1. 2014 ESC guidelines update on the diagnosis and management of acute pulmonary embolism Anticoagulation for the treatment of PE and secondary prevention of VTE

2. Pulmonary embolism: a major cause of morbidity and mortality PE: a major cause of mortality, morbidity (including CTEPH) and hospitalization Most serious clinical presentation of VTE with a high risk of early mortality* –9–11% 30-day mortality –8.6–17% 3-month mortality Few PEs are diagnosed correctly before death Konstantinides et al, 2014 N=317,000 *Registries and hospital discharge datasets of unselected patients; # 2004 data from 6 EU countries (total population 454.4 million)

3. Persistent threat of VTE recurrence Risk of recurrence is highest early after index event, and declines thereafter 1,2 –Poor quality of anticoagulation (failure to maintain therapeutic levels with VKAs) is a risk factor for early recurrence 1 Risk of recurrence never disappears –Even after 10 years, risk of recurrence is not zero 3 Typically, a recurrent event occurs in the same clinical form as index event 1 1. Konstantinides et al, 2014; 2. Limone et al, 2013; 3. Prandoni et al, 2007 Venous thromboembolic events per person-year Rates of recurrent VTE following the index DVT/PE event 2 Time period after index event (weekly intervals)

4. Anticoagulants for VTE treatment and secondary prevention For acute VTE, fast, effective anticoagulation is essential to prevent: Death from PE 1 Progression of DVT to PE 1 Recurrent VTE 2 For acute treatment VKAs: slow onset of action that necessitates an overlap period with a fast-acting parenteral anticoagulant (~5 days), or until INR is 2.0–3.0 for at least 24 hours 3 Novel OACs: all have a fast onset of action and have many advantages over VKAs 1. Kearon, 2003; 2. Limone et al, 2013; 3. Coumadin (warfarin sodium) Prescribing Information, 2011

5. Management of acute PE according to PE severity Spectrum of clinical presentation of PE is highly variable 1,2 PE can be stratified and managed according to the risk of early death* assessed at presentation of suspected PE 1,2 Risk stratification impacts on recommended diagnostic and treatment strategies 1,2 1. Torbicki et al, 2008; 2. Konstantinides et al, 2014 >15%<1% Shock and/ or hypotension *In-hospital death or death within 30 days of diagnosis Risk of early mortality* High riskLow riskIntermediate risk No shock and/or hypotension – further risk stratification required

6. Classification of PE severity according to early mortality risk Initial risk stratification of suspected or confirmed PE: recommended to identify patients at high risk of early mortality # (IB) Konstantinides et al, 2014 *Defined as systolic blood pressure 15 mins, if not caused by new-onset arrhythmia, hypovolaemia or sepsis; # in-hospital death or death within 30 days of diagnosis Suspected acute PE Shock or hypotension?* No Yes High-riskNot high-risk

7. Classification of PE severity according to early mortality risk Early mortality risk Risk parameters and scores Shock or hypotension PESI class III–V or sPESI >1* Signs of RV dysfunction on an imaging test Cardiac laboratory biomarkers High+(+) # + IntermediateIntermediate-high-+Both positive Intermediate-low-+Either one (or none) positive ‡ Low--Assessment optional; if assessed, both negative ‡ Konstantinides et al, 2014 *PESI class III–V: moderate to very high 30-day mortality risk; sPESI ≥1 point(s): high 30-day mortality risk; # neither calculation of PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock; ‡ patients with PESI class I–II/sPESI of 0, and elevated cardiac biomarkers/signs of RV dysfunction, are to be considered as intermediate-low risk

8. Comparison of original and simplified Pulmonary Embolism Severity Index (PESI) *sPESI: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another Konstantinides et al, 2014 ParameterOriginal versionSimplified PESI* AgeAge in years1 point (age >80 years) Male sex+10 points- Cancer+30 points1 point Chronic heart failure+10 points1 point Chronic pulmonary disease+10 points1 point Pulse rate ≥110 bpm+20 points1 point Systolic blood pressure <100 mm Hg+30 points1 point Respiratory rate >30 breaths/min+20 points- Temp <36 °C+20 points- Altered mental status+60 points- Arterial oxyhaemoglobin saturation <90% +20 points1 point

9. Risk-adjusted PE management algorithm Konstantinides et al, 2014 Clinical suspicion of PE High YesNo Diagnostic algorithm as for suspected not high-risk PE Diagnostic algorithm as for suspected high-risk PE Intermediate-low PE confirmed Primary reperfusion Anticoagulation; monitoring; consider rescue reperfusion Hospitalization; anticoagulation Consider early discharge and home treatment, if feasible PE confirmed Intermediate risk RV function and laboratory testing One positive/both ‘–’ Both ‘+’ PESI class III–VI/sPESI ≥1 PESI class I–II /sPESI=0 Shock or hypotension? Assess clinical risk (PESI or sPESI*) *sPESI: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another Intermediate-highLow

10. Early discharge and home treatment of PE Recommendations for early discharge and home treatment Class of recommendation Level of evidence Patients with acute low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided IIaB Konstantinides et al, 2014

11. Novel OACs: a treatment choice for low- to intermediate-risk PE patients (acute treatment) Recommendations for novel OACs as alternatives to VKA/parenteral anticoagulation Class of recommendation Level of evidence Rivaroxaban (15 mg bid for 3 weeks, followed by 20 mg od)IB Apixaban (10 mg bid for 7 days, followed by 5 mg bid)IB Dabigatran (150 mg bid, or 110 mg bid for patients ≥80 years of age or those under concomitant verapamil treatment) following acute-phase parenteral anticoagulation IB Edoxaban* following acute-phase parenteral anticoagulationIB Rivaroxaban, apixaban, dabigatran and edoxaban are not recommended in patients with severe renal impairment # IIIA *Edoxaban is in EU regulatory review for VTE treatment; # CrCl <30 ml/min for rivaroxaban, dabigatran and edoxaban, and <25 ml/min for apixaban Konstantinides et al, 2014

12. Duration of treatment recommendations Recommendations for duration of oral anticoagulationClass of recommendation Level of evidence PE secondary to a transient (reversible) risk factor: 3 months IB Unprovoked PE: ≥3 months IA First episode of unprovoked PE and low bleeding risk: consider extended treatment (>3 months) IIaB Second episode of unprovoked PE: indefinite duration IB Risk–benefit of continuing anticoagulation should be reassessed at regular intervals IC Currently, no assessment score for risk of VTE recurrence: persistent risk factors (as opposed to major, temporary) may affect decision on duration of anticoagulation after index PE Konstantinides et al, 2014

13. Rivaroxaban, dabigatran and apixaban should be considered for extended anticoagulation Recommendations for extended anticoagulationClass of recommendation Level of evidence Novel OACs: considered an alternative to VKA (except in patients with severe renal impairment*) Rivaroxaban: 20 mg od Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking verapamil) Apixaban: 2.5 mg bid IIaB#B# For patients refusing to take or unable to tolerate OACs, aspirin may be considered IIbB *CrCl <30 ml/min for rivaroxaban and dabigatran, and <25 ml/min for apixaban; # B refers to the level of evidence available for each drug separately Konstantinides et al, 2014

14. Summary of updates to the ESC PE guidelines Broad principles of PE risk stratification remain the same, but the process has been refined –Patients identified as having truly low risk of 30-day mortality (PESI class I–II or sPESI = 0) can be considered for at-home treatment –Further risk stratification into ‘intermediate-low’ and ‘intermediate-high’ categories can be considered to further aid management strategy decisions Novel OACs are recommended for acute phase PE treatment as an alternative option to LMWH/VKA, for patients with intermediate- or low-risk PE (class I level B) Novel OACs are recommended for extended therapy if required as an alternative option to VKA treatment (class IIa level B)

15. Clinical Evidence

16. Dosing regimens of novel OACs for treatment of VTE and prevention of recurrence Rivaroxaban 15 mg bid (21 days), followed by 20 mg od 1 * Apixaban 10 mg bid (7 days), followed by 5 mg bid (day 8 to month 6), followed by 2.5 mg bid (>6 months) 2 Single oral drug Increasing complexity VKA (INR adjusted, day 1 onwards) Parenteral agent (≥5 days) Bridging 4 1. Xarelto SPC, 2014; 2. Eliquis SPC, 2014; 3. Pradaxa SPC, 2014; 4. Coumadin (warfarin sodium) Prescribing Information, 2011 *In patients with moderate (CrCl 30–49 ml/min) or severe (CrCl 15–29 ml/min) renal impairment, 15 mg od should be considered if patient’s assessed risk for bleeding outweighs risk for recurrent DVT/PE; # 110 mg bid for patients ≥80 years or patients who receive concomitant verapamil Parenteral agent (≥5 days) Dabigatran 150 mg bid 3# Switching

17. 1. The EINSTEIN Investigators, 2010; 2. The EINSTEIN–PE Investigators, 2012; 3. Agnelli et al, 2013; 4. Schulman et al, 2009; 5. Schulman et al, 2014; 6. The Hokusai-VTE Investigators 2013 Phase III VTE treatment studies DrugTrialDesignTreatments and dosage Duration (months) Patients (n) Index event* Primary efficacy event Principal safety outcome RivaroxabanEINSTEIN DVT 1 Open- label Riva (15 mg bid for 3 weeks, then 20 mg od) vs enoxaparin/VKA 3, 6 or 123449DVTRecurrent VTE Major/clinically relevant non- major bleeding EINSTEIN PE 2 4832PE ApixabanAMPLIFY 3 Double- blind, double- dummy Apix (10 mg bid for 7 days, then 5 mg bid) vs enoxaparin/ warfarin 65395DVT /PE Recurrent VTE or related death Major bleeding DabigatranRE- COVER 4 Double- blind, double- dummy Parenteral/dabi (150 mg bid)* vs parenteral/ warfarin 6 2539 DVT /PE Recurrent VTE or related death Major bleeding RE- COVER II 5 2589DVT /PE EdoxabanHokusai- VTE 6 Double- blind, double- dummy Parenteral/edox (60 mg od or 30 mg od*) vs parenteral/warfarin 3–128240DVT /PE Recurrent VTE Major/clinically relevant non- major bleeding *All index DVT/PE events were acute, symptomatic and objectively confirmed

18. Novel OACs for VTE treatment: summary of clinical evidence All novel OACs were at least as effective (non-inferior) as parenteral/VKA treatment in phase III studies of VTE treatment and the prevention of recurrence: –Rivaroxaban: similar incidence of major/non-major clinically relevant bleeding (principal safety outcome) and significant reductions in major bleeding 1 –Apixaban: significant reductions in incidence of major bleeding (principal safety outcome) and major/non-major clinically relevant bleeding 2 –Dabigatran (with initial parenteral therapy): similar incidence of major bleeding (principal safety outcome) and a reduction in major/non-major clinically relevant bleeding 3 –Edoxaban (with initial parenteral therapy): significant reductions in major/ non-major clinically relevant bleeding (principal safety outcome) and a similar incidence of major bleeding 4 1. Prins et al, 2013; 2. Agnelli et al, 2013; 3. Schulman et al, 2014; 4. The Hokusai-VTE Investigators, 2013

19. Rivaroxaban for VTE treatment: summary of clinical evidence Rivaroxaban provides a single-drug approach for the treatment and secondary prevention of VTE with a convenient and effective dosing regimen –Rivaroxaban is the only novel OAC to be tested in a separate trial for patients with PE (with or without DVT), and offers insights into the largest study population of its kind Rivaroxaban may provide an equally effective treatment option to conventional therapy for patients with both low- and intermediate-risk PE, with lower rates of major bleeding complications versus parenteral/VKA treatment

20. BACK-UP SLIDES

21. Simplified PESI: post hoc analysis of EINSTEIN PE 0–1: low rates of major clinical outcome events during first 30 days of treatment versus scores ≥2 ≥2: more frequent adverse outcomes initially and longer term versus scores 0–1 Rivaroxaban showed lower rates of recurrent VTE and fewer instances of major bleeding in high-risk sPESI (≥2) patients versus LMWH/VKA Up to day 30 Full treatment period Erkens et al, 2013