Nuovi anticoagulanti a confronto: i risultati dei trials clinici

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Celia Magnani
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1 Nuovi anticoagulanti a confronto: i risultati dei trials clinici Walter Ageno Dipartimento di Medicina Clinica e Sperimentale Università dell Insubria Varese

2 ACCP 2012 Treatment of VTE 2012

3 Real-life treatment of acute VTE: RIETE registry Treatment PE±DVT Isolated DVT p (n=20,543) (n=21,283) Thrombolytics 0.9% 0.1% <0.001 UFH 12% 2.9% <0.001 LMWH 85% 95% <0.001 Fondaparinux 1.3% 1.6% VKA 73% 67% <0.001 Lecumberri R et al Thromb Haemost 2013

1% <0.001 UFH 12% 2.9% <0.001 LMWH 85% 95% <0.001 Fondaparinux 1.

Venous thromboembolism: drugs and strategies Current standard of care LMWH or Fonda s.c.* VKA Day 1 Day 5 11 At least 3 months RE-COVER + RE-COVER II DABIGATRAN (publ.

4 Venous thromboembolism: drugs and strategies Current standard of care LMWH or Fonda s.c.* VKA Day 1 Day 5 11 At least 3 months RE-COVER + RE-COVER II DABIGATRAN (publ. 2009/2013) HOKUSAI-VTE EDOXABAN (publ. 2013) LMWH s.c. dabi bid / edo OD Day 1 Day 5 11 At least 3 months EINSTEIN-DVT + EINSTEIN- PE RIVAROXABAN (publ 2010/2012) riva 15 mg BID 3 wk, then 20 mg OD AMPLIFY APIXABAN (publ. 2013) *Or unfractionated heparin or fondaparinux api 10 BID 1 wk, then 5 mg BID Day 1 At least 3 months BID = twice daily; LMWH = low molecular weight heparin; OD = once daily; s.c. = subcutaneous; VKA = vitamin K antagonist

dabi bid / edo OD Day 1 Day 5 11 At least 3 months EINSTEIN-DVT + EINSTEIN- PE RIVAROXABAN (publ 2010/2012) riva 15 mg BID 3 wk, then 20 mg OD AMPLIFY

5 Nunber of recurrences VTE: optimal treatment for acute initial period iv UFH / VKA versus VKA alone: VTE recurrences at 3 months: 7 % 20 % Brandjes et al. N Engl J Med 1992;327: Ximelagatran alone LMWH / VKA Idraparinux ow alone LMWH / VKA 2 HR = 2.09 [ ] 0 D1-7 D7-14 D15-30 THRIVE II-V study. Fiessinger et al. JAMA 2005;293: Van Gogh PE study. N Engl J Med 2007;357: Acute initial phase: period at risk requiring intensive parenteral treatments

8 6 4 Ximelagatran alone LMWH / VKA Idraparinux ow alone LMWH / VKA 2 HR = 2.09 [ 1.2 3.

6 Patients (%) Phase III VTE trials Recurrent VTE 4 3,5 3 2,5 2 1,5 2.3% 2.2% 2.1% 2.3% 2.3% 2.7% NOAC Control 1.6% 1.9% 1 0,5 0 * On Treatment RE-COVER EINSTEIN AMPLIFY Hokusai-VTE Dabigatran Rivaroxaban Apixaban Edoxaban 1. Schulman et al. N Engl J Med 2009;361: EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN PE Investigators. N Engl J Med 4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013 *

Schulman et al. N Engl J Med 2009;361:2342 2352 2. EINSTEIN Investigators. N Engl J Med 2010; 3.

7 Patients (%) Phase III VTE trials Major Bleeding 4 3,5 3 NOAC Control 2,5 2 1,5 1 0,5 1.4% 2.0% 1.0% 1.7% 0.6% 1.8% 1.4% 1.6% 0 RE-COVER EINSTEIN AMPLIFY Hokusai-VTE Dabigatran Rivaroxaban Apixaban Edoxaban 1. Schulman et al. N Engl J Med 2009;361: EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN PE Investigators. N Engl J Med 4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

8 RE- COVER 1# (Dabigatran) EINSTEIN DVT 2 (Rivaroxaban) EINSTEIN PE 3 (Rivaroxaban) AMPLIFY 4 (Apixaban) Hokusai- VTE 5 (Edoxaban) Patients, N Age (yrs) Female (%) Creatinine clearance <50 ml/min (%) NOAC VTE trials: Baseline characteristics NR DVT (%) PE±DVT (%) Unprovoked (%) NR Cancer (%) Previous VTE NR=not reported; # RECOVER II is still only available as an abstract and therefore is not included in the table Data from Hokusai-VTE are for history of cancer; active cancer was observed in 2.4% of patients overall 1. Schulman et al. N Engl J Med 2009;361: EINSTEIN Investigators. N Engl J Med 2010;363: ; 3. EINSTEIN PE Investigators. N Engl J Med 2012;366: Agnelli et al. N Engl J Med 2013;369: ; 5. The Hokusai-VTE Investigators. N Engl J Med 2013

6 100 35 40 Unprovoked (%) NR 62 65 90 65 Cancer (%) 5 6 5 3 9 Previous VTE 26 19 19 16 18 NR=not reported; # RECOVER II is still only available as an abstract and therefore is not included in the

9 Cumulative event rate (%) EINSTEIN PE Primary efficacy outcome: 3.0 time to first event (2.1%) Rivaroxaban N= (1.8%) Enoxaparin/VKA N=2413 HR=1.12; p< (non-inferiority) Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA ITT population The EINSTEIN Investigators. N Engl J Med 2012

0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk Rivaroxaban 2419 2350 2321

10 Cumulative event rate (%) EINSTEIN PE Principal safety outcome: major or non-major clinically relevant bleeding Enoxaparin/VKA N= % (Major 2.2%*) Rivaroxaban N= % (Major 1.1%*) Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA Safety population * 0.49 ( ) The EINSTEIN Investigators. N Engl J Med 2012

1%*) 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk Rivaroxaban 2412 2183 2133 2024 1953

11 Hokusai study: Subgroup analysis in PE patients with NT-proBNP 500 pg/ml HR=0.52 (95% CI, ) 6.2% 3.3% 15/454 30/484 The Hokusai-VTE Investigators. N Engl J Med 2013

12 ACCP 2012 Treatment of VTE 2012

15 RE-MEDY study design Screening/ baseline Treatment period Follow up 30 days Dabigatran etexilate 150 mg bid Anticoagulant therapy 3 12 months* and increased risk of recurrence 0 7 days until INR 2.3 Warfarin placebo Warfarin (INR ) Dabigatran placebo Confirmed VTE S R *Original protocol, 3 6 months of pre-treatment, then 18 months on study drug; amendment allowed 3 12 months of pre-treatment, then up to 36 months on study drug. S, screening; R, randomization. Up to 36 months* End of treatment

0) Dabigatran placebo Confirmed VTE S R *Original protocol, 3 6 months of pre-treatment, then 18 months on study drug;

16 Percentage Recurrent symptomatic VTE and VTErelated deaths HR 1.44 (95% CI: ) p = (non-inferiority) 1.8% 1.3% 26/ /1426 Risk difference 0.38 (95% CI: ); p < (non-inferiority).

17 Percentage Major bleeding 3 2,5 HR 0.52 (95% CI: ) p = ,5 1 0,5 48% RRR 0.9% 1.8% 0 RRR, relative risk reduction. Dabigatran 150 mg bid 13/1430 On treatment Warfarin 25/1426

18 Eleggibilità da piano terapeutico per Xarelto Prevenzione della TVP recidivante e dell EP dopo TVP PROSSIMALE acuta nell adulto Diagnosi confermata mediante ecografia ARTI INFERIORI nelle 48 ore precedenti Oppure Terapia con EBPM o ENF o fondaparinux

adulto Diagnosi confermata mediante ecografia ARTI INFERIORI

19 Pazienti non candidabili ai nuovi anticoagulanti orali Insufficienza grave (clearance creatinina < 30 ml/min-15 ml/min per alcuni farmaci?) Insufficienza epatica moderata-grave (Child-Pugh B-C); epatite acuta Terapia con farmaci non associabili (es. antiretrovirali) Gravidanza e allattamento Neoplasia attiva con indicazione a EBPM a lungo termine Concomitante EP con instabilità emodinamica

) Insufficienza epatica moderata-grave (Child-Pugh B-C); epatite acuta Terapia con farmaci non

20 I nuovi anticoagulanti nella terapia del TEV: conclusioni Studi di fase III pazienti con TVP ed EP dimostrano efficacia comparabile al trattamento standard e sicurezza complessivamente superiore Non vi sono segnali di differenze nei vari sottogruppi, soprattutto di pazienti più fragili I vantaggi pratici sono indiscutibili Siamo in attesa di dati da studi osservazionali/fase IV (Xalia)

complessivamente superiore Non vi sono segnali di differenze nei vari sottogruppi, soprattutto di

21 I nuovi anticoagulanti nella terapia del TEV: conclusioni 2 E fondamentale la selezione dei pazienti idonei per ciascun trattamento E fondamentale un adeguata istruzione dei pazienti E fondamentale un adeguato follow-up Aree incerte: Embolia polmonare con disfunzione ventricolare dx Neoplasia attiva (vs EBPM) Sedi inusuali

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