Disclosures. Objectives

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1 BRIGHAM AND WOMEN S HOSPITAL Treatment of Massive and Submassive Pulmonary Embolism Gregory Piazza, MD, MS Assistant Professor of Medicine Harvard Medical School Staff Physician, Cardiovascular Division Brigham and Women s Hospital April 6, 2017 HARVARD MEDICAL SCHOOL TEACHING AFFILIATE Disclosures BMS- grant/research support Daichii-Sankyo- grant/research support BTG- grant/research support Janssen- grant/research support exithera- advisory board Objectives 1. Discuss the risk stratification of pulmonary embolism (PE) 2. Highlight algorithms for optimal anticoagulation for PE 3. Apply evidence-based strategies to effectively manage massive and submassive PE 1

2 Spectrum of Disease Massive PE (~5%) Hypotension, syncope, cardiogenic shock, cardiac arrest Respiratory failure Often fatal if aggressive care not instituted Increased RV/LV Ratio and PE-Related Mortality Catastrophic PE (<1%) Super-massive PE Refractory cardiogenic shock Ongoing CPR 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 Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823 RV Dysfunction and Troponin Elevation Stein PD, et al. Am J Cardiol 2010;106:558 2

3 2014 ESC Guidelines: Risk Stratification of Acute PE 2014 ESC Guidelines: Risk-Based Management Algorithm for PE Konstantinides SV, et al. Eur Heart J 2014;35:3033 Konstantinides SV, et al. Eur Heart J 2014;35:3033 Which Immediate Anticoagulant to Use Anticoagulation Unfractionated Heparin Injectables or Non- Vitamin K Oral Anticoagulants Preferred in patients undergoing fibrinolysis, surgical or catheter embolectomy, or IVC filter insertion Preferred in patients who require only anticoagulation Direct Thrombin Inhibitors Used in patients with suspected or confirmed heparin-induced thrombocytopenia (HIT) 3

4 Efficacy of NOACs for VTE Treatment: Meta-Analysis Safety of NOACs for VTE Treatment: Meta-Analysis Relative Risk van der Hulle T, et al. J Thromb Haemost. 2014;12:320 0 Major Bleed Clin Rel Non Major Nonfatal ICH Fatal Bleed van der Hulle T, et al. J Thromb Haemost. 2014;12:320 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). Advanced Therapies Kearon C, et al. CHEST 2016 ;149:315 4

5 Advanced Therapies Fibrinolysis Catheter-Directed Therapy Surgical Embolectomy IVC Filter The Potential of Fibrinolysis Reverse mortality Prevent RV failure and hemodynamic collapse 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 Fibrinolysis for PE Meta- Analysis: Mortality Reduction Fibrinolysis for Submassive PE Meta-Analysis: Mortality 10 p < % p = p = p = Anticoagulation All-cause mortality Recurrent PE Major bleed ICH Fibrinolysis Chatterjee S, et al. JAMA 2014;311:2414 Chatterjee S, et al. JAMA 2014;311:2414 5

6 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 Catheter Techniques: Pharmacomechanical Therapy Mechanical Fragmentation Hydrodynamic (AngioJet ) Location of Bleed 5% 5% 15% 45% 30% Unknown source Gastrointestinal Retroperitoneal Intracranial Splenic Ultrasound-Accelerated Fibrinolysis (EKOS ) Large Clot Retrieval Devices (AngioVac ) Fiumara K, et al. Am J Cardiol 2006;97:127 6

7 ULTIMA: Primary Outcomes Reduction in RV/LV Ratio p < p = Baseline to 24 hours Baseline to 90 days 0.24 Heparin EKOS + Heparin Kucher N, et al. Circulation 2014;129:479 ULTIMA: Safety Outcomes SEATTLE II: Overview 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 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 Study Sites = 22 Total Trial Population = 150 Follow-up at 48 ±6 hours after start of the procedure CT measurement of RV:LV ratio Echocardiogram to estimate PA systolic pressure 7

8 Primary Efficacy Outcome: RV/LV Ratio RV/LV Ratio: Pre- and Post-Procedure p < Pre Post RV/LV Ratio Pre-Procedure 48 Hours Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 RV/LV = 2.5 RV/LV = 0.7 Courtesy of Keith M. Sterling, MD Mean Modified Miller Index Additional Outcome: Modified Miller Index Pre-Procedure 22.5 p < Hours 15.8 Angiographic Obstruction: Pre- and Post-Procedure Pre Post Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 Courtesy of Keith M. Sterling, MD 8

9 Overcoming the Hurdle of Intracranial Hemorrhage Predictors of Major Bleeding in SEATTLE II 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%) Sadiq I, et al. Vasc Med. 2017;22:44 Large Responder Poor Responder PRE BV10/ TBV: 5.3 RV Size: -37ml POST PRE BV10/ TBV: RV Size: +43ml POST -- Pre -- Post RV -- Pre -- Post RV RV RV 9

10 OPTALYSE PE: Optimizing US-Facilitated Catheter-Directed Fibrinolysis 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 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 PREPIC2: Anticoagulation ± IVC Filter for High-Risk PE Jaff MR, et al. Circulation 2011;123:1788 Mismetti P, et al. JAMA 2015;313:

11 Interpreting 3 Sets of Guidelines: Who Should Get Advanced Therapy Massive PE AHA ( reasonable ) ACCP ( suggested ) ESC ( recommended ) Role of Multidisciplinary PE Response Teams Submassive PE AHA (severe RV dysfunction and/or major biomarker elevation) ACCP (clinical gestalt) ESC (RV dysfunction and biomarker elevation [intermediatehigh risk]) CV Medicine Pulmonary Medicine Radiology Cardiothoracic and Vascular Surgery Other Acute PE Patient in the Emergency Department, on Inpatient Service, or in Intensive Care Vascular Medicine Interventional Cardiology Pulmonary Critical Care PERT Team Activation via Paging System PERT Evaluation by On-Call Physician Web-Based Video Conference Discussion and Consensus Echocardiography Cardiothoracic Surgery Radiology Options and Recommendations Presented to the Patient, Family, and Care Team ACTION Dudzinski D and Piazza G. Circulation. 2016;133:98 Take Home Points 1. Risk stratification is critical to identify PE patients who benefit from advanced therapy. 2. Selection of advanced therapies and anticoagulation strategies 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. 11