Bleed

International Normalized Ratio (INR):

The optimal anticoagulation level based with the lowest mortality is an INR of 2.2-2.3 as for every unit increase above 2.5 or below 2, the mortality increased by 2.2 (BJM 2002;325:1073-5). A 66% rate of pt being in the therapeutic range at one time is considered good by most major studies.

• For pt’s with DVT, ideal long-term oral anticoagulation with minimal complications may require dose adjustment to achieve an INR of between 2-2.5 (Curr Control Trials Cardiovasc Med 2004;5:1).

• Even for those >85 yo, the target INR for pt’s anticoagulated with warfarin for atrial fibrillation should be 2.5 (Ann Intern Med. 2004;141:745-752) (the risks of intracranial hemorrhage are not reduced with low-dose warfarin).

• A Dutch study on 4202 patients who were followed for 7788 patient-years found that the optimal intensity of anticoagulation for patients with mechanical heart valve prostheses was an INR of 2.5 to 2.9. For those with atrial fibrillation, the value was 3.0 to 3.4, and following myocardial infarction, the optimal INR was 3.5 to 3.9 (Arch Intern Med 2009;169:1203-1209).

Optimal Level of Oral Anticoagulant Therapy: (Arch Intern Med. 2009;169(13):1203-1209)

The lowest incidence of these adverse events occurred at international normalized ratios (INRs) of:

2.5 to 2.9 for patients with heart valve prostheses.

3.0 to 3.4 for those with atrial fibrillation.

3.5 to 3.9 in patients after MI. Note: These numbers are not generally the standard of care in 2009, see below.

INR Monitoring: Daily until within therapeutic range for at least 2 consecutive days if hospitalized (best). If an outpatient then 2-3X/ wk X 1-2wks until stable, then weekly X1-2 wks, if stable go to q2wks, then check q4wks if stable. If INR therapeutic for 8-10 weeks consecutively may increase the interval up to 6wks if pt’s with high compliance, increase frequency if illness, medication changes, h/o highly variable INR levels. If INR outside of taget range within 1 point, re-ck in 1-2wks. If >1 point out of range, adjust then re-ck in <1wk.

• Of 1019 pt’s presenting to two EDs who were taking warfarin, the INR was at a nontherapeutic level in 72%, subtherapeutic (<2) in 43% and supratherapeutic (>3) in 29% (Ann Emerg Med 2006;48:182-9)….. may argue for more liberal INR testing in pt’s who do not report a recent “in range” result.

• Extreme anticoagulation intensity significantly impacts the health of the elderly population; and improved control could significantly reduce the incidence of serious thromboembolic and hemorrhagic events (Chest 2007;131:1508-1515)…..on average, pt’s receiving therapy with oral anticoagulants in the community are in the therapeutic range only 55% of the time.

• INR testing intervals of 4 weeks or less are typically recommended for patients on long-term warfarin therapy but research suggests that less frequent testing may be safe for patients with stable INR values (Blood 2009;114:952-956)…..On multivariate analysis, age older than 70 years, absence of diabetes, absence of heart failure, and not receiving estrogen therapy were significant predictors of stable INR status with odds ratios of 1.54, 1.87, 1.43, and 1.32, respectively.

• Monitoring at 3-month intervals might be feasible for some stable Warfarin patients according to a study on 250 patients whose maintenance warfarin dose had been stable for at least 6 months (Ann Intern Med 2011;155:653)……Clinical outcomes (e.g., major bleeding, thromboembolism, death) did not differ between groups, although the study was not adequately powered to detect small differences in these outcomes….Eight patients in the 12-week group had extreme INRs and required unblinding……The authors estimate that a third of patients in their large anticoagulation clinic have stable maintenance doses of warfarin and could be eligible for longer-interval INR evaluations.

When to Adjust: Data suggest that warfarin dose shouldn’t be changed unless INR is 1.7 or 3.3 (when the target is 2.0–3.0) (J Thromb Haemost 2009;7:94)…..On average, clinicians used INR thresholds of 1.8 and 3.2 to trigger increases and decreases, respectively, in warfarin doses; However, statistical modeling indicated that, for optimal management, warfarin doses should have been changed when INRs were 1.7 or 3.3.

Fluctuating INR’s:

• Some pt’s on warfarin are often told to avoid foods high in vitamin K, but a diet too low in vitamin K makes it more difficult to manage INR because any change in dietary vitamin K can translate into big fluctuations in INR…..Instead, advise patients to aim for a consistent diet as this is usually enough to maintain a stable INR.

• A small percentage of warfarin pt’s have unpredictable fluctuations of clotting time or INR despite careful monitoring and dose adjustments. Some of the variation may relate to testing at different times of day following the dose of warfarin. Whenever it is practical to do so, patients should have their blood drawn at the same time of day and in the same laboratory.

• Some experts are trying low-dose Vit-K1 (100-200 mcg/day) (phytonadione, phylloquinone)(less evidence for using Vit-K2 = menatetrenone, menaquinone) supplements to stabilize the effect of warfarin in certain pt’s. This is what is more than most multivitamins (RDA of 80 mcg) and many stores sell this strength as a “stand-alone” product. Many patients will need a higher warfarin dose to balance the extra vit K.

• A consistent dose of Vit-K will make the pt less sensitive to changes in dietary Vit-K and therefore, have less INR fluctuations (Use of low-dose vitamin K to stabilize INR. Prescriber’s Letter 2009;25(6):250601). Pt’s with unstable control have a poorer dietary intake of vitamin K compared to pt’s with stable control of anticoagulation (Thromb Haemost 2005;93:872-5).

• Stable anticoagulation control occurred in significantly more pt’s taking Vit-K supplementation (150 mcg qd) than in pt’s taking placebo (54% vs 21%, NNT = 3)(Blood 2007;109:2419-23). If pt has trouble remembering alternating doses, try and have them take the even dose (ex 2mg) on even number days and the odd dose (ex 3mg) on odd days.

• A Swedish registry program resulted in a mean time in therapeutic range (TTR) of more than 75% (Eur Heart J 2011;32:2282)…..In 15,601 patients with an expanded target INR of 1.8–3.2, the mean TTR increased to 88.4%…..Mean warfarin dose fell with increasing age from 43 mg/week in patients aged 41–50 to 24 mg/week in those aged 81–90 (P<0.001)….the risk for major bleeding was 2.6% per treatment year, and the risk for thrombosis was 1.7% per treatment year overall and 1.4% in patients with AF…..Incidence of major bleeding increased significantly with increasing age (P<0.001).

How Often Must INR Be Checked in Patients Taking Warfarin in Stable Doses? Consider monitoring up to every 12 weeks for patients with a stable INR and no change in warfarin dose in at least 3 months. Monitor more often if there’s a change in dose, other meds, or diet. A randomized trial demonstrates no significant difference in time in therapeutic range between patients monitored every 4 weeks and those monitored every 12 weeks (Ann Intern Med 2011;155:653)….During 12 months of treatment, mean time in therapeutic range was 74% in the 4-week group and 72% in the 12-week group, a nonsignificant difference…….According to current guidelines, warfarin recipients should undergo international normalized ratio (INR) testing every 4 weeks……These results demonstrate that the frequency of monitoring warfarin’s effects can safely be reduced in patients who maintain therapeutic INRs on stable doses, which would substantially mitigate the inconvenience and cost associated with warfarin therapy.

Dosing Adjustment Nomogram for Maintenance Therapy:

GOAL INR 2.0 – 3.0		GOAL INR 2.5 – 3.5
< 2.0	• reload x 0-1 • increase by 5-15%	< 2.5
2.0 – 3.0	• no change	2.5 – 3.5
3.1 – 3.5	• decrease by 0-15%	3.6 – 4.0
3.6 – 4.0	• hold 0-1 dose • decrease by 5-15%	4.1 – 4.5
> 4.0	• hold until therapeutic • +/- minidose vitamin K • decrease by 10-20%	> 4.5

Frequency of Monitoring:

Initiation Therapy:

Flexible initiation method: Daily through day 4, then within 3-5 days.

Average daily dosing method: Within 3-5 days until INR > lower limit of therapeutic range, then within 1 week .

After hospital discharge: If stable: Within 3-5 days. If unstable: Within 1-3 days.

First month of therapy: At least weekly.

Maintenance Therapy:

Dose held today in pt with significant over anticoagulation: In 1 – 2 days.

Dosage change today: Within 1 – 2 weeks.

Dosage change < 2 weeks ago: Within 2 – 4 weeks.

Routine follow-up of medically stable & reliable pt’s: Every 4 – 6 weeks.

Routine follow-up of medically unstable or unreliable pt’s: Every 1 – 2 weeks.

Point of Care Testing: The CoaguChek was found to have a plasma INR agreement of +0.4 in 82% and the ProTime 3 in 39% (Mayo Clin Proc 2005;80:181-86). (CoaguChek meter costs $950, reagent strips cost $4.67). Case reports are highlighting inaccuracies in the point-of-care INRs in patients treated with dabigatran (Pradaxa) (Ann Pharmacother 2011;DOI: 10.1345/aph.1Q105)…….INR’s in patients taking dabigatran was falsely elevated…..the activated partial thromboplastin time (aPTT) provides a better qualitative assessment of anticoagulation status…..a nurse unfamiliar with dabigatran…..the point-of-care tested revealed an INR of 8.3, but the laboratory INR was determined to be 1.5. Home / Self Monitoring |

Billing tips: Overseeing warfarin therapy in the office rather than the lab is the first step to receiving appropriate reimbursement, since this decreases the amount of often-unreimbursed telephone care.

Level of office visit (CPT: 99211).

Lab: PT/INR (CPT: 85610).

Disease state being treated: (ICD-9: 427.31 if A-fib).

Other: Long-term management of oral anticoagulants (ICD-9: V58.61).

G0250 MD review interpret of of home INR test, $9.05 per 4 tests. (does not require face-to-face service).

99363: (new starts) Anticoagulation management for an outpatient taking warfarin, physician review and interpretation of INR testing, pt instructions, dosage adjustment (as needed) and ordering of additional tests; initial 90 days of therapy (must include a minimum of 8 INR measurements).

99364: (long-term Warfarin use) Anticoagulation management for an outpatient taking warfarin, physician review and interpretation of INR testing, pt instructions, dosage adjustment (as needed) and ordering of additional tests; each subsequent 90 days of therapy (must include a minimum of 3 INR measurements).

***NOTE: CMS, with the publication of the 2007 Physician Fee Schedule Final Rule, announced that Medicare will not separately pay for these codes (99363 and 99364) in 2007, considering the services to be bundled into the E/M codes that physicians already report. Other payers have not made their plans clear, but no payer has yet announced that it will pay for this service. If this situation changes, a more detailed educational piece about the use of these codes will appear in this column. If a significant, separately identifiable E/M service is performed on the same date as anticoagulation management, modifier -25 should be appended to that E/M code.

Adjusting with INR Goal of 2-3:

Goal: 2.5 (2-3 range) –> prevent systemic embolus in A-fib/ cardiomyopathy/ bioprosthetic valve, acute MI, valvular heart dz. Tx of DVT/ PE. High risk surgery as prophylaxis. Mechanical aortic prosthetic valve that is a St Jude bileaflet or CarboMedics bileaflet or Medtronic-Hall tilting disc aortic valve (normal left atrial size & NSR). (6^th ACP consensus conference. Chest 2001;119:S1)

INR<2–> incr weekly dose by 5-20%.

3-3.5–> decr weekly dose by 5-15%.

3.6-4–> Withhold next dose, decr weekly dose by 10-15%.

INR 4-5–> Withhold next dose, decr weekly dose by 10-20%.

Coronary Artery Disease & Anticoagulation Goals:

Pt’s with access to meticulous and routinely accessible INR monitoring: INR goal 2.5 with aspirin, 3.5 without aspirin. Duration of therapy: Long-term (up to 4 years).

High-risk pt’s with acute MI: INR goal 2-3 with aspirin. Duration of therapy: 3 months. (= Pt’s with large anterior wall MI, significant heart failure, intracardiac thrombus visible on echocardiography, history of thromboembolic event.)

Pt’s undergoing mitral valvuloplasty: INR goal 2.5. Duration of therapy: Three weeks before and four weeks after.

Adjusting with INR Goal of 2.5-3.5:

Goal: 3 (2.5-3.5 range) –> high risk mechanical prosthetic valves (see below) / thrombosis associated with antiphospholipid Ab syndrome.

Any mechanical valve that is: caged ball, caged disk, in the mitral position or h/o AF or prior systemic embolism despite adequate anticoagulant therapy or if in mitral location in pt with an enlarged L atrium/ not NSR (6^th ACP consensus conference. Chest 2001;119:S1). Those in the mitral and tricuspid position (0.5-3%/yr) are most likely to develop a thrombus as lower flow velocity than the aortic valve (0.5-5%/yr). Pt’s with aortic and mitral valve prosthesis’s benefit from high-intensity vitamin K antagonist therapy (target INR 3-4.5, lower for aortic, higher end for mitral) (J Am Coll Cardiol 2003;42:2042-8), as lower incidence of thromboembolic events.

INR <2–> give additional dose and incr weekly dose by 15%.

2-2.4–> incr weekly dose by 5-15%.

3.6-4.6–> decr weekly dose by 5-15%.

4.7-5.2–> withhold 0-1 dose, decr weekly dose 10-20%.

>5.2–> withhold 0-2 doses, decr weekly dose 10-20%.

High INR, Not Bleeding:

If giving Vit-K (phytonadione), need to balance risk of bleeding with the risk of over-correction leading to thromboembolism. See INR Reversal Methods |

5-6–> withhold next 1-2 doses of Warfarin, restart at lower dose (decr weekly dose by 10-20%) when INR in therapeutic range.

6-10–> Same as above, consider Vit-K 1-2.5mg PO if high risk for bleeding (frail, extremely rapid rise etc).

• For patients taking VKAs with INRs between 4.5 and 10 and with no evidence of bleeding, we suggest against the routine use of vitamin K (Chest. 2012;141:7S-47S)…..although it can bring the INR down faster than just holding warfarin, it doesn’t seem to decrease bleeding risk…..For most of these patients, hold the warfarin for a dose or two and then adjust it to get the INR in the appropriate range.

• Low-dose oral vitamin K (1.25 mg) did not reduce bleeding (although it did more rapidly returns the INR toward the therapeutic range,) in patients who have been overanticoagulated (INR 4.5 to 10) on warfarin……withdrawal of warfarin may be all that is necessary to manage such patients (Ann Intern Med 2009;150:293-300).

If rapid reversal required–> 0.5-2mg V-K SC or IV slow infusion if at incr risk of bleeding), re-check INR in 8hr, an additional dose of 0.5 mg V-K can be given if not reduced at 8hr or not therapeutic at 24hr. decr Weekly dose by 20-30% when INR returns to the desired range. The average time to an INR of <4 is 1.4 days with Vit-K and 2.6 days by withholding Coumadin.

10-20–> Give 2.5-5mg PO V-K x1 or 3mg V-K SC or IM (or 1 mg IV), re-check INR in 6hr (consider admission), repeat in not reduced or not therapeutic in 24hr. Withhold next 2 doses. Resume warfarin at lower dose when INR approaches target range….decrease weekly dose by 20-30%, re-check INR q6hr if admitted, qd if outpatient. Many institutions use 1-5 mg SC/IM/IV to avoid prolonged warfarin resistance. It is certainly within the standard of care to manage patients with an asymptomatic, supratherapeutic INR (>10) as outpatients (treated with vitamin K) so long as no worrying symptoms (e.g., headache) (Ann Emerg Med 2011;online May 30th)……”We were unable to find any studies that support a reduced risk of warfarin-associated bleeding caused by rapid INR reversal or inpatient admission.”

>20–> Withhold doses, give FFP or Prothrombin Complex depending on the urgency of the situation or 10mg V-K IV then q12h PRN. When restart, lower dose 30%.

Info: A study suggests that stopping warfarin may be enough (vitamin K may not be necessary) to restore normal clotting in patients who have been overanticoagulated and are not actively bleeding according to a multicenter trial randomized 355 patients (INR’s of 4.5 to 10.0) to 1.25 mg (1/4 of 5mg tab) vitamin K and 369 to placebo (Ann Inter Med 2009;150:293-300)…..the study did not demonstrate fewer bleeding events or ischemic events in patients given vitamin K, it did provide evidence that vitamin K speeds the return of normal INR values….The day after initiating vitamin K, the average decrease was 2.8 INR units in the vitamin K group versus 1.4 units in the placebo group.

• When restoration of INR is not considered urgent (no active bleeding), oral phytonadione is the better alternative compared with IV or SQ phytonadione in cases of excessive anticoagulation (Arch Intern Med 2003;163:2469-73).

• INR values above 10 may represent false elevations, consider repeating before reversing warfarin with vitamin K or interrupting therapy (Chest 2007;131:816-822)….falsely elevated INRs were more likely to have a pediatric tube used for sample collection, more likely to have had a traumatic venipuncture, and, among those receiving hemodialysis, more likely to have an indwelling central venous catheter for dialysis excess.

Bleeding & Therapeutic INR:

Link: Reversal with Vit-K & Closed Head-Injury Protocol |

Consider possible cancer or other pathological process at the bleeding site. May be prudent to lower INR to 1.5 temporarily.

High INR and Bleeding:

(Chest 2008;133:S160-198)

Minor Bleeding with no surgery or procedures required: Omit 1-2 doses of warfarin. Consider re-starting warfarin at a lower dose when in the therapeutic range. Consider a dose of oral Vit-K based on INR: If 5-9 @ 1-2.5mg. If >9 @ 2.5-5mg. Repeat INR in 1-2 days. Repeat dose of Vit-K as necessary.

Major Bleed / Not life-threatening:

Reverse incr INR with withholding warfarin, give FFP and/or V-K. If serious bleeding give Vit-K 10mg IV via slow infusion. If reversal needed for a procedure and INR <9 give 1-5mg IV/PO. If INR >9 give 5-10mg IV. Give FFP @ 15ml/kg and repeat if INR not in the desired range immediately following administration. Consider PCC or fFVIIa depending on the urgency. Check INR daily.

Serious Bleed (any INR) or Warfarin OD or Urgent Reversal Needed (immediate surgery):

Admit to hospital.

Rapid / Complete within 10-15 minutes: V-K 10mg IV + PCC (20-59 units/kg, see info below). Repeat dose of PCC if next INR >1.5. Consider F7 (rFVIIa) in place of PCC.

Fast / Partial (Major Bleeding or Need Surgery within 24 hours: V-K 10mg IV + FFP (15ml/kg) + FFP repeat based on INR

Urgent surgery or procedure: hold warfarin dose x1; give Vit-K 2.5-5 mg PO x1; monitor INR, expect decrease in 24h; repeat vitamin K 1.25-2.5 mg PO x1 PRN.

Prompt Reversal (4-6 hours): V-K 10mg IV. Oral Vit-K takes 12-24 hours. Takes 3-5 days if just omit warfarin dose.

Notes: After tx and planning to restart, may need to give heparin until the effects of Vit-K have been reversed and pt is responsive to Warfarin. If get bleeding, then long-term low-dose warfarin (INR 1.5 – 2.0 using doses of 0.5-10.0 mg/d) safely lowers risk of recurrent thrombotic embolism, as recurrent DVT, major hemorrhage or death was reduced by 48% (NEJM 2003 348:243) –contra in people at high risk of bleeding or who have experienced a hemorrhagic stroke. But, people with more moderate bleeding in the past should be considered for low-dose therapy, because the risk of bleeding is much < with the regular dose.

• Many patients who’ve had a warfarin-associated GI bleed can safely resume warfarin therapy soon after the bleeding event according to a retrospective study (Arch Intern Med. Published online September 17, 2012)….of 440 adults who stayed on warfarin continuously or resumed treatment within about a week (median time to retreatment, 4 days)…..Compared with patients who did not restart warfarin, those who continued or resumed treatment had a significantly lower 90-day incidence of thrombosis (0.4% vs. 5.5%) and death (6% vs. 20%). The most common causes of death were cancer, infection, and cardiac disease. “We believe that most patients with warfarin-associated GI bleeding and indications for continued long-term antithrombotic therapy should resume anticoagulation within the first week following the hemorrhage.”

Fresh-Frozen Plasma (FFP): Usual adult dose is 4-6 units (or 15ml/kg), this will increase coagulation factors by 20% immediately. Volume of 1 unit is 200-250 ml = 200-250 units of factors (1 unit/ml = amt of factor in 1ml of plasma in a normal pt). 200-250ml, has all coagulation Factors (insignificant amounts of vWF, F8 and F9), plasma, complement, no platelets. Risk of volume overload, particularly in cases of over anticoagulation associated with major bleeding. Risk of blood-borne pathogens.

Prothrombin Complex Concentrate (PCC): ~50 U/kg depending on urgency, has slight thrombogenic risk and may transmit pathogens. Re-check INR in 6hr, if not decr, give V-K q6hr PRN. Safer than FFP as virally inactivated, but thrombogenic effects can occasionally occur. Can calculate exact dose needed in IU: = (Target INR % – Present INR %) x wt in kg. INR % is based on the principle that 1ml of normal plasma contains 1 unit of each coagulation factor and the PCC expresses as a % of normal plasma corresponds to the mean level of vit-K dependent factors. Works in 30 min compared with 8-40 hrs with IV or PO.

Step #1: target INR 1 (=100%) if life-threatening bleed and low risk of thrombosis. INR 1.5 (40%) if serious bleed and moderate risk of thrombosis. INR 2 (25%) if moderate bleed and high risk of thrombosis.

Step #2: Convert present level INR to %:

>5 = 5%, 4-4.9 = 10%, 2.6-3.2 = 15%, 2.2-2.5 = 20%,

1.9-2.1 = 25%, 1.7-1.8 = 30%, 1.4-1.6 = 40%, 1 = 100%.

Step #3: Calculate PCC dose in international units: Ex: 80kg pt had a PE 3mo ago, now major GI bleeding, current INR is 7.5 (>5 =~5%), target in 1.5 (=~40%). Dose = (40-5)x80 = 2,800 ml or IU (NEJM 2003;349:675-83).

Kcentra (PCC, human): FDA has approved in 3/13, derived from pooled plasma, to reverse vitamin K antagonist (e.g., warfarin) anticoagulation in adults with major bleeding. Approval was based on a study of over 200 patients with acute major bleeding who were receiving anticoagulation with a vitamin K antagonist. The new therapy was as effective as plasma at stopping bleeding. It can also be administered more quickly than frozen plasma because it does not require thawing or blood group typing.

Kcentra will carry a boxed warning about the risk for blood clots. Additionally, it has been associated with arterial and venous thromboembolic complication — some fatal — so patients should be monitored for signs of thromboembolic events.

Recombinant activated F7a (NovoSeven): rFactor VIIa can be used at doses of 15-20 mcg/kg (Ann Int Med 2002;137:11). A rapid, safe and effective means of lowering INR’s >10 and for reducing bleeding risks in procedures. Expensive, costs $1.40/mcg ($3,500 for mean dose), initially made for hemophilia pt’s. rFactor VIIa for bleeding episodes may also work. Can also reverse LMWH if need emergent surgery @ 50 ug/kg pre-op, then repeated on post-op days x3 (Letter to editor. Mayo Clin Proc 2004;69:827). In pt’s on warfarin experiencing acute intracranial hemorrhage, an IV bolus of recombinant factor VIIa (rFVIIa) can quickly reverse the drug’s anticoagulant effects, this may expedite safe neurosurgical hematoma evacuation (Mayo Clin Proc 2004;79:1495-1500).

Life threatening or Warfarin OD: Any INR: Give PCC 50 U/kg, if PCC does not contain F-7, give V-K 10mg IV. Re-check INR in q6hr, may repeat V-K q 12hr.

If Hematoma: check X-ray, CBC, Platelets, PT, PTT.

Argatroban Drip: (AT3 inhibitor) Can be used as a form of anticoagulation if pt is high risk for clotting complications off coumadin.

PTT High: –> on Coumadin stop, bed rest, V-K PO, if obstructive liver dz give SC 5-10mg, + FFP, may get rebound hypercoagulability.

If warfarin is to be continued after a high dose of Vit-K1: Heparin can be used until the effects of vitamin K1 are reversed and the patient becomes responsive to warfarin therapy (Chest 1998;114:445S-469S).

Vitamin-K (Phytonadione):

[5 mg tab Rx, $~54/#30, 100 mcg tab OTC. Injection, aqueous colloidal: 2 mg/mL (0.5 mL); 10 mg/mL (1 mL)] Link: See Vit-K |

Can be given PO, SC, IV, IM. Given PO (2.5mg) will lower the INR with an onset in 12-48hr. Takes 4 days if just stop Warfarin intake. Give 1-2.5mg PO if INR 5-10 w/o bleeding, give 3-5mg PO if INR >9. Just 1 mg is often enough to lower the INR into the therapeutic range in low-risk pt’s with an INR of 5-9 (Prescriber’s Letter. 2009;16:4)…can order one-half or one-quarter of a 5 mg tab as easy to cut with a pill cutter…..Or give INJECTABLE Vit-K ORALLY…..Pharmacists can dispense it in an oral syringe and have patients mix it with juice to improve taste……Don’t give Vit-K SUBCUTANEOUSLY…its absorption is less predictable. And give it IV only for patients with very high INRs or serious bleeding…due to possible anaphylaxis.

Onset of action to increased coagulation factors: Oral: 6-10 hours; I.V.: 1-2 hours.

Peak effect: INR values return to normal: Oral: 24-48 hours; IV: 12-14 hours.

IV: Onset of IV (0.5-1mg) is faster (2-3hr to decr INR, max effect in 27hrs) than PO, however it has higher risks (2%) such as anaphylaxis and allergic reactions. Reserved for high risk pt’s, infuse slowly over 20-60 min, stop at any hint of adverse reaction (Mayo Clin Proc 2001;76:260). (Arch Intern Med 1998; 158).

• Oral Vit-K lowers INR more rapidly than SC Vit-K (Ann Intern Med 2002;137:251).

• A rapid IV infusion of K1 has been associated with dyspnea, flushing, and cardiovascular collapse, probably related to dispersing agents in the solution. A meta-analysis found that oral and IV Vit-K are superior to SC Vit-K for reversing excessive anticoagulation (Arch Intern Med 2006;166:391-7)…..52% of oral recipients, 70% of IV recipients, and 29% of SC recipients achieved INRs <4 at 24 hours.

Pt’s with Blunt Closed-Head Injury Protocol:

These pt’s have incr risk of intracranial hemorrhage (ICH) are at increased risk for death compared with similarly injured pt’s who do not take the anticoagulant.

• A protocol involving immediate triage to a tx area for evaluation by an emergency physician, immediate thawing of two units of universal-donor FFP (10-50 unit/kg) + 10 mg Vit-K IV and immediate CT of the head (J Trauma 2005;59:1131-9). Pt’s with negative findings on head CT were admitted and observed for 23 hours. Protocol pt’s had significantly lower rates of mortality (48% vs. 10%) and rates of progression of ICH (40% vs. 11%). Compared with 22 historical controls, protocol pt’s had significantly shorter times in triage (31 vs. 14 minutes), to completion of head CT (132 vs. 42 minutes), and to initiation of warfarin reversal (4.2 vs. 1.9 hours).

Resuming Anticoagulation after intracranial hemorrhage (ICH): (Clev Clin J Med 2010;77:791-99) Many clinicians start low dose SQ heparinoids at 24-72hr after ICH to prevent DVT and then over the next week increase to full dose anticoagulation or transition to oral anticoagulants. Those with lobar hemorrhage or cerebral amyloid angiopathy may remain at higher risk of ICH than VTE and therefore may be best managed without anticoagulants. Higher risk if large hematoma volume on presentation, “spot sign” = contrast extravasation on CT, warfarin use and higher INR’s.

• Any pt with an ICH on warfarin should be immediately reversed with PCC (Mayo Clin Proc 2007;82:82-92)..restarting once stable should be considered if secondary ischemic stroke prevention in AF in 2 to 4 weeks, but not if primary prevention.

• After an ICH necessitates warfarin discontinuation, the risk of recurrent hemorrhage when warfarin is restarted may be lower than the risk of thromboembolic events if warfarin therapy is not reinitiated (Arch Neurol 2008;65:1313-1318)……”the clinician deciding whether to restart anticoagulation therapy should weigh other factors, including the patient’s risk of falls, general medical condition, and other risk factors for systemic hemorrhage”……”Patients without these risks may benefit from reinstitution of warfarin therapy.”

Warfarin Drug Interactions:

Links: Cytochrome P-450 | Decr Metabolism | Incr Metabolism | Warfarin Reversal with Vit-K |

The safety of warfarin use can be compromised by many popular herbal and nonherbal supplements taken by individuals, with eight of the 10 most widely used supplements interacting with warfarin, and many of these associated with significant changes in the INR (Heart Rhythm Society 2010 Scientific Sessions; May 13, 2010; Denver, CO.)…..cranberry, garlic, ginkgo, and saw palmetto have been linked to increased rates of bleeding, whereas others have been shown to cause changes in prothrombin times, which would result in a need to alter warfarin doses, according to investigators.

Genetic influences on the response to warfarin: Response to warfarin exhibits wide interindividual variability. Careful monitoring of anticoagulation is required in all pt’s taking warfarin with the aim of achieving the narrow therapeutic range required and avoiding adverse effects resulting from underdosing or overdosing. Several warfarin dosing algorithms are available, but, early achievement of target INR with avoidance of overanticoagulation remains elusive. CYP2C9*2 & 3 polymorphisms are associated with incr risk of over-anticoagulation & bleeding (JAMA 2002;287:1690). Warfarin is mainly metabolized by the P450 isoform CYP2C9. Multivitamin supplements may contain Vit K and cause fluctuations in INR levels…see Monitoring & Fluctuating INR’s |

Warfarin-Acetaminophen Interaction: APAP can increase the anticoagulant effect of warfarin, but it does so inconsistently. Patient susceptibility varies, possibly on a genetic basis; occasional use of acetaminophen generally has little or no effect on the INR in patients on chronic warfarin therapy, but in some, even a few grams of the drug may cause a dramatic increase in INR (Med Lett Drugs Ther 2008;50:39)….It might be prudent to monitor INR in patients on chronic warfarin therapy more closely than usual when they take more than 2 g per day of acetaminophen for more than a few days.

• The mechanism of this interaction has not been established, but may be related to an acetaminophen metabolite inhibiting vitamin K-epoxide reductase, the target for warfarin’s anticoagulant effect (Thromb Haemost 2004;92:797).

• While taking APAP at dose of 650 mg QID lead to a pt’s INR’s to become erratic, the average Warfarin dose needed to maintain the INR tends to decrease (Blood. 2011;118(24):6269-73).

• Clinicians should educate patients on the wide use of acetaminophen in over-the-counter products and the potential interaction with their warfarin therapy. Patients should be counseled to report the use of any new over-the-counter or prescription drug to their healthcare providers. If acetaminophen is necessary at doses near or greater than 2 g/day for more than 1 day, an extra INR measurement may be appropriate.

Antimicrobials with Warfarin:

• Warfarin’s effect can be INDIRECTLY affected by other such as broad-spectrum antibiotics MIGHT increase warfarin’s effect by disrupting GI flora and impairing vitamin K production. Keep in mind that INR changes are also more likely if the patient is acutely ill…due to the infection, changes in diet, fever and inflammation (Prescriber’s Letter 2012;19:8).

• Some antibiotics are more likely than others to affect INR… due to a direct effect on warfarin metabolism. TMP/SMX and metronidazole are the worst culprits as they can significantly raise INR and increase bleeding risk 2- to 4-fold……monitor INR closely (ck in 3-5 days) and consider empirically lowering the warfarin dose 25% to 40% in patients at high risk for bleeding. Warfarin’s effect can also be significantly increased with most macrolides, azole antifungals, quinolones or doxycycline.

• Interactions are LESS likely with amoxicillin, azithromycin, oral cephalosporins and 3 days or less of a quinolone.

• Warfarin’s effect can be DECREASED if taken with dicloxacillin, nafcillin, rifampin, or griseofulvin. Check INR weekly for several weeks when starting rifampin and consider empirically increasing the warfarin dose by 25% to 50%.

• In a case-control study, all concomitant antibiotics were associated with increased risk for bleeding with Wararin; risk was highest with azole antifungals (inhibit CYP2C9, the enzyme responsible for metabolizing warfarin) (Am J Med 2012;125:183)…..Concomitant exposure to any antibiotic doubled the risk for a bleeding episode, compared with no such exposure (adjusted odds ratio, 2.0).

On magnetic resonance imaging at ages 7 to 13, significantly larger hippocampal volumes were associated with high maternal nurturance within the nondepressed group, even when analyses were adjusted for traumatic events, pre- and perinatal factors, and internalizing and externalizing scale scores (Proc Natl Acad Sci U S A 2012;109:2854)…..In earlier studies, smaller hippocampal volumes were associated with increased risk for post-trauma psychopathology in affected twins compared with nonaffected twins (Nat Neurosci 2002;5:1242) and with impaired cortisol stress responses in primate siblings (Biol Psychiatry 2007;62:1171).

• Recommend ations: Check the INR about 3 days after starting any antibiotic, especially if the patient is vomiting, not eating, or has a fever. It can take weeks for a change in INR to occur with rifampin, griseofulvin, and some others. Some suggest that if starting a broad spectrum Abx that as soon as you start, decrease the Coumadin dose ~25% (or can have pt take Coumadin every other day for the week they are on the Abx) as it kills all Vit-K producing bacteria in the gut. Monitor INR in 2-3 days if con’t same dose of coumadin.

Incr Catabolism of clotting factors–> androgens, thyroid hormones….monitor INR and adjust shortly after starting

Increased INR & PT (Potentiate Warfarin’s Effect):

Generally take 7-10 days, thus check frequently early on and adjust accordingly.

Inhibit Warfarin Metabolism–>

Acetaminophen, Allopurinol, Azithromycin, Cimetidine, Ciprofloxacin, Clarithromycin, Clofibrate, Disulfiram, Danazol, Erythromycin, Acute ETOH use, Gemfibrozil, Quinolone, Fluconazole, Fluvoxamine, Itraconazole, Ketoconazole, Metronidazole, Miconazole (even OTC vaginal preparations), Norfloxacin, Propafenone, Sulfonamides, TMP-SMX (quick effect).

Amiodarone: peak affect at 7wks with an incr INR of ~44%. With doses of 400, 300, 200, 100mg/d, decr Warfarin by 40, 35, 30 or 25% respectively (Chest 2002;121:19-23).

High Risk Abx: TMP/SMZ, metronidazole, erythromycin, clarithromycin, ciprofloxacin, enoxacin, Fluconazole (even a single dose can raise it lasting 8 days), Itraconazole and Ketoconazole. These interfere with warfarin via the cytochrome P450 system and this effect can occur quickly, possible within first 24 hours, and dissipates fairly quickly after discontinuation of the antibiotic. If using, best to reduce the Warfarin dose by 30% and monitor the INR in 3 days……or can have pt take their Coumadin every other day for the week they are on the Abx.

• An analysis of Medicare data has shown that adults taking warfarin had a twofold increased risk of serious bleeding when an antibiotic was introduced (Am J Med 2012;125:183-189).

Additive anticoagulant–>

Cefamandole (Methylthiotetrazole ring inhibits production of V-K dependent clotting factors), Cefmetazole, Cefoperazone, Cefotetan, Heparin, Moxalactam.

Unknown Mechanism–>

Chloral Hydrate, Lovastatin, Phenytoin, Vit-E, Quinidine, Propranolol, Omeprazole, Felbamate, Isoniazid, vaccines, high dose IV PCN, hepatotoxic drugs, hyperglycemic agents, hypolipidemic. Oxandrolone (Oxandrin).

SSRI’s: Patients taking coumarins together with SSRIs face increased risk of hospitalization for non-GI bleeding according to a Dutch study with 1848 pt’s (adjusted OR = 1.7)(Arch Intern Med. 2008;168(2):180-185)…..Users of NSAIDs had a similar increased risk of non-GI bleeding (adjusted OR, 1.7), whereas the risk of GI bleeding was higher (adjusted OR, 4.6).

Lipid meds: Initiation of a fibrate or statin that inhibits CYP3A4 enzymes — including fenofibrate, gemfibrozil, fluvastatin, simvastatin, and atorvastatin — increases the risk of hospitalization for GI bleeding in chronic warfarin users (Am J Med 2010;123:151-157)……may benefit from increased clinical vigilance, including enhanced INR monitoring.

Corticosteroids: The interaction between warfarin and oral corticosteroids now seems more significant than previously thought (Warfarin and corticosteroid interaction. Prescriber’s Letter 2007;23(4):230404) (mechanism is unknown, but prednisone and methylprednisolone are both substrates for CYP3A4)….The INR increases by about 1.2 points on average and about half of these pt’s require a drop in their warfarin dose.

Conditions–> liver dz, hyperthyroidism, febrile illness, CHF, decr V-K intake/ absorption.

Herbal Remedies–> Most have Coumarin effects, some are Salicylates, others antiplatelet. Alfalfa, Angelica, Aniseed, Arnica, Asafetida, Bogbean, Cassia, Celery extract, Clove, DHEA, Dong quai, Evening primrose oil, garlic, ginger (intestinal or hepatic P450, also may inhibit PLT aggregation, Clev Clin J Med 2004;71:651-6)), ginkgo, feverfew, fish oils, Vit-E (avoid >400 IU/d), Vit-C (avoid >500mg/d), Horse chestnut, Horseradish, Licorice, Meadow sweet, Melilotic, Poplar, Prickly ash, Quassia, Red clover, Sweet Woodruff, Tonka beans, Willow.

Foods: Mango fruit inhibits CYP2C19; therefore, inhibit R-warfarin metabolism and increase INR. Caffeine is a substrate for CYP1A2 and may compete with R-warfarin for metabolism. The hydrocarbons of char broiled food can induce CYP1A2, therefore can increase R-warfarin metabolism and decrease warfarin effect. Garlic can inhibit platelet aggregation and theoretically can potentiate the effects of warfarin. Ginger is thought to inhibit thromboxane synthetase and decrease platelet aggregation.

Glucosamine/chondroitin: Over 80 cases suggesting an interaction between glucosamine or glucosamine/chondroitin and warfarin have been reported to MedWatch. However, all but 20 had incomplete information or serious confounders. At least 20 additional case reports have been reported to the World Health Organization. Preliminary research suggests glucosamine may have antiplatelet activity. Also, chondroitin is structurally similar to heparin, which can increase INR slightly. However, neither laboratory evidence of hematologic changes or bleeding are known adverse effects of either glucosamine or chondroitin. Perhaps these supplements’ hematologic effects become clinically noticeable only in patients taking warfarin (Prescriber’s Letter 2008;24(6):240613)…..so far there’s no evidence of increased bleeding when these supplements are used with aspirin or clopidogrel.

Potential Interactions of Dietary Supplements that Increase in Risk of Bleeding: Acetyl-L-carnitine. Fish oil. Mate. Arnica. Flaxseed, Flaxseed oil. Melatonin. Alcohol, acute use. Fo-ti. Mesoglycan. Bishop’s weed. Forskolin. Milk thistle. Black tea. Forsythia. N-acetyl glucosamine. Bladderwrack. Gamma-linolenic acid. Nattokinase. Boldo. Garlic. Oolong tea. Borage seed oil. Ginger. Pantethine. Burdock. Ginkgo. Papaya. Caffeine. Ginseng, Siberian. Peppermint oil. Chondroitin sulfate. Glucosamine. Propionyl-L-carnitine. Cod liver oil. Grapefruit, Grapefruit juice. Red clover. Coltsfoot. Guarana. Reishi mushroom. Guggul. Resveratrol. Danshen. Holy basil. Saw palmetto. Devil’s claw. Honeysuckle. Sea buckthorn. Dong quai. Horse chestnut. Tiratricol. Epimedium. Ipriflavone. Turmeric. Eucalyptus oil. Jiaogulan. Vinpocetine. Evening primrose oil. Kava. Vitamin A. Fenugreek. L-carnitine. Vitamin E. Feverfew. Lycium. Willow bark. Wintergreen (Prescriber’s Letter 2005;21(5):210505). Many reports of drugs or foods that interact with warfarin are poor quality and present potentially misleading conclusions (Arch Int Med 2005;165:1095-1106). Early case reports seemed to indicate that an interaction between cranberry juice and warfarin exists, more recent clinical trials do not support this (Prescriber’s Letter 2007;23(6):230614).

Warfarin and Celebrex: Patients receiving warfarin can also receive Celebrex. Since Celebrex by itself does not affect platelet function or bleeding time, it can be an appropriate treatment option for patients taking warfarin, as long as the anticoagulation effect of warfarin is maintained at the proper level. To minimize any increased risk of bleeding, patients should be closely monitored (especially in the first few days) to see if any adjustment of their warfarin dosing is needed. New labeling states that subsequent to marketing, reports have been received of patients on warfarin who had increased anticoagulation and (in some cases) bleeding complications after treatment with Celebrex was started. The new labeling also cautions that when patients on warfarin start, or change, treatment with Celebrex, they should be monitored for any changes in the anticoagulant effect of the warfarin, particularly in the first few days.

Decreased INR & PT (Exogenous Factors):

Hypothyroidism, adrenal corticosteroid inhibitors, antacids, antianxiety agents, antiarrhythmics, Abx’s, anticonvulsants, antidepressants, antihistamines, antineoplastics, bile acid sequestrant, St Johns Wort, American ginseng (Panax quinquefolius).

Incr V-K in Herbal Remedies–> stinging nettle, green tea, great plantains, alfalfa, parsley. Soy milk (Ann Pharmcother 2002;36:1893-6).

Interactions of Dietary Supplements Possible Decrease in Warfarin’s Effects:

Acerola. Alcohol, chronic use. Alfalfa. Cherokee rosehip. Chlorella. Coenzyme Q10. Corn silk. EDTA. Ginseng, American. Ginseng, Panax. Green tea. Limonene. Rose hip. Smartweed. Soy (contains Vit-K). Spinach. St. John’s wort. Stinging nettle. Vitamin C. Vitamin K. Watercress.

Other Diets: Atkins, South Beach diets. High-protein, low-carb diets seem to increase albumin, which binds to warfarin. Less warfarin is available for anticoagulation…leading to lower INR. These diets might also induce liver enzymes…increasing warfarin metabolism. Both mechanisms can require a warfarin dose increase to maintain target INR.

Warfarin Resistance: Can be hereditary (polymorphisms in CYP2C9 and VKO-RC1) or acquired (high Vit-K intake, non-compliance, decreased absorption of warfarin, drug interactions or increased clearance / metabolism of warfain). Not the same as warfarin failure, which is a new thrombotic event despite a therapeutic INR. The most common cause is non-compliance, but there are cases of true hereditary resistance for which there are 2 approaches, either switch to another anticoagulant or increase the dosage (often as high as 100mg/d or more)(Clev Clin J Med 2009;76:724-30). In general, those that require more tha 105mg/wk (15mg/d) should be considered warfarin-resistant. These pt’s generally need much smaller doses of Vit-K to reverse the INR’s (Vit-K hypersensitivity).

Pharmacokinetic Resistance: Due to diminished absorption or increased elimination of warfarin. Genetic factors such as ultra-rapid metabolism due to multiplication of P450 enzymes. Hypoalbuminemia leads to increased free fraction of warfarin and thus a shorter plasma half-life. Hyperalbuminemia paradoxically can contribute to resistance due to drug binding. Hyperlipidemia, mostly trilycerides binds to Vit-K. Diuretics reduce the plasma volume and can decrease the response to warfarin.

Pharmacodynamic Resistance: Due to increased affinity of Vit-K. Production of clotting factors no dependent on Vit-K, Decreased VKOR sensitivity to warfarin. Prolongation of normal clotting factor activity.

W/u: Assess potential non-compliance. Consider malabsorption disorder (celiac, chronic pancreatitis, short gut syndrome, gastroenteritis). Check factor II and factor X activity.

If <40% normal, this suggests a therapeutic warfarin dose and thus unreliable INR…consider checking plasma warfarin level to confirm the dx.

If >40% normal, suspect pharmacokinetic or pharmacodynamic resistance. Check plasma warfarin level, if subtherapeutic it suggests pharmacokinetic resistance or non-compliance. If therapeutic, suggests pharmacodynamic resistance. Either way, consider increasing the daily warfarin dose or consider an alternative such as LMWH or Fondapinux.

**Ref:(Am Fam Phys 1999;59:3) (Chest 1995;108:4S) (Arch IM 1993;153:586-96) (Postgrad Med 1995;98:3)