Acute and long-term treatment of VTE. Cecilia Becattini University of Perugia

Acute and long-term treatment of VTE Cecilia Becattini University of Perugia

Acute and long-term treatment of VTE The goals The acute PE phase After the acute phase

Treatment for VTE Goals of acute treatment Reduce mortality Reduce early recurrences Goals of long-term treatment Complete treatment of acute VTE Reduce recurrences Goals of extended treatment Initial treatment Reduce recurrences in high risk pts Long term-treatment Extended treatment 5 days 3-6 months > 6 months

Acute and long-term treatment of VTE The goals The acute phase revascularization filters home-treatment After the acute phase

PE: results from large registries short-term mortality ICOPER 11% MAPPET 9% IPER 7% EMPEROR 5% RIETE HD stable patients 3% HD unstable 9%

PE: ESC model for risk stratification Eur Heart J 2014

2014 ESC model in clinical practice 906 patients with acute symptomatic objectively confirmed PE 30-day Mortality based on risk High Intermediate high Intermediate low Low Becattini et al, Eur Resp J 2016

Tenecteplase for intermediate-high risk PE All-cause mortality or hemodynamic collapse within 7 days of randomization Tenecteplase (n=506) Placebo (n=499) n (%) n (%) P value 13 (2.6) 28 (5.6) 0.015 Meyer G, N Eng J Med 2014 S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1

Tenecteplase for intermediate-high risk PE All-cause mortality within 7 days Tenecteplase (n=506) Placebo (n=499) n (%) n (%) P value 6 (1.2) 9 (1.8) 0.43 Hemodynamic collapse within 7 days bleeding 8 (1.6) 25 (5.0) 0.002 Major 32 (6.3) 6 (1.5) <0.001 Hemorrhagic stroke 10 1 Meyer G, N Eng J Med2014 S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1

Ultrasound-facilitated CDT for PE 150 patients with proximal PE and right ventricle dilation at CT preprocedure 48-h p Mean RV/LV diameter ratio Mean PA systolic pressure Mean modified Miller index 1.55 1.13 <0.0001 51.4 36.9 <0.0001 22.5 15.8 <0.0001 GUSTO severe bleeding GUSTO moderate bleeding 1 patient (0.5%) 15 patients (10%) Piazza G, JACC 2015

Interventional procedures for PE Limited number of controlled studies No evidence of reduction in mortality Risk for peri-procedural complications Long-term benefit of early HD improvement not well established

ESC Guidelines: clinical management

Vena cava filter for acute PE with DVT Recurrent VTE in patients randomized to vena cava filter implantation plus anticoagulation or anticoagulation alone Cumulative risk HR 1.36, 95% CI 0.47 3.91 filter controls Months since randomization Mismetti P, JAMA 2015

Treatment for PE & DVT THRIVE TREATMENT Ximelagatran (26 events) Enoxaparin/warfarin (24 events) 5 95% CI: 0.6%; 1.6% Cumulative risk (%) 4 3 2 ITT 2.1% 2.0% 1 0 0 30 60 90 120 150 180 Days after randomisation Fiessinger J-N et al. JAMA 2005;293:681 689

NOACs in VTE: study design Conventional anticoagulation: Heparin + warfarin Confirmed symptomatic DVT or PE R Treatment period 3, 6 or 12 mo NOA front-load maintaining dose Conventional anticoagulation: Heparin + warfarin Confirmed symptomatic DVT or PE R Treatment period 3, 6 or 12 mo LMWH NOA

NOACs vs conventional treatment

NOACs: across the VTE spectrum R L

PE: anatomical extent of PE as defined in NOACs trials Limited extent 25% of the vasculature of a single lobe Intermediate extent >25% of vasculature of a single lobe or multiple lobes with 25% of entire vasculature Extensive extent multiple lobes with 25% of entire vasculature The Hokusai-VTE Investigators. N Engl J Med 2013

Edoxaban in PE patients with increased BNP HR=0,52 HR=0,52 (IC (IC 95%: 0,28 0,98) 0,28 0,98) Pazienti (%) 15/454 30/484 Recidiva di TEV The Hokusai-VTE Investigators. N Engl J Med 2013

Treatment NOACs for pulmonary Treatment embolism of PE Study Primary endpoint Event, % (n/n) HR*/RR (95%CI) NOAC Warfarin RECOVER I & II (index PE) VTE/VTE-related death 2.9 (23/795) 3.1 (25/807) 0.93 (0.53 1.64) EINSTEIN-PE Recurrent VTE 2.1% (50/2419) 1.8% (44/2413) 1.12* (0.75 1.68) AMPLIFY (Index PE) Recurrent VTE / VTErelated death 2.3% (21/900) 2.6% (23/886) 0.90 (0.50 1.61) HOKUSAI (Index PE) Recurrent VTE 2.8% (47/1650) 3.9% (65/1669) 0.73* (0.50 1.06) HOKUSAI (Severe PE) (ProBNP 500 pg/ml) Recurrent VTE 3.3% (15/454) 6.2% (30/485) 0.52* (0.28 0.98)

NOACs in pulmonary embolism 5 phase III studies included: 11,539 patients OR 95% CI Recurrent VTE anti-xa anti-iia Major Bleeding* Clinically Relevant Bleeding* 0.89 (0.70-1.12) 0.89 (0.69-1.15) 0.87 (0.46-1.64) 0.30 (0.10-0.95) 0.89 (0.77-1.03) * two studies included Vedovati MC et al, Int J Cardiol 2014

Treatment for pulmonary embolism Eur Heart J 2014

The CHEST guidelines DVT of the leg or PE Concomitant cancer Yes No LMWH LMWH followed by VKAs NOACs Grade IIB *Same grade of recommendation for different NOACs Clive Kearon,et al. Chest 2016

Acute and long-term treatment of VTE The goals The acute PE phase revascularization for intermediate risk filters home-treatment After the acute phase

VTE in Italy: in vs out hospital management Dentali, Annals Med 2015

PE: duration of hospitalization over time Data from 23,858 patients included in the RIETE Registry Jimenez D, JAMA 2016

PE: 3-month outcome of home treatment 13 studies (1657 patients) with outpatients (<24 h), 3 studies (256 patients) with early discharge (<72 h) 5 studies (383 patients) with inpatients Zondag W et al., Eur Resp J 2013

Design Aujesky et al Zondag et al Agterof et al Otero et al Open-label, RCT Prospective cohort Prospective cohort Open-label, RCT HoT PE ongoing Prospective cohort, phase IV Eligibility criteria Systolic BP 100 mmhg 100 mmhg 90 mmhg 90 mmhg 100 mmhg Clinical prediction rule PESI class I or II Hestia - Uresandi 0-2 Modified Hestia Biomarkers No No NT-proBNP Troponin T No (analysis planned) Absence of RVD No No No TTE CT or TTE Renal function CrCl 30 CrCl 30 Creatinine <150 umol/l Platelet count 75 000/mm 3 - - - - Body weight 150 kg - - BMI <30 kg/m 2 Respiratory function Others Time of discharge SaO 2 90%, or PaO 2 60 mmhg No history of HIT <24 h vs inpatient management PE: home treatment SaO 2 >90% in air No history of HIT; no hepatic impairment <24 h <24 h SaO 2 >90% in air - No SaO 2 93%; NYHA I or II; severe COPD No surgery <15 days 3- to 5-day vs inpatient CrCl 15 SaO 2 >90% in air No history of HIT; no severe hepatic impairment 48 h of admission

Clinical prognostic rules and in-hospital mortality IMPACT PESI spesi Hestia Mortality in low risk (%) 0.4 0.6 0 0 Sensitivity (95% CI) 95.2 (7.41-99.8) 90.5 (68.2-98.3) 100 (80.8-100) 100 (80.8-100) Specificity (95% CI) 29.1 (26-32.5) 39.1 (35.6-42.6) 31.8 (28.6-35.2) 26.8 (23.8-30.1) PPV (95% CI) 3.5 (2.2-5.4) 3.8 (2.4-6.0) 3.8 (2.4-5.8) 3.5 (2.2-5.4) NPV (95% CI) 99.6 (97.2-100) 99.4 (97.4-99.9) 100 (98.1-100) 100 (97.8-100) IMPACT= In-hospital Mortality for Pulmonary embolism using Claims data Weeda ER et al., Thrombosis Journal 2016

Acute and long-term treatment of VTE The goals The acute PE phase After the acute phase optimal agent CTPH

Treatment for PE & DVT Current standard of care LMWH or Fonda VKAs RECOVER I & II DABIGATRAN HOKUSAI VTE EDOXABAN LMWH DABI 150 mg bid EDO 60 mg od EDO 30mg od EINSTEIN DVT+PE RIVAROXABAN Riva 15mg bid 3 wks RIVA 20 mg od AMPLIFY APIXABAN Api 10 mg bid 1 wk API 5 mg bid Day 1 Day 5-11

European Society for Vascular Medicine Long term course of PE 2nd Annual Congress May 8-10, 2016, Rome - Italy Study on the COurse of Pulmonary Embolism Acute PE 805 patients 647 patients included 158 patients excluded CTEPH Suspected CTEPH recurrent VTE Suspected recurrent VTE 11 patients 1.7% 95% CI 0.9 to 3.0 40 patients 6.2% 95% CI 4.5 to 8.3 Pesavento R et al., Submitted

European Society for Vascular Medicine Long term course of PE 2nd Annual Congress May 8-10, 2016, Rome - Italy Study on the COurse of Pulmonary Embolism RPO at 6m: 50.1% (46.2-54.0) HR 2.42*; 95% CI, 1.31-4.46 *adjusted for age,unprovoked PE, RPO, time of OAT withdrawal Pesavento R et al. ISTH 2016 Pesavento R et al. ISTH 2016

Thrombolysis & CTEPH 667 PEITHO patients 41.6±15.7 months at F-U after randomization Persistent dyspnea (mostly mild) 22.8% functional limitation 19.7% NYHA III-IV 7.4% No differences between the two treatment arms. Echocardiography did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. PEITHO Investigators, submitted

Thrombolysis & CTPH CTEPH confirmed in 4 TNK (1.4%) and 6 placebo (2.2%) patients (P=0.740). PEITHO Investigators, submitted

Acute and long-term treatment of VTE Evidence not enough for treatment upgrading in HD stable NOACs effective and safe for treatment of VTE No clinical benefit by time-definite treatment extension

Management of pulmonary embolism Cecilia Becattini University of Perugia, Italy