Clinical Trial Update

Very Low Dose and Shorter Duration Catheter-Directed Thrombolytic Therapy Proves to be Safe and Effective for Pulmonary Embolism

Victor F. Tapson, MD, Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Principal Investigator, OPTALYSE PE 

Results from a new study have moved the interventional pulmonary embolism field even further ahead by demonstrating significant improvement in right-heart strain with lower doses of tPA, making ultrasound-accelerated thrombolysis even safer.

Victor F. Tapson, MD, Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Principal Investigator, OPTALYSE PE 

Results from a new study have moved the interventional pulmonary embolism field even further ahead by demonstrating significant improvement in right-heart strain with lower doses of tPA, making ultrasound-accelerated thrombolysis even safer.

For the last 20 years, I have championed the cautious use of systemic thrombolytic therapy in massive pulmonary embolism (PE) as well as low-dose thrombolytic therapy in certain patients with acute intermediate-risk (submassive) and occasional high-risk (massive) PE. In the past, for patients with high-risk or “severe” intermediate-risk PE at high risk of bleeding from systemic thrombolysis — say a patient with a gastrointestinal (GI) bleed the previous week or a patient who had undergone recent surgery — catheter-directed thrombolysis with low doses of tissue-type plasminogen activator (tPA) was often the only treatment option more aggressive than anticoagulation. For some intermediate-risk patients, surgical embolectomy is also an option, but it’s not commonly performed at many centers.  
 
A significant proportion of patients with PE who are otherwise candidates for thrombolysis have some contraindications to systemic thrombolysis, such as recent surgery, trauma, or recent bleeding.   
 
In the past, we carefully selected patients for this therapy based on right ventricular (RV) appearance on echocardiography and/or computed tomography (CT) clot burden, heart rate, blood pressure, and oxygenation. We also looked at troponin and brain natriuretic peptide (BNP) levels. 
 
We still consider these clinical parameters, but we have been trying to improve our ability to risk-stratify patients with PE. The European guidelines1 have helped, but intermediate-risk PE patients are a heterogeneous group. In general, the more severe the RV abnormality, the more likely it is that the patient would benefit from thrombolysis. However, patients with very extensive clot burdens without significant RV compromise may also be good candidates for thrombolysis.
 
For these patients, we found that administering doses of tPA in the range of 10 mg (or urokinase at low doses) over 10 minutes or so would sometimes work. Ten minutes might have been a bit extreme, but we were often trying to treat very ill patients. We didn’t simply drip the tPA in. Instead, we’d push it through a syringe, with the infusion catheter jammed into the big proximal embolus. It worked in some cases for very fresh clot, but we never did a large enough series to develop a protocol. 
 
More recently, with the advent of ultrasound-facilitated, catheter-directed thrombolysis (EkoSonic Endovascular System) we were able to use fairly low doses of tPA, albeit with fairly long infusions. Although it may be convenient for physicians to start an infusion that runs all night and stop it when they come to the hospital in the morning, I believe that the longer the thrombolytic infusion runs, the higher the risk of bleeding. 
 
Now results from OPTALYSE PE (OPtimum Duration and Dose of r-tPA with the Acoustic Pulse ThromboLYSis ProcEdure for Submassive Pulmonary Embolism) demonstrate that even lower doses of tPA and shorter treatment durations are safe and effective for intermediate-risk PE.2 We presented the results of the OPTALYSE PE study at the American Thoracic Society (ATS) International Conference in Washington, D.C., in May 2017. 
 
The study’s 91 participants at 17 centers (by the ATS presentation, we had 101 participants and reported this total also) had acute proximal PE located in at least one main or proximal lobar pulmonary artery with a RV-to-left ventricular (LV) end-diastolic diameter ratio ≥0.9 on chest CT angiography. Participants were randomly assigned to one of four ultrasound-facilitated, catheter-directed thrombolysis regimens, which varied in duration and total amount of tPA:
  • Cohort 1 received 4 mg tPA each lung over 2 hours; 
  • Cohort 2 received 4 mg tPA each lung over 4 hours; 
  • Cohort 3 received 6 mg tPA each lung 6 hours;
  • Cohort 4 received 12 mg tPA each lung over 6 hours. 
All patients also received therapeutic anticoagulation. Half the dose went to each lung in the vast majority of cases.
 
At 48 hours post-procedure, all cohorts had a significant reduction in RV/LV ratio, ranging from -0.46 in cohort 1 to -0.48 in cohort 4, a reduction of 23% to 26%. This is consistent with results achieved in the SEATTLE II trial after a dose of 24 mg tPA given over 12 hours with bilateral catheters.3 The mean RV/LV ratio in SEATTLE II participants decreased from 1.55 pre-procedure to 1.13 at 48 hours post-procedure, a difference of 0.42, or 27%.
 
Patients in the OPTALYSE PE trial also saw statistically significant improvements in their Modified Miller Score (MMS; embolic burden on CT angiography), with increasing reduction from cohort 1 (mean -5% change) to cohort 4 (mean -26% change). The two lowest dose regimens both had less than 10% improvement in MMS.
 
The overall major bleeding rate was 3% for participants in OPTALYSE PE. Major bleeding events occurred only in cohorts 2 and 4, and I believe some of those bleeding events could have been avoided with better selection of patients. One patient developed intracranial hemorrhage following systemic administration of 50 mg tPA (for recurrent PE) delivered about 24 hours after the EKOS procedure; she recovered completely. It is highly unlikely that the intracranial hemorrhage in that case was related to the ultrasound-facilitated, catheter-directed thrombolysis of tPA. Another patient had abdominal pain immediately before the procedure and then had bleeding from a splenic pseudoaneurysm. It was coiled, and he survived and is now doing well. A second patient with intracranial hemorrhage had a prior history of abnormal platelet function and labile hypertension. This was the first intracranial hemorrhage reported in any of the 277 patients in the EKOS PE trials.
 
Although ultrasound-facilitated catheter-directed thrombolysis has a much better safety profile than systemic thrombolysis, the lower doses of tPA used in OPTALYSE PE seemed to reduce the risk of major bleeding complications even further. Participants in SEATTLE II, which evaluated the standard regimen of 24 mg tPA, had a 10% rate of major bleeding, for example, with no intracranial hemorrhages and no fatal bleeding events. There were no major bleeding events in the ULTIMA trial, which randomized 59 patients with acute PE to ultrasound-assisted catheter-directed thrombolysis and heparin, or to anticoagulation with heparin alone.4 The ULTIMA trial found that EKOS treatment had a similar safety profile to heparin alone, but was clinically superior in reversing RV dilation at 24 hours. In comparison, systemic thrombolysis carries a 2% to 3% risk of intracranial hemorrhage.5
 
Based on the preliminary data from OPTALYSE PE, there is no trend indicating that one treatment regimen is better than the other. But the two lowest doses of 8 mg resulted in the lowest MMS score change (cohorts 1 and 2). We saw a clinically significant improvement in RV/LV ratio in all 4 groups. Analyzing additional secondary endpoints of the study — echocardiogram parameters 90 days and 362 days post-procedure, change in pulmonary arteriogram and MMS 4 hours post-procedure, 6-minute walk test, and quality of life score — may give us a better idea of the most effective dosing regimen, as could a larger subsequent study. But the preliminary results of OPTALYSE PE and my own clinical experience leads me to confidently recommend a 6-hour infusion of a total of 12 mg tPA with EKOS to treat intermediate-risk PE. I do not believe the standard regimen of 24 mg tPA over 12 to 24 hours is any longer necessary to achieve optimal results. Clinicians may, however, still wish to individualize patients based on clinical parameters and perceived bleeding risk. 
 
Giving patients less tPA over a shorter period of time with catheter-based therapy has other benefits beyond reducing bleeding risk. A 6-hour infusion instead of a standard 15-hour infusion could result in a shorter ICU stay for the patient, and possibly a shorter hospital stay as well. 
 
Ultrasound-facilitated catheter-directed therapy is not the only catheter-based therapy used to treat intermediate-risk PE, but EKOS has, by far, the most data demonstrating effectiveness and safety, including one randomized trial, a larger prospective single-arm trial, and now OPTALYSE PE. 
 
The OPTALYSE study doesn’t address one of the major conundrums we continue to face in the treatment of PE: which patients do we treat with catheter-directed thrombolysis? Intermediate-risk and high-risk PE can vary in severity, and clinical guidelines unfortunately contain too many gaps to be of routine use in making treatment decisions. A patient whose blood pressure is <90 systolic for more than 15 minutes, but who is hemodynamically stable and comfortable, has high-risk PE, but could likely be treated with catheter-based therapy if he or she was not trending worse. Another patient with high-risk PE with a blood pressure of 70 systolic, despite receiving fluids and 3 pressors, and who is intubated with an oxygen requirement of 100%, will need aggressive systemic thrombolytics or embolectomy, or even extracorporeal membrane oxygenation (ECMO). Although we can’t extrapolate the low-dose recommendations of OPTALYSE PE without further study in high-risk PE, I believe shorter infusions with less tPA could be effective in treating patients with high-risk PE on the less severe end of the spectrum who might decompensate before a longer infusion of tPA is finished. 
 
One limitation of the study is that we did not have a heparin-alone arm. Some might say that ULTIMA already proved that we didn’t require a heparin arm. And we assumed, based on the ULTIMA data, that heparin alone would not result in a rapid and significant improvement. While a concomitant heparin arm in OPTALYSE PE would have been ideal, we have still shown that low-dose tPA via USCDT is safe and effective, and an advance in the field. Greg Piazza and Sam Goldhaber were instrumental in thinking the trial through and driving it to fruition. 
 
Since the study was presented, we commonly treat acute high-intermediate-risk PE and some stable high-risk PE patients with EKOS using a maximum dose of 12 mg tPA — 1 mg/hour/catheter with bilateral catheters — over 6 hours. This regimen is half the dose and duration than the standard regimen evaluated by previous trials, such as the prospective SEATTLE II trial, which found that a dose of 24 mg tPA administered either as 1 mg/hour for 24 hours with a unilateral catheter, or 1 mg/hour/catheter for 12 hours with bilateral catheters, safely improved RV function and dropped pulmonary artery pressure. 
 
References
  1. Konstantinides SV, Torbicki A, Agnelli G, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43): 3033-69, 3069a-3069k.
  2. Tapson V, Piazza G, Goldhaber SZ, et al. Optimum duration and dose of r-tPA with the acoustic pulse thrombolysis procedure for submassive pulmonary embolism. American Thoracic Society International Conference 2017; abstract. Available online at http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2835. Accessed September 19, 2017.
  3. Piazza G, Hohlfelder B, Jaff MR, et al; SEATTLE II Investigators. A prospective, single-arm, multicenter trial of ultrasound facilitated, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: The SEATTLE II study. JACC Cardiovasc Interv. 2015 Aug 24; 8(10): 1382-1392. 
  4. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28; 129(4): 479-486.
  5. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: Clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24; 353(9162): 1386-1389.
 
Dr. Victor Tapson can be contacted at victor.tapson@cshs.org.