È possibile cambiare posologia o farmaco sulla base dei test di laboratorio?

È possibile cambiare posologia o farmaco sulla base dei test di laboratorio? Armando D Angelo Servizio di Coagulazione ed Unità Ricerca Trombosi, IRCCS Ospedale San Raffaele, Milano XXVI CONGRESSO NAZIONALE FCSA Bologna, 5-7 Novembre 2015

Ovvero condurre la profilassi dell emofilia iatrogena

Heidbuchel H, et al. EHRA Guide, 2015

Heidbuchel H, et al. EHRA Guide, 2015 European guidelines have expressed a preference for NOACs over VKA in stroke prevention for AF patients, based on their overall clinical benefit.

Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Intracranial bleeding -69% -59% -34% -58% -69% -54% Fatal bleeding -42% -27% -50% -38% -65% -45% Vascular death ni -15% ni ni -15% -14% All-cause death ni ni ni ni -13% ni * Non inferior; -21% on treatment; p = 0.051

Heidbuchel H, et al. EHRA Guide, 2015 Therapy prescription with this class of drugs requires vigilance, also because the target patient population may be fragile and NOACs are drugs with potentially severe complications. Patients should return on a regular basis for on-going review of their treatment, preferably after 1 month initially, and later every 3 months. This review may be undertaken by general practitioners with experience in this field and/or by appropriate secondary care physicians.

Heidbuchel H, et al. EHRA Guide, 2015 Regular review has to systematically document (i) therapy adherence (ideally with inspection of the NOAC card, prescribed medication in blister packs, dosette packs or bottles, in addition to appropriate questioning); (ii) any event that might signal thromboembolism in either the cerebral, systemic or pulmonary circulations; (iii) any adverse effects, but particularly (iv) bleeding events (occult bleeding may be revealed by falling haemoglobin levels, see below); (v) new co-medications, prescriptions, or over-the counter; (vi) blood sampling for haemoglobin, renal (and hepatic) function.

Heidbuchel H, et al. EHRA Guide, 2015 It may also be useful to add the patient s baseline (non-anticoagulated) readings for relevant generic coagulation assays [such as aptt and PT] since this information may be important in the case of such a test being used to check the presence or absence of an NOAC effect in an emergency.

Patients 3.5 2.5 2.0 aptt Ratio 3.0 2.5 2.0 1.5 1.0 r 2 = 0.55 aptt Ratio 2.0 1.5 1.0 r 2 = 0.13 aptt Ratio 1.5 1.0 r 2 = 0.09 0.5 2.5 0 100 200 300 400 500 Dabigatran, ng/ml 0.5 3.0 0 50 100 150 200 250 300 Rivaroxaban, ng/ml 0.5 2.0 0 100 200 300 400 500 Apixaban, ng/ml PT Ratio 2.0 1.5 1.0 r 2 = 0.52 PT Ratio 2.5 2.0 1.5 1.0 r 2 = 0.34 PT Ratio 1.5 1.0 r 2 = 0.24 0.5 0 100 200 300 400 500 Dabigatran, ng/ml 0.5 0 50 100 150 200 250 300 Rivaroxaban, ng/ml 0.5 0 100 200 300 400 500 Apixaban, ng/ml

Heidbuchel H, et al. EHRA Guide, 2015 There are currently no data on cut-off values of any coagulation test below which elective or urgent surgery is possible without excess bleeding risk. No studies have investigated whether measurement of drug levels and dose adjustment based on laboratory coagulation pararmeters reduces the risk for bleeding or is associated with thrombo-embolic complications during chronic treatment.

Heidbuchel H, et al. EHRA Guide, 2015 Non-VKA anticoagulants do not require routine monitoring of coagulation: neither the dose nor the dosing intervals should be altered in response to changes in laboratory coagulation parameters for the current registered indications. However, assessment of drug exposure and anticoagulant effect may be needed in emergency situations, such as a serious bleeding and thrombotic events, need for urgent surgery, or in special clinical situations such as patients who present with renal or hepatic insufficiency, potential drug drug interactions or suspected overdosing

Kitchen S, et al. Br J Haematol 2014;166:830

Heidbuchel H, et al. EHRA Guide, 2015 Diluted thrombin time (dtt) tests (such as Hemoclot, Technoview, or Hemosil) are available that can more accurately predict dabigatran anticoagulation... and are suitable for the quantitative assessment of dabigatran concentrations. A normal dtt measurement indicates no clinically relevant anticoagulant effect of dabigatran. Calibrated tests for dabigatran are also available as ecarin chromogenic assay; these provide a linear correlation with dabigatran concentrations and are now commercially available. A calibrated quantitative anti-fxa assay may be useful in situations where knowledge of exposure is required to inform clinical decisions, like in overdose and emergency surgery. We advise you to inquire with your haematology laboratory whether the test is available.

Kitchen S, et al. BrJH 2014;166:830 Dabigatran Anti-Xa

Kitchen S, et al. Br J Haem 2014;166:830

Kitchen S, et al. BrJH 2014;166:830

Steady state plasma concentrations of DOACs (ng/ml) Dabigatran Rivaroxaban Apixaban Stroke prevention in NVAF Cmax 126; 52-275 (10-90 perc) [110 mg] 175; 74-383 (10-90 perc) [150 mg]?? Ctrough 65; 28-155 (10-90 perc) [110 mg] 91; 40-215 (10-90 perc) [150 mg]?? Treatment and secondary prevention of VTE Cmax 215; 22-535 (10-90 perc)? Ctrough 32; 6-239 (10-90 perc)?

Major bleeding complications DABI EDOX RIVA APIX AVK LD HD LD HD SD SD Poli et al % p-y % p-y % p-y % p-y % p-y % p-y % p-y Mean age (yrs) 71.5 72.0 73 70 83 Major bleeding 2.71 3.11 1.61 2.75 3.60 2.13 1.73 Intracranial bleeding Gastrointestinal bleeding 0.23 0.30 0.26 0.39 0.50 0.33 0.55 1.12 1.51 0.82 1.51 3.20 0.76 0.67 Fatal bleeding 0.19 0.24 0.13 0.21 0.20 0.19 0.27

HOWEVER

Heidbuchel H, et al. EHRA Guide, 2015

Reilly PA, et al. JACC 2014;63:321 72 year old male AF patient with diabetes and prior stroke (10th and 90th percentile)

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Patients on older OACs are accustomed to and many appear to like and expect frequent interactions with the Health Care system and its staff Switches from older OACs to NOACs are uncommon in the marketplace Most new AF patients are still prescribed an older OAC Prescribers often want to know the extent of anticoagulation each patient is receiving via their current anticoagulant External experts and the media have expressed concerns about a one size fits all OAC, since dose adjusted OACs may have optimized outcomes Xarelto competes effectively against Pradaxa despite inferior ROCKET data Eliquis is perceived to have the best outcomes data of all NOACs FDA has indicated that only path towards approval of 110 mg dose would be Modeling & Simulation results followed by a PK/PD study

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Evaluate the impact of dose adjustment (= titration ) on clinical outcome in AF patients by clinical trial simulation. Dose adjustment to 75, 110 and 150 mg BID based on trough concentrations at steady-state (Ctrough,ss) observed after one week of dosing with DE 150 mg BID. Identification of optimal cut-off concentrations for dose adjustment. Comparison to warfarin data.

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Cut-off values between 0 ng/ml and 250 ng/ml (step size 10 ng/ml) were evaluated to identify optimal cut-off concentrations for dose adjustment, resulting in 352 different combinations. 500 clinical trials with 5000 patients each were simulated for each of the 352 cut-off combinations. Patients characteristics were bootstrapped from RE-LY database. Ctrough,ss, ischemic stroke/see and major bleeding event rates were calculated.

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Dosing Reference Titration 75 mg BID - 25.5% 110 mg BID - 29.9% 150 mg BID 100% 44.6% Ctrough,ss N = 5000 Median P10-P90 Reference 97 49-199 Titration 77 49-102 Majority of patients eligible for 150 mg Signficant amount assigned to 75 mg Shift in exposure Median Ctrough,ss ~21% reduced Minimum exposure levels maintained 90th percentile significantly reduced

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Ischemic stroke/see Major bleeding Mean* 90% CI# Mean* 90% CI# Reference 1.26 1.01-1.55 4.38 3.98-4.89 Titration 1.34 1.08-1.63 3.49 3.08-3.96 * Risk of event within median RE-LY duration (~20 months), not annualized; # Clopper-Pearson (Exact); Range 10th-90th percentile Titration vs Reference Relative Risk P10-P90 Ischemic stroke/see 1.06 0.76-1.50 Major Bleeding 0.80 0.66-0.97 Titration vs. Reference Risk of ischemic stroke/see events comparable Risk of major bleeding events significantly reduced

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf The comparison of the projected dabigatran versus the observed warfarin outcome is not considered as ideal. Solution: comparison of observed dabigatran versus observed warfarin outcomes from RE-LY in a matching cohort. Difficulty: identification of the appropriate warfarin comparison group. ~26% of dabigatran treated patients are expected to be assigned to the 75 mgbid dose and are not considerable for further analysis. These patients are expected to be patients at higher risk for outcome events due to their demographic characteristics. It is therefore important to remove this population also from the warfarin group to ensure a fair comparison between both groups.

http//journals.bmj.com/site/bmj/dabigatran/compared_ema.pdf Comprehensive clinical trial simulation analyses identified promising cut-off values to assign optimal dabigatran doses of 150, 110 and 75 mg BID. Optimally treated (= titrated) dabigatran patients revealed a promising efficacy and safety profile compared to matched warfarin group. Future clinical studies might be required to confirm the results. Dose titration based on exposure is a promising approach to significantly reduce major bleeding events while maintaining the stroke protection in AF patients.

Intra-individual variability might influence dose selection. If only one measurement is taken per patient, >76% of patients are dosed correctly. At least 2 measurements are required to achieve an accuracy > 80%. Analysis by dose group showed that the target doses DE 75 and DE 150 mg are relatively robust against intraindividual variability (after 1 measurement, already 82% of patients are dosed correctly). The DE 110 mg dose group was identified as more sensitive towards intra-individual variability.

The time after dose of the Ctrough,ss value might influence dose selection. The time window between 10-14 hours results in a stable selection of the correct dose ( 80% correctly dosed patients). A more narrow time window of 11-13 hours would increase the precision to 90% correctly dosed patients. Analysis by dose group showed that the 110 mg BID target dose was most sensitive towards the sampling window.

Moore TJ et al. BMJ 2014 The EMA assessment, a company internal study, and an independent outside review all told the same story. Serious bleeds and death were occurring in older patients, median age of 80. Where details were known, data showed 26.1% of fatal bleeds were occurring within 10 days of starting treatment, and 67.8% within the first 30 days

Heidbuchel H, et al. EHRA Guide, 2015

FDA analysis of Rocket AF

PT dose-response relationship (Neoplastin Plus) PT Ratio 4.0 3.5 3.0 2.5 2.0 1.5 PT Ratio 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0 100 200 300 400 500 Rivaroxaban plasma concentration (ng/ml) 1.0 0 100 200 300 400 500 Apixaban plasma concentration (ng/ml)

FDA analysis of Rocket AF 1.04 1.20 1.44 1.88 PT R <30 30 90 200 ng/ml

Patients M/F Age (yrs) Creatinine (mg/dl) AF 88/71 76 ± 9 0.98 ± 0.39 VTE 30/11 60 ± 18 0.91 ± 0.25 N.A. 53/43 74 ± 13 1.01 ± 0.42

Patients Dosing M/F Age BW Creatinine CrCl (mg/day) (yrs) (Kg) (mg/dl) (ml/min) Apixaban 10 18/18 74 ± 10 81± 16 1.00 ± 0.40 89 ± 36 5 8/13 82 ± 8 68 ± 14 1.16 ± 0.56 53 ± 26 N.A. 28/13 79 ± 9-1.16 ± 0.66 - Rivaroxaban 20 34/21 65 ± 16 76 ± 13 0.90 ± 0.22 89 ± 32 15 6/3 73 ± 19 78 ± 14 1.11 ± 0.17 61 ± 17 N.A. 10/11 66 ± 14-1.00 ± 0.43 - Dabigatran 300 25/10 68 ± 9 81 ± 15 0.84 ± 0.17 100 ± 34 220 30/25 80 ± 6 74 ± 16 0.94 ± 0.32 64 ± 22 N.A. 12/11 73 ± 14-0.97 ± 0.32 -

Patients, dabigatran 500 500 Dabigatran, ng/ml 450 400 350 300 250 200 150 100 50 150 mg bid 110 mg bid Dabigatran, ng/ml Dabigatran, ng/ml 400 300 200 100 0 500 400 300 200 100 0 25 50 75 100 125 150 175 200 Cockroft-Gault CrCl (ml/min) 150 mg bid 110 mg bid 0 AF VTE 0 0 24 48 72 Time from dosing (hours)

Patients, dabigatran 500 150 50 Dabigatran trough, ng/ml 450 400 350 300 250 200 150 100 150 mg bid 110 mg bid p = 0.39 Intra-individual CV% (Dabigatran) 125 100 75 50 25 CV, % 40 30 20 10 0 0 50 100 150 200 250 Average Dabigatran concentration, ng/ml 50 0 0

Bleeding/thromboembolic events, Dabigatran Gender Age yrs Weight Kg Creatinine mg/dl C-G ml/min Daily dose Event Hours from dosing ng/ml aptt PT Ht% F 82 90 0.69 89 220 Emesis 29 144 1.45 1.35 40.9 F 85 59 0.73 61 220 ICH 31 122 1.60 1.28 40.6 F 76 65 0.86 57 220 Proctorrhagia 6 251 1.83 1.19 39.7 F 80 85 0.86 70 220 Epistaxis 12 236 2.02-41.8 F 72 75 1.08 56 300 Melena 15 178 1.42 1.30 38.9 M 89 41 1.47 20 220 Emesis 8 371 2.02 1.33 20.4 M 79 85 1.44 50 220 Melena 29 88 1.57 1.36 17.2 M 83-1.36-220 Hematoma NA 348 1.45 1.31 52.3 M 88 70 1.67 30 220 Anemia 10 494 3.47 3.40 33.3 M 48 120 0.92 141 300 DVT 12 57 1.20 - - F 87 80 1.12 58 220 IS 2 137 1.33 1.12 40.2 M 87 78 0.86 67 220 IS 12 139 2.23 1.49 35.1 F* 88-0.60-220 IS 6 44 1.14 1.03 45.6 * + ASA

Patients, rivaroxaban Rivaroxaban, ng/ml 300 250 200 150 100 50 20 mg 15 mg Rivaroxaban, ng/ml Rivaroxaban, ng/ml 300 250 200 150 100 50 0 300 250 200 150 100 0 25 50 75 100 125 150 175 200 Cockroft-Gault CrCl, ml/min 20 mg 15 mg 50 0 AF VTE 0 0 24 48 72 96 Time after dosing (hours)

Patients, rivaroxaban Rivaroxaban trough, ng/ml 300 250 200 150 100 20 mg 15 mg Intra-individual CV% (Rivaroxaban) 150 125 100 75 50 CV, % 150 125 100 75 50 25 12 h 24 h 0 0 50 100 150 200 Average Rivaroxaban concentration, ng/ml 50 25 0 0 AF VTE

Bleeding/thromboembolic events, Rivaroxaban Gender Age yrs Weight Kg Creatinine mg/dl C-G ml/min Daily dose Event Hours from dosing ng/ml aptt PT Ht% F 83-1.23 - NA Hematuria 24 12 - - 40.2 M* 67-1.40-20 Anemia 20 30 1.18 1.11 27.6 M* 71 80 1.08 71 20 ICH 19 201 1.22 1.83 38.9 F 71 - - - 20 Anemia NA 4 1.07 1.08 28.0 F 44 62 0.67 105 20 Methrorrhagia 27 57 1.26 1.20 33.1 F 81 49 0.80 43 20 IS 18 5 1.01 1.28 27.0 M 67 90 0.79 116 20 IS 20 46 1.27 1.23 42.9 M 34-0.60-20 DVT 15 27 1.09 1.02 37.5 * + ASA

Patients, apixaban 500 5 mg 500 450 400 350 2.5 mg Apixaban, ng/ml 400 300 200 Apixaban, ng/ml 300 250 200 100 0 500 400 0 25 50 75 100 125 150 Cockroft-Gault CrCl, ml/min 2.5 mg bid 5 mg bid 150 100 Apixaban, ng/ml 300 200 50 100 0 AF VTE 0 0 24 48 72 96 Time from dosing (hours)

Patients, apixaban Apixaban trough, ng/ml 500 450 400 350 300 250 200 150 500 450 400 350 300 250 200 150 5 mg 2.5 mg Intra-individual CV% (Apixaban) 150 125 100 75 50 CV, % 100.0 87.5 75.0 62.5 50.0 37.5 25.0 12.5 5 mg 2.5 mg 0.0 0 50 100 150 200 250 300 350 Average Apixaban concentration, ng/ml 100 50 100 50 25 0 AF VTE 0 AF VTE 0

Bleeding/thromboembolic events, Apixaban Gender Age yrs Weight Kg Creatinine mg/dl C-G ml/min Daily dose Event Hours from dosing ng/ml aptt PT Ht% F* 76 65 0.67 73 10 Emesis 14 221 0.93 1.07 39.8 F 82 72 1.48 33 5 Melena 16 106 1.21 1.32 28.0 F 82 69 2.10 23 5 Melena 12 228 1.14 1.29 21.0 M** 77-1.36-10 Melena 6 341 1.61 1.53 31.0 F 83-0.94-10 Epistaxis 6 202 1.01 1.15 38.3 F 81 65 0.73 62 10 Amaurosis 12 105 1.07 1.13 - M 81 69 0.71 80 10 IS 8 111 - - 38.1 * + ASA ** + Clopidogrel

Heidbuchel H, et al. EHRA Guide, 2015

Changes in anti-factor Xa levels (± SD) 1.4 1.2 ANTI-FACTOR Xa, IU/ML 1.0 0.8 0.6 0.4 0.2 0.0 12800 U 0 4 8 12 16 20 24 TIME (HOURS)

Anti-Factor Xa activity (LMWH) 6 6 5 5 Anti-Xa U/ml 4 3 2 Anti-Xa U/ml 4 3 2 1 1 0 0 100 200 300 400 500 Rivaroxaban plasma concentration (ng/ml) 0 0 100 200 300 400 500 Apixaban plasma concentration (ng/ml)

ten Cate H. TH 2012; 107: 803 5 The NOACs are all prescribed on a fixed-dose basis. In practice, this assumption has weaknesses; pharmacokinetic studies show that drugs like dabigatran show considerable variation in plasma drug concentrations, such that while the majority of patients will obtain an adequate plasma drug level, a measurable proportion will either achieve an insufficient, or a supra-therapeutic drug level, when given a fixed dose.

ten Cate H. TH 2012; 107: 803 5 One should not abolish the opportunity to further improve the efficacy and safety of new anticoagulants in practice, e.g. by searching for the optimal dose in the individual patient (tailored medication). This may, eventually, require laboratory based dose adjustment.