Patients seeking interventional treatment for chronic pain can have a variety of medical problems. The aging population in particular can present with complex medical conditions that require anticoagulation therapy.
In 2010, the American Society of Regional Anesthesia and Pain Medicine published a practice advisory regarding the use of regional anesthesia in patients receiving anticoagulation to enhance safety as well as quality patient care. The third edition of guidelines reports a consensus statement utilizing the collective experience of experts in neuraxial anesthesia and anticoagulation. The guidelines presented are comprehensive and based on case reports, clinical series, pharmacology, hematology and risk factors for surgical bleeding. This is a very complex issue for which there is no simple template to follow. Each case must be reviewed on an individual basis. There should be communication with the patient’s health care providers such as the cardiologist, regarding safest treatment options. This collaboration is essential in diminishing life-threatening bleeding complications associated with neuraxial anesthesia.
Typical scenarios interventional pain physicians encounter with patients on chronic anticoagulation therapy include:
• Patients on venous thromboembolic treatment
• Patients with vascular stents in place
• Epidural/spinal injections for patients having joint replacement surgery
• Extended period of DVT prophylaxis in orthopedic patients
The problems in patients who are on chronic anticoagulation therapy are:
• Therapy-associated mortality (5%-12%)
• Spontaneous bleeding requiring discontinuation of therapy (15%-20%)
• Heparin-induced immune-mediated thrombocytopenia (HIT) (3.5%-7%)
• 25% patients with HIT develop new venous and/or arterial thrombotic event
• Warfarin crosses placenta and cannot be given in pregnancy
• Dose adjustment of fondaparinux in patients with compromised renal function
This creates a challenge when preparing patients for invasive procedures. Patients undergoing interventional treatment for chronic pain, particularly neuraxial anesthesia, are at increased risk for complications associated with bleeding.
The risk of clinically significant bleeding is exacerbated by the following:
• Increased age
• Spinal cord or vertebral column abnormalities
• Needle placement difficulties
• Continued anticoagulation with neuraxial catheter in place.1
It is important to weigh the risk-benefit ratio when determining when to stop anticoagulant or antiplatelet therapy along with determining exactly when to restart treatment postintervention.
• The incidence of hemorrhagic complications and resulting neurologic deficit after neuraxial intervention is unknown.
• The incidence of bleeding is less than 1 in 150,000 epidurals and 1 in 220,000 spinal anesthetics.
• More recent surveys are revealing an incidence as high as 1 in 3000 in high-risk patient populations.
• High index of suspicion, prompt diagnosis, and treatment of bleeding is critical to decreasing the incidence of permanent neurological deficit.
A review of the literature from 1906 to 1994 by Vandermeulen et al4 reported:
• 61 cases of spinal hematoma reported to be associated with epidural or spinal anesthesia
• 60% of these cases occurred in the last 10 years of the study period
• 68% of the patients (n = 42) had hemostatic abnormality when the spinal hematoma occurred
• 8% of patients had reported bowel/bladder dysfunction
• Severe radicular back pain was not a presenting sign in many cases
• 38% of patients had partial or good neurologic recovery
• Spinal cord ischemia was reversible in patients that received a decompressive laminectomy within 8 hours of onset of neurologic dysfunction
These findings clearly emphasize the need for close monitoring, evaluation, and treatment of neurologic dysfunction. Because of the possibility of neurologic dysfunction, it is of critical importance to evaluate each patient for the risk versus benefit when determining whether a patient taking chronic anticoagulation therapy is an appropriate candidate for interventional pain management procedures.
This chapter discusses the most commonly utilized anticoagulant and antiplatelet agents and their relevant pharmacologic factors, including mechanism of action, indications, and when to stop and restart pre- and postprocedure to promote patient safety to prevent poor outcomes.
Our concerns are:
• When to stop ongoing anticoagulation therapy, and risks of thrombosis by stopping
• When to restart the therapy after the procedure, and risks of bleeding by restarting
• What laboratory test to order to normalize the coagulation profile
• Optimize the risks versus benefits ratio
Predisposing factors for deep vein thrombosis (DVT) and thromboembolic events:
• Patients with multiple trauma
• Conditions that promote venous stasis
• Lack of ambulation (postoperation, fractures)
• Low CO (CHF, MI)
• Morbid obesity
• Advanced age
• Race: higher in African Americans
• Sex: M > F
• Cancer and cancer therapy
Patients who require anticoagulation due to hypercoagulable states:
• Hypercoagulable syndromes: Recurrent thromboses, family Hx of thrombosis, Hx of spontaneous abortions, multiple exposures to heparin
• Activated protein-C resistance (venous)
• Antiphospholipid syndrome (Dx: anticardiolipin antibodies)
• Congenital deficiency of antithrombin III
• Protein C and S deficiency: vitamin K dependent
• Hyperhomocysteinemia: homocysteine is coagulant
Warfarin is used in a variety of medical conditions as an anticoagulant in the prevention of ischemic stroke, myocardial infarction as well as peripheral vascular disease as well for patients with stents to prevent deep thrombus formation and or pulmonary emboli.
• Direct thrombin inhibitor.
• Inhibits synthesis of vitamin K–dependent coagulation factors II, VII, IX, and X.
• Anticoagulation effects start after 12 to 16 hours of administration.
• Warfarin does not affect already synthesized coagulation factors.
• Peak effect is at approximately 40 hours.
• The half-life of warfarin is from 20 to 60 hours; with a mean of 40 minutes.
• The length of effect is 2 to 5 days.
• Vitamin K can be administered to reverse the effects of warfarin, although the replacement of vitamin K is slow and may take 24 to 30 hours.
• For emergency surgery/intervention use fresh frozen plasma.
For high risk thromboembolic patients a consultation with primary care physician to understand the risks of stopping the anticoagulation therapy and for possible bridging anticoagulation therapy to minimize the risks may need to be considered.
• Warfarin should be stopped 5 days before the planned procedure.
• PT/INR should be rechecked immediately prior to the procedure; must be normalized.
• If warfarin is started postoperation, catheter can be removed when INR is <1.5.
Dabigatran (Pradaxa), approved by the Federal Drug Administration (FDA) in October 2010, is the first oral anticoagulant approved in 50 years since coumadin. The FDA approved dabigatran primarily based on the outcomes of the RELY (randomized evaluation of long-term anticoagulation therapy) noninferiority study with 18,113 participants.5 It is utilized primarily to prevent the formation of clots and reduce the risk of stroke in patients with nonvalvular atrial fibrillation.
• Direct thrombin inhibitor.
• Dosed as 150 mg daily for patients with creatinine clearance of greater than 30 mL/min; for a creatinine clearance of 15 to 30 mL/min the dosage is reduced to 75 mg daily.
• No dietary restrictions, blood monitoring requirements, or dosage adjustments needed.
• Discontinued prior to invasive procedures based on the patient’s creatinine clearance values:
1 to 2 days prior to an invasive procedure if the creatinine clearance is equal to or greater than 50 mL/min.
3 to 5 days prior to an invasive procedure if creatinine clearance is of less than 50 mL/min.
• The half-life of dabigatran is 12 to 17 hours.5
• No reversal agent for this drug.
• ASRA does not support neuraxial techniques in patients on thrombin inhibitors. Being reevaluated by the FDA based on postmarketing reports of critical bleeding events. The FDA still believes dabigatran offers valuable health benefit when used as recommended.10
Other thrombin inhibitors: desirudin (Revax), lepirudin (Refludan), bivalirudin (Angiomax), and argatroban (Acova)
• Inhibit clot-bound thrombin.
• Indicated to treat heparin-induced thrombocytopenia to prevent thrombosis, and as an adjuvant to angioplasty; desirudin is FDA approved for prevention of DVT and PE after hip replacement.
• Monitor aPTT, present 1 to 3 hours after IV administration.
• Neuraxial techniques are not recommended until further studies have been completed due to long half-life and difficulty with reversal; no antidote known.
Heparin (unfractionated or UFH), an anticoagulant whose activity is dose related, as well as molecular size dependent, although its effects are not incremental and increase unequally with elevated doses.1
• Binds to antithrombin III and inhibits conversion of prothrombin to thrombin, prolonging clotting time; results in an increase in partial thromboplastin time (PTT).
• Prevents fibrin formation and limits expansion of thrombi; however, it is ineffective on platelet aggregation.11
• Prior to invasive interventions check PTT, hemoglobin and hematocrit levels.
• Subcutaneous heparin injection results in 1 to 2 hours activation time.
• Heparin given intravenously has an immediate anticoagulation effect and a short half-life of approximately 60 to 90 minutes.
• Hemostasis restoration for intravenous heparin is 3 to 4 hours after discontinuing the therapeutic dose.12
• Subcutaneous heparin duration of action is 8 to 12 hours.13
• Rapid reversal agent for heparin is protamine sulfate 1 mg for every 100 units of IV heparin; a protamine infusion may be necessary due to continued absorption.1
• Fresh frozen plasma should not be used to reverse the effects of unfractionated heparin as it provides additional antithrombin which may increase the bleeding effects of the medication.7
LOW MOLECULAR WEIGHT HEPARIN
Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep).
Low molecular weight heparins (LMWH) have some very different properties from UFH, the primary ones being that LMWH are not able to be measured regarding their anticoagulant effect; they have a prolonged half-life and they are not reversible with protamine.1 Each medication has specific indications including prevention of deep venous thrombosis, pulmonary embolism, and ischemic complications related to unstable angina and non–ST-segment-elevation myocardial infarction.
• Causes selective inhibition of Xa and mild anti-IIa preventing thrombus formation.
• PTT is not prolonged, so monitoring this parameter is not necessary.
• Use extreme caution when caring for patients taking low molecular weight heparins when considering spinal/epidural anesthesia,13 including interventional therapies for chronic pain.
If LMWH is being utilized as a bridging agent for high-risk patients requiring chronic anticoagulation, close monitoring is imperative to minimize the increased risk of bleeding.
Horlocker et al,1 purports age and gender (elderly women) are considerable patient risk factors along with concomitant use of multiple hemostasis-altering medications due to possible synergistic effects.
• Half-life of LMWH is approximately 4 hours.7
• Hemostatic restoration after discontinuing the therapeutic dose of the drug is 12 to 24 hours.12
• Invasive interventional guidelines include needle placement 24 hours after last dose of LMWH.
• May be restarted 24 hours after surgery and 2 hours after a block.
• Should not be restarted prior to the removal of epidural catheters.
• With a traumatic needle placement during an interventional procedure there is no need to cancel surgery; may still start 24 hours after surgery.
• The risk of hematoma increases with concomitant anticoagulant usage.11
• To monitor for side effects obtain: complete blood cell (CBC) counts, platelet level, and stool for occult blood during therapy.
• Patients who are obese or with renal dysfunction
Horlocker et al1 do not recommend using anti-Xa level routinely as it is not predictive of bleeding risk.
PENTASACCHARIDE AGENTS (FONDAPARINUX [ARIXTRA])
Indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism.8
• Antithrombin III mediated selective inhibitor of factor Xa that does not inhibit thrombin.7
• Anti-Xa assay can be used to monitor the effects of pentasaccharide agents.
• Half-life is approximately 21 hours or longer with renal insufficiency.
• Neuraxial techniques validated in clinical trials include single pass needle techniques and atraumatic needle placement. Indwelling neuraxial catheters should be avoided.
• Stop 24 to 30 hours prior to a procedure.
• No specific emergent antidote has been identified, although rFVlla can be used as a reversal agent.7
• After discontinuing fondaparinux (Arixtra) hemostatic restoration is reestablished in 24 to 30 hours.7
Antiplatelet agents include NSAIDs, thienopyridine derivatives (ticlopidine and clopidogrel), and platelet GP IIb/IIIa receptor antagonists (abciximab, eptifibatide, and tirofiban).
Aspirin is utilized to decrease the occurrence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and prevents thrombus formation after coronary artery bypass surgery. It can also be used for mild to moderate pain.
• Antiplatelet agent, “inhibits the synthesis of thromboxane (TXA) by irreversible acetylation of the enzyme cyclooxygenase.”6
• Irreversibly binds to cyclooxygenase-1 enzyme (COX-1) and inhibits TXA2 production in all platelets exposed to aspirin.7
• Low dose half-life is 2 to 3 hours; high dose half-life is 15 to 30 hours.
• Antiplatelet effect of aspirin lasts for 5 to 10 days or the life of a platelet6; therefore, 10 days is needed to restore hemostasis after discontinuing the therapeutic dose (the amount of time to produce platelets).12
• No specific antidote for aspirin, although 1 unit of platelet transfusion is the current mode of reversal.
• Aspirin is easily detected by the PFA-100 test.7
• Antiplatelet agent inhibiting an adenosine diphosphate (ADP)–dependent pathway for platelet activation. Also interferes with platelet-fibrinogen binding which affects platelet–platelet interactions.7
• Platelet dysfunction is greater with clopidogrel than with aspirin.7
• Platelet aggregometry test can be used to monitor platelet function.7
• Platelet function returns to normal 5 to 7 days after discontinuing the medication.
• Discontinue 7 to 10 days prior to surgery or procedure (low risk for cardiac event).
• If patient is high risk for cardiac event without anticoagulant, discontinue 5 days prior to procedure/surgery, ideally 10 days prior.
• Restart 24 hours postprocedure.
• Similar to aspirin, there is no antidote, although 2 units platelet concentrate can be used as a reversal agent.
Ticlopidine may also be used for cardiovascular and cerebrovascular diseases but is not preferred over clopidogrel due to delayed and prolonged effect.
• Antiplatelet that interferes with platelet-fibrinogen binding and ADP pathway for platelet activation.
• Steady state achieved in 14 to 21 days; may be accomplished sooner with higher doses.
• Discontinue 14 days prior to surgery or procedure; document platelet function just prior to procedure; normal platelet function may return in as little as 10 days, but conservatively should wait 14 days.
• Restart 24 hours postprocedure.
Platelet GP IIb/IIIa Receptor Antagonists
Abciximab (Reopro), eptifibatide (Integrilin), and tirofiban (Aggrastat)
Platelet GP IIb/IIIa receptor antagonists are most often used to treat acute coronary syndromes with or without a percutaneous coronary procedure.
• Interferes with platelet-fibrinogen binding and platelet-von Willebrand factor binding.
• Blocks the final pathway to platelet aggregation by inhibiting the GPIIb/IIIa receptors.
• Commonly coadministered with aspirin and heparin.
• Contraindicated if the patient has had surgery within the last 4 to 6 weeks.
• Time to normal platelet aggregation is 24 to 48 hours for abciximab; 4 to 8 hours for eptifibatide and tirofiban.
• During therapy, epidural procedures and puncture of non-compressible sites should be avoided per manufacturer’s recommendations. No further studies available to substantiate safety during neuraxial blockade. Additionally, combination with other anticoagulants being coadministered, greatly increase bleeding risks.
Those patient populations requiring anticoagulant and/or antiplatelet agents for various therapeutic purposes can present challenges for interventional pain procedures. Specifically, patients undergoing neuraxial anesthesia and nerve blocks (with or without catheters) are at increased risk for epidural and spinal hematomas. An understanding of mechanisms of action, half-life and dosing can assist in developing a treatment plan for patients requiring anticoagulation therapy. It is also helpful to coordinate with the other health care providers involved in monitoring a patient’s anticoagulation treatment and status, to develop a risk-benefit stratification approach to the treatment plan. Exactly when to stop and restart these medications, or if a substitution anticoagulant needs to be instituted, should be determined in collaboration with the patient’s other health care providers.