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Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban Raphael Marlu, Enkelejda Hodaj, Adeline Paris, Pierre Albaladejo, Jean Luc Crackowski, Gilles Pernod Thrombosis and Haemostasis 108.2/2012 Journal Club presented by: Megan Handley December 5, 2014 Background and Overview Background New anticoagulant medications have recently been approved for the treatment of venous thromboembolic disease (VTE) and for prevention of systemic embolism in non-valvular atrial fibrillation. They do not require frequent monitoring, and have little interactions with foods and other medications. However, unlike warfarin, these medications have no antidote. In the case of major bleeding or emergency surgery, the effects of these medications would need to be reversed immediately. In this study, the effect of all putative hemostatic agents on rivaroxaban (direct factor Xa inhibitor) and dabigatran (direct thrombin inhibitor) were tested via thrombin generation tests to determine which anticoagulation reversal strategy was most effective for each anticoagulation agent. Study Objective To test the ability of all purative non-specific hemostatic agents currently available, at various doses, to reverse the anticoagulation activity of rivaroxaban and dabigatran using thrombin generation tests. Methods Study Design Randomized, crossover ex vivo study in healthy volunteers. Subject Selection Inclusion Criteria Exclusion Criteria Age 18-45 years old BMI between 18 and 30 kg/m 2 White males Personal or family history of bleeding disorders. Renal or liver impairment Study Protocol 10 healthy, white, male subjects between the ages of 18 and 45 were included in the study between November 2010 and March 2011. They all gave written informed consent, and received financial compensation for their participation. Volunteers were randomized to receive either 150mg of dabigatran or 20mg of rivaroxaban in one oral dose. A 15-day washout period preceded the administration of the second drug for an identical investigation. Venous blood samples were collected just before drug administration and 2 hours after. Following a double centrifugation, platelet poor plasma was collected, quick-frozen, and stored at -80°C until the analyses were performed. The three reversal agents were recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (FEIBA), and the four-factor prothrombin complex concentrate (PCC). Thrombin generation was measured using Calibration Automated Thrombinography (CAT) reagents. Quantitative parameters included:

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Page 1: Journal Club PCC Megan Handley

Effect of non-specific reversal agents on anticoagulant activityof dabigatran and rivaroxaban

Raphael Marlu, Enkelejda Hodaj, Adeline Paris, Pierre Albaladejo, Jean Luc Crackowski, Gilles PernodThrombosis and Haemostasis 108.2/2012

Journal Club presented by: Megan Handley December 5, 2014

Background and OverviewBackground New anticoagulant medications have recently been approved for the treatment of venous thromboembolic

disease (VTE) and for prevention of systemic embolism in non-valvular atrial fibrillation. They do not require frequent monitoring, and have little interactions with foods and other medications. However, unlike warfarin, these medications have no antidote. In the case of major bleeding or emergency surgery, the effects of these medications would need to be reversed immediately. In this study, the effect of all putative hemostatic agents on rivaroxaban (direct factor Xa inhibitor) and dabigatran (direct thrombin inhibitor) were tested via thrombin generation tests to determine which anticoagulation reversal strategy was most effective for each anticoagulation agent.

Study Objective

To test the ability of all purative non-specific hemostatic agents currently available, at various doses, to reverse the anticoagulation activity of rivaroxaban and dabigatran using thrombin generation tests.

MethodsStudy Design Randomized, crossover ex vivo study in healthy volunteers. Subject Selection

Inclusion Criteria Exclusion Criteria Age 18-45 years old BMI between 18 and 30 kg/m2

White males

Personal or family history of bleeding disorders.

Renal or liver impairmentStudy Protocol

10 healthy, white, male subjects between the ages of 18 and 45 were included in the study between November 2010 and March 2011. They all gave written informed consent, and received financial compensation for their participation.

Volunteers were randomized to receive either 150mg of dabigatran or 20mg of rivaroxaban in one oral dose. A 15-day washout period preceded the administration of the second drug for an identical investigation. Venous blood samples were collected just before drug administration and 2 hours after. Following a double

centrifugation, platelet poor plasma was collected, quick-frozen, and stored at -80°C until the analyses were performed.

The three reversal agents were recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (FEIBA), and the four-factor prothrombin complex concentrate (PCC).

Thrombin generation was measured using Calibration Automated Thrombinography (CAT) reagents. Quantitative parameters included: endogenous thrombin potential (ETP-AUC) and the maximum concentration of thrombin (peak). Kinetic parameters included: lag time (LT) and time to reach the maximum concentration of thrombin (time to Peak, TTP).

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) were also determined.Outcome Measures

Endogenous thrombin potential (ETP-AUC) Thrombin peak Lag-time (LT) Time to peak (TTP)

Statistical Analysis

Quantitative data were expressed as means ± standard deviation (SD) Paired t-tests were used to analyze the reversal effect for each quantitative parameter. Normality assumption was checked with a Shapiro-Wilk’s test and the Wilcoxon signed-ranks test was used if

the normality assumption was violated. Spearman’s coefficient of rank correlation was used to assess the correction between the different parameters

of the thrombin generation test Two-sided significance tests were used throughout the study. Stata software was used for all analyses P-value < 0.05 was considered statistically significant.

ResultsMedication Table 1: Thrombin generation test parameters measured at baseline (H0) and 2 hours (H2) after oral intake

Page 2: Journal Club PCC Megan Handley

characteristics (prior to reversal)

of 20 mg rivaroxaban or 150 mg dabigatran. ETP-AUC (nM.min); Peak is the maximum concentration of thrombin (nM); LT (seconds); TTP (seconds). Data were expressed as means ± SD (n = 10).

RivaroxabanETP Peak LT TTP

H0 1076 (223) 216.2 (35.7) 2.29 (0.45) 4.38 (0.65)H2 839 (147) 73.7 (21.3) 5.59 (1.03) 11.2 (2.9)p <0.001 <0.0001 <0.0001 <0.0001

Rivaroxaban significantly prolonged PT by 1.37-fold (p<0.0001) 2 hours after administration, the effect of 20mg rivaroxaban was marked by the reduction of

thrombin peak by a factor of 3, representing the effect of rivaroxaban on thrombin generation. Modest reduction (22%) in the ETP-AUC The initiation phase of thrombin generation was profoundly altered, as LT and TTP were more than

doubled.

DabigatranETP Peak LT TTP

H0 1191 (247) 227.1 (40.2) 2.16 (0.31) 4.23 (0.62)H2 953 (182) 220.5 (49.2) 3.78 (1.21) 5.4 (1.25)p 0.0013 0.5 0.0009 0.002

Dabigatran significantly increased aPTT by 1.47-fold (p<0.0001) After receiving 150mg dabigatran, ETP-AUC was modestly reduced by 20% Thrombin peak unchanged Initiation phase of thrombin was significantly altered, as shown by the LT increase. The index rate of thrombin generation was not inhibited There was very good correlation between the ETP-AUC and the peak (rho=0.93, p<0.0001) and

between LT and TTP (rho=0.94, p<0.0001)Outcomes RIVAROXABAN

Page 3: Journal Club PCC Megan Handley

ETP-AUC At H2, all reagents but rFVIIa resulted in a dose-dependent increase in the ETP-AUC

o Lowest dose of PCC (0.25 U/mL) resulted in 37% decrease vs. H2o Lowest dose of FEIBA (0.25 U/mL) resulted in 50% decrease vs. H2

Only the lower doses of PCC (0.25 and 0.5 U/mL) and FEIBA (0.25 U/mL) reversed the ETP-AUC to near baseline H0 values (p=0.07)

Page 4: Journal Club PCC Megan Handley

Over-correction occurred for all other PCC and FEIBA concentrationsThrombin Peak

Significant dose-dependent correction of thrombin peak using PCC or FEIBA vs. H2 FEIBA at doses 1 and 2 U/mL corrected the thrombin peak close to its H0 value (p=0.2); however, these

doses resulted in over correction of ETP-AUC Lag-time

PCC resulted in slight reduction in LT (15% for 1U/mL) FEIBA resulted in 47% decrease in LT (p<0.0001) rFVIIa completely reversed the LT increase induced by rivaroxaban (2.24 seconds at H2 vs. 2.29 seconds

at H0). This was the only agent that corrected LT to near baseline H0 (p=0.6)Time to reach maximum concentration of thrombin (TTP)

PCC did not effect TTP rFVIIa and FEIBA significantly decreased TTP by 44% and 30% respectively vs. H2 (p<0.001).

DABIGATRAN

Page 5: Journal Club PCC Megan Handley

ETP-AUC

At H2, PCC and FEIBA increased the EUC-AUC of dabigatran-anticoagulated plasma in a concentration-dependent manner

Low doses of PCC or FEIBA reversed the ETP-AUC results close to baseline H0 (p=0.02)Thrombin Peak

Dramatic increase in thrombin generated occurred when PCC or FEIBA were used at regular or half doses.

All agents except rFVIIa were responsible for an increase in the thrombin peak above baseline H0 value (p<0.0001)

Maximum increase in thrombin peak with PCC at 1 U/mL and FEIBA at 2 U/mLLag-time

Both the highest dose of rFVIIa (3U/mL) and the three highest doses of FEIBA (range 0.5-2 U/mL) reduced the LT (p<0.001)Time to reach maximum concentration of thrombin (TTP)

Similar results observed for rFVIIa and FEIBA, with a significant effect of the lowest dose of FEIBA (0.25 U/mL, p=0.03)

Author’s ConclusionRIVAROXABAN REVERSALThe effect of rivaroxaban on the ETP-Peak was more pronounced than on the ETP-AUC. PCC strongly corrected ETP-AUC above the baseline values for the highest doses. rFVIIa only had a relevant effect on kinetic parameters. Rivaroxaban altered the LT and TTP, which have been found to be potentially relevant for determining the antithrombotic effect of rivaroxaban, or its reversal. rFVIIa, at all studied doses, showed complete reversion of the prolonged LT caused by rivaroxaban to the baseline H0 level. FEIBA corrected all TGT parameters compared to H2 at all studied doses. Only FEIBA corrected the markedly affected TPP by >20%. DABIGATRAN REVERSALThe overall generation of thrombin determined by ETP-AUC is moderately decreased with dabigatran therapy. LT was increased, without affecting the velocity of thrombin generation. PCC increased ETP-AUC. LT was described as correlated with circulating concentrations of dabigatran. rFVIIa at a higher dose and FEIBA corrected the LT to nearly baseline value.

Page 6: Journal Club PCC Megan Handley

CLINICAL IMPLICATIONS FEIBA combines the rFVIIa effect on LT and the PCC correcting-effect on peak value. Higher doses of FEIBA resulted in an

increase in ETP-AUC and peak, indicating an increase in total thrombin formation. The combined effects of FEIBA make thrombotic risk a safety concern. Ehlrich et al. reported the incidence of thrombotic adverse events as four per 100,000 FEIBA infusions. This incidence was dose-dependent. In the rivaroxaban studies, FEIBA did not increase thrombin generation above baseline. PCC has been proposed as a possible reversal agent for rivaroxaban. However in the study, PCC does not appear to correct the LT enough, and appears less efficient than FEIBA. Based on the study, FEIBA seems to be the most appropriate non-specific hemostatic agent to reverse rivaroxaban effects on the TGT.

In the case of dabigatran, rFVIIa is the only drug able to correct the thrombin generation curve. This effect was seen in the experiment with the higher dose of rFVIIa. This presents a safety concern for over-reversion and thrombotic risk. PCC increased ETP-AUC, but had no effect on TGT parameters. FEIBA dosed at 0.5U/mL corrected LT close to baseline, unlike the 0.25U/mL dose. The increase peak of thrombin generation above baseline remains below 400nM for FEIBA at 0.25 and 0.5U/mL. However, the ETP-AUC was overcorrected with the 0.5U/mL FEIBA dose. Therefore, PCC and especially FEIBA (at the lower normally used dose) seem to be reasonable agents to reverse the effects of dabigatran.

Critique & DiscussionWeaknesses Ex vivo observations were used, which are inferior to in vivo observations

Ex vivo design also prevents the duration of the responses seen in the study. The effects of renal insufficiency leading to potential overdose of the anticoagulation agents were not

studied due to the ex vivo design and the exclusion of those with renal insufficiency. Hemorrhagic conditions, which is the indication for anticoagulation reversal, were not studied due to

the ex vivo design. The population used was 18-45 year old healthy, white males, which does not match the patient

population of anticoagulation therapy. Dabigatran was dosed as a single 150mg dose, when in reality it is usually prescribed twice daily, and

accumulates at steady state. TGT were conducted in platelet-poor plasma, at a standard concentration of tissue factor. The effect

of drugs such as rFVIIa is likely to be different in vivo where there is extensive exposure to tissue factor.

The study also did not address the relevance of PT and plasma concentrations of the anticoagulation medications to judge the reversal effect.

Small amount of participants. Not a prospective, randomized, controlled trial (optimal study design)

Strengths Evaluating the various hemostatic agents in one trial was an effective way of comparing the effects of the agents on reversal of the two anticoagulation agents.

The use of various doses of the reversal agents was also a strength of the study. It highlighted the dose limitations and risks, as well as the dose-dependent discrepancies.

The crossover design creates consistency in response for the two agents since the study subject is the same.

Relevant Studies

Eerenberg et al. studied the reversal of rivaroxaban and dabigatran by PCC and found PCC effective in reversing rivaroxaban, but not dabigatran. PCC only resulted in slight correction of the thrombin generation tests in the Marlu et al. study. However, PCC was not compared to FEIBA in the Eerenberg trial. (2011)

Zhou et al. established a murine model of intracranial hemorrhage associated with rivaroxaban and examined the effectiveness of PCC, rFVIIa, and FFP in preventing intracerebral hematoma expansion. All agents were proven effective in prevention. The clinical symptom of bleeding was studied. All the tested agents were effective. Since bleeding was not observed in the Marlu study, results cannot be compared. (2013)

Zhou et al. conducted a similar study as above with dabigatran reversal. The evidence shows PCC, and less consistently, FFP prevent hematoma expansion associated with dabigatran. This study supports the result of PCC being somewhat effective in reversal, however FFP was not studied in the Marlu trial. (2011)

Lu et al. designed a modified form of factor Xa as an antidote for factor Xa inhibitors. The recombinant protein (r-Antidote) restored hemostasis in rabbits treated with rivaroxaban. (2013)

References:

Page 7: Journal Club PCC Megan Handley

-Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticogulant activity of dabigatran and rivaroxaban. Blood Coagulation. 2012. 108.2: 217-24.-Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy human subjects. Circulation. 2011. 124: 1573-9.-Zhou W, Zorn M, Nawroth P, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013 Mar;44(3):771-8.-Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011 Dec;42(12):3594-9.-Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013 Apr;19(4):446-51.