Systolic blood pressure and mortality in acute symptomatic pulmonary embolism

Systolic blood pressure and mortality in acute symptomatic pulmonary embolism Andrés Quezada a , David Jiménez a, ⁎, Behnood Bikdeli b,c,d ,LisaMoores e , Mateo Porres-Aguilar k , Mario Aramberri f , Jorge Lima g , Aitor Ballaz h , Roger D. Yusen i , Manuel Monreal j ,the RIETE investigators 1 a Respiratory Department, Hospital Ramón y Cajal and Universidad de Alcalá (IRYCIS), Madrid, Spain b Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York-Presbyterian Hospital, New York, USA c Center for Outcomes Research and Evaluation (CORE), Yale University School of Medicine, New Haven, USA d Cardiovascular Research Foundation (CRF), New York, NY, USA e F. Edward Hebert School of Medicine, Uniformed Services University, Bethesda, USA f Department of Medicine, Hospital Doce de Octubre, Madrid, Spain g Respiratory Department of Medicine, Hospital Universitario Nuestra Señora de Valme, Sevilla, Spain h Respiratory Department, Hospital Galdakao, Galdakao, Spain i Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine, St. Louis, MO, USA j Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Murcia, Spain k Division of Adult Thrombosis Medicine, Center of Excellence in Thrombosis and Anticoagulation Care (CETAC), Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada abstractarticle info Article history: Received 12 April 2019 Received in revised form 20 August 2019 Accepted 13 November 2019 Available online 14 November 2019 Keywords: Pulmonary embolism Systolic blood pressure Mortality Background: The optimal cutoff for systolic blood pressure (SBP) level to define high-risk pulmonary embolism (PE) remains to be defined. Methods: To evaluate the relationship between SBP levels on admission and mortality in patients with acute symptomatic PE, the current study included 39,257 consecutive patients with acute symptomatic PE from the RIETE registry between 2001 and 2018. Primary outcomes included all-cause and PE-specific 30-day mortality. Secondary outcomes included major bleeding and recurrent venous thromboembolism (VTE). Results: There was a linear inverse relationship between admission SBP and 30-day all-cause and PE-related mortality that persisted after multivariable adjustment. Patients in the lower SBP strata had higher rates of all-cause death (reference: SBP 110–129 mmHg) (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI], 2.0–4.2 for SBP b70 mmHg; and OR 1.7; 95% CI, 1.4–2.1 for SBP 70–89 mmHg). The findings for 30-day PE-related mortality were similar (adjusted OR 4.4; 95% CI, 2.7–7.2 for SBP b70 mmHg; and OR 2.6; 95% CI, 1.9–3.4 for SBP 70–89 mmHg). Patients in the higher strata of SBP had significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR 0.7; 95% CI, 0.5–0.9 for SBP 170–190 mmHg; and OR 0.6; 95% CI, 0.4–0.9 for SBP N190 mmHg). Consistent findings were also observed for 30-day PE-related death. Conclusions: In patients with acute symptomatic PE, a low SBP portends an increased risk of all-cause and PE- related mortality. The highest mortality was observed in patients with SBP b70 mmHg. © 2019 Elsevier B.V. All rights reserved. 1. Introduction Pulmonary embolism (PE) remains a major health issue [1]. Acute PE represents the third most common cause of vascular death worldwide [2]. Prior studies have demonstrated that low systolic blood pressure (SBP) is associated with high risk of death from worsening right ventricle (RV) failure and cardiogenic/obstructive shock in patients with acute symptomatic PE [3–5]. On the basis of these studies, experts and professional societies have recommended the use of thrombolytic therapy (or surgical thrombectomy) for patients with acute symptomatic PE and haemodynamic instability (i.e., SBP b90 mmHg) who do not have a prohibitive risk (e.g. major contraindications owing to bleeding risk) [6–8]. Predicting the likelihood of short-term PE-related mortality for a given SBP level is of utmost importance, in order to identify individual patients at high risk of PE-related death and low risk of bleeding that might have a favorable risk to benefit ratio for treatment with reperfusion therapies. By consensus, prior studies defined hemodynamically unstable PE as a SBP b90 mmHg [3–5]. However, most of such studies included a limited number of patients (usually b3000 patients), and International Journal of Cardiology 302 (2020) 157–163 ⁎Corresponding author at: Respiratory Department and Medicine Department, Hospital Ramón y Cajal and Universidad de Alcala (IRYCIS), 28034 Madrid, Spain. E-mail address: [email protected] (D. Jiménez). 1 A full list of the RIETE investigators is given in the appendix. https://doi.org/10.1016/j.ijcard.2019.11.102 0167-5273/© 2019 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard the majority of them focused on the outcome of all-cause mortality, which does not reflect the impact of pharmacological and interventional treatments in patients with acute symptomatic PE as well as PE-related death. It remains to be determined if an alternative SBP cut-off at presentation could more accurately capture the patients at risk, ideally identifying best candidates for advanced therapies [9]. In addition, there is lack of data with respect to PE outcomes in the group of patient who have elevated SBPs at presentation. To address this critical knowledge gap, this study used the data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE), a large ongoing, multi-center, multinational, prospective registry of consecutive patients with objectively confirmed, acute venous thromboembolism (VTE) [10–12] (1) to determine the relationship between admission SBP levels and short-term mortality and other important clinical outcomes, and (2) to define the optimal cutoff for SBP to identify high-risk PE. 2. Methods 2.1. Study design We used the prospectively collected data from patients enrolled in the RIETE registry. All patients provided written or oral informed consent for participation in the registry in accordance with local ethics committee requirements. For preparation of this manuscript, we followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines for observational cohort studies [13]. 2.2. Data source Previous publications have described the design and conduct of the RIETE registry [14,15]. Briefly, at each participating RIETE site, investigators aimed to enroll consecutive patients who had confirmed acute symptomatic or asymptomatic VTE. 2.3. Eligibility This current study included patients from RIETE who had a diagnosis of acute symptomatic PE from January 1, 2001, through August 31, 2018. Confirmatory testing consisted of high probability ventilation-perfusion (V/Q) scintigraphy [16], positive contrast-enhanced, PE-protocol, helical chest computerized tomography (CT) [single or multi-detector CT] for PE [17], or a non-diagnostic V/Q lung scan and confirmed lower limb deep vein thrombosis (DVT) on venous compression ultrasound [18]. 2.4. Variables Patients enrolled in RIETE had data collected from around the time of VTE diagnosis that included but were not limited to: demographics, body weight, presence of coexisting conditions such as chronic heart or lung disease, recent (b30 days prior to VTE) major bleeding, active cancer (defined as newly diagnosed cancer or cancer undergoing treatment [i.e. surgery, chemotherapy, radiotherapy, hormonal, or support therapy]), recent immobility (defined as non-surgical patients assigned to bed rest with bathroom privileges for ≥4 days in the 2-months prior to VTE diagnosis), surgery (defined as those who had undergone major surgery in the 2 months prior to VTE), clinical signs and symptoms on admission (including heart rate, SBP, and arterial oxyhemoglobin saturation), and laboratory results at hospital admission (including hemoglobin, platelet count, and serum creatinine). Markers of right ventricular dysfunction (either by echocardiography or CT) and cardiac biomarkers (cardiac troponins or brain natriuretic peptides [BNP]) were recorded where available. 2.5. Blood pressure measurement This study measured SBP around the time of PE diagnosis. Most of the times SBP was measured at the time of admission to the Emergency Department, though the RIETE protocol did not require a strict time window for measurement of vital signs. 2.6. Study outcomes The primary outcomes were 30-day all-cause and PE-specificmor- tality. The RIETE investigators used medical record review to assess vital status. For patients who died, further medical record review, and proxy interviews when necessary, assisted with determining the date and cause of death. For deaths confirmed by autopsy or those following a clinically severe PE, either initially or shortly after an objectively confirmed recurrent event, in the absence of any alternative diagnosis, the investigators were instructed to judge death as due to fatal PE. In addition, we examined the rates of nonfatal VTE recurrences and major bleeding events within 30 days following the diagnosis of PE. 2.7. Statistical analysis We compared the baseline demographics and clinical characteristics among patients categorized by the following admission SBP levels: b70, 70 to b90, 90 to b110, 110 to b130, 130 to b150, 150 to b170, 170 to b190, and 190 or greater mmHg. We then used hierarchical logistic regression (with hospital site as a random effect to account for clustering across centers) to assess the association between admission SBP and outcomes, after adjustment for potential patient-level confounders. For multivariable models, we considered factors previously demonstrated to be prognostically significant or thought to be clinically important, and covariates identified in bivariate analyses as predictors of mortality. The following models were generated sequentially to determine the successive influence of potential confounders on the relationship between admission SBP (reference group, 110–129 mmHg) and mortality: (1) unadjusted; (2) adjusted only for age and sex; and (3) adjusted for age, sex, and the following covariates: coexisting conditions (i.e., cancer, immobilization, chronic lung disease, chronic heart disease), severity of PE (i.e., heart rate, arterial oxyhemoglobin saturation, simplified Pulmonary Embolism Severity Index [sPESI] [19]), and laboratory results (i.e., creatinine levels, hemoglobin levels) at hospital admission. We assessed the sensitivity of our findings by repeating the primary analysis under varying assumptions about the study population in a sensitivity analysis for PE-related mortality. Sensitivity analyses comprised the exclusion of outlier hospitals (those with too few or too many patients), exclusion of patients younger than 50 years old, and exclusion of patients who received reperfusion therapies. We conducted statistical analyses with the use of STATA version 13.1 (STATA Corp, College Station, Texas). All hypothesis tests were twosided, with a significance level of 0.05. 3. Results 3.1. Study population The final analysis included 39,257 adults at 353 hospitals participating in the RIETE registry that had a diagnosis of acute symptomatic PE during the time period of January 1, 2001, through August 31, 2018 (eFigure). 3.2. Patient characteristics The distribution of admission SBP measurements approximated that of a normal distribution, with a mean admission SBP level of 129.3 mmHg (SD, 24.0 mmHg), and a median admission SBP level of 130.0 mmHg (IQR, 114.0–143.0 mmHg). 158 A. Quezada et al. / International Journal of Cardiology 302 (2020) 157–163 Baseline characteristics of the 39,257 study patients by strata of admission SBP levels are shown in Table 1. The relationship between SBP levels and baseline variables was complex: U-shaped for age; and inverted U-shaped for other variables (cancer, and elevated BNP). Patients in the lower SBP levels strata had a higher relative frequency of being male, having previous surgery, immobilization, and recent bleeding compared with patients in the higher SBP strata. Patients in the lower SBP strata had a lower prevalence of previous VTE, chronic lung disease, and chronic heart disease compared to patients in the higher SBP strata. Patients in the lower SBP strata had more signs of clinical severity (tachycardia, hypoxemia, higher sPESI scores, right ventricle dysfunction, and myocardial injury), and laboratory abnormalities (renal failure, anemia) compared to the higher quartiles. Use of thrombolytic therapy and insertion of an inferior vena cava (IVC) filter was more frequent in patients in the lower strata compared to patients in the higher strata (Table 1). In the RIETE registry, only 26 (1.9%; 95% confidence interval [CI], 1.3–1.8%) unstable patients with acute PE underwent surgical embolectomy. 3.3. Association of admission blood pressure and outcomes The entire cohort had a 30-day all-cause mortality of 5.4% (2139 of 39,257 patients), and a 30-day PE-related mortality rate of 1.7% (668 of 39,257 patients) (Table 2). Patients in the lower strata of SBP levels had significantly higher rates of 30-day all-cause death compared to patients with SBP 110–129 mmHg (reference category) (adjusted odds ratio [OR] 2.9; 95% CI, 2.0–4.2 for SBP b70 mmHg, and OR 1.7; 95% CI, 1.4–2.1 for SBP 70–89 mmHg] (Table 2). Patients in the higher strata of SBP had significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR 0.7; 95% CI, 0.5–0.9 for SBP 170–190 mmHg, and OR 0.6; 95% CI, 0.4–0.9 for SBP N190 mmHg] (Table 2). Consistent findings were also observed for 30-day PE-related death. As compared with patients in the reference stratum of SBP, patients with SBP b70 mmHg, and patients with SBP 70–89 mmHg had a 4.4- and 2.6-fold greater risk of 30-day PE- related death, respectively. Alternatively, patients with SBP 170–190 mmHg, and patients with SBP N190 mmHg had a nonsignificant reduction in the adjusted odds of 30-day PE-related death of 30%. Analyses of the SBP-mortality by decile of SBP are shown in Fig. 1.Adefinitive SBP threshold where mortality rates plateaued did not appear to exist, with mortality differences being greatest for SBP b70 mmHg. Of the 39,257 patients with acute symptomatic PE, 256 (0.6%; 95% CI, 0.6–0.7%) had an episode of nonfatal recurrence, and 1145 (2.9%; 95% CI, 2.7–3.1%) had a nonfatal major bleeding event within the first 30 days after initiation of therapy. After adjustment for all covariates, we did Table 1 Baseline characteristics by admission systolic blood pressure. Admission systolic blood pressure, mmHg Characteristic b70 70–b90 90–b110 110–b130 130–b150 150–b170 170–b190 ≥190 Pvalue Clinical characteristics No. (%) of patients 206 (0.5) 1147 (2.9) 5087 (13) 12,941 (33) 12,149 (31) 5373 (14) 1780 (4.5) 574 (1.5) Age, years (mean ± SD) 68.9 (16.4) 67.8 (17.3) 65.9 (18.1) 64.3 (18.3) 67.7 (16.2) 71.4 (13.6) 73.1 (12.6) 74.7 (11.3) b0.001 Age N80 years, n (%) 56 (27) 299 (26) 1193 (23) 2650 (20) 2780 (23) 1449 (27) 536 (30) 190 (33) b0.001 Male gender, n (%) 100 (49) 485 (42) 2186 (43) 6180 (48) 6010 (50) 2408 (45) 775 (44) 223 (39) b0.001 Weight, kilograms (mean ± SD) 75.5 (14.8) 73.0 (16.6) 72.8 (15.6) 75.6 (15.9) 77.6 (16.5) 77.4 (16.4) 77.0 (16.8) 76.1 (14.9) b0.001 Risk factors for VTE History of VTE, n (%) 18 (8.7) 126 (11) 626 (12) 1830 (14) 1885 (16) 881 (16) 262 (15) 86 (15) b0.001 Cancer, n (%) a 45 (22) 297 (26) 1347 (27) 3025 (23) 2581 (21) 1040 (19) 333 (19) 106 (18) b0.001 Recent surgery, n (%) b 28 (14) 175 (15) 628 (12) 1666 (13) 1421 (12) 505 (9.4) 126 (7.1) 49 (8.5) b0.001 Immobilization for ≥4 days, n (%) c 75 (36) 385 (34) 1455 (29) 2979 (23) 2422 (20) 1041 (19) 353 (20) 114 (20) b0.001 Comorbid diseases Chronic lung disease, n (%) 27 (13) 180 (16) 810 (16) 1793 (14) 1672 (14) 734 (14) 264 (15) 82 (14) b0.01 Chronic heart disease, n (%) 16 (7.8) 141 (12) 616 (12) 1049 (8.1) 1017 (8.4) 439 (8.2) 185 (10) 61 (11) b0.001 Recent major bleeding, n (%) 12 (5.8) 52 (4.5) 152 (3.0) 342 (2.6) 245 (2.0) 108 (2.0) 24 (1.3) 7 (1.2) b0.001 Clinical symptoms and signs at presentation Pulse, beats (mean ± SD) 107.5 (30.7) 106.0 (24.6) 96.7 (21.3) 91.6 (19.5) 90.9 (18.8) 91.4 (19.3) 92.5 (19.4) 93.3 (20.0) b0.001 Pulse ≥110 beats/min, n (%) 107 (52) 547 (48) 1480 (29) 2385 (18) 1996 (16) 966 (18) 350 (20) 127 (22) b0.001 Arterial oxyhemoglobin saturation (SaO 2 )b90%, n (%) 57 (28) 376 (33) 1195 (23) 2126 (16) 1936 (16) 913 (17) 309 (17) 116 (20) b0.001 sPESI (19) Low-risk, n (%) 0 (0) 0 (0) 998 (20) 4888 (38) 4604 (38) 1910 (36) 570 (32) 165 (29) – High-risk, n (%) 206 (100) 1147 (100) 4089 (80) 8053 (62) 7545 (62) 3463 (64) 1210 (68) 409 (71) b0.001 Echocardiography and cardiac biomarkers, n (%) RV dysfunction (n= 17,079) 75 (63) 318 (55) 997 (42) 1746 (31) 1570 (31) 619 (28) 211 (28) 62 (27) b0.001 BNP N100 pg/mL (n= 3041) 8 (62) 62 (74) 288 (74) 609 (65) 610 (62) 267 (62) 107 (66) 22 (51) b0.01 cTnI N0 ng/mL (n= 18,410) 78 (71) 370 (57) 1121 (44) 2109 (36) 1850 (33) 852 (33) 292 (34) 83 (31) b0.001 Laboratory findings Abnormal creatinine levels (N2 mg/dL) 84 (41) 382 (33) 1200 (24) 2217 (17) 2085 (17) 956 (18) 348 (20) 127 (22) b0.001 Hemoglobin, g/dL (mean ± SD) 12.4 (2.1) 12.3 (2.1) 12.6 (2.1) 13.0 (3.4) 13.2 (2.4) 13.3 (2.8) 13.4 (2.9) 13.5 (5.5) b0.001 Procedures Systemic thrombolysis, n (%) 53 (26) 155 (14) 213 (4.2) 218 (1.7) 162 (1.3) 50 (0.9) 13 (0.7) 1 (0.2) b0.001 IVC filter insertion, n (%) 9 (4.4) 66 (5.8) 171 (3.4) 391 (3.0) 325 (2.7) 121 (2.3) 37 (2.1) 12 (2.1) b0.001 Abbreviations: SD, standard deviation; VTE, venous thromboembolism; sPESI, simplified Pulmonary Embolism Severity Index; RV, right ventricle, BNP, brain natriuretic peptide; cTnI, cardiac troponin I; IVC, inferior vena cava. a Active or under treatment in the last year. b In the previous month. c Immobilized patients are defined in this analysis as non-surgical patients who had been immobilized (i.e., total bed rest with bathroom privileges) for ≥4daysinthemonthpriortoPE diagnosis. 159A. Quezada et al. / International Journal of Cardiology 302 (2020) 157–163 not find a significant relationship between admission SBP levels and risk for recurrence (adjusted OR 2.2; 95% CI, 0.5–9.2 for SBP b70 mmHg) or major bleeding (adjusted OR 1.5; 95% CI, 0.7–3.3 for SBP b70 mmHg) (Table 2). To explore the sensitivity of our findings, we repeated the analysis with varying assumptions about the patient population and hospitals (Table 3). Our results were not affected by the exclusion of younger patients (i.e., age b50 years), patients who received reperfusion therapies, or exclusion of the outlier hospitals. 4. Discussion In this cohort study of patients with acute symptomatic PE, we found an inverse linear relationship between admission SBP levels and 30-day all-cause and PE-related mortality, after use of various adjustment techniques. The highest mortality was observed among patients withadmission SBP b70 mmHg, with lower mortality rates observed for SBP of at least 130 mmHg. In contrast, compared with the normal SBP group, the risk of recurrent VTE or major bleeding was not significantly higher in low or high SBP groups. The association between SBP level on hospital admission and prognosis of patients with acute PE is not new. In fact, hemodynamic status remains the most important short-term prognostic factor for patients with acute PE [20]. However, this study is among the first that is adequately powered to evaluate the association between the full range of admission SBP and mortality following acute PE, and confirms that having a low SBP (b110 mmHg) was associated with an increased risk for death (both all-cause and PE-related mortality). In addition, having high SBP levels (N130 mmHg) was associated with lower risks. In our study, patients with lower SBP were also those with more signs of clinical severity (tachycardia, hypoxemia, high-risk sPESI, right ventricle dysfunction, and myocardial injury). All these variables have been associated with worse outcomes in patients with acute PE [21,22] and are likely to carry residual confounding, accounting, in part, for the reported associations. In this study, we expanded previous reports by providing the full range of admission SBP and mortality following acute PE, and could serve as a resource to inform discussions around PE management, including use of thrombolytic therapies. These findings have important practical implications. Many practice guidelines use a SBP b90 mmHg as the main criterion for identifying patients with acute PE who should receive thrombolytic therapy [7,8]. However, according to our data, a SBP b90 mmHg increased the risk of 30-day PE-related mortality by 2.6-fold (absolute risk, 13.6%), while thrombolysis increased the risk of major bleeding by 2.2-fold (absolute risk, 15.4%) compared with anticoagulation in 280 patients with unstable PE from 3 real-life registries [23]. These analyses also could be useful for research purposes, and the advance of design and analysis of clinical trials in PE. For example, they could provide a more evidenced informed approach to patient selection in trials of reperfusion treatments. Unlike other cardiovascular diseases, in patients with acute PE the association between SBP and mortality did not show a J-shape association. In fact, our study showed that high SBP levels were protective for all-cause and PE-related mortality. Elevated blood pressure levels on admission in patients with PE could be reflective of underlying hypertension, sympathetic surge, or a mixture of the two. Our study suggests that such a profile is indicative of markedly better outcomes. Studies of patients with atrial fibrillation treated with vitamin K antagonists (VKA) have demonstrated that higher levels of SBP were associated with an increased risk for hemorrhagic complications [24]. However, we failed to confirm these data in the population of patients with acute symptomatic PE. Similar to our results, Kooiman et al. found that hypertension (i.e., SBP N160 mmHg) was not an independent predictor of major bleeds during VKA treatment for acute VTE [25]. This study has several limitations. First, although SBP was measured around the time of PE diagnosis, the RIETE protocol did not require a Table 2 Event rates and logistic regression models for mortality, and separately for recurrence and bleeding, by admission systolic blood pressure. Characteristic b70 70–b90 90–b110 110–b130 130–b150 150–b170 170–b190 ≥190 No. (%) of patients 206 (0.5) 1147 (2.9) 5087 (13) 12,941 (33) 12,149 (31) 5373 (14) 1780 (4.5) 574 (1.5) 30-Day all-cause mortality No. of deaths 39 145 491 687 481 203 72 21 Mortality, (%) 18.9 12.6 9.6 5.3 4.0 3.8 4.0 3.7 30-Day all-cause mortality, OR (95% CI) Model 1, unadjusted 4.2 (2.9–5.9) 2.6 (2.1–3.1) 1.9 (1.7–2.1) 1 [Reference] 0.7 (0.6–0.8) 0.7 (0.6–0.8) 0.8 (0.6–1.0) 0.7 (0.4–1.1) Model 2, adjusted for age and sex 3.7 (2.6–5.4) 2.4 (2.0–2.9) 1.8 (1.6–2.1) 1 [Reference] 0.7 (0.6–0.8) 0.6 (0.5–0.7) 0.6 (0.5–0.8) 0.5 (0.3–0.8) Model 3, adjusted for all covariates a 2.9 (2.0–4.2) 1.7 (1.4–2.1) 1.5 (1.3–1.7) 1 [Reference] 0.7 (0.6–0.8) 0.7 (0.6–0.8) 0.7 (0.5–0.9) 0.6 (0.4–0.9) 30-Day PE-related death No. of deaths 21 70 178 199 117 56 20 7 Mortality, (%) 10.2 6.1 3.5 1.5 1.0 1.0 1.1 1.2 30-Day PE-related death, OR (95% CI) Model 1, unadjusted 7.3 (4.5–11.6) 4.2 (3.1–5.5) 2.3 (1.9–2.8) 1 [Reference] 0.6 (0.5–0.8) 0.7 (0.5–0.9) 0.7 (0.5–1.2) 0.8 (0.4–1.7) Model 2, adjusted for age and sex 6.5 (4.0–10.4) 3.8 (2.9–5.1) 2.2 (1.8–2.7) 1 [Reference] 0.6 (0.5–0.7) 0.6 (0.4–0.8) 0.6 (0.4–0.9) 0.6 (0.3–1.3) Model 3, adjusted for all covariates a 4.4 (2.7–7.2) 2.6 (1.9–3.4) 1.8 (1.5–2.2) 1 [Reference] 0.6 (0.5–0.8) 0.6 (0.5–0.9) 0.7 (0.4–1.1) 0.7 (0.3–1.4) 30-Day recurrent VTE No. of events 3 14 34 83 81 28 11 2 Event rate, (%) 1.5 1.2 0.7 0.6 0.7 0.5 0.6 0.3 30-day recurrent VTE, OR (95% CI) Model 1, unadjusted 2.3 (0.7–7.3) 1.9 (1.1–3.4) 1.0 (0.7–1.6) 1 [Reference] 1.0 (0.8–1.4) 0.8 (0.5–1.2) 1.0 (0.5–1.8) 0.5 (0.1–2.2) Model 2, adjusted for age and sex 2.5 (0.8–8.0) 2.1 (1.2–3.7) 1.1 (0.7–1.6) 1 [Reference] 1.1 (0.8–1.5) 0.9 (0.6–1.4) 1.2 (0.6–2.2) 0.7 (0.2–2.8) Model 3, adjusted for all covariates a 2.2 (0.5–9.2) 1.7 (0.8–3.4) 1.0 (0.6–1.7) 1 [Reference] 1.1 (0.7–1.6) 1.2 (0.7–1.9) 1.2 (0.7–2.3) 0.7 (0.2–3.0) 30-Day major bleeding No. of events 13 52 170 350 336 150 53 21 Event rate, (%) 6.3 4.5 3.3 2.7 2.8 2.8 3.0 3.7 30-Day major bleeding, OR (95% CI) Model 1, unadjusted 2.4 (1.4–4.3) 1.7 (1.3–2.3) 1.2 (1.0–1.5) 1 [Reference] 1.0 (0.9–1.2) 1.0 (0.8–1.2) 1.1 (0.8–1.5) 1.4 (0.9–2.1) Model 2, adjusted for age and sex 2.3 (1.3–4.0) 1.6 (1.2–2.2) 1.2 (1.0–1.5) 1 [Reference] 1.0 (0.8–1.1) 0.9 (0.8–1.1) 1.0 (0.7–1.3) 1.2 (0.7–1.8) Model 3, adjusted for all covariates a 1.5 (0.7–3.3) 1.3 (0.9–1.9) 1.1 (0.9–1.4) 1 [Reference] 1.0 (0.9–1.3) 0.9 (0.7–1.2) 1.0 (0.7–1.4) 1.1 (0.6–2.0) Abbreviations: OR, odds ratio; PE, pulmonary embolism; VTE, venous thromboembolism. a Includes age, sex, and the following covariates: coexisting conditions (i.e., cancer, immobilization, chronic lung disease, chronic heart disease), severity of PE (i.e., heart rate, arterial oxyhemoglobin saturation, simplified Pulmonary Embolism Severity Index [sPESI]), and laboratory results (i.e., creatinine levels, hemoglobin levels) at hospital admission. 160 A. Quezada et al. / International Journal of Cardiology 302 (2020) 157–163 A) B) Fig. 1. Adjusted associations between systolic blood pressure and A) all-cause mortality and B) PE-related death. All models are adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate,arterial oxyhemoglobinsaturation, simplified Pulmonary Embolism Severity Index,creatinine levels, and hemoglobin levels at hospital admission. Table 3 Sensitivity analysis for PE-related mortality rates. c Model No. of patients No. of hospitals Odds ratio (95% CI) Main model 39,270 353 4.4 (2.7–7.2) Excluding outlier hospitals a 33,142 231 3.9 (2.2–7.0) Excluding hospitals with an annualized volume b5 patients per year 36,585 256 3.3 (1.9–5.8) Excluding hospitals with an annualized volume N80 patients per year 34,295 344 3.9 (2.2–6.8) Excluding patients b50 years old 30,770 345 4.6 (2.8–7.7) Excluding patients b65 years old 24,803 338 4.1 (2.3–7.2) Excluding patients who received reperfusion therapies b 35,962 345 2.9 (1.5–5.7) a Hospitals that were outliers in terms of volume were excluded because their annualized volume was b5orN80 patients per year. b Systemic thrombolysis, catheter-directed therapy, or surgical embolectomy. c Odds ratios and 95% confidence intervals (CIs) are presented comparing the lowest decile of systolic blood pressure (b70 mmHg) with the reference group (110–130 mmHg). Models were adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, arterial oxyhemoglobin saturation,sPESI, creatinine levels, and hemoglobin levels at hospital admission. Confidence intervals take into account clustering according to center. 161A. Quezada et al. / International Journal of Cardiology 302 (2020) 157–163 strict time window for measurement of SBP and other vital signs. Further, there were no subsequent measurements of SBP in RIETE. In addition, RIETE does not include information related to use of vasopressors. Therefore, it is possible that some patients with PE receiving vasopressor therapy have been misclassified as having a normal blood pressure. However, the direction of this bias is toward null. In fact, despite this limitation, we noticed a strong association between reported SBPs and short-term outcomes. In conclusion, in a large study of patients with acute PE, there was a negative linear association between SBP at presentation and all-cause, as well as PE-related mortality. Although standard dichotomization of SBP (I.e., SBP b90 vs. ≥90 mmHg) may be useful for guideline recommendations, our results will allow for more accuracy regarding clinical decision-making. Standardization of timing for measurement of SBP, and assessment of the prognostic significance of its serial measurement in a formal study in future can further elucidate the impact of isolated and serial SBP measurements on outcomes of patients with PE. Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2019.11.102. Author contributions Study concept and design: Quezada, Jimenez, Bikdeli, Moores, Monreal. Acquisition of data; analysis and interpretation of data; statistical analysis: Quezada, Jimenez, Bikdeli, Moores, Porres-Aguilar, Aramberri, Lima, Ballaz, Yusen, Monreal. Critical revision of the manuscript for important intellectual content: Quezada, Jimenez, Bikdeli, Moores, Porres-Aguilar, Aramberri, Lima, Ballaz, Yusen, Monreal. Study supervision: Jiménez, Monreal. The corresponding author, David Jiménez, had full access to all the data in the study and had final responsibility for the decision to submit for publication. Source of funding This study (PI15/00207) has been partially supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+I 2013-2016) and cofinanced by the European Development Regional Fund “Awayto achieve Europe”(ERDF). Declaration of competing interest Dr. Bikdeli reports that he serves as experts on behalf of plaintiffs in litigation related to a specifictypeofIVCfilters. The current study is the idea of the investigators and not performed at the request of a third party. Acknowledgements We express our gratitude to SanofiSpain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG's support was limited to the part of RIETE outside Spain, which accounts for a 25.31% of the total patients included in the RIETE Registry. We also thank the RIETE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support. Appendix A. Appendix Coordinator of the RIETE Registry: Manuel Monreal. RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner and Dominique Farge-Bancel. RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), Hanh My Bui (Vietnam). RIETE Registry Coordinating Center: S & H Medical Science Service. Appendix B. Appendix Members of the RIETE Group. SPAIN: Adarraga MD, Agud M, Aibar MA, Alfonso J, Amado C, Arcelus JI, Azcarate-Agüero P, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón- Andrés B, Blanco-Molina A, Camon AM, Cañas I, Carrasco C, Castro J, Cerdà P, Chasco L, de Ancos C, del Toro J, Demelo P, Díaz-Peromingo JA, Díaz-Simón R, Elias-Hernández T, Escribano JC, Falgá C, Farfán AI, Fernández-Capitán C, Fernández-Criado MC, Fernández de Roitegui K, Fidalgo MA, Font C, Font L, Furest I, García MA, García-Bragado F, García-Morillo M, García-Raso A, Gavín-Blanco O, Gavín-Sebastián O, Gayol MC, Gil-Díaz A, Gómez V, Gómez-Cuervo C, González-Martínez J, Grau E, Gutiérrez J, Hernández-Blasco LM, Iglesias M, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou I, Lacruz B, Lecumberri R, Lima J, Llamas P, Lobo JL, López-Jiménez L, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Loring M, Lumbierres M, Madridano O, Maestre A, Marchena PJ, Martín del Pozo M, Martín-Fortea P, Martín-Martos F, Martínez-García MA, Martínez- González L, Mellado M, Moisés J, Monreal M, Montesa C, Morales MV, Nieto JA, Núñez MJ, Olivares MC, Olivera PE, Otalora S, Otero R, Panadero-Macía M, Pedrajas JM, Pellejero G, Pérez-Ductor C, Pérez- Jacoiste A, Pérez-Rus G, Peris ML, Porras JA, Riera-Mestre A, Rivas A, Rodríguez-Cobo A, Rodríguez-Hernández A, Rosa V, Rubio CM, Ruiz- Artacho P, Ruiz-Ruiz J, Ruiz-Sada P, Sahuquillo JC, Sala-Sainz MC, Salgueiro G, Sampériz A, Sánchez-Cámara S, Sánchez-Martínez R, Sánchez-Muñoz-Torrero JF, Sancho T, Soler S, Suárez S, Suriñach JM, Tiberio G, Tolosa C, Torres MI, Trujillo-Santos J, Uresandi F, Valero B, Valle R, Vela JR, Vidal G, Villares P; ARGENTINA: Gutiérrez P, Vázquez FJ, Vilaseca A; BELGIUM: Vanassche T, Vandenbriele C, Verhamme P; CZECH REPUBLIC: Hirmerova J, Malý R; ECUADOR: Salgado E; FRANCE: Benzidia I, Bertoletti L, Bura-Riviere A, Debourdeau P, Farge-Bancel D, Helfer H, Hij A, Mahé I, Moustafa F; GERMANY: Schellong S; ISRAEL: Braester A, Brenner B, Tzoran I; IRAN: Sharif-Kashani B; ITALY: Barillari G, Bilora F, Bortoluzzi C, Brandolin B, Ciammaichella M, Dentali F, Di Micco P, Imbalzano E, LandolfiR, Maida R, Mastroiacovo D, Mumoli N, Pace F, Pesavento R, Pomero F, Prandoni P, Quintavalla R, Rocci A, Siniscalchi C, Tufano A, Visonà A, Vo Hong N, Zalunardo B; LATVIA: Kalejs RV, Skride A, Strautmane S; REPUBLIC OF MACEDONIA: Bosevski M, Zdraveska M; SWITZERLAND: Bounameaux H, Mazzolai L; USA: Bikdeli B, Caprini J, Tafur AJ; VIETNAM: Bui HM. 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