Pulmonary embolism severity assessment and prognostication

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Pulmonary embolism severity assessment and prognostication Deisy Barriosa, Raquel Morilloa, Roger D. Yusenb, David Jiméneza,⁎ a b

Respiratory Department, Ramón y Cajal Hospital, IRYCIS, Alcala de Henares University, Madrid, Spain Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine, St. Louis, MO, USA

A R T I C L E I N F O

A B S T R A C T

Keywords: Pulmonary embolism Prognosis Mortality Survival

For patients who have acute symptomatic pulmonary embolism (PE), risk of short-term death and adverse outcomes should drive the initial treatment decisions. Practice guidelines recommend that patients who have a high-risk of PE-related death and adverse outcomes, determined by the presence of haemodynamic instability (i.e., shock or hypotension), should receive systemically administered thrombolytic therapy. Intermediate-high risk patients might benefit from close observation, and some should undergo escalation of therapy beyond standard anticoagulation, particularly if haemodynamic deterioration occurs. Low-risk for adverse outcomes should lead to early hospital discharge or full treatment at home. Validated prognostic tools (i.e., clinical prognostic scoring systems, imaging studies, and cardiac laboratory biomarkers) assist with risk classification of patients who have acute symptomatic PE.

1. Introduction

short-term adverse outcomes. These low-risk patients lack significant signs of acute cardiopulmonary compromise (e.g., hypotension, marked hypoxemia) and have a low short-term risk of developing complications that include all-cause mortality, recurrent venous thromboembolism (VTE), and major bleeding. Since cardiac biomarkers and cardiac imaging results have poor predictive values for these adverse outcomes in patients who have acute PE, guidelines suggest the use of clinical prognostic scores to identify low-risk PE patients [7,8]. The most frequently used prognostic scoring systems in clinical practice for patients who have acute symptomatic PE are the Pulmonary Embolism Severity Index (PESI) [9], its simplified version (sPESI) [10], and the Hestia criteria [11] (Tables 1–3). In a recent open-label, noninferiority, randomized, controlled trial of inpatient versus outpatient (discharged from the emergency department [ED] within 24 h of randomization) initial subcutaneous twice-daily enoxaparin therapy in patients who had acute PE and a low-risk of short-term adverse outcomes according to the PESI, one (0.6%) of 171 outpatients compared with none of 168 inpatients (0%, 95% upper confidence limit [UCL] 2.7%; non-inferiority P = 0.011) developed recurrent VTE within 90 days [12]. Only one (0.6%) patient in each treatment group died within 90 days (95% UCL 2.1%; P = 0.005), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3.6%; P = 0.031) These results supported use of the PESI for the identification of low-risk PE patients who can safely undergo home PE management. Of note, in addition to basing eligibility on a low PESI score, the study used numerous additional criteria (e.g., no hypotension, hypoxemia, high bleeding risk, and barriers to treatment and

Over the past two decades, technological and clinical research methods advances have improved acute pulmonary embolism (PE) diagnostic accuracy, risk stratification, and treatment. Contemporary multinational observational data showed temporal changes in patient management that were associated with reductions in all-cause and PErelated mortality [1,2]. The clinical presentation of acute PE ranges from mild symptoms to sustained hypotension or shock [3]. Depending on the estimated risk of an adverse outcome, admission to an intensive care unit (ICU) and early recanalization (i.e., thrombolysis, catheter or surgical embolectomy) may be indicated for patients deemed high-risk for developing complications associated with PE [4,5]. Alternatively, early hospital discharge or home treatment may be considered for patients who have a negligible short-term risk of complications [6]. 2. Identification of patients who have PE and a low risk for early adverse outcomes A previously healthy 43-year-old man presented with right-sided aching chest pain that worsened with deep inspiration. On physical examination, the patient had a blood pressure of 120/85 mm Hg, a heart rate of 80 beats per minute, and a pulse oximetry oxygen saturation of 97% while breathing ambient air. A contrast-enhanced computed tomography pulmonary angiogram showed an isolated right lower lobe segmental PE (Fig. 1). Most clinicians would consider this patient as having a low-risk for ⁎

Corresponding author at: Respiratory Department and Medicine Department, Ramón y Cajal Hospital, IRYCIS, Alcalá de Henares University, 28034 Madrid, Spain. E-mail address: [email protected] (D. Jiménez).

http://dx.doi.org/10.1016/j.thromres.2017.09.007 Received 26 February 2017; Received in revised form 4 July 2017; Accepted 4 September 2017 0049-3848/ © 2017 Elsevier Ltd. All rights reserved.

Please cite this article as: Barrios, D., Thrombosis Research (2017), http://dx.doi.org/10.1016/j.thromres.2017.09.007

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Table 3 Hestia criteria. Variable Hemodynamically unstable?a Thrombolysis or embolectomy necessary? Active bleeding or high risk of bleeding?b Oxygen supply to maintain oxygen saturation > 90% for > 24 h? Pulmonary embolism diagnosed during anticoagulant treatment? Intravenous pain medication > 24 h? Medical or social reason for treatment in the hospital > 24 h? Creatinine clearance of < 30 mL/min?c Severe liver impairment?d Pregnant? Documented history of heparin-induced thrombocytopenia? If one of the questions is answered with YES, the patient cannot be treated at home. a Include the following criteria, but are left to the discretion of the investigator: systolic blood pressure < 100 mm Hg with heart rate > 100 beats per minute; condition requiring admission to an intensive care unit. b Gastrointestinal bleeding in the preceding 14 days, recent stroke (< 4 weeks ago), recent operation (< 2 weeks ago), bleeding disorder or thrombocytopenia (platelet count < 75 × 109/L), uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg). c Calculated creatinine clearance according to the Cockcroft-Gault formula. d Left to the discretion of the physician.

Fig. 1. PE-protocol chest computed tomography showing a right lower lobe segmental pulmonary embolism (arrow).

Table 1 Pulmonary Embolism Severity Index. Predictor variable

Points

Age Male sex History of cancer History of heart failure History of chronic lung disease Pulse ≥ 110 beats/min Systolic blood pressure < 100 mm Hg Respiratory rate ≥ 30 breaths/min Temperature < 36 °C Altered mental status Arterial oxyhemoglobin saturation (SaO2) < 90%

Years + 10 + 30 + 10 + 10 + 20 + 30 + 20 + 20 + 60 + 20

patients died (one of the major bleeding [intracranial] events; none due to PE) during 3 months of follow-up [11]. This study provided evidence that HESTIA can identify reasonably low-risk patients for initial outpatient PE therapy. Some studies have evaluated the benefit of adding cardiac biomarkers and/or imaging testing to clinical prognostic scores for identification of patients with acute PE at low risk for short-term complications. The PROgnosTic valuE of Computed Tomography scan in haemodynamically stable patients with acute symptomatic PE (PROTECT) study prospectively assessed the prognostic value of right ventricular (RV) dysfunction assessed by multidetector computed tomography pulmonary angiography (CTPA) [16]. The PROTECT investigators elucidated whether the addition of CTPA and/or echocardiography prognostic information to the sPESI model improved the identification of patients at low-risk for adverse outcomes [17]. Of the 143 (17% of the entire study population) patients deemed low-risk according to sPESI (i.e., 0 points) who also had a negative CTPA for RV dysfunction, 3 (2.1%; 95% CI, 0.4–6.0%) experienced a complicated course during the study period, and none died. In contrast, 1.2% (95% CI, 0.1–4.2%) of patients who had a low risk sPESI and CTPA-assessed RV dysfunction had a complicated course and 1 patient (0.6%; 95% CI, 0–3.2%) died. In the subgroup of patients who had a low-risk sPESI and no RV dysfunction on CTPA, the addition of echocardiographic prognostic information did not significantly modify the probability of an adverse outcome [17]. This study questioned the additional prognostic information gained by assessing RV function on CTPA in patients who have a low-risk PESI, and it provided evidence that echocardiography does not assist with short-term prognostication in the setting of a lowrisk PESI and a lack of RV dysfunction on CTPA. Regarding blood test cardiac biomarkers, the PROTECT study also showed that the combination of the sPESI and brain natriuretic peptide (BNP) testing had a negative predictive value (NPV) for a complicated course of 99.1% and 100% in derivation and validation cohorts, respectively [18]. In contrast, the recent VESTA randomized controlled trial did not demonstrate the additive prognostic value of cardiac biomarkers to the HESTIA prognostic score for identifying low-risk patients with acute PE [19]. The study enrolled 550 patients who had low-risk PE according to the Hestia criteria: 275 patients were randomly assigned to direct discharge from the ED, and 275 were assigned to a prognostic strategy involving the measurement of NT-proBNP levels [19]. Investigators only discharged the latter patients from the ED if NT-proBNP was ≤ 500 ng/L (88% of patients). Otherwise, they

A total point score for a given patient is obtained by summing the patient's age in years and the points for each predictor variable when present. The score corresponds with the following risk classes: ≤65 class I; 66–85 class II; 86–105 class III; 106–125 class IV; and > 125 class V. Patients in risk classes I and II are defined as low-risk. Table 2 Simplified Pulmonary Embolism Severity Index. Variable

Points

Age > 80 years History of cancer History of chronic cardiopulmonary disease Pulse ≥ 110 beats/min Systolic blood pressure < 100 mm Hg Arterial oxyhemoglobin saturation (SaO2) < 90%

1 1 1 1 1 1

Sum the variable points to produce the total point score. The score corresponds with the following risk classes: 0, low risk; ≥1, high risk.

follow-up adherence) to determine eligibility. Multiple retrospective and prospective studies have validated the prognostic accuracy of the simplified version of the PESI, the sPESI [13–15], but it has not been used in a PE management study or in a randomized trial of inpatient versus immediate outpatient therapy of acute PE. The HESTIA criteria for determining eligibility for outpatient PE therapy address a broad range of issues that include risk for bleeding, clotting, dying, and inability to successfully receive home PE therapy. A single-arm, multicenter, prospective, management cohort study used the Hestia criteria to select patients for home once-daily subcutaneous nadroparin treatment within 24 h of PE diagnosis. Of the 297 (51% [297/581] of those screened) enrolled patients, 6 (2.0%, 95% confidence interval [CI], 0.8–4.3%) patients had recurrent VTE (five PE [1.7%] and one DVT [0.3%]), while only two (0.7%; 95% CI, 0.1–2.4%) patients had major bleeding and three (1.0%; 95% CI, 0.2–2.9%) 2

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admitted the patients (NT-proBNP > 500 ng/L; 12% of patients) to the hospital. The VESTA study used a non-inferiority margin of 3.4% for the composite primary endpoint of PE-related or bleeding-related mortality, cardiopulmonary resuscitation, or intensive care admission that was assessed during the 30 days of follow-up after randomization. In the total trial cohorts, the primary endpoint occurred in none of the 275 (0%; 95% CI, 0–1.3%) patients assigned to NT-proBNP testing, in comparison to 3 of 275 patients (1.1%; 95% CI, 0.2–3.2%) in the direct discharge group (P = 0.25). Thus, the VESTA study showed that use of NT-proBNP did not improve the identification and outpatient treatment of Hestia criteria-defined low-risk patients with acute PE. In summary, prognostic scores may identify patients who have acute symptomatic PE and a low-risk for short-term adverse outcomes, and may assist with identification of patients who are appropriate for early hospital discharge or management of PE entirely at home. Evidence from a broad body of medical literature suggests that the addition of imaging or cardiac biomarker variables to prognostic scores that solely rely on clinical variables does not improve their ability to identify patients who have a low-risk of adverse outcomes after being diagnosed with acute symptomatic PE. The sPESI and the Hestia criteria are currently being compared in the Hospitalization or Out-treatment Management of Patients with Pulmonary Embolism randomized controlled trial (NCT 02811237).

Fig. 3. Transthoracic echocardiogram showing right ventricular dilation (RV to LV ratio = 1.4), with bowing of the interventricular septum into the left ventricle.

high risk group has RV dysfunction on imaging and an abnormal cardiac biomarker, while the intermediate-low risk group at most has one of these two variables present. 3.1. Assessment of right heart strain Studies have validated the use of BNP, NT-proBNP, CTPA, and transthoracic echocardiography for assessing right heart strain [22–25]. A meta-analysis of 13 studies which included both normotensive and hypotensive patients who had acute PE demonstrated that 51% had elevated BNP/NT-pro-BNP values and that these markers had a significant association with short-term all-cause mortality (odds ratio [OR] 7.6; 95% CI, 3.4–17.1) [26]. Lankeit et al. found that NT-proBNP above a cut-off value of 600 pg/mL was associated with a 6-fold increased risk for an adverse outcome, defined as PE-related death or at least one of the following major complications: 1) need for intravenous catecholamine administration; 2) intubation; and 3) cardiopulmonary resuscitation [27]. A recent systematic review showed that CT-assessed RV dysfunction had almost a 2-fold (OR 1.8; 95% CI, 1.3–2.6) association with increased risk of mortality in normotensive patients with PE [28]. Another systematic review and meta-analysis showed that CTassessed RV enlargement was associated with a two-fold increased risk of death at 30 days [24]. Multiple studies, including large registries, of patients who have symptomatic PE and normal blood pressure, have reported a 2.0–2.5 fold increased risk of mortality in those who have echocardiographic RV dysfunction in comparison to those without it [29–31]. Interestingly, studies have shown large variations in agreement between CTPA and echocardiography for detection of RV dysfunction. One study found good prognostic accuracy of CTPA for detecting RV dysfunction, by using echocardiography as the reference standard (area under the curve [AUC] 0.86; 95% CI, 0.82–0.91) [32], while two other studies showed that multidetector CTPA and transthoracic echocardiography agreed on the presence or absence of RV overload in only around 50% of patients [17,33]. Thus, we suggest the combination of CTPA and echocardiographic criteria to evaluate for RV dysfunction in patients who have intermediate-high risk PE (i.e., determined by a positive PESI or sPESI in conjunction with an abnormal laboratory cardiac biomarker). Recently, Wyzgal et al. prospectively assessed the prognostic value of copeptin, the C-terminal fragment of provassopressin, in 107 stable (n = 104) and unstable (n = 3) patients with acute symptomatic PE [34]. The predefined endpoint of the study was 30-day all-cause mortality, and a complicated clinical course that included at least one of following: 30-day all-cause mortality, cardiopulmonary resuscitation, thrombolysis, and need for catecholamines or intubation. Using a cutoff value of 17.95 pmol/L, copeptin had sensitivity of 100%, specificity 49.5%, positive predictive value (PPV) of 16.9% and negative predictive value (NPV) of 100% [34].

3. Identification of patients with PE who have an intermediatehigh risk for early adverse outcomes A 47-year-old woman presented to the ED with 10 days of persistent dyspnea. On physical examination, she had a blood pressure of 99/ 67 mm Hg, a heart rate of 111 beats per minute, and an oxygen saturation of 92% while breathing ambient air. Troponin I was elevated at 0.51 ng/mL. Computed tomography pulmonary angiogram showed a saddle PE (Fig. 2), and transthoracic echocardiography showed right ventricular dilation (Fig. 3). Intermediate-high risk PE describes haemodynamically stable patients who have confirmed PE, and a risk of PE-related complications higher than the intermediate-low risk group (discussed below) and lower than the high-risk group [20]. Identification of the subgroup of normotensive patients at higher risk for complications associated with PE would facilitate selection of patients who should undergo intensive monitoring and escalation of therapy if clinical deterioration occurs [21]. A combination of clinical variables, and markers of right heart strain and myocardial injury assist with classification of patients into the intermediate-risk category and its subcategories of intermediate-low and intermediate-high [8]. While both intermediate-risk PE subgroups (i.e., high and low) have an elevated PESI or sPESI score, the intermediate-

Fig. 2. PE-protocol chest computed tomography showing a saddle pulmonary embolism (arrow).

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No studies have simultaneously compared the prognostic performance of multiple imaging or laboratory markers of right heart strain. Since assessment of right heart strain helps identify intermediate-high risk patients that might benefit from close observation and even escalation of therapy beyond standard anticoagulation, we suggest the use of echocardiographic criteria to identify those patients with more severe RV dysfunction at highest risk of clinical deterioration and PErelated mortality.

Table 4 PREP score. Prognostic factor

Categories

Points

Altered mental statea

No Yes No Yes No Yes < 100 100–249 250–499 500–999 ≥ 1000 0.2–0.49 0.5–0.74 0.75–1.00 1.00–1.25 ≥ 1.25

0 10 0 6 0 6 0 1 2 4 8 0 3 5 8 11

Cardiogenic shock Cancer

3.2. Assessment of myocardial injury

BNP (ng/L)

Studies have validated the use of troponin I and T, high-sensitive troponin, and heart-type fatty acid-binding protein (H-FABP) for assessing myocardial injury in patients who have acute PE [35–38]. Becattini et al. performed a meta-analysis of acute PE studies to assess the prognostic value of elevated troponin levels for short-term death and a composite of adverse outcome events (overall death and any of the following: shock, need for thrombolysis, intubation, catecholamine administration, cardiopulmonary resuscitation, or recurrent PE). Troponin only had a PPV of 43.6% (95% CI, 36.9–50.3%) [39]. In another study that included 156 normotensive patients with acute PE, highsensitive troponin demonstrated an excellent sensitivity and NPV (both 100%) for the prediction of an adverse outcome, defined as death or at least one of the following major complications: 1) need for intravenous catecholamine administration; 2) endotracheal intubation; and 3) cardiopulmonary resuscitation [40]. Alternatively, the PPV was only 8%. Lauke et al. found that a high level of H-FABP (cut-off value of 6 mcg/ L), another cardiac biomarker, was associated with a 17-fold increased risk for an unfavorable outcome, defined as death, cardiac arrest, mechanical ventilation, use of catecholamines, and recurrence of acute PE [41]. Regarding management of patients who have acute PE and associated RV dysfunction, the PEITHO study determined the efficacy and safety of early thrombolytic treatment in 1006 normotensive patients with RV dysfunction, as detected on an echocardiogram or CT scan, and evidence of myocardial injury, as indicated by a positive troponin test [21]. Since “only” 5.6% of patients in the placebo arm developed the primary outcome (death from any cause or haemodynamic decompensation within 7 days after randomization), PEITHO suggested that the combination of RV dysfunction and myocardial injury might not suffice to identify normotensive PE patients who have an appropriate risk:benefit ratio for reperfusion therapies. We recommend use of cardiac biomarkers to assess for myocardial injury in patients who have intermediate-high risk PE. However, since studies have not simultaneously compared the prognostic performance of cardiac laboratory biomarkers, we cannot suggest the use of any specific one over the other.

RV/LV ratio

Abbreviations: BNP, brain natriuretic peptide; RV, right ventricle; LV, left ventricle. Sum the prognostic factor points to produce the total point score. Range of total prognostic score, 0–41. The total points correspond to the following risk classes: ≤ 6, class I, low risk; 7–17, class II, intermediate risk; and ≥18, class III, high risk. a Altered mental state was defined as disorientation, stupor, or coma.

with each test alone regarding the identification of patients with acute PE at high risk for PE-associated mortality [43].

3.4. Prognostic models Several prognostic scoring systems (e.g., PREP score, FAST score, PROTECT multimarker index, Bova score) exist for identification of PE patients who have an intermediate-high risk for short-term PE-related adverse events. The clinical implications of these scores for patient management remain to be shown. The PREP score includes altered mental state, cardiogenic shock on admission, cancer, BNP, and RV/left ventricle ratio (Table 4) [22]. The original PREP score identified three risk groups (I, II, and III) that had 30-day adverse event (i.e., all-cause death, secondary cardiogenic shock, or objectively confirmed recurrent VTE) rates of 1.8%, 11.7%, and 22.2%, respectively. The FAST score includes H-FABP (≥ 6 ng/mL), heart rate (≥ 100 bpm) and syncope (Table 5) [45]. Dellas et al. found that a FAST score ≥ 3 points had a PPV of 22% (95% CI, 14–33%) for 30-day complications (i.e., all-cause death or at least one of the following major complications: (i) need for catecholamine administration; (ii) mechanical ventilation; or (iii) cardiopulmonary resuscitation). The PROTECT multimarker model consists of sPESI, BNP, cardiac troponin I (cTnI), and complete compression ultrasound imaging for concomitant lower extremity DVT (www.PEprognosis.org) [18]. In the original study, the PPV of the PROTECT score for the prediction of a complicated course was 26% in the derivation cohort and 21% in the validation cohort. A patient level meta-analysis (n = 2874) derived a simple grading

3.3. Concomitant deep vein thrombosis Studies have confirmed the prognostic value of concomitant lower extremity deep vein thrombosis (DVT) in patients who have acute symptomatic PE [42,43]. In a prospective cohort study that enrolled 707 outpatients diagnosed with a first episode of acute symptomatic PE, those with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR] 2.05; 95% CI, 1.24–3.38; P = 0.005) and PEspecific mortality (adjusted HR 4.25; 95% CI, 1.61–11.25; P = 0.04) compared to those without concomitant DVT [42]. A recent systematic review further confirmed that concomitant DVT has an association with increased risk of mortality in patients who have acute symptomatic PE (OR 1.9; 95% CI, 1.5–2.4) [44]. While incorporation of ultrasounddetected concomitant lower extremity DVT into the sPESI did not significantly improve identification of low-risk PE patients in the PROTECT study [18], one study suggested that the combination of lower limb ultrasound testing with prognostic tools that detect myocardial injury or RV dysfunction might offer an advantage compared

Table 5 FAST score. Predictor variable

Points

H-FABP ≥ 6 ng/mL Syncope Tachycardia

1.5 1.5 2.0

Abbreviations: FAST, H-FABP, syncope and tachycardia; HFABP, heart-type fatty acid-binding protein. Sum the predictor variable points to produce the total point score. The total score corresponds with the following risk classes: < 3, low risk; ≥ 3, high risk.

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Table 6 Bova score. Predictor variable

Points

Systolic blood pressure 90–100 mm Hg Cardiac troponin elevation Right ventricular dysfunction (echocardiogram or CT scan) Heart rate ≥ 110 beats per minute

2 2 2 1

Abbreviations: CT, computed tomography. Assign for the presence of each predictor variable. Sum the variable points to produce the total point score (Bova risk score; range, 0–7). Bova risk staging increased with point totals: stage I (0–2 points), stage II (3–4 points), or stage III (> 4 points).

system (i.e., the Bova score) that gives points for heart rate ≥ 110 beats per minute, systolic blood pressure 90–100 mm Hg, RV dysfunction, and elevated cardiac troponin (Table 6) [46]. The model identified three stages (I, II, and III) that had 30-day PE-related complication rates of 4.2%, 10.8%, and 29.2%, respectively. A recent study showed good Bova score reproducibility and provided additional evidence of validity for Bova score identification of intermediate-high risk acute symptomatic PE patients [47]. A recent study prospectively compared the performance of the Bova score and a modified (i.e., using high-sensitivity troponin T instead of H-FABP) FAST score for risk stratification of 388 consecutive normotensive patients who had acute symptomatic PE [48]. The study used PE-related death, need for mechanical ventilation, cardiopulmonary resuscitation, or the administration of catecholamines during the first month after the diagnosis of acute PE as the primary endpoint. The PPV with regard to the primary endpoint were similar (modified FAST score, 19%; 95% CI, 13–27%; Bova score 19%; 95% CI, 11–30%). In summary, observational studies have suggested that the combination of abnormal clinical variables (i.e., tachycardia, mild hypotension, or syncope), laboratory evidence of myocardial injury, and imaging evidence of RV dysfunction, particularly in those who have concomitant lower extremity DVT, identifies a subgroup of normotensive patients who have about a 20% risk of short-term major PE-related complications. We cannot suggest the use of any prognostic scoring system over another to identify patients who have intermediate-high risk PE. Though the clinical implications of these scores for patient management remain to be shown, we suggest that patients in the intermediate-high risk PE category might benefit from intensive monitoring and thrombolytic therapy if haemodynamic deterioration appears [7].

Fig. 4. PE-protocol chest computed tomography showing large pulmonary emboli in the main right pulmonary artery (arrow).

Table 7 PE thrombolysis-associated intracranial haemorrhage risk score. Risk factor

Points

Peripheral vascular disease Prior myocardial infarction Age > 65 years Prior stroke

1 1 1 5

Add risk factor points to obtain total risk score. Scores of 0, 1, 2 and ≥ 5 points were associated with ICH risks of 1.2%, 1.9%, 2.4% and 17.8% respectively.

patient by adding the points for each of the risk factors. Scores of 0, 1, 2 and ≥ 5 points were associated with ICH risks of 1.2%, 1.9%, 2.4% and 17.8% respectively. The ability of the model to discriminate cases of ICH from those not having ICH as represented by the c-statistic was 0.65 (95% CI, 0.59–0.71). The study validation cohort showed similar results. According to this study, systemic thrombolysis for PE should not be used in patients who have a history of stroke. Patients with any of the other identified risk factors need to be evaluated in the light of their clinical presentation, and a balanced judgment of the risk-benefit tradeoff is warranted. 5. Conclusions

4. Identification of patients with PE who have a high risk for early adverse outcomes

For patients who have acute symptomatic PE, clinicians should make initial treatment decisions based on the short-term risk of death and other PE-associated and treatment-associated adverse outcomes, patient preferences, and other patient-specific factors that could affect treatment safety and efficacy.

A 55-year-old man presented with sudden onset of shortness of breath after air travel. On physical examination, he had a blood pressure of 70/ 40 mm Hg, a heart rate of 120 beats per minute, and an oxygen saturation of 88% while breathing ambient air (Fig. 4). Clinical guidelines [7,8,49] classify this patient as high-risk for a short-term complicated course. High-risk PE is characterized by the presence of PE-associated arterial hypotension or shock, and has a high risk of short-term mortality [50,51]. For patients who have high-risk PE, pulmonary perfusion needs to be rapidly restored and guidelines suggest treatment with systemic thrombolytic agents if contraindications do not exist [7,8,49]. Every patient in whom thrombolysis is contemplated should undergo assessment for the risk of major bleeding, particularly intracranial haemorrhage (ICH). Recently, Chatterjee et al. used a large administrative database (the National/Nationwide In-patient Sample-NIS) to identify risk factors for ICH in PE patients who were treated with thrombolysis, and they developed and validated a risk score including independent predictors of ICH [52]. They found four independent predictors for ICH: peripheral vascular disease (1 point), age > 65 years (1 point), prior myocardial infarction (1 point), and prior stroke (5 points) (Table 7). A score was calculated for each

Conflict of interest statement D.B. and R. M. have nothing to disclose. R.Y. has received research funding from Bayer HealthCare Pharmaceuticals, Inc., Portola, Inc., Pfizer, Inc. and Bristol-Meyers Squibb in the past 3 years. He has served as a consultant for Bayer HealthCare, Inc., Bristol-Meyers Squibb, Glaxo-Smithkline, Janssen, Johnson & Johnson, Ortho Pharmaceuticals, Inc., Organon, Inc., Pfizer, Inc., Portola, Inc., Sanofi-Aventis, SCIOS, Inc. in the past 3 years. D.J. has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, Pfizer, ROVI and Sanofi; served as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI and Sanofi; received grants for clinical research from 5

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Sanofi and ROVI. [28]

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