stroke
Label
Acute Coronary Syndrome (ACS)

DefinitionEtiologyEpidemiologyPathophysiologyClinical Presentation
WorkupGoalsMed ChoicesClinical TrialsPipeline AgentsResourcesRefs
Definition:

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

 

Back to Top
Etiology:
  • 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.

 

Back to Top
Epidemiology:

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

 

Back to Top
Pathophysiology:

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)

LightBox-2-Causes-Stages of Atherosclerosis

 

Back to Top
Clinical Presentation:

Chest Pain

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

Associated symptoms

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

 

Back to Top
Investigation and Workup:

HISTORY

  • Quality, duration, location, and radiation of chest pain, occurring at rest or on exertion
  • Prior history of angina, myocardial infarction or other cardiac events/surgery/angioplasty
  • History of syncope ±chest pain
  • Medication history
  • Risk factor assessment
    • Diabetes mellitus
    • Hypertension
    • Cerebrovascular disease
    • Bleeding/ coagulative disorders
    • Smoking
    • Alcohol and drug use/ abuse (especially cocaine)

PHYSICAL EXAM

  • Vital signs: Blood pressure, heart rate, respiratory rate
  • Chest: Pain/ tenderness
  • Extremities: Cold/ pallor/ edema/ diaphoresis

LABORATORY

  • 12 lead ECG
  • Complete blood count
  • Troponin, creatine kinase (CK)
  • Blood urea nitrogen (BUN), serum creatinine, electrolytes
  • Liver function test
  • Activated partial thromboplastin time (aPTT)
  • International normalized ratio (INR)
  • Urinalysis, and toxicology screen
  • Fasting lipid profile

IMAGING AND ELECTROPHYSIOLOGY

  • Chest x-ray
  • Echocardiogram (ECHO)
  • Exercise stress test
  • Coronary angiography

 

Back to Top
Treatment Goals:
  • Relieve symptoms of ischemia (e.g. chest pain)
  • Decrease mortality and complications such as heart failure
  • Prevent thrombus formation/ recurrence (encourage medication compliant, lifestyle changes, provide education)

 

Back to Top
Therapeutic Choices:

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

Include continuous monitoring of ECG, vitals and oximetry. Initiation of O2 inhalation, maintain IV access and catheterize to monitor, fluid intake/output.

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.

A) TREATMENT STRATEGIES FOR UNSTABLE ANGINA

AND NSTEMI

2-Black-Image-ACS- Treatment-Treatment Strategy

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 mg. 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 24 hrs, 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: Start 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 6 hrs 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) may be used 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 ACS patients including those requiring PCI and/or CABG unless known specific contraindication; followed by monotherapy.

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

Back to Title

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 strategies

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 ~1year
  • 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 hrs

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 hrs

 

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)

Back to Title

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
  • Foley catheter
  • 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 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.

Back to Title

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 heart failure
  • 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)

Back to Title

D) POST MI RISK ASSESSMENT

Indicated for patients:

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

Assessments:

E) MONITOR FOR COMPLICATIONS FOLLOWING

ACUTE MI

Patients may require medical attention if experiences:

 

  • Recurrent chest pain
    • Requires urgent evaluation by the cardiologist
  • Pleuritic pain (rule out acute pericarditis)
    • Typically occurs within 1-4 days post MI
  • Malaise, fever, chest pain (rule out dressler syndrome)
    • Typically occurs 1-8 weeks after MI
  • Palpitations, lightheadedness, syncope (rule out arrhythmias)
    • Requires urgent attention
  • Hypotension, shortness of breath, pallor, sweaty, cold, clammy, weak pulses (rule out cardiogenic shock/heart failure)
    • Requires urgent attention
  • There could be Mechanical and structural complications following acute MI, patients are advised to discuss them at length on follow up visits
  • Abrupt onset of transient neurological symptoms may suggest "TIA". Depending on severity may require urgent ER assessment and management

 

Back to Top

MEDICATIONS

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

Back to Title

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)

Back to Title

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

Back to Title

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

Back to Title

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)

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)

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

 

Back to Top
Clinical Trials:
  • OASIS-6-Effects of Fondaparinux on Mortality and Reinfarction in Patients With Acute ST-Segment Elevation Myocardial Infarction
  • CURE trial-Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation
  • PLATO-Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes
  • Re-LY-Dabigatran versus Warfarin in Patients with Atrial Fibrillation
  • ROCKET AF- Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

 

Back to Top
Pipeline Agents:
  • TRACER study-Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes
  • TIMACS study-Early versus Delayed Invasive Intervention in Acute Coronary Syndromes

 

Back to Top
Pharmacist Resources:

1. Tips for Patient Care

Encourage

  • Advise patient to establish a daily routine for pill-taking at the time of discharge and remind about the importance of medication adherence
  • Reinforce smoking cessation, discuss targets and provide rewards for encouragement
  • Encourage to make lifestyle modification to improve control of hypertension and hyperlipidemia
  • Help and encourage patient in reduction of emotional stress

Drugs

  • If possible than help simplify medical regimen (combination pills)
  • Appreciate lower starting doses in elderly patients
  • Stool softeners in the immediate post-MI period may help prevent straining with bowel movements
  • Consider concurrent risk factors and disease states with the prescribed therapy

Avoid or exercise caution with:

  • Nondihydropyridine CCB in heart failure
  • Short-acting nifedipine in angina
  • ACE inhibitors or ARBs in patients with bilateral renal artery stenosis or unilateral disease with a solitary kidney

Unlabeled/alternate uses includes but are not limited to:

  • Antiplatelets
    • Clopidogrel: Reduction of restenosis after stent placement
    • Dipyridamole: Stroke prevention (in combination with aspirin)
  • Fibrinolytic agents
    • Alteplase: Acute ischemic stroke
  • Nitroglycerine / Isosorbide dinitrate
    • Esophageal spastic disorders
  • Beta 1-adrenergic blocking agents
    • Atenolol: Acute ethanol withdrawal, migraine headache prophylaxis
  • Calcium channel blocking agents
    • Verapamil: Prophylaxis of migraine

Counseling

  • Ensure patient, family and/or care givers are well informed about disease and its management
  • Include family or social support in lifestyle modification
  • Consider informing patients of their global risk to improve the effectiveness of risk factor modification

Alerts

  • Reactive depression is common
  • Physician may request discontinuation of clopidogrel or oral anticoagulants 2-7 days prior to surgery to decrease the risk of bleeding
  • Blood glucose levels should be tightly controlled in diabetics

Tips

  • Advise patient to keep SL nitroglycerin and how to use appropriately during chest pain
  • Adherence of medications should be assessed and reinforced at each visit
  • Hormone replacement therapy is not indicated for primary or secondary prevention of cardiovascular events in postmenopausal women

Expected outcome

  • About 30% of patients with unstable angina have an MI within 3 months of onset
  • If good cardiac function is maintained 6 wk after acute MI, most patients can return to all their normal activities
  • In post MI patients, outcome depends on the interaction between
    • Residual LV dysfunction
    • Potential for recurrent ischemia
    • Risk of arrhythmia

 

2. Scales and Tables

 

Back to Top
References:

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. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
  • 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
  • Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
  • 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
  • DOI: 10.1093/eurheartj/ehi187
  • Genest J, McPherson R, Frohlich J, et al. Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol.2009; 13(10):567-579
  • DOI: 10.1016/S0828-282X(09)70715-9
  • Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
  • Hess EP, Agarwal D, Chandra S, et al. Diagnostic accuracy of the TIMI risk score in patients with chest pain in the emergency department: a meta-analysis. CMAJ. 2010; 182:1039-1044
  • 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
  • Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
  • Longo D, Fauci A, Kasper D, et al (eds). Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011
  • McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
  • 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, 12th Edition. New York: McGraw-Hill; 2008
  • Pagana KD, Pagana TJ eds. Mosby's Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
  • Skidmore-Roth L. ed. Mosby's drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
  • Skidmore-Roth L, ed. Mosby's nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011

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
  • Arnold JM, Yusuf S, Young J, et al. Prevention of Heart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003; 107: 1284-1290
  • Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151
  • 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
  • Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519-30

 

Back to Top
explore
Reviewers

EXPERT REVIEWER:
Milan Gupta, MD, FRCPC, Associate Clinical Professor of Medicine, McMaster University, Staff Cardiologist, William Osler Health System, Brampton, ON Canada
.......................................... PHARMACY REVIEWER:
Wendy Gordon, B.Sc.(Pharm), ACPR, Pharm.D, Coordinator, Clinical Pharmacy Services, Fraser Health, Provincial Health Services Authority, BC Canada

Upcoming eDucate Webinar Series
 
Copyright © 2011-2017 Innovate R&D
stroke

educate Are you a Healthcare professional or patient?

Healthcare Professionals would include: Physicians (MD,OD), Physician assistants, Nurses, Pharmacists,Allied Health Workers (PT, OT, SLP, etc), Chiropractors, Paramedics, Optometrists, Dentists, Podiatrists etc, and students within these disciplines.

educate ** You are required to register **

eDucate is committed to optimizing the delivery of health information across the Healthcare continuum. To this end eDucate uses a wide array of learning tools, including Webinars, Quick Review Charts, Graphs, Brochures, Videos and Slide Presentations.

Register and join over 65,000 individuals have leveraged the eDucate portal for their medical information needs during the past 2 years.

Professional Membership Benefits include free access to all archived and upcoming Webinars:

educate DISCLAIMER: This website is owned and operated by The Innovate Research and Development LP (Innovate R&D). All references herein to Innovate R&D shall be deemed to include any subsidiary, affiliate, associate or successor corporation of Innovate R&D. By entering and using this site, you agree to the "Terms of Use"for this website. If you do not agree to these terms and conditions then exit from this site immediately. Although Innovate R&D updates this website regularly with material believed to be accurate at the time of posting, Innovate R&D does not guarantee the accuracy, completeness, timeliness or currency of the material and consequently Innovate R&D expressly disclaims any liability for errors or omissions in the material contained in the website. The Innovate R&D website and all contents are provided as-is, and all representations and warranties, express or implied, relating to the website or the content are disclaimed, including any implied warranty of merchantability, fitness for a particular purpose or non-infringement, as well as any warranty of quality, functionality, accuracy, currency, completeness, reliability, operability, use performance or absence of viruses. In no way or event will Innovate R&D or any party that has been involved in the creation, production, promotion and marketing be liable to you or any other party for perceived direct or indirect damages. You assume all responsibility and risk of loss resulting from the use of our website.