered at physician discretion. An additional bivalirudin bolus of 0.3 mg/kg was given if the activated clotting time (ACT) five minutes after the initial bolus Treatment (measured with the Hemotec assay) was <225 seconds. (2) Heparin alone arm: A bolus dose (100 U/kg) of heparin was given before coronary angiography in the catheterization laboratory. Additional heparin bolus (20U/kg) was administered if the post-bolus ACT was <225 seconds. NOTE: Provisional (bailout) tirofiban use was allowed in the bivalirudin and heparin alone groups for no-reflow, slow flow, visible thrombus or other thrombotic complications. According to Chinese experts consensus, intra-coronary tirofiban should be initialized as 500-750μg, and can be repeated after 3-5min, with a total dose no more than 1500-2250μg. Intra-venous tirofiban administration should be initialized with a bolus of 2
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10μg/kg (within 3min) and followed by a 0.15μg/kg/min infusion for 18-36 hours. (3) Heparin plus tirofiban arm: Study medications were started before coronary angiography in the catheterization laboratory. Heparin 60 U/kg and tirofiban 10 μg/kg boluses (administrated within 3 min) were given followed by a 0.15 μg/kg/min tirofiban infusion for 18-36 hours. Additional heparin bolus (20U/kg) was administered if the post-bolus ACT was <200 seconds. Primary endpoint： Net adverse clinical events (NACE) at 30 days, defined as a composite of major adverse cardiac and cerebral events (MACCE, all-cause death, re-infarction, ischemia-driven target vessel revascularization or stroke) and any bleeding events.
Secondary endpoints： • NACE at 12 months; • MACCE at 30 days and 12 months; Study endpoints • Any bleeding events (evaluated by BARC classification) at 30 days and 12 months.
Safety endpoints: • Stent thrombosis (definite or probable by ARC definition) at 30 days and 12 months ; • Thrombocytopenia at 30 days; • Any other abnormal symptoms, signs or laboratory test results with clinical significance.
Approximately 2100 patients. Number of patients 700 patients in bivalirudin arm; 700 patients in heparin arm; 700 patients in heparin plus tirofiban arm Follow-up 12 months Eligible patients Patients with AMI in whom an emergency PCI is planned (1) Patients aged from 18~80 years, male or female； (2) AMI (STEMI or NSTEMI) patients with planned emergency PCI. • STEMI within 12 hours after symptom onset or within 12~24 hours with ongoing chest pain, continuous ST segment elevation or new left bundle block. Inclusion criteria • NSTEMI within 72 hours after symptom onset. (3) Staged revascularization for non-culprit vessel should be performed after 30 days. (4) Antiplatelet agents (aspirin and clopidogrel, both loading and maintenance dose) are given before PCI per guidelines. (5) Subjects or legal representatives voluntarily participated and signed
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informed consent, willing to accept study medications and clinical follow-ups. (1) Patients not suitable for PCI; thrombolytic therapy administered before randomization; cardiogenic shock; (2) Any anticoagulant (heparin/LMWH, fondaparinux, warfarin or bivalirudin) or tirofiban administered within 48 hours before randomization; (3) Active or recent major bleeding or bleeding predisposition, including retinal or vitreous hemorrhage within one month, GI or urinary track hemorrhage within 3 months, intracranial hemorrhage within 6 months or cerebral infarction within 3 months; (4) Patients at high risk of secondary bleeding, including active gastric ulcer, ulcerative colitis, intracranial aneurysm, etc.; (5) Major surgery (including ophthalmologic operation or neurosurgery) within 1 month;
Exclusion criteria (6) Clinical syndrome suspicious for aortic dissection, pericarditis or endocarditis; (7) Uncontrolled blood pressure (>180/110 mmHg); (8) Known hemoglobin <10 g/dL or platelet count <100 × 109/L; (9) Aminotransferase level >3x the upper limit of normal; 10) Severe renal insufficiency (eGFR<30 mL/min/1.73m2); (11) History of heparin induced thrombocytopenia; (12) Known allergy to study medications or device (heparin, bivalirudin, tirofiban, aspirin, clopidogrel, stainless steel, contrast medium or hirudin) or allergic constitution; (13) Patient pregnant or lactating, or planned pregnant within 1 year; (14) Study subjects with poor compliance judged by investigators or patient ever participated in another clinical trial and has not completed the follow-up to the primary endpoint. Start of the study：August, 2012. Study timelines First patient enrolled: August, 2012 Last patient finished: December, 2013 All primary and major secondary endpoints will be analyzed both on an intent-to-treat basis (all patients analyzed as part of their assigned treatment group) and on a per protocol basis (patients analyzed as part Statistical method of their assigned treatment group only if they actually received their assigned treatment). The primary statistical analyses will be by intent-to-treat.
Version/date V1.03/2012-04-09
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24 Table of Contents
1. Background …………………………………………………………. 7
2. Objectives …………………………………………………………. 8
3. Introduction of study drug …………………………………………………………. 8
3.1 Bivalirudin …………………………………………………………. 8
3.2 Heparin …………………………………………………………. 9
3.3 Tirofiban …………………………………………………………. 10
4. Previous clinical research …………………………………………………………. 11
5. Design, randomization and blinding …………………………………………………………. 13
5.1 Study design …………………………………………………………. 13
5.2 Study procedure …………………………………………………………. 13
5.3 Randomziation …………………………………………………………. 13
5.4 Blinding …………………………………………………………. 13
6. Study population …………………………………………………………. 15
6.1 Target population …………………………………………………………. 15
6.2 Inclusion criteria …………………………………………………………. 15
6.3 Exclusion criteria …………………………………………………………. 15
6.4 Criteria of removal, treatment discontinuation and drop out ………………………………… 16
7. Methods …………………………………………………………. 17
7.1 Study medications …………………………………………………………. 17
7.2 Follow-up …………………………………………………………. 18
7.3 Treatment …………………………………………………………. 18
8. Endpoints …………………………………………………………. 19
8.1 Primary endpoint …………………………………………………………. 19
8.2 Secondary endpoints …………………………………………………………. 19
8.3 Safety endpoints …………………………………………………………. 19
9. Study flowchart …………………………………………………………. 20
10. AE/SAE reporting …………………………………………………………. 21
10.1 Definition of AE/SAE …………………………………………………………. 21
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10.2 Observation and recording of AEs …………………………………………………………. 22
10.3 Procedure of SAE reporting …………………………………………………………. 22
11. Data collection …………………………………………………………. 22
11.1 Filling in CRF …………………………………………………………. 22
11.2 CRF auditing …………………………………………………………. 23
12. Statistical analysis …………………………………………………………. 23
12.1 Sample size calculation …………………………………………………………. 23
12.2 Analysis population …………………………………………………………. 24
12.3 Statistical method …………………………………………………………. 24
13. Quality control …………………………………………………………. 25
14. Clinical event committee …………………………………………………………. 25
15. Ethics Committee …………………………………………………………. 26
16. Study management …………………………………………………………. 26
16.1 Modification in the protocol …………………………………………………………. 26
16.2 CRF tracking …………………………………………………………. 26
16.3 Training …………………………………………………………. 26
16.4 Replacement of research center …………………………………………………………. 27
16.5 Clinical follow up …………………………………………………………. 27
17．Responsibilities of each party …………………………………………………………. 27
17.1 Responsibilities of sponsor …………………………………………………………. 27
17.2 Responsibilities of investigators …………………………………………………………. 27
17.3 Responsibility of CRO …………………………………………………………. 29
Appendix 1：Definitions …………………………………………………………. 30
Appendix 2：Informed consent …………………………………………………………. 35
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27 1. Background
28 It is an important issue to balance the benefits of antithrombotic therapy and risk 29 of bleeding in patients with acute myocardial infarction (AMI, including ST-segment 30 elevation MI [STEMI] and non- ST-segment elevation MI [NSTEMI]) undergoing an 31 invasive primary angioplasty strategy. The aim of the study is to investigate the 32 efficacy and safety of domestic bivalirudin in patients with AMI during primary PCI, 33 thus to optimize antithrombotic therapy. 34 Intensified dual anti-platelet therapy is the cornerstone of antithrombotic therapy 35 in patients with AMI undergoing primary angioplasty strategy, and GP IIb/IIIa 36 inhibitor (GPI) is superior to placebo when they are added to dual anti-platelet therapy. 37 Strengthening anti-platelet therapy is a key strategy in high-risk patients undergoing 38 PCI. However, routine addition of GPI may increase risk of bleeding, and recent 39 studies showed that bleeding could lead to higher mortality. Therefore, the balance 40 between benefits and bleeding risk should be fully evaluated during anti-thrombotic 41 therapy. Recent studies demonstrated that bivalirudin could reduce thrombotic events 42 to a degree comparable to standard anticoagulation therapy, but resulted in less 43 bleeding events. The ACCF/AHA/SCAI 2009 guidelines recommended it as 44 anticoagulation therapy for STEMI emergency PCI at the highest level (I/B). 45 However, little clinical research of bivalirudin in Asian patient population has been 46 performed. The aim of the study is to investigate the efficacy and safety of domestic 47 bivalirudin in patients with AMI during primary PCI, and to provide more evidence 48 for optimizing anticoagulation therapy. 49 Bivalirudin is a direct thrombin inhibitor, and a synthetic congener of hirudin. By 50 highly specific inhibition of thrombin, it can prolong activated clotting time to prevent 51 thrombus during catheterization. The reversible inhibition of thrombin is short, 52 resulting in infrequent bleeding events, therefore, it is safer than traditional 53 anticoagulation drug, heparin. Thrombin can activate platelet, leading to platelet 54 aggregation and release of platelet-derived micro-particles. Bivalirudin can prevent 55 platelet activation indirectly by inhibiting thrombin. 56 Bivalirudin is superior to heparin in following aspects: (1) Anticoagulation 57 effects of bivalirudin are achieved by direct and specific inhibition of thrombin, and 58 are independent of antithrombin III; (2) It has a highly predictable dose-response 59 curve, and no routine blood monitoring is needed; (3) It has a short plasma half-life,
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60 and is reversible. This feature is very important when hemorrhagic complications 61 occur. In previous studies of anticoagulation therapy during PCI, bivalirudin was 62 superior to heparin, and GPI did not show any benefits when added to bivalirudin; in 63 studies enrolling patients at various risk, bivalirudin resulted in better clinical 64 outcomes compared to heparin when used during PCI. Considering the benefits of oral 65 anti-platelet therapy, it is important to investigate effects of bivalirudin on clinical 66 prognosis in high-risk AMI patients undergoing PCI after 300-600mg loading dose of 67 clopidogrel. 68 2. Objectives
69 The study is a large-scale, prospective, multicenter, active-control,
70 parallel-group, open-label randomized trial. Bivalirudin will be used in patients with
71 AMI undergoing an invasive primary angioplasty strategy, and approximately 2100
72 patients will be enrolled. The control therapies include heparin and heparin plus
73 tirofiban. Efficacy and safety of domestic bivalirudin will be evaluated in those
74 patients at 30 days, 6 months and 12 months after the procedure.
75 3. Introduction of study drugs 76 3.1 Bivalirudin 77 3.1.1 Pharmacology
78 Bivalirudin is a direct, specific, reversible inhibitor of thrombin, and its
79 anticoagulation effect is independent of antithrombin III. It inhibits thrombin
80 irrespective of whether the thrombin is free in solution or bound to fibrin, and
81 inhibits thrombin activity directly. Following cleavage at Arg3-Pro4, bivalirudin no
82 longer binds to thrombin, thus allowing thrombin to resume its pro-hemostatic
83 functions, therefore, its effects is short and reversible. Ex vitro study from healthy
84 participants showed that, the prothrombin time (PT), activated partial thromboplastin
85 time (APTT), and thrombin time (TT) all rose in a linear fashion with increasing
86 doses of bivalirudin. Binding of bivalirudin to free thrombin or thrombin bound to
87 fibrin is independent of platelet-derived micro-particles. The same level of
88 anticoagulation effects could be achieved in patients undergoing PCI as healthy
89 participants. Bivalirudin is administered by intravenous route, and produces a rapid
90 anticoagulant effect. The half-life of bivalirudin is 25 minutes, and patients’
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91 coagulation system becomes normal 1h after cessation of treatment. There is no
92 specific antidote for bivalirudin.
93 3.1.2 Drug interactions
94 Bivalirudin does not bind to plasma protein or red blood cells.
95 Co-administration of bivalirudin with heparin, warfarin, or thrombolytic agents has
96 not been associated with increased risks of major bleeding events.
97 3.1.3 Adverse reactions
98 One of common adverse reactions of bivalirudin is bleeding, usually occurring
99 at the puncture site of the artery, or other body part. Bleeding should be highly
100 suspected when abrupt hypotension, volume loss, or other unclear symptoms occur,
101 and bivalirudin should be stopped. Other rare adverse reactions include
102 thrombocytopenia, anemia, allergy, ventricular tachycardia, chest pain, bradycardia,
103 dyspepsia, rash, back pain, headache and hypotension.
104 3.2 Heparin
105 3.2.1 Pharmacology
106 Heparin is a polymer with a molecular weight ranging from 3 to 30 kDa, and
107 the average molecular weight of most commercial heparin preparations is in the
108 range of 12 to 15 kDa. Heparin binds to the enzyme inhibitor antithrombin III (AT),
109 and the activated AT then inactivates thrombin and other proteases involved in blood
110 clotting, including factor Xa, IXa, Xia and XIIa, which is the main mechanism of
111 action of heparin. Heparin has a more potent effect on thrombin than on factor Xa,
112 with an anti-IIa/anti-Xa activity ratio of approximately ten.
113 Heparin is extensively bound to plasma proteins. Heparin does not cross the
114 placental barrier and is not distributed into breast milk. Heparin is not removed by
115 hemodialysis. The dose-response relationship of heparin is not linear. Anticoagulant
116 effect increases disproportionately in intensity and duration as the dose is increased.
117 The plasma half-life of heparin increases from approximately 60 minutes with a 100
118 unit/kg dose to about 150 minutes with a 400 unit/kg dose. After bolus intravenous
119 injection of low doses, heparin disappears from the blood exponentially with a
120 dose-dependent half-life; at higher doses, heparin disappears with a concave-convex 9
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121 pattern. Under continuous intravenous infusion there is a non-linear relationship
122 between the dose of heparin injected and the steady-state plasma concentration. After
123 subcutaneous injection, the bioavailability of the anti-factor Xa activity increases
124 with the dose delivered and tends toward 100% at high doses.
125 3.2.2 Drug interactions Oral anticoagulants: Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. Platelet inhibitors: Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. Other interactions: Digitalis, tetracyclines, nicotine, or antihistamines may partially counteract the anticoagulant action of heparin sodium.
126 3.2.3 Adverse reactions
127 Hemorrhage is the chief complication that may result from heparin therapy. An
128 overly prolonged clotting time or minor bleeding during therapy can usually be
129 controlled by withdrawing the drug. Generalized hypersensitivity reactions have
130 been reported, with chills, fever and urticaria as the most usual manifestations, and
131 asthma, rhinitis, lacrimation, headache, nausea and vomiting and anaphylactoid
132 reactions. Osteoporosis following long-term administration of high doses of heparin,
133 cutaneous necrosis after systemic administration, suppression of aldosterone
134 synthesis, delayed transient alopecia, priapism and rebound hyperlipidemia on
135 discontinuation of heparin sodium have also been reported. 136 3.3 Tirofiban
137 3.3.1 Pharmacology
138 Tirofiban is an intravenously administered nonpeptide glycoprotein IIb/IIIa
139 receptor antagonist which specifically inhibits fibrinogen-dependent platelet 10
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140 aggregation and prolongs bleeding times in patients with acute coronary syndromes.
141 When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a
142 dose- and concentration-dependent manner. When given according to the
143 recommended regimen, >90% inhibition is attained by the end of the 30-minute
144 infusion. It is cleared from the plasma largely by renal excretion, with about 65% of
145 an administered dose appearing in urine and about 25% in feces, both largely as
146 unchanged tirofiban. Its half-life is 1.5~2h.
147 3.3.2 Drug interactions
148 Use of thrombolytics, anticoagulants, and other antiplatelet agents and
149 co-administration of antiplatelet agents, thrombolytics, heparin, and aspirin increase
150 the risk of bleeding.
151 3.3.3 Adverse reactions
152 Bleeding is the most commonly reported adverse reaction. Patients treated with
153 tirofiban plus heparin were more likely to experience decreases in platelet counts
154 than were those on heparin alone. Severe allergic reactions including anaphylactic
155 reactions have occurred during the first day of infusion 156 157 4. Previous clinical research
158 In the early phase, bivalirudin was evaluated in patients undergoing PCI in the
159 Hirulog Angioplasty study (NEJM, 1995,333:764-9). The double-blind, randomized
160 trial enrolled 4098 patients undergoing angioplasty for unstable or post-infarction
161 angina. The results showed that bivalirudin did not significantly reduce the incidence
162 of the primary end point (11.4%, vs. 12.2% for heparin) but did result in a lower
163 incidence of bleeding (3.8% vs. 9.8%, P<0.001). In the prospectively stratified
164 subgroup of 704 patients with post-infarction angina, bivalirudin therapy resulted in
165 a lower incidence of the primary end point (9.1% vs. 14.2%, P=0.04) and a lower
166 incidence of bleeding (3.0% vs. 11.1%, P<0.001).
167 The ACUITY study (NEJM, 2006,355:2203-16) investigated the role of
168 thrombin-specific anticoagulation with bivalirudin in patients with high-risk acute
169 coronary syndromes. 13,819 patients with acute coronary syndromes were assigned 11
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170 to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a
171 glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or
172 bivalirudin alone. The results showed that bivalirudin plus a glycoprotein IIb/IIIa
173 inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was
174 associated with noninferior 30-day rates of the composite ischemia end point (7.7%
175 and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical
176 outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin
177 plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the
178 composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk,
179 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of
180 major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65)
181 and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86;
182 95% CI, 0.77 to 0.97).
183 The HORIZONS-AMI study（NEJM, 2008,358:2218-30）evaluated the safety
184 and efficacy of bivalirudin in patients with ST-segment elevation myocardial
185 infarction who were undergoing primary PCI. 3602 patients were assigned to
186 treatment with heparin plus a glycoprotein IIb/IIIa inhibitor or to treatment with
187 bivalirudin alone. The two primary end points of the study were major bleeding and
188 combined adverse clinical events, defined as the combination of major bleeding or
189 major adverse cardiovascular events, including death, reinfarction, target-vessel
190 revascularization for ischemia, and stroke (hereinafter referred to as net adverse
191 clinical events) within 30 days. The results showed that anticoagulation with
192 bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors,
193 resulted in a reduced 30-day rate of net adverse clinical events (9.2% vs. 12.1%;
194 relative risk, 0.76; 95% confidence interval [CI] 0.63 to 0.92; P=0.005), owing to a
195 lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to
196 0.77; P<0.001). Treatment with bivalirudin alone, as compared with heparin plus
197 glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death
198 from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95;
199 P=0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 12
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200 to 1.00; P=0.047). One-year outcomes in the HORIZONS-AMI trial continued to
201 show that bivalirudin is associated with a lower rate of major bleeding (15.6% versus
202 18.3%, p=0.0001) and mortality (3.5% versus 4.8%, p=0.037). In HORIZONS-AMI,
203 there was an increased risk of acute stent thrombosis within 24 hours in the
204 bivalirudin group, which might due to delayed onset of pharmacodynamic effects of
205 clopidogrel.
206 207 5. Study design, randomization and blinding
208 5.1 Study design
209 This study is a prospective, multicenter, randomized, active controlled,
210 open-label, superiority trial.
211 5.2 Study procedure
212 Patients meet ALL the inclusion criteria and NONE of the exclusion criteria
213 will be randomly assigned to 3 arms after informed consent is signed. Study
214 medications will be given in the cath lab before angiography. Activated clotting time
215 (ACT) will be measured 5 min after heparin or bivalirudin administration. Repeat
216 bivalirudin or heparin bolus will be given if ACT is less than standard level
217 according to protocol. Bailout tirofiban can be used in patients allocated in the
218 bivalirudin arm or heparin arm if there is significant thrombus in the culprit vessel.
219 Patients will be visited at 30 days, 6 months and 12 months via telephone or clinic.
220 Detailed study procedures are listed in table 1.
221 5.3 Randomization
222 Patients meeting ALL the inclusion criteria and NONE of the exclusion criteria
223 will be enrolled. Randomization will be performed in catheterization laboratory
224 immediately after informed consent is signed, using computer-generated block
225 randomization sequence sealed in an envelope.
226 5.4 Blinding
227 Study medications are known by both investigators and subjects. However,
228 independent clinical events committee is blinded to the treatment allocation.
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232 Table 1：Study procedure table
Visit 1 Visit 2 Visit 3 Baseline 30 days 6 months 12 months
window ±7d ±14d ±30d
Informed consent X
Inclusion/exclusion criteria X
Randomization X
Medical history/demographic features X
Vital signs X
Routine blood and urine test X
Biochemical test X
CK/CKMB and troponin T X
Activated clotting time X
12- leader electrocardiogram X
Important clinical symptoms X X X X
Clinical evaluation X X X X
Adjunctive medications X X X X
Coronary angiography X
Adverse cardiac events recording X X X
Adverse events recording X X X
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233 6. Study population：
234 6.1 Target population：
235 2100 patients who meet the inclusion criteria and receive study medications
236 before coronary angiography.
237 6.2 Inclusion criteria
238 (1) Patients aged from 18~80 years, male or female；
239 (2) AMI (STEMI or NSTEMI) patients with planned emergency PCI.
240 STEMI within 12 hours after symptom onset or within 12~24 hours with ongoing
241 chest pain, continuous ST segment elevation or new left bundle block.
242 NSTEMI within 72 hours after symptom onset.
243 (3) Staged revascularization for non-culprit vessel should be performed after 30 days.
244 (4) Antiplatelet agents (aspirin and clopidogrel, both loading and maintenance dose)
245 are given before PCI per guidelines.
246 (5) Subjects or legal representatives voluntarily participated and signed informed
247 consent, willing to accept study medications and clinical follow-ups.
248 6.3 Exclusion criteria：
249 (1) Patients not suitable for PCI; thrombolytic therapy administered before
250 randomization; cardiogenic shock;
251 (2) Any anticoagulant (heparin/LMWH, fondaparinux, warfarin or bivalirudin) or
252 tirofiban administered within 48 hours before randomization;
253 (3) Active or recent major bleeding or bleeding predisposition, including retinal or
254 vitreous hemorrhage within one month, GI or urinary track hemorrhage within 3
255 months, intracranial hemorrhage within 6 months or cerebral infarction within 3
256 months;
257 (4) Patients at high risk of secondary bleeding, including active gastric ulcer,
258 ulcerative colitis, intracranial aneurysm, etc.;
259 (5) Major surgery (including ophthalmologic operation or neurosurgery) within 1
260 month;
261 (6) Clinical syndrome suspicious for aortic dissection, pericarditis or endocarditis;
262 (7) Uncontrolled blood pressure (>180/110 mmHg);
263 (8) Known hemoglobin <10 g/dL or platelet count <100 × 109/L;
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264 (9) Aminotransferase level >3x the upper limit of normal;
265 10) Severe renal insufficiency (eGFR<30 mL/min/1.73m2);
266 (11) History of heparin induced thrombocytopenia;
267 (12) Known allergy to study medications or device (heparin, bivalirudin, tirofiban,
268 aspirin, clopidogrel, stainless steel, contrast medium or hirudin) or allergic
269 constitution;
270 (13) Patient pregnant or lactating, or planned pregnant within 1 year;
271 (14) Study subjects with poor compliance judged by investigators or patient ever
272 participated in another clinical trial and has not completed the follow-up to the
273 primary endpoint.
274
275 6.4 Criteria of patient removal, treatment discontinuation and drop out
276 6.4.1 Criteria of removal
277 Patient should be removed if:
278 • Misdiagnosis.
279 • Without any record of physical or laboratory test results.
280 • Do not meet the inclusion criteria or meet at least one exlusion criteria.
281 The reason of removal should be written down and the case report form (CRF) should
282 be preserved for audit check. Removal patients will not be included in the efficacy
283 analysis but could be included in the safety analysis if there are any records regarding
284 efficacy or safety.
285 6.4.2 Criteria of treatment discontinuation
286 Discontiuation of any study medication is defined as stopping experimental
287 treatment. The reason of discontinuation should be clearly noted in the original
288 medical records and CRF.
289 Treatment should be discontinued if:
290 • Patient withdrawal of informed consent.
291 • Intolerable side effects of study medications
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292 • Severe allergy that cannot be relieved by anti-allergic therapy
293 • Adverse events or abnormal laboratory test results indicating that
294 continuation of treatment would be inappropriate.
295 • Patient suffered from severe complications which necessitated withdrawing
296 study medications.
297 • Major deviation of the study protocol.
298 • Severe adverse event that threaten the patient’s health.
299
300 6.4.3 Criteria for drop out
301 All patients enrolled in the trial shall be retained until completion of follow-up.
302 Patients have the right to withdraw from the study at any time without penalty, and
303 would not lose any benefits. The reasons that patients drop out may include but are
304 not limited to:
305 Severe adverse events causing termination of the study.
306 Unexpected illness for which further treatment would be inappropriate.
307 Lost to follow-up.
308 Patient withdrew informed consent.
309 Other reasons causing termination of the study.
310 Poor patient compliance which might affect efficacy or safety.
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312 If patients met the above criteria and stop participating in the study, the
313 “completion of study” page in their case reports should be completed. Investigators
314 must report to their respective ethics committees when and why patients stopped
315 participating in the study (according to the procedures specified in each test body). If
316 patient withdrawal was caused by an AE/SAE, clinical follow-up should be performed
317 until the AE/SAE is resolved or stabilized.
318
319 7. Methods
320 7.1 Study medications：
321 Bivalirudin for injection ： 250mg per ampoule, manufactured by Salubris
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322 Pharmaceutical Co. Ltd, Shenzhen, China
323 Heparin Sodium injection： 100mg per ampule
324 Tirofiban hydrochloride Sodium Chloride Injection: 100mg per package
325
326 7.2 Follow-up：
327 Clinical follow-up will be performed at 30 days, 6 months and 12 months after
328 randomization.
329
330 7.3 Treatment
331 Patients enrolled will be randomly assigned to receive bivalirudin alone, heparin
332 alone or heparin plus tirofiban in a 1:1:1 ratio. Treatments for 3 arms are as follows:
333
334 7.3.1 Bivalirudin alone arm：
335 Bivalirudin is given before coronary angiography in the catheterization laboratory,
336 initialized with a bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/hr during
337 the PCI procedure and for at least 30 minutes but no more than 4 hours after
338 procedure. Following this mandatory infusion, a reduced dose infusion (0.2 mg/kg/hr)
339 for up to 20 hours may be administered at physician discretion. An additional
340 bivalirudin bolus of 0.3 mg/kg is given if the activated clotting time (ACT) five
341 minutes after the initial bolus (measured with the Hemotec assay) is <225 seconds.
342 7.3.2 Heparin alone arm:
343 A bolus dose (100 U/kg) of heparin is given before coronary angiography in the
344 catheterization laboratory. Additional heparin bolus (20U/kg) is administered if the
345 post-bolus ACT was <225 seconds.
346 NOTE: Provisional (bailout) tirofiban use is allowed in the bivalirudin and heparin
347 alone arms for no-reflow, slow flow, visible thrombus or other thrombotic
348 complications. According to Chinese experts consensus, intra-coronary tirofiban
349 should be initialized as 500-750μg, and can be repeated after every 3-5 min, with a
350 total dose no more than 1500-2250μg. Intravenous tirofiban administration should be
351 initialized with a bolus of 10μg/kg (within 3min) and followed by a 0.15μg/kg/min
352 infusion for 18-36 hours.
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353 7.3.3 Heparin plus tirofiban arm:
354 Study medications are started before coronary angiography in the catheterization
355 laboratory. Heparin 60 U/kg and tirofiban 10 μg/kg boluses (administrated within 3
356 min) are given followed by a 0.15 μg/kg/min tirofiban infusion for 18-36 hours.
357 Additional heparin bolus (20U/kg) is administered if the post-bolus ACT was <200
358 seconds.
359 7.3.4 Adjunctive medications during perioperative period
360 Dual antiplatelet therapy shall be given before randomization:
361 (1) Aspirin: 300mg loading followed by 100mg/d maintenance dose definitely.
362 (2) Clopidogrel: 300mg or 600 mg loading followed by 75mg/d maintenance dose
363 for 12 months. If a maintenance dose of clopidogrel (75mg/d) was given for at least
364 5 days before randomization, loading dose can be omitted.
365 Anticoagulant agent ： Anticoagulant agent (heparin, LMWH, etc.) post
366 procedure is not recommended other than in patients who are at high risk of
367 thrombosis. LMWH administration is at physician’s discretion for patients
368 undergoing IABP or temporary pacemaker implantation.
369
370 8. Endpoints
371 8.1 Primary endpoint
372 Primary endpoint is net adverse clinical events (NACE) at 30 days. NACE is defined
373 as a composite of major adverse cardiac and cerebral events (MACCE, all-cause death,
374 re-infarction, ischemia-driven target vessel revascularization or stroke) and any
375 bleeding events.
376 8.2 Secondary endpoints：
377 NACE at 12 months;
378 MACCE at 30 days and 12 months;
379 Any bleeding events (evaluated by BARC classification) at 30 days and 12
380 months.
381 8.3 Safety endpoints
382 Stent thrombosis (definite or probable by ARC definition) at 30 days and 12
383 months;
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384 Thrombocytopenia at 30 days;
385 Any other abnormal symptoms, signs or laboratory test results with clinical
386 significant.
387
388
389 9. Study flowchart：
390 See Figure 1.
AMI patients with planned emergency PCI
2100 AMI patients meet all inclusion criteria and none of exclusion criteria
Randomization (1:1:1)
Bivalirudin alone Heparin alone Heparin plus tirofiban N=700 N=700 N=700
Bail-out tirofiban shall be given under the circumstance of slow flow, no-reflow, visible thrombus or any thrombotic complications
Coronary angiography/PCI
Collection of stent thrombosis within 24 hours and all in-hospital adverse events (MACCE and bleeding, etc.)
Clinical follow-up at 30 days, 6 months and 12 months
Primary efficacy endpoint (death, re-infarction, stroke, clinically driven TVR and any bleeding) Safety endpoints (stent thrombosis, thrombocytopenia, etc.) 391 392 393 Figure 1. Study flowchart 394 395 396
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397 10. AE/SAE reporting 398 399 There are two classifications of adverse events: adverse event (AE), and serious adverse
400 event (SAE). Adverse events must be monitored until resolved or adequately explained. All
401 serious and unanticipated adverse events must be reported, regardless of the cause. They
402 should be reported to the local IRB/EC and Sponsor within 24 hours of knowledge of the
403 event.
404 10.1 Definition of AE / SAE
405 AE
406 Any adverse medical events occurring in a clinical trial, not necessarily
407 having a causal relationship with the study treatments. Adverse events could be
408 any signs (including abnormal laboratory values), symptom, or temporary disease,
409 whether related or unrelated to the study drug use. An adverse event may be
410 categorized as the following:
411 • Mild – signs or symptoms that do not interfere with the patients’ usual
412 activities or is transient and resolves without treatment of sequelae.
413 • Moderate – interferes with the patients’ usual activities and/or requires
414 symptomatic treatment.
415 • Severe – symptoms causing severe discomfort and significant impact the
416 patient’s usual activities and requires treatment.
417 SAE
418 A study-related event that is fatal, life-threatening, requires inpatient
419 hospitalization or prolongation of an existing hospitalization, requires
420 intervention to prevent permanent impairment/damage, or results in persistent or
421 significant disability.
422
423 10.2 Observation and recording of AEs
424 Investigators should collect and record all AEs occurring from the time of signing
425 informed consent for each subject to end of the follow-up in the clinical study.
426 For AEs, only medical events with clinical worsening compared to baseline are
427 recorded. Abnormal evaluation results at screening or baseline examination are not
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428 considered AEs.
429 For any AEs required to be recorded and described in the raw data, investigators
430 must determine their type, date, measures taken, outcomes, as well as their relevance
431 to study medications.
432 Subjects with AEs should receive clinical follow-up until the adverse event has
433 subsided (to a normal state or to baseline condition), or the patients achieves a stable
434 condition, or investigators believe the patients has reached a reasonable condition. If
435 the AEs did not subside to the above conditions, the investigators should continue to
436 provide the necessary treatment, and report and record the patient’s progress. For
437 special circumstances, AEs should be treated in accordance with the instructions of
438 relevant administrative departments.
439
440 10.3 Procedure of SAE reporting
441 The Investigator must complete the SAE form for each SAE, whether related or
442 not to study drug. The event should be reported to the Investigational Review Board
443 (IRB)/ Ethics Committee (EC), national regulatory authority, sponsor and CRO within
444 24 hours (from the point in time when the SAE is identified by the site). The
445 information provided must be sufficient to allow for independent medical assessment
446 of the event. The Investigator should provide any additional follow-up information
447 regarding the event to the sponsor as soon as it becomes available.
448
449 11. Data collection
450 11.1 Filling in case report form (CRF)
451 • Principal investigator shall authorize personnel to fill in CRF.
452 • Investigators shall fill in the CRF in accordance to GCP principles and CRF
453 instructions to ensure that true, accurate and complete examination results are
454 transcribed into the CRF in a timely and standardized manner.
455 • Data recorded in the CRF should be verified with source medical recordings.
456 • Any change in the CRF should be marked with a deletion line. The correction
457 should be written down beside with the investigator’s signature and date.
458 • Any abnormal data (great deviation from normal or clinically unacceptable)
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459 should be verified and illustrated by the investigator.
460 • CRF data will be maintained by the sponsor and clinical research institutions.
461 11.2 CRF auditing
462 Monitors should audit patient consents and enrolment periodically in each
463 participating center:
464 • To ensure that data in the CRF are correct and are consistent with the original
465 medical records.
466 • To ensure all errors and missing data are corrected or illustrated and signed
467 by the investigator.
468 • To ensure each therapeutic change, concomitant medication and complication
469 is recorded accurately.
470 • To ensure that all patient withdrawals or loss of follow-up are recorded in the
471 CRF.
472 • To ensure that all AEs are recorded and all SAEs are reported per standard
473 procedure.
474 • To ensure that the delivery, storage and recycling of study drugs abide to
475 regulatory requirements and are recorded.
476
477 12. Statistical analysis
478 BRIGHT is a prospective, multicenter, randomized, open label, active controlled
479 trial. AMI patients with planned emergency PCI will be enrolled and randomly
480 assigned to be treated with bivalirudin, heparin alone or heparin plus tirofiban.
481 Analysis for primary endpoint will be performed at the time that 30 day follow-up for
482 all subjects are completed. Analysis for secondary endpoints will be performed when
483 12-month follow-up are completed.
484 12.1 Sample size calculation
485 The primary endpoint is 30-day NACE, a composite of all-cause death,
486 reinfarction, ischemia driven TVR, stroke or any bleeding. Incidence of primary
487 endpoint will be compared between bivalirudin group and two control groups
488 sequentially. Only when both p values of two step tests (bivalirudin versus heparin
489 alone and bivalirudin versus heparin plus tirofiban) are less than 0.05, then the
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490 conclusions of bivalirudin being superior to controls will be accepted.
491 The study hypothesis is that bivalirudin is superior to both heparin alone and
492 heparin plus tirofiban on 30-day NACE.
493 H0: PB=PC
494 H1:PB≠PC, α=0.05 (two-sided)
495 PB denotes NACE rate in the bivalirudin group, PC NACE rate in the control group.
496 Assuming a 30-day NACE rate of 11.5% in the heparin alone group and 12.1%
497 in the heparin plus tirofiban group, allowing for 5% lost to follow-up, with a
498 two-sided alpha of 0.05, 700 patients per group would provide >90% power to
499 demonstrate a 45% reduction with bivalirudin for each comparison. Enrollment of
500 2,100 total patients (~700 per group) was therefore planned.
501
502 12.2 Analysis populations
503 All primary and major secondary endpoints will be analyzed both on an
504 intent-to-treat basis (all patients analyzed as part of their assigned treatment group)
505 and on a per protocol basis (patients analyzed as part of their assigned treatment group
506 only if they actually received their assigned treatment). The primary statistical
507 analyses will be by intent-to-treat.
508 • Intention-to-treat (ITT) set: Patients who meet the study inclusion criteria, sign
509 the written informed consent and receive study medications after randomization
510 and have any assessment for the primary endpoint will be included in the ITT set.
511 ITT set will be used as baseline characteristics and endpoint analysis.
512 • Per protocol (PP) set: Patients with a successful procedure and complete
513 follow-up information will be included in the PP set.
514
515 12.3 Statistical method
516 Data will be analyzed using SPSS V19.0 software package. Two sided test with
517 alpha level of 0.05 will be used.
518 Baseline demographic and clinical variables will be summarized for each of the
519 treatment groups for the ITT set. All continuous variables will be summarized using
520 means, standard deviations, medians, interquartile ranges, minimums and maximum
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521 values and two-sided 95% confidence intervals. Categorical variables will be
522 summarized using frequencies and percentages with two-sided exact 95% confidence
523 intervals. P-values comparing the two treatment groups will be presented for
524 descriptive purposes. Continuous data will be summarized using mean and standard
525 deviation and compared using Student’s t-test or one-way ANOVA. Time-to-event data
526 were compared with the log-rank test.
527 Pre-specified subgroups for analysis include gender, age, type of AMI, heart
528 failure, diabetes, anemia, renal insufficiency, arterial access, multivessel disease,
529 history of cardiovascular events, high bleeding risk, and PCI for left anterior
530 descending coronary artery.
531
532 13. Quality Control
533 Sponsor shall appoint monitors to conduct systematic monitoring for the study in
534 accordance with GCP principles to ensure the study is carried out according to the
535 protocol and the case report form is identical with original data. The monitors should
536 also assess compliance corresponding to the regulations and protocol.
537 Investigators must ensure the integrity of the medical files. All study files will be
538 reviewed by the sponsor and monitors. Monitors should ensure the following: the
539 rights of the subjects should be protected; original data should comply with GCP and
540 protocol requirements.
541
542 14. Clinical Event Committee (CEC)
543 A Clinical Events Committee (CEC) is organized for this study. The committee is
544 composed of a number of interventional cardiologists who are not participations in
545 this study. The committee shoulders the mission for the classification of clinical
546 events and the development of specific criteria of clinical endpoints used in this study.
547 The CEC will request the original data as necessary. All CEC members are familiar
548 with the protocol of this study. All events are judged based on ARC, BARC and other
549 standard definitions (Appendix 1). The Committee shall regularly make assessments
550 and judgments on death, myocardial infarction, ischemia-driven target vessel
551 revascularization, stent thrombosis, bleeding, stroke and thrombocytopenia events
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552 which occur during the trial.
553
554 15. Ethics Committee
555 Before study initiation, the study director must submit the study protocol, informed
556 consent form and other related study documents to the Ethics Committee to obtain its
557 approval for conducting the clinical trial. After receiving the application, the Ethics
558 Committee will convene a meeting to review, discuss and issue written comments
559 attached with the list of participants, professional information and signature of
560 primary investigator. During the study, the sponsor or contract research organization
561 appointed by the sponsor should promptly report serious adverse events, including
562 risks to subjects and other issues. Any modification to the protocol should be
563 approved and recorded by the Medical Ethics Committee.
564
565 16. Study Management
566 16.1 Modification in the protocol
567 Any modification in the protocol should be released by sponsor and signed by
568 investigators. The updated protocol should be saved as an annex. Any modification to
569 protocol should be approved and recorded by the Medical Ethics Committee.
570 If deviations from the protocol are necessary, investigators should inform the sponsor
571 as soon as possible, and discuss the specific situation to reach an agreement. The
572 reason for deviation from the protocol should be recorded.
573 If the telephone or address is changed during the study, the sponsor will inform
574 investigators in writing without modification to protocol.
575 16.2 CRF tracking
576 All CRFs of subjects who signed an informed consent should be turned over
577 regardless of whether the study is completed. Any questions or comments on the case
578 report form must be submitted directly to the sponsors and CRA.
579 16.3 Training
580 Sponsor must ensure that all staff involved in the study have been trained by the
581 sponsor or the organization designated by sponsor before the study starts. An
582 investigators’ meeting should be convened for all investigators to be familiar with the
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583 protocol as well.
584 16.4 Replacement of research center
585 Research centers which are replaced must be documented. The only reasons to replace
586 a research center are slow enrollment and poor compliance.
587 16.5 Clinical follow-up
588 All AE/SAE should be followed up; see details in the relevant sections.
589
590 17. Responsibilities of each party
591 17.1 Responsibilities of Sponsor
592 1) Design the study protocol and sign contracts with the investigators and contract
593 research organization;
594 2) Provide instruction of the drug used in the study to the investigators and monitors;
595 3) Provide relevant training to the investigators before study initiation;
596 4) Collect and keep clinical data and information；
597 5) Collect and keep relevant information, such as clinical programs, medical records,
598 the ethics committee opinions, adverse event reports, statistical analysis, basic data
599 and final clinical report;
600 6) Report side effects to the administration;
601 7) Provide rights and ability to terminate the study.
602 17.2 Responsibilities of Investigators
603 1) Be familiar with and strictly follow the study protocol;
604 2) Complete the clinical study within the stipulated time, including 30-day, 6-month,
605 and 12-month clinic and telephone follow-up;
606 3) Submit the study protocol to local ethics committee and update progress to
607 sponsor;
608 4) Be familiar with relevant data (nature, efficacy and safety of the study drug);
609 5) Conduct the clinical trial in qualified medical institutions capable of handling all
610 kinds of emergency situations to ensure the safety of subjects; laboratory test results
611 should be accurate and reliable;
612 6) Obtain consent from the medical institutions, and ensure the clinical study is
613 completed within the stipulated time. All stuff members should be familiar with their
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614 responsibilities to ensure a sufficient number of subjects are enrolled;
615 7) Ensure that subjects signed the informed consent forms prior to study initiation,
616 and ensure their safety;
617 8) If serious adverse events occur, investigators must immediately take appropriate
618 therapeutic measures for the subjects, and report the events to the Ethics Committee,
619 the sponsor, and the State Food and Drug Administration within 24h after informed of
620 these events. Meanwhile, investigators should ensure the subjects receive appropriate
621 treatment in case of adverse events;
622 9) Ensure that the data is true, accurate, complete, timely, and legally recorded in the
623 medical files and CRF;
624 10) Accept the monitoring and auditing of the monitors as well as inspecting of drug
625 supervision and management department so as to ensure the quality of the clinical
626 study;
627 11) Ensure no conflict exists with other clinical studies；
628 12) The interests of the subjects are priority in any situation. Protecting subjects from
629 adverse events is consistent with the protocol, but any AEs and deviations from the
630 protocol should be described in the final report;
631 13) Any modification (for subjects’ safety) that deviate from the protocol should be
632 reported to the Ethics Committee and the sponsor;
633 14) If unexpected events occur, investigators should terminate the clinical study and
634 notify the subjects and their doctors;
635 15) Take primary responsibility to ensure the validity, clarity and reliability of all
636 documents relating to the study;
637 16) Any modification to the original data must be signed by an authorized person and
638 dated, and the original records must be retained for future reference;
639 17) After completion of the follow-up for the study, investigators should submit a
640 final study report to the sponsor;
641 18) They also should maintain confidentiality obligations regarding information
642 provided by the sponsor during the entire process of the study.
643 17.3 Responsibilities of CRO
644 1) Monitor the entire process of the study;
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645 2) Promptly update any adverse events or deviations to sponsor and investigators;
646 3) Follow the protocol and report any variances from the protocol to sponsor in
647 writing;
648 4) Use study drugs strictly according to the protocol, and report any devaitions to
649 sponsor;
650 5) Conduct systematic monitoring for the study in accordance with GCP principles;
651 6) Obtain the informed consent of the subjects;
652 7) In accordance with national regulations, the case record form should be recorded
653 on time and consistent with the data from the subject；
654 8) Record and report any adverse events to sponsor;
655 9) Retain records for subjects, as well as any study terminations;
656 10) After completion of the follow-up for the study, the CRO should submit a final
657 study report to the sponsor and investigators;
658 11) They also should maintain confidentiality obligations regarding information
659 provided by the sponsor during the entire process of the study.
660
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661 Appendix 1. Definitions
662
663 Death: Deaths that are not caused by definite non-cardiac factors are deemed as
664 cardiac deaths. Specifically, any unexpected deaths in subject are deemed as cardiac
665 deaths, even if they also have potential fatal non-cardiac diseases (for example, cancer
666 and infection).
667 Cardiac death: any deaths without known cause, and deaths caused by immediate
668 heart-related factors (such as MI, low cardiac output heart failure or fatal arrhythmia)
669 are deemed as cardiac deaths, including those related to surgery and accompanied
670 treatment.
671 Vascular death: deaths caused by cerebrovascular diseases, pulmonary embolism,
672 aneurysm rupture or other vascular diseases.
673 Non-vascular death: any deaths that are not covered in the definitions above,
674 including those caused by infection, pyemia, pulmonary diseases, accident, suicide or
675 injury.
676
677 Myocardial infarction. Myocardial infarction is defined according to the third
678 Universal Definition of Myocardial Infarction.
679 Type 1: Spontaneous myocardial infarction.
680 Spontaneous myocardial infarction related to atherosclerotic plaque rupture,
681 ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in
682 one or more of the coronary arteries leading to decreased myocardial blood flow or
683 distal platelet emboli with ensuing myocyte necrosis. The patient may have
684 underlying severe CAD but on occasion non-obstructive or no CAD.
685 Type 2: Myocardial infarction secondary to an ischaemic imbalance
686 In instances of myocardial injury with necrosis where a condition other than CAD
687 contributes to an imbalance between myocardial oxygen supply and/or demand, e.g.
688 coronary endothelial dysfunction, coronary artery spasm, coronary embolism,
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689 tachy-/brady-arrhythmias, anaemia, respiratory failure, hypotension, and hypertension
690 with or without LVH.
691 Type 3: Myocardial infarction resulting in death when biomarker values are
692 unavailable
693 Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new
694 ischaemic ECG modification or new LBBB, but death occurring before blood samples
695 could be obtained, before cardiac biomarker could rise, or in rare cases cardiac
696 biomarkers were not collected.
697 Type 4a: Myocardial infarction related to percutaneous coronary intervention
698 (PCI)
699 Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn
700 values >5 x 99th percentile URL in patients with normal baseline values (≤99th
701 percentile URL) or a rise of cTn values >20% if the baseline values are elevated and
702 are stable or falling. In addition, either (i) symptoms suggestive of myocardial
703 ischaemia, or (ii) new ischaemic ECG modification or new LBBB, or (iii)
704 angiographic loss of patency of a major coronary artery or a side branch or persistent
705 slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable
706 myocardium or new regional wall motion abnormality are required.
707 Type 4b: Myocardial infarction related to stent thrombosis
708 Myocardial infarction associated with stent thrombosis is detected by coronary
709 angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or
710 fall of cardiac biomarkers values with at least one value above the 99th percentile
711 URL.
712 Type 5: Myocardial infarction related to coronary artery bypass grafting
713 (CABG)
714 Myocardial infarction associated with CABG is arbitrarily defined by elevation of
715 cardiac biomarker values >10 x 99th percentile URL in patients with normal baseline
716 cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves
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717 or new LBBB, or (ii) angiographic documented new graft or new native coronary
718 artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new
719 regional wall motion abnormality.
720
721 Stent thrombosis: Stent thrombosis is defined according to the definite or probable
722 criteria of the Academic Research Consortium (Circulation 2007;115:2344-51).
723 1. Definite stent thrombosis
724 Presence of an acute coronary syndrome with angiographic or autopsy evidence of
725 thrombus or occlusion.
726 2. Probable stent thrombosis
727 Unexplained death within 30 days after the procedure, or acute myocardial infarction
728 involving the target-vessel territory without angiographic confirmation.
729 3. Possible stent thrombosis
730 All unexplained death occurring at least 30 days after the procedure.
731
732 Stent thrombosis classification by time frame
733 1. Acute stent thrombosis
734 Occurring within 24 hours after the index PCI.
735 2. Subacute stent thrombosis
736 Occurring between 24 hours and 30 days after the index PCI.
737 3. Late stent thrombosis
738 Occurring between 31 and 360 days after the index PCI.
739 4. Very late stent thrombosis
740 Occurring later than 360 days after the index PCI.
741
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742 Ischemia-driven Target Vessel Revascularization. Ischemia-driven target vessel
743 revascularization is defined as repeat PCI or bypass surgery of the target lesion(s) and
744 any additional lesions in the main epicardial coronary artery or branches containing
745 the target lesion, with one or more of the following conditions:
746 1. Patient had ischemic symptoms and ECG-changes referable to the target lesion.
747 2. Diameter stenosis ≥50% at follow-up angiography and a positive functional study
748 corresponding to the area served by the target vessel.
749 3. Diameter stenosis <50% at follow-up angiography but a markedly positive
750 functional study or ECG-modification corresponding to the territory supplied by
751 target vessel.
752 4. Diameter stenosis ≥70% at follow-up angiography in absence of documented
753 clinical or functional ischemia.
754
755 Stroke. Stroke is defined as an acute event of non-hemorrhagic cerebrovascular origin
756 causing focal or global neurologic dysfunction lasting > 24 hours, which is confirmed
757 by both clinical and radiographic criteria.
758
759 Bleeding. Bleeding is defined according to the Bleeding Academic Research
760 Consortium (Circulation 2011;123:2736-47).
761 Type 0: no bleeding.
762 Type 1: bleeding that is not actionable and does not cause the patient to seek
763 unscheduled performance of studies, hospitalization, or treatment by a healthcare
764 professional; may include episodes leading to self-discontinuation of medical therapy
765 by the patient without consulting a healthcare professional.
766 Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be
767 expected for a clinical circumstance, including bleeding found by imaging alone) that
768 does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following
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769 criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional,
770 (2) leading to hospitalization or increased level of care, or (3) prompting evaluation.
771 Type 3:
772 Type 3a: Overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided hemoglobin
773 drop is related to bleed); any transfusion with overt bleeding.
774 Type 3b: Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is
775 related to bleed); cardiac tamponade; bleeding requiring surgical intervention for
776 control (excluding dental/nasal/skin/hemorrhoid); Bleeding requiring intravenous
777 vasoactive agents.
778 Type 3c: Intracranial hemorrhage (does not include microbleeds or hemorrhagic
779 transformation, does include intraspinal); Subcategories confirmed by autopsy or
780 imaging or lumbar puncture; Intraocular bleed compromising vision.
781 Type 4: CABG-related bleeding: Perioperative intracranial bleeding within 48 h;
782 Reoperation after closure of sternotomy for the purpose of controlling bleeding;
783 Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period;
784 Chest tube output ≥2L within a 24-h period.
785 Type 5: fatal bleeding.
786 Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but clinically
787 suspicious.
788 Type 5b: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation.
789
790 Acquired thrombocytopenia. Acquired thrombocytopenia is defined as a platelet
791 count decrease by >50% or by >150×109/L from baseline.
792
793
794
795
796
797
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798 Appendix 2. Informed consent
799 （V2.01）
800 Title：BivaliRudin in Acute Myocardial Infarction versus Heparin and GPI plus Heparin: a
801 Randomized Controlled Trial.
802 Research center: ______
803
804 1. Research aim and profile
805 Since you have been confirmed or suspected as being diagnosed with an acute myocardial
806 infarction, you will undergo emergency coronary angiography. If necessary, a percutaneous
807 coronary intervention, PCI (Including the balloon expansion of narrow blood vessels and placing a
808 stent) may be performed. So you are invited to attend the study.
809 PCI therapy is a conventional treatment in patients with coronary heart disease (CHD).
810 Anticoagulant drugs such as heparin or low molecular heparin must be used as a routine during
811 PCI. Bivalirudin, a new anticoagulant drug, had significantly lower drug related bleeding rates
812 than traditional heparin therapy in large scale clinical studies such as REPLACE-2、ACUITY、
813 HORIZONS-AMI. Bivalirudin was the preferred recommended drug for PCI anticoagulation in
814 the 2011 joint guidelines of the foundation of the American College of Cardiology, the American
815 Heart Association and the American Society for Cardiovascular Angiography and Interventions.
816 The present study is enrolling AMI patients undergoing PCI to observe whether bivalirudin
817 improves the efficacy and safety compared to traditional heparin or heparin treatment plus
818 tirofiban. Patients participating in this study will be randomly assigned to three treatment groups:
819 bivalirudin alone, or unfractionated heparin alone, or unfractionated heparin plus a glycoprotein
820 IIb/IIIa inhibitor. The care provide for patients treated with each kind of therapy are otherwise
821 equal. Drug therapy would begin before PCI, and depending on the drug a continuous intravenous
822 infusion may be continued for up to 36 h after PCI.
823 Patients in each group will take antiplatelet drugs as follows: 1) aspirin: 300mg before PCI,
824 100 mg every day long term after PCI; 2) clopidogrel: 300mg - 600mg before PCI, 75 mg each
825 day for 1 year. Patients who have already used clopidogrel 75mg per day for 5 days need no
826 loading dose. Aspirin and clopidogrel are both the conventional drugs taken around the time of
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827 PCI. You need to take them whether or not you participate in the study.
828
829 2. Protocols
830 2.1 Therapy procedure
831 Your doctor will determine whether you are eligible to participate in this study according to your
832 clinical history (including any medications you are taking), in-hospital examination, routine tests
833 and ECG. After discharge, you need outpatient follow-up at 30 days, 6 months and 12 months.
834 Interview 1(0-3 day before PCI)
835 Patients will be randomized to one of the three groups if suitable for participation in this study
836 and after signing the informed consent. Different drug treatments would be done according to
837 randomization. Other standard drugs (except the study drugs) would be determined by your doctor.
838 You will undergo coronary angiography. In order to observe blood coagulation function, doctors
839 will take 5 ml blood from the arterial sheath for laboratory tests.
840 Interview 2 (30 days after PCI):
841 The doctor will ask for your symptoms. When necessary, your doctor will check for vital signs
842 and take blood tests as an outpatient, or you will receive treatment as necessary during any
843 hospital admissions. The doctor will record any therapies provided.
844 Interview 3 (6 months after PCI):
845 The doctor will ask for your symptoms. When necessary, your doctor will check for vital signs
846 and take blood tests as an outpatient, or you will receive treatment as necessary during any
847 hospital admissions. The doctor will record any therapies provided.
848 Interview 4 (12 months after PCI):
849 The doctor will ask for your symptoms. When necessary, your doctor will check for vital signs
850 and take blood tests as an outpatient, or you will receive treatment as necessary during any
851 hospital admissions. The doctor will record any therapies provided.
852 2.2 Study time and number of patients
853 A total of 2400 patients would participate in preliminary screening in the present study. Finally
854 2100 patients would be enrolled in the study. The approximate time span is 12 months. This study
855 would will be carried out in 80 heart centers.
856 2.3 Limitations and responsibilities of subjects
857 If you have any symptoms or discomfort or hear of any lab abnormalities, please inform your
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858 study doctor immediately. Contact information will be listed on the informed consent.
859
860 3. Side effects, risks, and discomfort
861 3.1 Side effects
862 Adverse reactions of bivalirudin have been studied in about 3000 patients. Results showed that
863 the drug was well tolerated. Bleeding is the most common complication (usually at the arterial
864 puncture site, sometimes from other body parts). Other rare adverse reactions are:
865 thrombocytopenia, anemia, allergic reactions, ventricular tachycardia, angina pectoris, bradycardia,
866 dyspnea, rashes, backache, headaches, low blood pressure.
867 If you are randomized to a regular treatment group (heparin or heparin plus tirofiban), these
868 drugs can have similar side effects. And every patient whose diagnosis was coronary heart disease
869 (CHD) and in whom PCI was performed would receive anticoagulant therapy, regardless of in this
870 study.
871 3.2 The possible influence to the fetus
872 Females:
873 Participating in the study may be dangerous to the unborn fetus. If you are a pregnant woman or
874 got pregnant during the study, these dangers could affect you or your unborn child. Women should
875 use contraception during study. Acceptable methods including oral contraceptives, intrauterine
876 device and protective screen containing spermicide (diaphragm, condoms). Contraceptives should
877 be approved by the doctor.
878 Before the study begin, every women of child-bearing potential will undergo a pregnancy test.
879 Pregnancy tests may be performed repeatedly due to the uncertainty of the test. Please inform your
880 doctor if you are pregnant.
881 Pregnancy is a reason to stop the study. If you become pregnant during study, you must
882 withdraw from the study. If you become pregnancy within 28 days of the use of the study drugs,
883 please contact with your doctor for safety monitoring. You should let your obstetrician know you
884 have participated in this study. Your cardiologist collect pregnancy data from the obstetrician for
885 safety monitoring.
886
887 Males:
888 If your spouse or partner becomes pregnancy when you are participating in the study or within 28
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889 days of use of the study drugs, please let your doctor know. If your spouse or partner has already
890 become pregnancy, she will be asked to sign a consent form to permit your research doctor to
891 collect pregnancy data from her obstetrician just for safety monitoring.
892 3.3 Discomfort
893 You may develop discomfort such as pain at the blood collecting site, burning or blood clot, feel
894 dizzy or faint at needling, or allergy to tape.
895
896 4. Your potential benefits
897 In the study protocol, the drugs and dosing regimens in the regular treatment groups (heparin
898 group and heparin plus tirofiban) have been approved by the government, and have been
899 in clinical use for several decades. Bivalirudin, which has been approved by the government, is
900 also used in routine clinical practice. Bivalirudin has been reported to result in lower bleeding and
901 death rates than control groups in some studies. There are other anticoagulant drugs such as
902 low molecular heparin and fondaparinux sodium that are used in clinical practice, although the
903 guideline recommendation levels for these two drugs are lower than bivalirudin, heparin and
904 tirofiban. Patients in the bivalirudin group may benefit from this study, and other patients may be
905 benefit from information obtained from the present study. If you are enrolled in the study, the costs
906 may be lower than routine medicine service. If you are randomized to bivalirudin, the bivalirudin
907 will be free. If you are randomized to regular treatment group (heparin or heparin plus tirofiban),
908 you will get free clopidogrel tablets for 1 month. Your study doctor will pay close attention and
909 you will have careful follow-up so that adverse events may be processed quickly.
910 5. Compensation
911 We do not want you to have any health problems due to the study. If you suffer from bleeding
912 which is identified by medical department that is caused by bivalirudin, you will be provided with
913 appropriate free treatment.
914 6. Withdrawal
915 You have the right to decide whether to participate in the study. You can choose not to participate
916 in the study or withdraw at any time during the study. Your decision will not affect your medical
917 service at the time of hospitalization. There will be no loss of your entitled benefits. After your
918 dropping out of the study, we will analyze data collected before you dropped out unless you do not
919 agree that we may do so.
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920 In some cases, your doctor will withdraw you from the study. This may occur if you do not follow
921 the study doctor's guidance; if you develop a serious disease that is irrelevant to present study; if
922 the present study is not advantageous to you in your doctor’s opinion; if the study was halted by
923 research group, management agency or Ethics Committee; if pregnancy or planned pregnancy or
924 breastfeeding occurs.
925 7. Privacy
926 Your record and health data in present study will be kept secret. But these files will be provided
927 to the Ethics Committee and department of drug supervision and administration.
928 Signing this consent form indicates that you have agreed to the above mentioned staffing and
929 authority obtaining your data. We will take measures to protect your privacy, and your identity
930 will not appear in any research documents, reports, or published articles, now or in the future.
931 After your withdrawing from the study, we will analyze data collected before unless you do not
932 agree that we may do so.
933 Finally, the research data will be published as an academic paper. But your identity will not be
934 disclosed in this paper, and no one will be able to guess your identity.
935 Your participating in the present study (even if you withdraw) means you agree with no limitation
936 of your data being transmitted to the department of drug supervision and administration.
937 8. Answer questions about the study
938 Before you sign up, you should ask any and all questions about the study. The research staff will
939 also answer your questions anytime during the study.
940
941
942 Name: ID:
943 If you have any questions about how the study carrying out or potential side effects please contact:
944 Research Doctor: Tel:
945 Research Coordinator: Tel:
946 The present study has been approved on paper by Ethics Committee of General Hospital of
947 Shenyang Military region. If you have any questions about you rights in the study, please contact:
948 Ethics Committee of General Hospital of Shenyang Military region
949 No.83 Wenhua Road, Shenyang, Liaoning Province, 110016, Tel:+86-24-28856472
950
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951 Informed consent (for signature) 952 953 I have read all the words of the above guidelines. I voluntarily agree to participate in the study”
954 BivaliRudin in Acute Myocardial Infarction vs Glycoprotein IIb/IIIa and Heparin: a Randomised
955 Controlled Trial.”
956 1. I have recovered Informed consent with signature and date. I understand the purpose, nature,
957 protocol, potential risk, and benefit of this study, and other standard treatments for my disease. I
958 have had plenty of time to ask any questions. I have been provided satisfactory answers.
959 2. I agree to cooperate with the research doctor and comply with the requirements of this study.
960 3. I have been told that I must contact with doctor if illness or symptom arises so I may receive for
961 effective treatment.
962 4. I understand that this study fully follows the declaration of Helsinki, and Chinese Clinical
963 research regulations and specifications. The present study has been approved on paper by the
964 Ethics Committee of General Hospital of Shenyang Military region.
965 5. I can choose not to participate in the study or withdraw at any time during the study. My
966 decision will not affect my medical service at the time of hospitalization.
967 6. My participating in the present study (even if I withdraw) means you agree with no limitation of
968 dealing with my data in clinical research. My privacy will be kept secret and will not appear in
969 any research documents, reports, or published articles.
970 I agree to participate in the study.
971
972 Patient Name (signature): Date:
973 Tel:
974
975 I have detailed introduced the purpose, nature, protocol, potential risks and benefits of this study.
976 The subject has agreed to be enrolled in the study with signature and date.
977 Investigator (signature) Date:
978 Tel:
979
980
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