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New Horizons in Pulmonary Embolism Treatment
Catheter-directed therapies changing treatment paradigm for patients with massive and submassive PE.
As catheter-directed therapies have advanced in recent years, they are becoming a critical part of the strategy for treatment of patients with massive and submassive pulmonary embolism.
While the field had been plagued with a paucity of data, there has been a torrent of new research in the past 2 years, and it has helped interventionalists and other specialists refine who are the best candidates for catheter-based treatment of massive or, especially, submassive pulmonary embolism (PE).
“It is an auspicious time for submassive PE,” Akhilesh K. Sista, MD, assistant professor of radiology at Weill Cornell Medical College, New York City, said during a presentation at the International Symposium on Endovascular Therapy (ISET), held in February in Hollywood, Florida. “If you look at what happened in the last 2 years, it is impressive. We have come a long way in the last couple of years, and momentum is gathering.”
Goals of Catheter-Directed Therapy
Keith M. Sterling, MD, director of cardiovascular and interventional radiology at Inova Alexandria Hospital in Virginia and associate professor of radiology at George Washington University School of Medicine, said during the ISET session that successful catheter-directed therapy for PE must meet the following goals: recovery of right ventricular function, decrease in pulmonary vascular resistance and pulmonary artery pressure, increase in systemic arterial pressure, improvement of symptoms and survival and decrease in risk for developing chronic thromboembolic pulmonary hypertension (CTEPH).
To assess odds for success, interventionalists must consider what treatments might be appropriate for different clinical scenarios, Sterling said.
“Massive PE can be broken down into crashing and noncrashing, while submassive PE can include those patients bordering on massive, those with significant RV dysfunction, and those bordering on low risk,” he said. “Other factors to consider are the patient’s bleeding risk and the skills and equipment you have available at your hospital.”
Possible treatments for massive PE, he said, include IV thrombolytics, extracorporeal membrane oxygenation (ECMO) and catheter-directed therapy with or without thrombolysis. For those at bleeding risk, clinicians should consider surgical embolectomy, suction embolectomy or mechanical fragmentation, he added.
In patients with submassive PE, catheter-directed thrombolysis may be considered for patients “bordering on massive or significant RV dysfunction,” while surgical embolectomy or suction embolectomy should be considered for those at bleeding risk, he said. Those at lower risk should be considered for anticoagulation and monitored closely for decompensation, he noted.
Simply treating these patients with IV thrombolysis may not be the best idea because that therapy has shown a 13% risk for major bleeding and a 1.8% risk for intracranial hemorrhage in randomized trials, and a 20% risk for major bleeding and a 3% risk for intracranial hemorrhage in clinical practice, Sterling said. Due to these risks, treatment with systemic thrombolysis is withheld in up to two-thirds of patients with high-risk PE, he noted.
By contrast, the best results with catheter-directed thrombolytic therapies are obtained when the catheter is properly placed to enable direct infusion of the lytic agent into the clot, because this allows for higher local concentration but lower overall dose of the therapy, Sterling said.
“Catheter-directed thrombolysis is widely available and can be used as an adjuvant with mechanical techniques, with a standard multi-sidehole infusion catheter, and with an ultra-sound-accelerated catheter,” he said.
Available Data
When there were few data to support the use of catheter-directed therapies for PE, there was no consistency in how these tools were used or in what experts expected. With the torrent of publications that have come out recently, the field may be growing more unified.
Among the landmark publications in 2014 and 2015, Sista said, were the PEITHO study, the largest trial to date on systemic thrombolysis; three large meta-analyses; ULTIMA, the first randomized controlled trial for catheter-directed thrombolysis; SEATTLE II, the largest single-arm study for catheter-directed thrombolysis; and PERFECT, a large prospective registry on catheter-directed thrombolysis (see Table).
Sista said there has been much interest in studying whether intra-clot delivery of thrombolytic therapy results in less bleeding, enabling safer dosing.
However, he noted that this has not been proven definitively. In SEATTLE II, the cohort was not free from major bleeding.
While SEATTLE II, ULTIMA and the PERFECT registry have shown that catheter-directed thrombolysis is associated with reduced pulmonary arterial systolic pressures, these studies have not assessed death, deterioration, recurrent PE or recurrent hospitalization, according to Sista.
“These are all incredibly important endpoints if we are doing to say that [catheter-directed thrombolysis] is the next thing to be the primary therapy for submassive PE,” Sista said.
Victor F. Tapson, MD, FCCP, FRCP, director of the Venous Thromboembolism and Pulmonary Vascular Disease Research Program at Cedars-Sinai Medical Center, agreed, noting that more data on short- and long-term mortality, CTEPH, recurrent PE and quality of life are needed.
“Catheter-based therapy is effective in the short term at reducing clot burden and improving RV function. We have few randomized trial data other than ULTIMA. We have suggestions of long-term benefit. However, there is no proof that catheter-based, or systemic thrombolysis, prevents CTEPH or reduce mortality. Current thrombolytic infusions are often 12 to 24 hours. New regimens are being explored. More catheter-based techniques are being explored. More research is also needed in both submassive and massive PE patients,” Tapson said at ISET.
Guidance Unclear
In addition, not much in the way of guideline-directed practice has made it into the clinical community.
In January, the American College of Chest Physicians released new recommendations for catheter-based therapy.
One recommendation is that in patients with acute PE treated with a thrombolytic agent, systemic thrombolytic therapy using a peripheral vein is suggested over catheter-directed thrombolysis, with a grade of 2C, according to Tapson.
Another recommendation, also given a grade of 2C, states that “in patients with acute PE associated with hypotension and who have a high bleeding risk; failed thrombolysis; or shock that is likely to cause death before systematic thrombolysis can take effect, if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention.”
However, Tapson, said, “the bottom line is that I don’t think these are helpful guidelines for most of us.”
Future Directions
Experts await results of the OPTALYSE PE study, a multicenter, prospective, randomized-dosing trial. All patients enrolled will receive tissue plasminogen activator (tPA) administered with an ultrasound-assisted catheter-directed thrombolysis system (EkoSonic Endovascular System, EKOS). They will be randomly assigned different doses and infusion times.
“There is an important question of whether we can shorten infusion and decrease dose,” Sterling said.
Further research must be done to determine whether catheter-directed thrombolysis can be a routine first-line therapy for submassive PE, Sista said. “Is it safe? Is it clinically effective in the short term? What is the best technique to optimize efficacy, safety and cost effectiveness? Is it clinically effective in the long term?” — by Katie Kalvaitis and Erik Swain
- References:
- Chatterjee S, et al. JAMA. 2014;doi:10.1001/jama.2014.5990.
- Kucher N, et al. Circulation. 2013;doi:10.1161/CIRCULATIONAHA.113.005544.
- Kuo WT, et al. Chest. 2015;doi:10.1378/chest.15-0119.
- Meyer G, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1302097.
- Piazza G, et al. JACC Cardiovasc Interv. 2015;doi:10.1016/j.jcin.2015.04.020.
- Tapson VF, et al. Session V: New Horizons: Advances in Management of Pulmonary Embolus. Presented at: International Symposium on Endovascular Therapy; Feb. 6-10, 2016; Hollywood, Fla.
- For more information:
- Akhilesh Sista, MD, can be reached at 525 E. 68th St., Payson Pavilion 5, New York, NY 10065; email: aks9010@med.cornell.edu.
- Keith M. Sterling, MD, can be reached at Department of Cardiovascular and Interventional Radiology, 4320 Seminary Road, Alexandria, VA 22304; email: ksterling@alexandriaradiology.com.
- Victor F. Tapson, MD, can be reached at 127 S. San Vicente Blvd., Suite A6100, Los Angeles, CA 90048; email: tapso001@mc.duke.edu.
Disclosures: Sterling reports serving on the speaker’s bureau for BTG/EKOS, consulting/advising for Penumbra, and serving as principal investigator of the ACCESS-PTS and OPTALYSE PE studies (sponsored by BTG/EKOS). Sista reports no relevant financial disclosures. Tapson reports consulting/advising for BTG/EKOS, Inari, Daiichi Sankyo, Janssen and Bayer, and receiving research grants from BTG/EKOS, Janssen, Bayer, Bio2 Medical and Portola.