Nuovi anticoagulanti orali ed interazioni farmacologiche: le buone e cattive compagnie. Alessandra Chinaglia UTIC ospedale Maria Vittoria, Torino

Transcript

1 Nuovi anticoagulanti orali ed interazioni farmacologiche: le buone e cattive compagnie Alessandra Chinaglia UTIC ospedale Maria Vittoria, Torino

2 WARFARIN INR

3 NAO Conoscere i potenziali pericoli

4 Interazioni NAO - altri farmaci P-glycoprotein (P-gp) transport CYP3A4-type cytochrome P450-dependent elimination

5 Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function for the body against foreign substances Wessler; J Am Coll Cardiol 2013;61:

6

7

8 Inibitori P-gp X X DABIGATRAN: Ketoconazolo (+153%), dronedarone (+ 73% - 99%), amiodarone (+ 50% - 58%), quinidine (+ 53% - 56%), verapamil, claritromicina RISCHIO EMORRAGICO

9 Assorbimento e metabolismo dei NAO H. Heidbuchel et al Europace 2015

10 H. Heidbuchel et al Europace 2015

11 Preclusa la combinazione con NAO (Controindicata) Indicazione a ridurre la dose del NAO Mantenere la dose di NAO, a meno che esistano altri «gialli» Non dati clinici o di farmacocinetica Non raccomandato

12 We would consider amiodarone a yellow factor for all drugs, to be interpreted in combination with other yellow factors.

13 Yellow factors

14 Diltiazem has a lower inhibitory potency of P-gp, resulting in non-relevant interactions, although there is a 40% increase in plasma concentrations of apixaban

15 There is a strong effect of dronedarone on dabigatran plasma levels, which constitutes a contraindication for concomitant use.

16

17 Dipendente dalla formulazione: - Preparazione a rilascio immediato: entro 2 h dalla assunzione di dabigatran aumenta il livello plasmatico del 180%. - Preparazione a lento rilascio: aumento del 60% Indicazione a ridurre la dose del dabigatran ( orange ).

18 Rifampicina: potente P-gp inducer DABIGATRAN RIVAROXABAN- APIXABAN: riduzione 67%; RISCHIO TROMBOSI

19 RISCHIO TROMBOSI

20 Erba di San Giovanni (Hypericum perforatum) pianta officinale del genere Hypericum proprietà antidepressive e antivirali Potente induttore P-gp Riduce la concentrazione plasmatica di NAO Rischio trombotico

21

22

23 Yellow factors

24 Insufficienza renale

25 Insufficienza renale Aumenta il rischio trombotico Aumenta il rischio emorragico = Pessima compagnia

26 ARISTOTLE: Efficacy and safety according to creatinine clearance (Cockcroft-Gault) Apixaban Warfarin Hazard Ratio (95% CI) P value %/yr (No. of events) Stroke / SE Interaction: egfr >80 ml/min % (70) 1.12% (79) egfr >50-80 ml/min % (87) 1.69% (116) egfr 50 ml/min % (54) 2.67% (69) Major Bleeding Interaction: 0.03 egfr >80 ml/min % (96) 1.84% (119) egfr >50-80 ml/min % (157) 3.21% (199) egfr 50 ml/min % (73) 6.44% (142) All-cause death Interaction: egfr >80 ml/min % (169) 2.71% (195) egfr >50-80 ml/min % (244) 3.56% (251) egfr 50 ml/min % (188) 8.30% (221) Apixaban better Warfarin better Adapted from Hohnloser et al. Eur Heart J 2012; 2012;e-published August 29, doi: /eurheartj/ehs274.

27

28 Antiaggreganti L associazione NAO + terapia antiaggregante aumenta il rischio di sanguinamento almeno del 60% (simile all associazione con warfarin).

29 STENT: BMS=DES

30 Buone compagnie

31 Conclusioni Controllare le terapie concomitanti alla prescrizione Avvertire il paziente che segnali sempre eventuali nuove terapie anche non cardiologiche Memorizzare le «cattive compagnie» Controllare periodicamente la creatinina

32

33 For dabigatran, the aptt may provide a qualitative assessment of dabigatran level and activity. The relationship between dabigatran and the aptt is curvilinear.39 In patients receiving chronic therapy with dabigatran 150 mg BID, the median peak aptt was approximately two-fold that of control. Twelve hours after the last dose, the median apttwas 1.5-fold that of control, with,10% of patients exhibiting two-fold values. Therefore, if the aptt level at trough (i.e h after ingestion) still exceeds two times the upper limit of normal, this may be associated with a higher risk of bleeding, and may warrant caution especially in patients with bleeding risk factors. 39 Conversely, a normal aptt in dabigatran-treated patients has been used in emergency situations to exclude any relevant remaining anticoagulant effect and even to guide decisions on urgent interventions.45 Although these reports are encouraging, such a strategy has not been systematically tested. It is important to be mindful that the sensitivity of the various aptt reagents is different. Dabigatran has little effect on the PT and INR at clinically relevant plasma concentrations, resulting in a very flat response curve. The INR is, therefore, unsuitable for the quantitative assessment of the anticoagulant activity of dabigatran.39 The ecarin clotting time (ECT) assay provides a direct measure of the activity of DTIs, but is not readily available. Calibrated tests for dabigatran are also available as ecarin chromogenic assay; these provide a linear correlation with dabigatran concentrations and are now commercially available. They may allow faster ECT measurements. When the ECT is prolonged at trough (greater than three-fold elevation over baseline) with BID dosing of dabigatran, this may be associated with a higher risk of bleeding.40 An ECT close to the baseline (determined in the individual laboratory) indicates no clinically relevant anticoagulant effect of dabigatran.

34

35 Of patients, 6952 (38.4%) received concomitant aspirin or clopidogrel Dans, Circulation. 2013;127:

38 Percent with Event Primary Outcome: Stroke (ischaemic or haemorrhagic) or systemic embolism Warfarin / Prior Stroke Apixaban / Prior Stroke Warfarin / No Prior Stroke Apixaban / No Prior Stroke Treatment Apixaban Warfarin Apixaban Warfarin Prior Stoke Yes Yes No No Months Adapted from Easton JD et al. Lancet Neurol 2012; 11:

39 Stroke and non CNS embolism Dabigatran110 vs. WARFARIN Rate(% per year) P(INTER) Dabigatran150 vs. WARFARIN P(INTER) D110 D150 WAR AGE < AGE AGE >= CCLEAR CCLEAR CCLEAR > Dabigatran better Warfarin better Dabigatran better Warfarin better Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

40 Major bleeding Dabigatran110 vs. WARFARIN Rate(% per year) P(INTER) Dabigatran150 vs. WARFARIN P(INTER) D110 D150 WAR AGE < AGE AGE >= CCLEAR CCLEAR CCLEAR > Dabigatran better Warfarin better Dabigatran better Warfarin better Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

41

42

43

44

45

46 Il paziente: valvolari Insufficienza renale Insufficienza epatica Gli altri farmaci antiaggreganti Gli alimenti

47 Valvulopatie? Citazione 10-13

48

49 Definition of non-valvular atrial fibrillation and eligibility for non-vitamin K antagonist oral anticoagulants FA non-valvolare si riferisce alla FA che si verifica in assenza di protesi meccaniche e in assenza di stenosi mitralica moderata grave (solitamente di origine reumatica) (tabella 1). Entrambi i tipi di pazienti sono stati esclusi dagli studi dei NOACs. H. Heidbuchel et al Europace 2015

50 Avezum, CIRCULATIONAHA

51

52

53

54 Exposure to dabigatran increased with coadministration of the strong P-gp inhibitors ketoconazole (by up to 153%), dronedarone (by 73% to 99%), amiodarone (by 50% to 58%), quinidine (by 53% to 56%), verapamil, and clarithromycin in phase I studies (25,26). A reduced dose of dabigatran (75 mg twice daily) is recommended when combined with dronedarone or ketoconazole in patients with moderate renal impairment (estimated creatinine clearance [CrCl] 30 to 50 ml/min). Dabigatran should not be used in patients with severe renal impairment (CrCl 15 to 30 ml/min) if a P-gp inhibitor is being administered or in patients with end-stage renal failure (CrCl <15 ml/min), regardless of cotherapies (24,25). Staggering the administration of P-gp inhibitors by 2 to 4 h after the administration of dabigatran could reduce the potential effect of increased exposure.

55 Given the relatively narrow therapeutic index of oral anticoagulant drugs, unless dedicated pharmacokinetic studies demonstrate otherwise, dabigatran (and other novel oral anticoagulant drugs) should be used with caution in the presence of strong P- gp inhibitors and inducers (26).

56 (i) precluding the use of a given NOAC in combination (i.e. contraindication or discouragement for use); (ii) orange interactions, with the recommendation to adapt the NOAC dose, since they result in changes of the plasma levels or effect of NOACs that could potentially have a clinical impact; and (iii) yellow interactions, with the recommendation to keep the original dose, unless two or more concomitant yellow interactions are present. Two or more yellow interactions need expert evaluation, and may lead to the decision of not prescribing the drug ( red ) or of adapting its dose ( orange ). Unfortunately, for many potential interactions with drugs that are often used in AF patients no detailed information is available yet. These have been shaded in the table.

57

58 In contrast, drug interaction studies with the P-gp substrates atorvastatin, digoxin, and clarithromycin did not result in any pharmacokinetic changes of either dabigatran or the coadministered drugs

59 RIVAROXABAN ketoconazole and ritonavir, which inhibited P-gp-mediated efflux of rivaroxaban and reduced drug efflux to 45% and 76% of control values, respectively (29). As with dabigatran, the concomitant administration of rivaroxaban with strong P-gp inducers (e.g., rifampin) should be avoided because the exposure to rivaroxaban is reduced, thus placing patients at risk for thrombosis. Caution should additionally be exercised with the use of rivaroxaban in patients with renal impairment (CrCl <50 ml/min) and with drugs that are strong CYP3A4 inhibitors (30).

60 Concomitant administration of strong P-gp inhibitors (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) increases exposure to apixaban, thus increasing the risk for bleeding. The FDA recommends decreasing the dose of apixaban to 2.5 mg twice daily when administered with strong P-gp inhibitors and recommends avoiding coadministration of apixaban and strong P-gp inhibitors in patients already on the reduced dose of apixaban (32). Conversely, the concomitant administration of strong P-gp inducers (e.g., rifampin, St. John s wort) decreases the exposure to apixaban, thus increasing the risk for stroke.the FDA recommends avoiding the coadministration of apixaban and strong P-gp inducers (32).