New Anticoagulants Monitoring or Not Monitoring?

Transcription

1 New Anticoagulants Monitoring or Not Monitoring? For monitoring M.M. Samama, C. Guinet, L. Le Flem, J. Conard Hôtel-Dieu-Cochin University Hospital (Paris, France) and Biomnis, Ivry sur Seine, France

2 Disclosure Relevant Financial Relationship(s) : None Off Label Usage : None Consultant for : BAYER SCHERING PHARMA AG, SANOFI AVENTIS, ELI LILLY, DAIICHI SANKYO Member of advisory board/steering Committee : B.M.S., PFIZER LABORATORY, JOHNSON & JOHNSON Invited speaker/chairperson : SANOFI AVENTIS, G.S.K., BAYER SCHERING PHARMA AG, BOEHRINGER INGELHEIM, ROVI LABORATORY, ROTEM

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4 New Oral Antithrombotics A need for Lab Monitoring? For Mismetti et al., Against Bounameaux et al., Journal Thrombosis and Haemostasis 2010;8(4):

5 Evolution of the Role of Laboratory Monitoring No monitoring No routine monitoring A standardized test should be available Which test is appropriate for each new anticoagulant? Timing of blood collection Expression and interpretation of results Drug accumulation? Correlation lab results and clinical events? Dose adjustment guildelines not available

6 Evolution of the Role of Laboratory Monitoring No Monitoring, WHY? Patients response highly predictable Data from pharmacologic and pharmacokinetics studies Wide therapeutic window No standardized blood test available Clinical trials performed without monitoring Remark : No information on the potential increase in safety with laboratory monitoring

7 IN WHICH PATIENTS? Renal or liver impairment Emergency surgery Bleeding (minor /major / life threatening) Thrombosis recurrence Suspected co-medication influence Patients compliance Suspected overdose Reversal treatment Peri-operative management

8 Evolution of the Role of Laboratory Monitoring No Monitoring, WHY? Patients response highly predictable - Pharmacodynamics and Pharmacokinetics studies and recent work demonstrate a significant interindividual variability

9 Modelisation of Rivaroxaban in Orthopedic Surgery Mueck W el al, 2007 International J Clin Pharm and Therapeutic Vol 45 ( )

10 Measurement in Rivaroxaban in 41 patients (THR or TKR) receiving 10 mg X 1 Statistics Rivaroxaban (ng/ml) concentrations obtained with: DiFXI (Hyphen Biomed) Modified Rotachrom (Stago) Minimum 0 0 Maximum Median Mean Coefficient of variation (%) 72% 83% Lower confidence limit (95%) Upper confidence limit (95%) MM Samama et al, in Press

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12 Rivaroxaban in major orthopedic surgery Rivaroxaban 10 mg x 1 (mean Cmax) Litterature Freyburger(n=40) 125 ng/ml (91-196) 130 ng/ml ± 83 ng/ml Our study (n=41) 140 ng/ml (0-412) Flaujac (n=17) 104 ± 82 (7-272) Mani H (n=80) ± 51.8 ( )

13 Dabigatran 150 mg sd PTH (Bistro Ib) Stangier J Clin Pharmacol : 555 CV (%) of plasma concentration of dabigatran, 12 h after 150 mg administration PETRO-EX: 91 %, RELY: 81 %, BISTRO II: 87 %

14 Evolution of the Role of Laboratory Monitoring No Monitoring, WHY? No standardized blood test available? Standardized anti-xa activity measurement for direct F Xa inhibitors is available. In parallel Hemoclot a diluted thrombin clotting time or Ecarin chromogenic test are available for dabigatran

15 Calibration Rivaroxaban PT with 4 calibrated plasmas Temps de coagulation (sec) 45,0 40,0 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 Calibration TP rivaroxaban y = 0,0569x + 13,076 (neoplastine +) R 2 = 0,9977 Temps plasma calibré Temps patient Rivaroxaban (ng/ml)

16 Evolution of the Role of Laboratory Monitoring No Monitoring, WHY? Patients in clinical trials and patients in real life? Recent work has reported several life threatening bleedings associated with importante alteration clotting test (PT, aptt, Hemoclot ) and increased plasma drug concentration. - Drug accumulation frequently due to severe renal clearance alteration

17 Case 1 : Emergency surgery (Bowel Ischemic Lesion) in 72 y o woman Basal CrCL 50 ml/min who underwent THR and received Dabigatran 220 mg x days later hypotension, oliguria, Hb 8 g/dl) followed by a hypovolemic shock and CrCL 14 ml/min and peritonitis. Per operative bleeding +++ (RBC 22 units FFP 40 units) + Kaskadil and NovoSeven

18 Case 3 : An 86 y o woman, CrCL 25,5 ml/min, uneventful THR Dabigatran 150 mg x 1. At day 7 haemoglobin 6.8 gr/dl Dabigatran was stopped (peri operative hematoma revealed (6 x 4 x 22 cm). She received RBC (2 units) and Dabigatran was re started. 11 days later haemorrhagic shock and diffuse bleeding. Dabigatran was stopped. CT scan hip hematoma 15 x 6 x 26 cm. Severe coagulopathy resistant to r.viia 1.30

19 Case 4 : 86 y.o. man TKR dabigatran 220 mg x 1 Cockroft 58 ml/mn, Sepsis, Cockroft on the day 8 14 ml/mn, Massive digestive bleeding.12 RBC, 12 FFP, rviia, prothrombin complex. Successful hemodiafiltration and late death from septic shock A. Lillo Le Louët et al, Thromb Haemost 2012;108

20 Clinical challenges in a patient with Dabigatran induced fatal hemorrhage Case summary : A 78 y.o. woman treated for AF with bleeding secondary to Dabigatran. Hospitalized with severe coagulopathy PT 147 sec, aptt > 200 sec Respiratory failure, hypotension and bright red blood per rectum. CrCL 15 ml/min (CrCL unknown at initiation of Dabigatran 150 mg x 2). Treated with fresh frozen plasma, packed red blood cells, platelets PCC (profilnine ) cryo precipitate followed on day 3 by hemodialysis. Patient died on day 5. Autopsy : Massive hemorrhage to the retroperitoneal abdominal cavity gastro-intestinal and pleural cavity (Total : 5 L of blood). «Although PCC and plasma temporarily decreased the blood coagulation, bleeding continued». Casso LE et al, Amer Heart J of Geriatric Pharmacotherapy 2012;10(2):

21 Comparison Dabigatran/Warfarin in patients with mechanical heart valves RE ALIGN Dabigatran* 150 mg twice a day or 300 mg twice a day Warfarin INR 2 to 3 * Measure Dabigatran at steady state Plasma trough levels > 50 ng/ml Hemoclot assay on day 4 with Dabigatran calibrators Van de Werf F et al, Am Heart J 2012; 163;

22 Conclusion New Anticoagulants Monitoring or Not Monitoring? For monitoring Measurement of drug activity and/or concentration is needed in several clinical situations. Interindividual variability observed in clinical studies in contrast to the «highly predictable response». Several case reports of major/fatal bleeding in literature Alarms from health authorities regarding the bleeding risk especially in elderly patients (control before treatment then every 6-12 months of renal clearance) Occasional laboratory measurement could improve the benefit/risk ratio.

23 Conclusion New Anticoagulants Monitoring or Not Monitoring? For monitoring There is no clinical trial which has compared results of treatment with and without coagulation monitoring. Patients treated with NOACs may present with some signs of minor bleeding. At this stage, no clear guideline is available. However, clotting tests could assess if drug accumulation is present. In these patients, blood collection at trough levels, i.e. just before a new drug administration, could be more informative than measurement at Cmax.

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25 Case 2 : Emergency surgery for colon volvulus in an 87 y o man treated by Amiodarone and Dabigatran 75 mg x 2 - On day 12, third episodes of colon volvulus, CrCL 20 ml/min Before colectomy 8 units of FFP and 12 h later haemorrhagic shock. The outcome was favourable after transfusion over 10 days of 22 RBC and 23 FFP

26 New oral anticoagulants and major bleeding Alveolar hemorrhage in a 85 y.o. male with history of interstitial pulmonary fibrosis and treated for 6 months with Dabigatran 110 mg x 2 for AF J Thromb Thrombolysis 2012 Husari A et al Acute onset severe gastro-intestinal bleeding in a 58y.o. postop. patient taking rivaroxaban after total hip arthroplasty. Severe rectal bleeding J Med Case Rep 2012;6:129 Fatal gastro-intestinal bleeding in a 92 y.o. man with AF, who received a single dose of 150 mg Dabigatran. Profuse rectal bleeding. An actively bleeding gastric ulcer was discovered. Clin Toxicol Phila 2012;50(7):

27 New oral anticoagulants and major bleeding Two cases of hemopericardiac and cardiac tamponade associated with Dabigatran use in two males 70 y.o. and 77 y.o. respectively. Ann Pharmacother. 2012;46(7-8):e18 Catastrophic hemorrhage after mild traumatic brain injury Case report : A 83 y.o. man, receiving Dabigatran 150 mg x 2 for 1 month for AF, was admitted in an emergency department after a ground-level fall at home. PT 17.2 sec (N 13 sec) aptt > 43 sec (N 24 35) Normal platelet count Thrombin time > 150 sec (N sec) Extensive progression of the hemorrhage: rviia was given. Patient died shortly thereafter. J Neurosurg 2012;116:

28 The use of Dabigatran in elderly patients A 84 y.o. woman - 40 kg body weight - admitted in intensive care unit for severe rectal bleeding. AF treated with Amiodarone and Dabigatran 75 mg x 2 for 4 months. At admission : CrCL 32 ml/min PT > 60 sec aptt very prolonged Platelets Fatal massive rectal bleeding after fecaloma digital evacuation cardiac arrest and death. Plasma concentration of Dabigatran : ng/ml (expected < 300).

29 Massive digestive bleeding in a 86 y.o. man with total hip replacement Hematemesis and rectal bleeding 8 days after initiation of a thromboprophylactic treatment with Dabigatran 220 mg x 1 Basal : CrCL 58 ml/min 14 ml/min (Sepsis) on day 8 Transfusion : 12 RBC units + 12 FFP units + 1 platelet concentrate + Kanokad (4 Factors PCC) + rviia 90 µg/kg Dabigatran (plasma concentration) : 2350 ng/ml, decreased progressively after hemodialysis. Legrand M et al. Arch Intern Med. 2011;171(14):