A constellation of clinical symptoms of myocardial ischemia stemming from reduced coronary blood flow due to either vasospasm, or vaso-occlusive disease most often due to atherosclerosis.

Classified as:

• ST segment elevation MI: Acute occlusion of coronary blood supply with persistent ST segment elevation on ECG and elevated cardiac biomarkers
• Non-ST segment elevation MI: Transient partial coronary artery narrowing with raised cardiac biomarkers and without persistent ST segment elevation
• Unstable angina (UA): Transient coronary artery narrowing or occlusion, without persistent ECG changes and negative cardiac biomarkers

• Atherosclerotic coronary artery disease
• Coronary emboli/ spasm
• Dissection of aorta or coronary arteries
• Vasoconstricting agents or illicit drugs e.g. cocaine

RISK FACTORS

Non-modifiable:

• Age
  • Men ≥50 years
  • Women ≥60 years
• Gender
  • Male > Female
• History of vascular disease (coronary artery disease, stroke, peripheral vascular disease)
• Family history of premature (<55 years) vascular disease
• Ethnicity

Modifiable:

• Hypertension
• Hyperlipidemia
• Cigarette smoking
• Diabetes mellitus
• Obesity/ abdominal obesity
• Metabolic syndrome
• Sedentary lifestyle
• Hypercoagulability
• Stress

FRAMINGHAM RISK ASSESSMENT

Used to determine the most appropriate treatment for managing cholesterol in patients without overt vascular disease or high-risk diabetes.

The risk factors included in the Framingham calculation are:

• Age
• Total cholesterol
• High-density lipoprotein (HDL) cholesterol
• Systolic blood pressure – not treated
• Systolic blood pressure – treated
• Smoking
• Diabetes

The modified total cardiovascular Framingham Risk Score is now recommended in Canada

• Low risk is defined as an individuals with an FRS of less than 10%
• Intermediate is defined as an individuals with an FRS of 10% to 19%
• High risk is defined as an individuals with an FRS of 20% or greater

Indication for Screening:

Suggested screening with a full lipid profile, every 1 to 3 years for the following:

• Males ≥ 40 years
• Females ≥ 50 years or who are post-menopausal

In addition, adults with the following risk factors should be screened at any age:

• Diabetes mellitus
• Hypertension
• Cigarette smoking
• Obesity (body mass index greater than 27 kg/m²)
• Calculate BMI = weight in kilograms / (height in meter)²
• Central Obesity:
• Family history of premature coronary artery disease (CAD)
• Clinical signs of hyperlipidemia
• Erectile dysfunction
• Estimated glomerular filtration rate of less than 60 mL/min/1.73 m²
• Evidence of atherosclerosis
• Rheumatoid arthritis, systemic lupus erythematosis, psoriasis
• HIV infection on highly active antiretroviral therapy

Ref: Genest J. et al. Can J Cardiol 2009; 25(10):567-579.

Canada:

• Prevalence: 1.3 million Canadians are living with heart disease
• Incidence of MI: Approximately 70,000/year
• Deaths due to MI: Approximately 16,000/year
• Hospitalizations due to ischemic heart disease: Approximately 160,000/year

USA:

• Prevalence: Approximately 17 million diagnosed with coronary artery disease (CAD)
• Incidence of first MI: Approximately 785,000/year
• Incidence of all MI (first, recurrent or silent): Approximately 1.45 million/year
• Hospitalizations due to ischemic heart disease: Approximately 1.6 million/year
  • Ratio of unstable angina:MI = ~60:40
  • Ratio of NSTEMI:STEMI = ~70:30

Atherosclerosis within coronary vessels underlies the main trigger for acute coronary syndrome (ACS).

Mechanism:

• Low-density lipoprotein (LDL) particles penetrate the endothelium → initiate atherosclerosis by recruiting macrophages → inflammation and increased plaque growth overtime
• Plaque rupture → platelet aggregation → thrombus → partial or complete vessel occlusion → decrease oxygenation → myocardial hypoxia → ischemia/infarction
• If untreated, the ensuing area of necrosis continues to spread. Completely blocked coronary arteries may cause full thickness injury/infarction (STEMI), while partial occlusion causes non-full thickness myocardium injury (NSTEMI)

Chest Pain

• Precordial chest pain or discomfort for >20 minutes
• Approx. 18% coronary attacks are preceded by angina
• Silent MI (~25%); patients often asymptomatic pain

Associated symptoms

• Lightheadedness/ dizziness/ fatigue
• Restlessness/ palpitations
• Nausea/ vomiting
• Dyspnea/ tachypnea/ orthopnea
• Cold clammy skin
• Syncope

HISTORY

• Quality, duration, location, and radiation of chest pain, occurring at rest or on exertion
• Prior history of angina, MI or other cardiac event/surgery/angioplasty
• History of atherosclerosis (coronary artery disease, previous stroke/TIA, peripheral vascular disease)
• History of syncope ±chest pain
• Medication history
• Risk factor assessment
  • Diabetes mellitus
  • Hypertension
  • Cerebrovascular disease
  • Bleeding/ coagulative disorders
  • Smoking
  • Alcohol and drug use/abuse (specially cocaine)

PHYSICAL EXAM

a) Vital Signs

• Heart rate
• Blood pressure (BP)
• Respiratory rate
• Temperature

b) Assess Chest for

• Tenderness/ third and fourth heart sounds
• Rales/ crackles
• Pericardial friction rub

c) Extremities: Cold/ pallor/ edema

d) Neck: Jaw tenderness/ elevated JVP/ pain radiating to

the jaw and/or shoulder

e) Abdomen: Epigastric pain/ guarding

LABORATORY

a) 12 lead ECG

• T wave changes reflect myocardial ischemia
• ST segment elevation reflects myocardial injury
• If infarction occurs, the ST segment may return to baseline within hours
• New Q waves appear within hours to days → signifies previous MI
• Q-waves may persist for the lifetime

b) Cardiac Biomarkers

Troponins have largely replaced CPK and LDH

Troponin T (TnT) and Troponin I (TnI)

Most sensitive test for myocardial infraction

• Rises: 3-6 hours
• Peaks: 18-24 hours
• Troponin values increase over time:
  • Normal: 0.00-0.24 µg/L
  • Equivocal: >0.24-0.40
• Duration: TnI = 5-10 days; TnT = 0-14 days
• Troponin I (more specific than troponin T)

Other (less commonly used biomarkers)

• Creatine phosphokinase (CPK)
• Lactic dehydrogenase (LDH)

c) Complete blood count (CBC)/ESR

d) PT/PTT/INR

e) BUN/creatinine

f) Serum electrolytes

g) Serum and urine glucose level

h) Arterial blood gases (ABGs)

i) Liver function tests (LFTs)

j) Lipid profile

• Should be checked within 24 hrs of ACS to avoid acute phase reactant effect

k) Urinalysis

l) Toxicology screen

m) Blood cultures (if infection is suspected)

IMAGING

Imaging should not delay implementation of reperfusion therapy (unless a potential contraindication, such as suspected aortic dissection)

Chest x-ray (portable): used to determine

• Aortic dissection → wide mediastinum
• Pneumothorax → absence of lung markings
• Pulmonary edema → presence of fluid

Transthoracic ECHO (TTE) OR Transesophageal ECHO (TEE):

Useful in diagnosis of:

• MI – Wall motion abnormalities right ventricular (RV) infarction
• Cardiac structural abnormalities e.g. aneurysm, valvular sclerosis/stenosis, thrombi etc.
• Pericardial effusion

Stress Test:

Assess coronary patency by myocardial uptake of radioactive dye (e.g. Technetium 99m Tc and Thallium-201)

Contrast computed tomography (CT) scan-chest: Used to differentiate STEMI from aortic dissection

MRI with Gadolinium-rarely used: Enhancement of infarcted area and to differentiate STEMI from aortic dissection

Coronary angiography: Considered after the initial management in patients with

• Evidence of ongoing ischemia (ECG findings or symptoms)
• Hemodynamic instability
• Recurrent ventricular tachyarrhythmia

Goal: Minimize myocardial injury, preserve heart function and prevent complications.

Approach: Assess hemodynamic stability, implement emergency measures as required, determine treatment strategies and interventions to proceed.

1) ASSESSMENT FOR HEMODYNAMIC INSTABILITY

Often indicated by altered mental status, confusion, disorientation, severe hypotension, symptoms of shock and life threatening arrhythmias.

2) EMERGENCY MEASURES

• ECG and continuous monitoring
• Pulse oximetry and blood pressure monitoring
• Oxygen inhalation
• Maintain IV and catheterize
• Monitor fluid intake/output
• Pain management
• Evaluation for reperfusion therapy
  • Risk of thrombolytic therapy and contraindication for PCI

TREATMENT STRATEGIES FOR ACS

Treatment strategy is based upon risk group, i.e. low vs. high risk patients, and predicts outcome according to TIMI risk score.

• TIMI risk score – Predicts outcome in patients with ACS

A) TREATMENT STRATEGIES FOR UNSTABLE ANGINA

AND NSTEMI

i) EARLY CONSERVATIVE STRATEGY (low risk group)

• No history of recurrent attacks
• No evidence of myocardial injury

Treatment in emergency room (ER):

Prompt attention in an ER for consideration of:

OXYGEN inhalation

NITROGLYCERIN:

• Sublingual 0.3 to 0.4 mg, every 5 minutes up to 3 total dose
• For ongoing pain and/or hypertension; consider IV nitroglycerin

MORPHINE SULFATE:

• 2-4 mg IV slowly, with increments of 2-8 mg IV repeated at 5-15-minute intervals; maximum dose of 10. Relieves pain, dyspnea, and anxiety

FENTANYL: (if allergic to morphine or hypotensive)

• 25-50 mcg IV (or intranasal)

BETA-BLOCKER:

Initiated orally in low and moderate doses, within first 24hrs, in patients who do not show the signs of low output state, heart failure, and heart block or have active asthma or reactive airway disease. Titrate according to heart rate and blood pressure.
IV metaprolol is of value in patients with ongoing ischemia with hypertension and who are not at risk of heart failure or cardiogenic shock.

Example:

Metoprolol within 24 hours, if no contraindications exist

• IV 5 mg every 2-10 mins up to a maximum dose of 15 mg
• Oral (low dose) 25 mg once daily; followed by 50 mg PO every 6hrs for 48 hrs, and then 100 mg every 12 hrs, or as tolerated

CALCIUM CHANNEL BLOCKERS (CCBs):

Oral or IV administration of a non-dihydropyridine CCB (e.g. dilitazem and verapamil) in hemodynamically stable patients with ongoing acute coronary syndrome (ACS) in whom beta blockers are contraindicated.

Example: Diltiazem

• Immediate-release: Start 30 mg PO TID or BID; May increase 3 mg/dose every 1-2 days; usual 180-360 mg/day in divided doses; Max: 360 mg/day
• Extended-release: Initial 120-180 mg PO once daily, increase over 7-14 days; Max: 480 mg/day

STATIN (e.g. atorvastatin, rosuvastatin)

ANTICOAGULANT

Heparin

Unfractionated heparin (UFH)

• Initial bolus of 60 U/kg (~4000-5000 U), then 12 U/kg/h (~1000 U/h) infusion should be administered promptly and adjusted to maintain aPTT ~1.5-2.0 times control

Low-molecular-weight heparin (LMWH)

• Enoxaparin: 1.0 mg/kg SC every 12hrs; or use every 24hrs if CrCl <30 mL/min

ANTIPLATELETS:

Acetylsalicylic acid (ASA):: Typically 162 mg PO at presentation

• Followed by 81 to 325 mg daily
• If aspirin allergy or major intolerance, clopidogrel may be substituted

Clopidogrel:

• Administer 300 mg PO loading dose, followed by 75 mg daily. Used in conjunction with ASA or monotherapy for those intolerant to ASA

Dual antiplatelet therapy:

ASA plus Clopidogrel or Ticagrelor: Usually for 1 year in all acute coronary syndrome (ACS) patients including those requiring PCI and/or CABG unless known specific contraindication; followed by monotherapy.

• ASA (81 mg ) plus Clopidogrel (75 mg)

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ii)EARLY INVASIVE STRATEGY (high risk group)

• Recurrent ischemia on medical management
• Evidence of myocardial injury
• Congestive heart failure
• Left ventricular dysfunction
• Sustained ventricular tachycardia
• Prior coronary revascularization
  • PCI within 6 months
  • Coronary artery bypass grafting (CABG)

Medical Management

Nitroglycerin, opiates, beta blockers, CCBs, statins are used as shown above

• ➢ Anticoagulant
• ➢ Antiplatelet
• ➢ Intervention strategie

ANTICOAGULANT

Heparin/LMWHs

• As used above

Fondaparinux:

• 2.5 mg SC once daily; up to 8 days or until hospital discharge

Bivalirudin:

Always given with ASA or clopidogrel

• Angiography: Initial IV bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/h prior to angiography and continued through angiography and as required
• PCI: Give additional bolus of 0.5 mg/kg and increase infusion to 1.75 mg/kg, then reduce infusion to 0.25 mg/kg/h following post PCI

Argatroban:

• Bolus 350 mcg/kg IV over 3-5 minutes and start 25 mcg/kg/minute IV infusion; check activated clotting time (ACT) after 5-10 minutes of bolus infusion and titrate to keep ACT 300-450

ANTIPLATELETS:

Aspirin:

Typically 162 mg PO at presentation

• Followed by 81 to 325 mg daily
• If aspirin allergy or major intolerance, clopidogrel may be substituted

Clopidogrel

• Administer 300 mg PO loading dose, followed by 75 mg daily. Used as monotherapy if ASA intolerance, but most often as dual therapy

Dual antiplatelet therapy:

Is often given for 1 year in all acute coronary syndrome (ACS) patients including those requiring PCI and/or coronary artery bypass graft (CABG) unless known to specific contraindication; followed by monotherapy.

ASA plus Clopidogrel:

• 300 mg PO loading dose; followed by 75 mg/day plus ASA (81 mg)
• For at least 1 month in patients who receive BMS (bare-metal stent)
• For at least 1 year in patients who receive DES (drug-eluting stent)

ASA plus Ticagrelor:

• Initial single loading dose of 180 mg PO then 90 mg every 12 hrs. plus ASA 75 to 150 mg once daily for 1 year unless contraindicated

ASA plus Prasugrel:

• Acute coronary syndrome (ACS) managed with PCI. Initial 60 mg PO loading dose; usual 10 mg PO at bed time plus ASA 75-325 mg/day for ~1 year
• Note: Contraindicated in patients with prior stroke or TIA; and has a relative contraindication in patients with age >75 years or weight less than 60 kg.

GLYCOPROTEIN IIb/IIIa INHIBITORS (optional use as decided by cardiologist)

Used in combination with ASA and heparin.

Eptifibatide or Tirofiban: Maybe considered in all acute coronary syndrome (ACS) including those with PCI

Abciximab: Considered in ACS requiring PCI

Abciximab:

• 0.25 mg/kg IV bolus 10-60 min prior to start of PCI; Max. 10 mcg/min Followed by an infusion of 0.125 mcg/kg/min for 12 hours

Eptifibatide:

• 180 mcg/kg IV bolus just prior to PCI, followed by continuous infusion of 2 mcg/kg/min (max. of 15 mg/hr). Second bolus of 180 mcg/kg given 10 minutes after initial bolus. Infusion should be continued for up to 18-24 hrs

Tirofiban:

• 25 mcg/kg IV over 3 minutes at the time of PCI; 0.15 mcg/kg/min infusion continues for up to 18-24 hours

Interventions and Surgeries

• Diagnostic angiography
• Primary percutaneous coronary intervention (PCI)
  • Early reperfusion therapy reduces the infarct size and increase survival
• Coronary artery bypass graft (CABG)

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B) TREATMENT STRATEGY FOR STEMI

Once a patient meets the diagnostic criteria for STEMI treatment includes:

General measures

• BP monitoring and pulse oximetry
• Supplemental O₂
• Two peripheral IV lines
• Continuous cardiac monitoring

Medical Management

• Nitroglycerin, opiates, beta blockers, statins, anticoagulant, antiplatelet therapy are used as shown above

Interventions and Surgeries

1) Diagnostic angiography

2) Coronary reperfusion therapy

a) Primary percutaneous coronary intervention (PCI)

• More effective than Fibrinolytic therapy; the latter is only indicated when PCI is not available or being delayed
• Early reperfusion therapy reduces the infarct size and increase survival

b) Fibrinolytic therapy

If PCI not an option/available

Fibrin selective agents:

• Tissue plasminogen activator (tPA)-Alteplase: 15 mg IV bolus 0.75 mg/kg over 30 min then 0.5 mg/kg over 60 min IV
• Recombinant plasminogen activator(r-PA)-Reteplase: 10 Unit IV bolus over 2 mins given 30 min apart; hold second dose if life threatening bleeding or anaphylactic reaction occurs
• TNK-tPA-Tenecteplase: Single IV bolus: 30 mg if <60 kg; 35 mg if 60-70 kg; 40 mg if 70-80 kg; 45 mg if 80-90 kg; 50 mg if >90 kg body weight

Fibrin non-selective agents:

• Streptokinase: 1.5 million Units over 30-60 min IV

3) Coronary artery bypass graft (CABG)

Emergency CABG

Approximately 10% of acute coronary syndrome (ACS) patients requires CABG during the index admission.

Indications

• Severe left main artery disease
• Refractory ischemia
• Failed PCI
• Multi vessel disease with reduced left ventricular ejection fraction
• Cardiogenic shock

Bleeding Risk:

• The use of combined ASA plus clopidogrel prior to CABG is assessed by risk of early fatal event vs. risk of major bleeding. If the risk of the former outweighs the latter then the surgery is conducted with dual therapy (such as refractory ischemia despite optimal medical treatment, and those with high-risk coronary anatomy. e.g. severe left main stenosis with severe right coronary artery disease). However if risk of bleed outweighs recurrent fatal event then hold clopidogrel for 3-5 days prior to CABG

Ref: Fitchett et al. Can J Cardiol 2009:25(12):683-689.

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C) POST MI MEDICAL THERAPY-TREATMENT OPTIONS

Nitroglycerin

• As indicated for recurrent chest pain

Beta blockers

• In general are used to help control angina and improve survival in patients with prior MI and heart failure due to systolic dysfunction

ACE inhibitors

• Reduces short term mortality, and is beneficial in patents with EF<40%
• Administeration within 24 hours reduce incidence of CHF and recurrent MI
• Contraindicated in hypotension, hyperkalemia, acute kidney failure, renal stenosis

Angiotensin II receptor blockers (ARBs)

• Benefits similar to ACEIs in ACS
• Can be used in ACEIs intolerant patients
• Combination ARB plus ACEI: Limited value in select patients

Aldosterone receptor antagonists (e.g. spironolactone)

Beneficial in:

• Post MI patients with LV ejection fraction of ≤40%
• Symptomatic HF
• DM without significant renal dysfunction

Requires caution in hyperkalemia and renal insufficiency

Statins

• Initiated during hospitalization for ACS
• Continued use is recommended in patients incurring MI while on statin therapy
• Goal is at least 50% reduction in LDL or LDL <2.0 mmol/L (70 mg/dL)
• Dyslipidemia targets

Antiplatelet Therapy: For prevention of recurrent thrombosis

• ASA plus Clopidogrel/Ticagrelor/Prasugrel – used for 1 year as discussed above and then followed by monotherapy (usually ASA indefinitely)

Anticoagulant therapy: For cardioembolic prophylaxis

• Warfarin (INR 2-3): Indicated in large anterior wall MI for 3 months or presence of AF
• Dabigatran: Consider if AF present and creatinine clearance (CrCl) >30 mL/min
  • Age <80 year: 150 mg PO BID
  • Age >80 years: 110 mg PO BID
• Rivaroxaban: Consider if AF present
  • 20 mg PO once daily if CrCl ≥50 mL/min
  • 15 mg PO once daily if CrCl 30-49 mL/min
• Apixaban: Consider if AF present
  • GFR >25 ml/min: 5 mg PO BID
  • Alternatively 2.5 mg BID may considered in patients with at least 2 of: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥133 micromole/L (1.5 mg/dL)

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D) POST MI RISK ASSESSMENT

Indicated for patients:

• Presenting >24 hours after symptoms
• Who received thrombolytic therapy
• Receiving medical therapy alone

Assessments:

• TIMI risk score
• GRACE score
  • GRACE score calculator
• Stress testing
• Cardiac catheterization
  • In high risk individuals

E) COMPLICATIONS FOLLOWING ACUTE MI

Recurrent chest pain

• Evaluate, monitor and report:
  • Auscultate for friction rub
  • Presence of murmur
  • Repeat ECG and ECHO, send labs

Acute pericarditis

• Evaluate, monitor and report:
  • Pleuritic pain
    • – Typically occurs within 1-4 days post MI
    • – Relieved in upright position
  • Laboratory
  • ECG (diffuse ST elevation)
• Treatment
  • Aspirin
  • NSAIDs
  • Prednisone 1 mg/kg/day

Dressler syndrome

• Evaluate, monitor and report:
  • Malaise, fever, chest pain
  • Autoimmune mediated
  • Typically occurs 1-8 weeks after MI
  • Laboratory
    • – Leukocytosis
    • – High ESR
    • – Echocardiogram (ECHO)-pericardial effusion
• Treatment
  • Aspirin
  • NSAIDs
  • Prednisone

Arrhythmias

• Evaluate, monitor and report:
  • Palpitations, lightheadedness, syncope
  • Laboratory
  • ECG/ telemetry
• Treatment
  • Pacemaker
  • Implantable cardioverter defibrillator (ICD)

Cardiogenic shock

• Evaluate, monitor and report:
  • Hypotension, shortness of breath (SOB), pallor, diaphoresis, cold clammy skin and weak pulses
  • Requires urgent attention
• Treatment
  • Pressure support with inotropic agents
  • Intra-aortic balloon pump
  • PCI or CABG as indicated

Stroke

• Abrupt onset of neurological disturbance, e.g. hemiparesis, loss of speech or vision
• If symptoms persistent it is defined as “Stroke”
• If symptoms are transient suspect transient ischemic attack (TIA)
• Rule out ischemic vs. hemorrhagic insult supported by further workup and investigations
  • CT brain
  • Carotid doppler/ computed tomography angiography (CTA)/ magnetic resonance angiography (MRA)
  • ECG/ telemetry
  • Echocardiogram (ECHO)

Mechanical and structural complications following acute myocardial infarction (MI)

• Left ventricular aneurysm
• Ventricular pseudoaneurysm
• Papillary muscle rupture
• Ventricular septal rupture
• Treatment
  • Stabilize patient hemodynamically
  • Surgical repair

ANTIPLATELETS

• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelor
• Glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa inhibitors)

Mechanisms:

Aspirin

• Works through cyclooxygenase pathway (COX 1-2 )
• Inhibits platelet aggregation
• Antipyretic, anti-inflammatory and analgesic action
• Antiplatelet effects last ~7-10 days

Clopidogrel/ Prasugrel

• Binds to adenosine diphosphate (ADP) → impairs activation of receptor complex → inhibits platelet aggregation
• Antiplatelet effects last ~7-10 days

Ticagrelor

• Selective and reversibly bound antagonists of the adenosine diphosphate (ADP) P2Y12 receptor
• Ticagrelor acts on platelet P2Y12 receptors and prevents ADP-mediated platelet activation and aggregation, by interacting with a binding site different from that of ADP (non-competitive antagonism)

GPIIb/IIIa inhibitors

• Selectively binds to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor on the surface of platelets
• Prevents binding of fibrinogen, von Willebrand factor and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets
• Decrease platelet aggregation and prevents thrombosis

Dose:

Aspirin

Acute coronary syndrome

• 162-325 mg PO once daily

MI prevention/ Vascular prophylaxis

• 75-325mg PO daily

Clopidogrel

Unstable angina, MI

• Loading dose 300 mg, followed by 75 mg PO daily; in combination with aspirin 75-325 mg initially, then 75-162 mg/day

Percutaneous coronary intervention (PCI)

• Loading dose 300-600 mg given as early as possible before or at the time of PCI followed by 75 mg PO once daily

Recent MI/ Recent stroke/ Peripheral arterial disease (PAD)

• Oral: 75 mg PO once daily

Prasugrel

Acute coronary syndrome managed with PCI:

• Initial 60 mg PO loading dose; usual 10 mg PO at bedtime with Aspirin 75-325 mg/day

Ticagrelor

• Initial single 180 mg PO loading dose; then 90 mg PO every 12 hrs
• Note: Ticagrelor should be taken with acetylsalicylic acid (ASA) between 75 mg and 150 mg PO once daily, unless specifically contraindicated.

Switching from Clopidogrel to Ticagrelor:

• Administer the first 90 mg dose of Ticagrelor 24 hours following the last dose of Clopidogrel

Abciximab: (dose and uses)

• Unstable angina refractory to medical therapy
• Percutaneous coronary intervention (PCI)

Eptifibatide (dose and uses)

• Acute coronary syndrome / PCI ± stent
• Dose in renal impairment

Tirofiban (dose and uses)

• UA/NSTEMI
• STEMI + PCI
• Dose in renal impairment

NITRATES:

• Nitroglycerin
• Isosorbide dinitrate
• Isosorbide mononitrate

Mechanisms:

Stimulates intracellular cyclic-GMP, results in

• Vascular smooth muscle relaxation and peripheral vasodilatation
• Decrease pre and after-load thus reduces myocardial oxygen demand
• Nitroglycerin dilates coronary arteries

Dose:

Nitroglycerin (dose and uses)

• Acute angina
• Angina prophylaxis
• Acute MI

Isosorbide dinitrate

Acute angina/Prophylactic management

• Sublingual: 2.5-5 mg every 5-10 minutes for maximum of 3 doses in 15-30 minutes

Long-term angina-prophylaxis

• 5-20 mg PO BID-TID, followed by maintenance dosage of 10-40 mg BID-TID
• Extended-release tabs: 40-80 mg PO every 8-12 hrs

Isosorbide mononitrate

Angina

• 5-20 mg PO BID; Max. 40 mg/day
  • Titration: Increase to 10 mg PO BID in first 2-3 days
• Extended release tablet: 30-60 mg PO every morning; Max. 240 mg/day
  • Titration: Increase as required, with at least 3 day interval

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ANALGESIC – centrally acting:

• Morphine
• Fentanyl

Mechanism:

Binds to opiate receptors at many sites within the CNS, causes

• Increases pain threshold-inhibits ascending pain pathway
• Alter perception of and emotional response to pain
• Generalized CNS depression

Dose:

Morphine

• 2-4 mg IV slowly, with increments of 2-8 mg IV repeated at 5-15 minutes intervals; maximum dose of 10 mg. Relieves pain, dyspnea, and anxiety

Fentanyl

• 50-100 mcg/dose IV/IM every 1-2 hrs as required

ANTICOAGULANT

• Injectable
  • Heparin
  • Enoxaparin (LMWH)
  • Dalteparin (LMWH)
  • Fondaparinux
  • Bivalirudin
  • Argatroban
• Oral
  • Warfarin
  • Dabigatran
  • Rivaroxaban
  • Apixaban

Mechanisms:

• Inhibits thrombus formation
• May prevent propagation of existing thrombi
• No direct lytic effect on established thrombi
• Prolongs aPTT

Doses:

Heparin (unfractionated)

• PCI ± concurrent GPIIb/IIIa inhibitor
• STEMI: Adjunct therapy
• UA/NSTEMI

– Heparin nomogram

Enoxaparin (LMWH):

• STEMI
• UA/NSTEMI
• PCI adjunct therapy

Dalteparin (LMWH)

UA / NSTEMI

• 120 IU/kg body weight SC every 12 hrs for 5-8 days with simultaneous aspirin; Max. 10,000 IU/dose
• Discontinue once patient is clinically stable

Fondaparinux (factor Xa inhibitor)

STEMI

• 2.5 mg IV stat; Then 2.5 mg SC once daily for up to 8 days or until hospital discharge

UA / NSTEMI

• Administer 2.5 mg SC once daily for up to 8 days or until hospital discharge
• Renal impairment: Contraindicated if CrCl <30 mL/minute

Bivalirudin:

Should be administered with ASA, concomitantly Clopidogrel can also be administered

• UA/ NSTEMI
• Percutaneous coronary intervention (PCI)
• Subsequent to heparin (UFH/LMWH)

Argatroban:

• Percutaneous coronary intervention (PCI)
• Post PCI
• Dose in hepatic impairment

Warfarin

Prevention/Treatment of thrombosis/Embolism

• Start 2-10 mg PO once daily for 1-2 days then adjust dose according to INR results
• Desired INR 2-3 for non-mechanical valves. May be acceptable for aortic bileaflet mechanical valve without thromboembolism risk factors
• OR
• INR 2.5-3.5, if concomitant mitral mechanical valve or aortic mechanical valve

Ref: Bonow Ro, Carabello BA, Chatterjee K et al. Circulation. 2008; 118: e523-e661.

Warfarin dosing – Suggested protocol in adults (no mechanical valve)

Warfarin dosing – Suggested protocol in adults (with mechanical valve)

Warfarin reversal – Suggested protocol

Dabigatran

Dosage (Canada):

• Age <80 year: 150 mg BID if creatinine clearance >30 mL/min
• Age >80 years: 110 mg BID if creatinine clearance >30 mL/min
• Contraindicated in creatinine clearance <30 mL/min

Conversion from Dabigatran to parenteral anticoagulant

• Wait 12 hrs after the last dose of Dabigatran before switching to a parenteral anticoagulant

Conversion from Vitamin K antagonists (e.g. warfarin) to Dabigatran

• Dabigatran should only be started after Vitamin K antagonists have been discontinued, and the patient’s INR found to be <2.0

Conversion from Dabigatran to Vitamin K antagonists (e.g. warfarin)

• Stop Dabigatran for 12 hrs then begin Warfarin protocol/normogram (see above)

Rivaroxaban

Nonvalvular atrial fibrillation:

• 20 mg PO once daily for CrCl >50
• 15 mg PO once daily for CrCl 30-49

Apixaban

Nonvalvular atrial fibrillation:

• GFR >25 ml/min: 5 mg PO BID
• Alternatively 2.5 mg BID may considered in patients with at least 2 of the following:
  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥133 micromole/L (1.5 mg/dL)

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Beta-adrenergic blocking agents:

• Cardioselective:
  • Acebutolol
  • Atenolol
  • Metoprolol
• Non-Cardioselective:
  • Carvedilol
  • Nadolol
  • Propranolol
  • Timolol

Mechanism:

• Block beta receptors
• Decreases heart rate and cardiac output
• Decreases renin release (more efficacious in populations with elevated plasma renin activity such as younger white patients)

Dose:

Cardioselective:

Acebutolol

Angina / Ventricular arrhythmia

• 400 mg/day PO in divided doses; usual 600-1200 mg/day in divided doses Max.1200 mg/day

Atenolol

Post myocardial infarction

• 50 mg/day PO daily or BID or 100 mg daily (as tolerated)

Metoprolol

Angina

• Immediate release: Start 25 mg PO BID; maintenance 50-200 mg PO BID; Max. 400 mg/day; begin with low dose and increase dose at weekly intervals to desired effect
• Extended release: Initial 100 mg/day; Max. 400 mg/day

Myocardial infarction (acute)

• Initial 5 mg IV every 2 mins for 3 doses then 50 mg PO every 6 hrs x 48 hrs starts 15 minutes after last IV dose; maintenance dose 100 mg PO BID
  • Note: If initial IV dose is not tolerated then give 25-50 mg PO every 6 hrs
• Secondary prevention: Immediate release (IR) 25-100 mg PO BID; optimize dose based on heart rate and blood pressure; continue indefinitely

Non-Cardioselective:

Carvedilol

LV dysfunction following MI

• Immediate release: Initial 3.125-6.25 mg PO BID; increase dosage at intervals every 3-10 days; may increase to 25 mg PO BID if required
• Extended release (available in USA only): Initial 10-20 mg/day PO daily; increase dosage at intervals every 3-10 days; target dose of 80 mg/day PO daily as tolerated

Nadolol

Angina / Hypertension

• Initial 40 mg/day daily; typically 40-80 mg/day daily; Max. 320 mg/day daily
  • Titration: Gradually increase every 3-7 days until optimum clinical response is obtained or maximum dose achieved

Propranolol

Post-MI

• 60-80 mg/day PO TID as tolerated; may increase to 180-240 mg/day (divided doses)

Timolol

Myocardial infarction, secondary prevention

• Start 10 mg PO BID within 4 weeks of MI

Angina

• Initial 10 mg PO BID; range 10-60 mg/day PO divided BID-TID

ACE (angiotensin-converting enzyme) inhibitors:

• Captopril
• Enalapril
• Lisinopril
• Perindopril
• Ramipril
• Trandolapril

Mechanisms:

• Inhibits renin-angiotensin aldosterone system and bradykinin degradation
• Stimulate vasodilating prostaglandin synthesis
• Reduce sympathetic nervous system activity
• Relatively less effective in those of African descent and in the elderly

Dose:

Captopril

LV dysfunction following MI

• Start 6.25 mg PO daily; followed by 12.5 mg PO QID
  • Titration: Increase to 25 mg PO TID over every 3-7 days; followed by gradual increase over weeks to 50 mg PO TID as tolerated

Enalapril

Acute MI

• Initial 2.5 mg PO daily within 48h post-MI, quickly titrate dose up; usual 10 mg PO QID

Lisinopril

Acute MI

• 5 mg PO immediately, then 5 mg at 24 hours, 10 mg at 48 hours, and 10 PO daily for 6 weeks

Perindopril

Coronary artery disease

• Initial 4 mg PO daily for 2 weeks; then increase as tolerated to 8 mg PO daily

Ramipril

LV dysfunction following MI

• Start 2.5 mg PO BID; then increase every 3 weeks if possible to target of 5 mg PO BID

Cardiovascular event prevention

• Start 2.5 mg PO daily for 1 week; then increase as tolerated to 10 mg once daily or BID

Trandolapril

Post-MI heart failure or LV dysfunction

• Initial 1 mg/day PO daily; Max. 4 mg/day; then increase as tolerated to 4 mg/day

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Angiotensin receptor blocking agents (ARB):

• Telmisartan
• Irbesartan
• Losartan
• Valsartan

Mechanisms:

• Block AT1 angiotensin receptors
• Blocks the vasoconstrictor and aldosterone secreting effect of angiotensin II
• Reduce vasoconstriction

Dose:

Telmisartan

Cardiovascular risk reduction

• Initial 80 mg PO daily

Valsartan

Left ventricular dysfunction after MI

• 20 mg PO BID; Max. 160 mg
  • Titration: Increase dose to target of 160 mg BID as tolerated

Irbesartan

Cardiovascular risk reduction/ Hypertension

• Initial 150 mg PO daily; may increase to 300 mg daily; Max. 300 mg

Losartan

Cardiovascular risk reduction/ Hypertension

• 50 mg PO daily; Max. 100 mg

Aldosterone receptor blockers:

• Spironolactone
• Eplerenone

Mechanism:

• Block aldosterone receptors in renal collecting tubule → results in increased excretion of sodium and water and decreased excretion of potassium
• Spironolactone is often co-administered with thiazide or loop diuretics in the treatment of edema and hypertension

Dose:

Spironolactone

Heart failure, severe (NYHA-class III/IV)

• 12.5-25 mg/day; Max. 50 mg/day
  • Titration: Increase to 50 mg/day after 8 weeks or as tolerated in worsening CHF

Edema

• 25-200 mg/day PO once daily or in two divided doses

Eplerenone

Heart failure (post-MI)

• Initial 25 mg PO daily
  • Titration: Increase to 50 mg daily within 4 weeks, or as tolerated
• Note: Adjust the dose as per serum potassium concentrations

Calcium channel blocking agents (CCBs):

• Diltiazem
• Verapamil

Mechanisms:

• Blocks the inward movement of calcium by binding to the L-type calcium channels in the heart and in smooth muscle of the peripheral vasculature
• This decreases intracellular calcium leading to a reduction in muscle contraction
• Significantly reduces afterload, with no effect on preload

Dose:

Non-Dihydropyridines

Diltiazem

Angina

• Immediate-release: Start 30 mg PO TID or QID; may increase 30mg/dose every 1-2 days; usual 180-360 mg/day BID; Max. 360 mg/day
• 24h extended-release: Initial 120-180 mg PO daily, increase over 7-14 days; Max. 480 mg/day

Verapamil

Angina

• Immediate-release: Initial 80-120 mg PO QID; usual range 80-160 mg PO QID
  • Elderly or small stature: 40 mg 3 times/day
• 24h extended-release: 180 mg PO daily; Max. dose 480 mg/day
  • If inadequate response, may increase dose at weekly intervals to 240 mg/day PO, then 360 mg/day, then 480 mg/day if required and as tolerated

Statins (HMG-CoA reductase inhibitor):

• Atorvastatin
• Simvastatin
• Fluvastatin
• Lovastatin
• Pravastatin
• Rosuvastatin

Mechanism:

• Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
• This reduces the conversion of mevalonic acid from HMG-CoA
  • An early precursor of cholesterol
• This results in compensatory increase in the number of low-density lipoprotein (LDL) receptors on hepatocyte membranes
• This stimulates LDL catabolism and leads to reduction in LDL production

Dose:

Atorvastatin

• Start 40-80 mg PO daily; adjust dose based on patient’s tolerability and recommended LDL-C goal

Simvastatin

• 40 mg PO daily at bedtime; usual range 10-40 mg/day
  • Do not exceed 20 mg/day if given concomitantly with amiodarone or verapamil
  • Do not exceed 40 mg/day if given concomitantly with diltiazem
  • CrCl <10 mL/minute: Start 5 mg/day with close monitoring

Fluvastatin

• 40 mg PO daily at bedtime; may increase to 80 mg/day PO once daily or in 2 divided doses

Lovastatin

• Start 20 mg PO daily at bedtime; may increase to 40 mg PO daily at bedtime after at least 4 week interval

Pravastatin

• Start 40 mg PO daily at bedtime; may increase up to 80 mg PO to achieve desired effect, after at least every 4 week. Starting dose in renal impairment is 10 mg PO at bedtime

Rosuvastatin

• Start 5-10 mg PO daily at bed time; may increase every 2-4 weeks; usual dose 20 mg/day

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Fibrinolytic agents:

• Fibrin selective agents:
  • Alteplase (tPA)
  • Reteplase (r-PA)
  • Tenecteplase (TNK-tPA)
• Fibrin non-selective agents:
  • Streptokinase
  • Urokinase (uPA)

Mechanisms:

• These agents stimulates plasminogen activator → forms a complex by binding with fibrin and plasminogen
• This complex → converts residual plasminogen into plasmin, a proteolytic enzyme capable of hydrolyzing fibrin
• Unopposed plasmin digests fibrinogen and other plasma proteins, including factors V and VIII

Dose:

Alteplase (tPA)

In ST-elevation MI (STEMI)

• Titrated according to weight (≤67 kg or >67kg), infused over 3 hr or 1.5 hr (accelerated)

Reteplase (r-PA)

ST-elevation MI (STEMI) / Pulmonary embolism (PE)

• 10 IU IV over 2 minutes; then repeat 30 mins later
• Hold the second dose if serious bleeding or anaphylaxis occurs

Tenecteplase (TNK-tPA)

ST-elevation myocardial infarction (STEMI)

• IV bolus over 5 sec, recommended total dose should not exceed 50 mg and is based on weight

Streptokinase

Acute evolving transmural myocardial infarction

• IV infusion: Usual dose 1.5 million IU over 60 minutes
• Intracoronary infusion: 20,000 IU bolus, then 2000 IU/min for 1 hrs; total dose 140,000 IU

Urokinase (uPA)

Coronary artery thrombosis and Acute MI

• 2-3 million IU IV over 45-90 minutes
  • Give 50% or 100% of the dose as IV bolus (e.g. over 5 minutes); remainder, if any, as a continuous infusion
  • Administer concurrently with heparin

Diagnosis:

• Acute pain related to myocardial ischemia and decreased myocardial oxygen supply as manifested by severe chest pain and tightness, radiation of pain to the neck and arms
• Ineffective tissue perfusion (cardiac) related to myocardial injury and potential pulmonary congestion as manifested by decrease in BP, dyspnea, arrhythmias, peripheral edema, and oliguria
• Anxiety related to perceived or actual threat of death, pain, possible lifestyle changes as manifested by restlessness, agitation, and verbalization of concern over lifestyle changes and prognosis as evidenced by client’s statement, “What is going to happen when I die? Everyone relies on me”
• Activity intolerance related to fatigue secondary to decreased cardiac output and poor lung and tissue perfusion as manifested by fatigue with minimal activity, and inability to care for self without dyspnea, and increased heart rate
• Ineffective therapeutic regimen management related to lack of knowledge of disease process, rehabilitation, home activities, and medications as manifested by frequent questioning about illness, management, and care after discharge

Potential complications to be recognized in time include:

• Acute pulmonary edema
• Heart failure
• Cardiogenic shock
• Dysrhythmia and cardiac arrest
• Pericardial effusion and cardiac temponade

Goals:

• Relief of pain and ischemic signs and symptoms
• Prevention of further myocardial damage, by maintaining perfusion and decreasing the workload
• Should be able to recognize early signs of complications
• To recognize any respiratory dysfunction
• To reduce anxiety
• Adherence by complying with self care programme

Relieving pain and other signs and symptoms of ischemia:

• Assess document and report the following to the physician:
  • Description of chest pain including, location, radiation, duration, intensity and precipitating and alleviating factors
  • Malaise, nausea, restlessness
  • Change in blood pressure, respiration, oxygen saturation and heart sounds
  • Pulmonary edema
  • Altered level of consciousness
  • Urinary output (reduced)
  • Skin color and temperature
  • The above assessment helps in assessing cause of the chest pain and provides a baseline with which post therapy symptoms can be compared
• Obtain a 12 lead ECG during a symptomatic event
  • To rule out or help confirm the diagnosis and differentiate angina from extension of MI or pericarditis
• Administer oxygen as prescribed
  • To promote increased oxygenation to myocardium and prevent further ischemia
• Administer the medications as prescribed and closely monitor for clinical response and potential side effects or adverse events
  • Nitroglycerin, morphine, beta blockers and aspirin are all the first line of defense in preserving myocardial tissue
• Bed rest/reduced activity reduces myocardial O₂ demand
• Ensure a restful environment to help reduce fear, and consequently reduce catecholamine levels → reduces cardiac O₂ consumption

Enhancing respiratory function:

• Fluid overload can potentially impair gaseous exchange
  • Assess and report abnormal heart sounds, murmurs, abnormal breath sounds especially crackles (every 4 hrs or sooner if required)
  • Monitor for peripheral edema
• Patient should adhere to the prescribed activity which is determined individually to maintain blood pressure and heart rate within normal range
• Patient should be taught to adhere to the low sodium and low caloric diet plan

Promoting adequate tissue perfusion:

• Assess (every 4 hrs or sooner if required), document and report the following to the physician:
  • Hypotension
  • Tachycardia other dysrhythmia
  • Activity intolerance
  • Changes in mentation
  • Reduced urinary output (<200 ml per 8 hrs)
  • Cool, moist and cyanotic extremities
• All the above may be associated with a low cardiac output state

Strategies for reducing anxiety:

• Determine, document and report to the doctor the patient’s and their family’s level of anxiety and coping strategies
• Assess and suggest the need of spiritual counseling as required
• Assess and suggest the need of social services and refer accordingly
• Allow the patient to express anxiety and fear and take time to answer questions and concerns
• Allow flexible visiting hours
• Encourage family to stay with client as appropriate
• Encourage active participation in a cardiac rehab programmes
• Stress reduction techniques → Rest, relaxation, meditation, biofeedback, exercise (as tolerated) may all help enhance feeling of well being
• Use a calm, reassuring approach

Monitoring and managing potential complications of myocardial infarction:

Complications that can occur after MI can be life threatening, so close monitoring is required as follows

• Assess document and report any change in heart rate, rhythm and heart sounds
• Changes in blood pressure, temperature, respiratory status and urinary output
• Report ECG changes or any changes in other laboratory values (e.g. creatinine, potassium)
• Changes in level of consciousness
• Change in skin color
• New neurological symptoms: focal weakness, speech or vision loss might signify stroke and should be reported immediately

Significant changes in the above should prompt urgent notification to MD, and emergency measures instituted as required.

Promoting home and community based self care:

Patient with MI must learn to adjust his/her lifestyle, to promote heart – healthy living by

• Avoiding activities that leads to chest pain, dyspnea, or undue fatigue
• Avoiding extremes of heat or cold and walking against the wind
• Avoiding factors/conditions that promote stress
• Pursuing activities that relieve and release the stress
• Being aware of ideal body weight and waist circumference
• Losing weight as required
• Exercising daily (walking)
• Smoking cessation and use of tobacco; avoid second hand smoke
• Developing heart healthy eating patterns and avoiding large meals and hurrying while eating
• Modifying meals to align with therapeutic lifestyle changes(TLC) or adopt dietary approach diet for hypertension, e.g. DASH diet
• Compliance with medications and other suggested medical regimens
• Following recommendation that ensures blood pressure and blood sugar are in control

– Adopting an activity program:

• Engage in activities that gradually improves physical conditioning
• Set goals/ targets for increasing frequency and intensity of exercise
• Monitoring heart rate during physical activity
• Be aware of the suggested targets for heart rate
• Avoid strenuous training that might exceed suggested maximum heart rate
• Avoid sudden “explosive” activities that require sudden burst of energy and extreme muscle tension
• Avoid strenuous exercising immediately following meals
• Assist client to understand energy conservation principles, such as bed rest
• Encourage alternate rest and activity periods

– Managing symptoms:

• Patient and family members should be knowledgeable in signs and symptoms of acute cardiac symptoms and seek help immediately
• Emergency medical services (EMS) should be contacted if chest pressure or pain is not relieved in 15mins after taking 3 sprays of nitroglycerin
• Shortness of breath, fainting, slow or rapid heart beat, or swelling of feet or ankles should all be reported to the doctor

Expected Patient Outcome:

• Relieve angina
• Avoidance of initial or recurrent MI
• Improved respiratory function
• Adequate tissue perfusion
• Decreased anxiety
• Adherence to a self care program
• Absence of complications

• Seek urgent physician assessment if recurrent signs and symptoms of acute coronary syndrome (ACS)
• Urgent labs and follow up ECG, troponin, hemoglobin
• Attention to wound care if applicable
• Monitor for blood loss/bleeding
• Change in colour of stools (consider occult blood)
• Physician may advise to discontinue clopidogrel or oral anticoagulants prior to surgery to decrease the risk of bleeding
• Signs and symptoms of other there comorbidities (diabetes mellitus, acute kidney injury)
• Pedal pulse (assess for hypoperfusion)
• Stroke symptoms (loss of speech, vision, weakness, clumsiness, unsteadiness, confusion)
• Strict blood glucose control in diabetic patients
• Overzealous patients with early excessive activity

Core Resources:

• Antman EM, Cohen, M, Bernink, PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision-making. JAMA. 2000; 284:835-842
• Bell AD, Roussin A, Cartier R. et al. The Use of antiplatelet therapy in the out-patient setting: Canadian Cardiovascular Society Guidelines. Can J Cardiol. 2011;27: S1-S59
• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist association. Toronto: Webcom Inc. 2012
• Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2^nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
• Dirksen, S., Lewis, S., & Collier, I., Heitkemper, M., O’Brien, P., & Bucher, L. (2010). Medical-Surgical Nursing in Canada: Assessment and management of clinical problems (2^nd ed.). Toronto: Mosby Elsevier
• Fitchett D, Eikelboom J, Fremes S, et al. Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: A position statement of the Canadian Cardiovascular Society. Can J Cardiol 2009;25(12):683-689
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• Gonçalves PD, Ferreira J, Aguiar C, Seabra-Gomes R. TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTE‐ACS. Eur Heart J (May 2005) 26 (9): 865-872
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• DOI: 10.1503/cmaj.092119
• JG Howlett, RS McKelvie, J Costigan, et al. The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs. Can J Cardiol 2010;26(4):185-202
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• Nova Scotia Guidelines for Acute Coronary Syndromes. Halifax, NS: Cardiovascular Health Nova Scotia; 2008
• O’Rourke R, Walsh R, Fuster V, eds. Hurst’s the Heart Manual of Cardiology, 12^th Edition. New York: McGraw-Hill; 2008
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Online Pharmacological Resources:

• e-Therapeutics
• Lexicomp
• RxList
• Epocrates
• Cardiovascular Health Nova Scotia
• Health Canada

Journals/Clinical Trials:

• Anderson HV, Cannon CP, Stone PH et al. One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol. 1995;26(7):1643-1650
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• Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003; 362(9386):782-8
• Morrow DA, Scirica BM, Fox KA, et al. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J. 2009; 158(3):335-41
• Patel M, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-891
• DOI: 10.1056/NEJMoa1009638
• Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045-1057
• DOI: 10.1056/NEJMoa0904327
• Yusuf S, Zhao F, Mehta SR, et al. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med 2001; 345:494-502
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