Thesis
Reference
Risk Stratification in patients with acute pulmonary embolism
MARTI, Christophec
Abstract
Risk stratification is one of the cornerstones of the management of acute pulmonary embolism (PE) and may affect the choice of both diagnostic and therapeutic strategies. Critical steps requiring risk stratification in patients with acute PE include identification of patients at very high risk of early mortality requiring immediate diagnostic and rescue therapies; identification of patients at low-risk of complications who can be treated as outpatients and identification of normotensive patients with an increased risk of complications requiring reperfusion therapy or close monitoring.
MARTI, Christophec. Risk Stratification in patients with acute pulmonary embolism. Thèse de privat-docent : Univ. Genève, 2020
DOI : 10.13097/archive-ouverte/unige:135707
Available at:
http://archive-ouverte.unige.ch/unige:135707
Disclaimer: layout of this document may differ from the published version.
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Clinical Medicine Section Department of Medicine
"
Risk Stratification in patients with acute pulmonary
embolism"
Thesis submitted to the Faculty of Medicine of the University of Geneva
for the degree of Privat-Docent by
Christophe Albéric MARTI
Geneva
2019
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RISK STRATIFICATION IN ACUTE
PULMONARY EMBOLISM
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Table of contents
Summary ... 4
Acknowledgements ... 5
Abbreviations ... 6
Introduction ... 7
Epidemiology of acute pulmonary embolism ... 7
Clinical course and physiopathology ... 7
Rationale for risk stratification ... 8
Risk stratification step one: Identification of patients at high risk of mortality. ... 10
Risk stratification step 2: Estimating 30-day mortality based on clinical parameters ... 13
Risk stratification step 3: Further categorisation of normotensive PE ... 19
Clinical scores ... 19
Markers of right ventricular dysfunction or injury ... 20
Impact studies evaluating thrombolytic therapy for normotensive PE with RVD ... 22
Markers of Circulatory failure ... 26
Thrombotic burden ... 26
Combination of clinical parameters, Markers of RVD or injury and markers of circulatory failure ... 27
Between scores comparison ... 31
Implications for practice of the intermediate-high risk category ... 33
Conclusions and perspectives ... 35
References ... 37
Tables and Figures ... 41
Tables ... 41
Figures ... 41
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Summary
Risk stratification is one of the cornerstones of the management of acute pulmonary embolism (PE) and may affect the choice of both diagnostic and therapeutic strategies. Critical steps requiring risk stratification in patients with acute PE include identification of patients at very high risk of early mortality requiring immediate diagnostic and rescue therapies; identification of patients at low-risk of complications who can be treated as outpatients and identification of normotensive patients with an increased risk of complications requiring reperfusion therapy or close monitoring
The presence of shock or patent circulatory failure is associated with a high risk of immediate mortality and requires a rapid diagnostic strategy and rescue reperfusion therapy. In this setting, bedside echocardiography may be sufficient to establish the diagnosis of PE and reperfusion therapies such as medical or mechanical thrombolysis are recommended. The benefit of thrombolytic therapy in haemodynamically unstable PE has been demonstrated in small randomised controlled trials and is supported by large observational studies.
In haemodynamically stable patients with confirmed PE, the second step of risk stratification is the estimation of 30-day mortality based on clinical parameters. The different versions of the Pulmonary Embolism Severity Index (PESI and simplified PESI) have been extensively validated and allow the identification of low-risk patients who can be treated as outpatients. The safety of this strategy has been evaluated in an interventional impact study.
Finally, haemodynamically stable patients with non-low PESI scores (PESI ≥ III or sPESI ≥ 1) are considered at intermediate risk of mortality and require hospital admission. While most of these patients will have a favourable outcome with anticoagulant therapy, some of them might benefit from a more aggressive approach including reperfusion therapies or admission to a monitored unit. This heterogeneous group of patients may be further stratified based on the presence of RVD on imaging and elevation of cardiac biomarkers.
Patients with normotensive PE and signs of RVD and/or elevation of cardiac biomarkers have an increased risk of mortality and need for rescue reperfusion. However, this latter categorisation has poor positive predictive value and is insufficient to identify patients who would benefit from a more aggressive therapy. Interventional studies in patients with normotensive PE and RVD failed to demonstrate a benefit of thrombolytic therapy.
Therefore, efforts to improve risk stratification among patients with normotensive PE have been made by combining clinical and biological biomarkers, utilisation of novel biomarkers or alternative predictors of respiratory or circulatory failure. Some of these models have shown interesting prognostic accuracy and might contribute to improve the management of this subgroup of patients. However, further validation and impact studies are required before recommending their implementation in clinical decision making.
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Acknowledgements
My sincere thanks go to
Arnaud Perrier, François Sarasin, Martine Louis Simonet and Jean-Luc Reny for their trust and support throughout the years
Olivier Grosgurin, Pauline Darbellay-Fahroumand, Thomas Agoritsas, Jérôme Stirnemann, Sebastian Carballo, Mathieu Nendaz and Jacques Serratrice, my fellows and colleagues in the division of General Internal Medicine
Olivier Rutschmann, Majd Ramlawi and Elisabeth Andereggen, my colleagues and partners at the Emergency Department
Virginie Prendki and Nicolas Garin for our enriching collaborations
All the residents and senior physicians for their skills and friendship in the daily clinical duties
Paramedical teams at the Emergency Department and at the Medical intermediate care Unit for their rewarding collaboration
My parents for their love and support
Yasmina, Malik and Imane, my beloved family
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Abbreviations
AC: Anticoagulation AUC: Area under curve BNP: Brain natriuretic peptide CT: Computed tomography
CTPA: Computed tomography pulmonary angiography CTPEH: Chronic thromboembolic pulmonary hypertension DOACs: Direct oral anticoagulants
DVT: Deep vein thrombosis
ESC: European society of cardiology
H-FABP: Heart-type fatty acid-binding protein ICU: Intensive care unit
IMC: Intermediate care unit
LMWH: Low-molecular weight heparin LR: Likelihood ratio
NT-proBNP: N-terminal brain natriuretic peptide PE: Pulmonary embolism
PESI: Pulmonary embolism severity index
RIETE: Registro Informatizado de la Enfermedad Trombo Embolica venosa RVD: Right ventricular dysfunction
RVP: Right ventricular pressure
sPESI: Simplified pulmonary embolism severity index TT: Thrombolytic therapy
UFH: Unfractionated heparin
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Introduction
Pulmonary embolism (PE) is the third most frequent cardiovascular disease1. Pulmonary embolism is defined as the obstruction of a pulmonary artery by material, most frequently thrombi originating from the lower limbs. PE may present as an acute symptomatic disease (acute PE) or may be diagnosed incidentally or as a chronic disease (chronic thrombo-embolic pulmonary hypertension CTEPH). Risk assessment is a cornerstone in the management of acute PE as it will impact the decision to admit the patient to the hospital or to a monitored unit (intermediate care (IMC) or Intensive care unit (ICU)) and the need for more intensive interventions such as systemic thrombolysis or mechanical thrombectomy2. The present manuscript will review the rationale and evidences supporting risk stratification strategies in the management of acute PE.
Epidemiology of acute pulmonary embolism
Pulmonary embolism (PE) has a wide variety of presentations, ranging from an asymptomatic incidental finding to circulatory collapse or sudden death. The incidence rises with age and is estimated over 500/100,000 in populations over 75 years old. In Europe, PE accounts for about 300,000 deaths annually3. Large registries of unselected patients report a 30 day mortality between 9% and 11%, and three-month mortality between 8.6% and 17%4-6. Mortality rates declined over time between 1999 and 2015 among medicare beneficiaries7. The vast majority of fatal cases of PE is due to PE presenting as sudden fatal PE or undiagnosed PE, while adequately diagnosed PE only represent about 7% of fatal cases3. Interestingly, PE attributable mortality represents only about one third of the three months mortality in patients with PE, the remaining being attributable to co-morbid illnesses such as cancer or other diseases or treatment complications.5,6.
Clinical course and physiopathology
Acute PE usually results from the dislodgement of thrombotic material of the lower limbs and embolization to the pulmonary arterial system. Obstruction of the pulmonary arterial vessel occurs when the size of the embolus exceeds the size of the affected vessel and may therefore occur more or less proximally according to the size of the embolus. Small thrombi result in the obstruction of segmental or sub-segmental arteries which may lead to pulmonary infarction, while multiple or larger size thrombi may lead to an acute increase in pulmonary vascular resistance (PVR). Among previously healthy individuals, the correlation between the degree of pulmonary arterial obstruction and pulmonary pressure is non-linear. Pulmonary pressure elevation is negligible until obstruction involves more than 30-50% of the arterial bed but increases rapidly over this threshold8. Moreover, hypoxic vasoconstriction of the pulmonary
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arterial system may further increase PVR leading to right ventricular pressure overload and eventually right ventricular dysfunction (RVD). An acute increase in mean pulmonary arterial pressure above 40mmHg results in right-ventricular dilatation and failure. Acute RVD may lead to hemodynamic instability. Hemodynamic instability or shock is present in a small percentage of patients with PE (around 5%5,9). The mechanisms leading to RV failure and cardiogenic shock are described in figure 1. According to the European society of cardiology (ESC), haemodynamic instability is defined by a systolic blood pressure inferior to 90 mmHg for more than 15 minutes, hypotension requiring vasopressors, or clear evidence of shock.Figure 1: Factors leading to haemodynamic collapse in acute PE according to the ESC 10
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
Rationale for risk stratification
Risk stratification is an important step in various medical conditions and publications evaluating prognostic scores or biomarkers are abundant. Risk stratification may allow to stratify patient’s severity in therapeutic trials or may be used to guide specific diagnostic or therapeutic interventions. Risk stratification often relies on prognostic scores based on clinical or biological parameters. Traditional steps in the development of a prognostic tool include derivation, internal and external validation and eventually impact studies evaluating the benefit of a prognostic-tool based clinical decision making compared to usual care. While derivation and validation studies are plentiful, impact studies are scarce11. The critical steps in the development and validation of clinical prediction rules are illustrated in Table 1.
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Table 1: Steps in the development and evaluation of clinical prediction rules.(adapted fromReilly et al11)
Level of evidence Definition and standards of evaluation Implications for clinicians
Level 1: Derivation Identification of predictors using multivariate model; blinded assessment of outcomes
Needs validation before clinical use
Level 2: Narrow validation Verification of predictors tested prospectively in 1 setting; blinded assessment of outcomes
Needs validation in varied settings May be used cautiously in similar patients
Level 3 Broad validation Verification of predictors in varied settings with wide spectrum of patients
Needs impact analysis, may use with confidence in accuracy
Level 4 Narrow impact analysis Prospective demonstration in 1 setting that use of the model improves outcomes
May use to inform decisions in similar settings
Level 5: broad impact analysis Prospective demonstration in various settings that use of the model improves outcomes
May use in varied settings with confidence that it will improve outcomes
In the setting of acute PE, various clinical decisions may require accurate risk stratification.
These main steps are: identification of patients at very high risk of early mortality who will require immediate diagnostic and rescue therapies; identification of patients a t low-risk of complications who will safely be treated as outpatients; identification of patients with an increased risk of complications requiring reperfusion therapy or close monitoring.
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Risk stratification step one: Identification of patients at high risk of mortality.
The first step in risk stratification of acute PE is the identification of patients at very high risk of early mortality requiring immediate diagnostic and rescue therapies. As discussed previously, the most feared complication of acute PE is RV overload and dysfunction which may lead to cardiogenic shock and death. Therefore, patients with patent haemodynamic instability (shock) are at highest risk of death. According to the ESC criteria, haemodynamic instability is defined by a systolic blood pressure inferior to 90 mmHg for more than 15 minutes, hypotension requiring vasopressors, or clear evidence of shock. These patients are described as “high-risk PE” in the European nomenclature or “massive” PE in the North-American literature12. In a recent systematic review including four prospective cohorts and forty thousand consecutive patients with PE, 3.9% had high-risk PE. Short-term mortality was 19% among patients presenting with unstable PE versus 5.7% among patients with stable PE (OR 5.9; 95%CI 2.7 to 13.0)9.
In a large European registry (Registro Informatizado de la Enfermedad Trombo Embolica Venosa, RIETE), patients with high risk PE had a 17.5 fold higher risk of 30-day mortality compared to patients with Deep Vein Thrombosis (DVT).6 The identification of patients at high- risk impacts the diagnostic and therapeutic strategies. In these circumstances, the traditional diagnostic strategy based on clinical probability estimation, DDimers dosing and computed tomography may be modified and the presence of signs of right ventricular overload on bedside echocardiography may be sufficient to establish the diagnosis of PE if the patient is too unstable to be transported to CTPA2,13.
In the presence of haemodynamically unstable PE, therapeutic strategy relies on haemodynamic and respiratory support and prompt anticoagulation using unfractionated heparin (UFH) and reperfusion therapies such as medical or mechanical thrombolysis. The benefit of systemic thrombolysis in high-risk PE has been demonstrated in small randomised controlled trials (RCTs) and large observational databases9,14. In the study by Jerjes-Sanchez et al, eight patients with high-risk PE were randomised to anticoagulation alone or anticoagulation and streptokinase14. The four patients randomised to AC died and the four patients randomised to thrombolysis survived. However, this small size, open-label trial was limited by imbalance between groups, the four patients allocated to heparin having worsening PE with haemodynamic instability despite AC at inclusion. Recent RCTs evaluating thrombolytic therapy usually excluded high-risk PE 15-17, while older studies did not report separately outcomes for high-risk PE18,19. Observational studies support the use of thrombolytic therapy (TT) in high-risk PE. In a large American database, in-hospital mortality was 15% among patients with unstable PE receiving TT
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and 47% among patients with unstable PE treated with anticoagulation alone. In a recent meta- analysis including four prospective cohorts of patients with acute PE, TT was associated with reduced odds of short term mortality. (Figure 2 and 3). Despite adjustment for potential confounders, residual confounding cannot be excluded given the observational design of these studies.Figure 2: In-hospital mortality in patients with unstable PE according to Stein et al.20(Reproduced with permission from Elsevier)
Figure 3: Odds of mortality in patents with unstable PE treated with TT vs AC in the meta- analysis by Quezada et al9. (Reproduced with permission from Elsevier)
TT is thus probably beneficial in high-risk PE despite its haemorrhagic complications, based on limited data from RCTs and extensive data from observational studies. However, real life observations show that this treatment remains underused. In a large north-American database
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including more than two million patients with PE over ten years, 70% of unstable patients did not receive TT.20 This underutilisation of TT may be explained by the reluctance of physicians to administer TT because of its bleeding complications. Also, the criteria for unstable PE in the ESC definition based exclusively on the presence of hypotension are probably a bit simplistic and warrant to be corroborated by clinical or biological evidence of circulatory failure, such as confusion, renal failure or lactate elevation.Conclusion step 1: Identification of high-risk patients based on the presence of haemodynamic instability is recommended for rapid diagnosis and prompt reperfusion therapy (moderate evidence)
2019 – Privat-Docent – C Marti 13 Risk stratification step 2: Estimating 30-day mortality based on clinical parameters
After identification of patients with haemodynamic instability warranting rapid diagnosis and treatment, the remaining patients with suspected PE will benefit from a diagnostic work-up based on the clinical probability of PE, D-Dimers dosing in case of non-high clinical probability and CT angiography. The diagnostic strategy for suspected PE in haemodynamically stable patients is provided in Figure 4.
Figure 4: Diagnostic algorithm in haemodynamically stable patients according to the ESC10
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
After diagnostic confirmation, therapeutic anticoagulation (AC) using low-molecular weight heparin (LMWH), UFH, penta-saccharides or direct oral anticoagulants (DOACs) is indicated and hospital admission is considered. Historically, patients with acute PE were admitted to the hospital, while patients with DVT were often treated as outpatients. Therefore 30-day mortality prediction rules have been developed to identify patients with acute PE at low risk of mortality who could be safely treated as outpatients.
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The most widely validated prediction tool is the pulmonary embolism severity index (PESI). This prediction rule was derived and internally validated in 2005 in a cohort of 15.531 patients21.The PESI score comprises 11 clinical variables (Table 2) and stratifies patients with pulmonary embolism into five severity classes. In the original cohort 30-day mortality rates were of 0-1.6%in class I, 1.7-3.5% in class II, 3.2-7.1% in class III, 4.0-11.4% in class IV21.
Table 2. PESI and sPESI calculation
Variable PESI Simplified
PESI
Age > 80 y Age,(years) 1
Male gender +10
Comorbidities
Active cancer +30 1
Cardiac failure +10
Chronic pulmonary disease +10 1*
Clinical signs
Pulse ≥ 110 par min. +20 1
SBP <100 mm Hg +30 1
Respiratory rate ≥ 30 / min. +20
Temperature < 36°C +20
Confusion +60
Oxygen saturation < 90% +20 1
PESI Class I <66, Class II 66 to 85, Class III 86 to 105, Class IV 106 to 125, Class V >125 pts
*1 point assigned for Cardiac failure OR chronic pulmonary disease
The PESI score has been extensively validated in at least 19 cohorts including a total of 23 997 patients with a pooled sensitivity of 0.91 (95% CI 0.90 to 0.92) and a pooled specificity of 0.41 (95% CI 0.40 to 0.42) to predict 30-day mortality.22 Although the overall discriminative power of this score is moderate (AUC around 0.79), it has a high negative predictive value using a cut-off of PESI ≥ II. However, PESI score calculation requires the incorporation of eleven weighted variables and transformation of the score into risk categories making its utilisation uneasy in clinical practice. (Table 3)
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Therefore, a simplified version of the PESI (sPESI) was derived including 6 clinical variables and one point attributed to each variable (table 3)23. According to a 2012 meta-analysis including 50 021 patients, the AUC of sPESI was 0.79 for all-cause mortality with a pooled sensitivity of 0.92 and a pooled specificity of 0.38, which is similar to the original PESI score.The pooled mortality was 2% among patients with low PESI (PESI I-II) and 1.8% among patients with low-risk sPESI (sPESI <I).24
A non-inferiority interventional study compared PESI based outpatient management of patients with acute PE with hospital admission25. Three hundred forty-four patients with low-risk PE (PESI class I-II) were randomly allocated to outpatient versus inpatient management. Ninety- day mortality was non-inferior in outpatients compared to patients admitted in-hospital (0.6% in both groups, Upper Confidence Limit for difference 2.1 %) as well as PE recurrence (0.6% in outpatients versus 0% for inpatients, upper Confidence Limit for difference 2.7%). At three months, three outpatients (1.8%) but no inpatient developed major bleeding (Upper Confidence Limit for difference 4.5%).
In summary, both PESI and sPESI perform well in identifying patients with acute PE at low-risk of mortality and have been widely validated, including in an impact study based on the original PESI score. However, the sample size of this interventional study was small, and there was a trend towards an increased risk of bleeding complications in the outpatients group. Moreover these studies were performed before the era of direct anticoagulants which might influence the safety of home treatment of patients with acute PE. In a single arm study evaluating early discharge of low risk PE (normotensive, absence of RVD and absence of serious comorbidities) treated with rivaroxaban, the rate of major bleeding at 3 months was low (1.2%).26
Other prognostic scores have been proposed 22,27-29. The pooled sensitivity and specificity of these prediction rules are provided on table 3. However, a 2015 systematic review evaluating eleven different prediction rules concluded that only PESI, sPESI, Aujesky score, Paiva score and the ESC criteria were sufficiently sensitive to identify low-risk patients. A subsequent meta- analysis showed that in-hospital mortality was higher in the ESC low-risk group (3.1%) than in the low-risk PESI group30.
The Aujesky score incorporates 10 variables similar to the original PESI score and has been externally validated in 4 cohorts including 16,735 patients22,28. The components of the principal prediction rules are provided on table 4.
The Paiva score is the application of the Global registry of Acute Coronary Events (GRACE) risk score to patients with acute PE. This score showed interesting discriminating performance in a validation study27 but has been less extensively validated than PESI and requires biological and
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electrocardiographic variables. The components of selected PE prognostic scores are provided on table 4.Table 3 Operative characteristics of the different prediction rules for short-term mortality22,27 Clinical prediction
rule
Number of cohorts;
Patients
Sensitivity (CI) Specificity (CI)
PESI 19; 23 997 0.89 (0.87-0.90) 0.49 (0.44-0.53)
sPESI 9; 26 610 0.92 (0.89-0.94) 0.38 (0.32-0.44)
ESC 7; 2 463 0.88 (0.77-0.94) 0.38 (0.28-0.49)
Aujesky 4; 16 735 0.97 (0.95-0.99) 0.24 (0.18-0.31)
Paiva 1; 206 1.0 (0.89-1.0) 0.26(0.21-0.35)
Table 4: Components of selected PE risk stratification scores
Variable PESI21 Aujesky 28 sPESI23 Paiva27
Age
Sexe
Cancer
Cardiac failure
COPD
Chronic renal Insufficiency
Cerebrovascular disease
T° < 36
RVD
Tachypnoea
Confusion
BP < 100 mmHg
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HR >100-110/min
Cardiac arrest
SaO2 < 90%
↑ Creatinine
↑ Cardiac enzymes
ST deviation
In conclusion, different severity scores may allow to identify patients at low-risk of mortality.
PESI and sPESI are the most widely validated prediction tools and a multicentric impact study has been conducted using the PESI score. The conclusion of this interventional study is that outpatient treatment of PE patients based on PESI stratification is safe in terms of mortality and PE recurrence, but a trend towards an increased risk of bleeding complications was observed among outpatients. Therefore, outpatient treatment of patients with low-risk PE based on a clinical decision rule such as PESI is recommended with a moderate level of evidence.
Table 5: Level of evidence supporting the use of different prognostic models
Prediction rule PESI sPESI ESC criteria Paiva score Definition and standards of evaluation
Level 1: Derivation + + + + Identification of predictors using multivariate model; blinded assessment of outcomes Level 2: Narrow validation + + + + Verification of predictors tested prospectively in 1
setting; blinded assessment of outcomes Level 3 Broad derivation ++ ++ + Verification of predictors in varied settings with
wide spectrum of patients
Level 4 Narrow impact analysis
+ - +/-* Prospective demonstration in 1 setting that use of
the model improves outcomes
Level 5: broad impact analysis
- - - Prospective demonstration in various settings that
use of the model improves outcomes
*one interventional study evaluating early discharge based on modified ECS criteria26
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Conclusion step 2: Identification of low-risk patients based on PESI or sPESI isrecommended for outpatient treatment (moderate evidence)
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Risk stratification step 3: Further categorisation of normotensive PE
The identification of patients with high-risk PE based on the presence of haemodynamic instability and of low-risk PE based on severity scores such as PESI and sPESI allows the classification of about 3.9% of patients as high-risk PE and about 40% as low-risk PE30.The remaining patients (normotensive patients with PESI III-V or sPESI ≥ 1), representing about one half of patients with acute PE are classified as intermediate risk PE and require hospital admission. The overall 30-day mortality of this group of patients varies between 5% and 15%.21,23,31 However this group of patients is highly heterogeneous and the attributable PE mortality represent only about one third of the overall 3-months mortality of patients with acute PE5,6. The vast majority of normotensive PE inpatients will have a favourable outcome with anticoagulation alone but a significant proportion of them might deteriorate and require more aggressive therapy such as mechanical or medical reperfusion, cardiopulmonary resuscitation or haemodynamic support. Therefore, efforts to identify patients at higher risk of deterioration have been performed over the last decade in order to identify a subgroup of patients with intermediate-risk PE who might benefit from initial aggressive therapy or admission to a monitored unit. Clinical scores, markers of RVD or injury, markers of circulatory failure, markers of thrombotic burden or combination of these have been proposed for further risk stratification of normotensive PE.
Clinical scores
As previously discussed, PESI and sPESI scores are widely validated prognostic tools to predict mortality in acute PE. However, these scores have several drawbacks for the identification of higher-risk patients requiring aggressive therapy or ICU admission.
First, despite a high negative predictive value, these scores have poor specificity and their positive predictive value for early mortality is low. In the original PESI study, 30-day mortality was 3.2 to 7.1% among patients with PESI class III, and 4.0 to 11.4% in class IV21.
Second, these scores were mainly validated to predict mortality and seldom to predict the need for treatment escalation. As previously discussed, PE attributable mortality only represents a fraction of the overall 3-months mortality of patient with acute PE. In the ICOPER registry, 45%
of deaths were ascribed to PE and 17.6% to cancer5 while fatal PE represented only 19.4% of the 3 months mortality in the RIETE registry6. These deaths, due to the decompensation or progression of co-morbid diseases such as malignancy are unlikely to be prevented by aggressive treatment of the thromboembolic event or admission to a monitored unit. Therefore, the predictive value of PESI or SPESI to predict the need for treatment escalation may probably
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be lower that its ability to predict death. Finally, clinical scores like PESI or sPESI rely heavily on demographic and co-morbid conditions rather than the severity of the acute PE event.Therefore, similarly to Pneumonia severity index (PSI) for patients with community acquired pneumonia, these scores probably perform well to identify early mortality but not necessarily avoidable early mortality32. For example, an elderly patient with acute PE, active malignancy and cerebrovascular disease is certainly at increased risk of death but will not necessarily benefit from an aggressive therapy or monitoring. Because of these limitations, PESI and sPESI are not recommended to guide admission to the ICU or reperfusion therapies, and researchers have investigated other predictors which may reflect more closely PE severity and its impact on RV function.
Markers of right ventricular dysfunction or injury
Acute RVD is one of the most feared complications of acute PE and is the most common mechanism leading to fatal PE. Therefore, various clinical symptoms or biological markers of RVD have been investigated as potential tools to stratify normotensive patients.
Vital signs such as increased heart rate or tachypnoea are associated with an unfavourable outcome5,6. Similarly, the presence of syncope has been associated with echocardiographic signs of RVD and an increased risk of mortality (OR 1.73) and a two-fold increase in PE related 30-day adverse events33. Electrocardiographic changes34, Troponin I and T, brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP and Heart Fatty acid binding protein have been proposed to assess the presence of RVD or injury. The prognostic value of Troponin I and T has been summarized in a meta-analysis including 1985 patients35. Elevated troponins were associated with short-term mortality (OR 5.24), PE-related death (OR 9.4) and this association was consistent for troponin I and T and the subgroup of normotensive patients (OR 5.9) for early mortality. The overall mortality was 17.9% among normotensive patients with an elevated troponin and 2.3% among patients with normal levels of troponin. A subsequent meta-analysis questioned the prognostic value of elevated troponins with poorly discriminative positive (2.26) and negative (0.59) likelihood ratios (LRs) in normotensive patients and suggested that this biomarker should be combined with other prognostic factors.36 The prognostic value of cardiac biomarkers is provided in Figure 8. Interestingly, these two meta-analyses included low and intermediate risk PE according to PESI criteria. When troponin are measured among patients with low-risk PE, (sPESI 0 or PESI I-II) they remain associated with early mortality (OR 6.25) but their predictive positive value is low (3.8%).37
Brain natriuretic peptide (BNP) and its n-terminal portion (NT-proBNP) are secreted by cardiomyocytes in response to ventricular stretching due to volume or pressure overload. The prognostic value of these biomarkers has been evaluated in at least eight studies.38,39
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In the meta-analysis by Sanchez et al. the pooled unadjusted relative risk for 30-day mortality was 9.5 (CI 3.1 to 28.6) for BNP and 8.3 (95%CI 3.6 to 19.3) for NT-proBNP.39 Sensitivity, specificity and positive and negative LRs for BNP and proBNP are provided in table 6.Interestingly, troponin and BNP/proBNP have been shown to have additive prognostic value.38,40 Finally, Heart-type fatty acid-binding protein (H-FABP) has been proposed as an alternative marker of myocardial injury and has been shown to have similar or superior performance compared to troponin and BNP although it has been less extensively validated.41,42
Table 6: Prognostic value of markers of RVD
Marker Sensitivity (95% CI)
Specificity +LR -LR
Troponin39 81 (23 to 100) 84 (77 to 90) 5.0 0.22
BNP39 88 (65 to 96) 70 (64 to 75) 2.4 0.27
Pro-BNP 93 (14 to 100) 58 (14 to 92) 2.2 0.12
RVD US39 70 (46 to 86) 57 (47 to 66) 1.6 0.52
RVD CT39 65 (35 to 85) 56 (39 to 71) 1.5 0.58
H-FABP41 65 (NA) 79 (NA) 3.1 0.44
CT angiography and echocardiographic signs of RVD:
RVD may lead to an increase in cardiac biomarkers but RV volume or pressure overload may also be identified on CTPA and echocardiography. CTPA signs of RVD include an elevated RV/left ventricular (LV) end diastolic diameter ratio (cut-off of 0.9 or 1.0), interventricular septum bowing, pulmonary artery enlargement, and retrograde reflux of contrast into the vena cava.
Right-to-left ventricular ratios can easily be estimated using ventricular diameters ratio using the largest transverse diameters which may be measured on different CTPA slices. (Figure 5)
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More sophisticated methods using volumetric measures of ventricles have been proposed in order to take into account the complex tri-dimensional shape of right and left ventricles. Axial and volumetric ratios have good inter-observer correlation and similar performance to predict mortality43. The sensitivity and specificity of CTPA RVD is provided on table 6. Septum bowing has an excellent specificity (100%) but poor sensitivity (26%) and inter-observer reproducibility limiting its clinical utilization.8Figure 5: CTPA RV/LV ratio (personal illustration)
RV dilatation, may also be evaluated using bedside echocardiography. Increased right to left ventricular ratio, hypokinesis of the free RV wall and the presence of pulmonary hypertension estimated from tricuspid regurgitation velocity have been reported to be associated with an increased risk of early complications. The prognostic value of echocardiographic RV dilatation is reported on table 6. Despite a consistent association with short-term mortality, CTPA or echocardiographic RVD have a poor positive predictive value when they are used alone. 10,39
Impact studies evaluating thrombolytic therapy for normotensive PE with RVD
As the presence of RVD appeared to be consistently associated with an unfavourable prognosis in patients with normotensive PE, several RCTs aimed to evaluate the potential benefit of reperfusion strategies among these patients. Systemic thrombolysis using plasminogen activators has been the most widely studied reperfusion strategy. Plasminogen activators, such as urokinase, alteplase or tenecteplase have a fibrinolytic effect which allows rapid clot dissolution and has been shown to improve hemodynamic parameters in patients with high-risk PE14,19. As these studies were performed over fifty years, the definition of RVD varied across studies. A summary of the available evidence about thrombolytic therapy for acute PE is provided in Table 7:
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As presented in Table 7, older studies often included PE patients with variable severity criteria including the extent of pulmonary arterial thrombotic burden on imaging while the most recent RCTs included mainly patients with RVD.Table 7: Characteristics of RCT evaluating thrombolytic therapy in acute PE (adapted from Marti et al.17)
1stAuthor /year of publication
Number of patients
Severity criteria High-risk PE
included
Thrombolysis
Becattini 201044 58 RVD No Tenecteplase 30-50mg
Dalla Volta 1992 36 Miller score > 11 No Alteplase 100mg/2h
Dotter1979 31 No Yes Streptokinase 2-11 MIU 18-72 h
Fasullo 201145 72 RVD No Alteplase 100mg/2h
Goldhaber 1993 101 No No Alteplase 100mg/2h
Jerjes-Sanchez 1995 8 Massive Yes Streptokinase 1.5 M IU/2h
Kline 2013 83 RVD or hypoxemia No Tenecteplase 30-50 mg/2h
Konstantinides 200215 256 RVD or pHTA No Alteplase 100mg/2h
Levine1990 58 No No Alteplase 0.6mg/kg/2min
Ly 1978 20 >1 lobe Yes Streptokinase 72 h
Marini 1988 30 >9 segments No Urokinase 2.4-3.3 MIU /12-72h
Meyer 201416 1005 RVD and troponin No Tenecteplase 30-50mg
Sharifi 2013 121 ≥2lobes No Alteplase 50mg/2h
Stein 1990 13 ≥ 1 lobe No Alteplase 40-80mg/40-90 min
UPET 1970 160 No Yes Urokinase 12 h
Becattini et al. randomised 58 patients with RVD to receive tenecteplase or placebo44. RVD was defined as right/left ventricule ratio > 1 in the apical 4-chamber view on echocardiography. The reduction of right to left ventricule ratio at 24 hours was greater among patients allocated to tenecteplase but this study was not powered to evaluate clinical outcomes.
Fasullo et al. randomised 72 patients with acute PE and RVD to receive alteplase or placebo45. RVD was defined as the presence of a right/left ventricule ratio > 1 in the apical 4-chamber view and RV hypokinesis and signs of acute pulmonary hypertension on echocardiography. Patients allocated to alteplase showed an earlier improvement of RV function and a reduction in overall mortality (6/35 (17%) vs 0/37, p=0.027). Major bleeding occurred in 2 (5.4%) patients receiving alteplase and one (2.9%) receiving placebo. (Figure 6)
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Konstantinides et al. evaluated the benefit of thrombolysis in patients with intermediate-risk PE.Intermediate-risk PE was defined as a confirmed acute PE and presence of RVD. RVD was defined as the presence of either RV enlargement with loss of inspiratory collapse of the inferior vena cava or presence of pulmonary hypertension on echocardiography or new electrocardiographic signs of RV strain. Two hundred fifty-six patients were allocated to alteplase plus heparin or heparin alone. The incidence of the composite primary endpoint (death or treatment escalation) was significantly lower among patients receiving alteplase (11 vs 24.6%, p=0.006). This benefit was mainly due to a lower risk of treatment escalation and in- hospital mortality did not significantly differ between groups. (3.4 vs 2.2%, p=0.71). Major bleeding occurred in 2.6% of patients receiving alteplase and 0.8% of those allocated to heparin. This study has been criticised because treatment escalation criteria were not strictly defined in the protocol. Finally, only one third of included patients had echocardiographic signs of RVD, the majority having been included based on electrocardiographic changes such as inverted T waves which are no longer considered in the risk stratification of intermediate –risk PE.
Figure 6: Benefit of TT for Early mortality by PE severity according to Marti et al.17
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
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The most informative evidence regarding the benefits of thrombolytic therapy in normotensive PE with RVD was provided by the PEITHO trial.16 This large RCT included 1005 patients with an acute PE and RVD on imaging (CT-angiography or echocardiography) and myocardial injury (elevated troponin T or I). Patients were randomly assigned in a 1 to 1 ratio to UFH plus tenecteplase or UFH alone. The incidence of the primary outcome (death or hemodynamic collapse within 1 week) was significantly lower among patients allocated to tenecteplase than to UFH alone (2.6% vs 5.6%, p=0.02). This difference was mainly driven by an increased risk of hemodynamic decompensation among patients allocated to UFH (5.0 vs 1.6%) while mortality was low and did not significantly differ between groups (1.2 vs 1.8%). The cost of thrombolytic therapy was a significant increase in the risk of both major (11.5 vs 2.4%) and intracranial bleeding (2.0 vs 0.2%). When the three studies including exclusively acute PE with RVD are pooled, the uncertain benefit in overall mortality appears mitigated by the significant increase in both major and intracranial bleeding17 (Figure 7 and 8). The increased risk of major bleeding was more pronounced in studies using tenecteplase, but direct comparison studies are insufficient to confirm this indirect observation46.Figure 7: Benefits of thrombolytic therapy according to PE severity according to Marti et al.17
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
Figure 8: Risks of thrombolytic therapy according to type of TT according to Marti et al.17
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
In summary, the absolute risk of PE-related death is probably insufficient among patients with hemodynamically stable PE and isolated RVD and/or injury to warrant thrombolytic therapy and
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overcome its haemorrhagic complications. However, these patients remain at significant risk of early deterioration and the publication of the PEITHO trial in 2014 prompted researchers to improve risk stratification among normotensive patients in order to identify patients at higher risk with a potentially more favourable Risk/benefit ratio.Markers of Circulatory failure
An alternative approach to assess the severity of PE is to evaluate its repercussion on cardiac output by measuring markers of cellular dysoxia or circulatory failure. Plasma lactate determination is an important prognostic marker of organ dysfunction and is widely used in patients with sepsis or trauma.47 Several studies evaluated the prognostic value of plasma lactate among patients with acute PE.48,49 In a retrospective study including 287 PE patients, Vanni et al. reported a significant association between plasma lactate elevation (>2mmol/L) and in-hospital mortality (OR 4.6; 95%CI 1.57 to 13.53)48. This association was confirmed in a subsequent prospective study which showed a significant association between lactates elevation and both 30-day mortality (HR 11.67; 95% CI 3.32 to 41.03) and death or clinical deterioration (HR 8.14; 95% CI 3.83 to 17.34)49. Interestingly, this association was independent of shock or hypotension, RVD or elevated troponins in the multivariate model, suggesting a potential additional prognostic value of plasma lactate elevation. The positive predictive value of blood lactate elevation was 17.3% (95%CI11.9 to 20%) for 30-day mortality in this study including 4.4% patients with hypotension and an overall mortality of 6.3%. These findings were further confirmed in another prospective cohort of 496 normotensive patients which reported an association between plasma lactate elevation and the early (7days) risk of clinical deterioration with a positive predictive value of 10.4 % and a negative predictive value of 98.3%.50Copeptin, a precursor of vasopressin which is released in response to hypotension may also have a prognostic value in patients with PE. A prospective study including 268 normotensive PE patients showed an association between copeptin level >24pmol/L and 30-dy mortality or adverse outcome. The positive predictive value was 11% (95% CI 7 to 19%) and the negative predictive value 98% (95% CI 95 to 99%), suggesting that this biomarker could be combined with markers of RVD such as NT-proBNP or highly sensitive troponin T.51
Thrombotic burden
The radiological estimation of thrombotic burden has been evaluated as a potential prognostic marker in patients with acute PE. The proximal localisation of emboli (saddle or main pulmonary artery), and the obstruction index (Qanadli or Miller scores) have been shown to be associated with the presence of markers of RVD and 30-day adverse events.52-54
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In a meta-analysis including 49 studies and 13 162 patients thrombus load was associated with adverse clinical outcome (OR 2.4; 95%CI 1.4 to 4.3), PE-related mortality (OR 17.6; 95%CI 5 to 62) but not all-cause mortality (OR 1.6; 95%CI 0.7 to 3.9). Central location of thrombus was associated with PE adverse event (OR 2.4; 95%CI 1.4 to 4.3) but not significantly with all-cause mortality (OR 1.7; 95%CI 0.7 to 4.2)55. It is unclear if these variables have additional prognostic value to the presence of signs of RVD on CTPA:Combination of clinical parameters, Markers of RVD or injury and markers of circulatory failure
As previously discussed, clinical scores, markers of RVD or injury or markers of circulatory failure are important predictors of an unfavourable outcome in PE patients. However, these prognostic markers used alone have limited positive predictive value which limits their potential utility to identify patients who would require a more aggressive therapy. In order to improve the risk stratification of patients with acute PE, various combinations of clinical variables, markers of RVD or injury and markers of circulatory failure have been proposed over the last decade and will be reviewed in the next paragraphs.
ESC criteria: The 2014 ESC criteria for risk-stratification of patients with acute PE rely on a three-steps process based on the presence of shock, the predicted mortality based on clinical variables (PESI or sPESI) and the presence of signs of RVD or injury.2 This classification results in four categories which are summarized on Figure 9.
Figure 9: Classification of patients with acute PE based on early mortality risk according to the ESC2
(Reproduced with permission from OXFORD UNIVERSITY PRESS)
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The ESC criteria did not follow the traditional derivation process of clinical prediction rules but were proposed by experts based on the best available evidence in their 2014 recommendations.Since their publication, several validation studies have been published reporting positive predictive values for early mortality or clinical deterioration comprised between 10 to 15% for the intermediate-high risk category (Table 8).
Table 8: Predictive value of ESC criteria for the intermediate-high risk category Study 1stauthor
and year
Outcome PPV
(95% CI)
AUC
Vanni 201756 7-day PE mortality or hemodynamic collapse
13%
(8 to 19.5)
NA
Hobohm 201657 30-day adverse outcome
15%
(10 to 22)
0.76
(0.68 to 0.84) Masotti 201658 In-hospital mortality 9.2%
(NA)
0.70
(0.65 to 0.75) Cugno 201859 30-day mortality 14.8%
(NA)
0.77
(0.67 to 0.87)
Although the follow-up duration and outcomes varied across studies, the 2014 ESC criteria appear to have an improved positive predictive (10 to 15%) value compared to patient selection based on the sole presence of RVD like in the PEITHO trial.
Despite their moderate overall discriminative performance, the ESC criteria rely on moderate to strong evidence to support clinical decision regarding the high risk category (indication for reperfusion) and low-risk category (outpatient management). They allow to identify a subgroup of normotensive patients at an increased risk of deterioration which might benefit from a more aggressive management but with a limited positive predictive value and the absence of impact studies.
Bova score: The Bova score was derived in 2014 60 in 2874 patients with acute PE aggregated from six different prospective studies. Haemodynamically unstable patients were excluded from the analysis. Model predictors included heart rate, systolic blood pressure and markers of RVD or injury (cardiac troponin or BNP) (Table 9 and 10) resulting in a seven points model. RVD was detected using echocardiography (RV/LV > 0.9 or 1, RV free wall hypokinesis, RV end-diastolic
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diameter > 30mm or estimated Pap > 30mmHg). The primary composite outcome was PE related death, hemodynamic collapse or recurrent PE at 30 days. 30-day complications differed significantly across categories of the model (0-2 points 4.2%; 3-4 points 10.8%; >4 points 29.2%). The area under the ROC curve was 0.73 (95% CI 0.68-0.77) and 5.8% of patients were classified in the stage III category.Table 9: Components of the Bova score
Predictor points
SBP 90-100 mmHg 2
Elevated troponin 2
RV dysfunction 2
Heart rate > 100/min 1
The Bova score was externally validated in several prospective and retrospective cohorts.57,61,62 In a retrospective cohort including 1083 normotensive patients, the cumulative incidence of PE related complications(PE related death, hemodynamic collapse or recurrent PE) at 30 days was 4.4% for stage I, 18% for stage II and 42% for stage III (3.1, 6.8 and 10.4 for 30-day PE mortality) with an AUC of 0.74.62
In another retrospective cohort including 994 normotensive patients, 5.9% of patients were classified in the stage III category. Death or haemodynamic collapse at 7 days occurred in 18.6% of patients in the stage III category. When lactate elevation was added to the Bova score, the proportion of patients in the stage III category increased to 11.2 % with a primary outcome rate of 25.9 % allowing the recognition of a twofold higher number of patients reaching the primary outcome. 7-days haemodynamic collapse occurred in 15.3% of patients in the class III category, and 24.1 % of patients in the model including lactate elevation.56
Finally, in a prospective validation study including 388 normotensive patients, the incidence of an adverse 30-day outcome (PE-related death, catecholamines, Cardio-pulmonary resuscitation or mechanical ventilation) was 19%in the class III category and the AUC 0.8057.
TELOS: The TELOS score was derived in a prospective cohort of 496 normotensive PE patients.
The primary outcome was PE related death or haemodynamic collapse within 7 days. Variables associated with the primary outcome included plasma lactate > 2mmol/L, RVD signs on echocardiography, heart rate > 100/min and systolic BP 90-100 mmHg. A single model including
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RVD, troponin elevation and plasma lactate concentration resulted in a 17.9% positive predictive value for the category with RVD, elevated troponin and plasma lactate concentration>2mmol/L.50
The TELOS rule was further validated by the same group in a prospective cohort of 994 normotensive patients. 5.9% of patients were allocated to the intermediate-high risk category according to the TELOS criteria with a cumulative incidence of the primary outcome (death or haemodynamic collapse at 7 days) of 21.1%.56
SHIELD: The SHIELD score was derived from a retrospective monocentric cohort of 554 normotensive patients and externally validated on another retrospective cohort from a second hospital.
Predictors of the model included Shock index ≥1, HypoxemIa, Lactate and RVD.
RVD was defined as the presence of elevated troponin, NT-pro BNP and RV/LV ratio>1 using CTPA.63 The risk of adverse event at 30 days (PE-mortality or rescue thrombolysis) for each tercile was 0.6%, 1.8% and 16.4% respectively. (AUC 0.90, 95%CI 0.85 to 0.94) in the derivation cohort and 0.6%, 1.9% and 15.3% in the external validation cohort (AUC 0.82;
95%CI 0.75 to 0.87).
Table 10: Predictors in several prediction rules
ESC2 Bova60 TELOS50 Paiva27 SHIELD
Age
Sexe
Cancer
Cardiac failure
COPD
Chronic renal Insufficiency
Cerebrovascular disease
T° < 36
Shock index
Tachypnoea
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Confusion
BP < 100 mmHg
HR >100-110/min
Cardiac arrest
SaO2 < 90%
↑ Creatinine
↑ Cardiac enzymes
ST deviation
Lactates
RVD
Other prediction rules:
Additional combinations of clinical or biological markers have been proposed. Lankeit et al derived a clinical prediction rule including H-FABP (1.5 point), syncope (1.5 point) and heart rate
>100/min (2 points)). (FAST score). The positive predictive value of a score ≥3 was 20.5% and the AUC 0.85 (95%CI0.75 to 0.95).64 This score was further validated in another cohort of the same center with a positive predictive value of 18.9% and an AUC of 0.82 (95% CI 0.75 to 0.89).57
Jimenez et al. derived a multimarker model including sPESI, troponin, BNP, and lower limb ultrasound testing on 848 outpatients and validated the model on a second cohort of 529 normotensive patients. The cumulative incidence of a 30-day complicated course was 27%
among patients with sPESI ≥1, elevated troponin and BNP and presence of DVT on lower limb ultrasound.40 Other combinations of clinical variables and markers of RVD or injury or circulatory failure have been studied with less extensive validation.27,51,65
Between scores comparison
Several studies aimed to compare the performance of various prediction rules.
Vanni et al. compared the prognostic accuracy of the ESC 2014 criteria, TELOS and Bova score in a cohort of 994 normotensive patients with PE. The Bova and TELOS scores classified the same proportion of patients in the intermediate-high risk category (5.9 and 5.7%) with a similar
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rate of early adverse event (18.6 and 21.1% 7-day death or haemodynamic collapse), while the ESC criteria classified a higher proportion of patients in the intermediate-high risk category (12.5%, p< 0.001) with a lower rate of events (13% p=0.18).56 The predictive value of the different prediction models are provided on table 11.Table 11: PE complications at 7 days in the intermediate-high risk group defined by different models according to Vanni et al56
Total cohort (n=994)
Bova score (n=59)
TELOS score (n=57)
ESC model (n=115)
Bova + lactate (n=112) Primary
outcome1 63 (6.3%) 11 (18.6%) 12 (21.1%) 15 (13%) 29 (25.9%) PE-related
death 31 (3.1%) 6 (10.2%) 6 (10.5%) 8 (7%) 14 (12.5%)
Haemodynamic
collapse 56 (5.6%) 9 (15.3%) 9 (15.8%) 13 (11.3%) 27 (24.1%) All-cause
death 32 (3.2%) 6 (10.2%) 7 (12.3%) 9 (7.8%) 17 (15.1%)
1Defined as PE mortality or haemodynamic collapse at 7 days
Hohbohm et al. compared the accuracy of the FAST, Bova score and ESC 2014 criteria to predict an adverse 30-day outcome in a cohort of 388 normotensive PE. The overall incidence of adverse event (PE-related death or haemodynamic collapse) at day 30 was 6.4% and 30-day mortality 3.6%. The three scores had similar positive predictive value (18.9%, 19% and 15%
respectively) and the proportion of patients classified in the intermediate-high risk category was comprised between 16.2% (Bova score) and 34.3% (ESC criteria).
In summary, prediction rules including clinical parameters, markers of RVD or injury and/or markers of circulatory failure seem to identify a subgroup of normotensive PE patients with a 10 to 20 % short term risk of adverse event. Most components of these scores are available in current clinical practice (except echocardiographic assessment of RVD which might be substituted by CTPA when not available). The accuracy of these models appear similar despite some variations in their positive predictive values across studies which are partly explained by variations in the outcome definitions.
2019 – Privat-Docent – C Marti 33 Implications for practice of the intermediate-high risk category
As discussed in the previous section, recent prediction rules allow to identify a subset of normotensive PE patients with an early risk of adverse event comprised between 10 and 20%.
These prediction rules share some common variables such as vital signs, markers of RVD or injury or markers of circulatory failure and some of them have been externally validated in several cohorts. However, the clinical implications of these prediction rules have not yet been assessed in impact studies. By extrapolating findings from RCTs evaluating thrombolytic therapy, the risk-benefit ratio of TT maybe extrapolated to populations with an increased risk of basal PE related adverse events. Table 12 a and b and Figures 10-11 illustrate the extrapolated risks and benefits of TT in a cohort with a basal risk similar to the PEITHO population (a) and a basal risk corresponding to the intermediate-high risk Bova category (b) assuming a constant relative effect of treatment on safety and efficacy outcomes and a constant basal bleeding risk.
Table 12a: Extrapolated absolute effect of TT in normotensive patients with RVD (basal incidence from the PEITHO trial)
Outcomes Relative effect17 Anticipated absolute effect
Basal risk with ACa Risk difference with TT
All-cause mortality 0.59 18 per 1000 8 fewer per 1000
PE adverse eventc 0.34 56 per 1000 36 fewer per 1000
PE mortality 0.29 6 per 1000 4 fewer per 1000
Major bleeding 2.91 24 per 10002 46 more per 1000
Intracranial bleeding 3.18 2 per 10002 4 more per 1000
Table 12b: Extrapolated absolute effect of TT assuming basal risks observed in the Bova intermediate–high risk category62
Outcomes Relative effect17 Anticipated absolute effect
Basal risk with ACb Risk difference with TT
All-cause mortality 0.59 102 per 1000b 40 fewer per 1000
PE adverse eventc 0.34 420 per 1000b 220 fewer per 1000
PE mortality 0.29 100 per 1000b 70 fewer per 10006
Major bleeding 2.91 24 per 1000a 46 more per 1000