Severe pulmonary embolism: Catheter-based thrombolysis and medical treatment

Severe pulmonary embolism: Catheter-based thrombolysis and medical treatment Rolf P. Engelberger, MD Division of Angiology Cantonal Hospital Fribourg & University Hospital Bern, Switzerland

Overview Reperfusion treatment - Systemic thrombolysis - PETHO Trial - TOPCOAT Trial - Catheter-based therapy - ULTMA - PERFECT - SEATTLE - Surgical thrombectomy Perspectives Conclusion

Reperfusion therapy Konstantinides et al, JACC 2016

Haemodynamic collapse in acute PE Reperfusion Therapy Konstantinides et al, 2014 ESC Guidelines, EHJ 2014

Reperfusion therapy for acute PE Aim: Early resolution of pulmonary obstruction, decrease thrombus burden Reduction of pulmonary artery pressure and resistance mprovement of RV function Konstantinides et al, 2014 ESC Guidelines, EHJ 2014

Overall mortali COPER: PE Mortality 100 N = 2392 80 60 Massive PE BPsys <90 40 20 Non-massive PE BPsys >90 0 0 30 60 90 Days Kucher et al. Circulation 2006

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Courtesy of Prof S. Konstantinides

Kline Multicenter, double blinded RCT Subjects: 83 pts with intermediate-risk PE (RV strain by Echo or biomarkers) ntervention: - Weight adapted single bolus of tenecteplase + LMWH (n=40) - Placebo + LMWH (n= 43) Patient-oriented outcomes Kline et al J Thromb Haemost 2014

Kline Primary outcomes: a) Early (first 5 days): Composite of death, shock, intubation or major hemorrhage within 5 d - Placebo: 3 pts (1x death, 2x intubation) - Tenecteplase: 1 pts (fatal intracranial hemorrhage) b) Mid-term (at 90 day follow-up): Composite of recurrent PE, poor functional capacity (RV dysfunction with dyspnoe/exercise intolerance), or SF36 physical component summary score <30 - Placebo: 13 pts (30%) - Tenecteplase: 5 pts (13%) Overall, 16 (37%) pts treated with placebo and 6 (15%) treated with tenecteplase had an adverse outcome (p<0.02) Kline et al J Thromb Haemost 2014

With 15 trials involving 2057 patients Marti et al, EHJ 2015

Efficacy outcomes: Bleeding complications: Marti et al, EHJ 2015

Kearon et al, Chest 2016

Stein et al, Am J Med 2012

Approved thrombolytic regimens Konstantinides et al, 2014 ESC Guidelines, EHJ 2014

Contraindications for thrombolytic therapy Konstantinides et al, 2014 ESC Guidelines, EHJ 2014

ntraclot versus Systemic Thrombolysis for PE Blood Flow Pattern in Occlusive Pulmonary Embolism n-vitro pulmonary artery glas modell (5 l/min) simulating blood flow using illuminated suspended microspheres: High-velocity vortex formation proximal to the leading edge of the occlusion n-vivo tests (6 dogs) confirmed flow reversal proximal to the embolic occlusion and rapid wash out (0.40-0.64 s) into non-occluded arteries even if the injection was performed directly proximal to the occlusion Schmitz-Rode T, et al. Cardiovasc ntervent Radiol 1998; 21:199-204

Catheter-based therapy for acute PE

Catheter intervention without local thrombolysis Adapted from Engelberger/Kucher, Circulation 2011

Catheter intervention with local thrombolysis Adapted from Engelberger/Kucher, Circulation 2011

Complications Vascular access complications Right ventricular failure from distal embolization or contrast injections Bleeding from anticoagulation or thrombolysis Hemolysis, hemoglobinuria Arrhythmia Contrast-induced anaphylaxis and contrastinduced nephropathy Pulmonary hemorrhage/ hemoptysis

ULTrasound Accelerated Thrombolyss of PulMonAry Embolism Kucher et al, Circulation 2014

Ultrasound accelerated thrombolysis Ultrasound pulses Mechanism of Action Fibrin separation Active drug delivery by acoustic streaming Ultrasound delivered in: High frequency (2.2 Mhz) Low power (0.5 W per element) Pulses of varying waveforms Fibrin without Ultrasound Fibrin With Ultrasound Braaten et al. Thromb Haemost 1997; 78:1063-8.

Ultrasound accelerated thrombolysis EKOS EkoSonic Mach 4e Endovascular System 5.4 F Drug Delivery Catheter Ultrasound Core wire nfusion side-hole catheter with a multi-element ultrasound core 12 cm nominal treatment zone length typically used for PE therapy

nclusion criteria Acute symptomatic PE confirmed by contrast-enhanced chest CT with embolus located in at least one main or proximal lower lobe pulmonary artery RV/LV ratio > 1 on echocardiography

Hemodynamically stable patients with acute symptomatic PE UFH 80 U/kg Bolus V, UFH continuous infusion of 18 U/kg/min V (max 1800 U/h) Contrast-Enhanced Chest CT: Filling defect in at least one main or proximal lower lobe pulmonary artery Baseline ECHO: RV/LV ratio > 1 4 hours UFH V alone (N=25 with evaluable RV/LV ratio on echocardiograms at baseline and 24 hours) UFH V + EkoSonic procedure: Ultrasound-assisted tpa of 10 mg over 15 hours per catheter (Maximum total dose 20 ± 1 mg over 15 ± 1 hours) (N=25 with evaluable RV/LV ratio on echocardiograms at baseline and 24 hours) Primary endpoint assessed by blinded core-lab: Reduction in RV/LV ratio from baseline to 24h Secondary endpoints: Mortality, recurrent PE, major & minor bleeding at 90 days

RV/LV Ratio 1,5 Primary endpoint: RV/LV ratio P<0.0001 P<0.0001 P<0.0001 P=0.31 1,28 1,20 1,17 1,0 0,99 0,95 0,98 0,5 Baseline 24 hrs 90 days Baseline 24 hrs 90 days EKOS+Heparin Heparin

Reduction in RV/LV Ratio Primary endpoint: RV/LV ratio 0,6 P<0.0001 P=0.03 0,4 0,2 0,0 0,30 Baseline to 24 hrs 0,38 Baseline to 90 days EKOS+Heparin 0,03 Baseline to 24 hrs Heparin 0,22 Baseline to 90 days

Secondary endpoint analysis Clinical outcomes at 90 days EKOS + Heparin Heparin N = 30 N = 29 p-value Death 0 0% 1* 3% 0.49 Recurrent venous thromboembolism 0 0% 0 0% 1.00 Major bleeding 0 0% 0 0% 1.00 Minor bleeding 3** 10% 1 3% 0.61 * rehospitalization and death from advanced pancreatic cancer ** two patients with transient mild hemoptysis without medical intervention, one patient with groin hematoma requiring manual compression one patient with transient anal bleeding following endoscopic removal ofcolon polyp

Conclusions n intermediate-risk PE, low-dose (up to 20 mg rt-pa over 15 hours) USAT was superior to anticoagulation with heparin alone in reversing RV dilatation and dysfunction at 24 hours, without an increase in bleeding complications Although there was a late catch up with heparin alone, we found greater improvement in RV dilatation and RV dysfunction after low-dose USAT at 90 days Kucher et al, Circulation 2014

Engelberger et al, EHJ 2015

Clinical presentation ntermediaterisk PE (n=38) High-risk PE (n=14) Transient hypotension* without vasopressors Transient hypotension with vasopressors Prolonged hypotension despite vasopressors Active cardiopulmonary resuscitation - 36 % - 29 % - 14 % - 21 % * Defined as systolic blood pressure < 90mmHg for at least 15 minutes 1 1 Jaff MR, et al. Circulation. 2011

Clinical course during procedure ntermediaterisk PE (n=38) High-risk PE (n=14) Symptom improvement 94 % 72 % Stabilisation of hemodynamics* 94 % 93 % Resolution of hypoxemia** 83 % 36 % * Hypotension resolved, vasopressor dose reduced or discontinued, cardiogenic shock resolved, signs of RV failure improved) within 24h of the end of the procedure ** Oxygen saturation of >92% on room air within 24 h of the end of the procedure

Complications ntermediaterisk PE (n=38) High-risk PE (n=14) Bleeding 1 Minor 16 % 35 % Major 3 % 7 % 3-month mortality 0 % 14 % Overall 3.8 % (95% C 0.5-13%) nternational society on thrombosis and haemostasis: Major bleeding : 1) Fatal bleeding, and/or 2) Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, 3) and/or Bleeding causing a fall in hemoglobin level of 20 g/l, or leading to transfusion of two or more units of whole blood or red cells. 1 Schulman S, Kearon C. J Thromb Haemost. 2005

[mmhg] Mean pulmonary artery pressure 60 mean pulmonary artery pressure 50 40 30 20 10 0 before after Jaff et al, Circulation 2011

[L/min/m 2 ] Cardiac index 6 cardiac index 5 4 3 2 1 0 before after

Echocardiographic RV/LV-Ratio 2,5 Echocardiographic RV/LV-Ratio 2 1,5 1 0,5 0 before TPES trial: weight-adjusted iv tenecteplase vs heparin in patients with intermediate-risk PE patients after Becattini et al, Thromb Res 2010

Piazza et al, JACC CV interv 2015

SEATTLE Single-arm, multicenter trial for low-dose USAT including 150 pts 31 with massive and 119 with submassive PE nclusion criteria: - Proximal PT with RV/LV ratio 0.9 on CT, with Sx for < 14d Treatment regimen: - 24 mg tpa (1mg/h for 24h with unilateral catheter, or 1mg/h/catheter for 12h with bilateral catheter) Primary outcomes: - Efficacy outcome: change in RV/LV ratio at 48h - Safety outcome: major periprocedural (<72h) bleeding Piazza et al, JACC CV interv 2015

SEATTLE Piazza et al, JACC CV interv 2015

Kuo et al, Chest 2015

PERFECT Registry Prospective multicenter registry including 101 pts: 28 massive and 73 submassive PE Catheter-directed therapy - Submassive PE: CDT (64%) or USAT (36%) with 0.5-1mg/h tpa (or 100000 U/h urokinase) - Massive PE: immediate catheter-directed mechanical or pharmacomechanical thrombectomy using catheter-directed fragmentation of PE, +/- intraclot lytic injection and aspiration. Following mechanical clot debulking, a potential low-dose hourly drug infusion - Outcomes - Clinical success - was defined as meeting all the following criteria: stabilization of hemodynamics; improvement in pulmonary hypertension, right-sided heart strain, or both; and survival to hospital discharge. - Primary safety outcomes - were major procedure-related complications and major bleeding events Kuo et al, Chest 2015

PERFECT Registry Outcomes Clinical success was achieved in 24 of 28 (86%) pts with massive PE 71 of 73 (97%) pts with submassive PE Complications 6 deaths 4 in massive PE (14%) 2 in submassive PE (3%) No major procedure-related complications, major hemorrhages, or hemorrhagic strokes. Kuo et al, Chest 2015

PERFECT: CDT versus USAT Kuo et al, Chest 2015

Summary Catheter-based therapy Kuo et al, Chest 2015

Comparison systemic thrombolysis vs CDT - No randomized trials - USA: National npatient Sample database 2010-2012 - 1 521 out of 110 731 pts hospitalized for PE treated with «thrombolysis» - Systemic thrombolysis in 1169 pts - CDT in 352 pts - Outcomes - Primary: in-hospital mortality - Secondary: combined in-hospital mortality and CH - Propensity-matched comparison (1:3) Patel et al, Catheter Cardiovasc nterv 2015

Comparison systemic thrombolysis vs CDT Patel et al, Catheter Cardiovasc nterv 2015

Long-term benefit of early hemodynamic improvement? RCT systemic thrombolysis (100mg alteplase over 2 hours) vs heparine alone in submassive PE patients 1 After 6 months: persistent improvement of echocardiographic parameters of RV function RCT systemic thrombolysis (urokinase or streptokinase) vs heparine alone 2 After mean FU of 7.4 years, assessed with right heart catheter: At rest, mean PAP and PVR significantly higher in the heparin group compared with the thrombolytic group (22 vs. 17 mmhg, p<0.05, and 351 vs. 171 dynes s(-1) cm(-5), p<0.02, respectively) During exercise both parameters rose to a significantly higher level in the heparin group 1 Fasullo et al, Am J Med Sci 2011 2 Sharma et al, Vasc Med 2000

Perspectives for catheter-based reperfusion therapy Optimal duration/drug dose for USAT (CDT)? Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism (OPTALYSE PE) RCT comparing 2h (4/8mg rtpa), 4h (4/8mg), 6h (6/12 vs 12/24mg) No randomized data USAT vs other catheterbased reperfusion therapies No long-term data Catheter-based treatment instead of systemic thrombolysis? www.clinicaltrials.gov NCT02396758

The SPECAL Trial Surgical Pulmonary Embolectomy versus Catheterdirected thrombolysis n the treatment of pulmonary embolism: a monocentric randomized phase non-inferiority study Primary objective: Non-inferiority of catheter-directed thrombolysis to surgical pulmonary embolectomy regarding efficacy in reversal of RV dilatation in high- and intermediate-high risk patients with acute PE Principal nvestigators: Profs Nils Kucher & Lars Englberger, nselspital

NOAC and reperfusion therapy? NOAC Trials patients with RECOVER: - pulmonary embolism with hemodynamic instability or requiring thrombolytic therapy AMPLFY & ENSTEN PE & HOKUSA - Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of venous thromboembolism (VTE). were excluded Schulman et al, NEJM 2009; Buller et al, NEJM 2012; Agnelli et al, NEJM 2013; Buller NEJM 2013

Reperfusion therapy for acute PE

ESC 2014 High-risk PE

ESC 2014 ntermediate- or low-risk PE

ACCP 2016: PE with hypotension

ACCP 2016: PE with hypotension

ACCP 2016: PE without hypotension

ACCP 2016: Systemic thrombolysis vs CDT?

Conclusion Reperfusion therapies have an important place in the managment of selected PE patients Systemic thrombolysis with more randomized trials, remain preferred reperfusion therapy according to the latest guidelines Catheter-based therapies have several advantages over systemic thrombolysis Role of catheter-based therapies needs to be better defined

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