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Thrombolytic therapy for PE reduced mortality, increased major bleeding risk
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Patients with acute pulmonary embolism who underwent thrombolytic therapy demonstrated a reduced risk for all-cause mortality than those treated with conventional anticoagulation, according to results of a meta-analysis.
However, thrombolytic therapy was associated with increased risk for major bleeding events and intracranial hemorrhage.
Jay Giri
“We discovered that thrombolysis was associated with a clear reduction in deaths in grey-area, intermediate-risk, pulmonary embolism patients,” researcher Jay Giri, MD, MPH, assistant professor of clinical medicine in the division of cardiovascular medicine at University of Pennsylvania’s Perelman School of Medicine, said in a press release. "Of course, this potential benefit must be balanced against potential bleeding risks, which we also attempted to clarify.”
Giri and colleagues evaluated data from 16 randomized trials that compared thrombolysis vs. standard anticoagulation, including low–molecular-weight heparin, vitamin K antagonist, fondaparinux (Arixtra, GlaxoSmithKline) or unfractionated heparin. The meta-analysis included 2,115 patients.
The majority of patients (70.87%) had intermediate-risk PE, whereas 9.93% had low-risk PE, 1.47% had high-risk PE and 18.2% had undefined risk.
Overall, patients who received thrombolysis demonstrated a significantly reduced risk for all-cause mortality (OR=0.53; 95% CI, 0.32-0.88; number needed to treat, 59). Thrombolytic therapy also was associated with a reduced risk for recurrent PE (OR=0.40; 95% CI, 0.22-0.74; number needed to treat, 54).
However, thrombolysis was associated with significantly increased risk for major bleeding (OR=2.73; 95% CI, 1.91-3.91; number needed to harm, 18) and intracranial hemorrhage (OR=4.63; 95% CI, 1.78-12.04; number needed to harm, 78).
The bleeding risks were particularly apparent among patients aged older than 65 years (OR=3.10; 95% CI, 2.1-4.56). Researchers determined thrombolysis did not significantly increase bleeding risk among patients aged 65 years or younger (OR=1.25; 95% CI, 0.50-3.14).
When researchers limited their analysis to patients with intermediate-risk PE — or those who were hemodynamically stable with objective evidence of right ventricular dysfunction — they determined thrombolysis was associated with decreased mortality (OR=0.48; 95% CI, 0.25-0.92) but increased risk for major bleeding events (OR=3.19; 95% CI, 2.07-4.92).
“Future research can help identify subgroups of patients who are most likely to obtain this mortality benefit and least likely to be harmed by bleeding, particularly intracranial hemorrhage,” Giri said. "Additionally, research should focus on standardization of dosages of medication in thrombolysis, as well as explore the optimal method of administration — namely intravenous versus catheter-directed therapy into the pulmonary arteries — to determine maximal clinical benefits with minimization of bleeding risk.”
A key question remains whether standard of care should be changed, Joshua A. Beckman, MD, of the cardiovascular division of Brigham and Women’s Hospital, wrote in an invited commentary.
“The net clinical benefit of thrombolysis suggests evidence of modest efficacy for thrombolysis in intermediate-risk PE, rendering the need for decision-making on a patient-by-patient basis,” Beckman wrote.
The results also raise two questions that must be addressed in future research, according to Beckman.
“Should thrombolytic therapy in intermediate-risk patients older than 65 years be avoided?” Beckman wrote. “While the risk of bleeding is increased in older patients, the point estimate for mortality is similar to that in younger patients. Risk stratification for bleeding may favor use of thrombolysis in patients older than 65 years. Second, would the net clinical benefit be better with consistent use of catheter-based thrombolysis using lower doses of fibrinolytic agents for significant pulmonary artery thrombus reduction? Additional clinical trials are needed to guide optimal use of thrombolytic therapy in patients with PE.”
For more information:
- Beckman JA. JAMA. 2014;311:2385-2386.
- Chatterjee S. JAMA. 2014;doi:10.1001/jama.2014.5990.
Disclosure: The researchers report consultant/advisory or board member roles with, research funding from and equity interest in AstraZeneca, Boston Scientific, Cardiostem, Cordis Corporation, EKOS Corporation, Embolitech, GenWay, Johnson & Johnson, Soteria, Vascular Magnetics and VIVA Physicians. Beckman reports board member/consultant roles with and grant funding from AstraZeneca, Bristol-Myers Squibb, Boston Scientific, Ferring Pharmaceuticals, Merck, Novartis and VIVA.
Perspective
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Nigel Key, MB, CHB, FRCP
This is an important meta-analysis that provides a “reality check” on the current status of systemic thrombolytic therapy for PE.
It should be noted that this study does not focus on thrombolysis delivered by catheter into the pulmonary artery. The conclusions could be viewed as “half full” or “half empty.” On the positive side, the data suggest that fibrinolysis can improve upon the efficacy of the existing therapeutic standard (anticoagulation), which is considered to be very effective in its own right. On the other hand, the increase in major bleeding and intra-cranial hemorrhage — particularly in older patients — means that clinicians will need to continue to choose between these options on a case-by-case basis.
Going forward, the need for even more fibrin-specific fibrinolytic agents that are associated with a lower risk of bleeding remains a high priority in PE and in ischemic stroke, as it was 30 years ago, when recombinant tissue plasminogen activator (tPA) was first introduced. Several technologies, such as fibrinolytic-bearing nanoparticles, may achieve this aspiration within the next decade.
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