Rebuttal From Dr Jiménez
Chest - Volume 143, Issue 2 (February 2013) - Copyright © 2013 The American College of
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Point/Counterpoint Editorials
Rebuttal From Dr Jiménez
David Jiménez, MD, PhD*
Respiratory Department, Ramón y Cajal Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
*
Correspondence to: David Jiménez, MD, PhD, Respiratory
Department, Ramón y Cajal Hospital, Instituto Ramón y Cajal de
Investigación Sanitaria, 28034 Madrid, Spain
E-mail address: djc_69_98@yahoo.com
Financial/nonfinancial disclosures: The author has reported to CHEST the following conflict of interest: Dr Jiménez is a member of the
Steering Committee of the Pulmonary Embolism International Thrombolysis Trial.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)60074-4
DOI 10.1378/chest.12-2448
My colleagues Drs Bilello and Murin[1] contend that thrombolytics should not be used for
submassive pulmonary embolism (PE) using two arguments: (1) Studies have not demonstrated a
survival benefit from thrombolysis in patients with acute submassive PE, and (2) studies have
not validated an explicit prediction rule for identifying the subgroup of normotensive patients
with PE who are at high risk of PE-related complications, in contrast to hemodynamically
unstable patients “based upon their high mortality rate and the physiologic rationale that they
should benefit from the more rapid dissolution of the clot, and resultant relief of vascular
obstruction….”[1]
I concede that trials have not demonstrated a survival benefit from thrombolysis in patients with
submassive PE. However, only one randomized controlled trial (by Jerjes-Sanchez and
colleagues[2]) has provided evidence of a survival benefit of lytic therapy compared with heparin
for the initial treatment of patients with PE and cardiogenic shock. In this study of eight
randomized patients, none of the four patients who received intrapulmonary streptokinase died,
compared with four of the four patients who received intrapulmonary heparin. Interestingly, the
four patients in the heparin group did not initially have symptoms and had recurrent PE as the
presentation of massive PE before entry into the trial.
For patients with submassive PE, the Management Strategies and Prognosis of Pulmonary
Embolism Trial-3 (MAPPET-3) randomized 258 hemodynamically stable patients with acute PE
and either pulmonary hypertension or right ventricle dysfunction to receive IV recombinant
tissue plasminogen activator, 100 mg over 2 h, followed by unfractionated heparin infusion or
placebo tissue plasminogen activator plus heparin anticoagulation.[3] Of note, this study of
patients without cardiogenic shock randomized 32 times more patients than did the JerjesSanchez[2] trial. Compared with heparin anticoagulation alone, fibrinolysis resulted in a
significant reduction in clinical deterioration requiring escalation of therapy (10.2% vs 24.6%,
P = .004), although it did not improve survival.
I also concede that none of the meta-analyses demonstrated a reduction of death after
thrombolysis in hemodynamically stable patients with acute PE.[4] Interestingly, thrombolytic
therapy also did not demonstrate a significant reduction in death in meta-analyses of trials that
enrolled patients with major (hemodynamically unstable) PE.[5]
Despite the lack of a clear survival benefit associated with thrombolytic therapy for acute
symptomatic PE, consensus guidelines recommend treatment with thrombolysis in patients with
acute symptomatic PE and associated (ie, not caused by new-onset arrhythmia, hypovolemia, or
sepsis) hemodynamic instability that they define as shock or persistent arterial hypotension (ie, a
systolic BP <90 mm Hg or a pressure drop of >40 mm Hg for 15 min). However, such patients
have very heterogeneous characteristics. The MAPPET-3 Registry of 1,001 patients with acute
PE[6] demonstrated rates of death due to PE in patients with cardiac arrest, cardiogenic shock, and
arterial hypotension of 60%, 23%, and 14%, respectively. Extrapolation of these rates to patients
with subclinical hemodynamic impairment (eg, hemodynamically stable patients with right
ventricle dysfunction, myocardial injury, and residual DVT) produces a higher than expected rate
of fatal PE (20%) in comparison with those with isolated arterial hypotension.[7]
Because randomized clinical trials have shown more consistent data supporting the use of
thrombolytic therapy in patients with submassive PE than have data from studies in those with
massive PE, and because data from large multicenter cohort studies have demonstrated that a
subgroup of normotensive patients with PE have a poor prognosis, as described herein,
thrombolytic therapy should undergo further study in various subgroups of patients who present
with acute symptomatic submassive PE.
Acknowledgments
Other contributions: I thank Roger D. Yusen, MD, MPH, for his helpful comments on earlier
versions of this manuscript.
REFERENCES:
1 Bilello KL, Murin S: Counterpoint: should systemic lytic therapy be used for submassive pulmonary embolism?
No. Chest 143. (2): 299-302.2013;
2 Jerjes-Sanchez C, Ramírez-Rivera A, de Lourdes García M, et al: Streptokinase and heparin versus heparin alone
in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis 2. (3): 227-229.1995;
3 Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W, Management Strategies and Prognosis of
Pulmonary Embolism-3 Trial Investigators : Heparin plus alteplase compared with heparin alone in patients with
submassive pulmonary embolism. N Engl J Med 347. (15): 1143-1150.2002; Abstract
4 Tardy B, Venet C, Zeni F, Coudrot M, Guyomarc'h S, Mismetti P: Short term effect of recombinant tissue
plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a metaanalysis involving 464 patients. Thromb Res 124. (6): 672-677.2009; Abstract
5 Wan S, Quinlan DJ, Agnelli G, Eikelboom JW: Thrombolysis compared with heparin for the initial treatment of
pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 110. (6): 744-749.2004;
Abstract
6 Kasper W, Konstantinides S, Geibel A, et al: Management strategies and determinants of outcome in acute major
pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 30. (5): 1165-1171.1997; Abstract
7 Jiménez D, Aujesky D, Moores L, et al: Combinations of prognostic tools for identification of high-risk
normotensive patients with acute symptomatic pulmonary embolism. Thorax 66. (1): 75-81.2011;