Table 1.

Generic domain—clinical outcomes and their definitions

Generic domain: Level 1 variables
All-cause mortality	Death from any cause
Cardiovascular mortality	Death that is primarily from a cardiovascular cause: Related to HF, cardiogenic shock, native, mechanical or bioprosthetic valve dysfunction, myocardial infarction, stroke, thromboembolism, bleeding, tamponade, vascular complication, arrhythmia or conduction system disturbances, cardiovascular infection (e.g. mediastinitis, endocarditis), or other clear cardiovascular cause. Intraprocedural death—caused by immediate/latent complications of a cardiovascular procedure. Sudden death—Sudden natural death presumed to be of cardiac cause that occurs within 1 h of onset of symptoms in witnessed cases, and within 24 h of last being seen alive when it is unwitnessed. In autopsied cases, it is defined as the natural unexpected death of unknown or cardiac cause. Death of unknown causes.6,20,46
Myocardial infarction	Myocardial infarction, as defined according to the latest universal definition of MI, currently: a rise and/or fall of cardiac troponin with at least one value above the 99th percentile and/or symptoms suggestive of ischaemia, new significant ECG changes, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology or identification of a coronary thrombus by angiography/intracoronary imaging or by autopsy. History of myocardial infarction also includes episodes of symptoms suggestive of myocardial ischaemia, which are accompanied by presumed new ischaemic ECG changes or ventricular fibrillation; coronary intervention-related myocardial infarction; and CABG-related myocardial infarction.47
Stroke	An acute episode of focal or global neurological dysfunction (lasting for ≥ 24 h or until death) caused by an infarction or haemorrhage in the brain, spinal cord, or retina resulting in cell damage based on pathological, imaging, or other objective evidence. Stroke does not include non-vascular neurological deficits. Ischaemic stroke is defined as an acute episode of focal, cerebral, spinal, or retinal dysfunction that is caused by central nervous system infarction, where the neurological dysfunction lasts for ≥24 h. Ischaemic stroke may result in haemorrhage (haemorrhagic transformation). Haemorrhagic stroke is defined as an acute episode of focal or global neurological dysfunction of the brain, spinal cord or retina that is caused by a spontaneous (not traumatic) collection of intraparenchymal, intraventricular, and/or sub-arachnoid blood, where the neurological dysfunction lasts for ≥24 h. Haemorrhagic stroke does not include sub-dural hematomas. Unspecified stroke is defined as an acute episode of focal or global neurological dysfunction that is caused by a presumed infarction or haemorrhage to the central nervous system, where the neurological dysfunction lasts for ≥24 h but with insufficient information to allow categorisation as either ischaemic or haemorrhagic stroke.48
HF	A new clinical diagnosis of HF made by a healthcare professional. HF is a clinical syndrome characterized by typical symptoms (e.g. dyspnoea) and/or signs (e.g. ankle swelling), caused by a structural and/or functional cardiac abnormality (e.g. left ventricular hypertrophy or impairment), and associated with elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion from a cardiogenic origin at rest or with exercise.49
Generic domain: Level 2 variables
Acute kidney injury	Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 h; or an increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume <0.5 mL/kg/h for 6 h.50
All-cause re-hospitalisation	Unscheduled admission to hospital for any reason, defined as a being admitted for more than 24 h or past a calendar day.6,20
Bleeding events	Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional. Type 2: any clinically overt sign of haemorrhage that is actionable but does not meet criteria for Type 3, Type 4 (coronary artery bypass graft surgery [CABG]-related), or Type 5 (fatal bleeding) bleeding. The bleeding must require diagnostic studies, hospitalization, or treatment by a healthcare professional. In particular, the bleeding must meet at least one of the following criteria: Requires intervention, defined as a healthcare professional–guided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. Bleeding leads to hospitalization or an increased level of care, defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care. The bleeding prompts evaluation, defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing (laboratory or imaging). Type 3a: any transfusion with overt bleeding; overt bleeding plus haemoglobin drop ≥3 to <5 g/dL (provided haemoglobin drop is related to bleeding). Type 3b: overt bleeding plus haemoglobin drop ≥5 g/dL (provided haemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control (excluding dental/nasal/skin/haemorrhoid); bleeding requiring intravenous vasoactive drugs. Type 3c: intracranial haemorrhage; sub-categories confirmed by autopsy or imaging, or lumbar puncture; intraocular bleed compromising vision. Type 4: CABG–related bleeding; peri-operative intracranial bleeding within 48 h; re-operation after closure of sternotomy for the purpose of controlling bleeding; transfusion of ≥5 units of whole blood or packed red blood cells within a 48-h period; chest tube output ≥2 L within a 24-h period. Type 5: fatal bleeding.22
Cardiac arrest	Cardiac arrest is defined as a verified sudden cessation of cardiac mechanical activity causing unresponsiveness, absence of normal breathing and no signs of circulation (excluding syncope or profound vagally mediated bradycardia) with ventricular fibrillation, rapid ventricular tachycardia or bradycardia resulting in loss of consciousness, pulseless electrical activity, or asystole as the major causes. Return of spontaneous circulation (ROSC) is defined as the resumption of a sustained heart rhythm that perfuses the body after cardiac arrest. Signs include a palpable pulse, measurable blood pressure and/or respiratory effort.51
Cardiogenic shock	Cardiogenic shock is defined as any one of the following: (1) ‘beginning’ cardiogenic shock or compensated shock where a patient may be volume overloaded, tachycardic, and/or hypotensive but no evidence of hypoperfusion on physical exam or laboratory studies. It also includes patients with a (2) ‘classic’ cardiogenic shock with evidence of hypoperfusion on physical exam and laboratory studies ‘cold and wet.’ Invasive haemodynamics (if available) demonstrate the classic depressed cardiac index associated with cardiogenic shock. Cardiogenic shock also includes patients with (3) ‘deteriorating’ and includes above patients plus failure of initial interventions in restoring adequate perfusion in 30 min and further escalation is required. Cardiogenic shock also includes (4) ‘escalation’ cardiogenic shock which is an increase in the number or intensity of intravenous therapies to address hypoperfusion, or addition of mechanical circulatory support after the initial 30-minute period of observation and treatment. It can also include patients who are highly unstable, often with circulatory collapse and/or refractory cardiac arrest with ongoing CPR. They are being supported by multiple simultaneous acute interventions including ECMO-facilitated CPR (eCPR).52
Cause-specific hospitalisation	Unscheduled hospitalisation due to either cardiovascular or non-cardiovascular causes. Unscheduled hospitalisation is defined as a being admitted for more than 24 h or past a calendar day. Cardiovascular causes include conditions such as HF, cardiogenic shock, bioprosthetic or native valve dysfunction, myocardial infarction, stroke, thromboembolism, bleeding, tamponade, vascular complication, arrhythmia or conduction system disturbances, cardiovascular infection (e.g. mediastinitis, endocarditis), or other clear cardiovascular cause. Non-cardiovascular cause includes (but is not limited to) respiratory failure not related to cardiovascular disease (e.g. pneumonia), renal failure, liver failure, infection (e.g. urosepsis), cancer, trauma, and suicide.6,53
DVT	DVT is the formation of a thrombus (blood clot) in a deep vein, usually in the legs, but may also include the arms, which partially or completely obstructs blood flow.54
Device implantation	Implantation of any of: Transvenous permanent pacemaker is an electronic device that is implanted in the subcutaneous tissue and gives the heart an electrical stimulation through transvenous wires. Leadless pacemaker is an electronic device that is implanted directly into the right ventricle. Transvenous ICD is a device that is used to correct abnormal heartbeat through transvenous wires. Subcutaneous ICD is an ICD with a presternal lead and is positioned between the latissimus dorsi and serratus muscle within the subcutaneous tissue. Extravascular ICD is an ICD with a substernal lead and the device in the subcutaneous tissue of the lateral thorax. CRT device and pacemaker (CRT-P) is defined as a biventricular pacemaker that sends electrical stimulation to both ventricles. CRT-D is a biventricular pacemaker and defibrillator.55,56
Heart transplant	Surgery in which a failing, diseased heart is replaced with a donor heart.57
Hospitalized ventricular tachycardia	The patient was hospitalized with ventricular tachycardia, defined as ≥3 consecutive beats with a rate >100 beats per minute originating from the ventricles, independent from atrial and atrioventricular (AV) nodal conduction.46
ICD therapy delivery	Delivery of either an ICD shock or antitachycardia pacing.55
Mechanical circulatory support	Use of mechanical circulatory support devices, such as left ventricular assist device.
AF or AFL	AF is defined as a supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AF is at least 30 s, or entire 12-lead ECG. AFL is defined as a supraventricular tachyarrhythmia with co-ordinated but overly rapid atrial electrical activation, usually with some degree of AV node conduction block. The minimum duration of an ECG tracing of AF required to establish the diagnosis of clinical AFL is at least 30 s, or entire 12-lead ECG.58
Pulmonary embolism	A condition in which one or more emboli, usually arising from a thrombus formed in the veins, are lodged in and obstruct the pulmonary arterial system.59
Systemic embolism	Systemic embolism is defined as a hospital encounter with a principal diagnosis of an arterial embolism and thrombosis,60 excluding stroke or transient ischaemic attack.
Transient ischaemic attack	Transient ischaemic attack is a transient focal neurological signs or symptoms lasting <24 h presumed to be due to focal brain, spinal cord, or retinal ischaemia, but without evidence of acute infarction by neuroimaging or pathology, or with no imaging performed.61
Unplanned cardiac surgery	Unplanned cardiac surgery is defined as an unplanned surgical intervention to the heart and the great vessels.62
Worsening HF	HF is a clinical syndrome characterized by typical symptoms (e.g. dyspnoea) and/or signs (e.g. ankle swelling), caused by a structural and/or functional cardiac abnormality (e.g. left ventricular hypertrophy or impairment), and associated with elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion from a cardiogenic origin at rest or with exercise. Worsening HF is defined as either an unplanned HF hospitalisation or urgent outpatient visit for HF. Unplanned HF hospitalisation is defined as a patient requiring an unscheduled hospital admission for a primary diagnosis of HF with a length of stay that either exceeds 24 h or crosses a calendar day (if hospital admission and discharge times are unavailable). To satisfy the criteria for a worsening HF event, the patient must have an urgent, unscheduled office or emergency visit for HF with signs, symptoms, and diagnostic testing results identical to those already described above. The patient must also require treatment for HF such as significant dose increase of oral diuretics, intravenous diuretics or mechanical or surgical intervention for HF. Importantly, clinic visits for scheduled administration of HF therapies or procedures (e.g. intravenous diuretics, intravenous vasoactive agents, or mechanical fluid removal) do not qualify as non-hospitalized HF events.6,49,63

Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; CABG, coronary artery bypass; CPR, cardiopulmonary resuscitation; CRT, cardiac resynchronisation therapy; DVT, deep vein thrombosis; ECG, electrocardiogram; HF, heart failure; ICD, implantable cardioverter defibrillator.