My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

 

References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral 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):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Should prothrombin complex concentrates be used to reverse anticoagulation from direct factor Xa inhibitors?

Due to insufficient and occasionally conflicting evidence, the use of prothrombin complex concentrates (PCCs) for reversal of direct factor Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban) is NOT recommended.1 This is because PCCs have no effect on the anti-Xa assay, the most accurate measure of anticoagulation for direct factor Xa inhibitors.

Although several in vitro and in vivo studies initially suggested that PCCs may be effective for this purpose, anti-Xa activity has not been measured in these studies2-4; PT and aPTT are not reflective of the anticoagulation activity of direct factor Xa inhibitors.

In fact, a 2014 study found no difference in the anti-Xa activity between 11 patients on rivaroxaban who were given a 4-factor PCC (Beriplex®, the European brand name for Kcentra®) and 12 patients on rivaroxaban receiving saline.5 Though small, this is the best published in vivo data to date examining the effect of 4-factor PCC on the anti-Xa levels of patients on direct factor Xa inhibitors.

A theoretical concern with the use of PCCs is increased risk of thrombosis when the therapeutic effect of these direct oral anticoagulant (DOACs) is gone (half-life ~12 h) while the thrombogenic effects of PCCs persist (eg, in critically ill, postoperative, or sedentary patients).

The good news is that more specific reversal agents are in the pipeline. 1 Stay tuned! 

 

References:

  1. Dzik WH. “Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal.” J Thromb Haemost 2015;13 (Suppl 1):S187-94. https://www.ncbi.nlm.nih.gov/pubmed/26149022
  2. Perzborn E, Heutmeier S, Laux V, et al. “Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro.” Thromb Res 2014 Apr;133:671-81. https://www.ncbi.nlm.nih.gov/pubmed/24529498
  3. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.” Circulation 2011 Oct 4;124:1573-9. https://www.ncbi.nlm.nih.gov/pubmed/21900088
  4. Zahir H, Brown KS, Vandell AG, et al. “Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate.” Circulation 2015 Jan 6;131:82-90. https://www.ncbi.nlm.nih.gov/pubmed/25403645
  5. Levi M, Moore KT, Castillejos CF, et al. “Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.” J Thromb Haemost 2014;12:1428-36. https://www.ncbi.nlm.nih.gov/pubmed/24811969

Contributed by Hanny Al-Samkari MD, Mass General Hospital, Boston, MA.

 

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Should prothrombin complex concentrates be used to reverse anticoagulation from direct factor Xa inhibitors?

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

 

Patients with atrial fibrillation (AF) who need percutaneous coronary intervention (PCI) after acute coronary syndrome or for stable angina pose a treatment challenge as oral anticoagulants (OACs) and dual antiplatelet therapy (DAPT) are often used concurrently to decrease the risk of systemic thromboembolism and stent thrombosis. However, “triple therapy”, including aspirin, a P2Y12 inhibitor, and an OAC (eg, warfarin or a direct oral anticoagulant-DOAC), also increases the risk of bleeding, necessitating several recent landmark trials to better address the subject.

Two modest-sized RCTs (WOEST and ISAR-TRIPLE) reported that when compared to triple therapy (DAPT plus warfarin), double therapy (single antiplatelet agent plus INR-targeted warfarin) is associated with reduced risk of bleeding complications without an increased risk of thrombotic events. 1,2

Two larger RCTs, PIONEER AF-PCI and RE-DUAL PCI, studied rivaroxaban and dabigatran, respectively, in patients with non-valvular AF undergoing PCI and found a reduction in bleeding events in patients receiving double therapy (single antiplatelet agent plus DOAC) compared to triple therapy (DAPT plus warfarin), without an increased risk of thrombotic complications. 3,4

Collectively, these studies suggest that it may be safe to treat patients with increased risk of bleeding with double therapy (even immediately following PCI) without an increase in thrombotic events. If triple therapy is elected, duration should be minimized, clopidogrel should be preferred over more potent P2Y12 inhibitors, and a PPI should be considered.

 

References:

  1. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381:1107-15. https://www.ncbi.nlm.nih.gov/pubmed/23415013
  2. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65:1619-29. https://www.ncbi.nlm.nih.gov/pubmed/25908066
  3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1611594
  4. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. Published online, Aug, 27, 2017. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708454

 

Contributed by Amulya Nagarur, MD, Mass General Hospital, Boston, MA

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

What is the significance of a prolonged activated partial thromboplastin time (aPTT) in my patient with suspected antiphospholipid syndrome (APS)?

APS is an acquired hypercoagulable state which presents classically as recurrent arterial and/or venous thrombosis and is a major cause of late first- and second-trimester spontaneous fetal loss. In addition to thrombotic complications, diagnosis of APS requires the presence of ≥ 1 of the following antiphospholipid antibodies on 2 occasions ≥12 weeks apart: 1) anti-ß2-glycoprotein 1 antibodies; 2) anticardiolipin antibodies; and 3) lupus anticoagulant (LA)1.  

An unexpected prolongation of aPTT may be a clue to the presence of APS and may be explained by the in vitro prevention of the assembly of the prothrombinase complex—which catalyzes the conversion of prothrombin to thrombin— by LA2,3.  

Because the phospholipid component of the reagent used in aPTT tests determines its sensitivity to LA, aPTT results may vary, influenced by the type and concentration of phospholipids used in the assay. Other factors such as acute phase reaction associated with increased fibrinogen and factor VIII levels may also impact the results by shortening the aPTT and potentially masking a weak LA2.

 

 

References 

  1. Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome.Blood. 2009;113:985-94.
  2. 2. Abo SM, DeBari VA. Laboratory evaluation of the antiphospholipid syndrome. Ann Clin Lab Sci 2007;37:3-14.
  3. Smock KJ, Rodgers GM. Laboratory identification of lupus anticoagulants. Am J Hematol. 2009;84(7):440-2.

 

 

Contributed by Ricardo Ortiz, medical student, Harvard Medical School

What is the significance of a prolonged activated partial thromboplastin time (aPTT) in my patient with suspected antiphospholipid syndrome (APS)?

My hospitalized patient has developed hyperkalemia while on heparin prophylaxis. Can heparin really cause hyperkalemia and what is its mechanism?

Heparin is one of the most overlooked causes of hyperkalemia in hospitalized patients, occurring in 5-8% of treated patients, including those on thromboprophylaxis1.

The risk of heparin-induced hyperkalemia is increased in the elderly, those with preexisting diabetes mellitus or renal insufficiency, as well patients on concomitant use of certain drugs such as spironolactone, ACE inhibitors, NSAIDs, and trimethoprim2.  Hyperkalemia is usually detected after at least 3-4 days of treatment with subcutaneous heparin, and usually resolves within a few days of  discontinuation of therapy1,2.  Fractionated heparin products such as enoxaparin may also be associated with hyperkalemia2 but the risk appears to be lower1.

The mechanism of heparin-induced hyperkalemia appears to be through suppression of aldosterone synthesis by inhibiting the function of the glomerulosa zone of the adrenal medulla2,3.  Such inhibitory action is usually of no consequence when renal function is normal and potassium excretion is not otherwise impaired.

 

References

  1. Potti A, Danielson B, Badreddine R, et al. Potassium homeostasis in patients receiving prophylactic enoxaparin therapy. J Thromb Haemost 2004;2:1208-9. http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2004.00791.x/pdf
  2. Thomas CM, Thomas J, Smeeton F, et al. Heparin-induced hyperkalemia. Diabetes Res Clin Pract 2008;80:e7-e8. https://www.ncbi.nlm.nih.gov/pubmed/18343525
  3.  Liu AA, Bui T, Nguyen HV, et al. Subcutaneous unfractionated heparin-induced hyperkalemia in an elderly patient. Australas J Ageing 2009;28:97. https://www.ncbi.nlm.nih.gov/pubmed/19566805
My hospitalized patient has developed hyperkalemia while on heparin prophylaxis. Can heparin really cause hyperkalemia and what is its mechanism?

Can novel oral anticoagulants (NOAC) be reversed?

Since their relatively recent introduction, a major concern over NOAC use has been the lack of available reversal agents akin to vitamin K or fresh frozen plasma used to reverse anticoagulation effect of warfarin.

Fortunately, there are currently three potential NOAC reversal agents on breakthrough or fast-track status at the FDA, facilitating their rapid approval based on phase III trials:

  • Idarucizumab, a humanized mouse antibody fragment, or Fab, targeted specifically for reversal of dabigatran
  • Andexanet alfa, a class-specific antidote for reversal of direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), as well as an indirect factor Xa inhibitor, enoxaparin
  • Ciraparantag (PER977), a synthetic water-soluble compound that reverses direct thrombin (dabigatran), direct factor Xa (apixaban, rivaroxaban, edoxaban), and indirect factor Xa inhibitors (enoxaparin) (1). 

So stay tuned…Help may be on the way!

1. Ansell JE. Universal, class-specific, and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41:248-52.  https://www.ncbi.nlm.nih.gov/pubmed/26449414

Contributed by William L. Hwang, MD, Mass General Hospital, Boston, MA.

Can novel oral anticoagulants (NOAC) be reversed?

How should I choose between the novel oral anticoagulants (NOACs)?

Although warfarin has long been the standard treatment for venous thromboembolism (VTE) and thomboprophylaxis in atrial fibrillation (AF), the need for its frequent monitoring, potential drug interactions, and narrow therapeutic window made it far from ideal. Since 2009, NOACs have become viable alternative agents owing to their more predictable and safer pharmacological profiles. NOACs include several direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and a direct thrombin inhibitor (dabigatran). Approved indications include: (1) thromboprophylaxis in nonvalvular AF; (2) treatment of deep venous thrombosis or pulmonary embolism; and (3) primary prevention of postoperative VTE. 

Compared to warfarin, NOACs are associated with a reduced risk of intracranial hemorrhage, and in the case of apixaban, lower risk of gastrointestinal bleeding; rivaroxaban and edoxaban have been associated with a higher risk of gastrointestinal bleeding.   Apixaban is also the only NOAC whose dose can be safely reduced in chronic kidney disease, including those on hemodialysis. 

References

 

1. Baber U, Mastoris I, and Mehran R. Balancing ischaemia and bleeding risks with novel oral anticoagulants. Nat Rev Cardiol 2014;11:693-703.  https://www.ncbi.nlm.nih.gov/pubmed/25367652 

2. Ansell JE. Universal, class-specific, and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41:248-52. https://www.ncbi.nlm.nih.gov/pubmed/26449414

 

Contributed by William L. Hwang, MD, Mass General Hospital, Boston, MA

How should I choose between the novel oral anticoagulants (NOACs)?