July 2015 FAQs

What are the new recommendations for 13-valent pneumococcal conjugate vaccine (PCV13) in older adults?

Background

Streptococcus pneumoniae (S. pneumoniae) is a leading cause of infectious disease in the United States, with significant implications in a wide variety of infections including bacteremia, meningitis, pneumonia, sinusitis, and acute otitis media. Currently there are 2 different vaccines recommended to prevent pneumococcal infections. In 1983, the 23-valent pneumococcal polyvalent vaccine (PPSV23 – Pneumovax® 23) was approved for the prevention of pneumococcal disease in adults and children 2 years of age or older who are at increased risk of pneumococcal disease and those 50 years of age and older.¹ In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13 – Prevnar 13®) was initially approved for prevention of invasive S pneumoniae infections and prevention of otitis media in children 6 weeks to 5 years of age.² This indication for prevention of invasive pneumococcal disease (IPD) was expanded to include patients ≥ 50 years of age on December 30, 2011. On June 20, 2012, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of PCV13 in patients > 19 years of age with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid (CSF) leak, or cochlear implants.³ Recently the ACIP updated their recommendations for PCV13, recommending use in healthy adults 65 years of age and older in addition to their previous recommendations for PCV13 use as part of a 4-dose series in infants at 2, 4, 6, and 12 to 15 months of age and in adult patients with immunocompromising conditions.^4,5 It is anticipated that these new recommendations will decrease the incidence of IPD in adults 65 years of age and older who had a reported 13,500 cases of IPD in 2013.⁶

Comparison of PCV13 and PPSV23

The PPSV23 vaccine is a sterile solution of purified capsular polysaccharides from 23 strains of S pneumoniae.¹ In contrast, PCV13 is comprised of S pneumoniae capsular antigen polysaccharides linked to a non-toxic diphtheria protein.⁷ The most notable difference between PCV13 and PPSV23 is the S pneumoniae serotypes covered by each of the vaccines, which are described in Table 1.^1,7 Although PCV13 provides protection against fewer S pneumoniae serotypes than PPSV23, PCV13 has been shown to be noninferior, and sometimes superior, to PPSV23 in functional antibody response for certain serotypes.^7-9 Two immunogenicity studies conducted in older adults suggest possible improved immune response with PCV13 compared to PPSV23.^8,9 In one study with adults 60 to 64 years of age with no pneumococcal immunization history, PCV13 elicited titers to the 12 serotypes common to both pneumococcal vaccines that were comparable with or higher than the PPSV23 titers.⁸ In adults 70 years of age and older who had been immunized with PPSV23 at least 5 years prior, PCV13 produced titers that were comparable for 2 of the serotypes and higher for the remaining 10 serotypes common between the 2 vaccines.⁹

Table 1. Comparison of S pneumoniae serotype coverage between PCV13 and PPSV23.^1,7

In accordance with the decision by the Food and Drug Administration (FDA) to approve PCV13 for use in adults > 50 years of age through the accelerated approval pathway in 2011, the CAPiTA trial (a randomized, double-blind, placebo controlled trial) was conducted in 85,000 adults > 65 years of age. The trial was conducted from 2008 to 2013 in the Netherlands to assess the impact of PCV13 on pneumococcal disease.^10,11

Patients were eligible for enrollment if they had no episodes of pneumococcal vaccination and no immunocompromising conditions.¹¹ A total of 90 patients treated with placebo had a confirmed community-acquired pneumonia compared with 49 who received the vaccine (45.6% vaccine efficacy; 95% confidence interval [CI] 21.8% to 62.5%; p<0.001). PCV13 showed a 45.0% (95% CI 14.2% to 65.3%; p=0.007) efficacy against vaccine-type nonbacteremic/noninvasive pneumococcal pneumonia and a 75.0% (95% CI 41.4% to 90.8%; p<0.001) efficacy against vaccine-type IPD. Serious adverse events were similar between the groups, but there were more local and systemic events in the PCV13 group. These events were mostly mild to moderate in nature, and included redness, swelling, pain, and limitation of arm movement.

Current Recommendations for the Use of PCV13 and PPSV23 in Adults

After reviewing current data regarding efficacy, safety, and immunogenicity of PCV13, the ACIP now recommends adults > 65 years of age receive a dose of PCV13, followed by a dose of PPSV23 6 to12 months later (minimum interval between vaccines is 8 weeks; the vaccines should not be coadministered).¹⁰  Recommendations for patients > 65 years of age who have been previously vaccinated with PPSV23 are summarized in Table 2. The recommendations for patients aged > 19 years old with immunocompromising conditions, functional or anatomic asplenia, CSF leak, or cochlear implants remain the same from the 2012 recommendations (Table 3).³

Table 2. Summary of ACIP recommendations for use of PCV13 in adults > 65 years of age.¹⁰

Table 3. Summary of ACIP recommendations for use of PCV13 in immunocompromised^a adults 19 to 64 years of age.³

^aImmunocompromised patients include those with functional or anatomic asplenia, congenital or acquired immunodeficiencies, HIV, leukemia, lymphoma, Hodgkin’s disease, generalized malignancy, solid organ transplant, multiple myeloma, chronic renal failure or nephrotic syndrome, chronic use of immunosuppressing medications including systemic long-term corticosteroids and radiation therapy, CSF leaks, and cochlear implants.

References

1. Pneumovax-23 [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2015.
2. FDA expands use of Prevnar 13 vaccine for people ages 50 and older. Food and Drug Administration Website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm285431.htm. Updated March 6, 2014. Accessed May 22, 2015.
3. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61(40):816–819.
4. Nuorti JP and Whitney CG. Prevention of pneumococcal disease among infants and children – use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2010;59(RR-1111):1-18
5. Bennett NM, Whitney CG, Moore M, Pilishvili T, Dooling KL. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;61(40):816-819.
6. Pneumococcal vaccines: CDC answers your questions. Centers for Disease Control website. http://www.immunize.org/catg.d/p2015.pdf. Updated December 2014. Accessed May 29, 2015.
7. Prevnar-13 [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2015.
8. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 2013;31(35):3577–3584.
9. Jackson LA, Gurtman A, Rice K, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 2013;31(35):3585–3593.
10. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine  and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63(37):822-825.
11. Bonten MJ, Huijts SM, Bolkenbaas M, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med. 2015;372(12):1114-1125.

Prepared by:

Karolyn Horn, PharmD PGY1 resident

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

July 2015

The information presented is current as of May 22, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What is the safety information available on the use of NOACs in patients with renal impairment?

The information available on use of the non-vitamin K oral anticoagulants (NOACs) in patients with renal impairment is derived from pharmacokinetic studies, case reports, open-label trials, subgroup analyses, and meta-analyses.  Information from these sources is summarized below.  Individual clinical trials evaluating outcomes in patients with renal impairment are not described separately since the meta-analyses include results of those clinical trials.  However; 2 open-label edoxaban trials and 1 retrospective cohort dabigatran study, not included in the meta-analyses, are included in this summary.

Pharmacokinetic Studies

Dabigatran

The pharmacokinetics of a single oral dose of dabigatran was compared in patients with renal impairment (n=23) and hemodialysis (n=6) to healthy volunteers (n=6).¹  Patients with renal impairment were classified based on creatinine clearance (CrCl) to have mild (CrCl 51 to 80 mL/min), moderate (CrCl 31 to 50 mL/min), or severe (CrCl < 30 mL/min, range in patients was 11 to 30 mL/min) renal impairment.  Healthy volunteers had CrCl >80 mL/min.  Patients on hemodialysis received 50 mg dabigatran prior to a 4-hour dialysis session. All other patients received a 150 mg dabigatran dose.  All patients were Caucasian with a mean age ranging from 40 to 56 years across groups.  After a single 150 mg oral dose of dabigatran in volunteers, the half-life (t_1/2) doubled from 13 hours in healthy volunteers to 27 hours in patients with severe renal impairment.  The area under the curve (AUC) of plasma drug concentration over time was 1.5, 3.1 and 6.3 times higher in patients with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. The maximum plasma drug concentration (Cmax) was about 2 times greater in patients with severe renal impairment compared to patients with normal renal function.  In patients with moderate renal impairment, the half-life was 18 hours and Cmax increased by 1.7 fold.  Prior to the start of hemodialysis, the AUC and t_1/2 were 2 times higher compared to healthy subjects. Hemodialysis removed approximately 68% of the drug at 4 hours.

Using data from over 9500 patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, a pharmacokinetic modeling and simulation study aimed to determine an appropriate dose for patients with severe renal impairment.²  According to the simulation, a dabigatran dose of 75 mg twice daily used for patients with atrial fibrillation (AF) and severe renal impairment (CrCl 15 to 29 mL/min) provided the same plasma level concentrations achieved in patients with AF and CrCl > 30 mL/min who received 150 mg twice daily.

Dabigatran pharmacokinetics was evaluated in 10 patients on hemodialysis who received a single 110 mg dose.³  The age of the patients ranged from 25 to 69 years.  The Cmax achieved within 2 hours of dose administration was similar to concentrations achieved in patients with no renal impairment who received a single 150 mg dose.  Elimination of dabigatran was significantly lower off dialysis compared to during a hemodialysis session.  Anticoagulant activity measured by the Hemoclot assay demonstrated greater anticoagulant activity 2 to 3 hours after dose administration (corresponding to Cmax) compared to baseline; however, reduced to baseline by the end of a 4-hour dialysis session and after 24 and 48 hours of dose administration.

Rivaroxaban

The pharmacokinetics of a single oral rivaroxaban10 mg dose in volunteers with impaired renal function (n=24) was compared to subjects with normal renal function (n=8).⁴  Categories of renal function based on CrCl were classified as: normal, ≥ 80 mL/min; mild impairment, 50 to 79 mL/min; moderate impairment, 30 to 49 mL/min; severe impairment, < 30 mL/min (range 17 to 26 mL/min).  Creatinine clearance was calculated as a 24-hour clearance based on serum and urine creatinine concentrations.  Each group consisted of 8 subjects.  The mean age range across groups was 42 to 60 years.  The AUC increased by 44%, 52%, and 64% in patients with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function.  The t ½ increased from 8.3 hours in subjects with normal renal function to 9.5 hours in patients with severe renal impairment. With respect to pharmacodynamic activity, Factor Xa inhibition increased in patients with mild, moderate, and severe renal impairment by 50%, 86%, and 100%, respectively, and prothrombin time (PT) prolongation increased by 4%, 17%, and 20%, respectively.  

Apixaban

Published literature on the pharmacokinetics of apixaban in patients with renal impairment is limited.  Results of an open-label pharmacokinetic study obtained from the product’s manufacturer demonstrated variable effects on apixaban concentrations in patients with varying degrees of renal impairment.⁵  The Cockgroft-Gault equation was used to calculate CrCl.  Renal function was categorized as normal in subjects with CrCl > 80 mL/min (n=8), mild renal impairment if CrCl 51 to ≤ 80 mL/min (n=10), moderate if CrCl 30 to 50 mL/min (n=7), and severe renal impairment if CrCl < 30 mL/min and not on dialysis (n=7).  All subjects received a single dose of apixaban 10 mg orally.  A variable change in the mean Cmax occurred in subjects with renal impairment compared to subjects with normal function; a 2.2% increase, a 28% increase, and a 6.2% decrease in Cmax was observed in mild, moderate, and severe renal impairment, respectively. Similarly, subjects with moderate renal impairment had the greatest increase in AUC (77.6%) from the mean AUC observed with normal renal function compared to subjects with mild (30.6%) or severe renal impairment (26%).  The half-life of apixaban in subjects with normal renal function was 15.1 hours compared to 14.6 hours, 17.6 hours, and 17.3 hours in subjects with mild, moderate, and severe renal impairment, respectively.  Factor Xa inhibition was similar across various levels of renal function.  A single 5 mg dose of apixaban administered to patients receiving hemodialysis demonstrated a 17% increase in AUC after a hemodialysis session started 2 hours after drug administration. ⁶

A pharmacokinetic model-based study evaluated factors affecting apixaban exposure using data obtained from a phase II study and found renal function as a covariate of total body clearance and AUC.⁷ The median trough concentration of apixaban increased by 70% and 24% in patients with moderate (n=53) and mild renal impairment (n=308), respectively, compared to patients with normal renal function (n=492).  Total body clearance decreased by 40% with moderate renal impairment and by 22% with mild renal impairment.  Patients with moderate renal impairment were older (76 vs. 67 years) and weighed less (68 vs. 82 kg) compared to patients with normal renal function.  Taking into account the risk of bleeding and risk of VTE with apixaban exposure, the authors of this study concluded that dose adjustment of apixaban is not necessary in patients with moderate renal impairment.  Apixaban exposure in patients with severe renal impairment and on dialysis was not evaluated. 

Edoxaban

The pharmacokinetics of a 15 mg edoxaban dose was evaluated in 40 subjects with normal renal function (CrCl > 80 mL/min), renal impairment categorized as mild (CrCl 50 to 80 mL/min), moderate (CrCL 30 to 49 mL/min), and severe (CrCl < 30 mL/min, not on dialysis) and in patients on peritoneal dialysis.⁸  The mean half-life increased from 8.6 hours in subjects with normal renal function to 9.4 hours, 16.9 hours, and 12.2 hours in patients with moderate renal impairment, severe renal impairment, and on peritoneal dialysis, respectively.  Total systemic exposure (AUC) increased by 32%, 74%, 72% and 93% in patients with mild, moderate, and severe renal impairment and on peritoneal dialysis, respectively.  Although plasma clearance was lower in patients with renal impairment, there were no statistically significant increases in Cmax.

In a population-based pharmacokinetic analysis that pooled data from 4 studies, the renal clearance of edoxaban was found to have a linear correlation to CrCl and nonrenal clearance was significantly decreased by increasing age and lower body weight.⁹  Based on results of pharmacokinetic modeling, a 50% dose reduction of edoxaban in patients with severe renal impairment is recommended.  A recent pharmacokinetic study of edoxaban in patients requiring hemodialysis evaluated a single 15 mg edoxaban dose and also concluded that this lower dose was well tolerated in patients on hemodialysis.¹⁰  Additionally, hemodialysis did not demonstrate significant reductions in edoxaban plasma concentrations.

Case reports

Dabigatran

Several case reports of adverse bleeding outcomes associated with the use of dabigatran in patients with renal impairment have been published.^11-17  A majority of the reports involved patients who were 70 years of age and older with moderate to severe renal impairment.  Dabigatran doses ranged from 75 to 150 mg twice daily.  Adverse outcomes included GI bleeding, hemopericardium, retroperitoneal and pleural hemorrhage, rectal bleeding, epistaxis, and hematuria.  In a retrospective review of dabigatran cases reported to the American Association of Poison Control Centers (AAPCC), characteristics of the cases and adverse outcomes were evaluated.¹⁸  Between October 2010 and December 2012, 802 reports of dabigatran exposure were received. Of these, 733 (91%) reports occurred in adults of which 70% occurred in patients 65 years and older. The most common adverse outcomes reported were bleeding, prolonged prothrombin time or aPTT, hypotension, or renal failure.  Of the total cases, 13 deaths were reported, 23 cases were classified as having a major outcome, and 50 cases had a moderate outcome.  Twelve of the 13 deaths occurred in patients over the age of 65 years and all of the cases that had a major outcome occurred in the older population.  Six of the 13 deaths involved patients with increased serum creatinine or renal failure and an age range of 74 to 93 years.  The use of dabigatran 150 mg occurred in 4 of the 6 cases of death and 75 mg was used in the other 2 cases.  Use of dabigatran in patients with renal dysfunction and increased age were concluded to be factors that could lead to serious outcomes.

Rivaroxaban

An 88-year old female, with atrial fibrillation and renal insufficiency, who refused warfarin prophylaxis, was given rivaroxaban 15 mg once daily.¹⁹  After 11 days of use, rivaroxaban was discontinued due to concerns of bleeding.  Although there was no evidence of bleeding, anti-factor Xa-activity, PT, INR and aPTT remained elevated 28 hours after drug discontinuation indicating a longer than usual duration of action possibly due to higher plasma drug concentrations and/or reduced drug elimination.

Open-label/retrospective cohort trials

Edoxaban

Two open-label Phase 3 trials conducted in Japan aimed to compare outcomes of dose-adjusted edoxaban in patients with severe renal insufficiency.^20,21  In one trial of 93 patients with non-valvular AF, patients with CrCl between 15 and 29 mL/min received edoxaban 15 mg once daily and patients with CrCl ≥ 50 mL/min  were randomized to either edoxaban 30 mg or 60 mg once daily for 12 weeks.²⁰  Major bleeding, clinically relevant non-major bleeding (CRNM), any bleeding, and adverse drug reactions were evaluated to compare safety.  Plasma drug concentrations, PT, INR, and aPTT were also compared between the 3 treatment groups.  There were no reports of major or CRNM bleeding in the edoxaban 15 mg group. The incidence of any bleeding with edoxaban 15 mg, 30 mg, and 60 mg was 20%, 22.7%, and 23.8%, respectively and the differences in incidences were not statistically significant.  All reports of bleeding with edoxaban 15 mg were categorized as minor.  Plasma edoxaban concentrations after 2 weeks of use in patients with severe renal impairment taking edoxaban 15 mg were similar to patients with less renal impairment taking edoxaban 60 mg.  The PT, INR and aPTT values in patients with severe renal impairment on edoxaban 15 mg fell between those taking edoxaban 30 mg and 60 mg.  The authors concluded that use of a lower dose of edoxaban 15 mg for 12 weeks in patients with severe renal impairment had similar safety and plasma and biomarker concentrations compared to patients with normal or mild renal impairment taking higher doses.

In another short-term study of elderly Japanese patients undergoing lower limb orthopedic surgery, the safety of renally dosed edoxaban for VTE prophylaxis was evaluated.²¹ Patients with CrCl between 15 and < 20 mL/min received edoxaban 15 mg daily (n=7), those with CrCl between 20 and < 30 mL/min were randomized to either edoxaban 15 mg daily (n=22) or fondaparinux 1.5 mg SC daily (n=20) and patients with CrCl between 50 and ≤ 80 mL/min received edoxaban 30 mg daily (n=30).  Treatment was continued for 11 to 14 days and follow-up occurred 25 to 35 days after the last dose. Patient’s mean age ranged from 78 to 92 years; a higher percentage of patients with a body weight < 60 kg received edoxaban 15 mg (95.5%) compared to fondaparinux (90%) and edoxaban 30 mg (73.3%). The incidence of any bleeding with edoxaban 15 mg, 30 mg, and fondaparinux was 20.7%, 33.3%, and 40%, respectively and the differences in incidences were not statistically significant.  The incidence of CRNM bleeding was 3.4%, 6.7%, and 5% with edoxaban 15 mg, 30 mg, and fondaparinux, respectively. No major bleeding events were reported in the any of the treatment groups.  A majority of the reports of bleeding with edoxaban 15 mg were categorized as minor.  Predose edoxaban plasma concentrations were higher in the edoxaban 15 mg in patients with the worst renal function compared to other groups; however, postdose concentrations, PT and aPTT were not significantly different between groups.  According to the authors, these results demonstrated that edoxaban 15 mg in elderly patients with severe renal impairment who undergo orthopedic surgery is well tolerated.  The lack of difference between treatment groups may have been due to the smaller than planned sample size needed to find a significant difference.

Dabigatran

A recent retrospective cohort study aimed to determine underlying patient factors associated with gastrointestinal (GI) bleeding and dabigatran use.²²  Using a US insurance database, over 20,000 patients who received dabigatran for nonvalvular atrial fibrillation between October 2010 and December 2012 were identified.  Gastrointestinal bleeding occurred in 446 (2.1%) of these patients.  Patients who had renal impairment, heart failure, alcohol abuse, previous H.pylori infection, concomitant antiplatelet or digoxin use, or who were over the age of 55 years had a higher risk of experiencing a GI bleed with dabigatran use.  The adjusted hazard ratio (HR) for experiencing a GI bleed with dabigatran use was 1.67 (95% CI 1.24-2.25). Furthermore, renal dose adjustment of dabigatran did not appear to affect the risk of GI bleeding.

Meta-analyses

Three recent meta-analyses have sought to compare efficacy and safety outcomes of NOACs to warfarin in patients with renal impairment from large clinical trials.^23-25 The most recent analysis by Nielsen and colleagues evaluated outcomes from 7 trials involving a total of over 72,000 patients with AF receiving 1 of the 4 agents for stroke prophylaxis.²³  Efficacy outcomes included stroke or systemic embolism and the safety outcome was major bleeding. These outcomes were stratified according to baseline renal function.  Renal function was classified as normal for patients with CrCl ≥ 80 mL/min; mild renal impairment as CrCl between 50 and 79 mL/min, and moderate renal impairment as CrCl between 25 and 49 mL/min.  The ARISTOTLE study (apixaban vs. warfarin) excluded patients with CrCl <25 mL/min and all other studies excluded patients with CrCl < 30 mL/min.  The Cockgroft-Gault equation was used to calculate CrCl in most studies.  For trials involving rivaroxaban and apixaban, doses were adjusted for renal impairment as outlined in the product’s labeling described in the Table. In the edoxaban study, patients were randomized to either 60 mg or 30 mg and the dose was reduced by 50% in patients with moderate renal impairment (CrCl 30 to 50 mL/min). In the dabigatran studies, patients received either dabigatran 110 mg twice daily or 150 mg twice daily; the dose was not adjusted based on renal function.

Compared to warfarin, major bleeding was significantly less with dabigatran 110 mg (HR 0.76, 95% CI 0.62 to 0.94) and apixaban (HR 0.77, 95% CI 0.65 to 0.94) in patients with mild renal impairment.²³ There was no difference in major bleeding between warfarin and dabigatran 150 mg.  Compared to warfarin, efficacy was improved with apixaban (HR 0.74, 95% CI 0.56 to0.97) and dabigatran 150 mg (HR 0.68, 95% CI 0.50 to 0.92) in patients with mild renal impairment.  No difference in efficacy was observed between warfarin and dabigatran 110 mg. Results for other NOACs were not reported in this group of patients.

Hazard ratios for safety and efficacy were reported for all NOACs in patients with moderate renal impairment.²³  Of these, only apixaban (HR 0.50, 95% CI 0.38 to 0.66), edoxaban 30 mg (HR 0.31, 95% CI 0.23 to 0.42), and edoxaban 60 mg (HR 0.63, 95% CI 0.50 to 0.81) had a lower risk of bleeding compared to warfarin.  All other agents demonstrated no difference in the risk of bleeding compared to warfarin. No difference in efficacy was reported between warfarin and the other NOACS except for dabigatran 150 mg (HR 0.56, 95% CI 0.37 to 0.85).

Indirect comparisons of safety and efficacy between the NOACs were also conducted.²³  In patients with mild renal impairment, dabigatran 110 mg and apixaban were safer compared to rivaroxaban; edoxaban 30 mg had less risk of major bleeding compared to all other NOACs.  Greater efficacy was observed in patients with mild renal impairment with rivaroxaban 10 mg and dabigatran 150 mg compared to edoxaban 30 mg.  The risk of major bleeding in patients with moderate renal impairment was lower with edoxaban 30 mg compared to all other NOACs; apixaban also had a lower risk of bleeding compared to both doses of dabigatran, rivaroxaban, and edoxaban 60 mg. In this group of patients, efficacy outcomes were similar when comparing NOACs, except dabigatran 150 mg demonstrated greater efficacy compared to edoxaban 30 mg. 

Evaluating the agents that demonstrated greater safety and similar efficacy according to the results of the analysis, the authors concluded that for patients with mild renal impairment the use of dabigatran 110 mg, apixaban, or edoxaban 30 mg are preferred and for patients with moderate renal impairment, apixaban is suggested as the preferred agent.²³  It is unclear why edoxaban 30 mg would be preferred in patients with mild renal impairment as its efficacy was not found to be similar to dabigatran or rivaroxaban.

Two other meta-analyses have also evaluated similar safety and efficacy outcomes in patients with varying levels of renal impairment but neither analysis included edoxaban trials.^24,25  In the analysis by Harel and colleagues, results were reported in patients with either CrCl <50 mL/min or CrCl >80 mL/min.²⁴  Studies evaluating NOAC use for AF or VTE secondary prophylaxis were included (n=8 studies).  Although overall NOAC use was not significantly different with respect to safety and efficacy compared to warfarin, subgroup analysis of individual agents revealed some differences.  Compared to warfarin, dabigatran demonstrated a lower risk of bleeding in patients with CrCl ≥ 80 mL/min (RR 0.72, 95% CI 0.57 to 0.91) based on pooled results of 3 studies.  Based on 1 study, apixaban had less bleeding risk compared to warfarin in patients with CrCl ≤ 50 mL/min (RR 0.52, 95% CI 0.40 to 0.68).  

In the meta-analysis of 10 studies involving patients with AF or VTE, renal impairment was defined similarly to the analysis by Nielsen.²⁵  Moderate renal insufficiency was defined as CrCl between 30 and 49 mL/min and mild as CrCl between 50 and 79 mL/min.  The analysis demonstrated less major and non-major bleeding in patients with mild renal insufficiency with NOACs compared to warfarin in patients with AF and similar bleeding risks compared to LMWH or LMWH followed by VKA in patients with VTE. In patients with moderate renal impairment, there was no difference in major or non-major bleeding rates with overall NOAC use or with individual agents compared to warfarin.  The authors concluded that NOACs are safe to use in moderate renal impairment when given at recommended doses.

Conclusion

Pharmacokinetic studies demonstrate accumulation of NOACs in renal impairment. The extent of accumulation varies among the agents which can be explained by the varied degree of renal excretion of each agent (see Table).  Of the 4 agents, apixaban has the lowest extent of renal excretion and the limited pharmacokinetic data demonstrate a variable effect of renal impairment on drug accumulation.  Age and body weight are additional factors to consider in patients with renal impairment when determining appropriate apixaban dosing.  When evaluating the results of any of these pharmacokinetic studies, however, some factors to consider are that the pharmacokinetics are based on a single dose of the drug rather than repeated doses, the classification of renal impairment was not similar across the studies, all agents have not been studied in dialysis patients, and the age of the patients included was relatively young.

Most of the available case report literature on NOACs is with dabigatran but this may be due to it being the first agent available for use.  Important information that can be derived from these case reports is that adverse events occurred in some cases despite dose adjustment and a majority of the events occurred in patients 70 years and older. In a large retrospective cohort study, renal impairment and age greater than 55 years were identified as factors associated with GI bleeding in dabigatran users.

Open-label studies evaluating the safety of adjusted doses of edoxaban in patients with renal impairment demonstrate a low incidence of bleeding with use of 15 mg for patients with severe renal impairment. The efficacy, however, of this lower dose was not evaluated in these open-label studies.  Furthermore, according to the product labeling, the current recommended dose of edoxaban in patients with CrCl as low as 15 mL/min is 30 mg once daily. However, data supporting safety of edoxaban 30 mg in severe renal impairment is limited as the edoxaban trial that is evaluated in the meta-analysis by Nielsen excluded patients with CrCl <30 mL/min. 

Results of meta-analyses suggest that most agents demonstrated no difference in bleeding compared to warfarin.  There is a suggestion that perhaps apixaban may be safer in patients with renal impairment; however, the data is based on only 2 trials.  A separate apixaban meta-analysis of 6 trials did not demonstrate a difference in major bleeding with apixaban compared to warfarin, enoxaparin, or aspirin in patients with moderate to severe renal impairment (defined as CrCl < 50 mL/min).²⁶  

Based on currently available data, dose adjustments of NOACs are recommended for patients with renal impairment.  The Table below provides the labeled recommendations for dose adjustment based on renal function and indication.  The Cockgroft-Gault equation is recommended by the product manufacturers to estimate CrCl.  Although not described in studies, the manufacturers of rivaroxaban, dabigatran, and edoxaban recommend use of actual body weight when estimating CrCl.^27-29  No specific recommendation on weight was provided by the manufacturer of apixaban; however, use of the Cockgroft-Gault equation as done in clinical practice is suggested.³⁰  Data on use of NOACs in patients with renal impairment is still evolving; therefore, caution on their use in this population is advised, particularly in elderly patients. 

Table. Dose recommendations for NOACs.^{6,23, 31-33}

Abbreviations: AF, atrial fibrillation; Cr, creatinine; CrCl, creatinine clearance; DVT, deep vein thrombosis;

ESRD, end stage renal disease; PE, pulmonary embolism.

References

1. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-268.
2. Lehr T, Haertter S, Liesenfeld KH, et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012;52(9):1373-1378.
3. Wilson JA, Goralski KB, Soroka SD, et al. An evaluation of oral dabigatran etexilate pharmacokinetics and pharmacodynamics in hemodialysis.  J Clin Pharmacol. 2014;54(8):901-909.
4. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703-712.
5. Personal communication [letter].  Eliquis pharmacokinetic data in renal impairment. Bristol Myers Squibb. May 2015.
6. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2014.
7. Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther. 2010;88(3):375-382.
8. Ridout G, de lat Motte S, Sramek P, Johnson L, Ling H, Mendell J, Salazar D. Effect of renal function on edoxaban pharmacokinetics and on population PK/PD model. Abstract 144. J Clin Pharmacol. 2009;49(9):1124.
9. Yin OQ, Tetsuya K, Miller R. Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol. 2014;70(11):1339-1351.
10. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015;113(4):719-727.
11. Béné J , Saïd W, Rannou M, Deheul S, Coupe P, Gautier S. Rectal bleeding and hemostatic disorders induced by dabigatran etexilate in 2 elderly patients. Ann Pharmacother. 2012;46(6):e14.
12. Maddry JK, Amir MK, Sessions D, Heard K. Fatal dabigatran toxicity secondary to acute renal failure. Am J Emerg Med. 2013;31(2):462.e1-462.e2.
13. Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46(4):e10.
14. Berthelot E, Lavenu-Bombled C, Orostegui-Giron L, Desconclois C, Assayag P. Impaired renal function and bleeding in elderly treated with dabigatran. Blood Coagul Fibrinolysis. 2014;25(6):618-620.
15. Fellows SE, Rosini JM, Curtis JA, Volz EG. Hemorrhagic gastritis with dabigatran in a patient with renal insufficiency. J Emerg Med. 2013;44(2):e221-e225.
16. George J, Levine R. Dabigatran overdose secondary to acute kidney injury and amiodarone use. N Z Med J. 2013;126(1370):110-112.
17. Ribés-Cruz JJ, Torregrosa-Maicas I, Ramos-Tomás C, et al. Dabigatran-induced upper intestinal bleeding in a patient with chronic kidney disease. Nefrologia. 2013;33(6):864-866.
18. Conway SE, Schaeffer SE, Harrison DL. Evaluation of dabigatran exposures reported to poison control centers. Ann Pharmacother. 2014;48(3):354-360.
19. Stöllberger C, Finsterer J. Prolonged anticoagulant activity of rivaroxaban in a polymorbid elderly female with non-convulsive epileptic state. Heart Lung. 2014;43(3):262-263.
20. Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J. 2015 Apr 28.
21. Fuji T, Fujita S, Kawai Y, et al. A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery. Thromb J. 2015;13(1):6.
22. Lauffenburger JC, Rhoney DH, Farley JF, Gehi AK, Fang G. Predictors of gastrointestinal bleeding among patients with atrial fibrillation after initiating dabigatran therapy. Pharmacotherapy. 2015 Jun 4. doi: 10.1002/phar.1597.
23. See comment in PubMed Commons belowNielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB. Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. 2015;104(5):418-429.
24. Harel Z, Sholzberg M, Shah PS, et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol. 2014;25(3):431-442.
25. Sardar P, Chatterjee S, Herzog E, Nairooz R, Mukherjee D, Halperin JL. Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can J Cardiol. 2014;30(8):888-897.
26. Pathak R, Pandit A, Karmacharya P, et al. Meta-analysis on risk of bleeding with apixaban in patients with renal impairment. Am J Cardiol. 2015;115(3):323-327.
27. Personal communication [letter]. Calculation of creatinine clearance in Pradaxa clinical trials. Boehringer Ingelheim Pharmaceuticals. May 2015.
28. Personal communication [letter]. Calculation of creatinine clearance in Xarelto clinical trials.  Janssen Scientific Affairs. May 2015.
29. Personal communication [letter]. Calculation of creatinine clearance in Savaysa clinical trials.  Daiichi Sankyo. May 2015.
30. Personal communication [letter]. Calculation of creatinine clearance in Eliquis clinical trials. Bristol Myers Squibb. May 2015.
31. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
32. Xarelto [package insert]. Titusville, NJ. Janssen Pharmaceuticals; 2015.
33. Savaysa [package insert]. Parsippany, NJ. Daiichi Sankyo, Inc.; 2015.

July 2015

The information presented is current as of June 15, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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How should patients receiving new oral anticoagulants be managed prior to planned surgical procedures?

Introduction

The newly approved anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban, collectively known as  non-vitamin K oral anticoagulants (NOACs), offer an attractive alternative to anticoagulation with warfarin in various prothrombotic conditions.¹  Patients may benefit from their unique pharmacologic properties, including shorter times to onset and offset, fixed dosing schedules, lack of monitoring requirements, and fewer drug interactions compared to warfarin.

The uptake of NOACs has been rapid.²  A study of prescription claims data from 2010 to 2013 identified that 62% of new prescriptions in patients with atrial fibrillation were for NOACs. Additionally, guidelines for atrial fibrillation have begun to favor the use of NOACs over warfarin in specific patient groups, such as those at high risk of intracranial bleeding or those unable to maintain compliance with frequent international normalized ratio (INR) monitoring.^3,4 Additionally, all NOACs are Food and Drug Administration (FDA)-approved for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and all but edoxaban are currently approved for prophylaxis of these conditions.^5-8

The growing number of patients receiving NOACs, combined with their relatively limited clinical experience, has led to questions regarding management in patients undergoing planned surgical procedures. Approximately 10% of all patients receiving anticoagulation each year undergo an invasive procedure that presents a risk for bleeding and requires interruption of anticoagulation.⁹ Bleeding associated with NOACs is concerning because no drug-specific antidotes are yet available.¹⁰ Despite the prevalent use of NOACs, there is a lack of data on their perioperative management compared to warfarin, for which management has long been well defined. No guidelines on the perioperative management of NOACs are currently available from well-known organizations such as the American College of Chest Physicians (ACCP), but some recommendations from manufacturers and clinicians are beginning to emerge.

Perioperative management of vitamin K antagonists

The most recent guideline on perioperative anticoagulation management from ACCP in 2012 did not provide recommendations on the perioperative management of NOACs because they had been approved by FDA shortly before publication of the guideline.⁹ Guidance was offered only for vitamin K antagonists (VKAs, including warfarin), which were recommended to be stopped approximately 5 days prior to surgery and resumed approximately 12 to 24 hours after surgery when hemostasis is adequate. Bridging anticoagulation with unfractionated heparin or low-molecular weight heparin (LMWH) was recommended for patients with a mechanical heart valve, atrial fibrillation, or venous thromboembolism (VTE) at high risk for thrombosis.

Characteristics of NOACs

The pharmacokinetic characteristics of NOACs differ substantially from those of warfarin and are considered when determining appropriate perioperative management.⁹ For example, the long half-lives of VKAs (eg, 36 to 42 hours for warfarin) affected recommendations in the 2012 ACCP guideline. Because of their long half-lives, discontinuation of VKAs for at least 5 days prior to surgery was recommended, which would ensure the passage of approximately 5 half-lives and thus the elimination of most drug prior to surgery.

In contrast, half-lives of NOACs are considerably shorter than those of VKAs (Table 1).^5-8 Additionally, all NOACs are eliminated at least to some extent renally, which may present an added level of complexity in determining appropriate perioperative discontinuation times in patients with varying levels of renal dysfunction.¹¹ Within the class, the proportion of drug renally eliminated is greatest for dabigatran (80%), followed by edoxaban (50%), rivaroxaban (33%), and apixaban (27%).^5-8 Because of their renal elimination, package inserts for all NOACs contain warnings or recommendations for dose reduction in patients with renal dysfunction.

Exposure to NOACs may also be altered by drug-drug interactions.¹ For example, apixaban and rivaroxaban are substrates of  cytochrome P450 (CYP450) 3A4 and p-glycoprotein (p-gp).^5,7 Drugs that are strong inhibitors of both of these pathways (eg, clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, ritonavir)  or strong inducers of both pathways (eg, carbamazepine, rifampin, phenytoin, St. John’s wort) may increase or decrease, respectively, exposure to both apixaban and rivaroxaban.^5,7 Similarly, exposure to dabigatran may be increased by coadministration with p-gp inhibitors in patients with renal impairment.⁶ Consideration should be given to potentially increased NOAC exposure in patients susceptible to these drug-drug interactions; however, no publications have yet incorporated these factors into perioperative management schemes.

Table 1. Pharmacokinetics and recommendations for preoperative discontinuation of NOACs.^5-8,12-16

Procedure-related risks

Decisions on perioperative anticoagulation management also must consider risks related to the procedure. ⁹ The 2012 ACCP guideline suggested a risk stratification scheme for thromboembolism (Table 2) and offered a list of higher bleeding risk procedures (Table 3), albeit with precautions. The guideline warns that patient-specific factors may trump the estimated risk for thrombosis based on the proposed classification scheme. Similarly, data informing the risk of bleeding associated with various procedures is limited by its origin predominantly in case series of limited surgery types and the lack of prospective validation.^9,17 Overall, weighing the risks for bleeding and thrombosis on a patient-specific basis is of paramount importance.

Preoperative management

Product labeling of all NOACs now includes general recommendations for their discontinuation prior to surgery (Table 1).^5-8 Renal function, as measured by creatinine clearance (CrCl), is used to stratify the time of preoperative discontinuation for dabigatran, while the labeling of other NOACs makes recommendations without regard to renal function. Generally, all NOACs should be discontinued at least 1 day prior to surgery, and longer if drug exposure is thought to be increased or when patients undergo higher bleeding risk procedures.

In addition to product labeling, recent publications have begun recommending more detailed management schemes for perioperative NOAC management; these consider procedure-related bleeding risk in addition to renal function (Table 1). ^1,17,19-23 Among those relying on data reviewed by FDA, some publications stratify time of preoperative discontinuation based on CrCl additionally for patients receiving rivaroxaban and apixaban.^1,13,20 However, no recommendations beyond those in the product labeling have been published for edoxaban, the most recently approved NOAC. Generally, publications recommend NOACs be discontinued for approximately 2 to 3 or 4 to 5 half-lives prior to low or high bleeding risk procedures, respectively.  Considering this general guidance, publications differ in their recommended times of preoperative discontinuation (Table 1). Therefore, clinical judgment should be exercised, with consideration for earlier discontinuation in patients who are deemed to have higher risk for bleeding.

To date, few systematic analyses have been performed on the perioperative management of NOACs. One prospective observational trial evaluated 541 patients receiving dabigatran managed with a protocol based on renal function and surgical bleeding risk, finding 30-day rates of major and minor bleeding were 1.8% and 5.2%, respectively, with 1 case of thromboembolism.¹⁵ However, very few patients (n=4) with severe renal dysfunction (CrCl ≤30 mL/min) were included, making conclusions regarding this patient group difficult. Other studies include prespecified subgroup analyses of patients with atrial fibrillation undergoing procedures during phase III trials of apixaban, dabigatran, and rivaroxaban.^16,24,25 In ARISTOTLE, 30-day rates of stroke, death, and major bleeding were similar between apixaban and warfarin, regardless of whether anticoagulation was discontinued preoperatively.²⁴ However, perioperative management strategies were neither randomized nor controlled. In contrast, a standardized perioperative management protocol was defined in the RE-LY trial for dabigatran, similar to that in Table 1.¹⁶ The analysis found no significant difference in major perioperative bleeding among approximately 4600 patients who underwent procedures while receiving dabigatran 110 mg or 150 mg compared to warfarin (3.8%, 5.1%, and 4.6%, respectively). A perioperative management protocol in the ROCKET-AF trial required discontinuation of rivaroxaban for 2 days before procedures in approximately 4700 patients.²⁵ Thromboembolic event rates were similar between rivaroxaban and warfarin (0.3% and 0.41%, respectively), as were rates of major bleeding (0.99% and 0.79%, respectively). Lastly, the protocol for the ENGAGE AF-TIMI 48 trial required discontinuation of blinded edoxaban or warfarin ≥3 days prior to procedures with high risk of bleeding, although no subgroup analyses are available.²⁶

Precautions

Because NOACs have pharmacokinetic profiles similar to those of LMWH, they should rarely need to be combined with LMWH in bridging anticoagulation prior to surgery.^1,5-8 Similarly, because of their rapid onset of action (generally 1 to 3 hours), NOACs should be resumed after procedures only once hemostasis is assured. Recommended resumption times are 1 day or 2 to 3 days, respectively, after low or high bleeding risk procedures.²⁰ This differs from the typically earlier resumption time for warfarin; the ACCP guideline recommends warfarin be resumed 12 to 24 hours after procedures because the average time to attainment of INR ≥2 is approximately 5 days.^1,9  Lastly, clinicians should bear in mind that published recommendations beyond those in product labeling of NOACs are currently based on limited data and may therefore be considered preliminary. The next series of ACCP guidelines will likely make more definitive recommendations on this issue, as some prospective clinical trials are underway to evaluate standardized perioperative NOAC management strategies.^27,28

Conclusion

The optimal strategy for perioperative management of NOACs has yet to be fully elucidated. Exposure to NOACs may be increased by impaired renal function or interacting medications, which should be considered in conjunction with the risks for bleeding and thrombosis associated with surgery when determining appropriate preoperative discontinuation times. Product labeling and recent publications provide increasingly more detailed recommendations, though these are based on limited data. Until future guidelines clarify this issue, clinicians should closely assess patients receiving NOACs perioperatively for potentially increased anticoagulant effects, while carefully weighing risks for bleeding and thrombosis when determining appropriate preoperative management.

References

1.         Barnes GD, Eagle KA, Froehlich JB. Perioperative management of oral anticoagulants: a focus on target-specific oral anticoagulants. Hosp Pract (1995). 2014;42(3):62-67.

2.         Desai NR, Krumme AA, Schneeweiss S, et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. Am J Med. 2014;127(11):1075-1082.

3.         Culebras A, Messe SR, Chaturvedi S, Kase CS, Gronseth G. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(8):716-724.

4.         You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e531S-e575S.

5.         Eliquis [package insert]. New York, NY: Pfizer Inc; 2014.

6.         Pradaxa [package insert]. Ridgefield, CT: Boeringer Ingelheim Pharmaceuticals, Inc; 2015.

7.         Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.

8.         Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2015.

9.         Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e326S-e350S.

10.       Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thrombosis and Haemostasis. 2015;113(5):931-942.

11.       Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2015. http://clinicalpharmacology.com/. Accessed June 12, 2015.

12.       Connolly G, Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOAC's. J Thromb Thrombolysis. 2013;36(2):212-222.

13.       Anderson M, Hassell KL, Trujillo TC, Wolfe B. When patients on target-specific oral anticoagulants need surgery. Cleve Clin J Med. 2014;81(10):629-639.

14.       Yates SW. Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. P T. 2014;39(12):858-880.

15.       Schulman S, Carrier M, Lee AY, et al. Perioperative management of dabigatran: a prospective cohort study [published online ahead of print May 12, 2015]. Circulation. 2015:10.1161/circulationaha.1115.015688.

16.       Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation. 2012;126(3):343-348.

17.       McKenzie JL, Douglas G, Bazargan A. Perioperative management of anticoagulation in elective surgery. ANZ J Surg. 2013;83(11):814-820.

18.       Liew A, Douketis J. Perioperative management of patients who are receiving a novel oral anticoagulant. Intern Emerg Med. 2013;8(6):477-484.

19.       Breuer G, Weiss DR, Ringwald J. 'New' direct oral anticoagulants in the perioperative setting. Curr Opin Anaesthesiol. 2014;27(4):409-419.

20.       Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954-2962.

21.       Tran H, Joseph J, Young L, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J. 2014;44(6):525-536.

22.       Schlitt A, Jambor C, Spannagl M, Gogarten W, Schilling T, Zwissler B. The perioperative management of treatment with anticoagulants and platelet aggregation inhibitors. Dtsch Arztebl Int. 2013;110(31-32):525-532.

23.       Healey JS, Brambatti M. Periprocedural management of oral anticoagulation in patients with atrial fibrillation: approach in the era of new oral anticoagulants. Can J Cardiol. 2013;29(7 Suppl):S54-59.

24.       Garcia D, Alexander JH, Wallentin L, et al. Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures. Blood. 2014;124(25):3692-3698.

25.       Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014;129(18):1850-1859.

26.       Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.

27.       Perioperative Anticoagulant Use for Surgery Evaluation Study (PAUSE). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02228798. Accessed June 12, 2015.

28.       Strategy of Continued Versus Interrupted Novel Oral Anti-coagulant at Time of Device Surgery in Patients With Moderate to High Risk of Arterial Thromboembolic Events (BRUISECONTROL2). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01675076. Accessed June 12, 2015.

July 2015

The information presented is current as of June 6, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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