12:50-1:50pm Risk-Based Evaluation and Management of VTE SPEAKER Gregory Piazza, MD, MS BRIGHAM AND WOMEN S HOSPITAL Risk-Based Evaluation and Management of VTE Gregory Piazza, MD, MS Assistant Professor of Medicine Harvard Medical School Staff Physician, Cardiovascular Division Brigham and Women s Hospital December 9, 2018 HARVARD MEDICAL SCHOOL TEACHING AFFILIATE Disclosures Italian PE Registry (IPER) BMS- grant/research support Daichii-Sankyo- grant/research support BTG- grant/research support Janssen- grant/research support Bayer- grant/research support Portola- grant/research support N = 1,787 6.7% in-hospital mortality 32% in-hospital mortality Unstable 3.4% in-hospital mortality Stable Casazza F, et al. Thromb Res 2012;130:847
Time is of the Essence: IPER Pathophysiology of Risk: Role of the RV Time course of death due to PE vs. other causes The risk of death from PE is measured in hours Casazza F, et al. Thromb Res 2012;130:847 Piazza G and Goldhaber SZ. Circulation 2010;122:1124 VTE Has Chronic Complications Post-PE Syndrome Spectrum: ELOPE Cohort Study Chronic Thromboembolic Pulmonary Hypertension (~4% of PE patients) Post-Thrombotic Syndrome (25-50% of treated DVT patients) Klok FA, et al. Blood Reviews 2014; 28: 221
Clinical Decision Rule for Assessing Risk of PE Evaluation and Risk Stratification Variable Points Clinical symptoms and signs of deep vein thrombosis (DVT) 3.0 Alternative diagnosis less likely than PE 3.0 Heart rate greater than 100 beats per minute 1.5 Recent immobilization or surgery 1.5 Previous venous thromboembolism 1.5 Hemoptysis 1.0 Malignancy receiving treatment or palliative care within the last 6 months 1.0 PE unlikely 4 points. PE likely >4 points. van Belle A, et al. JAMA 2006;295:172-9 Diagnostic Algorithm for PE Case No. 1 A 58-year-old man with hypertension presents with sudden onset dyspnea and pleuritic pain. 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. He undergoes CT angiography to assess for PE.
Spectrum of Disease Spectrum of Outcomes Massive PE (~5%) Hypotension, syncope, cardiogenic shock, cardiac arrest Respiratory failure Often fatal if aggressive care not instituted 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 Wood KE. CHEST 2002;121;877 Ammari Z, et al. Circulation. 2017;136:A14728 RV Enlargement on CT Predicts 30- Day Mortality Increased RV/LV Ratio and PE- Related Mortality Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823
https://www.youtube.com/watch?v=eoscba7kfck Impact of RV Dysfunction on PE Cumulative Mortality 25 20 RV Hypokinesis = 20.9% RV Dysfunction and Troponin Elevation % 15 10 5 Normal RV Function = 14.8% 0 0 14 30 60 90 Days from Diagnosis Goldhaber et al. Lancet 1999;353:1386 Stein PD, et al. Am J Cardiol 2010;106:558
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 Clinical Decision Rule for Assessing Risk of DVT Variable Active cancer 1 Paralysis 1 Recently bedridden for >3 days or major surgery within 4 weeks 1 Localized tenderness along the distribution of the deep venous system 1 Entire leg swelling 1 Calf swelling >3 cm when compared with the asymptomatic leg 1 Pitting edema 1 Collateral superficial veins (non-varicose) 1 Alternative diagnosis as likely or more likely than that of DVT -2 High Probability 3 points Points Diagnostic Algorithm for DVT Low clinical probability AND outpatient D-dimer level Normal Suspected deep vein thrombosis History and physical examination Assessment of clinical probability Increased Inpatient OR outpatient with intermediate/high clinical probability Venous ultrasound Moderate Probability 1-2 points Low Probability 0 points Wells PS, et al. JAMA 2006;295:199-207 Stop evaluation If ultrasound is negative and suspicion remains high, consider MR, CT, or contrast venography
Ultrasound for DVT Diagnosis Risk Stratification for Acute DVT Acute DVT Iliofemoral DVT Non iliofemoral DVT Consider catheterassisted fibrinolysis Pharmacomechanical Therapy Therapeutic anticoagulation and compression stockings Advanced Therapies Risk-Based Acute Management Fibrinolysis Catheter-Directed Therapy Surgical Embolectomy Mechanical Circulatory Support IVC Filter
Fibrinolysis for PE Meta-Analysis: Mortality Reduction Fibrinolysis for PE: Major Bleeding % p = 0.01 3.9 p = 0.003 3.0 p < 0.001 9.2 3.4 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 2.2 1.2 p = 0.002 1.5 0.2 Chatterjee S, et al. JAMA 2014;311:2414 Fiumara K, et al. Am J Cardiol 2006;97:127 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
ULTIMA: Primary Outcomes SEATTLE II: Overview Reduction in RV/LV Ratio p < 0.001 p = 0.07 0.35 0.3 0.24 0.03 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 Kucher N, et al. Circulation 2014;129:479 Study Sites = 22 Total Trial Population = 150 Primary Efficacy Outcome: RV/LV Ratio RV/LV Ratio: Pre- and Post- Procedure p < 0.0001 Pre Post 1.55 RV/LV Ratio 1.13 Piazza G, et al. JACC Cardiovasc Interv. 2015;8:1382 RV/LV = 2.5 RV/LV = 0.7 Courtesy of Keith M. Sterling, MD
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. 2015) Intracranial Hemorrhage (Fibrinolysis Group) 9/304 (3.0%) 10/506 (2.0%) 0/150 (0%) OPTALYSE-PE: Primary Efficacy End Point Surgical Embolectomy % -0.35-0.4-0.42-0.48 *p<0.05 for all Tapson VF et al. Presented at American Thoracic Society 2017. Am J Respir Crit Care Med. 2017;195:A2835 Surgical embolectomy requires a median sternotomy and cardiopulmonary bypass. Leacche M, et al. J Thorac Cardiovasc Surg 2005;129:1018 https://www.youtube.com/watch?v=szsqwimybn8
Jaff MR, et al. Circulation 2011;123:1788 PREPIC2: Anticoagulation ± IVC Filter for High-Risk PE Interpreting 3 Sets of Guidelines: Who Should Get Advanced Therapy Massive PE AHA ( reasonable ) ACCP ( suggested ) ESC ( recommended ) Submassive PE AHA (severe RV dysfunction and/or major biomarker elevation) ACCP (clinical gestalt) ESC (RV dysfunction and biomarker elevation [intermediatehigh risk]) Mismetti P, et al. JAMA 2015;313:1627
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 Testing the Open Vein Hypothesis Does immediate thrombus removal expedite relief of DVT symptoms, preserve venous valve function, and prevent PTS? ACTION Dudzinski D and Piazza G. Circulation. 2016;133:98 CAVENT Trial: Catheter-Directed Fibrinolysis for Iliofemoral DVT p = 0.047 p = 0.012 65.9 ATTRACT Trial: Pharmacomechanical Therapy for Iliofemoral and Femoral DVT Acute Symptomatic Iliofemoral or Femoral DVT Target N = 692 patients % 41.1 55.6 47.4 p = 0.07 3 0 Randomization (1:1) Standard Therapy Pharmacomechanical Therapy Long-Term Therapy Anticoagulation Compression Stockings End Points Rate of PTS QOL Safety Cost-Effectiveness Enden T, et al. Lancet 2012;379:31 http://www.attract.wustl.edu/dvt-study-overview Vedantham S. Am Heart J. 2013 Apr; 165(4): 523 530.e3.
ATTRACT: Safety Outcomes ATTRACT: Efficacy Outcomes Outcome Pharmacomechanical N=336 No- Pharmacomechanical N=355 p-value Major bleeding 1.7% 0.3% 0.049 (10 days) Any bleeding 4.5% 1.7% 0.034 (10 days) Fatal bleeding 0 0 - Intracranial hemorrhage 0 0 - Vedantham S. SIR meeting March 6, 2017 Outcome (24 months) Pharmacomechanical N=336 No- Pharmacomechanical N=355 p-value Any PTS 46.7% 48.2% 0.56 Recurrent VTE 12.5% 8.5% 0.09 SF-36 (Overall 11.8 10.1 0.37 QOL) VEINES (Venous QOL) 27.7 23.5 0.08 Moderate or Severe PTS Overall 17.9% Iliofemoral 18.4% Femoral-popliteal 17.1% Overall 23.7% Iliofemoral 28.2% Femoral-popliteal 18.1% 0.035 Vedantham S. SIR meeting March 6, 2017 2016 ACCP CHEST Guidelines In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over catheter-directed thrombolysis (Grade 2C). Anticoagulation Across a Continuum of Risk Kearon C, et al. CHEST 2016 ;149:315
Case No. 2 Phases of Treatment A 62-year-old woman with obesity and osteoarthritis presents with right leg edema and pain 3 weeks after left total knee replacement. She admits to being sedentary postoperatively. She was prescribed warfarin for thromboprophylaxis but stopped taking it after 2 weeks. Venous ultrasound demonstrates right femoral DVT. Anticoagulation Strategy in Evolution Efficacy of NOACs for VTE Treatment: Meta-Analysis Overlapping LMWH/Warfarin Bridge UFH/Warfarin Bridge Switching LMWH to Dabigatran (RE-COVER) LMWH to Edoxaban (HOKUSAI-VTE) 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) van der Hulle T, et al. J Thromb Haemost. 2014;12:320
Safety of NOACs for VTE Treatment: Meta-Analysis Relative Risk 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). van der Hulle T, et al. J Thromb Haemost. 2014;12:320 Kearon C, et al. CHEST 2016 ;149:315 VTE is a Chronic Disease Recurrent VTE is an Important Cause of Death Søgaard KK, et al. Circulation 2014;130:829 Søgaard KK, et al. Circulation 2014;130:829
Common VTE Risk Factors are Chronic and Non-Modifiable Mortality is Actually Higher after Provoked VTE Obesity Comorbid medical disease COPD/HF Inflammatory disorders (IBD, RA, lupus) Atherosclerotic cardiovascular disease Thrombophilia Acquired (antiphospholipid antibodies) Inherited (anticoagulant protein deficiencies) 12 4 6 17 Smoking Family history Alotaibi GS, et al. Am J Med. 2016;129:879 Enduring Risk of VTE: Lessons from Observational Studies and RCTs > 50% Effective Prevention of Recurrent Unprovoked VTE Study Intervention Recurrent VTE** PREVENT Warfarin, INR 1.5-2 vs. placebo 64% ELATE Warfarin, INR 2-3 vs. INR 1.5-2 63% 92% EINSTEIN-DVT Rivaroxaban vs. placebo 82% AMPLIFY-EXT Apixaban vs. placebo 81% RE-SONATE Dabigatran vs. placebo 93% Prandoni P, et al. Haematologica 2007;92:199 Schulman S, et al. N Engl J Med 2013;368:709 RE-MEDY Dabigatran vs. warfarin, INR 2-3 Non-inferior **Regardless of thrombophilia status
Extended Secondary Prevention for All VTE: EINSTEIN CHOICE Selecting the Optimal Agent for Extended Therapy Increased Risk of Recurrent VTE after Standard Therapy No Cancer Cancer Non-High Bleeding Risk and Willing to Continue Anticoagulation High Bleeding Risk OR Not Willing to Continue Anticoagulation LMWH Monotherapy?DOAC Weitz JI, et al. N Engl J Med 2017;376:1211 DOAC OR Low- or Conventional- Intensity Warfarin Low-Dose Aspirin OR Low-Dose Apixaban or Rivaroxaban Take Home Points 1. Risk stratification is a critical step in VTE evaluation to identify PE and DVT 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. Determining the optimal anticoagulation regimen should consider risk of recurrence, risk of bleeding, and patient preference.