Keywords
pulmonary embolism - risk stratification - clinical trials - anticoagulation - systemic
thrombolysis
Schlüsselwörter
Lungenembolie - Risikostratifizierung - klinische Studien - Antikoagulation - systemische
Thrombolyse
Acute Pulmonary Embolism: Contribution of the CTH to the Evolving Concept of Risk-Adapted
Management
Acute Pulmonary Embolism: Contribution of the CTH to the Evolving Concept of Risk-Adapted
Management
Acute pulmonary embolism (PE) is a significant contributor to the global burden of
cardiovascular disease.[1] In Europe, the number of deaths related to venous thromboembolism (VTE) was estimated
to be as high as 370,000 per year, corresponding to approximately 12% of all annual
deaths.[2] This also means that, when the fatalities primarily due to cancer are excluded,
acute PE represents the main direct cause of mortality within the first few weeks
following VTE diagnosis.[3]
[4]
Apart from the impact on the health and well-being of the population, the direct and
indirect costs related to PE and/or deep vein thrombosis are substantial and show
a steadily increasing trend in aging populations throughout the world, particularly
in Europe and North America.[5]
[6]
[7] Economic analyses also highlight in this context the high potential for cost savings
in the future, which can be achieved through the improvement of VTE preventive measures,
the implementation of evidence-based risk-adjusted management algorithms and the better,
timely identification of long-term sequelae of acute PE.
The severity of the acute PE event determines the expected (estimated) risk of early
death. This risk is influenced by:
-
The degree of dysfunction of the right ventricle (RV), as assessed by the presence
of acute RV pressure overload on imaging (echocardiography or computed tomography
pulmonary angiography [CTPA]) and/or elevated cardiac biomarkers (cardiac troponins
or natriuretic peptides) in the circulation.
-
Demographic and clinical factors, including relevant comorbidities, which have been
identified, standardized and validated in clinical prediction rules and scores.[8]
[9]
Haemodynamic instability and cardiogenic shock is at the top of the PE severity spectrum,
as it represents the most extreme manifestation of RV dysfunction/failure and a key
determinant of poor prognosis.[10] In fact, whereas 30-day mortality rates are as low as 0.5% in haemodynamically stable,
‘low-risk’ patients, they can be higher than 20% in patients with haemodynamic collapse.[11] This group of unstable patients (less than 5% of all patients diagnosed with PE)
represents the only accepted indication for the systemic thrombolytic or other reperfusion
therapy to prevent early death.[1] On the other hand, for the vast majority of normotensive PE patients with acute
PE, anticoagulation remains the primary treatment option.[1]
[12] According to current guidelines of the European Society of Cardiology (ESC), these
patients should further be stratified into an intermediate and low risk, to tailor
their initial management. Ideally, risk-adjusted treatment should implement: (1) early
discharge and continuation of anticoagulation treatment at home, in the case of low-risk
PE; or (2) hospital admission and clinical/haemodynamic monitoring in patients at
intermediate risk, as these patients may necessitate rescue reperfusion treatment
in the early period.
The principles of risk stratification of acute PE have been described,[1] and anticoagulant as well as reperfusion treatment modalities have made considerable
progress in the past decade.[13] The challenge is now, however, to integrate all the innovative elements into a holistic
treatment concept, to provide the basis for personalized, risk-adjusted care for patients
with acute PE. The aim of the integrated academic clinical trial programme of the
Center for Thrombosis and Hemostasis (CTH) at the University of Mainz is to develop
and prospectively validate, in multinational studies, strategies for reperfusion and
anticoagulant treatment of acute PE across the entire spectrum of early risk as well
as clinical pathways for post-PE patient care and follow-up. This article gives an
overview of the most important recently completed and on-going studies focusing on
these objectives.
Reperfusion Therapy of Acute PE: Beyond Cardiogenic Shock
Reperfusion Therapy of Acute PE: Beyond Cardiogenic Shock
Recently Completed CTH Studies, Which Have Helped to Shape the Current State of the
Art
The recommendations listed in the current ESC guidelines regarding the use of reperfusion
therapy in normotensive patients with acute PE are largely based on the results of
the international Pulmonary Embolism Thrombolysis (PEITHO) trial.[1]
[14] PEITHO aimed to investigate the efficacy and safety of a single-bolus systemic administration
of tenecteplase, in addition to standard anticoagulation therapy with heparin, in
normotensive patients with intermediate-risk acute PE. Intermediate risk was defined
by RV dysfunction as assessed by echocardiography or CTPA, and a positive test for
cardiac troponin T or I.[14] The results of PEITHO showed that, although associated with improved efficacy, systemic
thrombolysis does not result in net clinical benefit if used as first-line treatment
in patients with acute intermediate-risk PE, due to a high rate of major bleeding.[14] While supporting the current recommendation that routine full-dose intravenous thrombolysis
should not be prescribed to intermediate-risk patients, the results of PEITHO also
highlight that safer forms of reperfusion treatment have the potential to improve
the outcome of at least some of these patients at significant risk of early complications.[11]
Interventional reperfusion techniques, such as catheter-directed low-dose local thrombolysis
(CDT), might represent a valid alternative to surgical embolectomy for selected patients
with high-risk acute PE and an unacceptably high risk of major bleeding complications.
Beyond this relatively narrow indication, reduced-dose systemic thrombolysis[15]
[16] and pharmacomechanical catheter-directed reperfusion techniques[17]
[18] are emerging as a broader alternative to standard-dose systemic lysis. In fact,
in view of their presumed simplicity and safety, these modalities have also been proposed
for normotensive patients with acute PE. However, the evidence to support their use
in this latter setting is only based on data from cohort studies and registries, and
on a small randomized trial with surrogate outcomes.[1]
[17]
[18]
[19]
[20] An assessment of their efficacy and safety based on adequately sized prospective
controlled trials with clinical outcomes is urgently needed.[19] In particular, it needs to be confirmed that CDT, which is administered over a longer
period of up to 15 to 24 hours, is indeed characterized by a low intrinsic risk in
terms of major bleeding.[21]
[22] The results of a recent pooled analysis of prospective and retrospective studies
estimated a pooled rate of approximately 2 to 3% in patients undergoing CDT.[23] Preliminary data on low-dose systemic thrombolysis also suggest a good safety profile,
but remain to be confirmed by larger controlled trials.[15]
Outlook and Implications for Future CTH Academic Trials on Reperfusion Treatment
The first goal that must be achieved for the investigation of novel reperfusion therapies
in clinical practice is the identification of intermediate-risk patients at risk of
‘imminent’ haemodynamic decompensation, given that systemic thrombolysis will remain
the mainstay of treatment for patients presenting with overt haemodynamic instability.[1]
[19] The PEITHO trial, which was designed before the criteria of PE severity were standardized
in international guidelines, demanded no clinical criteria of ‘severe’ PE and it is
therefore likely that this was one of the reasons explaining the low absolute rate
of the combined primary outcome, particularly early mortality.[14] Clinical baseline criteria indicating a high early decompensation risk on anticoagulant
treatment alone have now been proposed on the basis of post hoc analyses of the PEITHO
population.[24] These criteria can be applied in future academic trials to ‘enrich’ the target intermediate-risk
population with patients more urgently in need of pharmaceutical or pharmacomechanical
reperfusion. Moreover, the impact of reperfusion strategies on long-term outcomes
should also be prospectively investigated in future trials. A recent analysis of a
subpopulation of PEITHO, followed for almost 3 years, suggested that thrombolysis
may not influence the risk of late death or long-term complications such as chronic
thromboembolic pulmonary hypertension (CTEPH).[14]
[25] Future multinational studies, which are currently being designed at the CTH in collaboration
with its international academic partners, will address this issue by including longer
follow-up periods and by pre-specifying the assessment of clinical, functional and
haemodynamic parameters best reflecting the patients' well-being over the long term.
Focus on Cost-Effective Management of Low-Risk Pulmonary Embolism
Anticoagulation represents the mainstay of therapy for acute PE and the prevention
of its chronic complications. Anticoagulant therapy consists of an initial phase (5–10
days) of treatment with heparin or oral anticoagulation, an intermediate phase of
treatment of about 3 months and an extended long-term phase for those in whom the
risk of recurrence is expected to outweigh the risk of anticoagulant-related bleeding.[9]
Studies on early discharge and home treatment of PE conducted thus far[3]
[4]
[5]
[6] adopted standard anticoagulation regimens of initial subcutaneous heparin administration
followed by a vitamin K antagonist. Only two of these trials had an in-hospital comparator
arm.[3]
[6] Taken together, the results suggest that home treatment is not inferior to in-patient
treatment with regard to early clinical outcomes. Despite this encouraging evidence,
however, the vast majority of patients with acute PE are still treated in-hospital
at the global level.[26]
The results of the trials investigating non-vitamin K antagonist oral anticoagulants
(NOACs) indicate that these drugs have a non-inferior efficacy profile and an improved
safety profile compared with vitamin K antagonists. This is true for all patients
with VTE, including symptomatic acute PE.[27] Moreover, single oral drug regimens for PE may minimize the patients' perceived
burden of anticoagulation, and possibly the costs related to hospitalization and bleeding
events.[28] An optimization of PE management must therefore include the identification of low-risk
patients who can be safely discharged early after diagnosis and continue with contemporary
ambulatory (NOAC) treatment.
Rationale and Design of the Home Treatment of Pulmonary Embolism (HoT-PE) Management
Trial
The main requirements for the identification of potential candidates for early discharge
include the clinical severity of PE, the presence and burden of co-morbidities, and
the feasibility of home treatment based on the patient's family and social environment.
Patients at low risk can be identified on the basis of clinical risk assessment models,
notably the Pulmonary Embolism Severity Index (PESI), its simplified version (sPESI)
or the Hestia decision rule. The Hestia criteria were used in three studies (607 patients),
whereas the PESI formed the basis for selection in two studies (242 patients) and
the sPESI in one small study (31 patients).[29] Overall, both the Hestia rule and the (s)PESI clinical parameters appear capable
of reliably identifying patients who are at low PE-related and overall risk. Consequently,
either of them may be used for clinical triage according to local experience and preference.
On the other hand, neither the PESI nor the Hestia rule provide direct information
on the status of the RV, a key determinant of early prognosis in acute PE. Therefore,
an additional selection criterion, namely the absence of RV dysfunction and of free-floating
thrombi in the heart on echocardiography (or CTPA), addresses the concerns generated
after the premature termination of a prior randomized trial based exclusively on clinical
assessment.[6] In fact, accumulating data suggest that the presence of RV dysfunction on imaging,
in patients classified as being at low risk of complications based on a clinical score
(e.g., PESI) alone, may be associated with an adverse outcome[30]
[31]; this may also be the case for a positive troponin result.[32]
The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective, international,
multicentre, phase IV, investigator-initiated and academically sponsored trial, aiming
to determine whether early discharge and out-of-hospital treatment of low-risk acute
PE patients with the oral factor Xa inhibitor rivaroxaban is feasible, effective and
safe.[33] In light of the already available data derived from the large phase III randomized
trials and since early discharge is already being practised (therefore not requiring
an ‘in-hospital’ control arm), the HoT-PE study was designed as a single-arm management
trial ([Fig. 1]). Consecutive patients with a confirmed diagnosis of acute PE are included, if they
have (1) no evidence of RV enlargement or dysfunction, and (2) no free-floating thrombi
in the right heart chambers, as determined by echocardiography or CTPA[11] ([Table 1]).
Table 1
Inclusion and exclusion criteria of the HoT-PE (Home Treatment of Pulmonary Embolism)
study
|
Inclusion criteria
|
Exclusion criteria
|
|
1. Age ≥18 y
2. Objectively confirmed diagnosis of acute PE by multidetector CT, V/Q lung scan
or selective pulmonary angiography, according to established diagnostic criteria,
with or without symptomatic DVT
3. Absence of RV enlargement or dysfunction, and of free-floating thrombi in the right
atrium or right ventricle on echocardiography or CT. On echocardiography, RV dysfunction
is absent when both of the following criteria listed below are met:
i. Right/left ventricular end-diastolic diameter ratio ≤0.9 (apical or subcostal
4-chamber view)
ii. No paradoxical motion of the interventricular septum
On CT, RV enlargement is absent when the following criterion is met: right/left short-axis
diameter ratio
4. Ability of patient to understand the character and consequences of a clinical trial
5. For women of childbearing potential, negative pregnancy test before enrolment and
medically accepted contraception throughout the trial
6. Signed and dated informed consent of the patient available before the start of
any trial procedures
|
1. Haemodynamic instability at presentation[a]
2. Use of a fibrinolytic agent, surgical thrombectomy, interventional (transcatheter)
thrombus aspiration or lysis, or use of a cava filter to treat the index episode of
PE
3. Active bleeding or known significant bleeding risk
4. Need for supplemental oxygen administration to maintain oxygen saturation >90%
5. Chronic treatment with a vitamin K antagonist, rivaroxaban or any other oral or
parenteral anticoagulant drug
6. Pain requiring parenteral administration of analgesic agents
7. Other medical conditions/comorbidities requiring hospitalization
8. Acute PE diagnosed in a patient already hospitalized for another condition
9. Non-compliance or inability to adhere to treatment or to the follow-up visits;
or lack of a family environment or support system for home treatment
10. Severe renal insufficiency (eGFR <15 mL/min/1.73 m2 by the MDRD formula), or end-stage renal disease
11. Severe hepatic failure
12. Pregnancy or lactation
13. History of hypersensitivity to the study drug
14. Treatment of the acute (index) episode with unfractionated heparin, low-molecular-weight
heparin, fondaparinux or a new oral anticoagulant for more than 48 hours, or with
more than a single dose of a vitamin K antagonist prior to inclusion in the study
15. Concomitant administration of strong inhibitors of P-gp and CYP3A4 such as azole
antimycotic agents or HIV protease inhibitors
16. Need for long-term treatment vitamin K antagonists, or for antiplatelet agents
except acetylsalicylic acid at a dosage ≤100 mg/d
17. Participation in other clinical trials within the last 6 months
18. Medical or psychological condition that would not permit completion of the trial
or signing of informed consent
19. Life expectancy less than 3 months
|
Abbreviations: CT, computed tomography; DVT, deep vein thrombosis; eGFR, estimated
glomerular filtration rate; HIV, human immunodeficiency virus; MDRD, Modified Diet
in Renal Disease formula for calculation of the glomerular filtration rate; PE, pulmonary
embolism; RV, right ventricular; V/Q, ventilation-perfusion (lung scan).
a Indicated by at least one of the following criteria: (1) systemic blood pressure
less than 100 mm Hg, or heart rate above 100 bpm, or a drop in systemic blood pressure
by more than 40 mm Hg for at least 15 minutes; (2) need for catecholamines to maintain
organ perfusion and systolic blood pressure above 100 mm Hg; (3) need for cardiopulmonary
resuscitation.
Fig. 1 Overview of the Home Treatment of Pulmonary Embolism (HoT-PE) management study. bid,
twice daily; od, once daily; PE, pulmonary embolism; VTE, venous thromboembolism.
(Reproduced with permission from Barco et al.[33])
Patients enrolled in the study receive the first dose of rivaroxaban less than 2 hours
before the time that the next subcutaneous injection of heparin would be due. Rivaroxaban
is prescribed at the approved dose, namely 15 mg twice daily over the first 3 weeks
followed by 20 mg once daily for a total of at least 3 months. Patients are discharged
from the hospital within 48 hours of presentation. The primary efficacy outcome is
symptomatic recurrent VTE or PE-related death within 3 months of enrolment. The secondary
efficacy outcomes include all-cause mortality, overall duration of hospital stay,
the number of re-hospitalizations due to PE or to a bleeding event, generic and disease-specific
quality of life, treatment satisfaction and the utilization of health care resources
at 3 weeks and 3 months. All outcomes are adjudicated by an independent committee.
HoT-PE is registered under the identifier of EudraCT number 2013–001657–28. The enrolment
of the last patient is expected by November 2018, depending on the results of the
pre-specified interim analysis after the inclusion of 525 patients in July 2018.
Adjusted Initial Anticoagulation Concept for Intermediate-Risk Pulmonary Embolism
Adjusted Initial Anticoagulation Concept for Intermediate-Risk Pulmonary Embolism
Normotensive patients at intermediate risk, i.e. with at least one indicator of elevated
PE-related risk, or with aggravating conditions or comorbidity, should be hospitalized.
Within this group, patients with signs of RV dysfunction on echocardiography or CTPA
accompanied by a positive troponin test should be monitored over the first hours or
days due to the risk of early haemodynamic decompensation and circulatory collapse.[14] Primary reperfusion treatment, notably full-dose systemic thrombolysis, is not routinely
recommended in these patients, since the risk of potentially life-threatening bleeding
complications appears too high.[14] However, rescue thrombolytic therapy or, alternatively, surgical embolectomy or
percutaneous catheter-directed treatment may become necessary for patients who develop
signs of haemodynamic instability.[1]
Rationale and Design of the Pulmonary Embolism International Trial (PEITHO)-2
Patients diagnosed with intermediate-risk PE represent as many as 50% of all patients
with acute PE and are characterized by a substantial risk of developing early adverse
outcomes (∼8% overall). All NOACs approved for the treatment of acute VTE have been
tested in large phase III trials including a significant proportion of patients with
acute PE. However, their safety and efficacy have not been systematically investigated
in patients enrolled based on their risk class. A post-hoc analysis of the Hokusai-VTE
study, which compared edoxaban versus standard of care (warfarin), focused on patients
with intermediate-risk PE, as defined by positive N-terminal pro-brain natriuretic
peptide (NT-proBNP) and right to left ventricular diameter ratio on CTPA as indicators
of RV dysfunction. The results suggested that recurrent VTE rates were lower with
edoxaban than warfarin.[34]
The ongoing PEITHO-2 (Pulmonary Embolism International Trial-2) study is a prospective,
multicentre, multinational, single-arm trial aiming to investigate whether acute intermediate-risk
PE patients can be safely managed with a short-term course of parenteral heparin anticoagulation
over the first 72 hours, followed by the direct oral thrombin inhibitor dabigatran
at the dosage of 150 mg twice daily over 6 months ([Fig. 2]). A reduced dose of 110 mg twice daily is recommended for patients aged 80 years
or older and for those receiving verapamil, according to the European Summary of Product
Characteristics. Patients with objectively confirmed diagnosis of symptomatic acute
intermediate-risk PE, with or without symptomatic deep vein thrombosis, who are haemodynamically
stable at presentation, are eligible for enrolment in the study ([Table 2]). The key inclusion criteria include the absence of haemodynamic decompensation
or collapse at presentation, and the presence of intermediate-risk PE, as defined
by elevated troponin levels or NT-proBNP, or by RV pressure dysfunction/enlargement
on echocardiography or CTPA.
Table 2
Inclusion and exclusion criteria of PEITHO-2 (Pulmonary Embolism International Trial-2)
|
Inclusion criteria
|
Exclusion criteria
|
|
1. Age ≥18 y
2. Objectively confirmed diagnosis of acute PE, with or without DVT[1]
3. No haemodynamic decompensation or collapse at presentation (none of the following):
i. Need for cardiopulmonary resuscitation;
ii. Systolic BP < 90 mm Hg, or drop by ≥40 mm Hg, for at least 15 minutes, with
clinical signs of end-organ hypoperfusion (cold extremities, urinary output < 30 mL/h,
mental confusion)
iii. Need for catecholamines to maintain adequate organ perfusion and a systolic
BP of > 90 mm Hg
4. Intermediate-risk PE (≥1 of the a, b or c criteria):
a. Elevated troponin levels[a]
b. NT-proBNP levels > 600 pg/mL
c. RV pressure overload/dysfunction on CT angiography or echocardiography:
i. CTPA: RV/LV end-diastolic diameter ratio >1.0
ii. echocardiography (any of the following):
- RV/LV end-diastolic diameter ratio > 1.0 (apical or subcostal 4-chamber view)
- RV end-diastolic diameter > 30 mm (parasternal long-axis or short-axis view)
- RV free wall hypokinesis (any view)
- Tricuspid regurgitant jet velocity > 2.6 m/s
- Absence of inspiratory collapse of the inferior vena cava
|
1. Any medical or psychological condition that would not permit signing of informed
consent or completion of the trial; unwillingness or inability to adhere to treatment
or to the follow-up visits
2. Pregnancy or lactation (or women of childbearing potential not practising a medically
accepted contraception during the trial)
3. History of hypersensitivity to dabigatran
4. Use of a fibrinolytic agent, surgical embolectomy, interventional (catheter-directed)
thrombus aspiration or lysis, or use of a vena cava filter
5. Active bleeding or known significant bleeding risk
6. Need for long-term treatment with any anticoagulant, or need for antiplatelet agents
except acetylsalicylic acid ≤100 mg/d
7. Artificial heart valves requiring treatment with an anticoagulant
8. Renal insufficiency with estimated creatinine clearance < 30 mL/min/1.73 m2
9. Chronic liver disease with aminotransferase levels two times or more above the
local upper limit of normal range
10. Concomitant administration of strong inhibitors of P-glycoprotein like ketoconazole,
cyclosporin, itraconazole or dronedarone
11. Life expectancy less than 6 months
|
Abbreviations: BP, blood pressure; CTPA, computed tomography pulmonary angiography;
DVT, deep vein thrombosis; LV, left ventricular; NT-proBNP, N-terminal pro brain natriuretic
peptide; PE, pulmonary embolism; RV, right ventricular; VTE, venous thromboembolism.
a Troponin elevation is defined as an abnormal result of any validated troponin test
based on the reference values determined by the local Department of Clinical Chemistry
at each participating site.
Fig. 2 Overview of design of the PEITHO-2 (Pulmonary Embolism International Trial-2) study.
CE, clinical evaluation; I, inclusion; LMWH, low-molecular-weight heparin; PE, pulmonary
embolism; T, time. (Reproduced with permission from Klok et al.[50])
The primary efficacy outcome is recurrent symptomatic VTE or death related to PE within
the first 6 months. The primary safety outcome is major bleeding as defined by the
International Society on Thrombosis and Haemostasis (ISTH). Secondary outcomes include
all-cause mortality, the overall duration of hospital stay (index event and repeated
hospitalizations) and the temporal pattern of recovery of right ventricular function
over the 6-month follow-up period. All outcomes are adjudicated by an independent
committee.
The PEITHO-2 study (EudraCT No.: 2015–001830–12) will determine which patients within
the large group and broad spectrum of intermediate-risk PE may need initial heparin
treatment and monitoring, and how long this initial parenteral phase should last.
Finally, the PEITHO-2 study will contribute to determine the extent and speed of cardiac
recovery after acute PE, and its prognostic role over the long term.
Long-Term Follow-up and Late Outcome after Acute PE
Long-Term Follow-up and Late Outcome after Acute PE
The risk to die or develop persistent serious disability after acute PE declines over
time but remains elevated for months or years, reflecting in part the severity of
the initial event and the burden of the individual's comorbidity.[9] More specifically, recurrent VTE occurs in approximately 22% of patients after 5
years,[35] whereas a small but non-negligible proportion (∼3%) of PE survivors are expected
to develop CTEPH during the first 2 years of follow-up.[36]
CTEPH is thought to result from incomplete resolution of pulmonary emboli[1]
[37]; therefore, appropriate management of (and after) acute PE may help limit its occurrence.
Although the diagnosis and management of CTEPH have made considerable progress in
recent years,[38]
[39] its clinical and haemodynamic predictors and/or prodromes, starting at diagnosis
of acute PE, have not been prospectively investigated and determined. Since CTEPH
is a potentially devastating, but also surgically ‘curable’, obstructive disease of
the pulmonary vessels with thrombofibrotic material, its prediction and early identification
may significantly improve the outcome of these patients.[40]
Beyond the objective not to miss clinically manifest CTEPH, the clinical follow-up
of PE patients after the (presumed) index PE event as well as the elaboration of a
cost effective ‘post-PE’ management algorithm represents a complex, unaccomplished
task. It is established, as reviewed in Klok and Barco,[41] that dyspnoea and/or poor physical performance may persist in up to 50% of patients
6 months to 3 years after the index PE, and up to 75% may perceive their own health
status as being ‘worse’ than before the acute PE episode. The concept of post-PE impairment
(PPEI), or the ‘post-PE syndrome’, has been proposed to provide an umbrella for a
rather heterogeneous group of patients presenting with complaints and/or abnormal
clinical findings, along with imaging, functional or haemodynamic abnormalities, several
months or years acute PE. In the minority of cases, these findings will be followed
by the development of CTEPH.[42]
[43]
[44]
[45] The definition of PPEI is still evolving, and its characteristics and the potential
predictors of further functional worsening remain to be identified.
Rationale and Design of the Follow-up after Acute Pulmonary Embolism (FOCUS) Cohort
Study
The prospective FOCUS cohort study aims to answer clinically relevant questions regarding
the predictors and prognostic factors of the transition from acute PE to PPEI and
(possibly) CTEPH. In this multicentre patient cohort, the participating sites are
large-volume expert centres, which have standardized and harmonized their existing
follow-up programmes after acute PE; they prospectively enrol consecutive, unselected
symptomatic PE patients and collect data during follow-up visits at predefined intervals
([Table 3]). A predefined sample size of more than 1,000 patients will allow adequate estimation
of PPEI or CTEPH rates as well as a prospective assessment of the changes leading to PPEI, which
has been prospectively defined in this study by a combination of clinical, functional,
haemodynamic and imaging abnormalities ([Table 4]). The approach of viewing CTEPH as part of a continuum of late PE sequelae has its
rationale in the assumption that persisting or progressive functional and/or haemodynamic
impairment after acute PE is an early indicator of the development of CTEPH.
Table 3
Design and data collection schedule of the follow-up after acute pulmonary embolism
(FOCUS) study
|
Variable
|
In-hospital
|
Follow-up
|
|
Enrolment
|
Discharge
|
3 mo
|
12 mo
|
24 mo
|
|
Medical history
|
x
|
|
|
|
|
|
Demographic data[a]
|
x
|
|
|
|
|
|
Clinical examination[b]
|
x
|
|
x
|
x
|
x
|
|
Imaging (PE diagnosis)
|
x
|
|
|
|
|
|
Echocardiography
|
x
|
x
|
x
|
x
|
x
|
|
Cardiopulmonary exercise testing
|
|
|
x
|
x
|
x
|
|
Laboratory diagnostic and safety tests[c]
|
x
|
x
|
x
|
x
|
x
|
|
Pharmacological treatment
|
x
|
x
|
x
|
x
|
x
|
|
Haemodynamic collapse
|
x
|
x
|
x
|
x
|
x
|
|
Survival status
|
|
x
|
x
|
x
|
x
|
|
Re-hospitalization
|
|
|
x
|
x
|
x
|
|
Stroke
|
|
x
|
x
|
x
|
x
|
|
Symptomatic recurrent DVT/PE
|
|
x
|
x
|
x
|
x
|
|
Bleeding events
|
|
x
|
x
|
x
|
x
|
|
Functional status[d]
|
|
|
x
|
x
|
x
|
|
Diagnostic work-up for CTEPH[e]
|
|
|
x
|
x
|
x
|
|
Generic quality of life[f]
|
|
|
x
|
x
|
x
|
|
Disease-specific quality of life[g]
|
|
|
x
|
x
|
x
|
Abbreviations; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein
thrombosis; PE, pulmonary embolism.
Source: Adapted from Konstantinides et al.[45]
a Date of birth, gender, height, weight.
b Presentation and symptomatology, vital signs; 12-lead ECG.
c Serum creatinine, creatinine clearance (MDRD-estimate), TSH, O2-saturation (pulse oximetry), haematocrit, thrombocytes, leucocytes, aPTT, PT, INR,
troponin T or I, NT-pro-BNP, BNP, CRP, D-dimer.
d WHO functional class, Borg dyspnoea index.
e CT pulmonary angiography, V/Q scan; selective pulmonary angiography, right heart
catheterization.
f EQ-5D questionnaire.[46]
g PEmb-QoL questionnaire.[47]
Table 4
Primary, secondary and safety outcomes of FOCUS
|
Co-primary outcomes[a]
|
|
1) Confirmed diagnosis of CTEPH at any time during the 2-year follow-up
|
|
2) Post-PE impairment, defined by deterioration (compared with the findings at discharge,
or to the previous follow-up visit) by at least one category, or persistence of the greatest severity category, in ≥1 of ‘a’ parameters plus deterioration by at least one category, or persistence of the greatest severity category, in ≥1 of ‘b’ parameters:
|
|
a) Echocardiographic parameters of pulmonary hypertension and/or RV dysfunction [b]
a1) RV basal diameter (D1)
a2) RA end-systolic area
a3) TAPSE
a4) LV eccentricity index
a5) Estimated RA pressure
a6) Systolic TR jet velocity
a7) Pericardial effusion
|
b) Clinical, functional and laboratory parameters of RV failure [b]
b1) New appearance of symptoms or progression of existing symptoms
b2) Clinical evidence of RV failure
b3) Syncope
b4) WHO functional class
b5) Six-minute walking distance
b6) BNP or NT-proBNP plasma levels
b7) Cardiopulmonary exercise testing
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|
Secondary outcomes
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-
Overall and disease-specific mortality during follow-up
-
Symptomatic recurrence of DVT or PE
-
Re-hospitalization for reasons related to VTE, CTEPH or complications of their treatment
-
New diagnosis of cancer
-
Acute myocardial infarction
-
Stroke
-
Functional limitation (peak O2 consumption and systolic blood pressure on cardiorespiratory exercise testing; 6-minute
walking distance and Borg dyspnoea index)
-
Evidence of pulmonary hypertension/right ventricular dysfunction on echocardiography
-
Evidence of pulmonary vascular abnormalities on cardiopulmonary exercise testing[c]
-
Generic and disease-specific quality of life using the EQ-5D and the PEmb-QoL questionnaires
|
|
Safety outcomes
|
|
1) Major bleeding during hospitalization for the index event, based on the ISTH definition[48]
2) Fatal bleeding at any time during follow-up
|
Abbreviations: BNP, brain natriuretic peptide; CTEPH, chronic thromboembolic pulmonary
hypertension; EQ-5D, Euro Quality of life five dimensions (questionnaire); ISTH, International
Society on Thrombosis and Haemostasis; NT-proBNP, N-terminal pro-brain natriuretic
peptide; PE, pulmonary embolism; PEmb-QoL, Pulmonary Embolism Quality of Life (questionnaire);
RA, right atrial; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion;
TR, tricuspid regurgitation; VTE, venous thromboembolism; WHO, World Health Organization.
Source: Adapted from Konstantinides et al.[45]
a See statistical analysis for details.
b See [Table 3] for severity classification of individual findings and parameters.
c Indicated by at least one of the following: PETCO2 at AT (end-tidal partial carbon dioxide pressure at anaerobic threshold) <31.33 mm
Hg; P(a-ET)CO2 > 5.18 mm Hg; EQ O2 (oxygen ventilatory equivalent) >30.5; EQ CO2 (carbon dioxide ventilatory equivalent) > 35.5; VE/VCO2 slope (ventilator efficiency for carbon dioxide) >37.5; P(A-a) O2 (alveolar–arterial oxygen gradient) > 36.97 mm.[49]
FOCUS enrols all-comers, i.e., unselected patients with acute PE, irrespectively of
the clinical severity, evidence and degree of RV dysfunction, or characteristics of
PE. The primary objective of the study is to determine the cumulative (2-year) incidence
of: (1) CTEPH and (2) persisting or progressive functional and/or haemodynamic PPEI
([Table 4]). Secondary objectives are to determine overall and disease-specific long-term mortality,
the incidence of major adverse cardiovascular events, predictors as well as indicators
of functional/haemodynamic impairment, fatal bleeding complications associated with
long-term anticoagulant treatment for VTE and the patients' generic and disease-specific
quality of life. All outcomes are adjudicated by an independent clinical events committee.
A multicentre biobanking substudy ‘Biochemical and Genetic Biomarkers in Sequelae
of Acute Pulmonary Embolism Study (FOCUS BioSeq)’ is being conducted within the FOCUS
cohort. The study has been registered in the German Clinical Trials registry (www.germanctr.de; identifier: DRKS00005939). Enrolment of the last patient was in October 2018; the
2-year follow-up will be completed 2 years later.
Conclusion
The concept of risk-adapted management of acute PE is relatively novel and is leading
to considerable improvement in clinical care. Present and future challenge is represented
by further implementation and systematic introduction into clinical practice of personalized,
risk-adjusted management strategies. The aim of the integrated academic clinical trial
programme of the CTH at the University of Mainz is to develop and prospectively validate,
in multinational studies, such strategies for the acute management, as well as long-term
patient care and follow-up, of acute PE.
