December 2015 FAQs

What is known about idarucizumab for dabigatran reversal?

Introduction

The landscape for anticoagulation therapy has changed dramatically in recent years with the development of novel oral anticoagulants (NOACs), which include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, edoxaban, and apixaban.¹ The main advantages of using dabigatran and other NOACs over warfarin are the less frequent monitoring requirements and fewer dose adjustments due to their dependable pharmacokinetics. The main disadvantages are the limited specific reversal agents and effective reversal strategies. Without an antidote, spontaneous bleeding and bleeding during emergency surgery or invasive procedures in patients receiving NOACs become an even greater concern. Each year, treatment interruption for surgery or invasive procedures is required in approximately 10% of patients receiving anticoagulation therapy.² In the major trial that led to Food and Drug Administration (FDA)-approval of dabigatran (the RE-LY trial), the rate of periprocedural bleeding (defined as 7 days before and 30 days after the procedure) in patients receiving dabigatran 150 mg daily was 5.1%. Major bleeding occurred in 17.7% of patients receiving dabigatran 150 mg daily who underwent urgent surgery. The evidence for use of activated prothrombin complex concentrate (aPCC), prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), and factor VIII inhibitor bypassing activity (FEIBA) as dabigatran reversal strategies is conflicting.^1,3 However, recent FDA-approval of idarucizumab has allowed for a novel option for management of dabigatran-induced bleeding.

Dabigatran bleeding management and reversal strategies

The currently available guidelines on the management of bleeding and perioperative bleeding complications in patients on dabigatran or other antithrombotic agents were published prior to the approval of idarucizumab.^3-5 For patients on NOACs who are bleeding, it is recommended to hold the anticoagulant and provide supportive care, which includes fluid replacement and hemodynamic support.⁴ Because dabigatran is 80% renally eliminated, it is important to optimize renal blood flow and prevent hypotension through fluid administration.¹ To reduce accumulation of dabigatran, aggressive hemodynamic support is necessary to prevent renal injury due to hypoperfusion.  Activated charcoal has shown to decrease dabigatran absorption in ex vivo experiments, but it has not been formally tested in humans. Activated charcoal would need to be administered within 2 to 3 hours of dabigatran ingestion given the rapid absorption rate of dabigatran. Dialysis can also be considered since dabigatran is only 35% protein bound. Up to 57% of total drug can be removed from plasma over 4 hours using a high-flux dialyzer with a blood flow rate of 300 mL/min and dialysate flow rate of 700 mL/min.⁶ However, this process can be time-consuming and requires the patient to be hemodynamically stable.¹ Other recommendations include transfusing red blood cells when necessary, and administering rFVIIa or PCC.

In an emergency surgery setting, dabigatran drug plasma concentrations can be a useful tool in determining whether or not the surgery should be delayed and how long it should be delayed.³ Urgent surgery can be performed if the dabigatran concentration is ≤30 ng/mL; this is the threshold concentration below which the risk of bleeding during surgery does not increase. For concentrations between 30 ng/mL and 200 ng/mL, surgery should be delayed by 12 hours and the level should be repeated 12 hours after the first measurement to ensure the threshold has been reached. For drug concentrations >200 ng/mL, surgery should be delayed a minimum of 24 hours and a new level should be obtained. In centers where drug plasma concentration measurements are unavailable, conventional coagulation tests such as prothrombin time and activated partial thromboplastin time can be used instead. These tests are less reliable, but are analogous to the drug plasma concentration assays in estimating drug concentrations and the corresponding surgery delays. In case of abnormal bleeding during surgery, treatment with PCC or FEIBA is proposed. These procoagulant therapies do not alter the elimination of the anticoagulant, and should be used with caution as they may be associated with an increased risk for thrombotic events.⁵

Idarucizumab

Idarucizumab was developed to fill the unmet need for dabigatran reversal. It is a humanized monoclonal antibody fragment that potently binds to the thrombin binding site on dabigatran.^1,6 The idarucizumab-dabigatran binding affinity is 350 times stronger than the affinity of dabigatran for thrombin, and the binding neutralizes the anticoagulant activity of dabigatran.⁶ Idarucizumab received FDA approval through the Accelerated Approval Pathway in October 2015.⁷ Along with data from 3 phase I trials in healthy volunteers, interim results from the phase 3, single-cohort, case series trial on the reversal effects of idarucizumab for dabigatran (RE-VERSE AD) contributed to the approval of idarucizumab.^6,7 Idarucizumab is manufactured by Boehringer Ingelheim, the same company that manufactures dabigatran (Pradaxa).

The phase 3 trial, RE-VERSE AD, is an ongoing, multicenter, prospective cohort study, for which an interim analysis of 90 patients was recently published.⁸ Included patients were receiving dabigatran and had experienced overt, uncontrollable or life-threatening bleeding (51 patients; Group A) or needed an invasive procedure or surgery within 8 hours (39 patients; Group B). All patients received 5 g of idarucizumab given as 2 x 50 mL boluses of 2.5 g each, given 15 minutes apart. The primary endpoint was the maximum percentage reversal of the effect of dabigatran as measured by dilute thrombin time (dTT) and ecarin clotting time (ECT) at the end of the first idarucizumab infusion to 4 hours after the second infusion. The secondary endpoints included the proportion of patients who had complete normalization of dTT and ECT in the first 4 hours, reduction in unbound dabigatran, and clinical outcomes such as restoration of hemostasis. The median values for patient age, creatinine clearance, duration of hospitalization, and time since last dose of dabigatran were 76.5 years, 58 mL/min, 8 days, and 15.4 hours, respectively. The majority of patients (92%) were on dabigatran for atrial fibrillation. The most common types of bleeding reported in group A were intracranial hemorrhage, gastrointestinal bleeding, and bleeding from trauma.  For group B, the most common indications for surgery were bone fractures and acute cholecystitis.

The interim analysis showed a median maximum percentage reversal of dabigatran effects of 100% after the first infusion (95% confidence interval, 100 to 100), for both dTT and ECT.⁸ The dTT was normalized in 98% of patients in group A and 93% in group B. The ECT was normalized in 89% of patients in group A and 88% in group B. After the first idarucizumab infusion, the unbound dabigatran was reduced from a median baseline concentration of 84 ng/mL in group A and 76 ng/mL in group B to less than 20 ng/mL, a level that produces little to no anticoagulant effect, in all except for one patient. In group A, median time to cessation of bleeding was 11.4 hours. Thirty-three of the 36 patients in group B (92%) who underwent an invasive procedure achieved normal intraoperative hemostasis. Serious adverse effects including gastrointestinal hemorrhage, postoperative wound infection, delirium, edema, and right ventricular failure occurred in 21 patients. Out of the 18 deaths overall (9 in each group), 5 were fatal bleeding events.

Five patients experienced thrombotic events, none of whom were receiving antithrombotic therapy at the time of the event.⁸ One of the 5 patients experienced a deep vein thrombosis and a pulmonary embolism within 2 days of idarucizumab administration while the rest of the patients experienced thrombotic events ≥7 days after idarucizumab administration. It is unclear whether the thrombotic events were due to the possible procoagulant effects of the intervention or due to lack of anticoagulation. According to the results of this interim analysis, idarucizumab shows prompt and complete reversal of dabigatran in a real-world setting. However, there is some concern for a possible procoagulant tendency of idarucizumab, and large scale trials are necessary to assess this potential safety issue.

Conclusion

Although there is some guidance for reversal strategies of NOACs, the efficacy of these strategies and agents is inconclusive. Idarucizumab is a recently-approved monoclonal antibody indicated for dabigatran reversal. While the REVERSE-AD study still plans to recruit up to 300 patients at 400 centers in 38 countries, the interim results look promising. The available data show a complete reversal of dabigatran anticoagulant effect in patients who required an emergency invasive procedure or had experienced uncontrolled bleeding. Some of the strengths of this study include enrolling a real-world population of acutely ill patients, using the preferred methods of quantifying anticoagulation activity of dabigatran, and exclusion of patients with normal clotting time baseline values from the efficacy analysis. Although this study lacks a control group, the study design and the convincing data on reversal of anticoagulation suggest that idarucizumab would be a suitable reversal agent in clinical practice. A complete data analysis upon study completion as well as larger trials would need to be performed to further assess idarucizumab for adverse events or possible procoagulant activity. Guidelines on anticoagulant reversal have yet to be updated, but it is clear that idarucizumab will have a role in reversing the effects of dabigatran in patients who are overtly bleeding or require urgent or emergency surgeries.

References

1. Crowther M, Crowther MA. Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential. Arterioscler Thromb Vasc Biol. 2015;35(8):1736-1745.

2. 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.
3. Pernod G, Albaladejo P, Godier A, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) – March 2013. Arch Cardiovasc Dis. 2013;106(6-7):382-393.
4. Makris M, Van veen JJ, Tait CR, Mumford AD, Laffan M. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol. 2013;160(1):35-46.
5. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141-145.
6. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
7. FDA Approves Praxbind® (idarucizumab), specific reversal agent for Pradaxa® (dabigatran etexilate mesylate). Boehringer Ingelheim website. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2015/10-16-2015-fda-approves-praxbind-idarucizumab-specific-reversal-agent-pradaxa-dabigatran-etexilate-mesylate.html. Accessed November 27, 2015.
8. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520.

Prepared by:
Elena Telebak
PharmD Candidate Class of 2016
College of Pharmacy
University of Illinois at Chicago

Edited by:
Lara K. Ellinger, PharmD, BCPS
December 2015

The information presented is current as of November 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 optimal duration of dual antiplatelet therapy after percutaneous coronary intervention?

Introduction

Percutaneous coronary intervention (PCI) has become a mainstay revascularization treatment for coronary artery disease.¹ Appropriate indications for PCI include acute coronary syndrome (ACS) and stable or unstable angina. Almost half of PCI procedures are elective which aim to reduce the risk of future cardiovascular events.^1,2 During PCI, a balloon catheter is used to open the vessel and stents are placed to help prevent vessel recoil, abrupt closure, and late restenosis.¹ While bare metal stents (BMS) were introduced initially, BMS have largely been replaced with drug-eluting stents (DES) as they are more effective at reducing the risk of restenosis.^1,3 However, in some cases, the stent can induce damage to the vessel wall.⁴ This damage triggers thrombosis in the area which can occlude the vessel lumen. The downside of using DES is that there is an increased risk of stent thrombosis compared to BMS. Antiplatelet agents have been historically used long term after stenting to prevent this occurrence, with aspirin used indefinitely and a P2Y₁₂ inhibitor added for a limited amount of time after the procedure. Dual antiplatelet therapy (DAPT) reduces the risk of major adverse cardiac events as well, but due to the increased bleeding risk when using these 2 agents together, DAPT is only used for a limited amount of time.^4,5 The optimal duration of DAPT that would minimize the risk for stent thrombosis without exposing the patient to an excess risk of bleeding has been a debate since P2Y₁₂ inhibitors have entered the market. Fortunately, evidence continues to build attempting to better describe the ideal length of time in which both antiplatelet agents should be used.

Practice guidelines

Currently, there are 2 clinical practice guidelines providing recommendations on how long to administer DAPT.^5,6 The American College of Chest Physicians 2012 guideline advocates 12 months of DAPT.⁶ This recommendation was drawn from a pooled analysis of the REAL-LATE and ZEST-LATE studies which did not find additional benefit for DAPT durations >12 months.⁷ The other guideline making recommendations on DAPT is the American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions practice guidelines for PCI. ⁵ This guideline recommends DAPT duration based on the procedure indication and the type of stent that was placed. For patients presenting with ACS and receiving either BMS or DES, at least 12 months of any P2Y₁₂ inhibitor with aspirin is recommended. Patients who have a DES placed for a non-ACS indication should receive clopidogrel with aspirin for at least 12 months if not at high risk for bleeding. Lastly, patients who have a BMS placed for a non-ACS indication should receive clopidogrel with aspirin for at least 1 month, but ideally up to 12 months. Both of these guidelines are becoming outdated and rely on older, observational evidence for making recommendations. Some clinicians consider longer durations of DAPT based on patient-specific factors, and until recently, there has not been strong supporting evidence for this practice.⁸ At this point, with published evidence continuing to build, the demand for a new consensus recommendation on the duration of DAPT is something many clinicians anticipate.

Clinical trials

Since the introduction of P2Y₁₂ inhibitors to the market, many randomized, prospective studies have examined the risk versus benefit of shorter and longer durations of DAPT after stenting.^9-18 The impetus of these studies was to determine the optimal duration of DAPT where the risk of adverse cardiovascular events due to stent thrombosis and the risk of bleeding are at their mutually lowest points. The Table summarizes published randomized controlled trials (RCTs) comparing different durations of DAPT and their associated outcomes. However, the majority of these studies were not adequately powered to find significant differences between lengths of therapy studied due to low event rates, early termination of trials, and inappropriate non-inferiority margins. Additionally, most of the studies had an open-label study design except for the DAPT and ISAR-SAFE trials which were double-blinded and placebo-controlled.

Table. Summary of the major clinical trials comparing different lengths of DAPT.^9-18

There have been 6 RCTs conducted to evaluate whether shorter durations of DAPT therapy provide an improved net clinical benefit when balancing stent thrombosis and bleeding risk.^9-14 Each trial established non-inferiority between shorter DAPT (3 or 6 month duration) and standard 12-month therapy for composite endpoints that encompassed ischemic events, major bleeding events, and death. However, the trials were terminated early or set a non-inferiority margin that was similar to or greater than the actual event rate. Therefore, these trials may not be adequately powered to detect a difference between shorter-duration and standard-duration therapy.

Three RCTs compared 12 months of DAPT to extended durations.^15-17 Additionally, the PRODIGY trial compared 6 months of therapy to extended DAPT (24 months).¹⁸ The DAPT trial was the only trial sufficiently powered to detect differences in the investigator-defined endpoint.¹⁷ A total of 9961 patients who had been treated with DAPT for 12 months after undergoing PCI for any indication were randomized to either continue or stop DAPT. Patients were assigned 1:1 to either placebo with aspirin or continued DAPT for a total of 30 months. The 2 co-primary endpoints were cumulative incidence of stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) during the randomized treatment period (from 12 to 30 months after PCI). The 30-month group was found to have reduced incidence of the stent thrombosis compared to the 12-month group (0.4% vs 1.4%; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.17 to 0.48; p<0.001). The incidence of MACCE was also reduced in the 30-month compared to the 12-month groups (4.3% vs 5.9%; HR, 0.71; 95% CI, 0.59 to 0.85; p<0.001). There was no significant difference between groups for the overall mortality rate; however, non-cardiovascular death was increased in the extended DAPT group (1% vs 0.5%; HR, 2.23; 95% CI, 1.32 to 3.78; p<0.002).  There was also an increased risk of moderate to severe bleeds with extended therapy (2.5% vs 1.6%, p=0.001) based on GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) criteria. One important limitation of the DAPT trial was that patients who were randomized were those who were compliant and did not have any adverse events during the initial 12 months of DAPT; so this removes some external validity, since these patients were intrinsically at lower risk of adverse events.

Meta-analyses

With so many clinical trials available on this topic, an abundance of meta-analyses have been conducted recently utilizing the existing trials to better describe the risks and benefits of shorter and extended durations of DAPT compared to the standard 12-month recommendation.^19-31 Overall, the meta-analyses had very consistent results. Shorter DAPT durations compared to 12 months of DAPT are associated with a decreased risk in bleeding with a similar incidence of stent thrombosis, myocardial infarction, all-cause mortality, cardiovascular mortality, and stroke. Extended DAPT therapy compared to 12 months of DAPT is associated with an increased risk in bleeding, but a reduction in stent thrombosis and myocardial infarction. Additionally, there is small, but significant increase in all-cause mortality with extended DAPT therapy.  One meta-analysis reported that for every 1000 patients treated annually, longer DAPT therapy would result in 8 fewer myocardial infarctions, but 2 more deaths and 6 more major bleedings compared to shorter DAPT therapy.²¹ Another meta-analysis reported that for every 1000 patient-years, longer DAPT therapy would be expected to prevent 4 stent thromboses and 7 myocardial infarctions, but would cause 4 more major bleeds compared to shorter DAPT therapy.²³ Finally, Giustino and colleagues reported that for every stent thrombosis averted with longer DAPT, approximately 2.1 clinically significant bleeding events (defined as major bleeding and some minor bleeding definitions) would be expected to occur.²⁹ 

Conclusion

Based on the currently available evidence, it is difficult to define the optimal duration of DAPT for a general population of patients requiring stent placement. The available clinical evidence shows that DAPT durations <12 months are likely non-inferior to 12 months of DAPT for ischemic events and mortality and is associated with a reduction in major bleeding.^9-14  Extended DAPT beyond 12 months is associated with a reduction in stent thrombosis and myocardial infarction, but also increases the risk of major bleeding and possibly all-cause mortality due to an increased risk in non-cardiovascular death.^15-18 Because of this discordance, a single “least risky” duration of treatment for all patients receiving stents is not a responsible way for DAPT to be administered. Therefore, the optimal duration of DAPT should be individualized decision based on patient-specific factors. For example, stent type, cardiac history, family history, bleeding risk, PCI indication, and lesion complexity could all factor into determining a patient’s optimal DAPT duration. For patients at high risk of bleeding, shorter DAPT durations could be considered as there has not been an established benefit for preventing ischemic events or death when compared to 12-month therapy. For patients who are at a high ischemic risk and a low bleeding risk, extended DAPT durations >12 months could be considered. It may be beneficial in the future to develop verified methods to quantify and qualify the risk of ischemic and bleeding events in patients receiving stents in order to provide clinicians better direction in choosing a regimen with maximal benefits.

References

1. Faxon DP, Bhatt DL. Percutaneous coronary interventions and other interventional procedures. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine. 19^th ed. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com/. Accessed July 23, 2015.
2. Cram P, House JA, Messenger JC, Piana RN, Horwitz PA, Spertus JA. Indications for percutaneous coronary interventions performed in US hospitals: a report from the NCDR(R). Am Heart J. 2012;163(2):214-221.
3. Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation. 2012;125(23):2873-2891.
4. Lüscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115(8):1051-1058.
5. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-122.
6. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e637S-668S.
7. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362(15):1374-1382.
8. Cutlip, D. Antiplatelet therapy after coronary artery stenting. In: UpToDate, Post TW. UpToDate. Waltham, MA: Wolters Kluwer; 2015. http://www.uptodate.com/contents/antiplatelet-therapy-after-coronary-artery-stenting.  Accessed July 20, 2015.
9. Gilard M, Barragan P, Noryani AA, et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65(8):777-786.
10. Schulz-schüpke S, Byrne RA, Ten berg JM, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015;36(20):1252-1263.
11. Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol. 2014;64(20):2086-2097.
12. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310(23):2510-2522.
13. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125(3):505-513.
14. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60(15):1340-1348.
15. Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014;384(9954):1577-1585.
16. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129(3):304-312.
17. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371(23):2155-2166.
18. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125(16):2015-2026.
19. Palla M, Briasoulis A, Siddiqui F, Alesh I, Afonso L. Long (>12 Months) and short (<6 Months) versus standard duration of dual antiplatelet therapy after coronary stenting: a systematic review and meta-analysis [published online ahead of print August 11, 2015]. Am J Ther. doi: 10.1097/MJT.0000000000000307.
20. Verdoia M, Schaffer A, Barbieri L, et al. Optimal duration of dual antiplatelet therapy after DES implantation: a meta-analysis of 11 randomized trials [published online ahead of print June 11, 2015]. Angiology. doi: 10.1177/0003319715586500.
21. Spencer FA, Prasad M, Vandvik PO, Chetan D, Zhou Q, Guyatt G. Longer- versus shorter-duration dual-antiplatelet therapy after drug-eluting stent placement: a systematic review and meta-analysis. Ann Intern Med. 2015;163(2):118-126.
22. Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials. BMJ. 2015;350:h1618.
23. Abo-Salem E, Alsidawi S, Jamali H, Effat M, Helmy T. Optimal duration of dual antiplatelet therapy after drug eluting stents: Meta-analysis of randomized trials. Cardiovasc Ther. 2015;33(5):253-263.
24. Pandit A, Giri S, Hakim FA, Fortuin FD. Shorter (≤6 months) versus longer (≥12 months) duration dual antiplatelet therapy after drug eluting stents: a meta-analysis of randomized clinical trials. Catheter Cardiovasc Interv. 2015;85(1):34-40.
25. Cassese S, Byrne RA, Ndrepepa G, Schunkert H, Fusaro M, Kastrati A. Prolonged dual antiplatelet therapy after drug-eluting stenting: meta-analysis of randomized trials. Clin Res Cardiol. 2015;104(10):887-901.
26. Liu C, Liu M, Chen D, et al. Effectiveness of prolonged clopidogrel-based dual antiplatelet therapy after drug-eluting stent implantation : Evidence-based meta-analysis. Herz. 2015;40(5):795-802.
27. Bulluck H, Kwok CS, Ryding AD, Loke YK. Safety of short-term dual antiplatelet therapy after drug-eluting stents: An updated meta-analysis with direct and adjusted indirect comparison of randomized control trials. Int J Cardiol. 2015;181:331-339.
28. Palmerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol. 2015;65(11):1092-1102.
29. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65(13):1298-1310.
30. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet. 2015;385(9985):2371-2382.
31. Tsoi MF, Cheung CL, Cheung TT, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: Meta-analysis of large randomised controlled trials. Sci Rep. 2015;5:13204.

Prepared by:
Zach Rosenfeldt
PharmD Candidate 2016
College of Pharmacy
University of Illinois at Chicago

Samantha Spencer, PharmD, BCPS
Clinical Assistant Professor
December 2015

The information presented is current as August 20, 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 role of topical tranexamic acid to prevent postsurgical bleeding from major cardiovascular and orthopedic procedures?

Introduction

Severe perioperative blood loss is a major surgical concern and has been associated with increased morbidity and mortality. In addition to preoperative anticoagulation and high- risk surgical procedures, some patient-specific factors have been identified that increase the risk of postoperative bleeding. These include advanced age and certain comorbidities such as renal and hepatic dysfunction, congestive heart failure, and chronic obstructive pulmonary disease.¹

Major surgical procedures including orthopedic and cardiac surgeries are associated with significant blood loss and therefore, allogenic blood transfusion is required in many cases. ^2,3  In the United States, surgical procedures account for the transfusion of about 15 million units of packed red blood cells (PRBC) every year.¹ Although often life-saving, blood transfusions are not benign and are associated with significant risk to the patient, added cost, and limited supplies.  Thus a variety of blood-conservation measures to reduce the exposure to allogeneic blood have been developed and implemented as part of perioperative care.  In addition to correcting treatable anemia and practicing optimal surgical and anesthetic techniques, the use of hemostatic pharmacologic agents to reduce and prevent bleeding is considered an option for blood conservation.⁴

Hemostatic agents

The ability of antifibrinolytics agents to prevent bleeding following surgery is well-established. In both cardiac and orthopedic surgeries, pharmacologic approaches to reduce bleeding have been extensively studied.⁵ Hemostatic agents include topical thrombin, topical fibrin, and antifibrinolytics. Of antifibrinolytics, tranexamic acid and aminocaproic acid are the 2 agents currently available in the United States because a third agent, aprotinin, was suspended in 2007 after a randomized controlled trial (BART study) revealed an increase in 30-day mortality among patients who received intravenous aprotinin compared to lysine analogues (tranexamic acid and aminocaproic acid).^6,7

Antifibrinolytic drugs exhibit their effect by the inhibition of fibrinolysis and thus reducing the local degradation of fibrin by plasmin increasing the clotting potential of blood and subsequently reducing blood loss.^2,8 Tranexamic acid has been used successfully to stop bleeding in various surgical settings including liver, cardiac, prostate, postpartum hemorrhage, and dental procedures.² Traditionally, antifibrinolytics agents have been administered intravenously in surgical setting. However, in light of growing safety concerns of increased risk of thromboembolic complications with intravenous administration, there has been a highlighted interest in the topical use of tranexamic acid with major surgical procedures. In addition to the ease of application, the thought is that topical use, or non-systemic administration, can increase local drug concentration and lower the systemic absorption, and thereby enhancing hemostatic effects and avoiding systemic complications such as thrombosis.³ Although multiple meta-analyses have not shown an increase in adverse events such as thromboembolic complications with the use of tranexamic acid in case reports tranexamic acid administration was found to cause cerebral thrombosis, arterial thrombosis, acute renal failure and coronary graft occlusion.^9,10

However, clinical efficacy data for topical administration with these agents, especially tranexamic acid, are inconsistent and the optimal treatment protocol is still unknown since the use of tranexamic acid is yet to be standardized.³ Several studies have investigated the safety of the use of topical fibrinolytics for reduction of postoperative bleeding, and these were summarized in a previous FAQ written in 2011 and available at the following hyperlink: https://pharmacy.uic.edu/departments/pharmacy-practice//centers-and-sections/drug-information-group/2014/2011/march-2011-faqs#q4. This review focuses on the newer evidence for the efficacy of topical tranexamic acid compared to placebo or intravenous administration in cardiac and orthopedic surgeries.

Topical tranexamic acid for cardiac surgery

Since 2011, three prospective clinical trials evaluated the efficacy of topical tranexamic acid following cardiac surgery were published. All of these trials were conducted in patients undergoing an elective, first-time cardiac procedure.  Of note, in these studies, topical administration refers to pouring the medication on the incision site.^11-13

In a randomized controlled trial by Shah et al, the efficacy of tranexamic acid in controlling postoperative bleeding was compared to normal saline.¹¹ Tranexamic acid poured into the pericardial cavity and over the mediastinal tissues before the closure of incision decreased post-operative blood loss in various cardiac procedures including coronary artery bypass graft (CABG), mitral valve replacement, and aortic valve replacement.  The study did not report PRBC transfusion requirements or the rates of thromboembolism.¹¹

The effect of topical application of tranexamic acid compared to normal saline on postoperative blood loss in off-pump CABG was investigated in a prospective study by Hosseini et al.¹² When poured into the pericardial and mediastinal cavities at the end of the surgery in patients undergoing CABG surgery, tranexamic acid consistently demonstrated a reduction in postoperative blood loss. In addition, the study showed a trend toward reduction of PRBC transfusion requirements with tranexamic acid administration. Similar findings were also reported in Aoki M, et al, as their study showed that topical tranexamic acid was associated with about 40% reduction in post-operative blood loss.¹³ Further details for these 3 studies are reported in the Table 1.

Table 1: Evidence for topical tranexamic acid in cardiac surgery ^11-13

Abbreviations: CABG, coronary artery bypass graft; DB: double blind; DVT: deep venous thrombosis; EF: ejection fraction; MI, myocardial infarction; NS: normal saline; PRBC, packed red blood cells; SCr, serum creatinine; TXA, tranexamic acid; RCT, randomized control trial; TBL, total blood loss.

Topical tranexamic acid in orthopedic surgeries

For orthopedic surgeries, there have been several meta-analyses evaluating topical tranexamic acid for total hip arthroplasty (THA) and total knee arthroplasty (TKA) published in the last few years.^14-16,20 Topical applications of tranexamic acid include both intra-articular and joint irrigation for TKA and intra-articular injection for THA.

Total knee arthroplasty (TKA)

In a meta-analysis by Yue et al, 12 studies were included, most of which were defined as high quality studies and were all published since 2010.¹⁴ The meta-analysis included 1179 knees undergoing TKA.  Different doses of tranexamic acid used ranging from 0.25 g to 3 g. In addition, the concentrations of topical tranexamic acid ranged from a low dose of 10 mg/mL to a high dose of 100 mg/mL.  The pooled results showed that tranexamic acid effectively decreased total blood loss, the rate of transfusion, and postoperative hemoglobin drop without increasing the risk of venous thromboembolism in TKA.

In the meta-analysis by Shemshaki et al, 31 high quality RCTs were included.¹⁵ It investigated the effect of tranexamic acid (topical and systemic) on total blood loss, rate of transfusion, and thromboembolic events. The findings of the study showed that when compared to control, both intravenous and intra-articular administration of tranexamic acid significantly reduced the total blood loss and the need for blood transfusion without increasing the risk of thromboembolic events. The intra-articular route had greater improvements in transfusion rates and thromboembolic events compared with the intravenous route, though this between-group difference was not statistically significant.

Results from a meta-analysis by Wang H et al showed that when compared with intravenous administration, topical application of tranexamic acid had comparative effectiveness on reducing both blood loss and transfusion rate without sacrificing safety in primary TKA.¹⁶ In addition, the findings of more recent randomized controlled trials added to the growing body of evidence supporting the comparative efficacy of topical tranexamic acid with intravenous administration in controlling blood loss.^17-19  Yet, another study by Hamlin et al showed that the topical application tranexamic acid resulted in with significantly less blood loss and less blood transfusion compared to the intravenous administration of tranexamic acid.¹⁹ Data from these meta-analyses are summarized in Table 2.

Total hip arthroplasty (THA)

The meta-analysis by Wang et al included 8 studies, 5 of which were randomized controlled trials and 3 non-RTCs and all were published between 2013 and 2014.²⁰ The inclusive trials have high quality. The pooled results showed that compared to a control group (placebo or nothing), topical application of tranexamic acid minimized hemoglobin decline, transfusion requirements, and total blood loss. In addition, the safety of tranexamic acid did not differ from placebo in terms of thromboembolic events.  Of note, the dose of tranexamic acid in the studies included ranged from 1 to 5 grams.

In the meta-analysis by Alshryda et al, in addition to finding that topical tranexamic acid is an effective and safe method for reducing the need for blood transfusions after both TKR and THR, it provided an indirect comparison of placebo-controlled trials of topical and intravenous tranexamic acid suggesting that topical administration of tranexamic acid may have superior efficacy compared to the intravenous route. ²¹

Table 2: Evidence for topical tranexamic acid in orthopedic surgery ^14-16,20

Abbreviations: CI, confidence interval; DB, double blind; DVT, deep venous thrombosis; IA, intra-articular; IV, intravenous; MA, meta-analysis; MD, mean difference; NS, normal saline; PCS, prospective cohort trial; PE, pulmonary embolism; randomized controlled trial; RD, risk difference; RR, rate ratio; TBL, total blood loss; THA, total hip arthroplasty; TKA, total knee arthroplasty; TXA, tranexamic acid.

Other Literature

Combination IV and IA vs IA alone or placebo

With the optimal regimen of tranexamic acid for the prevention of perioperative blood loss remains undetermined; many question the utility of combined intravenous and topical administration of tranexamic acid in orthopedic surgeries.  In a study by Lin SY et al, it was found that the post-operative hemoglobin drop and total drain amount were significantly less in the patients that received both intra-articular and intravenous tranexamic acid compared to topical administration or placebo groups.⁹ Similar findings were reported in a study by Xie J, et al, in which the combined use of intravenous and local tranexamic acid in primary unilateral THA effectively decreased total blood loss and increased postoperative hemoglobin levels without influencing complication rates.²²

Cost-savings analyses

In addition to the cost of surgery, the need for blood transfusion and the complications associated with it present added expenses. Due to changes in health care economics, the financial impact of tranexamic acid is very important to arthroplasty procedures.   In a cost-saving study,²³ it was found that topical tranexamic acid had the potential to significantly reduce the need for blood transfusions and decrease hospital man-hours per TKA. There was a 100% reduction in man-hours related to blood transfusions with the use of topical tranexamic acid compared with no tranexamic acid, and a 94.62% reduction with intravenous tranexamic acid. The overall cost of blood transfusions was decreased by 53.90% with the use of topical tranexamic acid and by 2.72% with intravenous tranexamic acid when compared with no tranexamic acid. The findings of another study that evaluated the cost-savings with THA showed that the facility-cost from blood transfusions was $286.90 per THA without tranexamic use compared to $123.38 per THA with IV tranexamic acid and $132.41 per THA with topical tranexamic acid. A substantial reduction in man-hours was also seen with topical tranexamic acid (68.89%) and with IV tranexamic acid (84.44%) compared to no tranexamic acid.²⁴ Furthermore, in a cost-benefit analysis at a single joint center, the topical application of tranexamic acid in TKA and THA was found to significantly reduce transfusion rates from 17.5% to 5.5%, resulting in a cost-savings per patient of $83.73.²⁵

Summary

With the number of orthopedic and cardiac surgeries increasing every year, especially as it has become more common among younger patients, finding an effective and safe approach to minimize blood loss, complications and cost associated with such procedures is warranted. The body of evidence supporting the safety and efficacy of topical tranexamic acid has grown tremendously in recent years making it a very attractive alternative to other methods of administration.  The studies presented in this review not only show that topical administration of tranexamic acid is safe and effective in reducing the perioperative blood loss, but was also shown to be superior to intravenous administration in some studies.

References:

1. Society of Thoracic Surgeons Blood Conservation Guideline Task Force and Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83(5 Suppl):S27-S86.
2. Huang F, Wu D, Ma G,Yin Z, Wang Q. The use of tranexamic acid to reduce blood loss and transfusion in major orthopedic surgery: a meta-analysis. J Surg Res. 2014;186(1):318-327.
3. Ipema HJ, Tanzi MG. Use of topical tranexamic acid for aminocaproic acid to prevent bleeding after major surgical procedures. Ann Pharmacother. 2012;46(1):97-107.
4. Baker JE, Pavenski K, Pirani RA, White A, Kataoka M, Waddell JP, et al. Universal tranexamic acid therapy to minimize transfusion for major joing arthroplasty: a retrospective analysis of protocol implementation. Can J Anaesth. 2015;62(11): 1179-1187.
5. Levy JH. Pharmacologic methods to reduce perioperative bleeding. Transfusion. 2008;48(1 Suppl):31S-38S.
6. Aprotinin Injection (marketed as Trasylol) Information. Food and Drug Administration website. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm142720.htm. Published May 14, 2008. Accessed October 10, 2015.
7. Fergusson DA, Hébert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358(22):2319-2331.
8. Alder Ma SC, Brindle W, Burton G, Gallacher S, Hong FC, Manelius I, et al. Tranexamic acid is associated with less blood transfusion in off-pump coronary artery bypass graft surgery: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2011;25(1):26-35.
9. Lin SY, Chen CH, Fu YC, Huang PJ, Chang JK, Huang HT. The efficacy of combined use of intraarticular and intravenous tranexamic acid in reducing blood loss and transfusion rate in total knee arthroplasty. J Arthroplasty. 2015;30(5):776-780.
10. Kim C, Park SS, Davey Jr. Tranexamic acid for the prevention and management of orthopedic surgical hemorrhage: current evidence. J Blood Med. 2015;6:239-244. doi: 10.2147/JBM.S61915.
11. Ali Shah MU, Asghar MI, Siddiqi R, Chaudhri MS, Janjua AM, Iqbal A. Topical application of tranexamic acid reduces postoperative bleeding in open-heart surgery: myth or fact? J Coll Physicians Surg Pak. 2015;25(3):161-165.
12. Hosseini H, Rahimianfar AA, Abdollahi MH, Moshtaghiyoon MH, Haddadzadeh M, Fekri A, et al. Evaluations of topical application of tranexamic acid on post-operative blood loss in off-pump coronary artery bypass surgery. Saudi J Anaesth. 2014;8(2):224-228.
13. Aoki M, Okawa Y, Goto Y, Ogawa S, Baba H. Local administration of tranexamic acid in off-pump coronary artery bypass. Asian Cardiovasc Thorac Ann. 2012;20(6):658-662.
14. Yue C, Pei F, Yang P, Xie J, Kang P. Effect of topical tranexamic acid in reducing bleeding and transfusions in TKA. Orthopedics. 2015;38(5):315-324.
15. Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Arch Orthop Trauma Surg. 2015; 135(4)573-588.
16. Wang H, Shen B, Zeng Y. Comparison of topical versus intravenous tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled and prospective cohort trials. Knee. 2014;21(6):987-893.
17. Nawabi DH. Topical tranexamic acid was noninferior to intravenous tranexamic acid in controlling blood loss during total knee arthroplasty. J Bone Joint Surg Am. 2015;97(4):343.
18. Gomez-Barrena E, Ortega-Andrew M, Padilla-Eguiluz NG, Perez-Chrzanowska H, Figueredo-Zalve R. Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, noninferiority clinical trial. J Bone Joint Surg Am. 2014;96(23):1937-1944.
19. Hamlin BR, DiGioia AM, Plakseychuk AY, Levison TJ. Topical versus intravenous tranexamic acid in total Knee arthroplasty. J Arthroplasty. 2015;30(3):384-386.
20. Wang C, Xu GJ, Han Z, Ma JX, Ma XL, Jiang X, et al. Topical application of tranexamic acid in primary total hip arthroplasty: a systemic review and meta-analysis. Int J Surg. 2015;15:134-139. doi: 10.1016/j.ijsu.2014.12.023.
21. Alshryda S, Sukeik M, Sarda P, Blenkinsopp J, Haddad FS, Mason JM. A systematic review and meta-analysis of the topical administration of tranexamic acid in total hip and knee replacement. Bone Joint J. 2014;96-B(8):1005-1015.
22. Xie J, Ma J, Yue C, Kang P, Pei F. Combined use of intravenous and topical tranexamic acid following cementless total hip arthroplasty: a randomised clinical trial [published online ahead of print September 9, 2015]. Hip Int. doi: 10.5301/hipint.5000291.
23. Moskal JT, Harris RN, Capps SG. Transfusion cost savings with tranexamic acid in primary total knee arthroplasty from 2009 to 2012. J Arthroplasty. 2015;30(3):365-368.
24. Harris RN, Moska JT, Capps SG. Does tranexamic acid reduce blood transfusion cost for primary total hip arthroplasty? A case-control study. J Arthroplasty. 2015;30(2):192-195.
25. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost benefit analysis of topical tranexamic acid in primary total hip and knee arthroplasty. J Arthroplasty. 2014;29(8):1512-1515.

Prepared by:

Suhair Shawar, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

December 2015

The information presented is current as October 8, 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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