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Due to the heterogeneity in the manifestation of bleeding events, there have been a number of bleeding definitions used in trials. The components used in bleeding classifications used to define severity are shown in Table 2.2. In trials and prospective studies bleeding severity is generally adjudicated by a number of study personnel at the time of the event.

The Thrombolysis in Myocardial Infarction (TIMI) bleeding classification was developed in conjunction with trials conducted by the TIMI study group, which primarily investigated interventions for patients with ACS. The original TIMI bleeding definition47 _{classified bleeding}

events as major if they were intracranial or resulted in a haemoglobin drop >5g/dL. Bleeding events were classified as minor if it was spontaneous and observed as gross haematuria or hematemesis or had a haemoglobin drop >3g/dL. The current iteration of TIMI bleeding48 _has

three levels of severity, major, minor and minimal. Major TIMI bleeding events are fatal, intracranial, or bleeding with a haemoglobin drop ≥5g/dL. Minor TIMI bleeding events are bleeding with a haemoglobin drop 3 to 5g/dL, requires intervention to stop bleeding, leads to hospitalisation or prompts medical evaluation. Minimal TIMI bleeding events are any that do not meet the criteria of major or minor. In the TRITON-TIMI 38 trial49 _{which compared the use}

of prasugrel versus clopidogrel in ACS patients the risk of TIMI major bleeding was 2.4% for patients randomised to prasugrel and 1.8% for patients randomised to clopidogrel. In the PEGASUS-TIMI 54 trial17 _{which assessed the use of prolonged dual antiplatelet therapy (aspirin}

and ticagrelor) in myocardial infarction survivors the risk of TIMI major bleeding was 2.3% for patients randomised to ticagrelor 60mg and 1.06% for patients randomised to placebo. TIMI

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minor bleeding was reported in 1.18% patients randomised to ticagrelor 60mg and 0.36% for patients randomised to placebo.

The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) bleeding definition50 _{classifies bleeding as severe or life-}

threatening, moderate or mild. Severe or life-threatening events include intracerebral haemorrhage or bleeding resulting in haemodynamic compromise and moderate bleeding events are those that require transfusion with no haemodynamic compromise. All other bleeding events are classified as mild. GUSTO is the only bleeding classification assessed here that does not account for haemoglobin drop (Table 2.2). In the GUSTO trial randomised patients with acute MI to streptokinase and subcutaneous heparin, streptokinase and intravenous heparin, t-PA and intravenous heparin or streptokinase, t-PA and intravenous heparin. 30 day GUSTO severe or life-threatening bleeding occurred in 0.3%, 0.5%, 0.4% and 0.6% of patients in the streptokinase and subcutaneous heparin, streptokinase and

intravenous heparin, t-PA and intravenous heparin and streptokinase, t-PA and intravenous heparin groups respectively. 30 day GUSTO moderate bleeding occurred in 5.6%, 5.8%, 5.1% and 5.6% of patients in the streptokinase and subcutaneous heparin, streptokinase and intravenous heparin, t-PA and intravenous heparin and streptokinase, t-PA and intravenous heparin groups respectively.

The ACUITY-HORIZONS bleeding classification51,52 _{defines major bleeding as intracranial or}

intraocular haemorrhage, bleeding that requires intervention, ≥5cm haematoma, retroperitoneal, ≥4g/dL haemoglobin drop without an overt source of bleeding, ≥3g/dL haemoglobin drop with an overt source of bleeding, any transfusion or reoperation for bleeding. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial53

randomised ACS patients to unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. Major and minor bleeding according to the ACUITY-HORIZONS and the TIMI bleeding classification were

reported. In the unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor group the risk of 30 day ACUITY-HORIZONS major and minor bleeding was 5.7% and 21.6% respectively and TIMI major and minor bleeding was 1.9% and 6.4% respectively. In the bivalirudin plus a glycoprotein IIb/IIIa inhibitor group the risk of 30 day ACUITY-HORIZONS major and minor bleeding was 5.3% and 21.7% respectively and TIMI major and minor bleeding was 1.7% and 6.1% respectively. In the bivalirudin alone group the risk of 30 day ACUITY-HORIZONS major and minor bleeding was 3.0% and 12.8% respectively and TIMI major and minor bleeding was 0.9% and 3.7% respectively. The Harmonising Outcomes with

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randomised STEMI patients undergoing PCI to heparin plus a glycoprotein IIb/IIIa inhibitor or to bivalirudin alone. ACUITY-HORIZONS major, TIMI major, TIMI minor, and GUSTO life- threatening or severe and GUSTO moderate bleeding events after 30 days follow-up were reported. In the heparin plus a glycoprotein IIb/IIIa inhibitor group 30 day ACUITY-HORIZONS major bleeding risk was 8.3%, TIMI major bleeding 5.0%, TIMI minor bleeding 4.6%, GUSTO life threatening or severe bleeding 0.6% and GUSTO moderate bleeding 5.0%. In bivalirudin group 30 day ACUITY-HORIZONS major bleeding risk was 4.9%, TIMI major bleeding 3.1%, TIMI minor bleeding 2.8%, GUSTO life threatening or severe bleeding 0.4% and GUSTO moderate bleeding 3.1%.

The Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) bleeding

classification54 _{has two levels of severity, major and minor. CURE major bleeding includes fatal}

bleeding, intracranial haemorrhage, bleeding that requires surgical intervention, bleeding resulting in hypotension, haemoglobin drop ≥5g/dL, bleeding requiring transfusion of 2-3units and intraocular bleeding. Minor bleeding events are those that led to discontinuation of treatment. The CURE trial54 _{randomised NSTE-ACS patients to clopidogrel or placebo in}

addition to aspirin for 3 to 12 months. In the clopidogrel group risk CURE major and minor bleeding was 3.7% and 5.1% respectively. In the placebo group risk of CURE major and minor bleeding was 2.7% and 2.4% respectively. In a study of ACS patients from CURE, OASIS, OASIS-2 studies combined the risk of major bleeding at 6 months was 2%.55

CURRENT-OASIS 7 bleeding classification56 _{defines severe, major and minor bleeding. Severe}

bleeding is defined as fatal, requiring transfusion ≥4units, haemoglobin drop ≥5g/dL, leading to hypotension, requiring surgery or intracranial. Major bleeding is defined as requiring

transfusion 2-3 units, disabling, intraocular. Minor bleeding refers to events requiring modification of drug regimens. The trial compared double dose versus standard dose

clopidogrel and high dose versus low dose aspirin in ACS patients undergoing PCI and reported CURRENT-OASIS 7 major, severe and minor bleeding as well as TIMI major bleeding events.57

The risk of 30 day CURRENT-OASIS 7 major bleeding, CURRENT-OASIS 7 severe bleeding, TIMI major bleeding and minor bleeding in patients randomised to double dose clopidogrel was 1.6%, 1.1%, 1.0% and 5.1% respectively. The risk of 30 day CURRENT-OASIS 7 major bleeding, CURRENT-OASIS 7 severe bleeding, TIMI major bleeding and minor bleeding in patients randomised to standard dose clopidogrel was 1.1%, 0.8%, 0.7% and 4.3% respectively. The risk of 30 day CURRENT-OASIS 7 major bleeding, CURRENT-OASIS 7 severe bleeding, TIMI major bleeding and minor bleeding in patients randomised to high dose aspirin was 1.5%, 1.1%, 0.9% and 5.0% respectively. The risk of 30 day CURRENT-OASIS 7 major bleeding, CURRENT-OASIS 7

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severe bleeding, TIMI major bleeding and minor bleeding in patients randomised to low dose aspirin was 1.3%, 0.9%, 0.7% and 4.3% respectively.

The Safety and Efficacy of Enoxaparin in PCI Patients, an International Randomized Evaluation (STEEPLE) bleeding classification58 _{defines major as fatal bleeding, retroperitoneal, intracranial}

or intraocular bleeding, bleeding that causes haemodynamic compromise, bleeding that requires surgical intervention, bleeding requiring transfusion ≥1 unit or bleeding with haemoglobin drop ≥3g/dL. STEEPLE minor bleeding is gross haematuria, prolonged epistaxis, gastrointestinal haemorrhage, haemoptysis, subconjunctival haemorrhage, haematoma ≥5cm, haemoglobin drop 2-3g/dL or uncontrolled bleeding requiring protamine sulphate. The

STEEPLE trial58 _{randomised patients undergoing elective PCI to enoxaparin or unfractionated}

heparin. As well as STEEPLE bleeding, TIMI major, TIMI minor and GUSTO moderate or severe bleeding events were reported. In the heparin group STEEPLE major bleeding risk was 2.8%, STEEPLE minor bleeding 5.9%, TIMI major bleeding 0.3%, TIMI minor bleeding 1.9% and GUSTO moderate or severe bleeding 1.5%. In the enoxaparin 0.5mg per kilogram group STEEPLE major bleeding risk was 1.2%, STEEPLE minor bleeding 4.8%, TIMI major bleeding 0.3%, TIMI minor bleeding 1.8% and GUSTO moderate or severe bleeding 0.6%.

The PLATelet inhibition and patient Outcomes (PLATO) bleeding classification59 _{has three}

defined levels of severity, major, minor and minimal bleeding. PLATO major bleeding includes fatal, intracranial, intrapericardial with cardiac tamponade, bleeding resulting in severe

hypotension, haemoglobin drop≥5g/dL, transfusion of ≥4 units or significantly disabling events. PLATO minor bleeding events are those that require medical intervention to treat or stop bleeding, 3-5g/dL haemoglobin drop or transfusion of 2-3 units. Minimal bleeding events are those that do not meet the major or minor criteria. The PLATO trial60 _{randomised ACS patients}

to treatment with ticagrelor or clopidogrel. In the ticagrelor group the risk of PLATO and TIMI major bleeding was 4.5% and 2.8% respectively. In the clopidogrel group the risk of PLATO and TIMI major bleeding was 3.8% and 2.2% respectively.

The Global Registry of Acute Coronary Events (GRACE) bleeding classification61 _{defines major}

bleeding as events that are fatal or result in stroke, intracerebral haemorrhage, require a transfusion of ≥2 units, or a decrease in haematocrit of≥10%. GRACE is multinational registry of ACS patients.62 _{Of the 24045 patients in GRACE hospitalised for ACS, 3.9% developed major}

bleeding.61 _{A later study of patients in the GRACE registry identified 2.8% of acute MI patients}

with major bleeding while hospitalised.63

The International Society of Thrombosis and Haemostasis (ISTH) bleeding classification64

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critical area or organ or bleeding causing a fall in haemoglobin ≥2g/dL or transfusion of 2 or more units. The ISTH bleeding endpoint has been used in a number of clinical trials involving novel oral anticoagulants in atrial fibrillation and venous thromboembolism populations. In the ARISTOTLE trial population atrial fibrillation patients were randomised to apixaban or warfarin and the primary safety endpoint was ISTH major bleeding whilst GUSTO severe and TIMI major bleeding events were also reported.14 _{The risk of ISTH major bleeding was 2.13% in the}

apixaban group and 2.09% in the warfarin group. The risk of GUSTO severe bleeding was 0.52% in the apixaban group and 1.13% in the warfarin group. The risk of TIMI major bleeding was 0.96% in the apixaban group and 1.69% in the warfarin group. Therefore in this setting ISTH major bleeding was shown to be a less conservative measure of major bleeding than the GUSTO and TIMI criteria.

The Bleeding Academic Research Consortium (BARC) bleeding classification3 _{was developed in}

an effort to standardise the definition of bleeding in research. The BARC bleeding classification has 5 levels of severity: Type 1 – bleeding that does not result in hospitalisation or consultation of healthcare professionals; Type 2 – overt haemorrhage with either nonsurgical intervention, hospitalisation or prompts evaluation; Type 3a – Overt bleeding with haemoglobin drop 3 to 5g/dL or transfusion; Type 3b – overt bleeding with haemoglobin drop ≥5g/dL, cardiac tamponade, or requires surgical or pharmacological intervention; Type 3c – Intracranial haemorrhage or intraocular haemorrhage; Type 4 – CABG related bleeding; Type 5 – fatal bleeding. In a study of coronary artery disease patients undergoing PCI pooled from 6 clinical trials, the overall risk of BARC type ≥ 2, BARC type≥ 3 and TIMI major bleeding 5.4%, 4.0% and 0.9% respectively.65 _{In a prospective cohort study of 4149 stable coronary artery disease}

patients, after two years follow up the risk of BARC type≥3 was 1.2%.66 2.3.2.1 Comparisons of bleeding classifications

There have been studies in prospective cohorts which sought to compare the incidence of bleeding events according to the various classification schemes and analysed the risks of subsequent mortality in a form of validation.

Kikkert et al67 _{followed-up a prospective cohort of 2002 STEMI patients and used the TIMI,}

ISTH, GUSTO and BARC classification schemes to define bleeding events. Overall, 19% patients had ISTH major bleeding, 6.3% had GUSTO moderate bleeding, 2.7% had GUSTO severe bleeding, 7.9% had TIMI minor bleeding, 5.0% had TIMI major bleeding, 4.4% had BARC type 2 bleeding, 8.5% had BARC Type 3a bleeding, 5.5% had BARC type 3b/3c bleeding, 1.3% had BARC Type 4 bleeding and 0.3% had BARC type 5 bleeding. In adjusted analysis the risk of one year mortality did not differ significantly between the levels of ISTH or GUSTO bleeding

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severity. Patients with TIMI major bleeding had 2 (95% CI: 1.32, 3.01) times the risk of mortality compared with patients that had TIMI minimal or no bleeding. Patients with BARC type 3b/3c bleeding had 1.84 (95% CI: 1.23, 2.77) times the risk of mortality compared with patients who had BARC type 0 or 1 bleeding. The risk of mortality in patients who had BARC type 4 bleeding was not significantly different to those with BARC type 0 or 1. In an analysis of the individual components of the bleeding classification scheme it was found that a

haemoglobin drop of ≥5 g/dL was associated with increased risk of mortality.

Vranckx et al68 _{validated the BARC bleeding classification in the TRACER trial population of}

NSTE-ACS patients. In follow up 15.3% of the patients had BARC type≥2 bleeding, 3.7% had TIMI major or minor bleeding and 4.0% had GUSTO severe or moderate bleeding. The rate of mortality following bleeding was highest in those who has GUSTO severe bleeding (30.0% at 2 years post-bleeding), followed by BARC type 3 bleeding (% at 2 years post-bleeding) and TIMI major bleeding (22.4% at 2 years post-bleeding). For the BARC classification, patients with Type ≥ 2 bleeding had increased mortality risk up to one year post-bleeding compared with patients that did not have a bleeding event. Patients with major TIMI bleeding had increased 1 year mortality risk compared with patients that had no TIMI bleeding. Patients with moderate or severe GUSTO bleeding had increased 1 year mortality compared with patients that had no GUSTO bleeding.

Kaatz et al69 _{highlighted the important of clinically relevant non-major bleeding, e.g. costs and}

management of such events, and sought to standardise the definition of non-major bleeding for patients treated with anticoagulants. Through reviewing trials of novel oral anticoagulants in atrial fibrillation and venous thromboembolism patients they found 47 distinct components used to define non-major bleeding. With this information they defined clinically relevant non- major bleeding as a sign or symptom of bleeding that does not meet the ISTH criteria for major bleeding64 _{but requires medical intervention, leads to hospitalisation or prompts face to face}

evaluation.