Focus: l embolia polmonare Per quanto la terapia anticoagulante orale? Giulia Magnani 27 Gennaio, 2018

Transcription

1 Focus: l embolia polmonare Per quanto la terapia anticoagulante orale? Giulia Magnani 27 Gennaio, 2018

2 NO DISCLOSURE

3 Pulmonary Embolism Venous thromboembolism (VT) is the third most common cause of cardiovascular death Since pulmonary embolism (PE) is, in most cases, the consequence of a deep venous thrombosis (DVT), most of the existing data are derived from studies that have examined VTE as a whole Oral anticoagulant (OAC) treatment is the mainstay for the treatment of VTE.

4 Anticoagulant (AC) Treatment phases of VTE Active treatment phase: To suppress the acute episode of thrombosis Acute Long term Pure secondary prevention: To prevent new episodes of VTE, that are unrelated to the index event Extended use 5 Days 3 Months > 3 Months, Indefinite Goldhaber SZ et al, Lancet 2012

5 Probability of VTE after stopping OAC Active Treatment: 3 months is enough 7 RCTs-Patient level meta-analysis VTE (2925 pts with VTE, 60% unprovoked and 40% provoked)) 1.0 or 1.5 vs 3 Months HR % CI vs 6 Months HR % CI Cumulative probability adjusted for age, sex, study, location of initial VTE and presence of a temporary risk factor, Mean FUP=1.4 Years Boutite F, Br Med J 2011; 342:d3036

6 Decision Stop Therapy 3 Months Continue Therapy? Long-term risk of VTE recurrence Risk of bleeding

7 Risk of Recurrence: Clinical Factors Provoked VTE With transient risk factors. Surgery. Trauma. Pregnancy. Estrogen... Unprovoked VTE No previous risk factors for VTE Provoked VTE With persistent risk factors. Active cancer. Thrombophilia Risk of recurrence Lowest Highest Journal of Thrombosis and Haemsotasis

8 Long-term Risk Cumulative incidence of recurrent VTE after discontinuing AC Year Idiopathic Secondary Cumulative Incidence (%) Prandoni P, Haematologica 2007;92:

9 Risk of Recurrence: Laboratory D-dimer 410 pts 75 yrs with a first unprovoked proximal DVT or PE FUP: 2.3 yrs after 3-7 months of AC treatment 319 pts with 2 negative D-dimer test (during OAC and 1 Month after stopping OAC) Kareon et al. Ann Intern Med 2015

10 Risk of Recurrence: Instrumental Right Ventricular dysfunction (RVD) 301 PE-pts Cumulative incidence of recurrent VTE Grifoni S. et al. Arch Intern Med. 2006

11 Long-term Risk of Bleeding: Scores GL ESC 2014: No recommendation for a specific standardized bleeding risk score GL ACCP 2016: List of 18 risk factors, 2 high bleeding risk (not validated) Classic bleeding risk scores not enough discriminative power VTE-BLEED Score High risk of bleeding ( 2 points) Thromb Haemost Jun 2;117(6):

12 How long is enough? The PADIS-PE Trial 348 patients with unprovoked PE randomized to: - 18 months warfarin - Placebo after 6 uninterrupted months of AC Recurrent VTE On treatment HR 0.15, 95% CI Overall HR 0.46, 95% CI Coutouraud et al. JAMA 2015

13 AC indefinite after VTE? Recurrent VTE in Patients with a First Episode of Idiopathic VTE after 3 Months of AC HR (95%CI) 0.05 ( ) <0.001 Recurrence Rate Reduce by 95% Major Bleeding 3.8%/yr Kearon C, N Engl J Med 1999; 340:901-7

14 Advances in the NOACs Era Efficacy in acute VTE Patients with VTE (43% with PE) AC Treatment for ~ 6 months Recurrent VTE, including VTE-related death van Es N. et al. Blood 2014; 124 (12):

15 Advances in the NOACs Era Safety in acute VTE Bleeding van Es N. et al. Blood 2014; 124 (12):

16 Extension studies Trial (NOAC) AMPLIFY EXT Apixaban RE-SONATE Dabigatran EINSTEIN EXT Rivaroxaban EINSTAN CHOICE Rivaroxaban RE-MEDY Dabigatran HOKUSAY-VTE (Post-hoc Ext) Edoxaban Dosage Duration of Initial Therapy (mos) Vs. Placebo Duration of Extended Therapy (mos) Recurrent VTE % Major bleeding (%) 2.5 mg bid 1.7 vs vs mg bid 1.7 vs vs mg bid vs vs mg od vs vs 0.0 Vs. Asprin 10 mg od 1.5 vs vs Up to mg od 1.2 vs vs. 0.3 Vs. Warfarin 150 mg bid vs. 1.3 NI 0.9 vs mg od vs. 0.4 NI 0.3 vs. 0.7

17 Extended Use of Dabigatran vs. Warfarin in VTE RE-MEDY Trial 2856 Patients at increased recurrent VTE Risk AC 3 to 12 months before rando. PEP: Recurrent VTE or Related Death AC Median duration: 8 8 months (IQR ) HR 95% CI 1.44 ( ) P =0.01 for non-inf TTR 65.3% Time after randomization (Months) Major or clinically relevant bleeding: HR 95%CI 2.92 ( ) P= S. Schulman N Engl J Med 2013;368:

18 Extended AC with edoxaban in pts with VTE: a post-hoc analysis of the Hokusai-VTE study 8240 patients with acute VTE (3319 presented with PE) PEP: Recurrent VTE over extended treatment period (>3-12 Months) Overall HR (95% CI) 0.97 ( ) On-treatment (95% CI) 0.78 ( ) TTR 64% Time after randomization (Days) Major bleeding HR (95%CI) 0.45 ( ) G. Raskob: Lancet Haematol 2016;3: e228 36

19 Hokusai VTE Cancer 1046 Patients with cancer and VTE PEP: Recurrent VTE or Major Bleeding HR 0.97 (95% CI ) P inf =0.006 LMWH at least 5 days edoxaban 60 mg od vs. s.c. dalteparin 200 IU/kg od 1 month dalteparin 150 IU/kg od Raskob G.E. et al., NEJM, 2017

20 Recurrent VTE (%) Recurrent VTE in patients with PE and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study 3319 haemodynamically stable patients with PE 965 with NT-proBNP concentration 500 pg/ml Warfarin (INR 2-3) Edoxaban 60 mg od HR (95%CI): 0.50 ( ), p=0.033 Days from Randomization Raskob G.E. et al., NEJM, 2017

21 Acute 5 Days Treatment options Long-term 3 Months Extended Use > 3 Months, Years or Indefinite UFH, LMWH, Fondaparinux Parenteral AC At least 5 Days VKA (INR ) Parenteral AC At least 5 Days Dabigtran 150 (110) mg bid Parenteral AC At least 5 Days Edoxaban 60 (30 mg) od Rivaroxaban 15 mg bid 21 Days 20 mg od 10 mg od Apixaban 10 mg bid 7 Days 5 mg bid 2.5 bid

22 Guidelines Provoked PE: 3 Months (IB) Unprovoked PE: At least 3 Months (IA) - 1 st Episode: Indefinite, low bleeding risk (IIaB) - 2 d Episode: Indefinite (IB) PE in cancer patients: Continue until the cancer is considered under control and possibly cured (IIaC) Extended AC: NOACs preferred over warfarin (IIB) Take in consideration pts s preference ACCP 2016, ESC 2014, CHEST 2016

23 Conclusions Recurrence VTE risk remains high in the long-term period, following AC treatment cessation Pts with unprovoked or cancer-associated VTE should receive extended treatment VKA are highly effective for prevention of recurrence, but with a significant bleeding risk NOACs overcome the limitations of VKA and are safer drugs, extending the indication of AC to a broader population We should continue to optimize the tools for selected candidates for indefinitive treatment, integrating both the recurrence and bleeding risk

24 Focus: l embolia polmonare Per quanto la terapia anticoagulante orale? Giulia Magnani 27 Gennaio, 2018