SESSION 4 12:45 2:15 PM

SESSION 4 12:45 2:15 PM Pulmonary Embolism Update SPEAKER Gregory Piazza, MD, MS Presenter Disclosure Information The following relationships exist related to this presentation: Gregory Piazza, MD, MS: Advisory Boards for Merck, exithera, and Zafgen. Contracted Research for Bristol-Myers Squibb Company; BTG EKOS; Daiichi Sankyo; and Janssen Pharmaceuticals, Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Objectives 1. Review the epidemiology of PE 2. Discuss the pathophysiology and risk stratification of PE 3. Apply evidence-based strategies to effectively manage PE Discussion Case A 67-year-old man with diabetes and hypertension presents to the Emergency Department with sudden onset dyspnea on exertion and pleuritic pain. On physical examination, he is tachycardic to 110 bpm, normotensive at 116/72 mmhg, and hypoxemic with an O 2 saturation of 88% on room air. His cardiac troponin T is elevated to 0.4 ng/ml. 100,000-180,000 PE-related deaths occur annually in the U.S. alone. VTE Incidence PE is the most preventable cause of death among hospitalized patients. www.surgeongeneral.gov/topics/deepvein/calltoaction Huang W, et al. Am J Med 2014;127:829

PE Hospitalization Rate is Increasing: Medicare Cohort While Mortality Decreases, Readmission Rate Remains High Minges KE, et al. Am J Cardiol 2015; 116:1436 Minges KE, et al. Am J Cardiol 2015; 116:1436 Italian PE Registry (IPER) N = 1,787 6.7% in-hospital mortality 32% in-hospital mortality Unstable Italian PE Registry (IPER) Time course of death due to PE vs. other causes 3.4% in-hospital mortality Stable Casazza F, et al. Thromb Res 2012;130:847 Casazza F, et al. Thromb Res 2012;130:847 Risk Factors for PE: Overview Pathophysiology Inherited Lifestyle Acquired Thrombophilias Family history Smoking Stress Diet/Obesity Age Malignancy Recent surgery, trauma, hospitalization, immobility Chronic medical illness Inflammatory Acute and chronic infection Chronic inflammatory diseases

High-Risk Medical Conditions VTE is a Chronic Disease Piazza G, et al. Thromb Haemost 2009;102:505 Søgaard KK, et al. Circulation 2014;130:829 Recurrent VTE is an Important Cause of Death Atherothrombosis: a Paradigm for Understanding VTE? Shared Pro-Inflammatory Risk Factors: Obesity Tobacco use Diabetes Stress Diet Chronic inflammatory disorders Venous Thrombosis Shared Pathophysiology: Hypercoagulability Endothelial Injury Inflammation Atherothrombosis Søgaard KK, et al. Circulation 2014;130:829 Piazza G and Ridker PM. Clin Chem 2015;61:313 NETs Are Prominent in the Organizing Stage of Human Venous Thrombosis Low-Dose Aspirin for Secondary Prevention of VTE Savchenko AS, et al. J Thromb Haemost 2014;12:860 Simes J, et al. Circulation 2014;130:1062

Treating Inflammation: Lessons from JUPITER Will Anti-Inflammatories Be An Option for Extended Prevention of VTE? HR 0.57; 95% CI 0.37-0.86 CANTOS Human monoclonal antibody to interleukin-1β (canakinumab) vs. placebo 10,000 stable patients following MI who have persistent elevation of hscrp Secondary outcome will assess rate of VTE 43% CIRT Low-dose methotrexate vs. placebo in 7000 patients with either stable MI or multivessel CAD and either type 2 DM or the metabolic syndrome Secondary outcome will assess rate of VTE Glynn RJ, et al. N Engl J Med 2009;360:1851 Piazza G. Vasc Med. 2015;20:102 PE Pathophysiology: Role of the RV Piazza G and Goldhaber SZ. Circulation 2010;122:1124 Piazza G, Goldhaber SZ. N Engl J Med 2011;364:351 Risk Stratification Jaff MR, et al. Circulation 2011;123:1788

Spectrum of Disease Massive PE (~5%) Hypotension, syncope, cardiogenic shock, cardiac arrest Respiratory failure Often fatal if aggressive care not instituted RV Enlargement on CT Predicts Increased 30-Day Mortality Submassive PE (~25%) Normotensive Right ventricular (RV) dysfunction is present Increased risk of adverse outcomes PE with normal BP and RV function (~70%) Normotensive Normal RV function Excellent prognosis with anticoagulation alone Goldhaber SZ, et al. Lancet 1999;353:1386 Schoepf UJ, et al. Circulation 2004;110:3276 Increased RV/LV Ratio and PE-Related Mortality Impact of RV Dysfunction on PE Cumulative Mortality 25 20 RV Hypokinesis = 20.9% % 15 10 5 Normal RV Function = 14.8% Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823 0 0 14 30 60 90 Days from Diagnosis Goldhaber et al. Lancet 1999;353:1386 RV Dysfunction and Troponin Elevation 2014 ESC Guidelines: Risk Stratification of Acute PE Stein PD, et al. Am J Cardiol 2010;106:558 Konstantinides SV, et al. Eur Heart J 2014;35:3033

2014 ESC Guidelines: Risk-Based Management Algorithm for PE Anticoagulation Konstantinides SV, et al. Eur Heart J 2014;35:3033 Which Immediate Anticoagulant to Use Efficacy of NOACs for VTE Treatment: Meta-Analysis Unfractionated Heparin Preferred in patients undergoing fibrinolysis, surgical or catheter embolectomy, or IVC filter insertion Injectables or Non- Vitamin K Oral Anticoagulants Preferred in patients who require only anticoagulation Direct Thrombin Inhibitors Used in patients with suspected or confirmed heparin-induced thrombocytopenia (HIT) van der Hulle T, et al. J Thromb Haemost. 2014;12:320 Safety of NOACs for VTE Treatment: Meta-Analysis 1.2 1 0.8 0.88 Relative Risk 0.99 0.76 0.94 0.87 Hokusai-VTE: Edoxaban vs. Warfarin p < 0.001 for noninferiority 0.6 0.6 0.58 0.4 0.2 0 0.41 Major Bleed Clin Rel Non Major 0.39 Nonfatal ICH 0.36 0.16 0.15 Fatal Bleed NOTE: Among 938 patients with PE and RV dysfunction, the rate of recurrent VTE was 3.3% in the edoxaban group and 6.2% in the warfarin group (HR, 0.52; 95% CI, 0.28 to 0.98) p = 0.004 for superiority van der Hulle T, et al. J Thromb Haemost. 2014;12:320 The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406

Anticoagulation Strategy in Evolution Overlapping Switching LMWH/Warfarin Bridge LMWH to Dabigatran (RE-COVER) UFH/Warfarin Bridge LMWH to Edoxaban (HOKUSAI-VTE) Optimal Anticoagulation for Acute VTE: 2016 CHEST Guideline Update In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban or edoxaban over VKA therapy (all Grade 2B). Oral Monotherapy Rivaroxaban (15 mg 2x/d for 3 wks, then 20 mg/d) (EINSTEIN) Apixaban (10 mg 2x/d for 1 wk, then 5 mg 2x/d) (AMPLIFY) Kearon C, et al. CHEST (2016), doi: 10.1016/j.chest.2015.11.026. Specific Reversal Agents Direct inhibitors of coagulation such as NOACs offer an opportunity to develop specific antidotes. Managing Bleeding: NOACs Severe/Life-Threatening Bleeding Company Agent Target Phase Boehringer- Ingelheim Portola Pharmaceuticals, Inc. Perosphere, Inc. Idarucizumab: Fully humanized monoclonal Fab Andexanet alfa: Recombinant, modified human Factor Xa Aripazine: Di-arginine piperazine Dabigatran only Factor Xa Inhibitors (Riva; Apix; Edox; Betrix) LMWH, fondaparinux All NOACs (Dabi; Riva; Apix; Edox) UFH, LMWH, fondaparinux FDA- Approved Akwaa F and Spyropoulos AC. Curr Treat Options Cardiovasc Med 2013;15:288 III II Dabigatran Charcoal (if ingestion <2 hours) Hemodialysis Idarucizamab (2.5 g x 2) Direct Factor Xa Inhibitors 4-factor PCC (50 U/kg) Advanced Therapies Advanced Therapies Fibrinolysis Catheter-Directed Therapy Surgical Embolectomy IVC Filter

The Potential of Fibrinolysis Reverse mortality Prevent RV failure and hemodynamic collapse Fibrinolysis for PE Meta- Analysis: Mortality Reduction 10 p < 0.001 9.2 Reduce RV pressure overload Rapidly resolve obstruction of pulmonary arterial tree Reduce circulating pulmonary vasoconstrictors Prevent recurrent PE Decrease thromboembolic burden in the lower extremities and pelvis Improve gas-exchange Increase pulmonary capillary bloodflow % 8 6 4 2 0 2.2 p = 0.01 3.9 p = 0.003 1.2 All-cause mortality Recurrent PE 3.0 Major bleed 3.4 p = 0.002 0.2 1.5 ICH Anticoagulation Fibrinolysis Chatterjee S, et al. JAMA 2014;311:2414 Fibrinolysis for Submassive PE Meta-Analysis: Mortality Full-Dose Systemic Fibrinolysis for Submassive PE: Efficacy at the Cost of Safety 5 5 4.5 4 p = 0.002 3.5 % 3 2.5 1.6 2 1.5 1 0.5 0 Hemodynamic Collapse p = 0.003 2.0 Hemorrhagic Stroke 0.2 TNK Placebo Chatterjee S, et al. JAMA 2014;311:2414 Meyer G, et al. N Engl J Med 2014;370:1402 Fibrinolysis for PE: Major Bleeding In a series of 104 patients with acute PE treated with fibrinolysis: 20 patients had major bleeding 1 patient had a fatal bleed (intracranial hemorrhage) 1 patient required surgery to stop the bleeding 7 patients had bleeding >3 units 15% Location of Bleed 30% 5% 5% 45% Unknown source Gastrointestinal Retroperitoneal Intracranial Splenic Potential Advantages of Catheter-Directed Fibrinolysis Avoids the high risk of major bleeding associated with systemic fibrinolysis Including intracranial hemorrhage More complete thrombus resolution Catheter-directed fibrinolysis targets the area of highest thrombotic burden More effective for subacute thrombus Pharmacomechanical therapy enhances fibrinolytic surface area by conditioning or fragmenting the thrombus Fiumara K, et al. Am J Cardiol 2006;97:127

ULTIMA: Primary Outcomes ULTIMA: Safety Outcomes Reduction in RV/LV Ratio 0.6 0.5 0.4 0.3 0.2 0.1 0 p < 0.001 p = 0.07 0.3 0.03 0.35 Baseline to 24 hours Baseline to 90 days 0.24 Heparin EKOS + Heparin Clinical outcomes at 3 months EKOS +Heparin Heparin N=30 N=29 p value Death 0 0% 1 3% 1.00 Recurrent VTE 0 0% 0 0% 1.00 Major bleeding 0 0% 0 0% 1.00 Minor bleeding 3 10% 1 3% 0.61 Kucher N, et al. Circulation 2014;129:479 Kucher N, et al. Circulation 2014;129:479 SEATTLE II: Overview Primary Efficacy Outcome: RV/LV Ratio p < 0.0001 1.55 CT-confirmed PE Symptoms 14 days Massive or submassive Meets all inclusion and no exclusion criteria RV enlargement as documented by initial CT RV:LV ratio 0.9 Ultrasoundfacilitated fibrinolysis t-pa 1 mg/hr for 24 hours (1 device) t-pa 1 mg/hr for 12 hours (2 devices) TOTAL t-pa Dose = 24 mg Follow-up at 48 ±6 hours after start of the procedure CT measurement of RV:LV ratio Echocardiogram to estimate PA systolic pressure RV/LV Ratio 1.13 Study Sites = 22 Total Trial Population = 150 Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 RV/LV Ratio: Pre- and Post-Procedure Additional Outcome: Modified Miller Index Pre Post Mean Modified Miller Index 22.5 p < 0.0001 15.8 RV/LV = 2.5 RV/LV = 0.7 Courtesy of Keith M. Sterling, MD Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382

Angiographic Obstruction: Pre- and Post-Procedure Pre Post Secondary Efficacy Outcome: PA Systolic Pressure 51.4 p < 0.0001 p < 0.0001 Mean PA Systolic Pressure (mmhg) 37.5 36.9 Courtesy of Keith M. Sterling, MD Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 SEATTLE II: Clinical Outcomes Clinical outcomes* N = 150 Mean length of stay ± SD, days 8.8 ± 5 In-hospital death, n (%) 3 (2) 30-day mortality**, n (%) 4 (2.7) Serious adverse events due to device, n (%) 3 (2) Serious adverse events due to t-pa, n (%) 2 (1.3) IVC filter placed, n (%) 24 (16) Major bleeding within 30 days**, n (%) GUSTO moderate** GUSTO severe** 15 (10) 14 (9.3) 1 (0.7) Intracranial hemorrhage, n (%) 0 (0) *All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor. **N = 149 (1 patient lost to follow-up) Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 Overcoming the Hurdle of Intracranial Hemorrhage Study ICOPER (Goldhaber SZ, et al. 1999) PEITHO (Meyer G, et al. 2014) SEATTLE II (Piazza G, et al. 2014) Intracranial Hemorrhage (Fibrinolysis Group) 9/304 (3.0%) 10/506 (2.0%) 0/150 (0%) Catheter vs. Systemic Fibrinolysis: Lessons from Nationwide Inpatient Sample 25 20 15 10 5 0 In-Hospital Death (%) p = 0.007 p = 0.003 21.8 22.9 13.4 13.4 In-Hospital Death/ICH (%) p = 0.17 7 7 Median LOS (d) Systemic Catheter Catheter-based fibrinolysis was more costly than systemic ($23,799 vs. $17,218, p<0.001) Patel N, et al. Catheter Cardiovasc Interv. 2015;86:1219 Catheter-Based Fibrinolysis for Acute VTE: 2016 CHEST Guideline Update In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over catheter directed thrombolysis (CDT) (Grade 2C). In patients with acute PE with hypotension and who have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (e.g. within hours), if available, we suggest catheter assisted thrombus removal (with or without local fibrinolysis) over no such intervention (Grade 2C). Kearon C, et al. CHEST (2016), doi: 10.1016/j.chest.2015.11.026.

OPTALYSE PE: Optimizing US-Facilitated Catheter-Directed Fibrinolysis Surgical Embolectomy for Massive and Submassive PE: Survival in 115 Patients RATIONALE: Unanswered Questions from SEATTLE II Can we lower the fibrinolytic dose to improve safety without compromising efficacy? Can we improve efficiency and decrease cost by reducing infusion time? Multi-Center, 150-Submassive PE Patient, Randomized, Controlled Trial % 89.8 93.4 92.6 75 68.4 86.7 65.8 80.4 2 mg/hour/catheter over 2 hours 1 mg/hour/catheter over 4 hours 1 mg/hour/catheter over 6 hours Study End Points Change in CT-determined RV/LV diameter ratio from baseline to 48 hours Change in Miller Index from baseline to 48 hours Treatment success (composite end point) Major bleeding at 72 hours Neely RC, et al. Ann Thorac Surg. 2015;100:1245 Poterucha TJ, et al. Circulation 2015;132:1146 PREPIC2: Anticoagulation ± IVC Filter for High-Risk PE Jaff MR, et al. Circulation 2011;123:1788 Mismetti P, et al. JAMA 2015;313:1627 Interpreting 3 Sets of Guidelines: Who Should Get Advanced Therapy Massive PE AHA ( reasonable ) ACCP ( suggested ) ESC ( recommended ) Acute PE Patient in the Emergency Department, on Inpatient Service, or in Intensive Care PERT Team Activation via Paging System PERT Evaluation by On Call Physician Web Based Video Conference Vascular Medicine Echocardiography Submassive PE AHA (severe RV dysfunction and/or major biomarker elevation) ACCP (clinical gestalt) ESC (RV dysfunction and biomarker elevation [intermediatehigh risk]) Interventional Cardiothoracic Cardiology Discussion and Consensus Surgery Pulmonary Radiology Critical Care Options and Recommendations Presented to the Patient, Family, and Care Team ACTION Dudzinski D and Piazza G. Circulation. 2016;133:98

Pulmonary Embolism Response Team: the MGH Experience 103 Confirmed PE 30 Low Risk (29%) Anticoagulation 26 Catheter-based therapy 2 No anticoagulation 2 Survival 100% 57 Submassive (55%) Anticoagulation 46 Systemic lysis 2 Catheter-based therapy 6 Surgery 1 No anticoagulation 2 Survival 98% 16 Massive (16%) Anticoagulation 8 Systemic lysis 2 Catheter based therapy 2 Surgery 2 No anticoagulation 2 ECMO 4 Survival 50% MGH PERT 2016 In 30 months, there were 394 unique PERT activations. Most PE were submassive (n=143, 46%) or massive (n=80, 26%). PERT treated 11% of PE patients with systemic or catheter-directed thrombolysis but most received anticoagulation alone (69%). Hemorrhagic complications were rare overall, especially among patients treated with catheter-directed thrombolysis. The all-cause 30-day mortality of PERT patients with confirmed PE was 12%. Carroll B, et al. Am J Respir Crit Care Med 189;2014:A1862 Kabrhel C, et al. Chest 2016 Mar 19. [Epub ahead of print] Take Home Points 1. Risk stratification is critical to identify PE patients who may benefit from advanced therapy. 2. Selection of advanced therapies depends on assessment of the patient s risk of adverse outcomes and major bleeding. 3. Multidisciplinary PE response teams have the potential to standardize PE care and improve access to advanced therapies. Discussion Case A 67-year-old man with diabetes and hypertension presents to the Emergency Department with sudden onset dyspnea on exertion and pleuritic pain. On physical examination, he is tachycardic to 110 bpm, normotensive at 116/72 mmhg, and hypoxemic with an O 2 saturation of 88% on room air. His cardiac troponin T is elevated to 0.4 ng/ml. Discussion Case His ECG shows sinus tachycardia. His complete blood count and chemistries are normal, but his cardiac troponin T is elevated to 0.4 ng/ml. He undergoes CT angiography to assess for PE.