Keywords
pulmonary embolism - deep venous thrombosis - thrombolytic therapy - right ventricular
function - catheter-based embolectomy
Pulmonary embolism (PE) is a common, life-threatening clinical entity encountered
by clinicians of all specialties. In spite of decades of clinical trials, only a limited
number of randomized controlled trials have compared thrombolytic therapy with conventional
anticoagulation in the treatment of PE.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11] These trials together account for less than 900 patients.[1]
[2]
[3]
[5]
[6]
[7]
[8]
[9]
[10]
[11] Furthermore, there have not been large enough studies that include the patients
most likely to benefit. In contrast, thrombolytic therapy had been studied in many
thousands of patients with acute myocardial infarction before its acceptance into
standard clinical practice.[12] Thus, controversies still remain with regard to the precise indications in acute
PE. We present background data, controversies, and general approaches to the use of
thrombolytic therapy in acute PE.
Although our focus is thrombolysis, it should be emphasized that anticoagulation clearly
improves mortality and should be instituted promptly when the clinical suspicion is
high or the diagnosis has already been made, with careful attention to contraindications.
Risk assessment and therapeutic decisions should be made as quickly as possible because
the reported mortality rate without treatment is approximately 30% compared with approximately
4 to 8% when treated.[13]
[14]
[15]
[16]
Standard therapy for acute PE includes therapeutic anticoagulation with weight-adjusted
subcutaneous low-molecular-weight heparin or fondaparinux. Renal function must be
considered with the latter two drugs.[13] In November 2012, oral rivaroxaban was approved for use in the United States for
acute deep venous thrombosis (DVT) and acute PE, and its use will likely increase
significantly. Importantly, anticoagulation only helps to prevent further thrombus
formation and cannot itself dissolve thromboemboli that are already present; therefore,
in certain circumstances more aggressive therapy is needed. Finally, when anticoagulation
is contraindicated, inferior venacaval filter placement should be undertaken.[13]
A crucial issue in acute PE is how to risk stratify patients; that is, how to translate
the overall severity of the PE event into a meaningful treatment plan. Although clinical
algorithms are useful in stratification, the clinical severity of acute PE is highly
variable, requiring careful evaluation on a case-by-case basis. The potential complications
from thrombolytic therapy adds another level of complexity to risk stratification.
When acute PE is proven or highly suspected and anticoagulation is initiated, more
aggressive strategies should be considered, including thrombolytic therapy. Risk stratification
involves a global assessment of the patient with a focus on right ventricular (RV)
function. Massive PE (associated with hemodynamic instability) is generally a more
straightforward decision.
Massive Pulmonary Embolism
Massive Pulmonary Embolism
In the patient with proven PE and clear hemodynamic instability and in the absence
of absolute contraindications, most clinicians will agree to initiate systemic thrombolytics.[13]
[14] However, the precise definition of hemodynamic instability and thus massive PE is
not always clear. Hemodynamic instability has generally been defined as a systolic
blood pressure less than 90 mm Hg.[13] A sustained drop in blood pressure to less than 90 mm Hg for at least 15 minutes
has also been used.[14] The American College of Chest Physicians guidelines (February 2012) state that “in
patients with acute PE associated with hypotension (eg, systolic BP < 90 mm Hg) who
do not have a high bleeding risk, we suggest systemically administered thrombolytic
therapy over no such therapy (Grade 2C).”[13] Some individuals normally run a low systolic blood pressure, so other clinical parameters
must be considered. On the contrary, a substantial drop in pressure, even if it remains
above 90 mm Hg systolic, should be taken seriously. A patient with syncope at rest
and proven PE may have an extensive clot burden by computed tomographic angiography
but not remain hypotensive when assessed. Such patients require careful assessment
with regard to their hemodynamic status. Other parameters (see Risk Stratification
and Submassive PE, below) should be considered when questions remain after blood pressure
has been determined and/or monitored.
Thus, the cases rarely stimulating disagreement are those in which the patient has
symptomatic hypotension requiring hemodynamic support. Although clinical experience
supports this approach, no clinical study has demonstrated unequivocally even in this
setting that thrombolytics improve mortality over anticoagulation alone.[13]
[14]
[15]
[16]
[17] Nonetheless, given the high mortality rate of this subgroup, few clinical researchers
could comfortably randomize such patients.
Risk Stratification and Submassive Pulmonary Embolism
Risk Stratification and Submassive Pulmonary Embolism
Risk stratification has been recommended in clinical guidelines, and the approach
continues to evolve. The management of either submassive PE (hemodynamically stable
but with abnormal RV function) or cases of extensive clot burden/saddle embolus with
minimal or no demonstrable RV dysfunction continue to be hotly debated. The Pulmonary
Embolism Severity Index has been studied and simplified.[18] Although it can predict outcomes, it appears most useful for identifying patients
at low risk who could be discharged early or managed entirely in the outpatient setting.
It cannot be used to estimate the potential impact of therapy on outcomes. The focus
has to be specific clinical parameters such as RV function.
The clinical approach includes a global assessment of the patient, including vital
signs, presence/degree of RV dysfunction, extent of emboli by computed tomography
or ventilation perfusion scan, biomarkers, oxygenation, and residual DVT.[14] Parameters reflecting severity that should be considered are listed in [Table 1]. Potential contraindications to thrombolytics (see below), associated comorbidities,
center expertise, and patient preference must be taken into consideration.
Table 1
Considerations in risk stratification
|
Clinical status of the patient
General appearance (acutely ill, confused, etc.)
Hypotension (relative or absolute)
Tachycardia/tachypnea
|
|
Electrocardiography
Tachycardia
RV strain
|
|
Echocardiography
RV enlargement/hypokinesis
Right atrial enlargement
Clot-in-transit
Patent foramen ovale or other shunt
|
|
Computed tomographic angiography
RV enlargement
Embolic burden/proximal extent of emboli
Presence/extent of venous thrombosis (if CTV is done)
|
|
Compression ultrasound
Presence/extent of venous thrombosis
|
|
Biomarkers
Serum troponin
Brain natriuretic peptide
|
|
Oxygenation[a]
|
Abbreviation: CTV, computed tomographic venography.
a Although severity of hypoxemia has been less well-studied in acute PE as an independent
predictor of mortality, it logically should be considered in risk stratification.
Although several parameters should be examined, a key focus is how well RV function
is being maintained. Echocardiography, particularly performed by an expert operator,
can provide detailed information. The RV status correlates directly with cardiogenic
shock and, hence, mortality.[16]
[17]
[19] Accurate, detailed assessment of RV function is not yet perfected, but extremes
of RV size and function may be useful in decision making. It is feasible that different
measures of RV size or function are associated with different prognoses. Several tools
have been proposed thus far. Findings that raise significant concern include a significantly
enlarged and/or hypokinetic RV with an interventricular septum that compromises filling
of the left ventricle, potentially leading to systemic hypotension.[14] One rapid technique is to simply measure the chamber proportions by computed tomographic
angiography; an increased right-to-left ventricle ratio ≥ 1 suggests RV dysfunction
and has been shown to predict mortality.[20]
[21]
Biomarkers are being routinely used for risk stratification. Elevated levels of brain
natriuretic peptide, pro-brain natriuretic peptide, and cardiac troponins (both T
and I) have been shown to correlate with RV compromise.[22]
[23]
[24] A meta-analysis of 1,985 PE patients from 20 clinical studies revealed that any
elevation of the troponin level (microinfarction) confers a fivefold increase in short-term
mortality.[23] Troponin levels appear to predict outcome not only for PE patients in shock but
also for those patients who are hemodynamically stable at presentation.[23]
The introduction of highly sensitive troponin assays appears to have improved their
diagnostic sensitivity.[25] Preliminary findings have suggested that a highly sensitive troponin T cutoff value
of 14 pg/mL may be associated with a high prognostic sensitivity and negative predictive
value for an adverse 30-day outcome after acute PE.[26] Although these findings may indicate that the novel highly sensitive troponin T
assay might be helpful for identifying patients appropriate for early discharge, they
might be expected to lower the specificity for detecting severe PE cases. In fact,
however, when combined with clinical risk stratification, they may improve the ability
to predict poor outcomes.[27]
Echocardiography and troponin data have been examined together. Jiménez and colleagues
reported data on 591 normotensive patients diagnosed with PE who were examined with
echocardiography or troponin testing and compression ultrasound of the legs.[28] The primary outcome of PE-related death within 30 days occurred in 37 patients (6.3%;
95% confidence interval [CI], 4.3 to 8.2%). Patients with both RV dysfunction and
concomitant DVT had a PE-related mortality of 19.6%, compared with 17.1% of patients
with elevated troponin I and concomitant DVT and 15.2% of patients with an elevated
troponin I and RV dysfunction. The use of any two-test strategy had a higher specificity
and positive predictive value compared with the use of any test by itself. The combination
of echocardiography or troponin testing and compression ultrasound of the legs improved
prognostication compared with the use of any test by itself for the identification
of those at high risk of PE-related death.[28] These data help to get at the core of the crucial debate of who should receive thrombolytic
therapy.
Residual clot burden in the legs has also been examined in the international multicenter
Registro Informatizado de la Enfermedad Tromboembolica.[29] These data suggest that patients with acute PE who have concomitant residual DVT
have a higher mortality. In an external validation cohort of 4,476 patients with acute
PE enrolled in this registry, concomitant DVT remained a significant predictor of
all-cause (adjusted hazard ratio, 1.66; 95% CI, 1.28 to 2.15; p < 0.001) and PE-specific mortality (adjusted hazard ratio, 2.01; 95% CI, 1.18 to
3.44; p = 0.01).[29] Although data are not from a prospective randomized trial, they are logical and
compelling.
Finally, extent of clot burden in the lungs has been studied. PE extent has been calculated
by the Qanadli obstruction index, in which the highest score is 40, and represents
complete obstruction of the main pulmonary artery.[21] In one large nonrandomized study of 579 patients, mean obstruction index values
were similar in patients who died and/or had clinical deterioration at 30 days compared
with patients who had a favorable prognosis.[21] However, central location of emboli was a predictor of all cause death and/or clinical deterioration in patients
with acute PE who were hemodynamically stable.[21] It is quite logical that clot burden correlates with mortality in acute PE; it must.
But predicting mortality based on this parameter alone is difficult. [Fig. 1] demonstrates a large PE; based on the size of this embolus, thrombolytic therapy
would be considered, but other parameters of severity would also be examined.
Fig. 1 Extensive bilateral pulmonary emboli are demonstrated by computed tomographic arteriography
(CTA). The patient was hemodynamically stable but was tachycardic (heart rate 130
beats/min) and required 60% oxygen by facemask. The troponin was positive, and brain
natriuretic peptide was elevated to three times the upper limits of normal. CTA revealed
significant right ventricular enlargement. This was also noted by echocardiography,
and there was marked right ventricular hypokinesis as well. Based on these features
in this patient with submassive PE, systemic thrombolysis was administered with marked
improvement and without complications. Intravenous heparin was continued during the
2-hour tPA infusion.
Few large, randomized thrombolytic trials have been conducted in submassive PE. In
a large prospective, randomized trial, Konstantinides et al demonstrated that patients
who received tissue plasminogen activator (tPA) were significantly less likely to
deteriorate clinically than those who received placebo (11 vs. 25%).[30] No mortality difference was demonstrated, but there was a higher rate of rescue
thrombolysis in the placebo group. Several smaller studies have been published. It
is anticipated that more definitive evidence will be available after the conclusion
of the international multicenter Pulmonary Embolism THrOmbolysis (PEITHO) study, which
compares thrombolysis with tenecteplase plus anticoagulation versus anticoagulation
alone in this subgroup of patients.[31]
Which Agent or Protocol Should Be Used?
Which Agent or Protocol Should Be Used?
There are no head-to-head trials indicating that a particular thrombolytic agent has
superior efficacy or safety; studies have generally compared thrombolysis to anticoagulation
alone.[15]
[17]
[19]
[30] Recombinant tPA (alteplase), streptokinase, and recombinant human urokinase are
the best studied thrombolytic agents for the treatment of acute PE. Streptokinase
is the least expensive but the most commonly associated with adverse effects, including
allergic reactions and hypotension.
Newer agents approved for acute coronary syndromes such as tenecteplase and reteplase
have not been approved for use in acute PE but have been studied.[15]
[17]
[32] In the Italian Tenecteplase Italian Pulmonary Embolism Study trial, the effect of
tenecteplase versus anticoagulation on RV dysfunction assessed by echocardiography
in hemodynamically stable patients with PE was evaluated in a multicenter, randomized,
double-blind, placebo-controlled study.[32] RV dysfunction was defined as a right/left ventricle end-diastolic dimension ratio > 1
in the apical four-chamber view, and reduction in RV dysfunction at 24 hours was the
primary efficacy endpoint. The results suggested that in hemodynamically stable patients
with PE, treatment with single-bolus tenecteplase is feasible at the same doses used
for acute myocardial infarction and is associated with reduction of RV dysfunction
at 24 hours. Whether this benefit is associated with an improved clinical outcome
without excessive bleeding is being explored with tenecteplase in the much larger
PEITHO trial.[31]
Available evidence suggests that shorter infusions (i.e., ≤2 hours) achieve more rapid
clot lysis and are associated with lower rates of bleeding than longer ones (i.e.,
12 hours).[13] Thus, of the approved agents, tPA has been recommended due to its short infusion
time.[13]
[14] In the PEITHO trial, the tenecteplase is delivered by an even faster bolus (5 to
10 seconds).[31]
Although it has been advised that anticoagulation be discontinued during the thrombolytic
infusion and restarted after the infusion when the activated partial thromboplastin
time is 80 seconds or less no data support the need to stop anticoagulation. However,
in many non-US countries, the anticoagulation infusion is continued during thrombolytic
therapy. When bleeding risk is deemed higher, standard unfractionated heparin may
be preferred based on its short action and reversibility. No randomized trial data
support this approach either. The Assessment of the Safety and Efficacy of New Thrombolytic
Regimens 3 study examined different anticoagulation regimens in acute myocardial infarction
patients receiving tenecteplase.[33] The conclusion was that enoxaparin was safe and superior to standard heparin in
this setting. Nonetheless, in acute PE for which thrombolytics are administered, there
is no clear standard of care in this regard.
Complications of Thrombolytic Therapy
Complications of Thrombolytic Therapy
Because thrombolytic agents are intravenous agents with systemic action, they lyse
clots anywhere within the vasculature. Thus, complications from bleeding, with intracerebral
hemorrhage being the most feared, become relevant, although the latter is relatively
rare when a careful risk assessment has been undertaken (similar to myocardial infarction).
In the International Cooperative Pulmonary Embolism Registry, intracranial bleeding
occurred in 3.0% of the 304 patients who received thrombolytic therapy, compared with
only 0.3% in the placebo group, suggesting that the risk is not only increased but
also that the “real-life” risk may be higher than in randomized clinical trials.[16]
Several absolute and relative contraindications to thrombolytic therapy have been
proposed to minimize the bleeding risk ([Table 2]). However, in extreme clinical circumstances, even absolute contraindications may
not preclude the use of thrombolytics in the eyes of some clinicians. Pooled data
from available randomized trials of thrombolytics for acute PE[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11] have shown a trend toward increased major bleeding events in the thrombolytic group
versus the group that received heparin alone; however, this does not reach statistical
significance (9.1 vs. 6.1%; odds ratio, 0.67; 95% CI, 0.40 to 1.12). However, minor
bleeding events were significantly increased in the thrombolytic group (22.7 vs. 10%;
odds ratio, 2.63; 95% CI, 1.53 to 4.54).[19]
Table 2
Absolute and relative contraindications to thrombolytic therapy
|
Absolute contraindications[a]
-
History of intracranial hemorrhage
-
Known intracranial neoplasm, arteriovenous malformation or aneurysm
-
Significant head trauma
-
Active internal bleeding
-
Known bleeding diathesis
-
Intracerebral or intraspinal surgery within 3 months
-
Cerebrovascular accident within 2 months
|
|
Relative contraindications
-
Recent internal bleeding
-
Recent surgery or organ biopsy
-
Recent trauma, including cardiopulmonary resuscitation
-
Venipuncture at noncompressible site
-
Uncontrolled hypertension
-
Diabetic retinopathy
-
Pregnancy
-
Age > 75 years
|
a Although absolute contraindications should be carefully assessed, some of these (except
concurrent intracranial hemorrhage) might not be “absolute” in the most extreme circumstances
of massive pulmonary embolism with hemodynamic compromise. (The decision to use thrombolytic
therapy depends on the clinician's assessment of PE severity, prognosis, and risk
of bleeding).[13]
When systemic thrombolytic therapy is contraindicated, other approaches can be considered.
These include catheter-based embolectomy and surgical embolectomy. The precise roles
of these techniques have not been precisely defined, however.
Surgical Pulmonary Embolectomy and Catheter-Based Techniques
Surgical Pulmonary Embolectomy and Catheter-Based Techniques
According to the data of Nationwide Inpatient Sample register from 1998 to 2008, 72,230
patients presented with unstable PE. Of these, only 1.2% underwent open pulmonary
embolectomy and 0.3% received catheter-tip embolectomy.[34] With accumulating experience with newer catheter devices communicating favorable
outcomes (albeit without randomized trial data) and the concerns of adverse effects
of systemic thrombolysis, there has been more interest in these interventions.[35]
There are certain clinical settings where the local management of emboli presents
as an appealing alternative; these include massive PE in patients with formal contraindications
to thrombolytics, less severe presentations with RV dysfunction, and, finally, as
an escalation therapy when systemic thrombolysis has failed.
Surgical Embolectomy
Unfortunately, surgical embolectomy has been associated with high mortality rates
(∼27%), and this concerns some clinicians.[34] A substantial contribution to this high mortality is the critically ill nature of
these patients. A few centers have liberalized their criteria for acute embolectomy
and have operated on patients with preserved systemic blood pressure presenting with
extensive clot burdens and concomitant RV dysfunction.[36] A series of 47 consecutive patients, meeting such criteria, who underwent surgical
pulmonary embolectomy (requiring cardiopulmonary bypass but under normothermic conditions
and avoiding cardioplegic arrest) showed a survival rate of 96% at 27 months of follow-up.
This high rate of survival was attributed to the multidisciplinary approach, rapid
diagnosis (including risk stratification), and, probably most important, improved
and immediate surgical technique.[36]
Catheter-Based Techniques
Modern catheter-based techniques include mechanical fragmentation and/or aspiration
of emboli (including rheolytic thrombectomy), often with intraembolic thrombolytic
injection. The latter “pharmacomechanical thrombolysis” technique exposes a greater
embolic surface area to the drug's effect.[37] Simple thrombolytic infusion into the pulmonary artery proximal to the embolus appears
to be no more efficacious than systemic delivery.[35]
[38]
Although various catheter-based devices exist, only minimal evidence-based data support
each of them; most of the literature consists of observational studies. Early studies
proved that a simple vacuum suction technique could be effective, and there has been
a recent resurgence of interest in this approach.[39] A commonly used method is the rotating pigtail fragmentation catheter, which usually
needs adjunctive aspiration due to distal clot embolization.[35]
[37] Another technique is the AngioJet rheolytic device (Possis Medical, MN) that uses
mechanical thrombolysis and concomitant thrombolytic injection.[40]
[41] Hemolysis may occur with this technique. The use of ultrasound to enhance thrombolytic
permeation of large emboli has been successfully used. The EKOS catheter (EKOS Corporation,
Bothell, WA) is one of the few catheter-based techniques being studied in both retrospective
nonrandomized and prospective randomized clinical trials.[42]
[43]
A novel and promising approach is the AngioVac aspiration system (AngioDynamics, Latham,
NY) that is composed of an extracorporeal bypass circuit that facilitates drainage,
filtration, and reinfusion of blood cleared from unwanted clot material.[44] Already approved by the U.S. Food and Drug Administration, this technique appears
to have promise as an aggressive technique to treat very large emboli, although few
data are published to date. [Table 3] offers a list of catheter-based techniques that have been reported.
Table 3
Catheter-based embolectomy: Available techniques
|
Technique
|
Examples
|
Manufacturers
|
|
Aspiration
|
Greenfield suction catheter
|
Boston Scientific, Watertown, MA
|
|
Local thrombolysis[a]
|
tPA (alteplase)
|
Genentech (Roche), Switzerland
|
|
Fragmentation
|
Rotatable pigtail catheter
|
Cook Europe, The Netherlands
|
|
Mechanical rheolysis
|
Amplatz device
|
Bard-Microvena, White Bear Lake, MN
|
|
Aspirex device[b]
|
Straub Medical, Wangs, Switzerland
|
|
Hydrolyser[b]
|
Cordis, Warren, NJ
|
|
AngioJet[b]
|
Possis, Minneapolis, MN
|
|
Oasis device
|
Boston Scientific
|
|
Angioplasty/stenting
|
Wallstent
|
Schneider Europe AG, Bülach, Switzerland
|
|
Gianturco Z stents
|
Cook Europe, Bjaerskov, Denmark
|
a More than 100 cases reported.
b More than 20 cases reported.
Based on the limited data available regarding the effectiveness of each therapy, the
choice of surgical or catheter-based embolectomy depends on the availability of resources
and institution's expertise.
Conclusions
Substantial progress in technology and clinical research methods have led to advances
in the diagnosis, treatment, and prevention of acute venous thromboembolism over the
past several decades. Although guidelines are useful, they are limited by the existing
evidence-based literature so that controversies remain with regard to when and how
to administer thrombolytic therapy.
The approach to submassive PE is probably the most controversial area in the field
of venous thromboembolism and one in which additional data are clearly needed. Meanwhile,
there should be strong consideration for aggressive therapy in certain “hemodynamically
stable” patients, such as when RV size and function, biomarkers, clot burden (lungs
and legs), and cardiovascular reserve suggest the potential for a high mortality.
No clear submassive PE subtype indicates the clear need for therapy beyond anticoagulation,
but the higher the clot burden, the more abnormal the RV (particularly in the presence
of a positive troponin), and the poorer the oxygenation, the lower the threshold should
be for proceeding with an aggressive approach.
With regard to catheter-based embolectomy procedures, it is still impossible to clearly
specify precise recommendations for use. It is also not possible to determine superiority
of a particular technique due to the lack of comparative and randomized trial data.
However, it appears reasonable to consider one of these procedures in patients with
proven massive PE and hemodynamic instability, especially when thrombolytic therapy
has failed or is contraindicated, as well as in submassive PE patients deemed at high
risk for poor outcome by the evaluating clinician. Many clinicians have concerns that
aggressive approaches to acute PE are underused.[45]
[46] More clinical trials should be conducted.
