Sudden cardiac versus non-cardiac death

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Sudden cardiac arrest is defined as the unexpected cessation of pumping blood into vital organs due to electrical disturbance in the pathway of SA node, AV node, Hiss Purkinje fibers or pumping failure due to cardiogenic shock, massive pulmonary thromboembolism, aorta dissection. ruptured left ventricular free wall. Without any intervention for immediate restoration of the circulation, biologic death or sudden cardiac death will happen minutes to weeks after cardiac arrest. Sudden death may be due to cardiac or noncardiac causes. Sudden cardiac death is responsible for 50% of cardiac death annually in the united state. In hospital cardiac arrest happens in 290,000 adults in the united states every year. The most common cause of sudden cardiac death is coronary artery disease and atherosclerosis process. The presence of underlying disorders such as malignancy or liver disease at the time of cardiac arrest makes the condition worst. Patients with acute myocardial infarction and in-hospital cardiac arrest with shockable rhythm have a better prognosis. Post CPR state management should be focused on neurologic complications, hemodynamic stability, and respiratory support.

Historical Perspective

There is no historical perspective available about sudden cardiac death.

Classification

There are some definitions related to cardiac arrest including:

Classification	Definition
Sudden cardiac death	Sudden and unexpected death within one hour of being symptomatic or whitin 24 hours in asymptomatic patient due to arrhythmia or hemodynamic instability
Sudden cardiac arrest	Suddenly cessation of cardiac activity,unresponsive patient with gasping respiration or no respiratory movement and unpalpable pulses due to cardiac etiology such as arrhythmia, pump failure or non cardiac etiology such as trauma, respiratory failure, electrolytes disturbance, drug overdose, drowning, asphexia
Aborted cardiac arrest	Unexpected circulatory collapse within one hour of being symptomatic, which is turned back after successful cardiopulmonary resuscitation
SIDS (sudden infant death syndrome),SADS (sudden arrhythmic death syndrome)	Structurally normal heart without any specific findings in autopsy or toxicology
SUDI (sudden unexplained death in infancy), SUDS (sudden unexplained death syndrome)	Sudden death without any specific findings in autopsy in adult (SUDS) or infants less than 1 year (SUDI)

Pathophysiology

• The pathogenesis of cardiac arrest is characterized by the myocardial inflammatory process in the setting of atherosclerosis, structural heart disease, genetic disorders, and environmental factors.
• The SCN5A, KCNH2, KCNQ1, RYR2, MYBPC3, PKP2, DSP genes mutation has been associated with the development of inherited causes of cardiac arrest and sudden cardiac death.

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Structural and functional causes of sudden cardiac death Coronary artery disease Cardiomyopathy Valvular heart disease Congenital heart disease Primary electrical abnormality Channelopathy

Trigger Myocardial infarction Myocardial ischemia/reperfusion Emotional, physical stress Hemodynamic decompensation Electrolyte imbalance Hypoxemia,acidosis Neurophysiological interactions Drugs

Arrhythmia mechanism Re-entry Automaticity Triggered activity Conduction block

Fatal arrhythmia Monomorphic ventricular tachycardia Polymorphic ventricular tachycardia Ventricular fibrillation Profound bradycardia Asystole Pulseless electrical activity

Causes

Sudden cardiac arrest may be caused by :

• Coronary artery abnormality such as coronary atherosclerosis, acute MI, coronary artery embolism, coronary arteritis

• Hypertrophy of myocardium such as HCM, hypertensive heart disease, primary or secondary pulmonary hypertension
• Myocardial disease such as ischemic cardiomyopathy, non-ischemic cardiomyopathy, myocarditis
• Valvular heart disease such as (aortic stenosis,aortic insufficiency, mitral valve prolapse, endocarditis

• Congenital heart disease such as congenital septal defect with Eisenmenger physiology

• Abnormality in conducting system such as wolf-Parkinson-white syndrome
• Electrical instability such as (CPVT, LQTS)

Differentiating sudden cardiac death from non-cardiac causes

Cardiac causes of sudden death

Non cardiac causes of sudden death:

Acute aortic insufficiency Acute coronary syndrome Aortic dissection Aortic stenosis Arrhythmogenic right ventricular dysplasia Brugada syndrome Cardiac tamponade Cardiomyopathy Catecholaminergic polymorphic ventricular tachycardia Commotio cordis Complete heart block Congenital heart disease Congestive heart failure Coronary artery disease Dilated cardiomyopathy Hypertrophic cardiomyopathy Jervell and Lange-Nielsen syndrome Long QT syndrome, both congenital and acquired Lyme disease Mitral valve prolapse Myocarditis Naxos disease Noncompaction Cardiomyopathy Papillary muscle rupture Prolonged Q-T Interval Syndrome Pulmonary embolism Romano-Ward syndrome Ruptured abdominal aortic aneurysm Prosthetic valve dysfunction Short QT syndrome Short QT syndrome type 1 Short QT syndrome type 2 Short QT syndrome type 3 Short QT syndrome type 4 Short QT syndrome type 5 Sick sinus syndrome ST Elevation Myocardial Infarction Stokes-Adams Syndrome Sudden Infant Death Syndrome Timothy syndrome Uhl anomaly Valvular Heart Disease Ventricular rupture Wolf-Parkinson-White syndrome with rapid conduction

3-methylglutaconic aciduria, type 1 Alpha-ketoglutarate dehydrogenase deficiency Amniotic fluid syndrome Arterial dissections with lentiginosis Anaphylaxis Aneurysm Apoplexy Appendicitis Asphyxia Birth injury Bleeding excessive Childbirth hemorrhage Diabetic ketoacidosis - typically from undiagnosed diabetes Drug allergy Drug overdose Encephalitis Fetal death Food allergy Gastrointestinal bleeding Homicide Hyperbilirubinemia transient, familial, neonatal Hypercalcemia Hypercapnia Hyperkalemia Hypokalemia Hypoxia Injury Insect bite Intracranial hemmorhage Marfan syndrome Meningitis Meningococcal disease Motor Vehicle accident Myasthenia Gravis Neurocysticercosis Opioid overdose Oxycontin overdose Pain killer overdose Pickwickian Syndrome Poisoning Pulmonary embolism Retroperitoneal bleed Sepsis syndrome Shock Sleep apnea Snake bite Status asthmaticus Stillbirth Stroke Subarachnoid hemorrhage Sudden Infant Death Syndrome Suicide Sleeping pill overdose Toxic/metabolic disturbances Tranquilizer addiction Tension pneumothorax Toxic/metabolic disturbances Thyrotoxicosis Toxic shock syndrome Transfusion reaction Venom

Epidemiology and Demographics

• The prevalence of sudden cardiac death is approximately 1.40 per 100,000 individuals in women to 6.68 per 100.000 individuals in men worldwide.

• In 2015, the incidence of adult in-hospital cardiac arrests was estimated to be 970 cases per 100,000 individuals in the united states.

Age

• Cardiac arrest is more commonly observed within the first year of life due to sudden infant death syndrome and also between 45-75 years old due to increased risk of coronary artery disease.
• There is a significant decrease in sudden cardiac death at age 75 and older due to decreasing risk of coronary artery disease.

Gender

• Men are more commonly affected with sudden cardiac death than women in all age groups.

Race

• Black individuals are more likely to develop cardiac arrest.

Risk Factors

• Common risk factors related to underlying coronary artery disease and inherited causes in the development of sudden cardiac arrest are:

• Hypertension
• Male gender
• Diabetes mellitus
• Hyperlipidemia
• Obesity
• Smoking
• Older age
• Obstructive sleep apnea due to hypoxia
• Early VF (within 48 hours of ACS increasing in-hospital mortality five times)
• Early repolarization patten in early phase of MI
• Family history of sudden death

Natural History, Complications and Prognosis

Sudden cardiac arrest occurs due to sudden disturbance in cardiac electrical propagation or failure of the heart to pumping the blood into vital organs.

• Early clinical features include abrupt palpitation, presyncope, syncope, chest pain, dyspnea, hypotension within one hour before cardiac arret
• Patients may progress to develop cardiac arrest , sudden collapse, loss of effective circulation, loss of consciousness.
• If left untreated or failed resuscitation, biological death may occur within minutes to weeks.
• Common complications in survivors of cardiac arrest include pneumonia, gastrointestinal bleeding, injuries related to resuscitation, liver function test disturbance, acure renal failure, electrolytes disturbances, seizure.
• Two-thirds of patients with out-of-hospital cardiac arrest admitted in intensive care unit die of neurological complications.
• Most of the in-hospital cardiac death occur due to multiorgans dysfunction and one forth of them die of neurological complications.
• Factors associated poor prognosis after in hospital cardiac arrest include:

• Age > 70 years old
• Underlying disorders such as pneumonia, hypotension, renal dysfunction, hepatic dysfunction
• Non shockable rhythm such as asystole or pulseless electrical activity

• Factors associated better prognosis after in-hospital cardiac arrest include:

• Early detection of cardiac arrest or being a witness
• Shockable rhythm such as VF, VT
• Women between 15-45 years old

• Prognosis of in-hospital cardiac arrest is generally better than out of hospital cardiac arrest and the 1-year survival rate of patients who survived to hospital discharge was approximately 25% in the GWTG-R registry.

Diagnosis

Diagnostic Criteria

• The diagnosis of sudden cardiac arrest is made when the following diagnostic criteria are met:

• Absence of a palpable pulse of the heart
• Absent carotid pulse
• Gasping respiration or NO respiration
• Loss of consciousness due to cerebral hypoperfusion

Components	Assessment and findings
Symptoms	Symptoms related to arrhythmia Palpitations, lightheadedness, syncope, dyspnea, chest pain, cardiac arrest Symptoms related to underlying heart disease: Dyspnea at rest or on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, edema Precipitating factors: Exercise, emotional stress
Past medical history	Heart disease: Coronary, valvular (mitral valve prolapse), congenital heart disease Thyroid disease Acute kidney injury Chronic kidney disease Electrolyte abnormalities  Stroke,embolic events  Lung disease  Epilepsy (arrhythmic syncope can be misdiagnosed as epilepsy)  Alcohol, illicit drug use  Use of over-the-counter medications caused QT prolongation and torsades de pointes  Unexplained motor vehicle accident
Medications	Antiarrhythmic medications  Medication with QT prolongation and torsades de pointes effect Cocaine,amphetamines Anabolic steroids  Medication-medication interaction that could cause QT prolongation and torsades de pointes
Family history	SCD, SCA, unexplained drowning in a first-degree relative SIDS, repetitive spontaneous pregnancy losses concerning cardiac channelopathies  IHD  Cardiomyopathy: Hypertrophic,dilated, ARVC Congenital heart disease  Cardiac channelopathies: Long QT, Brugada, Short QT, CPVT  Arrhythmias: conduction disorders, pacemakers/ICDs Neuromuscular disease associated with cardiomyopathies  Muscular dystrophy Epilepsy

Symptoms

• Symptoms related to arrhythmia or underlying heart disease within one hour before cardiac arrest may include the following:

• Palpitations
• lightheadedness
• syncope
• dyspnea
• chest pain
• cardiac arrest
• Dyspnea at rest or on exertion
• orthopnea
• paroxysmal nocturnal dyspnea
• chest pain, edema

Physical Examination

• Patients with cardiac arrest usually appear cyanotic.
• Physical examination may be remarkable for:

• Heart rate and regularity, blood pressure
• Jugular venous pressure
• Murmurs
• Pulses, bruits
• Edema
• Sternotomy scars

Laboratory Findings

• An elevated concentration of brain natriuretic peptide (BNP) predicts has been shown as the predictor of ventricular arrhythmia and sudden cardiac death.

Electrocardiogram

An ECG may be helpful in the diagnosis of Sudden cardiac death. Findings on ECG associated with sudden cardiac arrest include:

• Sinus tachycardia (39%)
• Abnormal T-wave inversions (30%)
• Prolonged QT interval (26%)
• Left/right atrial abnormality (22%)
• LVH (17%)
• Abnormal frontal QRS axis (17%)
• Delayed QRS-transition zone in precordial leads (13%)
• Pathological Q waves (13%)
• intraventricular conduction delays (9%)
• Multiple premature ventricular contractions (9%)
• Normal ECG (9%)

Class I (Level of Evidence: B)

Ambulatory ECG monitoring is recommended in patients with symptoms of syncope, presyncope, palpitation suspected ventricular arrhythmia

Class of recommendation	Level of evidence	Recommendation for ECG and exercise tredmile test
1	B	In patients with wide complex tachycardia and hemodynamically stable, 12 leads ECG should be obtained
1	B	Exercise stress test should be obtained in patients suspected arrhythmia-related exercise such as ischemic heart disease or cathecolaminergic polymorphic ventricular tachycardia
1	B	In patients with documented ventricular arrhythmia, 12 leads ECG should be obtained during sinus rhythm for evaluation of underlying heart disease

X-ray

A chest x-ray may be helpful in the diagnosis of the underlying cause of cardiac arrest such as cardiomegally, pulmonary congestion, massive pericardial effusion, widening aorta silhouette.

Echocardiography or Ultrasound

Echocardiography may be helpful in the diagnosis the cause of lethal arrhythmia and sudden cardiac arrest by assessment of the following:

• Regional wall motion abnormality
• Systolic function of left ventricle
• Evidence of myocardial infarction
• Valvular heart disease such as aortic stenosis
• Right ventricular cardiomyopathy
• Pericardial effusion, Tamponade
• Aorta dissection

Class I (Level of Evidence: B)

Echocardiography is recommended in patients with ventricular arrhythmia for evaluation of underlying structural heart disease

CT scan

Cardiac CT scan may be helpful in the diagnosis of the causes of cardiac arrest by evaluation of the following:

• LV volumes
• Ejection fraction
• Cardiac mass
• Anomalous origin of coronary arteries
• Coronary arteries calcification
• Pulmonary embolism
• Aorta dissection

Class I (Level of Evidence: C)

Coronary angiography or coronary CT angiography is recommended in patients recovered from unexplained cardiac arrest suspected ischemic heart disease

MRI

Cardiac MRI is an accurate modality for diagnosis of structural and functional causes of cardiac arrest by the evaluation of the following:

• Chamber volumes
• Left ventricular mass
• Left ventricular size, function
• Right ventricular size and function
• Regional wall motion abnormality

Class IIa (Level of Evidence: C)

Cardiac magnetic resonance imaging (CMR) or cardiac computer tomography is recommended in patients with ventricular arrhythmia for evaluation of structural heart disease

Other Imaging Findings

There are no other imaging findings associated with sudden cardiac death.

Other Diagnostic Studies

• In survivors of sudden cardiac death due to lethal arrhythmia from ischemic heart disease, coronary angiography and probable revascularization is recommended.

• Electrophysiology study is recommended for induction of bradyarrhythmia ,ventricular tachyarrhythmia, determination the indication for ICD implantation in dilated cardiomyopathy,ARVC, HCM.
• Electrophysiology study is not recommended in long QT syndrome (LQTS), cathecolaminergic polymorphic ventricular tachycardia (CPVT), short QTsyndrome (SQTS)..

Class I, Level of evidence:B

In patients who recovered from SCA due to ventricular arrhythmia suspected ischemic heart disease, coronary angiography and probabley revascularization is recommmended

Class I, Level of evidence:C

In patients with anomalous origin of a coronary artery leading ventricular arrhythmia or SCA, repair or revascularization is recommended

Class IIa, Level of evidence:B

In patients with ischemic or nonischemic cardiomyopathy or congenital heart disease presented with syncope arrhythmia and do not meet criteria for primary prevention ICD, an electrophysiological study is recommended for assessing the risk of sustained VT

Class III, Level of evidence:B

In patients who meet criteria for ICD implantation, an electrophysiological study is not recommended for only inducing ventricular arrhythmia

Class III, Level of evidence:B

An electrophysiological study is not recommended for risk stratification for ventricular arrhythmia in patients with Long QT syndrome, short QT syndrome, cathecolaminergic polymorphic ventricular arrhythmia

Class I (Level of Evidence: C)

In patients with SCA or SCD in their family member, genetic tests and genetic counselling is recommended

Treatment

Medical Therapy

• The mainstay of therapy for patients with cardiac arrest is starting cardiopulmonary resuscitation with minimizing interruption in chest compression.
• The rhythm should be reassessed. If the rhythm is VF orpulseless VT, the shock should be delivered immediately.
• If the rhythm is asystole or pulseless electrical activity (PEA), CPR should be resumed.
• Advanced life support (ALS) should be kept with minimizing interruption in chest compression including:

• advanced airway
• Continuous chest compressions
• after placing an advanced airway
• capnography
• IV/IO access
• vasopressors, antiarrhythmics therapy
• Correcting reversible causes including hypoxia, hypovolemia,hypothermia, hyperkalemia, hypokalemia,acidosis, tension pneumothorax, tamponade, toxins (benzodiazepines, alcohol, opiates, tricyclics, barbiturates, betablockers, calcium channel blockers)

• The followings should be considered immediately in post cardiac arrest patients:

• 12–lead ECG
• Perfusion/reperfusion in patients with acute myocardial infarction
• Oxygenation and ventilation
• Temperature control
• Treatment of reversible causes

• Management of patients in post-cardiac arrest status include:

• Treatment of the underlying disorder
• Hemodynamic stability and
• Respiratory support
• Controlling the neurologic complications

Recommendations for management of cardiac arrest

CPR (Class I, Level of Evidence A):

❑ CPR should be done according to basic and advanced cardiovascular life support algorithms

Amiodarone (Class I, Level of Evidence A) :

❑ In the recurrence of ventricular arrhythmia after maximum energy shock delivery and unstable hemodynamic, amiodarone should de infused

Direct current cardioversion : (Class I, Level of Evidence A)

❑ In ventricular arrhythmia and unstable hemodynamic, direct current cardioversion should be delivered

Revascularization:(Class I, Level of Evidence B)

❑ In patients with polymorphic VT and VF and evidence of acute STEMI in ECG, coronary angiography and emergency revascularization is advised

Wide QRS tachycardia: (Class I, Level of Evidence C)

❑ Wide QRS tachycardia should be considered as VT if the diagnosis is unclear

Intravenous procainamide (Class 2a, Level of Evidence A):

❑ In hemodynamically stable VT, intravenous procainamide is recommended

Intravenous lidocaine : (Class 2a, Level of Evidence B)

❑ Lidocaine is recommended in witness cardiac arrest due to polymorphic VT, VF unresponsed to CPR, defibrillation or vasopressor therapy

Intravenous betablocker : (Class 2a, Level of Evidence B)

❑ In polymorphic VT due to myocardial ischemia, intravenous betablocker maybe helpful

Intravenous Epinephrine : (Class 2b, Level of Evidence A)

❑ In cardiac arrest administration of 1 mg epinephrine every 3-5 minutes during CPR is recommended

Intravenous amiodarone : (Class 2b, Level of Evidence B)

❑ In hemodynamic stable VT, infusion amiodarone or sotalole maybe considered

High dose of intravenous epinephrine : (Class III , Level of Evidence A)

❑ In cardiac arrest, administration of high dose epinephrine>1 mg bolouses is not beneficial ❑ In refractory VF not related to torsades de pointes, administration of intravenous magnesium is not beneficial

Intravenous amiodarone : (Class III , Level of Evidence B)

❑In acute myocardial infarction, prophylactic administration of lidocaine or amiodarone for prevention of VT is harmful

Intravenous verapamil, diltiazem : (Class III , Level of Evidence C)

❑ In a wide QRS tachycardia with unknown origin, administration of verapamil and diltiazem is harmful

Sustained monomorphic VT

Hemodynamic stability

Stable

Unstable

12-Lead ECG, history, physical exam

Dirrect current cardioversion,ACLS

Notifying disease causing VT

Cardioversion(class1)

VT termination

Structural heart disease

Intravenous procainamide (class2a)

Yes, therapy of underlying heart disease

NO, cardioversion (class1)

NO, Ideopathic VT

Intravenous amiodarone or sotalole (class2b)

VT termination

Verapamil sensitive VT: Verapamil outflow tract VT: betablocker (class2a)

Effective

Non effective: cardioversion

Yes,therapy of underlying heart disease

NO, Sedation ,anesthesia, reassess antiarrhythmic therapy, repeating cardioversion

Therapy to prevent recurrence of VT

No VT termination

Catheter ablation (class1)

Catheter ablation (class1)

Verapamil , betablocker (class2a)

Intervention

Catheter ablation can only be performed for patients with sustained monomorphic ventricular tachycardia based on these characteristics:

• Incessant VT or electrical storm due to myocardial scar tissue
• Sustained VT and recurrent ICD shock in ischemic heart disease

Prevention

• Effective measures for the primary prevention of sudden cardiac death in individuals who are at risk of SCD but have not yet experienced an aborted cardiac arrest or life-threatening arrhythmias include ICD implantation based on the guideline.
• Secondary prevention strategy following aborted sudden cardiac death include revascularization, ICD implantation.

Abbreviations: MI: Myocardial infarction; VT: Ventricular tachycardia; VF: Ventricular fibrillation; LVEF: Left ventricular ejection fraction; ICD: Intracardiac defibrillation; NYHA: New York Heart Association functional classification; LVAD: Left ventricular assist device; EPS: Electrophysiology study

Recommendations for primary prevention of sudden cardiac death in ischemic heart disease

ICD implantation (Class I, Level of Evidence A):

❑ In patients with LVEF≤ 35% and NYHA class 2,3 heart failure despite medical therapy, at least 40 days post MI or 90 days post revascularization with life expectancy > 1 year 1 year

ICD implantation (Class I, Level of Evidence B) :

❑ In patients with LVEF ≤ 40% and nonsustained VT due to prior MI or VT ,VF inducible in EPS with life expectancy >1 year

ICD implantation : (Class IIa, Level of Evidence B)

❑ In patients with NYHA class 4 who are candidates for cardiac transplantation or LVAD with life expectancy > 1 year

(Class III, Level of Evidence C)

❑ ICD is not beneficial in patients with NYHA class 4 despite optimal medical therapy who are not candidates for cardiac transplantation or LVAD

Abbreviations: IHD: Ischemic heart disease; VT: Ventricular tachycardia; SCD: Sudden cardiac death; SCA: Sudden cardiac arrest; ICD: Intracardiac defibrillation; EPS: Electrophysiologic study

Secondary prevention in patients with IHD

SCA survivor or sustained monomorph VT

Cardiac syncope

Ischemia

LVEF≤35%

Yes: revascularization, reassessment about SCD risk (class1)

NO:ICD candidate

Yes:ICD (class1)

NO: medical therapy (class1)

Yes:ICD (CLASS1)

NO:EP study (class 2a)

Ventriculat arrhythmia induction

Yes: ICD (class1)

NO: monitoring

Overview

The term sudden cardiac death refers to natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Other forms of sudden death may be noncardiac in origin and are therefore termed sudden death rather than sudden cardiac death. Examples of this include respiratory arrest (such as due to airway obstruction, which may be seen in cases of choking or asphyxiation), toxicity or poisoning, anaphylaxis, or trauma.

It is important to make a distinction between this term and the related term cardiac arrest, which refers to cessation of cardiac pump function which may be reversible (i.e., may not be fatal). The phrase Sudden Cardiac Death is a public health concept incorporating the features of natural, rapid, and unexpected. It does not specifically refer to the mechanism or cause of death. Although the most frequent underlying cause of Sudden Cardiac Death is Coronary Artery Disease, other categories of causes are listed below.

Cardiac Arrest as a Subtype of Sudden Death

A cardiac arrest, also known as cardiorespiratory arrest, cardiopulmonary arrest or circulatory arrest, is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively during systole.

"Arrested" blood circulation prevents delivery of oxygen to all parts of the body. Cerebral hypoxia, or lack of oxygen supply to the brain, causes victims to lose consciousness and to stop normal breathing. Brain injury is likely if cardiac arrest is untreated for more than 5 minutes, To improve survival and neurological recovery immediate response is paramount.

Cardiac arrest is a medical emergency that, in certain groups of patients, is potentially reversible if treated early enough (See Reversible Causes, below). When unexpected cardiac arrest leads to death this is called sudden cardiac death (SCD). The primary first-aid treatment for cardiac arrest is cardiopulmonary resuscitation (commonly known as CPR) to provide circulatory support until availability of definitive medical treatment, which will vary dependant on the rhythm the heart is exhibiting, but often requires defibrillation.

FDA Guidance re Classification and Types of Cardiovascular and Non-Cardiovascular Death

Definition of Cardiovascular Death

The determination of the specific cause of cardiovascular death is complicated by the fact that we are particularly interested in one underlying cause of death (acute myocardial infarction (AMI)) and several modes of death (arrhythmia and heart failure/low output). It is noted that heart attack-related deaths are manifested as sudden death or heart failure, so these events need to be carefully defined. Cardiovascular death includes death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, and death due to other cardiovascular causes, as follows:

1.Death due to Acute Myocardial Infarction

This refers to a death by any mechanism (arrhythmia, heart failure, low output) within 30 days after a myocardial infarction (MI) related to the immediate consequences of the myocardial infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia. If these events occur after a “break” (e.g., a CHF and arrhythmia free period of at least a week), they should be designated by the immediate cause, even though the MI may have increased the risk of that event (e.g., late arrhythmic death becomes more likely after an acute myocardial infarction (AMI)). The acute myocardial infarction should be verified to the extent possible by the diagnostic criteria outlined for acute myocardial infarction or by autopsy findings showing recent myocardial infarction or recent coronary thrombus. Sudden cardiac death, if accompanied by symptoms suggestive of myocardial ischemia, new ST elevation, new LBBB, or evidence of fresh thrombus by coronary angiography and/or at autopsy should be considered death resulting from an acute myocardial infarction, even if death occurs before blood samples or 12-lead electrocardiogram (ECG) could be obtained, or at a time before the appearance of cardiac biomarkers in the blood.

Death resulting from a procedure to treat a myocardial infarction (percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or to treat a complication resulting from myocardial infarction, should also be considered death due to acute MI.

Death resulting from a procedure to treat myocardial ischemia (angina) or death due to a myocardial infarction that occurs as a direct consequence of a cardiovascular investigation/procedure/operation should be considered as a death due to other cardiovascular causes.

2.Sudden Cardiac Death

This refers to a death that occurs unexpectedly, not following an acute AMI, and includes the following deaths:

a. Death witnessed and instantaneous without new or worsening symptoms

b. Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the symptoms suggest AMI

c. Death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-defibrillator review)

d. Death after unsuccessful resuscitation from cardiac arrest

e. Death after successful resuscitation from cardiac arrest and without identification of a non-cardiac etiology (Post-Cardiac Arrest Syndrome)

f. Unwitnessed death without other cause of death (information regarding the patient’s clinical status preceding death should be provided, if available)

General Considerations

• A subject seen alive and clinically stable 12-24 hours prior to being found dead without any evidence or information of a specific cause of death should be classified as :sudden cardiac death.”. Typical scenarios include

• Subject well the previous day but found dead in bed the next day
• Subject found dead at home on the couch with the television on

• Deaths for which there is no information beyond “Patient found dead at home” may be classified as “death due to other cardiovascular causes” or in some trials, “undetermined cause of death.” Please see Definition of Undetermined Cause of Death, below, for full details.

3. Death due to Heart Failure or Cardiogenic Shock

This refers to a death occurring in the context of clinically worsening symptoms and/or signs of heart failure (see Chapter 7) without evidence of another cause of death and not following an AMI. Note that deaths due to heart failure can have various etiologies, including one or more AMIs (late effect), ischemic or non-ischemic cardiomyopathy, or valve disease.

Death due to Heart Failure or Cardiogenic shock should include sudden death occurring during an admission for worsening heart failure as well as death from progressive heart failure or cardiogenic shock following implantation of a mechanical assist device.

New or worsening signs and/or symptoms of congestive heart failure (CHF) include any of the following:

a. New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an increase in, treatment directed at heart failure or occurring in a patient already receiving maximal therapy for heart failure

b. Heart failure symptoms or signs requiring continuous intravenous therapy or chronic oxygen administration for hypoxia due to pulmonary edema

c. Confinement to bed predominantly due to heart failure symptoms

d. Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context of an acute myocardial infarction, worsening renal function, or as the consequence of an arrhythmia occurring in the absence of worsening heart failure

e. Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the consequence of an arrhythmia occurring in the absence of worsening heart failure

Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for greater than 1 hour, not responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary to cardiac dysfunction and associated with at least one of the following signs of hypoperfusion:

• Cool, clammy skin or
• Oliguria (urine output < 30 mL/hour) or
• Altered sensorium or
• Cardiac index < 2.2 L/min/m2

Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm Hg in less than 1 hour with positive inotropic or vasopressor agents alone and/or with mechanical support.

General Considerations

Heart failure may have a number of underlying causes, including acute or chronic ischemia, structural heart disease (e.g. hypertrophic cardiomyopathy), and valvular heart disease. Where treatments are likely to have specific effects, and it is likely to be possible to distinguish between the various causes, then it may be reasonable to separate out the relevant treatment effects. For example, obesity drugs such as fenfluramine (pondimin) and dexfenfluramine (redux) were found to be associated with the development of valvular heart disease and pulmonary hypertension. In other cases, the aggregation implied by the definition above may be more appropriate.

4.Death due to Stroke

This refers to death occurring up to 30 days after a stroke that is either due to the stroke or caused by a complication of the stroke.

5.Death due to Other Cardiovascular Causes

This refers to a cardiovascular death not included in the above categories (e.g. dysrhythmia unrelated to sudden cardiac death, pulmonary embolism, cardiovascular intervention (other than one related to an AMI), aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of cardiac surgery or non-surgical revascularization should be classified as cardiovascular deaths.

Definition of Non-Cardiovascular Death

Non-cardiovascular death is defined as any death that is not thought to be due to a cardiovascular cause. Detailed recommendations on the classification of non-cardiovascular causes of death are beyond the scope of this document. The level of detail required and the optimum classification will depend on the nature of the study population and the anticipated number and type of non-cardiovascular deaths. Any specific anticipated safety concern should be included as a separate cause of death. The following is a suggested list of non-cardiovascular* causes of death:

Non-Malignant Causes

• Pulmonary
• Renal
• Gastrointestinal
• Hepatobiliary
• Pancreatic
• Infection (includes sepsis)
• Non-infectious (e.g., systemic inflammatory response syndrome (SIRS))
• Hemorrhage, not intracranial
• Non-cardiovascular system organ failure (e.g., hepatic failure)
• Non-cardiovascular surgery
• Other non-cardiovascular, specify: ________________
• Accidental/Trauma
• Suicide
• Drug Overdose
• Death due to a gastrointestinal bleed should not be considered a cardiovascular death.

Malignant Causes

Malignancy should be coded as the cause of death if:

• Death results directly from the cancer; or
• Death results from a complication of the cancer (e.g. infection, complication of surgery / chemotherapy / radiotherapy); or
• Death results from withdrawal of other therapies because of concerns relating to the poor prognosis associated with the cancer

Cancer deaths may arise from cancers that were present prior to randomization or which developed subsequently. It may be helpful to distinguish these two scenarios (i.e. worsening of prior malignancy; new malignancy). Suggested categorization includes common organ systems, hematologic, or unknown.

Definition of Undetermined Cause of Death

Undetermined Cause of Death refers to a death not attributable to one of the above categories of cardiovascular death or to a non-cardiovascular cause. Inability to classify the cause of death may be due to lack of information (e.g., the only available information is “patient died”) or when there is insufficient supporting information or detail to assign the cause of death. In general, the use of this category of death should be discouraged and should apply to a minimal number of patients in well-run clinical trials. A common analytic approach for cause of death analyses is to assume that all undetermined cases are included in the cardiovascular category (e.g., presumed cardiovascular death, specifically “death due to other cardiovascular causes”). Nevertheless, the appropriate classification and analysis of undetermined causes of death depends on the population, the intervention under investigation, and the disease process. The approach should be prespecified and described in the protocol and other trial documentation such as the endpoint adjudication procedures and/or the statistical analysis plan.