Fibrinolytic therapy for intermediate-risk pulmonary embolism prevented hemodynamic decompensation but increased the risk for major hemorrhage and stroke, according to a randomized, double-blind trial published April 9 in the New England Journal of Medicine.
"Randomized clinical trials that test fibrinolytic agents versus heparin alone in patients with acute pulmonary embolism have enrolled, in total, fewer than 1000 patients over the past 40 years," write Guy Meyer, MD, from Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris, France, and colleagues from the Pulmonary Embolism Thrombolysis (PEITHO) Investigators.
"Although these drugs have been shown to rapidly improve hemodynamic variables, their effects on the clinical outcome, particularly in patients without hemodynamic instability at presentation, have not been determined. The [PEITHO] trial was designed to investigate the clinical efficacy and safety of fibrinolytic therapy with a single-bolus injection of tenecteplase, in addition to standard anticoagulation therapy with heparin, in normotensive patients with acute pulmonary embolism and an intermediate risk of an adverse outcome."
Inclusion criteria were right ventricular dysfunction on echocardiography or computed tomography and a positive test for cardiac troponin I or troponin T, reflecting myocardial injury. Death or hemodynamic decompensation (or collapse) within 7 days after randomization was the main study endpoint. Major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization were the primary safety endpoints.
"It is important to stratify any patient presenting with acute pulmonary embolism to the hospital or hospitalized; stratification is facilitated by performing right-to-left ventricle ratio on [computed tomography] pulmonary angiography, as well as blood test, including troponin or [N-terminal pro-brain natriuretic peptide (NT-proBNP)]," Menno V. Huisman, MD, PhD, professor of medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, the Netherlands, told Medscape Medical News when asked for independent comment.
Lower Risk for Hemodynamic Decompensation Offset by Bleeding Risk
The intention-to-treat analysis included 1005 of 1006 randomized patients. In the tenecteplase group, 13 (2.6%) of 506 patients died or had hemodynamic decompensation, as did 28 (5.6%) of 499 patients in the placebo group. This was a 66% reduction in risk with tenecteplase (odds ratio, 0.44; 95% confidence interval, 0.23 - 0.87; P = .02).
However, there was no significant reduction in mortality between randomization and day 7 (6 patients [1.2%] in the tenecteplase group and 9 [1.8%] in the placebo group; P = .42) or in 30-day mortality (12 deaths [2.4%] vs 16 deaths [3.2%], respectively; P = .42).
"The results show us that in patients with intermediate risk, routine anticoagulation for acute pulmonary embolism is sufficient since 7-day total mortality in these patients is low (1.8%) and not different from patients who received thrombolysis on top of anticoagulation (1.2%)," Dr. Huisman said. "This implies that the risk of fatal emboli is low when patients are carefully monitored and receive rescue thrombolysis."
Increased risks with tenecteplase included extracranial bleeding (32 patients [6.3%] vs 6 patients [1.2%]; P < .001) and stroke (12 patients [2.4%], of whom 10 had hemorrhagic stroke, vs 1 patient [0.2%] in the placebo group with stroke, which was hemorrhagic; P = .003).
"Importantly, only 17 of 500 patients randomized to the anticoagulation-only group received rescue thrombolysis, so it appears a good strategy, with overall risk to be minimized if a physician starts with anticoagulation only and performs rescue thrombolysis only in those patients who hemodynamically deteriorate during their course of LMW heparin treatment," Dr. Huisman added. "In this way, the high bleeding risk by thrombolysis is reserved for only those patients who need it, and most patients will escape it. [T]he likelihood that this deterioration occurs is within 3 days…so in these first days, close watching is essential."
On the basis of their findings, the authors conclude that in patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk for major hemorrhage and stroke.
Further Research Needed
"This was a well-designed, large, double-blind, randomized trial in patients with intermediate risk acute pulmonary embolism comparing straightforward thrombolysis plus anticoagulation vs anticoagulation only," Dr. Huisman said.
He noted additional study strengths of standard, well-accepted definitions of intermediate-risk acute pulmonary embolism, as well as predefined primary efficacy and safety endpoints and intention-to-treat analysis.
"Academic researchers initiated this study with a research grant from the tenecteplase manufacturer," Dr. Huisman continued. "Improved efficacy in thrombolysis was largely driven by the endpoint of hemodynamic collapse, an endpoint which itself is both subjective and, as acknowledged by the authors, of questionable clinical relevance."
Other study limitations pointed out by Dr. Huisman were lack of significant difference in pulmonary embolism–related death and increased risk for intracranial and extracranial hemorrhage counterbalancing the efficacy advantage.
"[T]he physician treating a patient with acute pulmonary embolism occasionally must navigate treacherous waters," C. Gregory Elliott, MD, from the Department of Medicine, Intermountain Medical Center, Murray, and the University of Utah School of Medicine in Salt Lake City, writes in an accompanying editorial. "The risk of fatal thromboembolism stands on one side, and the risk of fatal bleeding lies just opposite."
He notes that findings from PEITHO strengthen the case for risk stratification and for careful monitoring of patients at intermediate risk for death, but that they provide no definitive answer. The findings also reflect the relative safety of withholding fibrinolysis unless hemodynamic decompensation occurs.
The Programme Hospitalier de Recherche Clinique in France, the Federal Ministry of Education and Research in Germany, and Boehringer Ingelheim funded this study. Some of the study authors reported financial disclosures involving Boehringer Ingelheim (some including employment), Bayer Healthcare, Sanofi, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Pfizer, Portola, the Federal Ministry of Research and Education in Germany, EKOS Corporation, the University of Goettingen/BMBF, Actelion, GlaxoSmithKline, United Therapeutics, AOP-Orphan Pharmaceuticals, The Medicines Company, Bayer, St. Jude Medical, Edwards Life Sciences, the French Ministry of Health, Leo Pharma, RCV, GmbH, CO KG, Viena Sucursala Bucuresti, Abbott, Celgene, European Cardiovascular Research Center, Fresenius, LFB, Lilly, Medtronic and/or sanofi-aventis. Complete conflict-of-interest information is available on the journal's Web site. Dr. Huisman has disclosed no relevant financial relationships.
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Cite this: Fibrinolysis for Pulmonary Embolism Effective but Risky - Medscape - Apr 10, 2014.