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Anticoagulant-Related Bleeding: An Update for Pharmacists

INTRODUCTION

Warfarin is the most commonly prescribed vitamin K antagonist (VKA) anticoagulant in the United States. Current U.S. guidelines for stroke prevention in atrial fibrillation (SPAF) recommend warfarin over direct-acting oral anticoagulants (DOACs; apixaban, dabigatran, rivaroxaban) in patients with mechanical heart valves and those with creatinine clearance less than 15 mL/min.1,2 In addition, they recommend either warfarin or DOACs for patients with prior stroke, transient ischemic attack (TIA) or a CHA2DS2-VASc score of greater than or equal to 2.2 Current U.S. guidelines for treatment of venous thromboembolism (VTE) recommend DOACs over warfarin as initial therapy except in patients with CrCl less than 30 mL/min or poor adherence where warfarin is preferred.3 In patients with cancer and VTE, low-molecular weight heparins are preferred over warfarin and DOACs.3

Vitamin K antagonists produce their anticoagulant effect by interfering with the gamma–carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X. Vitamin K antagonists interfere with the cyclic conversion of vitamin K and vitamin K epoxide, which is required for gamma-carboxylation. Thus, the reduced form of vitamin K promotes gamma–carboxylation resulting in activation of coagulation factors II, VII, IX, and X. Warfarin inhibits vitamin K oxide reductase, which decreases the production of reduced vitamin K. Hepatic production of partially carboxylated and decarboxylated coagulation proteins results in the anticoagulation effect.4

Warfarin is monitored using the international normalized ratio (INR), with a target range of 2–3 for treatment of VTE and SPAF. There is a strong association between a patient’s time in therapeutic range (TTR) and bleeding risk and thromboembolic events.4 Patients managed in anticoagulation clinics have a higher percentage of their patients maintained in the therapeutic range.5 However, fewer than 50% of VKA-treated patients are managed in such clinics.5 INRs above 4, and particularly those above 9, are associated with an increased bleeding risk.6-11 For patients with AF, the risk of intracranial hemorrhage (ICH) doubles for every 1 unit rise in INR.6,9,11 For patients with INRs above 9, the risk of bleeding is 20-fold greater than for patients with INRs in the therapeutic range and is approximately 20% within 1 week following the elevated INR.6,9,10 The risk of bleeding with VKAs is 3-fold higher during the initiation phase when the INR is stabilizing.6,12

WARFARIN-ASSOCIATED MAJOR BLEEDING

The risk of major bleeding in warfarin-experienced patients in older trials has been reported to ranged from 0.4% to 1.9% per patient per year compared with an incidence of 0.3%–0.5% per patient per year in control study arms.6 The reported risk of ICH in older trials was 0.46%–0.7% per patient per year, and fatal bleeding was 0.25%-0.3% per patient per year.6 In contemporary trials comparing warfarin and DOACs for SPAF, the annual rates of major bleeding and ICH with warfarin were 3.4%–3.61% and 0.74%–0.85% per patient per year, respectively.13 The higher frequency of major bleeding is likely due to the inclusion of a higher percentage of warfarin-naive patients rather than warfarin-experienced patients.

The reported incidence of major bleeding and ICH with warfarin in clinical trials of VTE treatment and prevention are lower than those reported for SPAF, likely because the mean patient age is more than 10 years lower. Recent clinical trials comparing warfarin and DOACs for VTE treatment report major bleeding rates of 1.2%–2.2% per patient per year and a pooled warfarin ICH rate of 0.3% per patient per year.14,15

In clinical trials, the most frequent scale used to measure the incidence of major bleeding is the International Society on Thrombosis and Haemostasis (ISTH) bleeding definition in nonsurgical patients. Bleeds are considered major if they either (1) are fatal, (2) are symptomatic in a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartmental syndrome), (3) result in a hemoglobin drop of 2 g/dL or more, or (4) require administration of 2 units or more of whole blood or packed red cells.16

Compared with older VKA clinical trials, recent real-world observational trials comparing warfarin and DOACs for SPAF have reported higher warfarin major bleeding rates of 3.03% to 5.09% and ICH rates of 0.32% to 1.06% per patient per year.17 For example, the incidence rate of warfarin bleeding requiring hospitalization in the Truven MarketScan commercial and supplemental insurance U.S. database of more than 12,000 patients initiating warfarin in 2013 was 4.66 per 100 patient–years.18

The increased frequency of major bleeding may be the result of lower TTR reported in observational trials compared with clinical trials. The reported TTRs in contemporary trials comparing DOACs with warfarin were 55%-65% in SPAF trials and 57%-63% in trial of VTE treatment trials.13,14 The TTR in “usual care” is lower than that reported in clinical trials. For example, in a recent large AF registry, the mean patient TTR was 55%, and only 40% of patients had a TTR of 65% or more.19 In patients treated for SPAF, warfarin TTRs of 55% or more are associated with a lower stroke and systemic thromboembolism rates, while TTRs of less than 55% have a 2-fold increased risk of bleeding.20

Recently, the PROSPER score, estimated before VKA initiation, was developed as a tool that predicts a TTR of greater than 70% in older adults (65 years or older) treated for either SPAF or VTE.21 Variables included in the score were pneumonia, renal dysfunction, oozing blood (bleeding history), staying in the hospital 7 days or more, use of pain medications, lack of a dedicated and structured care system for anticoagulation, and prescription for antibiotics. The PROSPER score is a possible way of identifying patients who are likely to experience bleeding during warfarin anticoagulation and may be have better outcomes with DOACs.

Comparing DOACs to warfarin in a meta-analysis of SPAF trials, warfarin was associated with a similar risk of major bleeding but a higher risk of stroke, ICH, and mortality.22 For comparative trials of acute VTE treatment, a meta-analysis of trials comparing DOACs with warfarin showed reduced major bleeding and no difference in VTE and VTE-related mortality.23

MANAGEMENT OF WARFARIN-ASSOCIATED ELEVATED INR IN THE ABSENCE OF BLEEDING

The 2012 ACCP Chest Guideline and 2015 Anticoagulation (AC) Forum recommendations for managing elevated INRs in the absence of bleeding are described in Table 1.24,25 Patients should be interviewed to identify etiologies of INRs that are outside the therapeutic range, including causes such as missed doses, nonadherence, incorrect dosing, or warfarin interactions with other drugs or foods. Patients with previously stable INRs with a single slightly elevated INR (0.5 or less above target) may be managed by maintaining the same dose and repeating the INR in 1 to 2 weeks.26 In other patients, warfarin should be held for 1 or 2 doses and a lower maintenance dose considered.

Table 1. Guideline Recommendations for Managing Elevated INRs in the Absence of Bleeding
INRs 2012 ACCP Chest Guidelines AC Forum 2016 Guidelines
4.5–10 Recommends against the routine use of vitamin K Optional: Consider administering 1.25–2.5 mg oral vitamin K
>10 Oral vitamin K ≤5 mg Oral vitamin K 2.5 mg
Abbreviations: AC, Anticoagulation; ACCP, American College of Chest Physicians; INR, international normalized ratio.

Compared to withholding warfarin in patients with elevated INR, reversal of warfarin anticoagulation has not been shown to reduce bleeding risk in patients with INRs of 4.5 to 10.24,25 In patients who are not bleeding, oral vitamin K is preferred over intravenous (IV) vitamin K as there is slight risk of IV vitamin K1 (phytonadione)-associated anaphylaxis (3 of 100,000 patients).24,25 Subcutaneous vitamin K is not recommended in any situation because of its erratic absorption and unpredictable effect.25 Correction of an elevated INR with vitamin K requires at least 6 hours and more likely as long as 24 hours, since the process requires time for the liver to synthesize activated clotting factors.25

In patients with out-of-range INRs requiring dose adjustment and vitamin K administration, the INR should be monitored more frequently.22,23

When assessing whether the maintenance dose of warfarin should be lowered in response to an elevated INR, the potential cause of the elevation should be investigated. If the cause of the elevation is a drug interaction that results in an increased INR, consideration should be given to whether the interaction is a temporary one, such as the addition of an antibiotic, or one that is likely to be long-term, such as addition of amiodarone. For long-term interactions, a dose reduction is necessary. Temporary interactions may be managed with either no change in dose if the elevation in INR is minor, holding one or two warfarin doses, or a temporary dose reduction.

Errors in dosing may be uncovered with a careful review of warfarin doses taken over the past few weeks. Ask the patient to bring in all of their medications and if they use one, their filled pill box. Dosing adjustments are typically made in small increments using the total weekly dose and increasing or decreasing the total weekly dose by 10% to 15% to achieve a therapeutic INR. For dosing errors secondary to adherence problems, try to simplify the number of dosage strengths needed to make up the daily dose. For example, use a 7.5 mg tablet instead of a 2.5 mg and 5 mg tablet. When possible, recommend the same daily dose rather than variable daily dosing. For example, recommend 2 mg daily (14 mg weekly) rather than 2.5 mg 4 days per week and 2 mg daily 3 days per week (13.5 mg weekly). The higher the pill burden, the greater the risk of a patient medication error; simplifying the regimen whenever possible is preferred. Ask the patient to record their INRs and warfarin doses on a dosing calendar. Set up alarm alerts with the patient using a smartphone or other device, and recommend use of a pill box.

A major reduction in dietary vitamin K intake, such as in patients with malnutrition, may result in an elevated INR. Encourage the patient to consume regular meals containing vitamin K and consider a vitamin K-containing meal replacement beverage if appropriate.27

MANAGEMENT OF WARFARIN-ASSOCIATED MAJOR BLEEDING

There are several excellent reviews and guidelines describing the management of warfarin–associated bleeding using vitamin K, prothrombin complex concentrates (PCCs), fresh frozen plasma (FFP), and/or recombinant factor VIIa (rFVIIa).24,25,28,29

Management of warfarin-associated major bleeding depends on the site of bleeding and may involve supportive care such as hospitalization, placement of an intravenous (IV) line, administration of isotonic fluids, direct compression, and other resuscitation measures as necessary.28,29

Drug therapy for warfarin reversal is described in Table 2. Anticoagulation should be rapidly reversed with vitamin K 5 mg to 10 mg administered as a slow IV infusion.24,25,28 Thrombosis Canada recommends 5 mg IV vitamin K for INRs of 1.6–5.0 and 10 mg IV vitamin K for INRs above 5.28

Table 2. Dosing of 4-Factor Prothrombin Complex Concentrates for Warfarin-Associated Major Bleeding
Pre-treatment INR 2 to <4 4–6 >6
Dose (international units of factor IX / kg*) 25 35 50
Maximum dose (international units of factor IX) 2500 3500 5000
Based on use of the Kcentra product, as approved by the Food and Drug Administration.

*Maximum dosing body weight is 100 kg.

PCCs are classified as either 3-factor or 4-factor PCCs. Three-factor PCCs contain coagulation factors II, IX, and X, while 4-factor PCCs contain those factors plus coagulation factor VII. Three-factor PCCs also contain small amounts of the natural anticoagulants protein C and protein S, while 4-factor PCCs contain a higher concentration of proteins C and S and a small amount of heparin.30,31

In patients with warfarin-associated major bleeding, administration of a 4-factor PCC is recommended rather than FFP or 3-factor PCC.24,25,28 A systematic review of 18 studies in a total of 654 patients suggests that 4-factor PCCs are more effective than 3-factor PCCs for warfarin reversal.32 Patients with a recent history of heparin-induced thrombocytopenia should not receive 4-factor PCCs because of the presence of heparin in the product.28

The only PCC product approved by the Food and Drug Administration (FDA) for warfarin reversal is Kcentra, which contains factors II, VII, IX, and X, protein C, and protein S. It is dosed in factor IX units according to patient weight and INR (Table 2).30

In clinical trials, 4-factor PCC decreased the INR to 1.3 or less within 30 minutes.30 A summary of drug therapy for managing warfarin-associated major bleeding is presented in Table 3.

Table 3. Guideline-Recommended Management of Major Bleeding With Warfarin and Direct-Acting Oral Anticoagulants
Antidotes Warfarin Dabigatran Apixaban, Edoxaban, Rivaroxaban
Vitamin K •    
Activated charcoal*   • •
4-Factor prothrombin complex concentrates •   •
4-Factor activated prothrombin complex concentrates     •
Idarucizumab   •  
Recombinant factor VIIa     •
*If last dose taken within 2 to 6 hours.

FFP is not currently recommended for warfarin reversal but can be administered in patients with significant blood loss (such as for patients with hemoglobin <7.0 g/dL).24,28 Disadvantages of FFP compared with PCCs include the need for a larger infused volume (because clotting factors are not concentrated), longer preparation time (because of blood type matching), longer administration time (because of a higher volume), transfusion-related acute lung injury, and higher risk of infection transmission.24,31 While the costs of PCCs are higher than for FFP, PCCs have been shown to be cost-effective for emergency reversal of VKA anticoagulation.33

A recent meta-analysis of clinical trials comparing reversal of warfarin anticoagulation in patients with major bleeding or those requiring urgent surgery found that the use of PCCs reduced the INR more rapidly than FFP with a significant reduction in mortality. Fewer patients experienced signs and symptoms of volume overload, and the risk of thromboembolic events was similar.31 The risk of thromboembolism with either FFP (4.8%) or PCC (4.2%) is substantial and therefore thoughtful consideration is needed to balance patient outcome of bleeding versus thrombosis before reversing warfarin anticoagulation.31 Patients receiving PCCs should also be monitored for allergic hypersensitivity reaction such as urticaria, rash, flushing, wheezing, chest tightness, shortness of breath, bronchospasm, and anaphylaxis.30

A common error in clinical practice when warfarin needs to be reversed because of major bleeding is failure to administer vitamin K with clotting factors. In that case, the INR will fall following clotting factor administration but will subsequently rise within 12 to 24 hours because the half-lives of factors VII, IX, and X are shorter than the half-life of warfarin.34

Warfarin-associated ICH is the most serious type of bleeding; case fatality rates can be as high as 68%.35 The 2016 Neurocritical Care Society (NCCS) and the Society of Critical Care Medicine (SCCM) joint guidelines for management of anticoagulant-associated ICH offer recommendations similar to those described above: administration of 10 mg IV vitamin K, which can be repeated at 24 hours if the INR remains elevated (≥1.4) plus administration of 4-factor PCCs (rather than 3-factor PCCs or FFP).29

Practice guidelines do not currently recommend use of rFVIIa for managing warfarin-associated bleeding. 24.25,29,30 rFVIIa only contains one clotting factor, and the half-life of FVIIa (6 hours) is much shorter than warfarin (36 hours), suggesting that any initial lowering of INR will not be sustained.25 While small, retrospective studies suggest that rFVIIa reverses the INR as quickly as PCCs, rFVIIa is associated with a higher thromboembolism risk and is more expensive. For management of ICH, the NCCS and SCCM specifically recommend against the administration of rFVIIa.29

For moderate bleeding, IV vitamin K alone may be given in addition to withholding warfarin. The onset of INR lowering with IV vitamin K is about 6 hours; the full effect should be observed within 24 hours.24

MANAGEMENT OF DOAC-ASSOCIATED MAJOR BLEEDING

Clinical trials comparing DOACs with warfarin (INR 2–3) for SPAF and acute VTE treatment show the following:

  • Similar or lower major bleeding incidence for SPAF
  • Lower incidence of ICH for SPAF
  • Lower incidence of major bleeding for VTE treatment
  • Similar or higher incidence of clinically relevant, nonmajor bleeding for VTE treatment

There are several published guidelines for the management of DOAC-associated bleeding.28,29,36-38 Because the half-lives of DOACs are generally shorter than warfarin, withdrawal or interruption of the DOAC is all that is needed to manage minor bleeding. For major, life–threatening bleeding, management is needed similar to that for VKA-associated bleeding: mechanical compression, hemodynamic monitoring, volume replacement, and consideration of red blood cell transfusion.28,29,38

Drug therapy for management of major bleeding with DOACs is described in Table 3. If the DOAC was taken within 2 to 6 hours, a single dose of activated charcoal 50 g is recommended in addition to specific treatments.28,29,37

Major bleeding with dabigatran may be reversed with the antidote idarucizumab, a humanized monoclonal antibody fragment that binds both thrombin-bound dabigatran and free dabigatran with an affinity that is 350 times greater than that the drug has for thrombin. An idarucizumab dose of 5 g is administered as two consecutive rapid IV bolus doses or infusions that each deliver 2.5 g in 50 mL of infusate.39

In the REVERSE-AD trial, 301 patients with serious bleeding requiring immediate reversal of dabigatran were enrolled. Administration of idarucizumab resulted in reversal of coagulation tests (activated partial thromboplastin time, ecarin clotting time, and dilute thrombin time) with a reduction in dabigatran concentrations to below therapeutic range within 10–30 minutes of idarucizumab administration. The median time to observed hemostasis was 2.5 hours, and patients had a 30-day thromboembolic rate of 4.8% and a 5% mortality rate.40

A second dose of idarucizumab 5 g may be administered after 12 and 24 hours if a patient re–bleeds or has rebounds in coagulation tests.40 In the REVERSE-AD trial, all of the thromboembolic events occurring within 72 hours of idarucizumab administration were in patients who did not restart anticoagulation.40 The half-life of idarucizumab is 45 minutes; if needed, anticoagulation can be restarted within 24 hours.39 Hypersensitivity reactions such as rash, urticaria, hypotension, nausea and vomiting, and anaphylaxis, have been reported with the use of idarucizumab.39,40,41

Andexanet alpha is an investigational drug being studied for reversal of major bleeding secondary to direct-acting factor Xa inhibitors. Andexanet is a recombinant human truncated factor Xa decoy molecule with high affinity for factor Xa inhibitors. It has been modified to remove the gamma-carboxyglutamic acid domain, thus preventing it from competing with endogenous factor Xa for assembly within the prothrombinase complex. Upon administration, andexanet binds to factor Xa inhibitors and displaces factor Xa, which is then available for incorporation into the prothrombinase complex and generation of thrombin.

Andexanet itself does not have any anticoagulant or procoagulant effects.42 Andexanet is given as an IV bolus and infusion. Clinical trials have demonstrated a rapid effect. In the ANNEXA-4 study, anti-Xa levels fell by 86% in the 26 patients taking apixaban and by 92% in the 20 patients taking rivaroxaban by the end of a 2-hour infusion. The effect was immediate, with similar reductions seen by the end of the bolus. At 12 hours, 79% of patients were classified as having good or excellent hemostasis.43 At the time this program was prepared, andexanet was under re-review at FDA with a scheduled decision date of February 2, 2018.

In the absence of a specific antidote for direct-acting factor Xa inhibitors, current guidelines for management of major life-threatening bleeding caused by apixaban, rivaroxaban, or edoxaban recommend the use of 4-factor PCCs (50 U/kg).28,29,36,37,38 Some guidelines recommend activated PCC (aPCC), also known as factor eight bypassing activity (e.g., FEIBA, which contains activated factors VII, IX and X and nonactivated factor II) as an alternative to 4-factor PCC.28,29,37,38 An ex vivo study of rivaroxaban-spiked blood samples suggests that aPCC and rFVIIa are more effective than PCCs at reversing anticoagulant effect as measured by thromboelastometry.44 Doses of aPCC (e.g., FEIBA) in the guidelines vary widely from 50 U/kg to 80 U/kg; one guideline suggests a maximum 2000 units as an initial dose and another suggests a 200 U/kg maximum daily dose.28,29, 37,38 The data supporting the use of PCCs and aPCCs for anti-factor Xa inhibitor-associated bleeding are limited to ex vivo studies of healthy volunteers demonstrating reversal of anticoagulant effect and case reports or small observational studies of anticoagulated patients with bleeding.45-48

Adjunctive therapy with the antifibrinolytic agent tranexamic acid, a synthetic analog of the amino acid lysine, is also recommended in some guidelines, but clinical data to support its use for DOAC reversal are sparse.25,28,36,49 For cases of DOAC-associated bleeding unresponsive to other measures, administration of rFVIIa is recommended in some guidelines, but there are no clinical trials in humans.36,37,47

If a patient prescribed a DOAC experiences major bleeding, coagulation tests may assist in determining when reversal is appropriate. For dabigatran, the activated partial thromboplastin time (aPTT) and thrombin time are elevated but vary higher and lower throughout the dosing interval in response to dabigatran’s peaks and troughs during therapy. A normal aPTT cannot exclude low levels of dabigatran because of the variation in aPTT reagent sensitivity. The thrombin time is exquisitely sensitive to dabigatran’s effects. Therefore, a normal thrombin time can exclude the presence of significant dabigatran concentrations and thus the need to administer idarucizumab. The dilute thrombin time can be used to monitor the reversal of dabigatran’s effect of following idarucizumab administration. However, it is not widely available.

The ideal test to monitor the reversal of apixaban, edoxaban, and rivaroxaban is the agent–specific anti-factor Xa levels. While the prothrombin time (PT) may be elevated with rivaroxaban, PT reagents are often less sensitive to edoxaban and rivaroxaban.50 Because these laboratory tests are not widely used, clinicians must assess the clinical response when considering administering reversal agents.

CONCLUSION

Anticoagulant-associated bleeding is a significant cause of morbidity and mortality. Contemporary practice guidelines provide evidence and expert opinion–based recommendations for reversal management. Elevated INRs of 10 or higher in the absence of bleeding should be managed by withholding warfarin and administering oral vitamin K. Serious life-threatening warfarin-associated bleeding is managed with IV vitamin K and 4-factor PCCs.

Currently, dabigatran is the only DOAC with an available antidote. Idarucizumab rapidly reverses dabigatran associated major bleeding and excessive coagulation with an acceptable thrombosis rate. At the time this program was prepared, andexanet alpha was under re-review at FDA for reversal of life-threatening bleeding caused by apixaban, edoxaban, or rivaroxaban. In the meantime, various guidelines recommend either 4-factor PCCs or aPCCs with optional treatment with tranexamic acid and/or rFVIIa, but there continues to be a lack of clinical data in patients with bleeding associated with DOAC therapy.

Patient case 1: Elevated INR without bleeding

J.S. is a 72-year-old, 75-kg man with a history of hypertension, chronic AF, and ischemic stroke without residual deficits. His medications include losartan 100 mg PO twice daily, hydrochlorothiazide 12.5 mg PO daily, metoprolol 50 mg PO twice daily, and warfarin 2.5 mg PO daily (INR 2–3). Four days ago, he presented to his primary care physician with a 2-week history of cough productive of yellow sputum and fever to 100° F. At that time, he was prescribed doxycycline 100 mg PO twice daily for 14 days.

Today, J.S. presents to the anticoagulation clinic with an elevated INR of 6.1. His prior monthly INRs for the past 6 months were 2.8, 2.6, 2.2, 2.5, and 2.8. Upon interview, the patient states that he has not missed or taken any extra doses of warfarin. He denies changes in diet. The patient’s vital signs are blood pressure 120/70 mm Hg, heart rate 60 bpm, and afebrile. His hemoglobin is 14.5 g/dL (unchanged from 3 months ago) and the patient shows no overt signs of bleeding.

What is the most likely cause of an elevated INR in patient J.S.?
The addition of doxycycline has been shown to increase the INR and has been associated with bleeding.51 The mechanism of the interaction is not known.

According to current U.S. practice guidelines, how should this elevated INR in the absence of bleeding be managed?
Patient J.S. demonstrates an INR that is 3.1 (target of 2–3). He is not overtly bleeding. The patient has 10 days remaining of his 14-day course of antibiotics and he appears to be responding to therapy. Because the elevated INR is likely a result of a drug–drug interaction that is temporary, no long-term dosage change is necessary.

According both the 2012 ACCP Chest Guidelines and 2016 AC Forum Guidelines, 1–2 doses of warfarin may be held, the dose reduced temporarily then increased back to 2.5 mg daily after the course of doxycycline is completed. One option would be to hold 2 doses, and reduce the dose to 2 mg per day for 7 or 8 days then resume 2.5 mg daily.

Alternatively, the 2016 AC Forum guidelines offer an option of 1.25 mg or 2.5 mg of vitamin K in addition to holding the dose. Vitamin K is available as a nonprescription product at a strength of 100 mcg. In either situation, a repeat INR could be obtained in 3 days (after holding 2 doses) to reassess whether vitamin K is necessary and how many days the reduced maintenance dose should be prescribed for.

Patient case 2: Major bleeding with slightly elevated INR

R.L. is a 65-year-old, 75-kg woman with a history of stable ischemic heart disease (IHD), percutaneous coronary intervention 2 years ago for stable angina, hypertension, heart failure with preserved ejection fraction, and atrial fibrillation. She presents to the emergency department with hypotension and lower gastrointestinal bleeding. Her blood pressure is 100/68 mm Hg. Her medications taken prior to admission include warfarin 5 mg PO daily, aspirin 81 mg PO daily, enalapril 5 mg PO twice daily, and carvedilol 25 mg PO twice daily. Her laboratory tests include a normal chemistry panel, normal N-terminal pro-brain natriuretic peptide with a low hemoglobin of 9 g/dL, and elevated INR of 3.2. INRs over the past 3 months were 2.8, 2.7, 3.0, and 3.1. Her last hemoglobin 2 months ago was 13.9 g/dL. Her bleeding is classified as ISTH major bleeding with overt hemorrhage, hypotension, and a hemoglobin drop of more than 2 g/dL.

According to current practice guidelines, how should this elevated INR with major bleeding be managed?
This is a major bleed according to ISTH criteria with overt gastrointestinal bleeding, a 4.9 g/dL hemoglobin drop, and hypotension. All current home medications, including warfarin, should be stopped temporarily. The patient should be given normal saline cautiously because of her history of heart failure. Because of the presence of coronary artery disease (CAD), R.L.’s hemoglobin should be monitored frequently to assess whether blood product administration is necessary. Cardiology, gastroenterology, and hematology consults are appropriate for this patient. Radiographic imaging should be obtained to identify the source of her gastrointestinal bleeding. Treatments such as angiographic embolization should be performed as appropriate.

The initial treatment for an elevated INR with major bleeding should be IV vitamin K 5 mg or 10 mg as a slow infusion. A repeat INR should be obtained to assess the effect of vitamin K at 4–6 hours. Hemoglobin should be checked every 2 hours. If R.L.’s hemoglobin continues to fall or she remains unresponsive to fluids, administration of 4-factor PCC should be considered. For an INR of 3.2 in a 75-kg patient, the appropriate initial dose is 25 units/kg or 1875 factor IX units. The patient should be carefully monitored for thromboembolism following reversal.

Once hemostasis is achieved and the source of bleeding is identified, consideration must be given to the timing of reinitiation of anticoagulation. This patient has a CHA2DS2-VASc score of 5 with a risk of thromboembolism of 6.7% per year (moderate to high). Failure to restart anticoagulation following major gastrointestinal bleeding has been associated with a high stroke rate and excess mortality. It appears most appropriate to withhold warfarin for about 7 days and then restart the drug cautiously between 7 and 14 days post-bleed.52

This patient was also taking low-dose aspirin. Current recommendations for managing patients with CAD and AF suggest that anticoagulation alone is appropriate for patients with stable IHD and an indication for long-term anticoagulation.53,54 Therefore, this patient should not resume aspirin therapy.

Patient case 3: Emergency surgery during anticoagulation

P.M. is a 59-year-old man with a history of proximal left lower extremity deep vein thrombosis starting 2 months ago. He presents to the emergency department with a fractured right femur with bleeding following a motor vehicle accident. He is alert and oriented to person place and time. His vital signs are normal and stable. The patient requires immediate surgery to repair his femur. His only medication is dabigatran 150 mg PO twice daily, which he states was last taken 8 hours ago. He states he has not missed any doses in the past week. His chemistry panel and complete blood count are normal. His coagulation tests demonstrate an elevated activated partial thromboplastin time, INR, and thrombin time consistent with dabigatran effect.

Because this patient requires emergent surgery, how should his anticoagulation be reversed?
Idarucizumab 5 g (2 vials of 2.5 g each) can be administered as a rapid IV infusion. The onset of idarucizumab’s effect occurs within 10–30 minutes. The patient’s coagulation tests can be repeated. The best coagulation test to monitor reversal of dabigatran’s effect is the dilute thrombin time.50 A normal aPTT alone is insufficient to exclude a below-therapeutic dabigatran concentration. 50

Postoperatively, after hemostasis has been achieved, anticoagulation should be reinitiated because the patient has a recent deep vein thrombosis.

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