Should my patient with atrial fibrillation on hemodialysis be anticoagulated?

Whether patients with end-stage kidney disease (ESKD) and atrial fibrillation (AF) benefit from anticoagulation is a matter of controversy. 1,3 Although there may be some suggestion of benefit of warfarin for stroke prevention in this patient population, 2 there is also a higher concern for bleeding. 4-6 An increased risk of stroke among patients with ESKD and AF on warfarin has also been reported. 7

A 2018 Kidney Disease:Improving Global Outcomes (KDIGO) Controversies Conference concluded that there is “insufficient high-quality evidence” to recommend anticoagulation for prevention of stroke in patients with ESKD and atrial fibrillation. 8

However, the 2014 American College of Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm (HRS) guideline states that it is reasonable to consider warfarin therapy in patients with ESKD and non-valvular AF with CHA2DS2 -VASc score of 2 or greater (Class IIa recommendation, level of evidence B).8 Of interest, the FDA recently approved the use of a direct oral anticoagulant (DOAC), apixaban, in ESKD potentially providing an alternative to the use of warfarin when anticoagulation is considered.10

Perhaps the decision to anticoagulate patients with ESKD for atrial fibrillation is best made on a case-by-case basis taking into account a variety of factors, including the risk of thromboembolic event, the risk of bleeding complications as well as patient preference.

References

1. Genovesi S, Vincenti A, Rossi E, et al. Atrial fibrillation and morbidity and mortality in a cohort of long-term hemodialysis patients. Am J Kidney Dis 2008;51:255-62. https://www.ncbi.nlm.nih.gov/pubmed/18215703

2. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-35. https://www.ncbi.nlm.nih.gov/pubmed/22894575

3. Shah M, Avgil TM, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation2014;129:1196-203. https://www.ncbi.nlm.nih.gov/pubmed/24452752

4. Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis 2007;50:433-40. https://www.ncbi.nlm.nih.gov/pubmed/17720522

5. Holden RM, Harman GJ, Wang M, Holland D, Day AG. Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:105-10. https://www.ncbi.nlm.nih.gov/pubmed/18003768

6. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010;77:1098-106. https://www.ncbi.nlm.nih.gov/pubmed/20054291

7. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol2009;20:2223-33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754104/

8. Turakhia MP, Blankestijn PJ, Carrero J, et al. Chronic kidney disease and arrythias: conclusions from a Kidney Disease:Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J, ehy060. Published 07 March 2018. https://www.ncbi.nlm.nih.gov/pubmed/29522134

9. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2014;130:2071-104. http://circ.ahajournals.org/content/130/23/2071 

10. Moll S. Use of direct oral anticoagulants in patients on hemodialysis. Diffusion, October 11, 2017. http://www.hematology.org/Thehematologist/Diffusion/7794.aspx 

Contributed by Brad Lander, MD, Mass General Hospital, Boston, MA.

Should my patient with atrial fibrillation on hemodialysis be anticoagulated?

Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

There is virtually no utility to obtaining heritable thrombophilia testing in acute hospital setting. In fact, there are potential harms due to false-positive and false-negative results which in turn may lead to increasing anxiety in the patient and added cost due to repeat testing.

As many tests obtained as part of this workup are functional assays—eg, the protein S, C, or antithrombin activity, and activated protein C resistance (often used to screen for factor V Leiden)— they are easily impacted by the physiologic effects of acute thrombosis as well as all anticoagulants.1

More importantly, testing for inherited thrombophilia will not impact management in the acute setting, as decisions regarding duration of anticoagulation are often made later in the outpatient setting. The proper time to evaluate the patient for inherited thrombophilias (if indicated) is at least one week following discontinuation of anticoagulation (minimum 3 months from the time of the index event). 2 

Testing for antiphospholipid syndrome (APS) may be considered in this setting though it should be noted that the lupus anticoagulant assay is impacted by nearly every anticoagulant, resulting in frequent false-positive results1, and therefore should be performed before initiation of these agents (or delayed until later if anticoagulation has already begun). A false-positive result has downstream implications as many patients with acute, uncomplicated venous thromboembolism (VTE) are discharged on a direct oral anticoagulant (DOAC), and antiphospholipid syndrome is currently considered a relative contraindication to the use of DOACs in VTE.

References
1. Moll, S. “Thrombophilia: Clinical-practical aspects.” J Thromb Thrombolysis 2015;39:367-78. https://www.ncbi.nlm.nih.gov/pubmed/25724822
2. Connors JM. “Thrombophilia Testing and Venous Thrombosis.” N Engl J Med 2017; 377:1177-1187. http://www.nejm.org/doi/full/10.1056/NEJMra1700365 

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

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Continue reading “Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?”

Is there any utility to laboratory testing for inherited thrombophilia or antiphospholipid syndrome in my hospitalized patient with unprovoked acute pulmonary embolism?

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)?

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

Evidence supporting the efficacy of direct oral anticoagulants (DOACs) in obesity is limited. A major concern is the possibility of subtherapeutic anticoagulation in obese patients when standard doses of DOACs are used.

The International Society on Thrombosis and Haemostasis recommends1:

  • Standard fixed dosing of DOACs for patients with BMI ≤ 40 kg/m2 or weight ≤ 120 kg.
  • Avoiding DOACs in patients with BMI > 40 kg/m2 or weight > 120 kg. However, if a DOAC is needed, laboratory confirmation of therapeutic drug concentrations (eg, by checking anti-factor Xa depending on the agent) should be performed, and if subtherapeutic, a vitamin K antagonist (eg, warfarin) is recommended instead.

Based on the individual comparison of DOACs with warfarin in patients with “high” body weight (cut-off of 90 kg or 100 kg, depending on the study) and limited data, apixaban may be more effective in preventing recurrent venous thromboembolism or its related deaths. However, other DOACs, such as rivaroxaban, dabigatran, and edoxaban have also been used in patients with high body weight2.  

To add to the controversy, the efficacy of fixed dose dabigatran in obese patients has been questioned3 and some have recommended avoiding DOACs altogether in patients with BMI ≥ 35 kg/m2 or weight > 120 kg, until more data become available4.

As in many situations in medicine, a case-by-case decision based on clinical judgment and patient preferences may be the best way to go!

References

  1. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936273
  2. Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med 2015; 47: 61-8. https://www.ncbi.nlm.nih.gov/pubmed/25665582
  3. Breuer L, Ringwald J, Schwab S, et al. Ischemic Stroke in an Obese Patient Receiving Dabigatran. N Engl J Med 2013; 368: 2440–2. http://www.nejm.org/doi/pdf/10.1056/NEJMc1215900
  4. Burnett AE, Mahan CE, Vasquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE Treatment. J Thromb Thrombolysis 2016; 41: 206-32. https://www.ncbi.nlm.nih.gov/pubmed/26780747

 

Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

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)?