Counterpoint: Should Systemic Lytic
Therapy Be Used for Submassive Pulmonary
Embolism? No
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Point/Counterpoint Editorials
Counterpoint: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? No
Kathryn L. Bilello, MD, FCCPa
Susan Murin, MD, FCCPb,c,*
a
Department of Medicine, University of California San Francisco-Fresno Program, Fresno, CA
b
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, School of Medicine, Sacramento,
CA
c
Veterans Affairs Northern California Health Care System, Sacramento, CA
*
Correspondence to: Susan Murin, MD, FCCP, Division of Pulmonary,
Critical Care and Sleep Medicine, University of California, Davis, School
of Medicine, 4150 V St, Ste 3400, Sacramento, CA 95817
E-mail address: susan.murin@ucdmc.ucdavis.edu
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.Reproduction of this article is prohibited without
written permission from the American College of Chest Physicians. See online for more details.
PII S0012-3692(13)60073-2
DOI 10.1378/chest.12-2449
The outcome of acute pulmonary embolism (PE) depends on both the severity of the PE (clot
burden) and the presence and severity of preexisting cardiopulmonary disease in the patient.
Patients who develop shock or hypotension related to acute PE have a higher mortality than do
patients with PE who are hemodynamically stable. Mortality from acute PE ranges from 70% in
patients with cardiopulmonary arrest, to 30% in patients with cardiogenic shock, to 15% in
patients with hypotension. [1] , [2] , [3] Consensus guidelines recommend treatment with thrombolysis,
if not contraindicated, in hemodynamically unstable patients based on their high mortality rate
and the physiologic rationale that they should benefit from the more rapid dissolution of the clot
and resultant relief of the vascular obstruction that is known to occur with administration of lytic
agents. [4] , [5] In contrast, patients without hypotension have a mortality ranging from 0% to 10%,
[1] , [6]
and guidelines recommend that they be treated with anticoagulation alone. [4] , [5]
Within the group of patients with hemodynamically stable PE is a subgroup characterized as
having submassive PE, variably defined on the basis of right ventricular (RV) enlargement,
dysfunction, ischemia, or strain, as assessed by echocardiography, CT scan, serum markers
(troponin or brain natriuretic peptide [BNP] levels), ECG criteria, or other means. [7] , [8] , [9] , [10] , [11]
Multiple studies, including large registries, have reported a two to 2.5-fold increased risk of
mortality in patients with normal BP and RV dysfunction compared with those without RV
dysfunction. [1] , [3] , [8] , [12] Based on this elevated risk, some experts have advocated that patients
with submassive PE be treated more aggressively and have recommended the use of
thrombolytic therapy. [13] , [14] However, although patients with hemodynamically stable PE and RV
dysfunction and/or ischemia may have a worse prognosis, not a single study has been published
that demonstrates that normotensive patients with PE-induced RV dysfunction have a lower
mortality when treated with thrombolysis. Furthermore, although carefully selected patients with
submassive PE (deemed to be at low risk of bleeding) may benefit from thrombolysis, there is no
validated prediction rule that allows us to select these patients up front. Thus, any blanket
recommendation to treat all patients with submassive PE with thrombolysis cannot be supported.
Studies have generally defined submassive PE on the basis of RV dysfunction, which has, itself,
been defined in a wide variety of ways. Depending on the definition used, RV dysfunction can be
identified in 27% to 55% of normotensive patients with PE. [7] , [15] , [16] Many, but not all, studies
have identified higher short-term mortality in this population. [6] , [8] , [9] , [10] , [12] , [17] Among 1,035
patients with PE and systolic BP >90 mm Hg in the International Cooperative Pulmonary
Embolism Registry (ICOPER), the presence of RV hypokinesis was associated with a nearly
twofold risk of death (hazard ratio, 1.94).[12] A systematic review of 12 studies of RV dysfunction
in normotensive patients with PE suggested that RV dysfunction as assessed by
echocardiography and spiral CT scan or elevated cardiac biomarkers is associated with a higher
risk of short-term mortality;[8] the OR for short-term mortality based on echocardiography and
spiral CT scan studies was 2.4 (95% CI, 1.3-4.4). A meta-analysis of 20 studies in patients with
acute PE showed that high levels of troponins were associated with a high risk of short-term
death compared with normal levels (OR, 5.24; 95% CI, 3.28-8.38).[10] Separate analysis of the
seven studies that only included normotensive patients still showed an association between
elevated troponin levels and mortality (OR, 4.98; 95% CI, 2.64-9.39).[10] Similarly, a metaanalysis of 13 studies in patients with acute PE demonstrated that high BNP or N-terminal-proBNP levels were at a higher risk of a complicated in-hospital course (OR, 6.8; 95% CI, 4.4-10)
and 30-day mortality (OR, 7.6; 95% CI, 3.4-17).[9]
In contrast, a review of 157 patients in the Prospective Investigation of Pulmonary Embolism
Diagnosis (PIOPED) II study with stable BP and RV enlargement (measured on CT pulmonary
angiogram) showed no difference in the in-hospital rate of death from PE or all-cause mortality
between 78 patients with RV enlargement and 79 patients without RV enlargement.[17] Bova and
colleagues[6] prospectively evaluated the usefulness of six prognostic markers for predicting inhospital adverse events related to PE and 3-month mortality in 201 consecutive patients with
acute PE and normal BP. Only one patient (0.5%) died of PE during hospitalization, and inhospital and 3-month all-cause mortality were 2% and 9%, respectively. None of the prognostic
markers (RV dysfunction, troponin I, BNP, a validated clinical score, hypoxemia, or D-dimer)
predicted the primary study outcome, which was in-hospital PE-related death or clinical
deterioration, suggesting these prognostic markers are not useful for risk stratification of
normotensive patients with acute PE and should not be used to select patients for aggressive
treatment.
The most convincing reason for not recommending thrombolysis for patients with submassive
PE is that no study has shown a mortality benefit from doing so, and thrombolysis carries a
significant risk of bleeding with a reported fatal hemorrhage rate of 2%. [18] , [19] Although
thrombolysis is associated with more rapid clot resolution and more rapid improvements in RV
function and mean pulmonary artery pressure, these short-term benefits do not result in any longterm hemodynamic improvement. [20] , [21] , [22] , [23] In fact, after 1 week, the percentage of lung
perfusion resolution in patients treated with heparin is similar to that in patients treated with
thrombolysis.[20] Likewise, echocardiographic findings were similar after 7 days in patients
treated with heparin compared with those treated with a thrombolytic agent.[22]
Results of the clinical trials that compared treatment of acute PE with thrombolysis with
treatment with anticoagulation failed to show any benefit of thrombolytic therapy. [24] , [25] , [26] A
meta-analysis of 11 randomized trials comparing thrombolytic therapy with heparin in 748
patients showed no significant difference in mortality or major bleeding between groups.[24] A
subgroup analysis of trials that included hemodynamically unstable patients with acute PE (five
trials) did show a significant reduction in PE or death in patients treated with thrombolysis
compared with heparin. However, no benefit was seen in the six trials that excluded unstable
patients. A meta-analysis of all clinical trials directly comparing recombinant tissue plasminogen
activator with heparin in hemodynamically stable patients with acute PE was published in 2009.
Five studies involving 464 patients were included. No difference in death related to PE or PE
recurrence was seen, even in the subgroup of patients with RV dysfunction.[25] An updated
Cochrane Review concluded that thrombolytics compared with heparin did not reduce death or
PE recurrence in patients with acute PE.[26]
Recently published guidelines have indicated similar conclusions. In the ninth edition of the
Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines, the expert panel reviewed 13 randomized trials that
compared thrombolytic therapy alone to anticoagulant therapy alone and concluded that
thrombolysis may be associated with a reduction in mortality and recurrent PE but is associated
with an increase in major bleeding.[5] Based on the poor quality of the evidence, the panel issued
a weak recommendation for thrombolysis in patients with acute PE associated with hypotension
who do not have a high risk of bleeding. They reasoned that the high mortality of patients in
shock from acute PE justifies the risk of fatal bleeding even if the efficacy of thrombolysis is
modest. In most patients with PE without hypotension, the panel recommends against
thrombolytic therapy. They do make allowance for physician judgment, however, through the
following recommendation: “In selected patients with acute PE not associated with hypotension
and with a low risk of bleeding whose clinical presentation or clinical course after starting
anticoagulant therapy suggests a high risk of developing hypotension, we suggest administration
of thrombolytic therapy.”[5] The panel recognizes that there is no explicit prediction rule to
identify this subgroup of patients, however, and suggests that such patients be identified on the
basis of clinical instability and failure to improve on anticoagulant therapy. Although parameters
of RV size and function, as well as cardiac biomarkers, can assist the physician in selecting such
patients for thrombolysis, they do not have sufficient predictive power to serve as independent
selection criteria. In fact, the panel advises against their routine measurement.
The American Heart Association guidelines parallel those of the American College of Chest
Physicians. Fibrinolysis is reasonable in patients with massive PE (systolic BP <90 mm Hg) and
acceptable risk of bleeding complications.[4] For patients with submassive PE, their
recommendation is as follows: “Fibrinolysis may be considered for patients with submassive PE
judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening
respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of
bleeding complications.”[4]
The facts are that most patients with submassive PE treated with anticoagulation alone have a
low risk of dying (probably <3%).[4] The risk of fatal hemorrhage caused by the administration of
a thrombolytic agent is on the order of 2%. [18] , [19] Thus, thrombolysis should be used only in
patients with more severe compromise, the need for cardiopulmonary capacity, and at low risk of
intracranial hemorrhage. Current methodologies are overly sensitive in classifying many patients
without substantial compromise as having “submassive PE,” and thus this population, broadly
defined, does not clearly benefit from thrombolytic therapy. To date, not a single randomized
controlled trial has identified the subgroup of patients with submassive PE whose survival is
improved by the administration of thrombolytic therapy. Until that subgroup is defined, patients
with submassive PE are best served when the decision to administer a thrombolytic agent is
made on a case-by-case basis by thoughtful, well-informed physicians who carefully weigh the
risks and benefits and consider patient preferences, clot burden, acute physiology, comorbidities,
need for maximal cardiopulmonary capacity, and bleeding risk. Our position is not contrary to
ever giving thrombolytic therapy for submassive PE, but contrary to ever giving thrombolytic
therapy for submassive PE as a matter of routine.
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