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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 31  |  Issue : 1  |  Page : 9-12

Newer anticoagulants and their impact on interventional pain procedures


Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication5-May-2017

Correspondence Address:
Babita Ghai
Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_11_17

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  Abstract 


Heparins and coumarins have been ruling the anticoagulant class for the past 60 years, but the trend in the drug discovery, prominence of target-based approach, and high-throughput screening has brought newer molecules in the forefront. Newer oral anticoagulants (NOACs) with different therapeutic challenges have largely come up in the past 5 years and overcome the limitations of traditional anticoagulants. The debate for specific guidelines for their use has been on for years. Interventional pain physicians admonished that available guidelines for regional anesthesia in patients receiving anticoagulants were insufficient as pain procedures covered a far broader gamut reflecting diverse goals. Hence, experts from different groups and committees got together and summed up guidelines and stratified interventional pain procedures based separately on patient- and procedure-specific factors. Here, in this review, we discuss the NOACs and their impact on interventional pain procedures.

Keywords: Interventional pain procedures, newer anticoagulants, newer oral anticoagulants


How to cite this article:
Ghai B, Ahuja N. Newer anticoagulants and their impact on interventional pain procedures. Indian J Pain 2017;31:9-12

How to cite this URL:
Ghai B, Ahuja N. Newer anticoagulants and their impact on interventional pain procedures. Indian J Pain [serial online] 2017 [cited 2017 Dec 11];31:9-12. Available from: http://www.indianjpain.org/text.asp?2017/31/1/9/205710




  Introduction Top


Warfarin has been in practice for many years now, with the physicians being well versed with its activity profile, side effects, and methods of reversal.[1]

Newer oral anticoagulants (NOACs) with different therapeutic challenges have largely come up in the past 5 years.[2] The newer agents unlike the older ones do not have associated monitoring requirements and are easier to dose.[2] Here, in this review, we discuss the NOACs and their impact on carrying out interventional pain procedures.


  Anticoagulants - the Revolution Top


Heparins and coumarins have been ruling the anticoagulant class for the past 60 years, but the trend in the drug discovery, prominence of target-based approach, and high-throughput screening has brought newer molecules in the forefront, such as fondaparinux, dabigatran, and rivaroxaban to name a few.[1],[3] The novel NOACs have overcome the limitations of traditional anticoagulants to prevent or treat venous and arterial thromboembolic conditions.[3] They are broadly classified into direct thrombin inhibitors (ximelagatran and dabigatran) and direct factor Xa inhibitors (xarelto and apixaban). All these NOACs offer various advantages over the traditional anticoagulants such as rapid onset of action, shorter half-life, more stable anticoagulant effect, little or no food interactions so minimal dietary restrictions unlike warfarin, limited drug interactions, and lesser need of coagulation monitoring.[4] Despite these advantages, NOACs are associated with certain disadvantages also.[4] One of them being the lack of a countermeasure to treat major bleeding complications. Furthermore, the periprocedural management of patients on NOACs might pose some patient-specific concern. Some special consideration should be given to patients with impaired renal clearance of <30 mL/min, as these are majorly eliminated through the kidneys. Cost may also limit the use, in addition to lack of adherence due to lesser monitoring that is required.


  Newer Oral Anticoagulants Top


With the NOAC taking the medical field by storm and their advantages over the conventional warfarin and its analogs, their profile, pharmacokinetics, and drug–drug interactions are important points to keep into consideration while prescribing them so as to avoid dosing errors and missed doses.

A class of direct thrombin inhibitors works by binding to thrombin and blocking its interaction with substrates.[3] They are mostly administered through the parenteral route, for example, hirudin, bivalirudin, and argatroban, but dabigatran is a relatively newer and an oral antithrombin.[3]

Despite the benefits of NOACs, their prescription needs to be appropriately planned based on their peak activity timings and concentrations. Here, we compare the important pharmacological and pharmacokinetic properties of the NOACs in comparison to traditional warfarin [Table 1].[4]
Table 1: Comparison of pharmacokinetic characteristics of the newer oral anticoagulants with warfarin[4]

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Dabigatran

This is a first of the NOACs to get US-Food and Drug Administration approval and is a direct thrombin inhibitor. Its prodrug, dabigatran etexilate, gets hydrolyzed to the active form in the stomach.[5] It is proved to be effective in venous thromboembolism (VTE) prophylaxis after surgery in patients undergoing total hip or knee replacement and for prevention of stroke in patients with valvular atrial fibrillation.[5]

The direct Xa inhibitors, as the name suggests, directly bind to the active site of Xa, in turn inhibiting both platelet-bound and free factor Xa.[5]

Rivaroxaban

A direct inhibitor of factor Xa, rivaroxaban, is as effective as enoxaparin for treating VTE and in the prevention of embolic stroke during AF.[6] It acts by inhibiting factor Xa in a concentration-dependent manner and is rapid and reversible in its action.[7]

Apixaban

Another of the direct Xa inhibitors, this is an orally administered agent. Compared with some conventional anticoagulants such as enoxaparin, it is definitely associated with lower rates of bleeding.[8],[9]

Edoxaban

Another of the direct Xa inhibitors, trials have successfully proven effective anticoagulation of edoxaban in patients with atrial fibrillation.[8] Its anticoagulant activity seems to be irreversible even with protamine sulfate, Vitamin K, and tranexamic acid.


  Need for Guidelines for Interventional Pain Procedures for Patients on Newer Oral Anticoagulants Top


The risk of performing interventional pain injections while a patient is on anticoagulants has been debated for years.

Experts from different groups and committees such as the American Society of Regional Anesthesia and Pain Medicine, American Academy of Pain Medicine, North American Neuromodulation Society, European Society of Regional Anaesthesia and Pain Therapy, World Institute of Pain, and International Neuromodulation Society [9] got together and summed up guidelines. They stratified interventional pain procedures based separately on the patient- and procedure-specific factors.

Procedure-specific factors were divided into potential low, intermediate, and high bleeding risks [Table 2].[9] The guidelines were considered apt for intermediate- and low-risk category. However, high-risk procedures needed more attention regarding patient safety issues and improved outcomes.[9]
Table 2: Pain procedure classification: According to the potential risk for bleed[9]

Click here to view


Interventional pain physicians admonished that available American Society of Regional Anesthesia (ASRA) guidelines for regional anesthesia in patients on anticoagulants were insufficient as pain procedures covered a far broader gamut reflecting diverse goals.

Patients undergoing regional anesthesia usually have a nonpathological spine. However, patients with chronic cancer and noncancer pain undergoing pain procedures may suffer from ligamentum flavum hypertrophy, spondylosis, and spinal stenosis, which can compress the epidural venous plexus. Furthermore, patients postspine surgery may develop fibrosis, further compromising the epidural space leading to altered anatomy of epidural vessels. Other factors such as increase of fragility of epidural vessels and decrease of epidural fat with age, predispose to hematoma formation. Ganglia of stellate, middle cervical, celiac, and lumbar sympathetic plexus are other anatomical areas with significant undesirable vascularity.[10]

It has also been observed, chronic pain coexists with psychosocial and mental stress, resulting in a hypercoagulable state with reduced fibrinolytic capacity, increased in procoagulants (coagulation factor VII or Fibrinogen), and increased activity of platelets, and such a state places the patients at an increased risk of cerebrovascular and coronary events on discontinuation of the antiplatelet or anticoagulant medications.[10],[11],[12] All these need to be thoroughly discussed and planned with the concerned neurologist or cardiologist.

Recommendations

Certain recommendations have been made on the use of the anticoagulant class of medications, for different situations, so that it serves as a ready reckoner at the time of consultation.

For acenocoumarol and warfarin[6]

Low-risk procedures

Many of the low-risk procedures may be safe if international normalized ratio (INR) is in the therapeutic range (INR < 3). It is strongly recommended that risk stratification and decision of management to be taken in conjunction with the treating physician for patients with high bleeding risk.[13],[14]

Intermediate and high-risk procedures

Acenocoumarol should be stopped for 3 days and warfarin for 5 days, and INR should be normalized (<1.4).

After the procedure

Warfarin may be restarted the next day.

A “bridge therapy” can also be advised with low molecular weight heparin in patients with high risk of thrombosis in consultation with treating physician.

For newer oral anticoagulants

Due to lack of studies and literature on the intervals between the discontinuation of NOACs and central neuraxial procedures and then resumption of the discontinued drug. No recommendations for the NOACs have been laid down by the ASRA. The current guidelines being followed are summarized here: The Previous ASRA guidelines on regional anesthesia did not make any on NOACs, probably because of lack of studies. However, the current guidelines being followed are summarized here. [Table 3].[9]
Table 3: Summary of recommendations for newer oral anticoagulant discontinuation and resumption according to risk procedures and risk of venous thromboembolism

Click here to view


For dabigatran [9]

Low-risk procedures

It is strongly recommended that a shared assessment with the treating physician should guide the course of therapy. An interval of 2 half-lives (24–34 h) can be considered.

Intermediate- and high-risk procedures

There should be consideration of 5 half-lives (60 h) interval corresponding to 4–5 days between discontinuation of dabigatran and the procedure.

For end-stage renal disease

There should be consideration of 5 half-lives, but it should be kept in mind that in end-stage renal disease, the half-life is increased to around 28 h as compared to 12–17 h in patients having normal renal functions. Hence, a 6-day interval (5 half-lives) is usually considered.

After the procedure

Dabigatran can be resumed after 24 h interval. For patients having a high risk of VTE, dabigatran may be restarted 12 h after the intervention.

For rivaroxaban [9]

Low-risk procedures

It is strongly recommended that an assessment and risk stratification together with the treating physician should guide therapy. An interval of 2 half-lives (18–36 h) can be considered.

Intermediate- and high-risk procedures

There should be consideration of 5 half-life intervals (~65 h) corresponding to 3 days between discontinuation of rivaroxaban and the procedure.

After the procedure

A 24 h interval before rivaroxaban can be resumed. For patients having a high risk of VTE, half dose may be considered 12 h after the intervention.

For apixaban [9]

Low-risk procedures

It is strongly recommended that an assessment and risk stratification together with the treating physician should guide therapy. An interval of 2 half-lives (~30 h) can be considered.

Intermediate- and high-risk procedures

A 5 half-life interval (~75 h) is equivalent to 3 days between discontinuation of apixaban and the procedure is recommended. Apixaban depicting a wide variability in its pharmacokinetics, 3–5 days is recommended.

After the procedure

A 24 h interval before apixaban can be resumed. For patients with high risk of VTE, giving half dose 12 h after the intervention may be considered.


  Conclusion Top


With the pace, the NOACs are taking the market, it is likely that an increasing number of patients being given these NOACs will present for interventional pain and spine procedures. These new agents offer assertive advantages over the conventional agents in terms of efficacy, reduced monitoring needs, and lesser-unwanted side effects. The knowledge about their pharmacological profile is thus of paramount importance for the pain physicians before conducting any intervention.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Laroia ST, Morales S, Laroia AT. Beyond warfarin: The advent of new oral anticoagulants. Indian J Radiol Imaging 2015;25:375-9.  Back to cited text no. 1
    
2.
Gevirtz C. New anticoagulant medications and their impact on interventional pain procedures. Topics in Pain Management, Current Concepts and Treatment Strategies. Vol. 30. Lippincott Williams & Wilkins; 2015. p. 1-12.  Back to cited text no. 2
    
3.
Cappelleri G, Fanelli A. Use of direct oral anticoagulants with regional anesthesia in orthopedic patients. J Clin Anesth 2016;32:224-35.  Back to cited text no. 3
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4.
Shehab A, Elnour AA, Bhagavathula AS, Erkekoglu P, Hamad F, Al Nuaimi S, et al. Novel oral anticoagulants and the 73rd anniversary of historical warfarin. J Saudi Heart Assoc 2016;28:31-45.  Back to cited text no. 4
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5.
Weitz JI, Hirsh J, Samama MM; American College of Chest Physicians. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133 6 Suppl:234S-56S.  Back to cited text no. 5
    
6.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.  Back to cited text no. 6
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7.
Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: A new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010;30:376-81.  Back to cited text no. 7
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8.
Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: A systematic review. Ann Intern Med 2012;157:796-807.  Back to cited text no. 8
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9.
Narouze S, Benzon HT, Provenzano DA, Buvanendran A, De Andres J, Deer TR, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: Guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med 2015;40:182-212.  Back to cited text no. 9
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10.
von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: A biobehavioral pathway to coronary artery disease? Psychosom Med 2001;63:531-44.  Back to cited text no. 10
    
11.
von Känel R. Changes in blood coagulation in stress and depression – From evolution to gene regulation. Ther Umsch 2003;60:682-8.  Back to cited text no. 11
    
12.
Markovitz JH, Matthews KA. Platelets and coronary heart disease: Potential psychophysiologic mechanisms. Psychosom Med 1991;53:643-68.  Back to cited text no. 12
    
13.
Conway R, O'Shea FD, Cunnane G, Doran MF. Safety of joint and soft tissue injections in patients on warfarin anticoagulation. Clin Rheumatol 2013;32:1811-4.  Back to cited text no. 13
    
14.
Ahmed I, Gertner E. Safety of arthrocentesis and joint injection in patients receiving anticoagulation at therapeutic levels. Am J Med 2012;125:265-9.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Introduction
Anticoagulants -...
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