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Risk adapted management of acute pulmonary embolism in women
S29 Thrombosis Research 181S1 (2019) S29–S32
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Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r . c o m / l o c a t e / t h r o m r e s
Review Article
Risk adapted management of acute pulmonary embolism in women Mateo Porres-Aguilara, David Jiménezb,* a b
Department of Medicine, Division of Hospital Medicine, Northcentral Baptist Medical Center, San Antonio, Texas, USA Respiratory Department and Medicine Department, Ramón y Cajal Hospital and Alcalá University, IRYCIS, Madrid, Spain
ARTICLE INFO
ABSTRACT
Keywords: Pulmonary embolism Prognosis Women
Acute pulmonary embolism (PE) represents the third most common cause of cardiovascular death worldwide. Clinical practice guidelines recommend prompt risk stratification of patients with acute PE. Prognostication may accurately identify: 1) hemodynamically unstable (i.e., high-risk) patients with PE, who might benefit from recanalization therapies (i.e., thrombolysis, embolectomy); 2) intermediate- to high-risk patients with PE, who might require monitoring and recanalization procedures if early hemodynamic decompensation occurs; and 3) low-risk patients with PE, who might benefit from an abbreviated hospital stay or outpatient therapy. A fourth group of patients should not undergo escalated or home therapy (intermediate- to low-risk PE). Studies of patients with proven acute PE have shown conflicting data regarding the association between sex and presentation and short-term clinical course in patients with acute symptomatic PE. Therefore, at this time sex differences should not dictate different approaches to prognostication and management.
1. Introduction
come up with a uniform, standardized, evidence-based, and universal definition, with significant implications in practical management and conduct of clinical trials [7]. This clinical review emphasizes: 1) the importance of prognostication in patients with acute symptomatic PE; 2) how to perform such risk stratification; and 3) whether there are any sex-based differences in risk stratification strategies and outcomes of patients with acute PE.
Venous thromboembolism (VTE) remains a common catastrophic event worldwide, leading to approximately 100,000 to 200,000 deaths per year in the United States [1,2]. In addition, acute pulmonary embolism (PE) is the leading cause of preventable death among hospitalized patients [3,4]. The key to an effective treatment of PE in the acute phase lies in the assessment of the patient’s prognosis [5]. High-risk PE is characterized by the presence of PE-associated arterial hypotension or shock, and has a short-term mortality of at least 15%. For patients with high-risk PE, guidelines generally recommend consideration of treatment with thrombolytic agents [5]. For normotensive patients with PE, those with negative prognostic scores (low-risk PE) have excellent shortterm outcomes and might be suitable for an abbreviated hospital stay or outpatient therapy. Normotensive patients with positive prognostic scores constitute an intermediate-risk group, and the European Society of Cardiology (ESC) 2014 guidelines further divide this group into intermediate- to high-risk and intermediate- to low-risk [6]. Intermediate-high risk patients have both evidence of right ventricle (RV) dysfunction (assessed either by echocardiography or computed tomographic pulmonary angiography (CTPA)) and elevated cardiac biomarkers (i.e., cardiac troponin test), while intermediate- to lowrisk patients have either RV dysfunction or myocardial injury, or none. Since researchers and clinical societies do not completely agree on how to identify intermediate- to high-risk PE patients, it is imperative to
2. Importance of prognostication in patients with acute PE Guidelines recommend risk stratification of patients who have acute symptomatic PE [5,6]. Though studies have provided evidence of validity for PE prognostic models (e.g., Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI) and HESTIA), imaging testing (e.g., CTPA and echocardiography), and cardiac biomarkers (e.g., cardiac troponins and natriuretic peptides), few studies have assessed whether the use of prognostication changes patient outcomes. To help address this issue, Barbero et al. used their prospective single-center 2003–2016 PE registry to assess whether Emergency Department (ED) clinicians routinely prognosticated patients with acute PE, and whether prognostic assessment was associated with clinical outcomes [8]. They defined prognostic assessment completion for each PE patient based on the presence or absence of medical record documentation of the calculation of a validated clinical prognostic score and/or assessment of right ventricular dysfunction, and/or the assessment of myocardial injury by the health care provider. They assessed for an association
* Corresponding author at: Respiratory Department and Medicine Department, Ramón y Cajal Hospital and Alcalá University, IRYCIS, Madrid, Spain. E-mail address: [email protected] (D. Jiménez). Received 23 December 2018; Received in revised form 15 March 2019; Accepted 22 March 2019 This article is published as part of a supplement sponsored by the International Symposium on Women’s Health Issues in Thrombosis and Haemostasis and Sanofi 0049-3848/ © 2019 Published by Elsevier Ltd.
M. Porres-Aguilar and D. Jiménez
Thrombosis Research 181S1 (2019) S29–S32
between prognostic assessment completion and the primary outcome of the study, which consisted of all-cause mortality during the first month after the diagnosis of acute PE. Of the 2096 patients who were enrolled, 1754 (84%; 95% confidence interval (CI) 82–85%) had documentation of prognostic assessment. The authors found that use of prognostication for patients with acute PE is associated with shortterm mortality, irrespective of the prognostication model’s results [8]. In response to increasing patient complexity and increasing therapeutic alternatives, there has been a rise in the development of multidisciplinary groups of clinicians with expertise in the medical, surgical and interventional management of PE who collaborate in a novel way to improve patient care. This multidisciplinary team approach is termed the PE Response Team (PERT) [9]. Due to the concern with over activation in the case of patients with low-risk PE, initial risk stratification allows identification of those with intermediate- or high-risk PE who might benefit from PERT activation, and helps mitigate the problem of over activation. Prognostication research has helped with the design and conduct of randomized controlled trials that assessed the efficacy and safety of various interventions for patients with acute symptomatic PE [10,11]. The Outpatient versus inpatient Treatment for patients with acute Pulmonary Embolism (OTPE) trial was an open-label, non-inferiority, randomized controlled trial (RCT) of inpatient versus outpatient initial subcutaneous twice-daily enoxaparin therapy in patients who had acute PE [10]. The trial protocol required that patients had a low-risk of short-term adverse outcomes according to the PESI. The Pulmonary Embolism Thrombolysis Trial (PEITHO) was a randomized, double blind trial that compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk PE [11]. The trial protocol required the presence of RV dysfunction on CTPA or echocardiography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T for patient eligibility.
Table 1 Pulmonary Embolism Severity Index 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 mmHg Respiratory rate ≥30 breaths/min Temperature <36ºC Altered mental status Arterial oxyhemoglobin saturation (SaO2) <90%
Years +10 +30 +10 +10 +20 +30 +20 +20 +60 +20
A total point score for a given patient is obtained by summing the patient´s age in years and the points for each predictor 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
A total point score for a given patient is obtained by summing the points The score corresponds with the following risk classes: 0, low risk; ≥1, high risk
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% >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 less than 30 mL/min?c Severe liver impairment?d Pregnant? Documented history of heparin-induced thrombocytopenia?
3. How do we risk-stratify normotensive patients with acute PE? 3.1. Identification of low-risk PE Studies have found an association between clinical features of cardiopulmonary impairment (e.g., heart rate, blood pressure, respiratory rate, jugular venous pressure, tissue hypoperfusion, pulse oximetry, syncope), pre-existing conditions and comorbidities (cancer, chronic heart failure, chronic obstructive pulmonary disease (COPD)), and short-term prognosis in patients who have acute symptomatic PE. Investigators have combined these predictors into structured clinical prediction rules that may identify a subgroup of patients with acute PE at low-risk of short-term all-cause mortality. We suggest the use of prognostic scores as the first step for identification of normotensive patients who have acute symptomatic PE and a low-risk for short-term adverse outcomes [12]. Some clinicians are reluctant to use scores and prefer using clinical intuition (i.e., gestalt) for determining the risk. A recent study enrolled 154 consecutive patients with acute symptomatic PE, and compared the prognostic accuracy of the PESI, the sPESI, and clinical gestalt of two senior physicians (one with and one without experience in the management of patients with PE) and three residents with different levels of experience in PE. The study showed that well validated prognostic scores are not more accurate than implicit judgement by experienced clinicians [13]. The most frequently used prognostic scoring systems in clinical practice for patients who have acute symptomatic PE are the PESI [14], its simplified version (sPESI) [15], and the Hestia criteria [16] (Tables 1–3). While randomized clinical trials and management studies have validated the safety of the PESI and the Hestia criteria for outpatient therapy of low-risk PE patients, the sPESI has not been used in a management study or randomized trial as a decision tool to treat patients with acute PE at home directly. Alternatively, compared to the PESI and the Hestia criteria, the sPESI has shown the highest
If one of the questions is answered with “yes”, the patient cannot be treated at home a Include the following criteria, but is left to the discretion of the investigator: systolic blood pressure <100 mmHg 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 (less than 4 weeks ago), recent operation (less than 2 weeks ago), bleeding disorder or thrombocytopenia (platelet count <75×109/L), uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) c Calculated creatinine clearance according to the Cockcroft-Gault formula d Left to the discretion of the physician
accuracy for identification of patients with low-risk of short-term complications [17]. 3.2. Identification of intermediate- to high-risk PE The European Society of Cardiology (ESC) 2014 guidelines define intermediate- to high-risk PE as the combination of both RV dysfunction and myocardial injury [6]. The combination of RV dysfunction and a positive cardiac troponin test was used as an inclusion criterion in the PEITHO trial, which enrolled 1006 patients with acute PE [11]. Since the mortality rate of the trial was low, this combination might not identify a “sick enough” population. Therefore, researchers have developed several prognostic-scoring systems (e.g., PREP score, FAST score, PROTECT multimarker index, Bova score) for identification of S30
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Thrombosis Research 181S1 (2019) S29–S32
6. Conclusions
PE patients who have an intermediate–high risk for short-term PErelated adverse events. The Bova score gives points for heart rate ≥110 beats per minute, systolic blood pressure 90–100 mmHg, RV dysfunction, and elevated cardiac troponin [18]. 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- to high-risk acute symptomatic PE patients [19]. We suggest the combination of clinical variables, and markers of right heart strain and myocardial injury for identification of normotensive patients who have acute symptomatic PE and intermediate- to highrisk for short-term PE-related adverse outcomes.
Clinicians should make their treatment decisions for PE based on the early mortality risk, bleeding risk, patient preferences, and patient-specific factors that could affect treatment safety and efficacy. Evidence suggests that sex differences should not dictate different approaches to prognostication and management. Conduct of clinical trials that assess various treatment strategies separately for women and men will assist with decision-making for patients who have acute PE. Conflict of interest statement None declared. References
4. Sex-based differences in risk stratification strategies and outcomes of patients with acute PE
[1] US Department of Health and Human Services, The Surgeon General´s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism: 2008, http//www.surgeon General.gov/library/calls/deepvein/call-to-action-ondvt-2008.pdf. Accessed on 15 December 2018. [2] R.S. Wiener, L.M. Schwartz, S. Woloshin, Time trends in pulmonary embolism in the United States: evidence of overdiagnosis, Arch. Intern. Med. 171 (2011) 831–837. [3] A.S. Go, D. Mozaffarian, V.L. Roger, et al., Executive summary: heart disease and stroke statistics – 2014 update: a report from the American Heart Association, Circulation 129 (2014) 399–410. [4] A.T. Cohen, G. Agnelli, F.A. Anderson, et al., Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality, Thromb. Haemost. 98 (2007) 756–764. [5] C. Kearon, E.A. Akl, J. Ornelas, et al., Antithrombotic therapy for VTE disease: chest guideline and expert panel report, Chest 149 (2016) 315–352. [6] S.V. Konstantinides, A. Torbicki, G. Agnelli, et al., 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism, Eur. Heart J. 35 (2014) 3033–3069. [7] M. Porres-Muñoz, M. Porres-Aguilar, Intermediate-high-risk pulmonary embolism: standardizing definition and optimizing therapeutic strategies, Am. J. Med. 130 (2017) E-233. [8] E. Barbero, B. Bikdeli, D. ChiluizD, et al., Performance of early prognostic assessment independently predicts the outcomes in patients with acute pulmonary embolism, Thromb. Haemost. 118 (2018) 798–800. [9] M. Porres-Aguilar, J.E. Anaya-Ayala, G.A. Heresi, B.N. Rivera-Lebron, Pulmonary Embolism Response Teams: a novel approach for the care of complex patients with pulmonary embolism, Clin. Appl. Thromb. Hemost. (2018) doi:10.1177/1076029618812954. Epub ahead of print. [10] D. Aujesky, P.M. Roy, F. Verschuren, et al., Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial, Lancet 378 (2011) 41–48. [11] G. Meyer, E. Vicaut, T. Danays, et al., Fibrinolysis for patients with intermediaterisk pulmonary embolism, N. Engl. J. Med. 370 (2014) 1402–1411. [12] D. Jimenez, R.D. Yusen, Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy, Curr. Opin. Pulm. Med. 14 (2008) 414–421. [13] C.A. Quezada, C. Zamarro, V. Gomez, et al., Clinical gestalt versus prognostic scores for prognostication of patients with acute symptomatic pulmonary embolism, Med. Clin. (Barc.) 151 (2018) 136–140. [14] D. Aujesky, D.S. Obrosky, R.A. Stone, et al., Derivation and validation of a prognostic model for pulmonary embolism, Am. J. Respir. Crit. Care Med. 172 (2005) 1041–1046. [15] D. Jiménez, D. Aujesky, L. Moores, et al.; RIETE Investigators, Simplification of the pulmonary embolism severity index for prognostication in patients with symptomatic acute pulmonary embolism, Arch. Intern. Med. 170 (2010) 1383–1389. [16] W. Zondag, P.L. den Exter, M.J. Crobach, et al.; Hestia study investigators, Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism, Thromb. Haemost. 109 (2013) 47–52. [17] C.G. Kohn, E.S. Mearns, M.W. Parker, et al., Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate metaanalysis, Chest 147 (2015) 1043–1062. [18] C. Bova, O. Sanchez, P. Prandoni, et al., Identification of intermediate-risk patients with acute pulmonary embolism, Eur. Respir. J. 44 (2014) 694–703. [19] C. Fernandez, C. Bova, O. Sanchez, et al., Validation of a model for identification of patients with intermediate to high risk for complications in acute pulmonary embolism, Chest 148 (2015) 211–218. [20] J.S. Hochman, J.E. Tamis, T.D. Thompson, et al., Sex, clinical presentation, and outcome in patients with acute coronary syndromes, N. Engl. J. Med. 241 (1999) 226–232. [21] J. Marrugat, M. Gil, J. Sala, Sex differences in survival rates after myocardial infarction, J. Cardiovasc. Risk 6 (1999) 89–97. [22] E. Barrett-Connor, Sex differences in coronary heart disease, Circulation 95 (1997) 252–264.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among women [20]. While sex differences in arterial disease have received considerable attention [20–22], few studies have explored sex-based differences in population-based cohorts with acute PE. In a large study that included 276,484 discharges with acute PE from the Nationwide Inpatient Sample over a 9-year period (2003– 2011), women had an increased risk of in-hospital mortality compared to men [23]. Women experienced a higher need for transfusion (OR 1.38; 95% CI, 1.33–1.44) and occurrence of shock (OR 1.10; 95% CI, 1.01–1.18) during hospitalization. Furthermore, there was a significantly lower utilization of vena cava filters (OR 0.86; 95% CI, 0.84–0.89) in women compared with men. In contrast, Aujesky and colleagues found that men had a higher risk of 30-day death compared to women [24]. Two smaller studies and an analysis of 47,499 patients from the RIETE registry did not find a significant association between sex and prognosis [25–27]. Barrios et al. used data from a prospective observational registry to assess sex-based differences in presentation and outcome of patients with objectively confirmed acute symptomatic PE [28]. They found that adjusted 30-day allcause mortality was similar between women and men. Restricting the analyses to haemodynamically stable patients, women had a higher risk of 30-day all-cause mortality compared to men (adjusted odds ratio 1.56; 95% CI 1.07–2.28; p=0.02). Compared with men, women were 2.05 times more likely to experience a major bleed. Only one study has evaluated whether the predictive ability of commonly used prognostic tests differs between men and women. Masotti et al. enrolled 452 patients (272 women) with acute symptomatic PE, and retrospectively calculated the sPESI score [29]. Age ≥80 years and heart rate ≥110/min were found significantly more prevalent in women, whereas active cancer and cardiorespiratory disease were more prevalent in men. For sPESI scores of 0, all cause in-hospital mortality was 0% in both sexes. 5. Areas of uncertainty Studies have suggested that imaging of the right ventricle typically do not add much useful prognostic information to clinical scores in terms of decision-making regarding outpatient therapy [30]. However, a recent systematic review and meta-analysis found that the presence of RV dysfunction on admission was associated with early mortality in low-risk patients with acute PE [31]. Although we systematically assess RV size in the CTPA, we do not routinely order an echocardiogram in patients with low-risk PE. If these tests are available and positive, patients might be classified into the intermediate- to low-risk category. The optimal approach to assess RV function in patients with acute symptomatic PE lacks clarity. The results of two independent studies suggest that echocardiographic (and not CTPA) assessment of RV function might be required for identifying intermediate- to high-risk patients with acute symptomatic PE [32,33]. S31
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[23] S. Agarwal, D. Clark 3rd, K. Sud, et al., Gender disparities and outcomes and resource utilization for acute pulmonary embolism hospitalizations in the United States, Am. J. Cardiol. 116 (2015) 1270–1276. [24] D. Aujesky, D.S. Obrosky, R.A. Stone, et al., Derivation and validation of a prognostic model for pulmonary embolism, Am. J. Respir. Crit. Care Med. 172 (2005) 1041–1046. [25] A. Blanco-Molina, I. Enea, T. Gadelha, et al., Sex differences in patients receiving anticoagulant therapy for venous thromboembolism, Medicine (Baltimore) 93 (2014) 309–317. [26] D. Jiménez, D. Aujesky, L. Moores, et al.; RIETE Investigators, Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism, Arch. Intern. Med. 170 (2010) 1383–1389. [27] G. Panigada, L. Masotti, C. Rosi, et al., Thromboembolic burden, prognostic assessment and outcomes of females compared to males in acute pulmonary embolism, Acta Clin. Belg. 71 (2016) 142–148. [28] D. Barrios, R. Morillo, I. Guerassimova, et al., Sex differences in the characteristics and short-term prognosis in patients presenting with acute symptomatic pulmonary embolism, Plos One 12 (2017) e0187648.
[29] L. Masotti, G. Panigada, G. Landini, et al., Simplified PESI score and sex differences in prognosis for acute pulmonary embolism: a brief report from a real-life study, J. Thromb. Thrombolysis 41 (2016) 606–612. [30] D. Jimenez, D. Kopecna, V. Tapson, et al.; on behalf of the Protect investigators, Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism, Am. J. Respir. Crit. Care Med. 189 (2014) 718–726. [31] S. Barco, S.H. Mahmoudpour, B. Planquette, et al., Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis, Eur. Heart J. (2018) doi:10.1093/eurheartj/ehy873. Epub ahead of print. [32] D. Barrios, R. Morillo, J.L. Lobo, et al., Assessment of right ventricular function in acute pulmonary embolism, Am. Heart J. 185 (2017)123–129. [33] D.M. Dudzinski, P. Hariharan, B.A. Parry, et al., Assessment of right ventricular strain by computed tomography versus echocardiography in acute pulmonary embolism, Acad. Emerg. Med. 24 (2017) 337–343.
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Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s e v i e r . c o m / l o c a t e / t h r o m r e s
Review Article
Risk adapted management of acute pulmonary embolism in women Mateo Porres-Aguilara, David Jiménezb,* a b
Department of Medicine, Division of Hospital Medicine, Northcentral Baptist Medical Center, San Antonio, Texas, USA Respiratory Department and Medicine Department, Ramón y Cajal Hospital and Alcalá University, IRYCIS, Madrid, Spain
ARTICLE INFO
ABSTRACT
Keywords: Pulmonary embolism Prognosis Women
Acute pulmonary embolism (PE) represents the third most common cause of cardiovascular death worldwide. Clinical practice guidelines recommend prompt risk stratification of patients with acute PE. Prognostication may accurately identify: 1) hemodynamically unstable (i.e., high-risk) patients with PE, who might benefit from recanalization therapies (i.e., thrombolysis, embolectomy); 2) intermediate- to high-risk patients with PE, who might require monitoring and recanalization procedures if early hemodynamic decompensation occurs; and 3) low-risk patients with PE, who might benefit from an abbreviated hospital stay or outpatient therapy. A fourth group of patients should not undergo escalated or home therapy (intermediate- to low-risk PE). Studies of patients with proven acute PE have shown conflicting data regarding the association between sex and presentation and short-term clinical course in patients with acute symptomatic PE. Therefore, at this time sex differences should not dictate different approaches to prognostication and management.
1. Introduction
come up with a uniform, standardized, evidence-based, and universal definition, with significant implications in practical management and conduct of clinical trials [7]. This clinical review emphasizes: 1) the importance of prognostication in patients with acute symptomatic PE; 2) how to perform such risk stratification; and 3) whether there are any sex-based differences in risk stratification strategies and outcomes of patients with acute PE.
Venous thromboembolism (VTE) remains a common catastrophic event worldwide, leading to approximately 100,000 to 200,000 deaths per year in the United States [1,2]. In addition, acute pulmonary embolism (PE) is the leading cause of preventable death among hospitalized patients [3,4]. The key to an effective treatment of PE in the acute phase lies in the assessment of the patient’s prognosis [5]. High-risk PE is characterized by the presence of PE-associated arterial hypotension or shock, and has a short-term mortality of at least 15%. For patients with high-risk PE, guidelines generally recommend consideration of treatment with thrombolytic agents [5]. For normotensive patients with PE, those with negative prognostic scores (low-risk PE) have excellent shortterm outcomes and might be suitable for an abbreviated hospital stay or outpatient therapy. Normotensive patients with positive prognostic scores constitute an intermediate-risk group, and the European Society of Cardiology (ESC) 2014 guidelines further divide this group into intermediate- to high-risk and intermediate- to low-risk [6]. Intermediate-high risk patients have both evidence of right ventricle (RV) dysfunction (assessed either by echocardiography or computed tomographic pulmonary angiography (CTPA)) and elevated cardiac biomarkers (i.e., cardiac troponin test), while intermediate- to lowrisk patients have either RV dysfunction or myocardial injury, or none. Since researchers and clinical societies do not completely agree on how to identify intermediate- to high-risk PE patients, it is imperative to
2. Importance of prognostication in patients with acute PE Guidelines recommend risk stratification of patients who have acute symptomatic PE [5,6]. Though studies have provided evidence of validity for PE prognostic models (e.g., Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI) and HESTIA), imaging testing (e.g., CTPA and echocardiography), and cardiac biomarkers (e.g., cardiac troponins and natriuretic peptides), few studies have assessed whether the use of prognostication changes patient outcomes. To help address this issue, Barbero et al. used their prospective single-center 2003–2016 PE registry to assess whether Emergency Department (ED) clinicians routinely prognosticated patients with acute PE, and whether prognostic assessment was associated with clinical outcomes [8]. They defined prognostic assessment completion for each PE patient based on the presence or absence of medical record documentation of the calculation of a validated clinical prognostic score and/or assessment of right ventricular dysfunction, and/or the assessment of myocardial injury by the health care provider. They assessed for an association
* Corresponding author at: Respiratory Department and Medicine Department, Ramón y Cajal Hospital and Alcalá University, IRYCIS, Madrid, Spain. E-mail address: [email protected] (D. Jiménez). Received 23 December 2018; Received in revised form 15 March 2019; Accepted 22 March 2019 This article is published as part of a supplement sponsored by the International Symposium on Women’s Health Issues in Thrombosis and Haemostasis and Sanofi 0049-3848/ © 2019 Published by Elsevier Ltd.
M. Porres-Aguilar and D. Jiménez
Thrombosis Research 181S1 (2019) S29–S32
between prognostic assessment completion and the primary outcome of the study, which consisted of all-cause mortality during the first month after the diagnosis of acute PE. Of the 2096 patients who were enrolled, 1754 (84%; 95% confidence interval (CI) 82–85%) had documentation of prognostic assessment. The authors found that use of prognostication for patients with acute PE is associated with shortterm mortality, irrespective of the prognostication model’s results [8]. In response to increasing patient complexity and increasing therapeutic alternatives, there has been a rise in the development of multidisciplinary groups of clinicians with expertise in the medical, surgical and interventional management of PE who collaborate in a novel way to improve patient care. This multidisciplinary team approach is termed the PE Response Team (PERT) [9]. Due to the concern with over activation in the case of patients with low-risk PE, initial risk stratification allows identification of those with intermediate- or high-risk PE who might benefit from PERT activation, and helps mitigate the problem of over activation. Prognostication research has helped with the design and conduct of randomized controlled trials that assessed the efficacy and safety of various interventions for patients with acute symptomatic PE [10,11]. The Outpatient versus inpatient Treatment for patients with acute Pulmonary Embolism (OTPE) trial was an open-label, non-inferiority, randomized controlled trial (RCT) of inpatient versus outpatient initial subcutaneous twice-daily enoxaparin therapy in patients who had acute PE [10]. The trial protocol required that patients had a low-risk of short-term adverse outcomes according to the PESI. The Pulmonary Embolism Thrombolysis Trial (PEITHO) was a randomized, double blind trial that compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk PE [11]. The trial protocol required the presence of RV dysfunction on CTPA or echocardiography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T for patient eligibility.
Table 1 Pulmonary Embolism Severity Index 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 mmHg Respiratory rate ≥30 breaths/min Temperature <36ºC Altered mental status Arterial oxyhemoglobin saturation (SaO2) <90%
Years +10 +30 +10 +10 +20 +30 +20 +20 +60 +20
A total point score for a given patient is obtained by summing the patient´s age in years and the points for each predictor 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
A total point score for a given patient is obtained by summing the points The score corresponds with the following risk classes: 0, low risk; ≥1, high risk
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% >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 less than 30 mL/min?c Severe liver impairment?d Pregnant? Documented history of heparin-induced thrombocytopenia?
3. How do we risk-stratify normotensive patients with acute PE? 3.1. Identification of low-risk PE Studies have found an association between clinical features of cardiopulmonary impairment (e.g., heart rate, blood pressure, respiratory rate, jugular venous pressure, tissue hypoperfusion, pulse oximetry, syncope), pre-existing conditions and comorbidities (cancer, chronic heart failure, chronic obstructive pulmonary disease (COPD)), and short-term prognosis in patients who have acute symptomatic PE. Investigators have combined these predictors into structured clinical prediction rules that may identify a subgroup of patients with acute PE at low-risk of short-term all-cause mortality. We suggest the use of prognostic scores as the first step for identification of normotensive patients who have acute symptomatic PE and a low-risk for short-term adverse outcomes [12]. Some clinicians are reluctant to use scores and prefer using clinical intuition (i.e., gestalt) for determining the risk. A recent study enrolled 154 consecutive patients with acute symptomatic PE, and compared the prognostic accuracy of the PESI, the sPESI, and clinical gestalt of two senior physicians (one with and one without experience in the management of patients with PE) and three residents with different levels of experience in PE. The study showed that well validated prognostic scores are not more accurate than implicit judgement by experienced clinicians [13]. The most frequently used prognostic scoring systems in clinical practice for patients who have acute symptomatic PE are the PESI [14], its simplified version (sPESI) [15], and the Hestia criteria [16] (Tables 1–3). While randomized clinical trials and management studies have validated the safety of the PESI and the Hestia criteria for outpatient therapy of low-risk PE patients, the sPESI has not been used in a management study or randomized trial as a decision tool to treat patients with acute PE at home directly. Alternatively, compared to the PESI and the Hestia criteria, the sPESI has shown the highest
If one of the questions is answered with “yes”, the patient cannot be treated at home a Include the following criteria, but is left to the discretion of the investigator: systolic blood pressure <100 mmHg 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 (less than 4 weeks ago), recent operation (less than 2 weeks ago), bleeding disorder or thrombocytopenia (platelet count <75×109/L), uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) c Calculated creatinine clearance according to the Cockcroft-Gault formula d Left to the discretion of the physician
accuracy for identification of patients with low-risk of short-term complications [17]. 3.2. Identification of intermediate- to high-risk PE The European Society of Cardiology (ESC) 2014 guidelines define intermediate- to high-risk PE as the combination of both RV dysfunction and myocardial injury [6]. The combination of RV dysfunction and a positive cardiac troponin test was used as an inclusion criterion in the PEITHO trial, which enrolled 1006 patients with acute PE [11]. Since the mortality rate of the trial was low, this combination might not identify a “sick enough” population. Therefore, researchers have developed several prognostic-scoring systems (e.g., PREP score, FAST score, PROTECT multimarker index, Bova score) for identification of S30
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6. Conclusions
PE patients who have an intermediate–high risk for short-term PErelated adverse events. The Bova score gives points for heart rate ≥110 beats per minute, systolic blood pressure 90–100 mmHg, RV dysfunction, and elevated cardiac troponin [18]. 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- to high-risk acute symptomatic PE patients [19]. We suggest the combination of clinical variables, and markers of right heart strain and myocardial injury for identification of normotensive patients who have acute symptomatic PE and intermediate- to highrisk for short-term PE-related adverse outcomes.
Clinicians should make their treatment decisions for PE based on the early mortality risk, bleeding risk, patient preferences, and patient-specific factors that could affect treatment safety and efficacy. Evidence suggests that sex differences should not dictate different approaches to prognostication and management. Conduct of clinical trials that assess various treatment strategies separately for women and men will assist with decision-making for patients who have acute PE. Conflict of interest statement None declared. References
4. Sex-based differences in risk stratification strategies and outcomes of patients with acute PE
[1] US Department of Health and Human Services, The Surgeon General´s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism: 2008, http//www.surgeon General.gov/library/calls/deepvein/call-to-action-ondvt-2008.pdf. Accessed on 15 December 2018. [2] R.S. Wiener, L.M. Schwartz, S. Woloshin, Time trends in pulmonary embolism in the United States: evidence of overdiagnosis, Arch. Intern. Med. 171 (2011) 831–837. [3] A.S. Go, D. Mozaffarian, V.L. Roger, et al., Executive summary: heart disease and stroke statistics – 2014 update: a report from the American Heart Association, Circulation 129 (2014) 399–410. [4] A.T. Cohen, G. Agnelli, F.A. Anderson, et al., Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality, Thromb. Haemost. 98 (2007) 756–764. [5] C. Kearon, E.A. Akl, J. Ornelas, et al., Antithrombotic therapy for VTE disease: chest guideline and expert panel report, Chest 149 (2016) 315–352. [6] S.V. Konstantinides, A. Torbicki, G. Agnelli, et al., 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism, Eur. Heart J. 35 (2014) 3033–3069. [7] M. Porres-Muñoz, M. Porres-Aguilar, Intermediate-high-risk pulmonary embolism: standardizing definition and optimizing therapeutic strategies, Am. J. Med. 130 (2017) E-233. [8] E. Barbero, B. Bikdeli, D. ChiluizD, et al., Performance of early prognostic assessment independently predicts the outcomes in patients with acute pulmonary embolism, Thromb. Haemost. 118 (2018) 798–800. [9] M. Porres-Aguilar, J.E. Anaya-Ayala, G.A. Heresi, B.N. Rivera-Lebron, Pulmonary Embolism Response Teams: a novel approach for the care of complex patients with pulmonary embolism, Clin. Appl. Thromb. Hemost. (2018) doi:10.1177/1076029618812954. Epub ahead of print. [10] D. Aujesky, P.M. Roy, F. Verschuren, et al., Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial, Lancet 378 (2011) 41–48. [11] G. Meyer, E. Vicaut, T. Danays, et al., Fibrinolysis for patients with intermediaterisk pulmonary embolism, N. Engl. J. Med. 370 (2014) 1402–1411. [12] D. Jimenez, R.D. Yusen, Prognostic models for selecting patients with acute pulmonary embolism for initial outpatient therapy, Curr. Opin. Pulm. Med. 14 (2008) 414–421. [13] C.A. Quezada, C. Zamarro, V. Gomez, et al., Clinical gestalt versus prognostic scores for prognostication of patients with acute symptomatic pulmonary embolism, Med. Clin. (Barc.) 151 (2018) 136–140. [14] D. Aujesky, D.S. Obrosky, R.A. Stone, et al., Derivation and validation of a prognostic model for pulmonary embolism, Am. J. Respir. Crit. Care Med. 172 (2005) 1041–1046. [15] D. Jiménez, D. Aujesky, L. Moores, et al.; RIETE Investigators, Simplification of the pulmonary embolism severity index for prognostication in patients with symptomatic acute pulmonary embolism, Arch. Intern. Med. 170 (2010) 1383–1389. [16] W. Zondag, P.L. den Exter, M.J. Crobach, et al.; Hestia study investigators, Comparison of two methods for selection of out of hospital treatment in patients with acute pulmonary embolism, Thromb. Haemost. 109 (2013) 47–52. [17] C.G. Kohn, E.S. Mearns, M.W. Parker, et al., Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate metaanalysis, Chest 147 (2015) 1043–1062. [18] C. Bova, O. Sanchez, P. Prandoni, et al., Identification of intermediate-risk patients with acute pulmonary embolism, Eur. Respir. J. 44 (2014) 694–703. [19] C. Fernandez, C. Bova, O. Sanchez, et al., Validation of a model for identification of patients with intermediate to high risk for complications in acute pulmonary embolism, Chest 148 (2015) 211–218. [20] J.S. Hochman, J.E. Tamis, T.D. Thompson, et al., Sex, clinical presentation, and outcome in patients with acute coronary syndromes, N. Engl. J. Med. 241 (1999) 226–232. [21] J. Marrugat, M. Gil, J. Sala, Sex differences in survival rates after myocardial infarction, J. Cardiovasc. Risk 6 (1999) 89–97. [22] E. Barrett-Connor, Sex differences in coronary heart disease, Circulation 95 (1997) 252–264.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among women [20]. While sex differences in arterial disease have received considerable attention [20–22], few studies have explored sex-based differences in population-based cohorts with acute PE. In a large study that included 276,484 discharges with acute PE from the Nationwide Inpatient Sample over a 9-year period (2003– 2011), women had an increased risk of in-hospital mortality compared to men [23]. Women experienced a higher need for transfusion (OR 1.38; 95% CI, 1.33–1.44) and occurrence of shock (OR 1.10; 95% CI, 1.01–1.18) during hospitalization. Furthermore, there was a significantly lower utilization of vena cava filters (OR 0.86; 95% CI, 0.84–0.89) in women compared with men. In contrast, Aujesky and colleagues found that men had a higher risk of 30-day death compared to women [24]. Two smaller studies and an analysis of 47,499 patients from the RIETE registry did not find a significant association between sex and prognosis [25–27]. Barrios et al. used data from a prospective observational registry to assess sex-based differences in presentation and outcome of patients with objectively confirmed acute symptomatic PE [28]. They found that adjusted 30-day allcause mortality was similar between women and men. Restricting the analyses to haemodynamically stable patients, women had a higher risk of 30-day all-cause mortality compared to men (adjusted odds ratio 1.56; 95% CI 1.07–2.28; p=0.02). Compared with men, women were 2.05 times more likely to experience a major bleed. Only one study has evaluated whether the predictive ability of commonly used prognostic tests differs between men and women. Masotti et al. enrolled 452 patients (272 women) with acute symptomatic PE, and retrospectively calculated the sPESI score [29]. Age ≥80 years and heart rate ≥110/min were found significantly more prevalent in women, whereas active cancer and cardiorespiratory disease were more prevalent in men. For sPESI scores of 0, all cause in-hospital mortality was 0% in both sexes. 5. Areas of uncertainty Studies have suggested that imaging of the right ventricle typically do not add much useful prognostic information to clinical scores in terms of decision-making regarding outpatient therapy [30]. However, a recent systematic review and meta-analysis found that the presence of RV dysfunction on admission was associated with early mortality in low-risk patients with acute PE [31]. Although we systematically assess RV size in the CTPA, we do not routinely order an echocardiogram in patients with low-risk PE. If these tests are available and positive, patients might be classified into the intermediate- to low-risk category. The optimal approach to assess RV function in patients with acute symptomatic PE lacks clarity. The results of two independent studies suggest that echocardiographic (and not CTPA) assessment of RV function might be required for identifying intermediate- to high-risk patients with acute symptomatic PE [32,33]. S31
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[23] S. Agarwal, D. Clark 3rd, K. Sud, et al., Gender disparities and outcomes and resource utilization for acute pulmonary embolism hospitalizations in the United States, Am. J. Cardiol. 116 (2015) 1270–1276. [24] D. Aujesky, D.S. Obrosky, R.A. Stone, et al., Derivation and validation of a prognostic model for pulmonary embolism, Am. J. Respir. Crit. Care Med. 172 (2005) 1041–1046. [25] A. Blanco-Molina, I. Enea, T. Gadelha, et al., Sex differences in patients receiving anticoagulant therapy for venous thromboembolism, Medicine (Baltimore) 93 (2014) 309–317. [26] D. Jiménez, D. Aujesky, L. Moores, et al.; RIETE Investigators, Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism, Arch. Intern. Med. 170 (2010) 1383–1389. [27] G. Panigada, L. Masotti, C. Rosi, et al., Thromboembolic burden, prognostic assessment and outcomes of females compared to males in acute pulmonary embolism, Acta Clin. Belg. 71 (2016) 142–148. [28] D. Barrios, R. Morillo, I. Guerassimova, et al., Sex differences in the characteristics and short-term prognosis in patients presenting with acute symptomatic pulmonary embolism, Plos One 12 (2017) e0187648.
[29] L. Masotti, G. Panigada, G. Landini, et al., Simplified PESI score and sex differences in prognosis for acute pulmonary embolism: a brief report from a real-life study, J. Thromb. Thrombolysis 41 (2016) 606–612. [30] D. Jimenez, D. Kopecna, V. Tapson, et al.; on behalf of the Protect investigators, Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism, Am. J. Respir. Crit. Care Med. 189 (2014) 718–726. [31] S. Barco, S.H. Mahmoudpour, B. Planquette, et al., Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis, Eur. Heart J. (2018) doi:10.1093/eurheartj/ehy873. Epub ahead of print. [32] D. Barrios, R. Morillo, J.L. Lobo, et al., Assessment of right ventricular function in acute pulmonary embolism, Am. Heart J. 185 (2017)123–129. [33] D.M. Dudzinski, P. Hariharan, B.A. Parry, et al., Assessment of right ventricular strain by computed tomography versus echocardiography in acute pulmonary embolism, Acad. Emerg. Med. 24 (2017) 337–343.
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