STEMI resident survival guide

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STEMI Resident Survival Guide Microchapters
Overview
Causes
Pre-Hospital Care
FIRE
Complete Diagnosis
Pre-Discharge Care
Long Term Management
Do's
Don'ts
Gallery

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]; Rim Halaby, M.D. [3]

Overview

ST elevation myocardial infarction (STEMI) is a syndrome characterized by the presence of symptoms of myocardial ischemia associated with persistent ST elevation on electrocardiogram and elevated cardiac enzymes. The management of STEMI should be initiated without delay and the following timelines should be minimized (the 4 D's):

Door to Data

If a patient presents with chest discomfort, an electrocardiogram must be obtained immediately and no later than 5-10 minutes after arrival. In the patient with chest discomfort, an electrocardiogram should be obtained prior to obtaining insurance / payment information.

Data to Decision

If the electrocardiogram shows ST segment elevation, ST segment depression consistent with posterior MI, or a new left bundle branch block, a decision must be made within 5 to 10 minutes as to whether to administer a fibrinolytic agent or to proceed to primary angioplasty.

Decision to Drug or Device

Once a decision is made to administer a fibrinolytic agent or to proceed to primary angioplasty this should be carried out within 30 minutes.

Causes

Life Threatening Causes

STEMI is a life-threatening condition and must be treated as such irrespective of the underlying cause.

Common Causes

Pre-Hospital Care

Pre-hospital care can begin in the ambulance by Emergency Medical Services (EMS) personnel and it can decrease the delay in the management of STEMI patients. EMS services are staffed by either volunteers, fire fighters, or highly trained paramedics and their services depends on their level of training. Pre-hopital care is different among countries depending on the availability of EMS and highly trained paramedics. In the United States, volunteers and fire fighters are permitted to initiate emergency care prior to the arrival of highly trained paramedics by beginning CPR and if adequately trained, can defibrillate the patient using an automatic external defibrillator. Early access to EMS is promoted by a 9-1-1 system.

Prehospital Care

❑ Check the vital signs
❑ Order 12 lead ECG and transmit it to the receiving hospital
❑ Establish IV access
❑ Administer oxygen
❑ Administer medications (depending on the level of training)

Non-enteric coated aspirin
Sublingual nitroglycerin
Clopidogrel
Unfractionated heparin
Glycoprtein IIb IIIa inhibitors
Fibrinolytic therapy (especially in rural areas)

❑ Activate the cardiac cath team in the hospital
Resuscitation in case of cardiac arrest

CPR
Automated defibrillator
 
 

FIRE: Focused Initial Rapid Evaluation

A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.[1]

Boxes in red signify that an urgent management is needed.

 
 
 
Identify cardinal findings of STEMI:

Chest pain or chest discomfort

❑ Sudden onset
❑ Sensation of heaviness, tightness, pressure, or squeezing
❑ Duration> 20 minutes
❑ Radiation to the left arm, jaw, neck, right arm, back or epigastrium
❑ No relief with medications
❑ No relief with rest
❑ Worse with time
❑ Associated symptoms of palpitations, nausea, vomiting and sweating

Characteristic ECG changes consistent with STEMI

ST elevation in at least 2 contiguous leads of 2 mm (0.2 mV) in men or 1.5 mm (0.15 mV) in women in leads V2–V3 and/or of 1 mm (0.1mV) in other contiguous chest leads or the limb leads
ST depression in at least two precordial leads V1-V4 (suggestive of Posterior MI)
ST depression in several leads plus ST elevation in lead aVR (suggestive of occlusion of the left main or proximal LAD artery)
❑ New LBBB
Increase in troponin
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out life threatening alternative diagnoses:

Aortic dissection
(suggestive findings: back pain, interscapular pain, aortic regurgitation, pulsus paradoxus, blood pressure discrepancy between the arms)
Pulmonary embolism
(suggestive findings: acute onset of dyspnea, tachypnea, hemoptysis, previous DVT)
Cardiac tamponade
(suggestive findings: hypotension, jugular venous distention, muffled heart sounds)
Tension pneumothorax
(suggestive findings: sudden dyspnea, tachycardia, chest trauma, unilateral absence of breath sounds)

Esophageal rupture
(suggestive findings: vomiting, subcutaneous emphysema)
 
 
 
 
 
 
 
 
 
 
 
 
Assess appropriateness of perfusion therapy:

Contraindications to fibrinolytics
❑ Assess the femoral pulses (strength, bruit)

Pericarditis (suggestive findings: pericardial friction rub)
 
 
 
 
 
 
 
 
 
 
 
 
Consider right ventricular MI in case of:

Hypotension
❑ Elevated jugular venous pressure
❑ Clear lung fields
Peripheral edema
ECG changes suggestive of an Inferior MI

ST elevation in leads II, III and aVF
 
 
 
 
 
 
 
 
 
 
 
 
Order a right sided ECG in all patients with ST elevation in leads II, III and aVF:

❑ Clearly label the ECG as right sided
ST elevation of >1 mm in lead V4R suggests a right ventricular MI

Click here for right ventricular myocardial infarction
 
 
 
 
 
 
 
 
 
 
 
Check for hypoperfusion and left ventricular failure:

❑ Patient lies still
Cold skin
Skin mottling
Cyanotic skin and nail bed
Confusion or disorientation
Tachycardia

Click here for cardiogenic shock resident survival guide
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin initial treatment:
❑ Administer 162 - 325 mg of non enteric aspirin
❑ Orally, crushed or chewed
❑ Intravenously

❑ Administer 2-4 L/min oxygen via nasal cannula when saturation <90%

❑ Caution in COPD patients: maintain an oxygen saturation between 88% and 92%

❑ Administer beta-blockers (unless contraindicated)
Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state

Metoprolol IV, 5 mg every 5 min, up to 3 doses
Carvedilol IV, 6,25 mg, two times a day (titrate to heart rate)

❑ Administer sublingual nitroglycerin 0.4 mg every 5 minutes for a total of 3 doses
Contraindicated in suspected right ventricular MI, recent use of phosphodiesterase inhibitors, decreased blood pressure 30 mmHg below baseline
❑ Administer IV morphine if needed

❑ Initial dose 2-4 mg
❑ 2-8 mg every 5 to 15 minutes, as needed

❑ Administer 80 mg atorvastatin
❑ Monitor with a 12-lead ECG all the time

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
❑ Determine if PCI is available
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCI is available
 
 
 
PCI is not available
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
First medical contact to device ≥ 120 min
 
First medical contact to device time ≤ 120 min
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary PCI within 90 minutes
 
Fibrinolytic therapy within 30 min
 
Transfer for primary PCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm that the patient has one of the following indications:

❑ Symptoms of ischemia <12 hours (Class I, level of evidence A)
❑ Symptoms of ischemia <12 hours and contraindications to fibrinolytics irrespective of time delay (Class I, level of evidence B)
Cardiogenic shock irrespective of time delay (Class I, level of evidence B)
Heart failure irrespective of time delay (Class I, level of evidence B)

❑ Ongoing ischemia 12-24 hours following onset (Class IIa, level of evidence B)
 
Confirm that the patient has one of the following indications:
❑ Symptoms of ischemia <12 hours (Class I, level of evidence A)
❑ Ongoing ischemia 12-24 hours following onset (Class IIa, level of evidence C)

Confirm that the patient has no contraindications for fibrinolytics

 
 
 
 
 
 
 
 
 

Administer ONE of the following antiplatelet agents (before or at the time of PCI):
P2Y12 receptor inhibitors

Clopidogrel 600 mg
Ticagrelor 180 mg
Prasugrel 60 mg

Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years of age, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding
❑ IV GP IIb/IIIa inhibitors

Abciximab
❑ Loading dose 0.25 mg/kg IV bolus
❑ Maintenance dose 0.125 mg/kg/min
Eptifibatide
❑ Loading dose 180 mcg/kg IV bolus
❑ Another 180 mcg/kg IV bolus after 10 minutes
❑ Maintenance dose 2 mcg/kg/min
❑ Decrease infusion by 50% if creatinine clearance <50 mL/min
❑ Avoid in hemodialysis patients
Tirofiban
❑ Loading dose 25 mcg/kg
❑ Maintenance dose 0.15 mcg/kg/min
❑ Decrease infusion by 50% if creatinine clearance <30 mL/min

Administer ONE of the following anticoagulant therapy:
|Unfractionated heparin

If GP IIb/IIIa receptor antagonist is planned
❑ 50- to 70-U/kg IV bolus
If no GP IIb/IIIa receptor antagonist is planned
❑ 70- to 100-U/kg bolus

Bivalirudin

❑ 0.75-mg/kg IV bolus, then 1.75–mg/kg/h infusion
❑ Additional bolus of 0.3 mg/kg if needed
❑ Decrease infusion to 1 mg/kg/h when creatinine clearance <30 mL/min
 
Administer ONE of the following fibrinolytic therapy

Tenecteplase single IV bolus

❑ 30 mg for weight <60 kg
❑ 35 mg for weight 60-69 kg
❑ 40 mg for weight 70-79 kg
❑ 45 mg for weight 80-89 kg
❑ 50 mg for weight ≥60 kg

Reteplase 10 units IV boluses every 30 min
Alteplase

❑ Bolus 15 mg, infusion 0.75 mg/kg for 30 min (maximum 50 mg)
❑ Then 0.5 mg/kg (maximum 35 mg) over the next 60 min

Streptokinase 1.5 million units IV administered over 30-60 min


Administer a P12Y2 inhibitor
Clopidogrel

If age ≤ 75 years
❑ Loading dose 300 mg
❑ 75 mg daily for at least 14 days, up to one year
If age > 75 years
❑ Loading dose 75 mg
❑ 75 mg daily for at least 14 days, up to one year

Administer ONE of the following anticoagulant therapy
Unfractionated heparin

❑ IV bolus of 60 units/kg (maximum 4000 units)
❑ Then infusion of 12 units/kg/hour (maximum 1000 units)
❑ Adjust the infusion for a aPTT of 50-70 sec for 48 hours or until revascularization

Enoxaparin (for up to 8 days or until revascularization)

If age <75 years
❑ IV bolus 30 mg
❑ Then after 15 minutes, SC 1 mg/kg every 12 hours (maximum 100 mg for the first two doses)
If age ≥75 years
❑ SC 0.75 mg/kg every 12 hours (maximum 75 mg for the first two doses)
If creatinine clearance <30 mL/min
❑ SC 1 mg/kg every 24 hours

Fondaparinux

❑ Initial dose of 2.5 mg IV
❑ Then, SC 2.5 mg daily (for up to 8 days or until revascularization)
❑ Do not administer if creatinine clearance <30 mL/min
 
 
 
 
 
 
 
 
 
Consider urgent CABG if the coronary anatomy is not amenable to PCI and one of the following:

❑ Ongoing and recurrent ischemia
Cardiogenic shock
❑ Severe heart failure
❑ Other high risk features

 
Transfer to a PCI-Capable hospital for non primary PCI, if there is:

Cardiogenic shock (Class I, level of evidence B)
❑ Acute severe [[heart failureheart failure]] (Class I, level of evidence B)
❑ Spontaneous or easily provoked myocardial ischemia (Class I, level of evidence C)
❑ Failed reperfusion after fibrinolytics (Class IIa, level of evidence B)
❑ Reocclusion after fibrinolytics (Class IIa, level of evidence B)
❑ Successful fibrinolytic reperfusion, between 3 and 24 hours (Class IIa, level of evidence B)



Contraindications to Fibrinolytic Therapy

Shown below is a table summarizing the absolute and relative contraindications for fibrinolytic therapy among STEMI patients.

Absolute contraindications Relative contraindications
❑ Prior intracranial hemorrhage

Ischemic stroke within the last 3 months (Unless within 4.5 hours)
❑ Structural cerebral vascular lesion
❑ Primary of metastatic intracranial malignancy
❑ Suspicion of aortic dissection
❑ Increased bleeding tendency or active bleeding
❑ Severe head or facial trauma within the last 3 months
❑ Intracranial or intraspinal surgery within the last 2 months
❑ Severe hypertension uncontrolled by emergency therapy
❑ Previous treatment with streptokinase within the last 6 months

❑ Oral anticoagulation therapy

❑ Pregnancy
❑ Active peptic ulcer
❑ Previous history of chronic severe hypertension that is poorly controlled
❑ Elevated blood pressure at presentation, such as SBP >180 mmHg or DBP >110mmHg
❑ Previous history of ischemic stroke
Dementia
❑ Intracranial pathology that does not meet the absolute contraindications
CPR that lasted more than 10 min or that is traumatic
❑ Major surgery in the last 3 weeks
❑ Internal bleeding within the last 2-4 weeks
❑ Non compressible vascular punctures

Complete Diagnostic Approach

A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.[1]

Abbreviations: CABG: coronary artery bypass graft; ECG: electrocardiogram; LAD: left anterior descending; LBBB: left bundle branch block; MI: myocardial infraction; PCI: percutaneous coronary intervention

Characterize the symptoms:

Chest pain or chest discomfort

❑ Sudden onset
❑ Sensation of heaviness, tightness, pressure, or squeezing
❑ Duration> 20 minutes
❑ Radiation to the left arm, jaw, neck, right arm, back or epigastrium
❑ No relief with medications
❑ No relief with rest
❑ Worse with time

Dyspnea
Weakness
Palpitations
Nausea
Vomiting
Sweating
Loss of consciousness
Fatigue

 
 
 
 
 
 
Obtain a detailed history:

❑ Age
❑ Baseline blood pressure
❑ Previous MI
❑ Previous PCI or CABG
❑ Cardiac risk factors

Hypertension
Diabetes
Hypercholesterolemia
Smoking
Obesity

❑ List of medications


Identify possible triggers:
❑ Physical exertion
Psychological stress (anger, anxiety, bereavement, work related stress, natural disasters, wars or sporting events)
Sexual activity
❑ Air pollution or fine particulate matter
❑ Antecedant infection
❑ Heavy meal
Cocaine

Marijuana
 
 
 
 
 
 
 
Examine the patient:

Vital signs
Blood pressure

Blood pressure lower than baseline, suggestive of:
Cardiogenic shock (associated with tachycardia and end organ hypoperfusion), or
Right ventricular MI (associated with increased jugular venous pressure and clear lung fields), or
Bezold-Jarisch reflex (associated with either normal heart rate or bradycardia)
❑ Discrepancy between arms (suggestive or aortic dissection)
❑ Narrow pulse pressure (suggestive of heart failure)
❑ Wide pulse pressure (suggestive of mitral regurgitation or VSD)

Heart rate

Tachycardia (suggestive of heart failure)
Bradycardia (suggestive of heart block)

Pulses
Femoral pulse (if a patient is to undergo PCI)

❑ Strength
❑ Bruits

Skin
Xanthelasma (suggestive of dyslipidemia)
Xanthoma (suggestive of dyslipidemia)
Edema (suggestive of heart failure)
Cyanotic and cold skin, lips, nail bed (suggestive of cardiogenic shock)

Heart
Heart sounds

S3 (suggestive of heart failure)
S4 (associated with conditions that increase the stiffness of the ventricle)

Murmurs

Mitral regurgitation: blowing holosystolic murmur best heard at the apex
VSD: holosystolic murmur along the left and right sternal border
Free wall rupture: holosytolic murmur
Aortic regurgitation: early diastolic high-pitched sound best heard at the left sternal border (suggestive of aortic dissection with propagation to the aortic arch)

Pericardial friction rub (suggestive of pericarditis)

Signs of Right Ventricular MI:
❑ Elevated jugular venous pressure (suggestive of right ventricular MI)
❑ Presence of hepatojugular reflux (suggestive of right ventricular MI)

Lungs
Rales (suggestive of heart failure)

 

Pre-Discharge Care

Administer the following medications in patients without contraindications:

Aspirin 81-325 mg (indefinitely)
Beta blockers
Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state

Metoprolol tartrate
❑ Begin with 25 to 50 mg PO every 6 to 12 hour
❑ Then, metoprolol tartrate twice daily or metoprolol succinate once daily for 2-3 days
❑ Titate to 200 mg daily, OR
Carvedilol
❑ Begin with 6.25 mg twice daily
❑ Titrate to 25 mg twice daily

ACE inhibitor in case of anterior MI, ejection fraction ≤ 40% or heart failure
Contraindicated in hypotension, renal failure and hyperkalemia

Lisinopril
❑ Begin with 2.5-5 mg
❑ Titrate to 10 mg or higher daily, OR
Captopril
❑ Begin with 6.25-12.5 mg three times daily
❑ Titrate to 25 to 50 mg three times daily, OR
Ramipril
❑ Begin with 2.5 mg twice daily
❑ Titrate to 5 mg twice daily, OR
Trandolapril
❑ Begin with 0.5 mg daily
❑ Titrate to 4 mg daily, OR

Valsartan (in case of intolerance to ACE inhibitors)
Contraindicated in hypotension, renal failure and hyperkalemia

❑ Begin with 20 mg twice daily
❑ Titrate to 160 mg twice daily

Atorvastatin 80 mg daily


Administer antiplatelet therapy

For patients who underwent PCI, for one year
Clopidogrel 75 mg daily, OR
Prasugrel 10 mg daily, OR
Ticagrelor 90 mg twice a day

For patients who underwent fibrinolysis, for at least 14 days, up to one year
Clopidogrel 75 mg daily


Manage complications of STEMI
Implantable cardioverter-defibrillator at least 40 days following the MI in cases of:

LVEF <30% among patients in NYHA functional Class I (Class I, level of evidence A)
LVEF <35% among patients in NYHA functional Class II or III (Class I, level of evidence A)
LVEF <40% (Class I, level of evidence B)
❑ An irreversible non-ischemia related VT/ VF after more than 48 hours following STEMI (Class I, level of evidence B)[2]

❑ Temporary pacing for asymptomatic bradycardia refractory to medical therapy (Class I, level of evidence C)
Aspirin for pericarditis (Class I, level of evidence B)

❑ do not administer glucocorticoids or NSAIDs for pericarditis following STEMI (Class III, level of evidence B)

Assess the patient for ischemia:
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo coronary angiography and in whom a coronary angiography is not warranted due to the absence of high risk features (Class I, level of evidence B)
❑ Assess the left ventricular ejection fraction (Class I, level of evidence C)

 
 

Long Term Management

❑ Prepare a list of all the home medications and educate the patient about compliance
❑ Aspirin 81-325 mg (indefinitely)
Beta blockers
ACE inhibitors or ARB (in case of anterior MI, ejection fraction ≤ 40% or heart failure)
Atorvastatin 80 mg daily
Antiplatelet therapy

❑ Encourage lifestyle modification

Smoking cessation
❑ Physical activity
❑ Dietary changes

❑ Ensure the initiation of the management of comorbidities

Obesity
Dyslipidemia
Hypertension
Diabetes
Heart failure

❑ Educate the patient about the early recognition of symptoms of MI

❑ Educate the patient about the use of nitroglycerin 0.4 mg, sublingually, up to 3 doses every 5 minutes
 

Do's

  • Pre-hospital ECG is recommended. If STEMI is diagnosed the PCI team should be activated while the patient is en route to the hospital.
  • Administer a loading dose followed by a maintenance dose of clopidogrel, ticagrelor or prasugrel (if PCI is planned) as initial treatment instead of aspirin among patients with gastrointestinal intolerance or hypersensitivity reaction to aspirin.
  • Administer sublingual nitroglycerin in patients with ischemic chest pain; however, administer IV nitroglycerin among patients with persistent chest pain after three sublingual nitroglycerins.[3]
  • Rule out any contraindications for fibrinolytic therapy before its administration. If contraindications to fibrinolytics are present, the patient should be transferred to another hospital where PCI is available.
  • Consider bare-metal stent among STEMI patients with any of the following (Class I, level of evidence C):
    • High bleeding risk
    • Lack of compliance for a one year regimen of dual antiplatelet therapy
    • Surgery or invasive procedure within the next year
  • Achieve the following therapeutic activated clotting time when administering UFH:
    • 200 to 250 seconds with the concomitant administration of GPIIbIIIa receptor inhibitor
    • 250 to 300 seconds (HemoTec device) without the concomitant administration of a GPIIbIIIa receptor inhibitor
    • 300 to 350 seconds (Hemochron device) without the concomitant administration of a GPIIbIIIa receptor inhibitor
  • Make sure the dose of P2Y12 receptor inhibitors is appropriate among patients undergoing PCI after fibrinolytic therapy:
    • Patients who already received a loading dose of clopidogrel: No loading dose, clopidogrel daily
    • Patients who did not receive a loading dose of clopidogrel and PCI is performed ≤ 24 hours after fibrinolytic therapy: loading dose of 300 mg clopidogrel
    • Patients who did not receive a loading dose of clopidogrel and PCI is performed > 24 hours after fibrinolytic therapy: loading dose of 600 mg clopidogrel
    • Patients who did not receive a loading dose of clopidogrel and PCI is performed >24 hours after therapy with fibrin specific agent, or >48 hours after therapy with a non-fibrin-specific agent: prasugrel 60 mg
  • Recommend a long term maintenance dose of 81 mg of aspirin when the patient is administered ticagrelor.

Don'ts

  • Do not administer IV GP IIb/IIIa inhibitors to patients with low risk of ischemic events or at high risk of bleeding and who are already on aspirin and P2Y12 receptor inhibitors therapy.
  • Do not delay the time for reperfusion.
  • Do not administer prasugrel among patients with any of the following:
    • Prior history of strokes or TIAs (Class III, Level of evidence B)
    • Active pathological bleeding
    • Age ≥75 years of age, (except in high-risk patients such as diabetes or prior MI, where its use may be considered)
    • Urgent coronary artery bypass graft surgery (CABG) is likely
    • Presence of additional risk factors for bleeding such as body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding[6]

References

  1. 1.0 1.1 1.2 1.3 O'Gara, Patrick T.; Kushner, Frederick G.; Ascheim, Deborah D.; Casey, Donald E.; Chung, Mina K.; de Lemos, James A.; Ettinger, Steven M.; Fang, James C.; Fesmire, Francis M.; Franklin, Barry A.; Granger, Christopher B.; Krumholz, Harlan M.; Linderbaum, Jane A.; Morrow, David A.; Newby, L. Kristin; Ornato, Joseph P.; Ou, Narith; Radford, Martha J.; Tamis-Holland, Jacqueline E.; Tommaso, Carl L.; Tracy, Cynthia M.; Woo, Y. Joseph; Zhao, David X. (2013). "2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction". Journal of the American College of Cardiology. 61 (4): e78–e140. doi:10.1016/j.jacc.2012.11.019. ISSN 0735-1097.
  2. Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA, Freedman RA, Gettes LS; et al. (2008). "ACC/AHA/HRS 2008 guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: executive summary". Heart Rhythm. 5 (6): 934–55. doi:10.1016/j.hrthm.2008.04.015. PMID 18534377.
  3. Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M (1983). "Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy". Am J Cardiol. 51 (5): 694–8. PMID 6402912.
  4. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM; et al. (2011). "Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis". BMJ. 342: c7086. doi:10.1136/bmj.c7086. PMC 3019238. PMID 21224324. Review in: Evid Based Med. 2011 Oct;16(5):142-3
  5. Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N; et al. (2013). "Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials". Lancet. 382 (9894): 769–79. doi:10.1016/S0140-6736(13)60900-9. PMC 3778977. PMID 23726390. Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12
  6. "http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fe9c118-c44b-48d7-a142-9668ae3df0c6". Retrieved 6 February 2014. External link in |title= (help)


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