COAGULATION TESTING AND NEW ORAL ANTICOAGULANTS SOPHIE TESTA Haemostasis and Thrombosis Center ASST-Cremona, Italy
ANTICOAGULANT DRUGS Eikelboom JW, Weitz JI. Circulation 2010;6:1523-32
DRUGS UH LAB aptt AVK PT INR LMWH, pentasaccaride FXa DOAC FXa, dtt, ECA, ECT,
CONSIDERATION (I) 1. Pharmacological studies have shown that DOAC have predictable anticoagulant response in standard clinical conditions 2. Clinical trials have been successfully conducted with fixed dose regimens without laboratory controls and without the availability of specific antidotes, in two clinical conditions (NVAF and VTE)
CONSIDERATION (II) As a consequence, DOACs have been introduced in clinical practice : 1) at fixed daily doses 2) without lab controls (no coagulation testing recommended) 3) Without specific antidotes 1. Different perception about DOAC patients health care necessities 2. In Italy: regulatory health authorities defined rules for DOAC reimbursement, often interpreted as a sort of clinical guideline
DOACs POSOLOGY DOSING ADJUSTMENT IS BASED ON PHARMACOKINETIC CONSIDERATIONS (Clinical characteristics and renal function) Gong IY, Kim RB. Can J Cardiol 2013;29(7 Suppl):S24-33
BUT High inter/intra individual variability has been demonstrated Pharmacological modifications have been showed in relation to: drug interaction, liver and renal function, age and weight Antidotes have been introduced Laboratory measurements have been proposed in particular clinical conditions
VARIABILITY Drug interactions, renal and liver function, age, weight, genetic polymorphisms Dabigatran Rivaroxaban Apixaban Gong IY, Kim RB. Can J Cardiol 2013;29(7 Suppl):S24-33
EXPECTED C-PEAK AND C-TROUGH DOAC LEVELS IN NVAF AND VTE PATIENTS ENROLLED IN PHASE II-III CLINICAL STUDIES Gosselin RC, et al. Thromb Haemost 2018;118:437-50
Drug ( ng/ml ) Trough mean (min-max) ( ng/ml ) Peak median (min-max) Dabigatran 110 mg bid 93 (14-386) 190 (31-651) Dabigatran 150 mg bid 91 (16-494) 210 (43-538) Rivaroxaban 15 mg qd 27 (0-88) 208 (77-393) Rivaroxaban 20 mg qd 41 (5-119) 235 (61-449) Apixaban 2.5 mg bid 79 (26-248) 192 (55-300) Apixaban 5 mg bid 113 (42-283) 200 (102-416) Testa S, et al. Thromb Res 2016;137:178-83
EDOXABAN: INTER-INDIVIDUAL VARIABILITY Drug ( ng/ml ) Trough mean (min-max) ( ng/ml ) Peak median (min-max) Edoxaban 60 mg qd 39 (13-114) 294 (136-569) Edoxaban 30 mg qd 37 (11-147) 184 (10-529) 2018, submıtted
DOACs INTER-INDIVIDUAL VARIABILITY Population CV% Healthy and young volunteers ~ 20 Phase III randomized clinical studies ~ 40 Real world patients ~ up to 100
FURTHERMORE Based on phase II and III clinical trials, it has been assumed that during time: - anticoagulant levels are always acceptable - do not occur: 1. persistent drug accumulation and 2. persistent absence or insufficient drug activity If we compare: a) VKA complications are correlated with TTR b) LMWH, not generally monitored, are administered for short period
IS THIS INFORMATION USEFUL FROM A CLINICAL POINT OF VIEW?
FDA REPORTS: DOACs EXPOSURE-RESPONSE ASSOCIATION FOR EFFICACY AND SAFETY Dabigatran Rivaroxaban Apixaban Edoxaban Eikelboom JW, et al. JAMA Cardiol 2017;2:566-74
DOACs AND THE LAB Test Recommendation Comments CrCl AST/ALT Blood Cell Count 1.Before starting DOACs and in the follow up to continue treatments (or adapt posology). 2. CrCl is also considered as surrogate of good anticoagulant action 1. Before starting DOACs and in the follow up to continue treatments Should be recommended - CrCl not validated in older population - CrCl >30ml/min not correlated with afxa drugs No clear timing of controls Before starting and during the follow up PT/aPTT Not recommended to assess levels of anticoagulation Should be recommended before starting DOAC to assess haemostatic status DOAC specific test In special clinical conditions There is still no unanimous consensus
Testa S, et al. Thromb Res 2016;137:178-83
Olesen JB, et al. N Engl J Med 2012;367:625-35
DOACs MEASUREMENT 1. PERIODIC MEASUREMENT (MONITORING) TO DOSE- ADJUSTMENT 2. PERIODIC MEASUREMENT (CONTROL) TO HIGHLIGHT UNDER/OVER ANTICOAGULATION 3. MEASUREMENT IN SPECIAL CLINICAL CONDITIONS Eikelboom JW, et al. JAMA Cardiol 2017;2:566-74 Tripodi A, et al. Blood Transfus 2017 13:1-9. doi:10.2450/2017.0124-17
1. PERIODIC MEASUREMENTS (MONITORING) TO FREQUENT DRUG DOSE-ADJUSTMENT
Eikelboom JW, et al. JAMA Cardiol 2017;2:566-74
Eikelboom JW, et al. JAMA Cardiol 2017;2:566-74
Powell JR. JAMA 2015;313:1013-4
2. PERIODIC MEASUREMENT (CONTROL) TO HIGHLIGHT UNDER/OVER ANTICOAGULATION
Breuer L, et al. N Engl J Med 2013;368:2440-2
AIMS To evaluate a possible relationship between DOAC trough anticoagulant levels, measured at steady state within the first month of treatment, and thromboembolic events observed during one year follow-up Testa S, et al. J Thromb Haemost 2018;16:842-8
CHA 2 DS 2 -VASc >3.0 (291/595pts; 51.5%) Class I (n) (Lower drug levels) Class II, III,IV (n) (Highest drug levels) Total (n) Thrombosis 10 0 10 No Thrombosis 117 164 281 10/127 (7.9%) 0/164 (0%) Testa S, et al. J Thromb Haemost 2018;16:842-8
LOW DRUG LEVELS AND THROMBOTIC COMPLICATIONS IN HIGH RISK ATRIAL FIBRILLATION PATIENTS TREATED WITH DOACs 1. Our data show a relationship between low DOAC trough plasma levels and subsequent thrombotic events 2. Higher cardiovascular risk patients with low DOAC levels show significantly higher risk of thrombosis compared to patients with higher DOAC levels 3. DOAC measurement seems particularly indicated in higher cardiovascular risk patients Testa S, et al. J Thromb Haemost 2018;16:842-8
DRUG LEVELS AND BLEEDING COMPLICATIONS IN ATRIAL FIBRILLATION PATIENTS TREATED WITH DIRECT ORAL ANTICOAGULANTS To evaluate a possible relationship between DOACs C-trough and C-peak anticoagulant levels, measured at steady state within the first month of treatment, and bleeding events observed during one year follow up. Testa S, 2018 submitted
Normalized measured anticoagulant levels 3 p=0.2 p=0.003 2 1 0 No Bleeds Bleeds No Bleeds Bleeds Trough Peak Testa S, 2018 submitted
WHAT CAN WE LEARN? 1. Some patients show very low (or absent) drug levels 2. Some patients show very high DOAC levels (>10 times as compared with trough levels and 2-3 times as compared with peak levels) 3. More than 20% of patients show DOAC levels below or over the 10-90 percentile as measured in phase III clinical studies on patients with NVAF
THE MAS STUDY Aim of the study: To evaluate the correlation between DOAC anticoagulant levels, measured in 4000 consecutive patients with Non Valvular Atrial Fibrillation (1000 for each drug), and the occurrence of bleeding and thromboembolic complications during one year follow-up.
3. DOAC MEASUREMENT IN SPECIAL CLINICAL CONDITIONS Patients presenting in emergency with adverse events (Thrombosis, Bleeding) Immediate reversal of anticoagulation Perioperative management Renal disease Liver disease Suspicion or known interaction with other drugs Elderly patients Under/over weight Pengo V, et al. Thromb Haemost 2011;106:868-76
DOACs MEASUREMENT = HELPFUL TO GUIDE APPROPRIATE MANAGEMENT
Laboratory measurements were performed centrally and were not used to guide therapy dtt results were normal in ¼ of the study population. This group of patients would not be expected to benefit from the administration of idarucizumab It will be useful to have activity measurements available for the various DOACs in real time to help guide the treatment of such patients and to prevent overutilization of what will surely be a costly medication Bauer KA. N Engl J Med 2015;373:569-71
PERIOPERATIVE MANAGEMENT: THE GUIDELINES Schulman S. J Intern Med 2014;275:1-11
PERIPROCEDURAL MANAGEMENT OF DOAC SHOULD BE GUIDED BY ACCURATE LABORATORY TESTS Interruption of DOAC should not be based only on their respective half-life but also on the residual drug concentration Poor correlation between renal function and plasma concentration of apixaban and rivaroxaban was found except for dabigatran measured at trough (Testa S, et al. Thromb Res 2016;137:178-83) Mass spectrometry measured dabigatran level >20ng/ml in nearly 16% of patients undergoing high bleeding risk procedures (Douketis JD, et al. J Thromb Haemost 2016;14:89-97) Douxfils J et al, Reg Anesthesia and Pain Medicine, Sept 2016
1. At the beginning of DOAC treatment to confirm absorption and to know patients individual anticoagulant levels 2. Over/under weight 3. In case of potential interference with co-medication 4. Co-morbidities 5. Bleeding and thromboembolic complications 6. Surgical and invasive procedures Tripodi A, et al. Blood Transfus 2017 13:1-9. doi:10.2450/2017.0124-17
HOW TO MEASURE? 1. PT and aptt react differently with DOACs in relation to type of drug and type of reagent 2. Patients having the same DOAC plasma concentration may show different PT or aptt results 3. Normal PT/aPTT results cannot exclude significantly high concentrations of DOACs, such as abnormal prolongation could be caused by defects of coagulation other than those stemming from the drug being taken by the patients 4. Specific test are easily available (dtt, Ecarin Tests, specific calibrated afxa) 5. The use of PT or aptt in clinical practice to evaluate DOAC anticoagulant activity could cause dangerous misinterpretations Kitchen S et al, BJH 2015 Douxfils J et al, Thromb J 2014 Testa S, et al. J Thromb Haemost 2016;14:2194-2201 Gosselin RC, et al. Thromb Haemost 2018;118:437-50
CONCLUSION Patients on DOACs need structured follow up to ensure the efficacy and safety of their treatments and we are learning how to perform it Emergencies with DOACs are increasing, with the increase in DOAC-treated patients The need to know DOAC anticoagulant levels in many clinical conditions is growing and specific tests are available Using better strategies (i.e. DOAC measurement) we could enhance efficacy and safety and probably extend DOAC use to new indications