Novel anticoagulant treatment

Production of fibrin can be initiated through the activation of 1 of 2 converging coagulation cascades—the extrinsic pathway (so named because it initiates coagulation in response to tissue injury, as in trauma or surgery) and the intrinsic pathway (so named because all the elements required for blood clotting are present, even in the absence of injury).

The extrinsic pathway is initiated when tissue factor (TF)—a transmembrane glycoprotein receptor expressed on subendothelial layers of blood vessels—is exposed to the flowing blood following injury to the vasculature. Tissue factor is rapidly bound by circulating Factor VII (FVII). Binding is accompanied by autoactivation to FVII to form Factor VIIa (VIIa). The complex of TF and FVIIa cleaves Factor X (FX) into its active form, Factor Xa (FXa). Subsequently, FXa binds Factor V (FV) to form prothrombinase, the enzyme responsible for converting prothrombin into thrombin. In turn, thrombin cleaves fibrinogen to form fibrin, initiating the clot


In the intrinsic pathway, Factor XI (FXI), which is expressed on activated platelets, is autoactivated to Factor XIa (FXIa), which is capable of converting Factor IX (FIX) to Factor IXa (FIXa). In turn, FIXa activates FX in the presence of Factor VIII (FVIII). Here, the extrinsic and intrinsic pathways merge, with the binding of FXa to FV to form prothrombinase, the subsequent conversion of prothrombin into thrombin, and the thrombin-mediated formation of fibrin from fibrinogen. The extrinsic pathway can feed back into the intrinsic pathway as a result of thrombin-mediated activation of FXI.

Factor X plays a central role in thrombin generation based on its position at the start of the common pathway of the extrinsic and intrinsic coagulation systems. Once activated by either pathway, factor Xa becomes an essential component of the prothrombinase complex (together with factor Va, prothrombin, phospholipid, and calcium). Since assembly of the prothrombinase complex represents the penultimate step in thrombin generation interference with factor Xa activity directly affects the amount of active thrombin generated and, therefore, the amount of fibrin formed

new anticoagulant agents

Recently, 2 new anticoagulant agents - dabigatran and rivaroxaban - have been approved  for reduction of the risk of stroke in association with atrial fibrillation (dabigatran) and for prophylaxis of deep vein thromboembolism in patients undergoing knee or hip replacement surgery (rivaroxaban).
 Dabigatran is a direct thrombin inhibitor, preventing the conversion of fibrinogen to fibrin and subsequent thrombus formation.
 Rivaroxaban is a factor Xa inhibitor, blocking an essential step in the coagulation cascade for thrombus formation.
 Both agents are given in a fixed-dose regimen and do not require routine monitoring.
 Unlike well-established anticoagulants such as warfarin and unfractionated heparin, there are no clear antidotes for reversal of the anticoagulant effects of either of these newer agents. Although both have relatively short half-lives (12 to 17 hours for dabigatran and 5 to 9 hours for rivaroxaban) there may be situations where urgent reversal of anticoagulant effects is needed (e.g., emergency surgery, overdose, or life-threatening bleeding).

Pradaxa (dabigatran)

PRADAXA is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

DOSAGE AND ADMINISTRATION

• For patients with CrCl >30 mL/min: 150 mg orally, twice daily (2.1)
• For patients with CrCl 15-30 mL/min: 75 mg orally, twice daily. 

Assess renal function during therapy as clinically indicated and adjust therapy accordingly
Temporarily discontinue PRADAXA before invasive or surgical procedures when possible, then restart promptly.

Converting from or to Warfarin

When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the INR is below 2.0.
When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:

• For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
• For CrCl 30-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
• For CrCl <15 mL/min, no recommendations can be made.

Converting from or to Parenteral Anticoagulants

For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).
For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.

Surgery and Interventions

If possible, discontinue PRADAXA 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required
If surgery cannot be delayed, there is an increased risk of bleeding . This risk of bleeding should be weighed against the urgency of intervention.

Bleeding

RE- LY STUDY

The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age.
There was a higher rate of major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively).

Risk of Bleeding

Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.

Management of bleeding for patients treated with PRADAXA

1. EVALUATION OF ANTICOAGULANT ACTIVITY
2. IN EMERGENCY SITUATIONS IT IS ADVISABLE TO ASSESS THE ANTICOAGULATION STATUS OF A PATIENT RECEIVING PRADAXA. THERE IS A CLOSE CORRELATION BETWEEN THE PLASMA CONCENTRATION OF PRADAXA AND THE DEGREE OF ANTICOAGULANT EFFECT. THE HALF-LIFE OF PRADAXA IS 12-14 HOURS; 80% OF PRADAXA IS RENALLY CLEARED. PLEASE BE AWARE THAT IN PATIENTS WITH RENAL IMPAIRMENT THE HALF-LIFE OF PRADAXA WILL BE PROLONGED ACCORDINGLY.

  - TIME POINT OF BLOOD SAMPLING: THE ANTICOAGULANT RESPONSE DEPENDS ON THE TIME WHEN THE BLOOD SAMPLE WAS TAKEN IN RELATION TO THE LAST DOSE ADMINISTERED

   - LEVEL OF ANTICOAGULANT ACTIVITY: THE MOST SENSITIVE TEST IS THE THROMBIN TIME (TT) TEST. A NORMAL TT MEASUREMENT INDICATES NO CLINICALLY RELEVANT ANTICOAGULANT EFFECT OF PRADAXA. A NORMAL ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT) AND ECARIN CLOTTING TIME (ECT) ARE ALSO INDICATIVE OF NO PHARMACOLOGICALLY RELEVANT ANTICOAGULANT ACTIVITY OF PRADAXA
  

- PROTHROMBIN TIME (INR) IS NOT SUFFICIENTLY SENSITIVE FOR THE EVALUATION OF THE ANTICOAGULANT ACTIVITY OF PRADAXA. 

tests: semi-quantitative

Activated Partial Thromboplastin Time test:

• An aPTT >80 seconds or approximately 2-3-fold prolongation at trough (when the next dose is due) is associated with a higher risk of bleeding.
•  An aPTT of approximately 1.5-fold prolongation at trough is the expected level of anticoagulation after the intake of PRADAXA 150mg bid

Ecarin Clotting Time and Thrombin Time

ECT and TT tests assess the anticoagulant activity of direct thrombin inhibitors, such as PRADAXA. Due to the lack of standardization both assays may be prone to substantial interlaboratory variability. Therefore, no reference values for local laboratories can be provided.

tests: quantitative

Calibrated Hemoclot® Thrombin Inhibitor assay (HYPHEN BioMed, Neuville-sur-Oise, France): A diluted Thrombin Time (dTT) measure with the calibrated Hemoclot® assay of >200 ng/mL dabigatran plasma concentration prior to the next drug intake after 150 mg twice-daily dosing (trough measure, eg, 10–16 hours after the previous dose) is associated with a higher risk of bleeding.

Major bleeds criteria

• bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood.
• symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding).

life-threatening bleed criteria

• fatal
• symptomatic intracranial bleed
• reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention
• Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

algorithm for treatment of bleeding with dabigatran

• mild bleeding: a delay in dosing or discontinuation of the drug
• moderate to severe bleeding: mechanical compression, surgical intervention, fluid replacement, transfusion, oral charcoal (for ingestions < 2 h before), and hemodialysis.
• life-threatening bleeding: use of either PCC, FVIIa, and fresh frozen plasma  as well as charcoal filtration and hemodialysis

XARELTO (rivaroxaban)

factor Xa inhibitor indicated:

•  to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
•  for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE)
• for the reduction in the risk of recurrence of DVT and of PE
•  for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery

DOSAGE

Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation

• CrCl >50 mL/min: 20 mg once daily with the evening meal
• CrCl 15 to 50 mL/min: 15 mg once daily with the evening meal

Treatment of DVT , Treatment of PE (2.4)

• 15 mg twice daily with food, for first 21 days

▼after 21 days, transition to ▼

• 20 mg once daily with food, for remaining treatment

Reduction in the Risk of Recurrence of DVT and of PE

• 20 mg once daily with food

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

• Hip replacement: 10 mg once daily for 35 days
• Knee replacement: 10 mg once daily for 12 days

Discontinuation for Surgery and other Interventions

• If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding.
•  In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention.
• XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.

Bleeding

• the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin.
• In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies,the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively.
• XARELTO increases the risk of bleeding and can cause serious or fatal bleeding.
• Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
• A specific antidote for rivaroxaban is not available. 
• Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.
• Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
• There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid)
• There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban.
• Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical trials.

What methods are available for reversal of dabigatran and rivaroxaban

• recombinant factor VIIa (rFVIIa) and prothrombin complex concentrates (PCCs FEIBA ) have been suggested as agents for reversal for both dabigatran and rivaroxaban.
• FEIBA is an activated prothrombin complex concentrate, containing nonactivated factors I, IX, X, and activated factor VII - 50 or 100 U/kg
• recombinant factor VIIa (rFVIIa) - 0.5 or 1 mg/kg

reversal of rivaroxaban

• mechanical compression, surgical intervention, fluid replacement, transfusion
• discontinuation of the drug
• prothrombin complex concentrates (PCCs) - providing more factor X and Xa

Summary

Currently, there are no definitive treatments for reversal of the effects of dabigatran or rivaroxaban.  Treatment of excess bleeding due to either of these agents needs to be individualized, with close monitoring of patient response.