Abstract
Background:
Some earlier studies demonstrated an increased mortality risk attributed to delayed pulmonary embolism (PE) diagnosis. Therefore, we mainly aimed to determine the predictors of diagnostic delays and the effect of delayed diagnosis on mortality.
Methods:
We prospectively studied 756 consecutive patients admitted with PE between March 2007 and September 2017. The delayed diagnosis was defined as (1) patient presenting > 7 days after onset of symptoms, (2) diagnosis takes > 24 hours upon arriving in the ED, or (3) undergoing coronary angiography before establishing PE diagnosis.
Results:
A total of 127 (16.7%) patients met the delayed group’s criteria. Heart failure (OR= 2.257, 95% CI: 1.130-4.508, P= 0.021), diabetes mellitus (OR= 1.568, 95% CI: 0.996-2.469, P= 0.052), and precordial T wave inversions (OR=2.559, 95% CI: 1.649-3.970, P< 0.001) were linked to higher rates of delayed diagnosis, while hemoptysis (OR=0.254, 95% CI: 0.059-1.087, P= 0.065) and hemodynamic instability (OR= 0.434, 95% CI: 0.168-1.123, P= 0.085) negatively correlated with it. Delayed PE diagnosis did not significantly impact the overall survival during the follow-up. The unadjusted and adjusted mortality hazard ratio for delayed diagnosis were 1.198 (95% CI: 0.758- 1.894, P= 0.439) and 1.215 (95% CI: 0.762- 1.939, P=0.413), respectively. Older age, heart failure, and hemodynamic instability increased the risk of death (p<0.001).
Conclusion:
Hemoptysis, hemodynamic instability, diabetes mellitus, heart failure, and T wave inversions in precordial leads were the independent predictors of delayed diagnosis. Delayed PE diagnosis did not increase the patients' mortality rates.
Key Words: Delayed diagnosis, Mortality, Pulmonary embolism, Venous thromboembolism
Pulmonary embolism (PE) is a potentially lethal condition characterized by an occlusion in the pulmonary arteries (1). Various studies estimate an annual incidence of 60-70 or 39-115 per 100,000 population (2, 3), with an increased risk in older ages 2-5. PE accounts for up to 300,000 mortalities per year in the United States, placing it among the highest cardiovascular causes of death (2, 3). Nevertheless, public awareness of this disease stood at substantially lower rates compared to ischemic heart disease and stroke (2). Owing to the acute and life-threatening nature of an episode, diagnosing this condition requires the utmost attention to alter its potentially devastating trajectory. Circulatory failure can render the patients susceptible to worse outcomes compared with the patients without hemodynamic instability and right ventricular failure (3, 4). The role of earlier diagnosis on the patient’s outcome remains a matter of debate. While some studies suggest that earlier diagnosis reduces the associated adverse outcomes (4-6), other studies reported similar results between patients identified early or late (7-9). The low specificity and sensitivity of PE signs and symptoms remain a challenge for its earlier diagnosis (5, 10).
Therefore, as high as 50% of the patients with PE might face seven days or more lag between the onset of their symptoms and diagnosis, marking it as one of the most missed conditions in the routine clinical practice (5, 10). Several risk-factors were attributed to an increased rate of delayed PE diagnosis (5, 7, 11, 12). However, the discrepancies among these variables halted the emergence of a clear prognostic picture. In this study, we mainly aimed to determine the predictors of diagnostic delays and the effect of delayed diagnosis on mortality.
Methods
Study design: We studied 756 consecutive patients admitted with PE between March 2007 and September 2017 to Tehran Heart Center. The study was approved by the local institutional review board with the ethics code of IR.TUMS.MEDICINE.REC.1398.022. We did not include the patients who developed PE during their hospitalization in our center. Contrast-enhanced pulmonary multi-detector computed tomography (MDCT) angiography or ventilation-perfusion lung scintigraphy (V/Q scan) objectively confirmed the PE diagnosis. We assigned the patients into two groups of delayed and non-delayed diagnosis. The delayed diagnosis was defined as (1) patient presenting > 7 days after onset of symptoms in those not admitted through emergency department (ED), (2) diagnosis takes > 24 hours upon arriving in the ED, or (3) undergoing coronary angiography before establishing PE diagnosis 7. Patients developing cardiac arrest or hemodynamic instability were included in the delayed diagnosis group if post-mortem PE diagnosis was established.
The extracted data include demographics, past medical history, comorbidities, known PE risk factors, and patient's symptoms and physical examination findings at the time of arrival at the ED. Our central lab facilities carried out all the laboratory measurements in this study.
D-dimer levels were not requested in the first 24 hours in any of the patients in the delayed diagnosis group. We defined hemodynamic instability as a systolic blood pressure of less than 100 mmHg or the need for inotrope injection. This study was approved by the local institutional review board.
Statistical analysis: Continuous variables including age, heart rate, and systolic blood pressure were reported as mean with standard deviation (SD). They were normally distributed and was assessed using histogram chart and descriptive measures. Categorical variables were reported as frequency with percentage. The univariate effect of covariates on delayed diagnosis was calculated using logistic regression model. All variables with p-values< 0.15 in the univariate analysis were candidates to enter the multivariable model. A multivariable logistic regression model with backward elimination technique (considering removal and entry p-values as 0.1 and 0.05, respectively). Univariate and multivariable effects were reported through odds ratio (OR) with 95% confidence interval (CI). Calibration of the final predictive model was evaluated applying the Hosmer-Lemeshow test. The discrimination power of the final model was assessed using area under the ROC (receiver operating characteristic) curve (AUC) with 95% CI. The adjusted and unadjusted effect of delayed diagnosis on all-cause mortality was computed applying Cox’s proportional hazard model and the effects were reported as hazard ratio (HR) with 95% CI. Variables which were simultaneously associated with all-cause mortality and delayed diagnosis with p0.1 were considered as potential confounders. All statistical analyses were conducted using IBM SPSS for Windows Version 22.0 (Armonk, NY: IBM Corp.).
Results
Patient characteristics: In the study period, our center admitted 756 patients with a confirmed PE diagnosis. Of these patients, 127 (16.7%) met the delayed diagnosis group criteria, 24 (18.9%) of them undergoing coronary angiography before the PE diagnosis was established. The mean age of the included patients was 69.8±16.8) and 352 (46.4%) were females (table 1). The mean heart rate and systolic blood pressure of the patients were 100.9 and 129.9, respectively. The most prevalent symptoms were acute onset dyspnea (88.7%), pleuritic (30.3%), and non-pleuritic (19.9%) chest pains. Hypertension (41.9%), obesity (33.2%), recent immobilization (28.1%), smoking history (21.3%), coronary artery disease (19.5%), and diabetes mellitus (19.5%) were the most common underlying conditions or PE risk factors. S1Q3T3 accounted for the most common electrocardiographic pattern seen in 34.8% of the patients.
Table 1.
Characteristics of the patients and their univariate effect on the delayed diagnosis
| Parameters | Total (N=756) | Non-delayed Dx* (n=629) | Delayed Dx (n=127) | OR (95% CI) | Pvalue¶ |
|---|---|---|---|---|---|
| Patient characteristics | |||||
| Age | 60.4 (16.8) | 59.8 (16.9) | 63.0 (16.0) | 1.011 (1.000-1.023) | 0.057 |
| Gender (male) | 407 (53.6%) | 332 (52.5%) | 75 (59.1%) | 1.303 (0.885-1.918) | 0.179 |
| Heart rate | 100.9(19.86) | 100.5 (19.59) | 102.6 (21.16) | 1.005 (0.996-1.015) | 0.279 |
| Systolic blood pressure | 129.9 (21.62) | 129.4 (21.57) | 132 (21.86) | 1.005 (0.997-1.014) | 0.217 |
| Presenting signs and symptoms | |||||
| Dyspnea | 673 (88.7%) | 561 (88.8%) | 112 (88.2%) | 0.945 (0.522-1.709) | 0.852 |
| Pleuritic chest pain | 230 (30.3%) | 190 (30.1%) | 40 (31.5%) | 1.094 (0.706-1.694) | 0.687 |
| Non-pleuritic chest pain | 151 (19.9%) | 125 (19.8%) | 26 (20.5%) | 1.081 (0.653-1.788) | 0.762 |
| Syncope | 75 (9.9%) | 63 (10.0%) | 12 (9.4%) | 0.942 (0.492-1.804) | 0.858 |
| Hemodynamic instability | 62 (8.2%) | 57 (9.0%) | 5 (3.9%) | 0.413 (0.162-1.053) | 0.064 |
| Hemoptysis | 36 (4.7%) | 34 (5.4%) | 2 (1.6%) | 0.281 (0.067-1.187) | 0.084 |
| Underlying conditions and PE risk factors | |||||
| Hypertension | 318 (41.9%) | 257 (40.7%) | 61 (48.0%) | 1.349 (0.920-1.977) | 0.125 |
| Obesity | 252 (33.2%) | 212 (33.5%) | 40 (31.5%) | 0.911 (0.605-1.371) | 0.655 |
| Recent Immobilization | 213 (28.1%) | 182 (28.8%) | 31 (24.4%) | 0.798 (0.514-1.240) | 0.316 |
| Smoking history | 162 (21.3%) | 134 (21.2%) | 28 (22.0%) | 1.051 (0.663-1.666) | 0.832 |
| Coronary artery disease | 148 (19.5%) | 125 (19.8%) | 23 (18.1%) | 0.897 (0.548-1.467) | 0.665 |
| Diabetes Mellitus | 148 (19.5%) | 114 (18.0%) | 34 (26.8%) | 1.661 (1.068-2.585) | 0.024 |
| Recent major surgery (<3Weeks) | 108 (14.2%) | 91 (14.4%) | 17 (13.4%) | 0.919 (0.526-1.604) | 0.766 |
| Previous DVT | 65 (8.6%) | 56 (8.9%) | 9 (7.1%) | 0.785 (0.378-1.630) | 0.515 |
| Long haul travel | 64 (8.4%) | 51 (8.1%) | 13 (10.2%) | 1.299 (0.684-2.467) | 0.424 |
| Heart failure | 52 (6.9%) | 39 (6.2%) | 13 (10.2%) | 1.734 (0.897-3.351) | 0.102 |
| Estrogen use | 47 (6.2%) | 38 (6%) | 9 (7.1%) | 1.192 (0.562-2.531) | 0.647 |
| Cerebrovascular accident | 43 (5.7%) | 37 (5.9%) | 6 (4.7%) | 0.797 (0.329-1.931) | 0.616 |
| History of malignancy | 43 (5.7%) | 33 (5.2%) | 10 (7.9%) | 1.551 (0.744-3.235) | 0.241 |
| Peripheral artery disease | 5 (0.7%) | 5 (0.8%) | 0 (0%) | 2.246 (0.123-40.869) | 0.585 |
| Electrocardiographic (ECG) findings | |||||
| Normal ECG | 65 (8.6%) | 59 (9.3%) | 6 (4.7%) | 0.482 (0.203-1.141) | 0.097 |
| S1Q3T3 | 264 (34.8%) | 211 (33.4%) | 53 (41.7%) | 1.429 (0.968-2.110) | 0.072 |
| T wave inversions in precordial leads | 144 (19.0%) | 103 (16.3%) | 41 (32.3%) | 2.449 (1.596-3.755) | < 0.001 |
| RBBB | 110 (14.5%) | 88 (13.9%) | 22 (17.3%) | 1.295 (0.776-2.161) | 0.322 |
| S1S2S3 | 101 (13.3%) | 64 (10.1%) | 37 (29.1%) | 3.649 (2.299-5.790) | < 0.001 |
| Right axis deviation | 74 (9.7%) | 63 (10.0%) | 11 (8.7%) | 0.856 (0.438-1.675) | 0.651 |
| Pulmonary MDCT angiography findings | |||||
| Segmental involvement | 157 (20.7%) | 127 (20.1%) | 30 (23.6%) | 0.820 (0.520-1.287) | 0.385 |
| Saddle emboli | 127 (16.7%) | 109 (17.2%) | 18 (14.2%) | 0.699 (0.369-1.323) | 0.271 |
| RV strain | 126 (16.6%) | 86 (13.6%) | 40 (31.5%) | 2.919 (1.884-4.524) | < 0.001 |
*Abbreviations: Dx: Diagnosis, OR: Odd ratio, CI: Confidence interval, PE: Pulmonary embolism, DVT: Deep vein thrombosis, RBBB: Right bundle branch block, MDCT: Multi-detector angiography, RV: Right ventricular, GI: Gastrointestinal
**Categorical variables are presented as number and percentage, while continuous variables are presented as mean (± SD)
¶ Significant variables on the univariate analysis (P< 0.15) are illustrated in bold style.
Predictors of delay
- Univariate analysis: Older age, hypertension, diabetes mellitus, heart failure, S1Q3T3 pattern, inverted T waves in precordial leads, S1S2S3 pattern, and right ventricular (RV) strain in MDCT angiography were associated with a higher risk of delayed diagnosis. On the other hand, hemodynamic instability, hemoptysis, and normal ECG were less prevalent in the delayed diagnosis group.
- Multiple predictors of delayed diagnosis: Diabetes mellitus (OR= 1.568, 95% CI: 0.996- 2.469, P= 0.052), heart failure (OR= 2.257, 95% CI: 1.130- 4.508, P= 0.021), and inverted T waves (OR= 2.559, 95% CI: 1.649- 3.970, p<0.001) in the precordial leads independently predicted an increased risk of delayed diagnosis. Hemoptysis (OR= 0.254, 95% CI: 0.059- 1.087, P= 0.065) and hemodynamic instability (OR= 0.434, 95% CI: 0.168- 1.123, P=0.085) inversely correlated with a risk of delayed diagnosis. The AUC mounted to 0.645 (table 2).
Table 2.
Multiple predictors of delayed diagnosis
| Parameters | OR* | Pvalue¶ |
|---|---|---|
| Diabetes Mellitus | 1.568 (0.996-2.469) | 0.052 |
| Heart failure | 2.257 (1.130-4.508) | 0.021 |
| Hemodynamic instability | 0.434 (0.168-1.123) | 0.085 |
| Hemoptysis | 0.254 (0.059-1.987) | 0.065 |
| T wave inversions in precordial leads | 2.559 (1.649-3.970) | < 0.001 |
| Hosmer-Lemeshow goodness of fit test: P= 0.855 | ||
| AUC: 64.5% (95% CI: 59.2- 69.7%) | ||
*Abbreviations: OR: Odd ratio, CI: Confidence interval, AUC: Area under the curve
Enlisted variables are the significant ones in the multivariate analysis (p< 0.1)
PE treatment: Upon admission, a total of 65 (8.2%) and 126 (16.7%) patients had hemodynamic instability and saddle emboli, respectively. Thrombolytic therapy was initiated in 111 (14.7%) patients, 103 (16.6%) of them in the non-delayed diagnosis group. Only eight (6.3%) patients in the delayed diagnosis group received thrombolytic therapy (P= 0.004) (table 3).
Table 3.
PE treatments and their major complications among groups
| Parameters | Total (N= 756) |
Non-delayed Dx* (n= 629) |
Delayed Dx (n= 127) |
P-value¶ |
|---|---|---|---|---|
| Anticoagulant therapy | 745 (98.5%) | 621 (98.7%) | 124 (97.6%) | 0.357 |
| Thrombolytic therapy | 113 (14.9%) | 105 (16.6%) | 8 (6.3%) | 0.004 |
| GI bleeding | 12 (1.6%) | 8 (1.3%) | 4 (3.1%) | 0.133 |
| Heparin-induced thrombocytopenia | 10 (1.3%) | 10 (1.6%) | 0 (0%) | 0.313 |
| Intracranial hemorrhage | 4 (0.5%) | 3 (0.5%) | 1 (0.8%) | 0.660 |
*Abbreviations: Dx: Diagnosis, OR: Odd ratio, CI: Confidence interval significant variables (P< 0.05) are illustrated in bold style.
Two percent of the patients underwent surgical thrombectomy, all of whom were among non-delayed diagnosis patients. Six hundred and twenty one (98.7%) of the patients in the non-delayed diagnosis group and 124 (97.6%) of the patients in the delayed diagnosis group received anticoagulant therapy (P= 0.357).
Mortality risk: The in-hospital mortality rate was 6.7% (n=51). All-cause mortality was 19.6% (n=148) with a median follow-up time of 16.9 (95% CI: 14.8-18.9) months. The delayed diagnosis did not significantly impact the overall survival during the follow-up. The unadjusted and adjusted effect of delayed diagnosis on mortality were 1.198 (95% CI: 0.758-1.894, P=0.439) and 1.215 (95% CI:0.762- 1.939, P=0.413), respectively. Older age, heart failure, and hemodynamic instability increased the risk of death (p<0.001) (table 4). Figure 1 illustrates the cumulative hazard of all-cause mortality among delayed and not delayed diagnosis groups.
Table 4.
The effect of delayed diagnosis on the all-cause mortality
| Parameters | HR* (95% CI) | Pvalue¶ |
|---|---|---|
| Unadjusted | 1.198 (0.758-1.894) | 0.439 |
| Adjusted | 1.215 (0.752-1.939) | 0.413 |
| Age | 1.028 (1.016-1.041) | < 0.001 |
| Gender | 0.884 (0.631-1.238) | 0.474 |
| Hypertension | 0.990 (0.691-1.418) | 0.956 |
| Diabetes mellitus | 1.025 (0.676-1.552) | 0.908 |
| Heart failure | 2.243 (1.443-3.486) | < 0.001 |
| Hemodynamic instability | 4.787 (3.264-7.022) | < 0.001 |
*Abbreviations: HR: Hazard ratio, CI: Confidence interval
¶ Significant variables (P< 0.05) are illustrated in bold style
Figure 1.
The cumulative hazard of all-cause death
Follow-up echocardiography data: The follow-up echocardiography was performed about three months after admission in 610 (80.7%) patients. Other patients were dead or lost to follow-up. Patients in the delayed diagnosis group had similar rates of moderate to severe RV function (10.3% vs. 15.1%, P=0.200) and a higher rate of enlarged RV diameter (> 35 mm) (23.4% vs. 13.9%, P= 0.015) (table 5).
Table 5.
Follow-up echocardiography results
| Echocardiographic parameters | Non-delayed Dx* (n= 503) No (%) |
Delayed Dx (n= 107) No (%) |
Pvalue¶ |
|---|---|---|---|
| Moderate to severe RV dysfunction | 76 (15.1) | 11 (10.3) | 0.200 |
| RV diameter > 35 mm | 70/502 (13.9) | 25 (23.4) | 0.015 |
*Abbreviations: Dx: Diagnosis, RV: Right ventricular
¶ Significant variables (p< 0.05) are illustrated in bold style
Discussion
Previous studies reported a clinical presentation comparable to our study. They observed dyspnea in 77.1-84.1% of the patients with PE, pleuritic chest pain in 39.4-44.1%, non-pleuritic (substernal) in 15.2-16.3%, syncope in 5.5-26.2%, and hemoptysis in 4.5-7.6% 13-15. Slightly lower incidence of pleuritic and higher non-pleuritic chest pain (higher non-pleuritic to pleuritic ratio) observed in this cohort might be related to the cardiac-referral nature of our center. A meta-analysis reported precordial T wave inversions, S1Q3T3, and right bundle branch block (RBBB) prevalence at 29%, 24%, and 12%, respectively 16. These numbers were 19.0%, 34.8%, and 14.5% in our study, respectively. This comparison shows an increased incidence of S1Q3T3, lower observation of precordial T wave inversions, and similar RBBB rates.
Alike this cohort, hypertension, obesity, recent hospitalization, active malignancy, and smoking were the most common risk factors and underlying conditions in the EMPEROR cohort. However, they observed a much higher rate of underlying malignancy compared to us (22.3% vs. 5.7%) 13. The observed in-hospital and overall mortality rates in our study were lower than the previous studies. A study from Denmark estimated the 30-day mortality risk ranging from 17% in 2004 to 11% in 2014 17. In 2006, a year before the start of our registry, the in-hospital mortality rate in the United States was recorded at 7.8% 18. In-hospital fatality rate in Germany also ranged from 20.4% in 2005 to 13.9% in 2015 19. A study from England between 1997-2015 estimated 1- and 6-months survival rate at 85% and 72.4%, respectively 20. The multi-center international Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry reported an 8.65% 3-months mortality rate 21.
A considerable proportion of the patients in the delayed diagnosis group (18.9%) underwent coronary angiography. As several adverse events might complicate coronary angiography 22, delayed diagnosis may expose the patients to the unnecessary complications this procedure.
This cohort suggests that a delayed PE diagnosis does not increase the risk of patients’ mortality at follow-up. This finding confirms some of the earlier studies 11, 12, 23, 24. We hypothesize that similar mortality rates relate to two phenomena. First, the patients presenting later than seven days could have less severely symptomatic forms of PE, evident in the different hemodynamic instability rates. Second, under-treatment will possibly not affect the anticoagulation therapy of the patients with delayed diagnosis, as almost all of the patients admitted to our hospital will receive anticoagulation therapy, as warranted by the acute coronary syndrome (ACS) protocol. Nevertheless, miss-recognition of their condition might expose them to over-treatment with medications highly prescribed in our center, such as aspirin and clopidogrel.
A computerized model suggested that preemptive anticoagulant therapy before PE confirmation could improve the outcomes in patients with moderate and high-risk features 25. Although we did not directly test this hypothesis, our data indirectly suggest that pre-confirmation anticoagulant therapy might positively affect the outcome of the patients with PE. We identified hemoptysis and hemodynamic instability as the parameters related to a reduced risk of delayed PE diagnosis.
Researchers i n two earlier studies confirmed the effect of hemoptysis and expressed their surprise at this finding 5, 11. Nevertheless, most patients consider hemoptysis a serious symptom requiring urgent medical care 26, 27. Therefore, we believed they tend to admit earlier and get a PE diagnosis. Earlier research promotes this symptom as an important determinant of pretest probability 28, 29. Furthermore, as a cardiology care provider, PE puts itself at the top of our differential diagnoses list. All these points support the observed effect of hemoptysis on earlier PE diagnosis.
Hemodynamic instability at presentation indicates a critical red flag warranting an immediate diagnosis following stabilization 30. It can also serve as a root cause of conditions such as syncope that might increase the likelihood of PE and its earlier diagnosis 31, 32. We report diabetes mellitus and heart failure as indicators of increased risk of delayed diagnosis in the multivariate analysis. Earlier studies reported the presence of several comorbidities as risk factors for delayed diagnosis, such as chronic obstructive pulmonary disease (COPD), asthma, and heart failure 5, 11, 32-34. We think that these conditions might complicate the clinical picture of PE and mislead the physicians towards a more straightforward diagnosis. Furthermore, some underlying conditions, such as lung diseases, might imitate the observed PE symptoms and postpone the diagnosis 35.
This study reports the existence of inverted T waves in the precordial leads as an independent factor foretelling the risk of delayed diagnosis. This pattern presents RV dysfunction in the settings of PE 36. However, physicians can easily confuse this diagnosis with the presence of ischemia or several other cardiovascular disorders, causing this electrocardiographic pattern 37. Especially in our center, PE might be sacrificed for the sake of these cardiologic conditions.
Some earlier studies proposed the protective effect of chest pain against delayed PE diagnosis 5, 7, 38, 39. However, we did not observe any effect attributed to chest pain related to the time of diagnosis. A possible justification is that the patients who do not present with chest pain might suffer from other symptoms and risk factors (e.g., hemodynamic instability, hemoptysis, or history of recent surgery) that navigate the physicians towards the correct diagnosis.
Well-known risk factors of PE, including previous deep vein thrombosis (D VT), recent major surgery, and recent immobilization, correlated with an earlier diagnosis 5, 7, 12, 40. Surprisingly, we did not observe such a correlation. Many patients who performed major non-cardiac surgeries in other centers seek medical care in their index surgery hospital when an acute syndrome happens. However, our center does not perform any non-cardiac surgeries. Furthermore, our emergency room protocols prioritize a timely diagnosis of major chest syndromes, such as acute coronary syndromes, PE, and aortic dissection.
Therefore, acute PE gets special diagnostic attention, sometimes to an excessive extent. These factors might explain the lack of difference in the diagnosis of patients with and without risk factors.
Although RV diameter significantly increased in the delayed diagnosis group at follow-up, they demonstrated no increase in moderate to severe RV dysfunction. This conclusion is in line with a previous study 23. Our explanation for this finding sums up in three factors, i.e., 1) RV dysfunction facilitates PE diagnosis and patients with normal RV function might face a delayed diagnosis; 2) delayed diagnosis group also received anticoagulation therapy for other indications, mostly ACS; and 3) patients who presented later might have lower disease severity.
Our study’s main limitation lies in its single-center nature. We believe that by covering a period of 11 years and including high-quality data on a large set of patients in our registry, we managed to overcome this concern to great extents. Additionally, our center serves as a specialized referral center, and a subset of our findings might be inapplicable for general centers. Also, the possible PE patients who were sent home with a wrong diagnosis could not be included in our study, and such events might affect the findings reported in our study.
In conclusions Hemoptysis and hemodynamic instability inversely correlated with a delayed diagnosis in the multivariate analysis. Diabetes mellitus, heart failure, and T wave inversions in precordial leads were the independent predictors of an increased risk of delayed diagnosis. Delayed PE diagnosis did not increase the patients' mortality rates. Further studies with larger populations will enlighten future perspectives of researchers and health-care workers.
Ethical statements:
This study was approved by the local institutional review board and complies with the Declaration of Helsinki. All the participants had consent to participate.
Acknowledgments
Not applicable.
Funding:
We received no funding regarding this work.
Conflict of Interest:
The authors have no conflicts of interest regarding the contents published in this article.
Authors' contributions:
H.A: Concept design and data acquisition, S.H: Drafting manuscript and data acquisition, A.K: Drafting manuscript, S.Y: Data gathering in the follow-up clinic, A.J: Data analysis, Y.J: Concept design and data acquisition
References
- 1.Hepburn-Brown M, Darvall J, Hammerschlag G. Acute pulmonary embolism: a concise review of diagnosis and management. Intern Med J. 2019;49:15–27. doi: 10.1111/imj.14145. [DOI] [PubMed] [Google Scholar]
- 2.Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res. 2016;118:1340–7. doi: 10.1161/CIRCRESAHA.115.306841. [DOI] [PubMed] [Google Scholar]
- 3.Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) Eur Respir J. 2019;54:1901647. doi: 10.1183/13993003.01647-2019. [DOI] [PubMed] [Google Scholar]
- 4.Ota M, Nakamura M, Yamada N, et al. Prognostic significance of early diagnosis in acute pulmonary thromboembolism with circulatory failure. Heart Vessels. 2002;17:7–11. doi: 10.1007/s003800200036. [DOI] [PubMed] [Google Scholar]
- 5.Goyard C, Côté B, Looten V, et al. Determinants and prognostic implication of diagnostic delay in patients with a first episode of pulmonary embolism. Thromb Res. 2018;171:190–8. doi: 10.1016/j.thromres.2018.08.015. [DOI] [PubMed] [Google Scholar]
- 6.Benotti JR, Dalen JE. The natural history of pulmonary embolism. Clin Chest Med. 1984;5:403–10. [PubMed] [Google Scholar]
- 7.Jenab Y, Alemzadeh-Ansari MJ, Fehri SA, Ghaffari-Marandi N, Jalali A. Effect of delay in hospital presentation on clinical and imaging findings in acute pulmonary thromboembolism. J Emerg Med. 2014;46:465–71. doi: 10.1016/j.jemermed.2013.09.014. [DOI] [PubMed] [Google Scholar]
- 8.Ozsu S, Oztuna F, Bulbul Y, et al. The role of risk factors in delayed diagnosis of pulmonary embolism. Am J Emerg Med. 2011;29:26–32. doi: 10.1016/j.ajem.2009.07.005. [DOI] [PubMed] [Google Scholar]
- 9.Bulbul Y, Ayik S, Oztuna F, Ozlu T, Sahin S. The relationship between socio-demographic characteristics of patients and diagnostic delay in acute pulmonary thromboembolism. Ups J Med Sci. 2011;116:72–6. doi: 10.3109/03009734.2010.530701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Elliott CG, Goldhaber SZ, Jensen RL. Delays in diagnosis of deep vein thrombosis and pulmonary embolism. Chest. 2005;128:3372–6. doi: 10.1378/chest.128.5.3372. [DOI] [PubMed] [Google Scholar]
- 11.Torres-Macho J, Mancebo-Plaza AB, Crespo-Giménez A, et al. Clinical features of patients inappropriately undiagnosed of pulmonary embolism. Am J Emerg Med. 2013;31:1646–50. doi: 10.1016/j.ajem.2013.08.037. [DOI] [PubMed] [Google Scholar]
- 12.Jiménez Castro D, Sueiro A, Díaz G, et al. Prognostic significance of delays in diagnosis of pulmonary embolism. Thromb Res. 2007;121:153–8. doi: 10.1016/j.thromres.2007.03.028. [DOI] [PubMed] [Google Scholar]
- 13.Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry) J Am Coll Cardiol. 2011;57:700–6. doi: 10.1016/j.jacc.2010.05.071. [DOI] [PubMed] [Google Scholar]
- 14.Miniati M, Prediletto R, Formichi B, et al. Accuracy of clinical assessment in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med. 1999;159:864–71. doi: 10.1164/ajrccm.159.3.9806130. [DOI] [PubMed] [Google Scholar]
- 15.Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) Lancet (London, England) 1999;353:1386–9. doi: 10.1016/s0140-6736(98)07534-5. [DOI] [PubMed] [Google Scholar]
- 16.Shopp JD, Stewart LK, Emmett TW, Kline JA. Findings From 12-lead electrocardiography that predict circulatory shock from pulmonary embolism: systematic review and meta-analysis. Acad Emerg Med. 2015;22:1127–37. doi: 10.1111/acem.12769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lehnert P, Lange T, Møller CH, Olsen PS, Carlsen J. Acute pulmonary embolism in a national Danish cohort: increasing incidence and decreasing mortality. Thromb Haemost. 2018;118:539–46. doi: 10.1160/TH17-08-0531. [DOI] [PubMed] [Google Scholar]
- 18.Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the united states: evidence of overdiagnosis. Arch Intern Med. 2011;171:831–7. doi: 10.1001/archinternmed.2011.178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Keller K, Hobohm L, Ebner M, et al. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J. 2020;41:522–9. doi: 10.1093/eurheartj/ehz236. [DOI] [PubMed] [Google Scholar]
- 20.Kempny A, McCabe C, Dimopoulos K, et al. Incidence, mortality and bleeding rates associated with pulmonary embolism in England between 1997 and 2015. Int J Cardiol. 2019;277:229–34. doi: 10.1016/j.ijcard.2018.10.001. [DOI] [PubMed] [Google Scholar]
- 21.Laporte S, Mismetti P, Décousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation. 2008;117:1711–6. doi: 10.1161/CIRCULATIONAHA.107.726232. [DOI] [PubMed] [Google Scholar]
- 22.Tavakol M, Ashraf S, Brener SJ. Risks and complications of coronary angiography: a comprehensive review. Glob J Health Sci. 2012;4:65–93. doi: 10.5539/gjhs.v4n1p65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Pasha SM, Klok FA, van der Bijl N, et al. Right ventricular function and thrombus load in patients with pulmonary embolism and diagnostic delay. J Thromb Haemost. 2014;12:172–6. doi: 10.1111/jth.12465. [DOI] [PubMed] [Google Scholar]
- 24.den Exter PL, van Es J, Erkens PM, et al. Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism. Am J Respir Crit Care Med. 2013;187:1369–73. doi: 10.1164/rccm.201212-2219OC. [DOI] [PubMed] [Google Scholar]
- 25.Blondon M, Righini M, Aujesky D, Le Gal G, Perrier A. Usefulness of preemptive anticoagulation in patients with suspected pulmonary embolism: a decision analysis. Chest. 2012;142:697–703. doi: 10.1378/chest.11-2694. [DOI] [PubMed] [Google Scholar]
- 26.Prasad R, Garg R, Singhal S, Srivastava P. Lessons from patients with hemoptysis attending a chest clinic in India. Ann Thorac Med. 2009;4:10–2. doi: 10.4103/1817-1737.43062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Johnson JL. Manifestations of hemoptysis. How to manage minor, moderate, and massive bleeding. Postgrad Med. 2002;112:101–6, 108-9, 113. doi: 10.3810/pgm.2002.10.1335. [DOI] [PubMed] [Google Scholar]
- 28.van der Hulle T, Cheung WY, Kooij S, Beenen LFM, van Bemmel T, van Es J, et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet. 2017;390:289–97. doi: 10.1016/S0140-6736(17)30885-1. [DOI] [PubMed] [Google Scholar]
- 29.van Es J, Beenen LF, Douma RA, et al. A simple decision rule including D-dimer to reduce the need for computed tomography scanning in patients with suspected pulmonary embolism. J Thromb Haemost. 2015;13:1428–35. doi: 10.1111/jth.13011. [DOI] [PubMed] [Google Scholar]
- 30.Quezada CA, Bikdeli B, Barrios D, et al. Meta-analysis of prevalence and short-term prognosis of hemodynamically unstable patients with symptomatic acute pulmonary embolism. Am J Cardiol. 2019;123:684–9. doi: 10.1016/j.amjcard.2018.11.009. [DOI] [PubMed] [Google Scholar]
- 31.Alonso-Martínez JL, Sánchez FJ, Echezarreta MA. Delay and misdiagnosis in sub-massive and non-massive acute pulmonary embolism. Eur J Intern Med. 2010;21:278–82. doi: 10.1016/j.ejim.2010.04.005. [DOI] [PubMed] [Google Scholar]
- 32.Prandoni P, Lensing AW, Prins MH, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med. 2016;375:1524–31. doi: 10.1056/NEJMoa1602172. [DOI] [PubMed] [Google Scholar]
- 33.Pineda LA, Hathwar VS, Grant BJ. Clinical suspicion of fatal pulmonary embolism. Chest. 2001;120:791–5. doi: 10.1378/chest.120.3.791. [DOI] [PubMed] [Google Scholar]
- 34.Pourmand A, Robinson H, Mazer-Amirshahi M, Pines JM. Pulmonary Embolism among patients with acute exacerbation of chronic obstructive pulmonary disease: implications for emergency medicine. J Emerg Med. 2018;55:339–46. doi: 10.1016/j.jemermed.2018.05.026. [DOI] [PubMed] [Google Scholar]
- 35.Bauersachs RM. Clinical presentation of deep vein thrombosis and pulmonary embolism. Best Pract Res Clin Haematol. 2012;25:243–51. doi: 10.1016/j.beha.2012.07.004. [DOI] [PubMed] [Google Scholar]
- 36.Kucher N, Walpoth N, Wustmann K, Noveanu M, Gertsch M. QR in V1– an ECG sign associated with right ventricular strain and adverse clinical outcome in pulmonary embolism. Eur Heart J. 2003;24:1113–9. doi: 10.1016/s0195-668x(03)00132-5. [DOI] [PubMed] [Google Scholar]
- 37.Hayden GE, Brady WJ, Perron AD, Somers MP, Mattu A. Electrocardiographic T-wave inversion: Differential diagnosis in the chest pain patient. Am J Emerg Med. 2002;20:252–62. doi: 10.1053/ajem.2002.32629. [DOI] [PubMed] [Google Scholar]
- 38.Hendriksen JM, Koster-van Ree M, Morgenstern MJ, et al. Clinical characteristics associated with diagnostic delay of pulmonary embolism in primary care: a retrospective observational study. BMJ Open. 2017;7:e012789. doi: 10.1136/bmjopen-2016-012789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Walen S, Damoiseaux RA, Uil SM, van den Berg JW. Diagnostic delay of pulmonary embolism in primary and secondary care: a retrospective cohort study. Br J Gen Pract. 2016;66:e444–50. doi: 10.3399/bjgp16X685201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Rahimi-Rad MH, Rahimi-Rad S, Zarrin S. Delays in diagnosis and treatment of venous thromboembolism in a developing country setting. Tuberk Toraks. 2013;61:96–102. doi: 10.5578/tt.5348. [DOI] [PubMed] [Google Scholar]