Marko Miklič1
New Strategies in the Treatment
of Pulmonary Embolism
ABSTRACT
KEY WORDS: pulmonary embolism, catheter-based therapy, thrombolysis
Pulmonary embolism (PE) represents a major cause of cardiovascular morbidity and mor-
tality. Over the last few years, there has been an increase in the incidence of PE, while
simultaneously the mortality rates associated with PE have been declining. The improved
survival rates in PE are likely to result from the better availability of more precise diag-
nostic methods, better adherence to guidelines and the use of new enhanced therapeu-
tic options. Since hemodynamic compromise is the principal cause of poor outcome in
patients with acute PE, early identification of patients at risk and appropriate risk strat-
ification of patients with PE are essential for further management and can direct the use
of more invasive treatment strategies. Anticoagulation therapy is the cornerstone of treat-
ment for acute PE, while for hemodynamically unstable patients, systemic thrombolysis
is the recommended treatment of choice. However, systemic thrombolysis comes with
a cost of increased risk for major bleeding, including possibly fatal intracranial bleed-
ing. Interventional catheter-based therapies with mechanical thrombectomy or catheter-
-directed thrombolysis with very low doses of thrombolytic offer the possibility for this
bleeding risk to be minimized, while sufficient recanalization of pulmonary arteries allows
for hemodynamic stabilization and improves the patient’s symptoms. The decision when
to use interventional procedures over pharmacological treatment is still a matter of debate,
especially in the intermediate-high-risk group of PE patients. Ongoing studies compar-
ing one interventional method against another, and catheter-based therapies against anti-
coagulation are ongoing. While the results of these studies are eagerly awaited, imple-
mentations of local hospital protocols for optimal PE treatment with consultations between
multidisciplinary specialists in the so-called PE response team are suggested.
1 Marko Miklič, dr. med., Klinični oddelek za žilne bolezni, Univerzitetni klinični center Ljubljana, Zaloška cesta 7,
1000 Ljubljanaa; marko.miklic@gmail.com
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INTRODUCTION
Venous thromboembolism, encompass-
ing deep vein thrombosis and pulmonary
embolism (PE), represents the third most
frequent cause of cardiovascular disease,
with PE being one of the leading causes of
death in hospitalized patients. The incidence
of PE varies between regions and is report-
ed to range from 39–115 per 100,000 per-
sons, with a higher incidence amongst the
elderly. Due to the increasing use of diag-
nostic high-resolution contrast-enhanced
CT of the chest in everyday clinical prac-
tice, especially in cancer patients and
the aging population, the incidence of PE
has been increasing in the last 20 years.
However, time trend analysis suggests
that case fatality rates of acute PE may be
decreasing in the last years (1). This can be
explained by more incidental diagnosis of
PE and reports of minor subsegmental PE,
which may not have the same serious con-
sequences, but also by better patient and
physician disease awareness, adherence
to guidelines, and possibly also due to the
use of new more effective treatment strate-
gies.
Since the pulmonary circulation in
healthy individual is a low-pressure and
low-resistance circuit, the right ventricle
(RV) is especially susceptible to failure in
response to sudden increases in vascular
resistance, as is seen with acute PE. A fail-
ing RV leads to impaired left ventricle fill-
ing and increased pericardial pressure from
the enlarging right heart. Since the inter-
ventricular septum is affected, left ventri-
cular stroke output is also decreased, leading
to neurohormonal activation to stimulate the
contractility and inotropy of the myocardi-
um. Low cardiac output and pulmonary
vasculature obstruction cause ventila-
tion/perfusion mismatch, which contributes
to hypoxemia. The reduction in systemic
blood pressure together with the rise in RV
end-diastolic pressure impairs the right
coronary perfusion causing a further imbal-
ance between oxygen demand and myocar-
dial oxygen delivery, which leads to myocar-
dial ischemia, further worsening of RV
performance and ultimately death (1).
PATIENT STRATIFICATION
AND TREATMENT OPTIONS
Early identification of PE patients that are
at risk of hemodynamic compromise and
death is of paramount importance, and the
stratification of patients based on their clin-
ical state, comorbidities, laboratory markers
of myocardial ischemia and presence of
right heart dysfunction guides further thera-
peutic decisions. Incorporating validated
clinical scores, such as the Pulmonary
Embolism Severity Index (PESI) and the
simplified PESI, allows for the assessment
of a patient’s overall mortality risk and early
outcome.
Patients with hemodynamic instability
are stratified into a high-risk group, while
hemodynamically stable patients are further
stratified into a low- or intermediate-risk
group based on the above-mentioned cri-
teria.
The intermediate-risk group of patients
is further divided into intermediate-low and
intermediate-high-risk, with the latter hav-
ing both positive serum troponin and signs
of RV dysfunction on imaging, while the
intermediate-low-risk group has none or
only one of these criteria, but presenting
an elevated PESI score.
Patients with PE, whose condition is
hemodynamically stable and who have no
RV strain, normal cardiac biomarkers and
a low PESI score, are considered to have
low-risk PE.
Current treatment guidelines recom-
mend the prompt initiation of anticoagu-
lation therapy in all patients with PE and
also recommend systemic thrombolysis
(ST) in high-risk PE patients (1). ST is asso-
ciated with a high risk of major bleeding,
including possibly fatal intracranial hae-
morrhage, therefore, it is estimated that up
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to half of high-risk patients do not get ST due
to a perceived increased risk of bleeding (2).
In patients with intermediate-high-risk
PE, thrombolytic therapy with full dose
recombinant tissue-type plasminogen acti-
vator (rtPA) is associated with a significant
reduction in the risk of hemodynamic
decompensation or collapse, but it is par-
alleled by an increased risk of severe
extracranial and intracranial bleeding.
Smaller studies and meta-analyses have
shown a favourable safety profile of ST with
a reduced dose rtPA in these patients, which
still proved good efficacy, while an ongoing
study is set to confirm these findings (4).
With the advancement of interven-
tional therapies, new therapeutic options
became available for high- and intermedi-
ate-high-risk PE patients who are not can-
didates for ST. A reperfusion of the pul-
monary arteries can be achieved by inserting
a catheter into the proximal pulmonary
artery and aspirating the thrombus –
mechanical thrombectomy (MT). Large
bore aspiration catheters are used to remove
the thrombus, which can be done quickly
and without any patient sedation. Due to the
large diameter of the catheter, careful mani-
pulation and continuous patient monitoring
during the procedure is suggested (2).
Alternatively, a catheter can be left in
place for a few hours, and very low-dose
rtPA perfused through the catheter to
achieve local thrombolysis with minimal
systemic effect. The vast majority of data
for the latter procedure in PE patients
comes from using an ultrasound-facilitat-
ed catheter-directed thrombolysis (CDT).
Both MT and CDT are effective in reducing
the RV diameter and pulmonary artery
pressures after reperfusion, but there is lit-
tle data on hard clinical outcomes in PE
patients, such as death or hemodynamic col-
lapse from randomized controlled trials.
The FLAME study, which was a prospec-
tive nonrandomized interventional study
in high-risk PE patients with hemody-
namic instability, has shown that patients
who got MT had only a 1.9% in-hospital
mortality and a 15.1% probability of clin-
ical deterioration (5). These numbers are
much lower than expected in such a high-
-risk group, but those were selected patients
in a nonrandomized study.
While the need for immediate reper-
fusion therapy in the high-risk group of PE
patients is undeniable, this treatment strat-
egy is less clear in the intermediate-risk
group. As stated before, ST is effective, but
its use was counterbalanced by increased
risk of bleeding. It is still not known whether
using interventional catheter-based thera-
pies (CBT), MT or CDT, offers a better
safety and efficacy profile than ST or even
anticoagulation alone. There are ongoing
studies that will hopefully answer this
question. Meanwhile, implementations
of local hospital protocols for optimal PE
treatment with consultations between mul-
tidisciplinary specialists in the so-called PE
response team are suggested (1). Considering
the patient’s clinical state and the risk for
hemodynamic collapse and bleeding, a deci-
sion is to be made regarding the best treat-
ment option. An analysis of registry data
has identified certain patient characteris-
tics that are correlated with worse outcomes
in intermediate-high-risk PE patients. These
are elevated serum lactate levels, tachy-
pnoea, sinus tachycardia, systolic blood
pressure below 110 mmHg or shock index
(pulse/systolic blood pressure) above 1, ele-
vated markers of RV function and ischemia
(elevated troponin, elevated B-type natri-
uretic peptide, reduced RV function), cen-
tral and large thrombus burden (saddle PE),
concomitant proximal deep vein thrombo-
sis or a right heart thrombus (6). Currently,
CBT should be considered for patients with
high-risk PE in whom thrombolysis is con-
traindicated or has failed. Failure after ST
has been reported in up to 8% of patients
and is defined as no hemodynamic improve-
ment after two to four hours. CBT is also
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a treatment option for initially stable patients
in whom anticoagulant treatment fails,
i.e., those who experience hemodynamic
deterioration despite adequately dosed
anticoagulation, and should be considered
when no improvement is achieved after
24–48 hours of initial anticoagulation (2).
In patients with intermediate-risk PE
and after CBT, a full dose of parenteral anti-
coagulation, preferably with low-molecu-
lar-weight heparin, is recommended. For
stable patients, a switch to a direct oral anti-
coagulant (DOAC), such as apixaban, edox-
aban, rivaroxaban, or dabigatran is also
possible. In intermediate-risk PE patients,
a change to a DOAC after 72 hours of par-
enteral anticoagulant is safe, while in low-
-risk PE patients, an upfront DOAC therapy
with apixaban or rivaroxaban is possible (7).
CONCLUSION
PE treatment is evolving with new CBTs
offering an effective and fast reperfusion of
pulmonary vasculature in patients with
high- or intermediate-high-risk PE. While
these procedures are already performed in
everyday clinical practice, their benefit is
still to be proven. Results from ongoing ran-
domized trials will hopefully give us a bet-
ter insight into whom we should treat more
aggressively and whether these procedures
provide any benefit to PE patients in the
long term.
60 Marko Miklič New Strategies in the Treatment of Pulmonary Embolism
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