When Should I Utilize Aggressive Therapy for PE? Ido Weinberg, MD MSc Assistant Professor of Medicine Harvard Medical School Vascular Medicine Massachusetts General Hospital

Disclosures I have no relevant disclosures for this talk

Zsa Zsa Gabor Suffered a ‘Massive’ Clot that ‘Could Move to Her Heart’ February, 2013

Jerome Kersey of the Portland Trailblazers Recently Died of a Post-Op PE February, 2015

A 49 Year Old Woman with Chest Pain PMHx: None HR – BP – 110/60, 110 bpm, RR – 18 Troponin T – 0.4 (Positive) BNP – 1511 (Positive) Echocardiogram – RV dilatation and dysfunction

A 49 Year Old Woman with Chest Pain

What Now? Anticoagulation Alone or Add a Lytic Agent?

Pulmonary Embolism is not a Homogeneous Disease MASSIVE Shock / Hypotension SUBMASSIVE Normotensive + RV Strain LOW RISK None of the above

PE Therapeutic Options: All Over the Map Anticoagulation IV Thrombolysis IVC Filter Catheter Directed Thrombolysis Surgical Embolectomy Pharmaco-Mechanical Catheter Treatment ECMO

Most Patients with PE do Well The classification relies on outcome However, outcome also relies heavily on patient characteristics Mortality for patients with PE and shock exceeds 30% despite treatment Becattini C, Agnelli G. Predictors of mortality from pulmonary embolism and their influence on clinical management. Thromb Haemost. 2008; 100(5): 747–751 Abrahams van-Doorn P. and Hartmann IJC. Imaging Insights. 2011; 2: 705-715 Dalen JE. Chest. 2002; 122: 1801-17

Identifying Patients who don’t do Well is Limited Clot burden is not a prognostic marker Members ATF et. al. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2008; 29(18) :2276–2315

Thrombolysis in PE: Multiple Positive Physiological Effects Improved early clot resolution Reduced pulmonary arterial pressure Improved lung perfusion Improved early angiographic flow PIOPED Investigators. Chest. 1990; 97: 528-33 Levine M. et al. Chest. 1990; 98(6): 1473-9 Dalla-Volta S. et al. JACC. 1992. 20(3): 520-6 Goldhaber SZ. et al. Lancet. 1993; 341(8844): 517-11 Jaff MR. et al. Circulation. 2011; 123: 1788-1830 Daniels LB. AJC. 1997; 80: 184-8

There is One Obvious Downside…

The Higher the PE-Related Risk, the Easier to Administer Lytics

Thrombolysis Performed Better Than Anticoagulation for Massive PE The only randomized study for massive PE This is an old study that randomized only 8 patients to STK or Heparin 4 patients died – all in the heparin group. P=0.02 Follow-up at 2 years revealed the 4 thrombolysis patients to be alive and without PHTN Jerjez-Sanchez C. et al. J Thromb Thrombolysis. 1995; 2(3): 227-8

Thrombolysis for Unstable Patients Results in Improved Outcome Data from the Nationwide Inpatient Sample between 1999-2008 which represent 20% of all hospitalizations in the US 30% of patients received thrombolysis Case fatality rate attributable to pulmonary embolism in unstable patients was 820 of 9810 (8.4%) with thrombolytic therapy versus 1080 of 2600 (42%) with no thrombolytic therapy (P<0.0001) Stein PD. and Matta F. AJM. 2012; 125: 465-470

Thrombolysis for Unstable Patients Results in Improved PE-related Outcomes Only 16% of unstable patients with PE died during the first day, allowing time for thrombolysis administration Stein PD. and Matta F. AJM. 2012; 125: 465-470

Submassive PE Patients Represent Lower PE-Related Risk

Right Ventricular Dysfunction is Common after Sub-Massive PE This diagram represents RV pressure at the time of diagnosis and after 6 months in patients who were treated with heparin. The RV size and function was normal in most of these patients Kline JA. et al. Chest. 2009. 136: 1202-10

rtPA in Patients with Sub-Massive PE Resulted in Reduced RVSP As total mortality in low-risk PE is less than the complication rate with rtPA, there is no logic in this treatment in this population Why would you use thrombolysis on a submassive PE? Improving mortality is difficult. But preventing RV strain and PHT and CTEPH is a concern. Altogether, there is little information to support this. These are the RVSP results of 21 patients with sub-massive PE who received rtPA. However, the rtPA was given to those patients who developed hypotension or respiratory failure. At 6 months the RSVP decreased There was no difference between groups (rtPA/heparin) in the 6 minute walk distance. 46% of the patients of the heparin treatment who also had an increase in RVSP had dyspnea at rest or exercise intolerance (i.e. about 25% of all patients treated with heparin), compared to 28% in the rtPA group. No patient in either group had a serious bleed Kline JA. et al. Chest. 2009. 136: 1202-10 Konstantinides S. NEJM. 2008; 359(26): 2804-13

Less treatment escalation with lysis Prospective, randomized, double-blind, placebo-controlled trial of tPA+heparin (n=118) vs. placebo+heparin (n=138) for sub-massive PE The definition for sub-massive PE in this study was somewhat broad and included also ECG markers and not only very objective echo or CT markers No biomarker data Unstable patients and patients with increased bleeding risk were excluded Outcomes were measured at discharge or at 30 days of treatment, whichever came first The mortality rate was low in both treatment groups There was no mortality benefit. There was a benefit in the “less escalation of treatment” measure Recurrent PE was low in both groups. Bleeding was also not different between groups. Konstantinides S. et al . NEJM. 2002; 347: 1143-50

PEITHO: Reduced combined endpoint with thrombolysis for some N Engl J Med 2014;370:1402-11

PEITHO: Advantage driven by reduced hemodynamic collapse No mortality advantage Less treatment escalation N Engl J Med 2014;370:1402-11

More bleeding with thrombolysis N Engl J Med 2014;370:1402-11

PEITHO: Older Patient = No Benefit for Lysis N Engl J Med 2014;370:1402-11

TOPCOAT: Systemic Lysis for Sub-massive PE Underpowered Terminated at 86 patients J Thromb Haemost. 2014 Apr;12(4):459-68

TOPCOAT: Shorter ICU Stay with Lytics Courtesy of Jeffrey A. Kline, MD

TOPCOAT: Quicker Discharge with Lytics Courtesy of Jeffrey A. Kline, MD

TOPCOAT: More Bleeding with Lytics Courtesy of Jeffrey A. Kline, MD

TOPCOAT: Benefit for Lytics with Combined Outcomes Courtesy of Jeffrey A. Kline, MD

Contraindications to Lysis are Common MAPPET registry - In a registry of 1001 patients with massive or sub-massive PE in 204 participating centers Kasper W. et al. JACC. 1997; 30(5): 1165-71

Local thrombolysis for sub-massive PE

Would you invest in something that promises 10% profit within 30 days?

ULTIMA Randomized, Controlled Trial Ultrasound-Assisted Catheter-Directed Thrombolysis Acute Intermediate-Risk PE

ULTIMA: Design Randomized, Controlled Ultrasound-Assisted Catheter-Directed Thrombolysis Acute Intermediate-Risk PE Circulation. 2014 Jan 28;129(4):479-86

ULTIMA: Patients had Intermediate-Risk PE No BNP data Circulation. 2014 Jan 28;129(4):479-86

ULTIMA: Outcome Definitions The primary end point of ULTIMA was the difference in the RV/LV ratio from baseline to 24 hours Safety outcomes included death, hemodynamic decompensation as defined in the exclusion criteria, major and minor bleeding, recurrent venous thromboembolism (VTE), and serious adverse events up to 90 days after randomization Circulation. 2014 Jan 28;129(4):479-86

ULTIMA: Outcomes – Cont’d Major bleeding - Overt bleeding associated with a fall in the hemoglobin level of at least 2.0 g/dL or with transfusion of ≥2 U of red blood cells or involvement of a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) Minor bleeding - Clinically overt bleeding not fulfilling the criteria of major bleeding Circulation. 2014 Jan 28;129(4):479-86

Quicker Resolution of RV Dysfunction: Indirect Evidence of Efficacy Circulation. 2014 Jan 28;129(4):479-86

ULTIMA: Complications No major bleeding 4 minor bleeding: 3 patients in the USAT group (10%): Transient hemoptysis, access site groin hematoma 1 patient in the heparin group (3%): Muscular hematoma Circulation. 2014 Jan 28;129(4):479-86

SEATTLE II A prospective, single-arm, multicenter trial to: Evaluate the efficacy of ultrasound-facilitated, catheter-directed low- dose fibrinolysis to reverse RV dysfunction as measured by CT- determined RV/LV diameter ratio in patients with acute massive and submassive PE Assess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients with acute massive and submassive PE

Total Trial Population = 150 Study Overview 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 Ultrasound-facilitated 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 Study Sites = 21 Total Trial Population = 150

Outcomes: RV/LV Ratio Improvement 1.55 RV/LV Ratio 1.13 Used Core/In-Window 3/5/14- clean

Outcomes: PA Systolic Pressure Improvement 51.4 Mean PA Systolic Pressure (mmHg) 37.5 36.9 3/5/14- clean

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 (%) 2 (1.3) Serious adverse events due to t-PA, n (%) IVC filter placed, n (%) 24 (16) Major bleeding within 30 days**, n (%) GUSTO moderate** GUSTO severe** 17 (11.4) 16 (10.7) 1 (0.7) Intracranial hemorrhage, n (%) 0 (0) 3/5/14- clean 1 recurrent PE *All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor. **N = 149 (1 patient lost to follow-up)

What is GUSTO bleed? Severe or life-threatening Moderate Mild Intracerebral hemorrhage Resulting in substantial hemodynamic compromise requiring treatment Moderate Requiring blood transfusion but not resulting in hemodynamic compromise Mild Bleeding that does not meet above criteria Circulation. 2005 Apr 26;111(16):2042-9

So, What do you think of those 10% now?

There is Likely Less ICH with CDT than IV Lytics Study Intracranial Hemorrhage (Fibrinolysis Group) ICOPER (Goldhaber SZ, et al. 1999) 9/304 (3%) PEITHO (Meyer G, et al. 2014) 10/506 (2%) SEATTLE II (Piazza G, et al. 2014) 0/150 (0%) Study limitations include lack of control arm, lack of clinical outcomes, unclear use of CT size (instead of echo derived and the 1.55 RV/LV ratio seems very high), mixture of echo and CT outcomes

Meta-analysis of lysis for PE JAMA. 2014 Jun 18;311(23):2414-21

Mortality Benefit for Lytics in Sub-Massive PE JAMA. 2014 Jun 18;311(23):2414-21

Absolute risk / benefit analysis: Know the #’s JAMA. 2014 Jun 18;311(23):2414-21

PE Treatment Guidelines 1 2 3 Jaff MR. et al. Circulation. 2011; 123: 1788-1830

ED / ICU / Floor Team Pulmonary Vascular Medicine/Cardiology Usual PE Care vs. PERT ED / ICU / Floor Team Pulmonary Vascular Medicine/Cardiology Cardiac Surgery

PERT Members – Collaborative Approach Vascular Medicine and Intervention Pulmonary/ Critical Care Cardiac Surgery Cardiac and Thoracic Imaging Nursing Quality & Safety Research Echocardiography Cardiology Hematology/ Oncology Emergency Medicine

Conclusions Thrombolysis should be administered emergently to patients with massive PE Patient choice is crucial when considering IV tPA for sub-massive PE Many patients with PE cannot receive thrombolytic therapy