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Nov 2015 FAQs


What are the key features of the most recent guidelines for the management of patients with atrial fibrillation?

What recent evidence describes the comparative safety and efficacy of bivalirudin and heparins in patients undergoing percutaneous coronary intervention?

Can the intravenous formulation of vitamin K be administered orally?


What are the key features of the most recent guidelines for the management of patients with atrial fibrillation?


The American Heart Association (AHA), in collaboration with the American College of Cardiology (ACC) and the Heart Rhythm Society (HRS), released new guidelines for the management of patients with atrial fibrillation (AF) in December of 2014.1  The 2014 guidelines supersede the previously released 2006 guidelines as well as the 2 focused updates released in 2011 and are designed to be more clinician-friendly.  The guidelines include more summary and evidence tables for ease of use as a point-of-care reference, an increased emphasis on patient-centered care and shared decision making, and a focus on patient preference and careful evaluation of risks and benefits of different treatments for AF.  The guideline also emphasizes the differentiation between types of class III recommendations, with a distinction drawn between “no benefit” and “harm.” 

This overview will highlight some of the most salient changes made to the guidelines, with a focus on pharmacologic interventions for AF.  Where appropriate, information on category of recommendation (COR, Classes I through III) and level of evidence (LOE, evidence levels A through C) ratings will be provided. Class I recommendations indicate that benefits greatly outweigh the risks of following the recommendation, and that the recommended intervention should be performed.  Class IIa recommendations indicate that benefits outweigh risks and thus it is reasonable to follow the recommendation, while class IIb recommendations indicate that additional studies are needed but available evidence suggests that following the recommendation may be considered.  Class III recommendations indicate that there is either no benefit or harm to the patient.  A LOE of A indicates a recommendation based on multiple meta-analyses or randomized clinical trials; LOE B recommendations are based on data from nonrandomized studies or a single randomized trial.  Level of evidence C recommendations are based on expert consensus, case studies, or pre-existing standards of care.


Atrial fibrillation is a relatively common supraventricular tachyarrhythmia caused by dyssynchronous atrial activation.1 It is estimated to affect between 2.7 and 6.1 million adults in the United States.  The 2014 guidelines have simplified the classification of AF subtypes; the new classification scheme is summarized in Table 1 below.

Table 1. Simplified AF classification scheme.1   

AF Classification


Paroxysmal AF

• AF lasting < 7 days

• Episodes terminate spontaneously or with intervention (i.e. electrical or pharmacologic cardioversion)

• Episodes may recur at variable intervals

Persistent AF

• AF sustained for > 7 days

Long-standing persistent AF

• AF sustained for > 12 months

Permanent AF

• Clinician and patient have jointly decided that further efforts to restore or maintain sinus rhythm are no longer appropriate

Nonvalvular AF

• AF that is not associated with rheumatic mitral stenosis, heart valve, or previous valve repair

Current Recommendations: Anticoagulation

Stroke Risk Stratification

The Guidelines make a Class I, LOE B recommendation supporting the use of CHA2DS2-VASc as the preferred stroke risk scale (Table 2) when making decisions for prophylactic anticoagulation.1  The use of CHADS2 is no longer recommended.  This redistributes more patients, especially elderly females, from low to moderate and high risk categories.  However, this does not mean more anticoagulation for patients—the recommendations for anticoagulation have been modified considerably, with less emphasis placed on the use of aspirin and the option for no anticoagulation at all in patients with 0 or 1 risk factor.  The guidelines also evaluated bleeding risk assessment scales and recommend using the HAS-BLED scale preferentially over the HEMORR2HAGES or ATRIA scales when assessing a patient’s bleeding risk. 

Table 2. CHA2DS2-VASc scoring system and associated stroke risk.*1 

CHA2DS2-VASc Assessment

Total score

Adjusted stroke rate

(% per year)

Congestive Heart Failure (1)

Hypertension (1)

Age ≥ 75 (2)

Diabetes mellitus (1)

Stroke/TIA/Thromboembolic Event (2)

Vascular disease: MI, peripheral artery disease, aortic plaque (1)

Age 65-74 (1)

Sex category-Female  (1)





















*The number listed in parentheses is the score given for the particular risk factor (shown in Column 1). The adjusted stroke rate is based on the patient’s total score after assessing for presence of each risk factor (shown in Columns 2 and 3).

Anticoagulation options and selection

When discussing anticoagulation, the new guidelines place an emphasis on patient preference and stress the importance of providers discussing the risks and benefits of anticoagulation with patients.1  Continued reassessment of the need for anticoagulation is also recommended.   Oral anticoagulation is still recommended for patients with prior stroke or transient ischemic attack (TIA), those with mechanical heart valves, and patients with hypertrophic cardiomyopathy, regardless of risk according to their score on the CHA2DS2-VASc scale.  The updated guidelines have incorporated recommendations for the use of dabigatran, rivaroxaban, and apixaban as alternatives to warfarin on the basis of findings from the landmark RE-LY, ROCKET AF, ARISTOTLE, and AVERROES trials.  Dosing recommendations based on renal function are summarized in Table 3.  No recommendations are available regarding the role of the newest oral anticoagulant, edoxaban, in preventing stroke in patients with AF. 

Table 3. Dosing recommendations for oral anticoagulants.1

Renal function





CrCl > 50 mL/min

Dose adjusted to achieve an INR of 2 to 3

150 mg PO twice daily

20 mg PO daily with evening meal

2.5 or 5 mg PO twice dailya

CrCl 30 to 50 mL/min

150 mg PO twice daily

15 mg PO daily with evening meal

2.5 or 5 mg PO twice dailya

CrCl 15 to 30 mL/min

75 mg PO twice daily

15 mg PO daily with evening meal

No recommendation

ESRD not on dialysis (CrCl < 15 mL/min)

Not recommended

Not recommended

ESRD on dialysis

a Use 2.5 mg dose if patient fulfills ≥2 of the following criteria: age ≥ 80, serum creatinine ≥ 1.5 mg/dL, body weight ≤ 60 kg.

Abbreviations: CrCl, creatinine clearance; ESRD, end stage renal disease; PO, by mouth

Warfarin is still the anticoagulant of choice for patients with mechanical heart valves and in patients with end-stage renal disease (creatinine clearance < 15 mL/min) or those on hemodialysis.1 However, the guidelines have eliminated the recommendation for “lenient” or low-intensity anticoagulation with warfarin, targeting an international normalized ratio (INR) of 1.6 to 2.5 in patients unable to tolerate full anticoagulation (INR 2 to 3).1,3   

Antiplatelet therapy

The role of aspirin in the prevention of stroke in patients with AF has been downplayed significantly in the guidelines due to minimal evidence to support its benefit in stroke prevention and a similar risk of bleeding when compared to oral anticoagulants.1 Aspirin is no longer recommended in low-risk patients with a CHA2DS2-VASc score of 0 (Class IIa, LOE B) and may be considered in patients with a score of 1 (Class IIb, LOE C).

Aspirin is also no longer recommended in combination with clopidogrel following percutaneous coronary intervention or stenting due to an increased risk of bleeding (Class IIb, LOE B), and bare metal stents may be considered in lieu of drug eluting stents to minimize the duration of need for dual antiplatelet therapy (Class IIb, LOE C). 

The 2006 and 2014 recommendations for anticoagulation according to CHA2DS2-VASc are summarized in Table 4 below. 

Table 4. Recommendations for antithrombotic therapy according to risk factors.1,2

Risk factors according to CHA2DS2-VASc

2006 Recommendations

2014 Recommendations


• Aspirin (Class I, A)

• No treatment (Class IIa, B)


• Aspirin (Class IIa, A)

• Oral anticoagulation (Class IIa, A)


• No treatment (Class IIb, C)

        OR consider

• Aspirin (Class IIb, C)

• Oral anticoagulation (Class IIb, C)

≥ 2 or history of stroke or TIA

• Oral anticoagulation

Warfarina (Class I, A)

• Oral anticoagulation

Warfarina (Class I, A)

Rivaroxaban (Class I, B)

Dabigatranb (Class I, B)

Apixaban (Class I, B)

a Target INR 2 to 3

b Not recommended for patients with mechanical heart valves

Abbreviations: TIA, transient ischemic attack

Periprocedural interruption of anticoagulation and bridging

When interrupting anticoagulation for elective procedures, the new guidelines do not adhere as strictly to the 1-week recommendation for bridging warfarin.1 Although the authors acknowledge it is a widely accepted approach, the guidelines recommend consideration of individual stroke risk, procedural bleeding risk, and the duration the patient will be without anticoagulation (Class I, LOE C) when making decisions about bridging.  The guidelines also offer the option of not interrupting warfarin at all for procedures such as pacemaker implantation, defibrillator implantation, or radiofrequency catheter ablation.  Recommendations for periprocedural interruption of newer oral anticoagulants are sparse (Table 5). Bridging is still recommended in patients with mechanical heart valves (Class I, LOE C).  

Table 5. Recommendations for periprocedural interruption of anticoagulation.1




• Low thromboembolic risk: may hold warfarin x 1 week and allow INR to normalize before the procedure; resume warfarin once hemostasis has been achieved

• Patients at high thromboembolic risk (mechanical heart valves, prior stroke, CHA2DS2-VASc score ≥ 2): hold warfarin and bridge with UFH or LMWH (Class I, LOE C)

• Pacemaker/defibrillator implantation, RFA in patients with moderate-to-high stroke risk: may consider not interrupting warfarin


• Hold 2 doses prior to elective surgical procedurea

• Hold for ≥ 48 hours after procedure if complete hemostasis is needed (spinal puncture, major surgery)


• Hold 1 dose prior to elective surgical procedurea

• Hold for ≥ 48 hours after procedure if complete hemostasis is needed (spinal puncture, major surgery)


• Hold 2 doses prior to elective surgical procedurea

• Hold for ≥ 48 hours after procedure if complete hemostasis is needed (spinal puncture, major surgery)

aFor patients with normal renal function

Abbreviations: INR, international normalized ratio; LMWH, low molecular weight heparin; UFH, unfractionated heparin; RFA, radiofrequency ablation

In the setting of cardioversion, patients whose AF has lasted for greater than 48 hours or is of unknown duration should be anticoagulated for 3 weeks prior and for at least 4 weeks following cardioversion.1  The 3 weeks of pre-cardioversion anticoagulation may be omitted if transesophageal echocardiogram (TEE) is negative for thrombus, but patients should still be initiated on unfractionated heparin (UFH), low-molecular weight heparin (LMWH), or a new oral anticoagulant as soon as possible prior to cardioversion.  These agents are recommended due to their ability to achieve therapeutic anticoagulation rapidly prior to cardioversion.  Warfarin should not be used in this manner as it takes several days to achieve therapeutic levels of anticoagulation.  Regardless of which anticoagulant is used, the guidelines recommend ≥ 4 weeks of anticoagulation following cardioversion.

Current recommendations: rate and rhythm control

Rate Control

Rate control is recommended in patients with AF to prevent tachycardia-induced cardiomyopathy.1  Strict rate control with a target resting heart rate of < 80 beats per minute (bpm) is still recommended for patients with compromised left ventricular function or those who do not achieve adequate symptom relief at a higher resting heart rate.  However, in keeping with a 2011 focused update, the 2014 AF guidelines state that a lenient rate control strategy, with a target resting heart rate of 110 bpm may be reasonable as long as the patient achieves adequate symptom relief and left ventricular systolic function is preserved.  This recommendation has been changed from a Class III, LOE B to a Class IIb, LOE B recommendation based on the findings of the RACE-II trial, which followed 614 patients with permanent AF randomized to lenient (< 110 bpm) or strict (<80 bpm) rate control and found that lenient rate control was noninferior to strict rate control.3

Beta blockers and non-dihydropyridine calcium channel blockers (CCBs) are recommended first-line agents for ventricular rate control in AF, with oral amiodarone reserved as a second-line agent for refractory patients or those with contraindications to other agents.1  Digoxin is recommended only in combination with other agents because it is ineffective as a chronic oral therapy at controlling heart rate during exercise.  The guidelines also stress that intravenous rate control agents are to be reserved for situations in which rapid control of ventricular rate is required.  Such situations include acute onset AF in critically ill patients, those with myocardial ischemia, hemodynamic instability, or decompensation of HF.  Electrical direct-current cardioversion may also be used in this setting; however, patients with AF of  > 48 hours or unknown duration must be adequately anticoagulated prior to the procedure. 

Table 6 below provides dosing recommendations for rate control agents and Table 7 summarizes recommendations for preferred rate control agents in specific patient populations. 

Table 6. Usual dosing for recommended rate control agents.1


Usual Dosing

Beta Blockers


• PO: 25 to 100 mg once daily


• PO: 2.5 to10 mg once daily


• PO: 3.125 to 25 mg twice daily


• IV: 500 mcg/kg bolus over 1 minute, then 50 to 300 mcg/kg/min infusion

Metoprolol succinate (XR)

• PO: 50 to 400 mg once daily

Metoprolol tartrate (IR)

• PO: 25 to 100 mg twice daily

• IV:  2.5 to 5 mg bolus over 2 minutes; may repeat x 2 (total 3 doses)


• PO: 10 to 240 mg once daily


• IV:  1 mg bolus over 1 minute; may repeat x 2 (total 3 doses)

• PO: 10 to 40 mg 3 to 4 times daily

Non-dihydropyridine Calcium Channel Blockers


• IV: 0.25 mg/kg bolus over 2 minutes, then 5 to 15 mg/hour infusion

• PO: 120 to 360 mg once daily (ER formulation)


• IV:  0.075 to 0.15 mg/kg bolus over 2 minutes; May give additional 10 mg after 30 min if no response.  Transition to 0.005 mg/kg/min infusion

• PO: 180 to 480 mg once daily (ER formulation)

Digitalis glycosides


• IV loading dose: 0.25 mg with repeat dosing to a maximum of 1.5 mg over 24 hours

• PO: 125 to 250 mcg once daily

Other Agents


• IV: 300 mg over 1 hour, then 10 to 50 mg/hour over 24 hoursa

• PO: 100 to 200 mg once daily

aOther dosing schemes available

Abbreviations: ER, extended release; IR, immediate release; IV, intravenously; PO, orally

Table 7. Preferred rate control agents by patient population.1 

Patient population

Preferred agents for rate control


HF or LV dysfunction

• Beta blocker

• Digoxin

• Metoprolol, carvedilol preferred

• Avoid dronedarone

• Avoid non-dihydropyridine CCBs in decompensated HF or LV dysfunction

Chronic Obstructive Pulmonary Disease (COPD)

• Non-dihydropyridine CCBa

• Beta blocker (second line)

• Avoid amiodarone due to pulmonary toxicities

• Caution with beta blockers in patients with bronchospasm

Pre-excitation syndromes

• Beta blockerb

• Avoid digoxin, non-dihydropyridine CCBs, and IV amiodarone due to risk of ventricular fibrillation

Hypertension or HF with preserved LV function

• Beta blocker

• Non-dihydropyridine CCBa

• May add digoxin in HF


• Beta blocker

• May use non-dihydropyridine CCBa if beta blockers are contraindicated

Postoperative AF

• Beta blocker

• Non-dihydropyridine CCBa

• May consider preoperative amiodarone to reduce incidence of AF after cardiac surgery

a Diltiazem, verapamil

bBeta blockers should be used with caution as data are sparse

Abbreviations: CCB, calcium channel blocker; HF, heart failure; IV, intravenous; LV, left ventricular;

Rhythm control: cardioversion

Rhythm control strategies have not been shown to be superior to rate control strategies in improving outcomes or mortality, but these approaches may be useful for patients with existing tachycardia-mediated cardiomyopathy, difficulty achieving adequate rate control, or persistent symptoms despite adequate rate control.1 Younger patients and patients whose AF is a first occurrence or precipitated by acute illness may also be suitable candidates for rhythm control.  Patient preference must be taken into account. 

Rhythm control may be achieved through direct-current (electrical) cardioversion or through pharmacologic cardioversion.  Pharmacologic cardioversion is most effective within 7 days after the onset of an episode of AF.1  It can be achieved with intravenous ibutilide, though this requires close supervision and continuous electrocardiographic monitoring for ≥ 4 hours after administration as it carries a 3 to 4% risk of torsades des pointes.  Intravenous or oral amiodarone may also be used for cardioversion and is less associated with torsades des pointes. 

A single oral dose of flecainide or propafenone may be used both inpatient and outpatient for the “pill-in-the-pocket” method of restoring sinus rhythm after the onset of an episode of paroxysmal AF, though the initial cardioversion attempt must be done in a supervised setting.1  Ideal candidates for this self-treatment method include patients without structural heart disease whose AF episodes are infrequent and not associated with hemodynamic compromise. Either agent must be preceded by a dose of a beta blocker or non-dihydropyridine CCB at least 30 minutes prior to administration to prevent a rapid ventricular response.

Direct-current cardioversion may be attempted when AF is unresponsive to pharmacologic measures or in patients with pre-excitation mediated tachycardia.1  It can also be used in emergent situations when patients are hemodynamically unstable or require rapid restoration of sinus rhythm, as in the setting of an acute myocardial infarction.

Rhythm control: maintenance of sinus rhythm

Following cardioversion, pharmacotherapy for maintenance of sinus rhythm must be initiated.1  Therapy for rhythm control must be maintained as the efficacy of antiarrhythmic therapy is marginal and it is common for patients to have asymptomatic recurrences of AF even while patients are on appropriate maintenance therapy. Of note, even if a patient is on a rhythm control regimen, continuation of anticoagulation should be based on individual stroke risk rather than the response to antiarrhythmic therapy and frequency of AF recurrence.  If the decision to abandon rhythm control is made (i.e. AF is accepted and declared permanent), antiarrhythmic therapy should be discontinued. 

When selecting maintenance antiarrhythmic agents, the patient’s comorbidities, such as renal or hepatic dysfunction, lung disease, HF, or hypertrophic cardiomyopathy should be taken into account.1  Amongst the recommended agents are dofetilide, dronedarone, flecainide, propafenone, and sotalol.  Amiodarone is usually a second-line option due to its pulmonary, hepatic, and endocrine toxicities.  For patients with pre-excitation syndromes, radiofrequency catheter ablation and permanent ventricular pacing are recommended prior to initiation of antiarrhythmic therapy. 

Table 8 provides usual dosing recommendations for antiarrhythmic agents for both cardioversion and maintenance of sinus rhythm, and Table 9 summarizes recommended maintenance agents based on patient comorbidities.

Table 8. Usual dosing of antiarrhythmic drugs.1

Drug (Brand name)

Pharmacologic Cardioversion Dose

Maintenance Dose


Amiodarone (Cordarone)

• PO: 600 to 800 mg daily to a total load of 10 g

• IV: 150 mg over 10 minutes, then 1 mg/min x 6 hours, then 0.5 mg/min x 18 hours or change to oral dosing

• 100 to 200 mg PO once daily

• Broad-spectrum CYP and PGP inhibitor; exercise caution—many drug interactions1

• Avoid in pulmonary disease

• Contraindicated in patients with second or third degree heart block, sinoatrial node dysfunction, or iodine allergy4

Dofetilide (Tikosyn)

• PO: adjust according to CrCl in mL/min:  

  • > 60: 500 mcg twice daily
  • 40 to 60: 250 mcg twice daily
  • 20 to 40: 125 mcg twice daily
  •  < 20: not recommended

• 125 to 500 mcg PO every 12 hours

• Must be initiated in hospital (REMS program)1

• Prolongs QT interval

• CYP3A substrate; discontinue amiodarone x 3 months prior to initiation

• Contraindicated in congenital or acquired long QT syndromes

• Do not combine with trimethoprim, ketoconazole, verapamil, cimetidine, other CYP3A inhibitors, or HCTZ (↑ plasma levels)5

Disopyramide (Norpace)

• Not used

• IR: 100 to 200 mg PO every 6 hours

• ER: 200 to 400 mg PO every 12 hours

• CYP3A4 substrate1

• Prolongs QT interval

• Use with caution in HF

• Contraindicated in second or third degree heart block, congenital long QT syndromes6

Dronedarone (Multaq)

• Not used

• 400 mg PO every 12 hours

• CYP3A substrate; CYP3A, 2D6, and PGP inhibitor1

• Prolongs QT interval

• Contraindicated in pregnancy, decompensated or recently decompensated HF requiring hospitalization, NYHA class IV HF, second or third degree heart block, permanent AF, HR < 50 bpm, concomitant use of strong CYP3A inhibitors, concomitant use of other QT prolonging medications or herbal products, previous liver or lung toxicity related to amiodarone, QT interval ≥ 500 ms or PR interval > 280 ms, severe hepatic impairment, or hypersensitivity to dronedarone or excipients7

• Contraindicated in severe hepatic impairment

• Pregnancy category X

Flecainide (Tambocor)

• PO: 200 to 300 mg x 1 dose (“pill-in-the-pocket”)

• Use as needed to terminate episodes of paroxysmal AF; administer beta blocker or non-dihydropyridine CCB ≥ 30 minutes beforehand

• 50 to 200 mg PO every 12 hours

• Use with caution in HF, CAD1

• Contraindicated in patients with second or third degree AV block or right bundle branch block8

• Hepatic metabolism and renal excretion; caution in renal or hepatic impairment

Ibutilide (Corvert)

• IV: 1 mg over 10 minutes, may repeat once if necessary

• Not used

• Adjust dose for patients <60 kg: 0.01 mg/kg1

Propafenone (Rhythmol)

• PO: 450 to 600 mg x 1 dose (“pill-in-the-pocket”)

• Use as needed to terminate episodes of paroxysmal AF; administer beta blocker or non-dihydropyridine CCB ≥ 30 minutes beforehand

• IR: 150 to 300 mg PO every 8 hours

• ER: 225 to 425 mg PO every 12 hours

• Contraindicated in patients with cardiogenic shock or marked hypotension, sick sinus syndrome or AV block in the absence of a pacemaker, Brugada syndrome, bradycardia, electrolyte disturbances, HF, severe COPD or bronchospastic disorders9

• PGP and CYP2C9 inhibitor1

Sotalol (Betapace)

• Not used

• 40 to 160 mg PO every 12 hours

• Adjust dose in renal dysfunction1

• Prolongs QT interval

• Contraindicated in sinus bradycardia, second or third degree heart block, bronchial asthma, congenital or acquired long QT syndromes, decompensated HF, cardiogenic shock, or hypersensitivity to sotalol10

Abbreviations: AF, atrial fibrillation; AV, atrioventricular; CAD, coronary artery disease; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; ER, extended-release; HCTZ, hydrochlorothiazide; HF, heart failure; HR, heart rate; IR, immediate-release; IV, intravenously; ms, milliseconds; NYHA, New York Heart Association; PGP, P-glycoprotein; PO, orally

Table 9.  Recommended agents for maintenance of sinus rhythm.1

Patient Population

Recommended Agents


No structural heart disease

• Dofetilide

• Dronedarone

• Flecainide

• Propafenone

• Sotalol

• Amiodarone as second-line option

Left ventricular wall hypertrophy with wall thickness >1.5 cm

• Amiodarone

• Dronedarone

• Avoid flecainide, propafenone, dofetilide, sotalol

Coronary artery disease

• Dofetilide

• Dronedarone

• Sotalol

• Amiodarone as second-line option

Heart failure

• Amiodarone

• Dofetilide

• Avoid dronedarone in NYHA class III and IV HF

Previous myocardial infarction

• Amiodarone

• Dofetilide

• Avoid flecainide, propafenone

Athletes with paroxysmal or persistent AF

• Radiofrequency catheter ablation

• “Pill in the pocket” approach



• Administer beta blocker or non-dihydropyridine CCB ≥ 30 minutes before antiarrhythmic agent

Hypertrophic cardiomyopathy

• Amiodarone

• Disopyramide

• Combine disopyramide with beta blocker or non-dihydropyridine CCB

Pre-excitation syndromes

• Ibutilide

• Procainamide

• Radiofrequency catheter ablation

• Select  post-ablation agent after consultation with electrophysiologist.

Abbreviations: CCB, calcium channel blocker; HF, heart failure; NYHA, New York Heart Association

Catheter ablation of AF with ventricular pacemaker implantation may be considered for symptomatic  patients refractory to or intolerant of antiarrhythmic therapies (Class I, LOE A recommendation).1  Due to its association with torsades des pointes, the Vaughan-Williams Class Ia agent quinidine has been relegated to a second- or third-line option for use in patients who have failed or have contraindications to other agents. 


The 2014 AF guidelines have been revamped to place an increased emphasis on shared physician and patient decision making and consideration of individual patient preferences, risks, and benefits when initiating any treatments for AF.  Though the growing body of medical evidence has resulted in several substantial changes to the guidelines, there are also many areas for future research.  Optimal rate control targets have yet to be determined, and more research needs to be conducted with the newer oral anticoagulants in the elderly population and perioperative setting.  There is also a need for continued investigation into the relationship between AF and thromboembolic risk, and the mechanisms underlying the events that incite and propagate AF.


1.    January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-e267.

2.    Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2011;57(11):e101-e198.

3.     Wann LS, Curtis AB, Ellenbogen KA, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation. 2013;127(18):1916-1926.

4.    Cordarone [package insert].  Philadelphia, PA: Wyeth Pharmaceuticals, Inc.; 2015.

5.    Tikosyn [package insert]. New York, NY: Pfizer; 2013.

6.    Norpace [package insert].  New York, NY: G.D. Searle LLC; 2006.

7.    Multaq [package insert].  Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2014.

8.    Tambocor [package insert]. Northridge, CA: 3M Pharmaceuticals; 2006.

9.    Propafenone HCl [package insert].  Corona, CA: Watson Laboratories, Inc.; 2013.

10. Betapace [package insert].  Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2011.

Prepared by:
Kristin Kaneshiro PharmD
PGY2 Drug Information Resident
UIC Drug Information Group
University of Illinois at Chicago
November 2015

The information presented is current as of October 1, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What recent evidence describes the comparative safety and efficacy of bivalirudin and heparins in patients undergoing percutaneous coronary intervention?


Percutaneous coronary intervention (PCI) is a common method of revascularization in patients with acute coronary syndromes (ACS) such as ST-elevation myocardial infarction (STEMI), non-ST ACS (NSTE-ACS), and unstable angina (UA), as well as patients with severe coronary artery disease undergoing elective revascularization.1,2 Approximately 1 million patients per year in the U.S. undergo PCI, which has a success rate exceeding 95% in relieving angina symptoms and decreasing vessel obstruction to less than 50%. However, PCI is associated with rare but serious risks of bleeding, myocardial infarction (MI), and stroke. Due to the high risk of mortality associated with the latter two thrombotic complications, guidelines recommend the use of parenteral anticoagulation and antiplatelet therapy during PCI. 3-5

Among anticoagulant options, current guidelines for PCI in all clinical situations recommend the use of intravenous (IV) bivalirudin or heparins, including unfractionated heparin (UFH) and enoxaparin.3-5 Provisional (also termed “bailout”) use of a glycoprotein IIb/IIIa inhibitor (GPI; these include eptifibatide, tirofiban, and abciximab), predominantly in addition to heparin, may be utilized to prevent the development of thrombus or obstruction of flow in selected high-risk patients, such as those with large thrombus burden or inadequate loading with P2Y12 antiplatelet agents. Guidelines endorse preferential use of bivalirudin over UFH with GPI in patients who have a history of heparin-induced thrombocytopenia (HIT) or who are at high risk of bleeding (eg, patients ≥75 years of age).

Despite agreement among these guidelines, a variety of clinical trials continue to be performed that evaluate the comparative safety and efficacy of bivalirudin and heparin. This review summarizes findings in recent publications that add to the literature comparing bivalirudin and heparins in the setting of PCI.


Several recent meta-analyses were performed to assess the relative safety and efficacy of bivalirudin and heparins during PCI, each in specific situations of GPI use.6-9 These have compared bivalirudin alone to heparins with or without GPI use, both drugs with variable GPI use, and both drugs with similar GPI use.

A 2015 meta-analysis by Navarese and colleagues examined 13 clinical trials (n=24,605) that compared bivalirudin alone to heparins administered with and without routine use of GPIs in patients undergoing PCI for ACS.6 All but 2 trials used UFH exclusively. The primary outcome of 30-day mortality did not significantly differ between groups, regardless of whether GPIs were coadministered with heparins. Bivalirudin was associated with reduced risk of 30-day major bleeding, but only when GPIs were used routinely with heparin (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.45 to 0.6). However, this benefit to bivalirudin was offset by its increased risk of 30-day stent thrombosis when compared to heparin with routine GPI use (OR, 1.67; 95% CI, 1.13 to 2.45). This increased risk was not significant when bivalirudin was compared to heparin when GPIs were administered only provisionally (OR, 2.08; 95% CI, 0.35 to 12.32). Risk for acute stent thrombosis was significantly increased roughly 4.5-fold with bivalirudin compared to heparin, whether GPIs were coadministered with heparin or not.

A similar meta-analysis by Huang and colleagues of 20 clinical trials (n=33,622) compared bivalirudin to heparins with or without similar use of GPIs between agents.7 The authors found that when GPI use was not balanced, major bleeding was lower with bivalirudin (relative risk [RR], 0.67; 95% CI, 0.54 to 0.83), although mortality did not significantly differ. When GPI use was comparable between groups, no significant difference was detected in major bleeding or mortality. In trials with no GPI use in either group, major bleeding remained similar.

Adding to findings by Navarese and colleagues, a meta-analysis of 17 clinical trials (n=38,096) compared bivalirudin to UFH or low molecular weight heparin with planned or provisional use of GPIs in both groups.8 All but 3 trials utilized UFH exclusively. No significant differences were found between groups in the composite outcome of death, myocardial infarction or reinfarction, and revascularization; these results were consistent in subgroup analyses based on anticoagulant regimens, clinical setting (STEMI, NSTE-ACS, or elective PCI), or duration of follow up, which ranged from 1 to 12 months. An increased risk of stent thrombosis with bivalirudin was only seen in a subgroup analysis comparing bivalirudin to heparin when GPIs were used provisionally with both anticoagulants (RR, 3.09; 95% CI, 1.58 to 6.04). Similar to findings by Navarese, bivalirudin was associated with significantly lower risks of major bleeding (RR, 0.66; 95% CI, 0.54 to 0.81) and need for transfusion (RR, 0.72; 95% CI, 0.56 to 0.91). However, further analyses found the risk of major bleeding with bivalirudin increased significantly when the frequency of concomitant GPI use increased.

To address the question of comparative efficacy and safety when accounting for concomitant GPI use, Bavry and colleagues analyzed 15 clinical trials (n=25,824) in which the use of GPIs was similar between bivalirudin and heparins during PCI for ACS and elective purposes.9 All but 1 trial used UFH exclusively. Compared to heparins, bivalirudin was associated with an increase in overall hazard of stent thrombosis (OR, 1.49; 95% CI, 1.15 to 1.92) and acute stent thrombosis (OR, 2.00; 95% CI, 1.23 to 3.23). This increased risk was driven by trials in patients with ACS, and was not statistically significant when trials of patients undergoing elective PCI were analyzed independently. However, there were similar hazards of MI, major adverse cardiovascular events (MACE), and all-cause mortality between groups. Like previous findings, bivalirudin was associated with significantly lower hazard for major bleeding (OR, 0.80; 95% CI, 0.70 to 0.92 ), although this was primarily driven by trials using higher UFH doses (≥100 units/kg). Subgroup analysis of trials utilizing UFH doses ≤75 units/kg showed no significant difference in major bleeding.

Proposed explanations for the increased risk of stent thrombosis with bivalirudin include its short half-life, which could lead to a gap in therapeutic antithrombotic coverage when patients are transitioned to a P2Y12 inhibitor.6 Additionally, UFH can be easily monitored and titrated to achieve measurable therapeutic concentrations.9 The lower risk of major bleeding with bivalirudin may be associated with concomitant use of GPIs in addition to heparins, rather than intrinsic differences between the individual agents.

Clinical Trials

Two new analyses offer additional, though not definitive insight to these meta-analyses.10,11 One trial randomized patients undergoing PCI for ACS to receive UFH or bivalirudin, with further randomization of bivalirudin patients to receive or not receive a post-PCI infusion for an additional 4 to 6 hours.10 The use of GPIs was permitted in both groups and was similar. There were no significant differences in MACE or net adverse clinical events between groups. However, the risk of death from any cause was lower with bivalirudin (RR, 0.71; 95% CI, 0.51 to 0.99), which was primarily driven by lower rates of cardiovascular and cardiac death. Like recent meta-analyses, bivalirudin was associated with a higher risk of stent thrombosis (RR, 1.71; 95% CI, 1.00 to 2.93) and a lower risk of any bleeding (RR, 0.79; 95% CI, 0.69 to 0.91) or Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding (RR, 0.55; 95% CI, 0.39 to 0.78). Interestingly, these findings on bleeding outcomes occurred when UFH doses were 100 units/kg and lower; this contrasts findings by Bavry, where bleeding was reduced with bivalirudin only when UFH doses exceeded 100 units/kg. The addition of a post-PCI bivalirudin infusion did not significantly decrease the need for urgent revascularization, stent thrombosis, or net adverse clinical events, although BARC type 3 or 5 bleeding was significantly reduced (RR, 0.53; 95% CI, 0.30 to 0.96).

Lastly, a single-center prospective observational study was performed to compare bivalirudin to UFH, both without GPI use, in patients who underwent PCI.11 Because risk factors for bleeding (eg, peripheral vascular disease, renal disease, prior stroke) could have influenced physicians’ decisions to select either agent, the authors performed analyses in unmatched and matched cohorts. Overall, there were no significant differences in mortality, MI, vessel closure, repeat PCI, cerebrovascular accident, or bleeding between bivalirudin and UFH in either cohort. 


Overall, findings of recent meta-analyses do not appear to definitively indicate any overall differences in mortality regardless of the additional use of GPI with either bivalirudin or heparins during PCI. However, bivalirudin may be associated with comparatively lower bleeding risk, which may be attenuated when the use of GPIs is similar between agents and when doses of UFH are lower. This benefit is contrasted by the potentially increased risk of stent thrombosis with bivalirudin, which was demonstrated in various settings of concomitant GPI use. Clinicians who are faced with decisions of using bivalirudin or heparins in PCI should consider consequences of factors that have shown to modify the effects of these agents, including concomitant use of GPIs, dose of heparin, and patients’ risks for stent thrombosis and bleeding.


1.         Antman EM, Loscalzo J. Ischemic heart disease. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015.

2.         Faxon DP, Bhatt DL. Percutaneous coronary interventions and other interventional procedures. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: Mc-Graw-Hill; 2012. October 09, 2015.

3.         Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-e426.

4.         O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-e425.

5.         Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574-e651.

6.         Navarese EP, Schulze V, Andreotti F, et al. Comprehensive meta-analysis of safety and efficacy of bivalirudin versus heparin with or without routine glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndrome. JACC Cardiovasc Interv. 2015;8(1 Pt B):201-213.

7.         Huang FY, Huang BT, Peng Y, et al. Heparin is not inferior to bivalirudin in percutaneous coronary intervention-focusing on the effect of hlycoprotein IIb/IIIa inhibitor use: a meta-analysis. Angiology. 2015;66(9):845-855.

8.         Li J, Yu S, Qian D, He Y, Jin J. Bivalirudin anticoagulant therapy with or without platelet glycoprotein IIb/IIIa inhibitors during transcatheter coronary interventional procedures: a meta-analysis. Medicine (Baltimore). 2015;94(32):e1067.

9.         Bavry AA, Elgendy IY, Mahmoud A, Jadhav MP, Huo T. Critical appraisal of bivalirudin versus heparin for percutaneous coronary intervention: a meta-analysis of randomized trials. PLoS One. 2015;10(5):e0127832.

10.       Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med. 2015;373(11):997-1009.

11.       Abtahian F, Waldo S, Jang IK. Comparison of heparin and bivalirudin in patients undergoing percutaneous coronary intervention without use of glycoprotein IIb/IIIa inhibitors. Catheter Cardiovasc Interv. 2015;86(3):390-396.

Prepared by:
Kristin Progar, PharmD
PGY1 Pharmacy Practice Resident
University of Illinois at Chicago
November 2015

The information presented is current as of September 16, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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Can the intravenous formulation of vitamin K be administered orally?


Phytonadione (vitamin K1) is a water-insoluble vitamin that is indicated for the treatment of various coagulation disorders due to a lack of or a decrease in factors II, VII, IX, and X.1 Reversal of anticoagulation effects from vitamin K antagonists (VKAs) such as warfarin is one of the most common uses for this medication.  Vitamin K activates the liver to produce factors II, VII, IX, and X which are typically inhibited by warfarin.1,2  According to the product’s labeling, vitamin K solution for injection can be administered intravenously, intramuscularly, and subcutaneously with higher preference for the subcutaneous route due to the risk of anaphylaxis with the intravenous route.1,3 However, trials have shown that subcutaneous administration of vitamin K does not provide consistent correction to INR when reversing warfarin effects, and administration via the intramuscular route could result in hematoma.3,4 Therefore, the intravenous route is the preferred route for administration of injectable vitamin K in clinical practice. Intravenous vitamin K tends to have a more rapid onset at about 6 to 8 hours post administration compared to oral vitamin K. Both routes (intravenous and oral) will achieve the same anticoagulant reversal effects at 24 to 48 hours.3,5  Over-utilization of vitamin K could potentially result in thromboembolism when reversing warfarin effects or refractoriness to warfarin at the restart of therapy, and thus, careful consideration must be given to whether vitamin K even needs to be ordered or prescribed.1,3


There are a number of guidelines available regarding the management of an elevated INR in patients receiving VKAs. The American College of Chest Physicians (ACCP) updated their recommendations on the use of vitamin K in 2012. 6 The guideline recommends vitamin K in the following situations:

  • INR > 4.5 and <10.0 and NO active bleeding: vitamin K is not recommended.
  • INR ≥ 10.0 and NO active bleeding: give oral vitamin K.
    • The guideline did not provide specific dosing for oral vitamin K but the studies discussed in the guideline used oral doses ranging between 2 mg and 2.5 mg.
  • Major bleeding: administer four-factor prothrombin complex concentrate and intravenous vitamin K 5 mg to 10 mg.

Guidelines are also available from the British Committee for Standards in Haematology (BCSH) and the Australasian Society of Thrombosis and Haemostasis (ASTH). Similar to the ACCP recommendations, both guidelines discourage providers from administering vitamin K to patients with single digit INR levels and no active bleeding.4,5 The ASTH guideline also mentions that the intravenous preparation of vitamin K can be administered orally.5

Preparation and oral administration of injectable vitamin K

Injectable vitamin K can be administered orally either undiluted or as a compounded solution appropriate for oral administration. Table 1 provides the summary of key information and considerations that is discussed throughout the article.

Table 1. Key information on stability and consideration for administering injectable vitamin K orally.

Preparation method


Key consideration

Undiluted injectable vitamin K administered orally

  • Stable for 30 days at both room and refrigerated temperatures.
  • Might necessitate the use of a filter needle for withdrawal of vitamin K from the vial.
  • Requires storage in amber bottles/syringes.
  • Orange juice can mask its unpleasant taste.

Compounded oral solution utilizing injectable vitamin K

  • Stable for 6 months when refrigerated (4-6⁰C).
  • USP 795 recommends storage for 14 days at refrigerated temperatures for aqueous formulations.
  • Additional ingredients needed: Cremophor EL and water for injection.
  • Requires storage in amber bottles/syringes.
  • Cremophor EL has been associated with anaphylactoid reactions, changes in blood viscosity, and erythrocyte aggregation.

Direct administration of injectable vitamin K by oral route

Injectable vitamin K can be directly administered through the oral route. One study recommended using an insulin syringe with a filter needle to withdraw vitamin K from the vial.7 The taste of undiluted vitamin K can be unpleasant, and mixing it with orange juice can mask this taste.8

Wong and colleagues evaluated the stability of injectable vitamin K 2 mg/mL repackaged as 0.75 mL into amber glass and white polyethylene bottles for oral administration.9 The solutions were stored at room temperatures from 25 to 32⁰C and refrigerated temperatures of 4 to 8⁰C for 30 days. HPLC analysis showed that less than 10% of vitamin K was lost when stored in amber bottles for both temperatures. On the other hand, vitamin K stored in white plastic bottles experienced greater than 10% medication loss at 40 hours.9  Vitamin K is light sensitive and needs to be stored in amber containers.

Literature review

The efficacy of the intravenous preparation of vitamin K administered orally has been evaluated in four studies.

In 1998, Crowther and colleagues explored whether 1 mg of oral vitamin K would reverse INR.7 The study was completed at two tertiary teaching hospitals. Sixty-two patients with INR ranging between 4.5 and 10 enrolled into the study. Mean INR at presentation was 5.79 (range 4.5 to 9.5). At the time of the study, the tablet formulation of vitamin K was not available in Canada, and thus, the protocol required use of vitamin K injection.  A dose of 1 mg vitamin K was drawn up using an insulin syringe with a filter needle and then administered orally. The mean INR was at 2.86 (range 1.3 – 8.9) when levels were measured 16 hours post-dose, and 2.2 on day 2 and 2.14 on day 3. Patients did not experience any adverse events or bleeding complications.

The study by Crowther and colleagues from 2000 focused on the efficacy of low dose oral vitamin K for reversal of INR.10 The study included patients who presented with INRs between 4.5 and 10.0. Eighty-nine participants were randomized to receive either placebo (n=44) or intravenous vitamin K 1 mg given orally (n=45). Fifty-six percent of patients who received vitamin K and 20% of people in the placebo group had INRs between 1.8 and 3.2 (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.07 to 0.57, p=0.001) the day following vitamin K administration. Overall, there was a lower rate of bleeding reported with vitamin K as compared to placebo (OR 0.87, 95% CI 0.019-0.999, p=0.0499). Two thrombotic events were also discovered upon follow-up: a myocardial infarction 3 days following administration of vitamin K and a DVT 22 days following placebo. The authors concluded that low dose intravenous vitamin K administered orally is effective for reducing INR values of 4.5 to 10.0.

In 2002, Crowther conducted another trial that explored whether oral vitamin K was more effective than subcutaneous vitamin K.11 Fifty-one patients were included in this trial. The study was conducted at two teaching hospitals in Ontario, Canada and Varese, Italy. The inclusion and exclusion criteria were identical to those used in the above mentioned studies. Patients were randomly assigned to receive 1 mg of vitamin K either orally or subcutaneously.11 In Canada, injectable vitamin K was used for both oral and subcutaneous administration; and in Italy, patients were given a 1 mg/ml oral solution of vitamin K. The group of 26 patients randomized to receive oral vitamin K had an initial mean INR of 5.8 and the 25 patients receiving subcutaneous vitamin K had a mean INR of 6.2. Following vitamin K administration, 58% of patients receiving oral vitamin K and 24% of patients receiving subcutaneous vitamin K had INRs between 1.8 and 3.2 (OR 4.32, 95% CI 1.13 - 17.44, p = 0.015). Mean INR values were higher in the subcutaneous group compared to the oral group on the second and third days (p value not reported). Upon follow-up, there were no episodes of thromboembolism or bleeding reported. The authors concluded that oral vitamin K might be more effective than subcutaneous vitamin K in reestablishing therapeutic INR in patients presenting with INRs between 4.5 and 10.0.

A retrospective analysis by Baker and colleagues in 2006 employed a protocol in which intravenous vitamin K was administered orally according to the following regimen: for an INR > 8 but < 12 patients received 2.5 mg, and 5 mg was administered for an INR > 12.12 Vitamin K was prepared as a 2 mg/mL liquid by the pharmacy. INR measurements were repeated the morning following vitamin K administration. The analysis included 223 patients, who were divided into 3 groups based on initial INR: INR 8.0 to 11.9 (n=166), 12.0 to 20.0 (n=36), and >20.0 (n=21).

  • On presentation, median INR for the first group was 9.2 and fell to 3.8 roughly 14 hours following the administration of vitamin K. About 77% of patients had measured INRs between 2.0 and 4.9 on day 1, and 12 patients were subtherapeutic with INRs between 1.5 to 1.9.
  • The 36 patients presenting with INRs between 12.0 and 20.0 experienced decreases in INR to a median of 3.0 on day 1. About 52% of patients had INRs between 2.0 and 4.9, 17% were subtherapeutic with INR <2, and 9% of patients had INR values that remained between 8.0 and 11.9 on day 1.
  • In the third group (INR readings > 20), 44% had measured INR values between 2.0 and 4.9, 29% had INRs <1.9, and 10% of patients had INRs that remained between 8.0 and 11.9 on day 1 following vitamin K administration.

The authors concluded that the oral administration of intravenous vitamin K provides safe and predictable reversal of anticoagulation.

Compounding of oral solution from injectable vitamin K

Injectable vitamin K can also be compounded into a solution for oral use.9,13,14 Sewell and colleagues studied stability of vitamin K prepared with Cremophor EL for oral administration.13 Cremophor EL is a mixture of polyethoxylated castor oils that serves as a solubilizer and stabilizer for compounds. The recipe consists of combining 100 mg of injectable vitamin K with 2 g of Cremophor EL. The mixture is further diluted with water for injection to 100 ml. The solution needs to be sparged with nitrogen for three minutes and then passed through a 0.2 µm filter. The final solution is transferred to 1-mL amber syringes for oral administration. The authors concluded that the solution has a shelf-life of 6 months when stored at 4 to 6⁰C since the HPLC assay and sterility testing showed no loss of vitamin K and no microbial contamination for 25 weeks.

Cremophor EL has been previously associated with various undesirable reactions such as anaphylactoid reactions, changes in blood viscosity, and erythrocyte aggregation.13 Therefore, the study by Dandonneau and colleagues substituted simple syrup or water for injection  for Cremophor EL.14 The authors concluded that the suspension prepared with syrup can be stored for 111 days and the suspension with water for injection for 104 days at room temperature as long as both suspensions are packaged within amber bottles. This Canadian study was published in French, and the original reference is not catalogued in PubMed. Thus, the results of this study need to be carefully interpreted since no access to the original article is available, and methods of the study cannot be properly evaluated.

USP 795 guidelines

The United States Pharmacopeia (USP) recommendations for nonsterile compounding, USP 795, include statements regarding beyond-use dating.15 The USP 795 guideline states that oral formulations containing water should have beyond-use dating of 14 days at refrigerated temperatures. If oral solutions do not contain water, the beyond-use dating can be extended to 6 months or to the expiration date of individual ingredients, whichever is earlier. These recommendations need to be considered when assigning beyond-use dating for compounded formulations.


Injectable vitamin K can be given orally using the undiluted injectable formulation or compounded into an oral solution. Previous studies have shown that intravenous vitamin K is well tolerated when administered orally and works quickly to correct supratherapeutic INRs. Stability studies have been performed for undiluted and compounded vitamin K solutions but USP 795 recommendations need to be taken into consideration when deciding on appropriate beyond-use dating.


1.         Phytonadione injectable [package insert]. International Medication Systems. El Monte, CA. September 2009., September 28, 2015.

2.         Warfarin sodium [package insert]. Amneal Pharmaceuticals. Glasgow, KY. January 2012., September 28, 2015.

3.         Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S12-S21.

4.         Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol. 2011;154(3):311-324.

5.         Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS. An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198(4):198-199.

6.         Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-184S.

7.         Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost. 1998;79(6):1116-1118.

8.         Wilson SE, Watson HG, Crowther MA. Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review. CMAJ. 2004;170(5):821-824.

9.         Phytonadione. In: Trissel LA, ed. Trissel's Stability of Compounded Formulations. 5th ed. Washington, DC: American Pharmacists Association; 2012:391-392.

10.       Crowther MA, Julian J, McCarty D, et al. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet. 2000;356(9241):1551-1553.

11.       Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med. 2002;137(4):251-254.

12.       Baker P, Gleghorn A, Tripp T, Paddon K, Eagleton H, Keeling D. Reversal of asymptomatic over-anticoagulation by orally administered vitamin K. Br J Haematol. 2006;133(3):331-336.

13.       Sewell GJ, Palmer AJ. The formulation and stability of a unit-dose oral vitamin K1 preparation. J Clin Pharm Ther. 1988;13(1):73-76.

14.       Vanier M, Ngo T. Reversal of overanticoagulation with vitamin K1: a plea for oral administration. Can J Hosp Pharm. 2006;59:125-135.

15.       <795> Pharmaceutical compounding - nonsterile preparations. Revision Bulletin. January 1, 2014:1-7. Accessed September 28, 2015.

November 2015

The information presented is current as October 14, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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