Idarucizumab for Dabigatran Reversal Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015; 373(6):

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1 Idarucizumab for Dabigatran Reversal Pollack CV, Reilly PA, Eikelboom J, et al. N Engl J Med 2015; 373(6): Objective: To measure the safety of idarucizumab to reverse dabigatran anticoagulant effects in patients with serious bleeding or requiring an urgent procedure. Background: Currently, no clinically available specific antidotes to reverse non-vitamin K antagonist for life-threatening bleeding or urgent surgery needs. 3 products are in development (Costin, 2014); (Pharma, 2015);(Boehringer Ingelheim, 2015);(Canadian Agency for Drugs and Technologies in Health, 2015); (Glund S, 2015); (Pollack CV, 2015) Product idarucizumab adexanet alpha aripazine (PER977) Activity Dabigatran Factor Xa universal Mechanism a humanized, monoclonal antibody fragment binds in a 1:1 molar ratio to dabigatran competitively displaces dabigatran from thrombin*, 47,8 kda Factor Xa decoy; targets & sequesters direct & indirect Factor Xa inhibitors in the blood; apixaban, rivaroxaban, edoxaban, enoxaparin tested, ~ 39 kda Small molecule D-arginine compound; binds heparin, IIa, XA NOACs, UFH, LMWH, fondaparinux (H-bonding) 512 Da Biomarker Unbound dabigatran Anti-Factor Xa activity Whole Blood Clot Time Administration IV infusion or bolus** IV bolus Single bolus injection Storage Refrigeration Refrigeration Room T Development FDA Designated breakthrough therapy Phase III FDA Designated breakthrough therapy 2 nd part of phase III Starting Phase III TRIAL REVERSE-AD ANNEXA TM -A & R Manufacturer Boehringer Ingelheim Portola (PTLA) Perosphere Dabigatran etexilate (Pradaxa ): oral anticoagulant for stroke prevention (non-valvular Afib) & to treat or reduce risk of DVT and PE recurrence (t 1/2 ~12-17 h; effect lasts 2.5 to 3 days; V d ~50-70 L; 35% protein binding; hepatic metabolism to active form; 80% renal clearance). (Lexicomp, 2015) *MOA: The affinity of dabigatran for idarucizamab is ~ 350x the affinity for thrombin. (Pollack CV, 2015) **Dosing: Pre-marketing dosing (Boehringer Ingleheim communication): idarucizumab will be supplied as a single package containing two 50 ml vials (2 x 2.5g) to be given intravenously as two consecutive infusions over 5 to 10 minutes each or as bolus injections. No reconstitution will be needed. (Canadian Agency for Drugs and Technologies in Health, 2015) Registration: ClinicalTrials.gov NCT REVERSE-AD Trial: Ongoing, multicenter, prospective cohort study; Funding Boehringer Ingelheim, REVERSE-AD Total recruitment plan: 300 patients, 400 centers, 38 countries May 2014 to April 2017 Inclusion Criteria: Adults, 18 years or older taking dabigatran. 90 patients total. June 2014 to Feb 2015 More than 90% of patients were using dabigatran for stroke prevention due to Afib. Group A: uncontrollable or life-threatening bleeding requiring reversal per treating clinician (n=51). Group B: required surgery or invasive procedure within 8 hours or less (n=49).

2 Treatment: 5 g of IV idarucizumab administered as two 50-mL (2.5 g each) bolus infusions no more than 15 minutes apart. The dose was determined based on the dose calculated to reverse the total body load of dabigatran (Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Primary End Points: Maximum percent reversal assessed by measuring dilute thrombin time (DT) or ecarin clotting time using any point after the first infusion up to 4 h after the second infusion; activated prothrombin time (aptt), plasma concentration of dabigatran also measured. (ST Avecilla, 2012) %Reversal = [predose test result (s) minimum postdose test result (s)] x 100 [predose test result(s)-upper limit of the normal range (s)] Maximum value 100% (complete reversal) Blood samples for collected at: baseline, after first infusion of idarucizumab and between 10 and 30 minutes and after the second infusions, 1,2, 4, 12 and 24 hours. Secondary End Points: Clinical outcomes (per treating clinician) Proportion of patients with complete normalization of DT in the first 4 hours. Reduction in concentration of unbound dabigatran. Group A: extent of bleeding and hemodynamic stability, severity of bleeding (international Society on Thrombosis and Hemostasis & the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) scales. Intracranial hemorrhage compared to baseline (modified Rankin scale) Group B: hemostasis during intervention (normal, mildly, moderately or severely abnormal) Adverse events coding: Medical Dictionary for Regulatory Activities from infusion to 90 days post. Statistics: Descriptive statistics of maximum percentage reversal. Maximum clotting time set at 500 sec if imputation was consistent with other coagulation tests and unbound dabigatran concentrations. Table 1: Results & Adverse Effects RESULTS (ULN = upper limit of normal) Baseline Characteristics Median duration of hospitalization was 8 days Group A n=51 Group B N=39 Median Age: 77.0 Median: Age:76.0 Range: Range: Male: 63% Male: 46% Weight: 70.5 Weight: 73.0 kg BMI: /- 6.4 BMI: /- 6.3 White: 84% White: 90% Median CrCl(mL/min) ~ 59 +/-33 Median CrCl(mL/min)~ 65+/-36 Dabigatran: 110 mg (BID) ~ 67% Dabigatran: 110 mg (BID) ~ 62% Indication Afib ~ 92% Indication Afib ~ 100% 15.4 hours 8 days (2 to 93 day range) Bone fracture (8) Acute cholecystitis (5) Acute renal insufficiency, catheter placement (4) Other (22) Median time since last dose Median hospital stay Bleeding concern Hemodynamically unstable (16) Intracranial hemorrhage (18) GI bleed (20) Trauma (9) Other cause (11)

3 Follow Up/Withdrawal: follow up until death or at least 1 month; 1 withdrew informed consent, 1 withdrew & received palliative care, 3 missing information Patients with baseline clotting tests within normal range (DTT or ecarin) omitted from efficacy analysis Reversal: 88 to 98 % of with elevated clotting times at baseline Reversal: (22 normal DTT, 9 of 22 normal ecarin clot times) % Max Reversal Post Infusion 12 & 24 hours aptt & TT similar results 40 /51 patients included (78%) 98% (of 40) normalized DTT 89% normalized ecarin Median: 100% (100,100) 95% CI DTT 90% below ULN range Ecarin 72% below ULN range 28/39 patients included (72%) 93% (of 28) normalized DTT 88% normalized ecarin Median: 100% (100,100) 95% CI DTT 81% below ULN range Ecarin 54% below ULN range Group A: Bleeding Cessation Median Time ~ 11.4 h (35 of 51) Group B: 1 patient dialysis due to dabigatran overdose 2 patients too unstable for surgery; 1 patient had mildly abnormal hemostasis & 2 had moderately abnormal hemostasis in surgery (33/36 (92%) had normal hemostasis during procedure Blood Samples 86 4 h; 12 h; 24 h Missing data due to death or technical difficulties Dabigatran Concentrations Total: 132 ng/ml (5 to 886) Total: 114 ng/ml (7 to 3600) Unbound: 84 ng/ml (3 to 641) Unbound: 76 ng/ml (4 to 2880) Unbound dabigatran: 4 hrs post 1 st infusion: < 20 ng/ml for all but 1 patients 4 hrs post treatment: 83/86 (96%) levels near lower detection limits ng/ml; 848 ng/ml & 1510 ng/ml 12 hrs post treatment: 77/83 (93%) < 20 ng/ml 12 hrs post treatment: 62/78 (79%) < 20 ng/ml Idarucizumab Concentrations 4 hrs post treatment: 80% decrease in average plasma concentration Renal Effects Baseline clotting elevated for 68 patients Baseline elevated median Cl ~ 48 ml/min; time last dose 12.8 h 17 deaths (25%), 3(4.4%) thrombotic events if elevated Baseline clotting normal for 22 patients Baseline normal median Cl 67mL/min; time last dose 30.3 h 1 (4.5%) death, 2 (9%) thrombotic events if normal on either clotting test Intracranial bleeding higher (11 patients) with normal baseline on both clotting tests Adverse Effects Phase I trial (n=47): erythema at infusion site & hot flushes (1), epistaxis (2), hematuria (3) Deaths: 18 total (9 in each group A&B); 10 vascular causes (5 fatal bleeding events); death within 96 h (4 d) treatment linked to index event Thrombotic Events: 5 patients after idarucizumab administration (none receiving antithrombotic therapy) Early (< 72 h): DVT & PE 2 days)_ 1 % (no antithrombotic used) Late (> 72 h): DVT & PE & left atrial thrombus (1@ 9 days); DVT 7 days); non ST-seg elevate MI 13 days); ischemic stroke 26 days) Other Serious Adverse Events: 13 Group A, 8 Group B GI hemorrhage(2), postoperative wound infection, delirium, right ventricular failure (1), pulmonary edema (1)

4 Unbound Dabigatran (ng/ml) Changes in Unbound Dabigatran Over Time time (h) Group A Group B 2 Normalized Change in Unbound Dabigatran & Idarucizumab vs. Time Normalized Change time (h) Group B (Daba) Group B (Ida) Figure 1: Change in unbound dabigatran over time for Group A & B (top). Change in unbound dabigatran versus Idarucizumab over time. Time=0 is the start of the first infusion. Author s Comments & Conclusions: Idarucizumab rapidly & completely reversed dabigatran effects Increase in dabigatran at 12 and 24 h may be due to extravascular redistribution of dabigatran; patients may benefit from an additional dose of idarucizumab Trial Strengths: broad inclusion criteria, simple study design, confirmation that coagulation test results reflected dabigatran reversal (measurement of unbound drug; HPLC, mass spec) Limitations: lack of control group (no high quality evidence for using PT complex concentrate); use of cohort design (unethical to randomly assign patients placebo) Very few anticoagulation-reversal trials; this trial included real life circumstances excluded in other trials (acute trauma, urgent need for procedure, older average age) No safety concerns for giving idarucizumab

5 Comments/Interpretation: Population predominantly over weight, Caucasian; ethnicity unclear. Use of median values reflects wide range of data collected; limits interpretation. Half-life of dabigatran ~ h; median time to stop bleeding 11.4 h; how much of decrease is due to elimination of dabigatran? Half-life of idarucizamab not given but anticoagulation restart reported complete within 24 h post use Collecting data points earlier in the process may give additional information about onset & duration of action; larger sample size, better accuracy & precision needed. Effects of reversal at 12 and 24 hours on potential TE events should be assessed; Vd ~ 50 to 70L ; no evidence given that dabigatran is accumulated extravascularly. (Ingelheim, 2010) ; consider elimination rate in considering need for additional dosing Assess need for any reversal if last dose taken > 30 hours prior Possible immunogenicity if subsequent treatment is required (size ~ 1 kda or larger)? Works Cited Boehringer Ingelheim, Idarucizumab Media Fact Sheet. [Online] Available at: ingelheim.com/content/dam/internet/opu/us_en/documents/media_press_releases/2015/idarucizumab-media-fact- Sheet.pdf [Accessed 3 September 2015]. Boehringer Ingleheim, Press Release Archive: Idarucizumab reverses the anticoagulant effect of dabigatrain within minutes in patient study. [Online] Available at: [Accessed 30 August 2015]. Canadian Agency for Drugs and Technologies in Health, Issues in Emerging Health Technologies: Antidote Treatments for the Reversal of Direct Oral Anticoagulants. [Online] Available at: [Accessed 30 August 2015]. Costin, J., PER977[aripazine]-A Non Specific Anticoagulant Reversal Agent. [Online] Available at: [Accessed 3 September 2015]. Glund S, J. S. M. S. e. a., Safety, tolerability, and effi cacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a andomised, placebo-controlled, double-blind phase 1 trial.. Lancet, Volume 386, pp Lexicomp, Dabigatran Etexilate (Lexi-Drugs). [Online] Available at: [Accessed 3 September 2015]. Pharma, P., Adexanet alfa: FXa Inhibitor Antidote. [Online] Available at: [Accessed 1 September 2015]. Pollack CV, R. P. E. J. e. a., Idarucizumab for Dabigatran Reversal. N Engl J Med, 373(6), pp ST Avecilla, C. F. W. C. M. R., Plasma-Diluted Thrombin Time to Measure Dabigatran Concentrations During Dabigatran Etexilate Therapy. Am J Clin Pathol, Volume 137, pp