Download Point: Should Systemic Lytic Therapy Be Used for Submassive

Point: Should Systemic Lytic Therapy Be
Used for Submassive Pulmonary Embolism?
Yes
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Point/Counterpoint Editorials
Point: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? Yes
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: [email protected]
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)60072-0
DOI 10.1378/chest.12-2447
Abbreviations
BNP
brain natriuretic peptide
PE
pulmonary embolism
RV
right ventricular
Early mortality rates for pulmonary embolism (PE) range from <3% in clinically stable patients
to 58% in patients with cardiogenic shock.[1] The various mortality rates reported among studies
illustrate the heterogeneous clinical and prognostic spectrum in patients with PE.
Studies have provided evidence of PE-associated right ventricular (RV) dysfunction as the most
common cause of death during the first 30 days after the diagnosis of PE. [2] , [3] The initial PE,
recurrent PE, or underlying cardiopulmonary disease may initiate or exacerbate the cascade of
events. Cardiac failure from PE results from a combination of the increased wall stress and
cardiac ischemia that compromise RV function and impair left ventricular output. The degree of
increase in RV impedance is related predominantly to the interaction of the mechanical
obstruction and the underlying cardiopulmonary status.[4]
An understanding of the pathophysiology of PE provides the rationale for some components of
the risk stratification of patients with acute PE. Hemodynamic status at the time of presentation
with acute PE has the strongest prognostic implications for short-term mortality.[1] Massive PE
(ie, high-risk PE), characterized by the presence of PE-associated arterial hypotension or shock,
accounts for 5% of all cases of PE and has a short-term mortality of at least 15%.[3] However, a
subset of patients who initially present with hemodynamic stability have a mortality risk similar
to that of patients who present with shock.[5] The development of recurrent PE or the progression
of RV dysfunction may lead to hemodynamic compromise and death in these patients, who had
hemodynamic stability on initial presentation.[6] Thus, the long-standing approach to assessing
risk in patients with PE based solely on systemic arterial pressure may miss the identification of
key prognostic features and may delay further prognostic testing and implementation of more
appropriate therapy. In this scenario, risk stratification becomes critical to distinguish among
these different categories of patients. [7] , [8]
The application of risk stratification tools may help guide therapy for patients with acute PE.
Patients at high risk of death may potentially benefit from thrombolytic therapy. Patients treated
with a systemic IV fibrinolytic agent for acute PE have faster restoration of lung perfusion than
do those treated with IV heparin. [9] , [10] At 24 h after the initiation of thrombolytic therapy,
patients treated with IV heparin and adjunctive IV fibrinolysis manifest a 30% to 35% reduction
in total perfusion defect, whereas patients treated with IV heparin alone have no substantial
improvement in pulmonary blood flow. However, by day 7, blood flow improves to a similar
degree (65%-70% reduction in total defect) in those treated with heparin. Although thrombolysis
has angiographic and hemodynamic benefits compared with standard therapy with IV heparin for
patients with acute PE, studies have not convincingly demonstrated the superiority of
thrombolysis on clinical outcomes.
In the absence of large randomized clinical trials that demonstrate the benefit of thrombolytic
therapy on mortality, the 2012 American College of Chest Physicians guidelines suggested the
use of thrombolytic therapy for patients with acute symptomatic PE and hemodynamic instability
who do not have major contraindications owing to bleeding risk (grade 2C).[11] For patients with
submassive (ie, intermediate-risk) PE, controversy exists regarding the use of thrombolytics.
Trials That Have Evaluated Thrombolysis in Patients With Submassive PE
Two trials have specifically assessed the effect of thrombolysis in patients with submassive PE:
Management Strategies and Prognosis of Pulmonary Embolism Trial-3 (MAPPET-3)[12] and
Tenecteplase Italian Pulmonary Embolism Study (TIPES)[13] (Table 1). In the MAPPET-3
multicenter, randomized, double-blind, placebo-controlled study, Konstantinides and
colleagues[12] evaluated the effect of alteplase on the clinical outcome of patients with submassive
PE. The study randomized 256 hemodynamically stable patients with acute PE and either
pulmonary hypertension (defined as a tricuspid regurgitant jet velocity >2.8 m/s, present in
68.8% of the enrolled patients) or RV dysfunction (defined as RV enlargement combined with
loss of inspiratory collapse of the inferior vena cava, present in 31.2% of the enrolled patients) 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. The study used in-hospital death or clinical deterioration requiring escalation of
therapy (defined as catecholamine infusion, rescue fibrinolysis, mechanical ventilation,
cardiopulmonary resuscitation, or emergency surgical embolectomy) as the primary end point.
Compared with heparin anticoagulation alone, fibrinolysis resulted in a significant reduction in
the primary end point (10.2% vs 24.6%, P = .004). Mortality did not differ between the
randomized treatment groups. The study attributed the difference to a higher frequency of
escalation of therapy in patients randomized to anticoagulation with heparin alone compared
with those treated with fibrinolysis. Both randomized treatment groups had low rates of major
bleeding, although the heparin treatment group, surprisingly, had a trend toward more major
bleeding compared with the thrombolysis treatment group (3.6% vs 0.8%, P = .29).
Table 1 -- Randomized Clinical Trials Comparing Thrombolytics and Heparin in Patients
With Acute Submassive PE
PE-Related Death
All-Cause Death
Major Bleeding
Thrombo Hepa R
lysis
rin R
Study
95 Thrombo Hepa R
%
lysis
rin R
CI
95 Thrombo Hepa R
%
lysis
rin R
CI
95
%
CI
Konstanti
nides et
al[12]
6 of 118
6 of 1.1 0.3
138 7 9–
3.5
3
4 of 118
3 of 1.5 0.3
138 6 6–
6.8
3
1 of 118
5 of 0.2 0.0
138 3 3–
1.9
7
Becattini
et al[13]
0 of 28
0 of
30
… …
0 of 28
1 of
30
… …
2 of 28
1 of 2.1 0.2
30 4 0–
22.
35
6 of 1.1 0.3
168 5 8–
3.4
9
4 of 146
4 of 1.1 0.2
168 5 9–
4.5
2
3 of 146
6 of 0.5 0.1
168 7 5–
2.2
6
All studies 6 of 146
PE = pulmonary embolism; RR = relative risk.
In the TIPES multicenter, randomized, double-blind, placebo-controlled study, Becattini et al[13]
evaluated the effect of tenecteplase on RV dysfunction assessed by echocardiography in
hemodynamically stable patients with submassive PE. The study defined RV dysfunction as the
right/left ventricle end-diastolic dimension ratio >1 in the apical four-chamber view and/or >0.7
in the parasternal long axis, both in the absence of right ventricle hypertrophy. The study
randomized patients to receive weight-adjusted single-bolus IV tenecteplase or placebo. All
patients received IV unfractionated heparin. An independent committee, blinded to treatment
allocation, evaluated echocardiograms for the primary efficacy end point of reduction of RV
dysfunction at 24 h. In the 58 randomized patients, the tenecteplase group had a 0.31±0.08
reduction of the right to left ventricle end-diastolic dimension ratio at 24 h in comparison with a
reduction of 0.10±0.07 in the placebo group (P = .04). At 30 days, one patient randomized to
tenecteplase suffered a clinical event (recurrent PE), in comparison with three patients
randomized to placebo (one recurrent PE, one clinical deterioration, and one non-PE-related
death). Two nonfatal major bleedings occurred with tenecteplase (one intracranial), and one
occurred with placebo. Because the published randomized trials have not shown a survival
benefit of thrombolysis for patients with submassive acute PE (hemodynamically stable, but
associated with RV dysfunction), why do some physicians favor this approach?
Characterization of Patients With Submassive PE
Different groups of investigators have not agreed on standard definitions for echocardiographic
findings of RV dysfunction[14] (Table 2). In most thrombolytic trials, investigators used a single
echocardiographic criterion to assess RV dysfunction, which demonstrated a low positive
predictive value for PE-related in-hospital death. Thus, researchers should combine
echocardiographic criteria to identify those patients with more severe RV dysfunction at the
highest risk of clinical deterioration and PE-related mortality.
Table 2 -- Echocardiographic Criteria for Right Ventricular Dysfunction
Criteria
Right ventricular hypokinesis
Paradoxical septal systolic movement
Right ventricular end-diastolic diameter >30 mm
Right ventricular to left ventricular end-diastolic diameter ratio >1
Right ventricular to left ventricular end-diastolic diameter ratio >0.6
Tricuspid regurgitation velocity >2.8 m/s
Tricuspid regurgitation velocity >2.5 m/s in the absence of inspiratory collapse of the inferior
vena cava
Doppler pulmonary acceleration time <90 ms
Criteria
Doppler pulmonary acceleration time <80 ms
Right ventricular-atrial gradient >30 mm Hg
Dilation of the right pulmonary artery >12 mm/m2
Right ventricular wall thickness >5 mm
Loss of inspiratory collapse of the inferior vena cava
Patients with acute PE in association with RV dysfunction and preserved systemic arterial BP
should undergo further risk stratification to identify subgroups at the highest risk of clinical
deterioration because they may benefit the most from the administration of thrombolytic therapy.
Some studies have investigated the prognostic role of the combination of a simple laboratory test
(ie, measurement of the levels of a cardiac biomarker) and a noninvasive imaging method such
as echocardiography. A study of 591 normotensive patients given a diagnosis of PE assessed the
test characteristics of cardiac troponin I, transthoracic echocardiography, and lower-limb
ultrasound testing for prediction of 30-day PE-related mortality.[15] A three-test strategy that
combined all modalities (echocardiography, troponin, and lower-limb ultrasound testing) and
assessed RV dysfunction, myocardial injury, and thrombus burden had a trend toward improved
prediction of PE-related death in comparison with the use of any test by itself.
Effects of Thrombolysis on Outcomes
The Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry
(EMPEROR) of normotensive patients with acute PE demonstrated a 0.9% (95% CI, 0%-1.6%)
30-day mortality rate that the investigators directly attributed to PE.[16] The recently completed
Prognostic Value of Multidetector CT Scan in Hemodynamically Stable Patients With Acute
Symptomatic Pulmonary Embolism (PROTECT) study of normotensive patients with acute PE
showed a 30-day PE-related mortality of 1.3% (95% CI, 0.5%-2.1%).[17] Data from these and
other studies indicate that patients with submassive PE, treated with IV heparin in various
settings throughout the world, have a short-term mortality rate directly attributable to PE of
<3.0%. These data imply that even if adjunctive fibrinolytic therapy has extremely high efficacy
(eg, a 30% relative reduction in mortality), it probably has a <1% effect size on mortality due to
submassive PE. Thus, improvement in secondary outcomes, such as quality of life and qualityadjusted survival, and surrogate outcomes of decreases in escalation rates of therapy, persistent
RV dysfunction, and chronic thromboembolic pulmonary hypertension represent other important
goals of treatment.[18]
Risk of Bleeding With Thrombolytics
The risk of major bleeding, in particular intracranial hemorrhage, raises great concern about the
use of thrombolytics. Pooled data from controlled thrombolysis trials of patients with acute PE,
which compared either thrombolysis with heparin alone or different thrombolytic regimens with
each other, revealed a 13% cumulative rate of major bleeding and a 1.8% rate of
intracranial/fatal hemorrhage associated with thrombolysis.[19] More recent trials have had lower
rates of major hemorrhage in comparison with older trials, [9] , [12] in agreement with the notion that
thrombolysis-related bleeding rates may be lower when noninvasive imaging methods (instead of
pulmonary angiography with a pulmonary artery catheter puncture site in a central vein such as
the femoral vein) are used to diagnose PE.
Applying Thrombolysis Data to Clinical Practice
The ongoing Pulmonary Embolism International Thrombolysis Trial (PEITHO) (NCT00639743)
plans to enroll 1,000 normotensive patients who have an acute symptomatic PE associated with
RV dysfunction (detected by echocardiography or CT scan) and evidence of myocardial injury
(indicated by a positive troponin test).[20] The study randomizes patients to treatment with (1) IV
tenecteplase followed by IV heparin or (2) IV placebo followed by IV heparin. The study uses a
primary clinical end point of all-cause mortality or hemodynamic collapse within 7 days after
treatment.[20]
While awaiting the results of this trial, I consider using thrombolysis (of note, only in the
absence of contraindications) for normotensive patients with acute PE who have severe RV
dysfunction, myocardial injury, and concomitant proximal DVT at the time of PE diagnosis. This
practice may prevent major complications, including the need for emergency thrombolysis due to
rapid deterioration, within the first few days after the PE diagnosis.
Conclusions
Although studies have not shown a survival benefit from thrombolytic treatment in patients with
acute submassive PE, one study does suggest that lysis prevents clinical deterioration and the
need for escalation of care. Because of differences in patients' preferences, values, and riskbenefit ratios, physicians should decide about the use of thrombolysis on a case-by-case basis. In
patients with submassive PE, those who have signs of increased cardiac dysfunction and greater
clot burden may have a greater likelihood of benefitting from thrombolytic therapy than do those
without these findings.
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