Pulmonary embolism (PE), common in patients presenting with chest pain and dyspnea, remains a cardiovascular emergency with high morbidity and mortality despite important advances in cardiovascular diagnosis and treatment.1 It still remains as one of the most difficult problems confronting clinicians in the timely diagnosis of PE despite the improved recognition and diagnostic efficiency of the disease. Furthermore, the misdiagnosis of PE is still a critical issue in China as well as in other countries.2–5 Retrospective studies have shown that acute coronary syndrome (ACS) is one of the diseases for which PE is most often mistaken because of the considerable overlap in their clinical features.3–5 Since the long-term therapy of the two diseases is different, differentiation between PE and ACS has clinically significant implications. Early diagnosis and effective treatment of PE significantly decreases the mortality and recurrence of the disease.6 By reviewing and comparing the clinical records of 22 PE cases and 22 contemporary ACS cases matched by age and sex, we evaluated the factors causing the misdiagnosis of PE as ACS and the factors differentiating PE from ACS.
Medical records and methods
The study protocol was approved by the Ethical Committee of Beijing Army General Hospital. The medical records of 22 consecutive patients who were initially suspected of having ACS and finally were confirmed of having PE and who were treated at our hospital between 2001 and 2010 were retrieved. Twenty-two contemporary cases of ACS matched by age and sex were also recruited as controls. PE was diagnosed according to the guidelines of the European Society of Cardiology (ESC) on the diagnosis and management of acute PE in 2008.7 The 22 cases were confirmed as having PE by pulmonary arteriography (n=2), multi-slice computed tomographic pulmonary angiography (CTPA, n=16), and ventilation-perfusion scanning (n=4). The diagnosis of ACS was according to the diagnosis and management of ACS of the ESC.8 The 22 cases were confirmed to be having ACS by coronary angiography (CAG). Twelve-lead electrocardiograms (ECGs) were recorded and blood samples were obtained for biomarkers within 24 hours of presentation in all cases. Those who were not definitely diagnosed with PE or ACS, PE comorbid with ACS, or cases without intact clinical data were excluded from the study. Initial symptoms and signs, underlying diseases and risk factors for venous thromboembolism (VTE), ECGs and biomarkers, and treatments of the patients were retrospectively reviewed and summarized as percentages.
Clinical data between the two patient-groups were compared by χ2-test. Data analysis was performed using SPSS version 17.0 (SPSS Inc., USA). Statistical significance was taken as two-sided P value less than 0.05.
Among the 22 PE patients, 13 were male. The median age of the patients was 51 years (range 26-75 years).
Underlying diseases and risk factors for VTE
The main underlying cardio-cerebrovascular diseases of the two patient-groups were hyperlipidemia, hypertension, diabetes mellitus, coronary heart disease, congestive heart failure, cerebral thrombosis, and paroxysmal supraventricular tachycardia (Table 1). Risk factors for VTE were major surgical procedures (surgical operations for replacement arthroplasty, cholelithiasis, prostatic hypertrophy, and leg bone fracture), minor operations (radiofrequency ablation operation), staying in the intensive care unit for more than 48 hours, cervical cancer treatment, taking oral contraceptives, and deep venous thrombosis (DVT). Ten cases of PE and two cases of ACS were detected as having lower extremity DVT during hospitalization (Table 1). Though ACS patients have more frequent underlying cardio-cerebrovascular diseases than PE cases, no significant differences were found between the two patient-groups (P >0.05). With regard to the risk factors for VTE, the PE cases had significantly higher frequency of operation (P=0.048), staying in bed for more than 48 hours (P=0.048), and DVT (P=0.005) compared with that of ACS cases.
Symptoms and signs
Dyspnea, chest pain or chest distress, and palpitations are the main complaints of the two patient-groups. Tachycardia and tachypnea are the main signs of the two patient-groups (Table 2). The PE patients displayed significantly higher frequency of dyspnea (P <0.001) and lower extremity edema (P=0.034) compared to that of ACS cases.
ECG revealed that sinus tachycardia was common in both PE and ACS patients (Table 3). The PE patients displayed a higher frequency of right axis deviation (P=0.009), complete or incomplete right bundle-branch block (P=0.009), and S1Q3T3 pattern (prominence of the S wave in lead I, Q wave in lead III, and T wave in lead III; P=0.048) compared to that of ACS patients. Changes of T wave inversion, ST-segment depression, or elevation in precordial leads in ECGs of PE patients mimic that of ACS patients. No significant differences were found in the frequency changes of ST-T in precordial leads between the two patient-groups. Patients of ACS displayed a higher frequency of typical Q waves than that of PE patients (P=0.009).
Plasma cTnI and D-dimer
Plasma cTnI, and D-dimer increased in both PE and ACS cases. No difference was found in the frequency of plasma cTnI level exceeded the upper reference limit of our laboratory (0.1 μg/L) between the two groups (P >0.05). The PE patients who displayed significantly higher frequencies of plasma D-dimer exceeded the upper reference limit (0.5 mg/L) compared to that of ACS patients (P<0.001).
Arterial blood gas (ABG) analysis
The PE patients displayed a higher frequency of hypoxemia (artery blood oxygen pressure (PaO2) <80 mmHg (P=0.002) and increased alveolar-arterial oxygen partial pressure (P(A-a)O2, P <0.001) compared to that of ACS cases (Table 3).
All the patients received CAG after 1-5 days of presentation since they were suspected of having ACS (Table 4). Of the 22 PE cases, 11 revealed normal coronary arteries, seven revealed mild coronary lesions (lumens stenosis <50%), two moderate coronary lesions (lumens stenosis 50%-70%), and one showed diffuse disease with 71%-90% stenosis in the coronary arteries. No critical coronary lesions such as severe coronary lesions (lumen stenosis 91%-99%), occlusion, or thrombus in the coronary arteries were found. Since the results of CAG did not match the patients' clinical presentations, PE was suspected and further examinations such as pulmonary arteriography, CTPA, and lung ventilation-perfusion scan were performed and finally the diagnosis of PE was conformed. On the contrary, all the ACS patients displayed severe stenosis or thrombus in the coronary arteries.
Treatment and prognosis
All patients were given anticoagulant therapy of heparin or low molecular weight heparin when ACS was suspected. However, the treatment was modified when they were diagnosed with PE and the long-term therapy was different (Table 5). All the PE cases continued heparin or low molecular weight heparin treatment except for three who received thrombolysis of urokinase due to hemodynamic instability. One patient died of respiratory circulating failure during treatment. Of the 22 ACS cases, 17 underwent percutaneous coronary intervention (PCI) and five underwent coronary artery bypass graft (CABG). All survivors of PE succeeded with long-term anticoagulant therapy of warfarin, and all survivors of ACS succeeded with long-term antiplatelet therapy of aspirin and clopidogrel hydrogen sulfate or aspirin alone.
PE is considered in the differential diagnosis of many clinical presentations and in a wide variety of clinical settings. Our study showed how PE can mimic ACS, which presents a diagnostic challenge for clinicians. The timely diagnosis of PE is still a critical problem faced by all doctors of different specialties.
In fact, we found no differences in the underlying cardio-cerebrovascular diseases between the two patient-groups in the present study, although more patients with ACS are comorbid with hypertension, hyperlipidemia, diabetes mellitus, etc. In contrast to ACS patients, all PE patients have risk factors for VTE, especially after having major surgical procedures, staying in bed for ≥48 hours, or DVT.
There are two leading reasons for the misdiagnosis of PE as ACS in our study. The first one is that the two diseases resemble each other in several clinical aspects, such as symptoms and signs, ECG abnormalities, and biomarkers, which potentiate the difficulty in distinguishing PE from ACS.
ACS encompass a range of thrombotic coronary artery diseases, including unstable angina, both ST-segment elevation and non-ST-segment elevation myocardial infarction. Symptoms of ACS include chest pain, chest distress, dyspnea, diaphoresis, and light-headedness.9 In one review, sudden dyspnea was the sole presenting feature in 4%-14% of patients with acute myocardial infarction.10 All of the above symptoms are common in acute PE, either sudden in onset or evolving over a period of days to weeks, especially unexplained dyspnea.1,11 In addition, the two diseases can all present with hypotensive shock and syncope in severe conditions.9,11 In our study, both PE and ACS patients presented with dyspnea, chest pain or chest distress, palpitations, tachycardia, and tachypnea. The similar symptoms and signs make it difficult to accurately differentiate PE from ACS.
Both PE and ACS patients in our study presented with sinus tachycardia, non-specific ST-T changes, and T waves inversion, ST-segment depression, and even ST-segment elevation in precordial leads. ST-segment depression, transient ST-segment elevation, T-wave inversion in the precordial leads, or some combination of these findings are present in 30%-50% of ACS patients.8,12,13 Kim and his colleagues reported that T wave inversions in leads V1-V3 has the greatest sensitivity and diagnostic accuracy for early detection of right ventricular (RV) dysfunction, and normalization of the T wave inversions was associated with recovery of right ventricular dysfunction in acute PE.14 It is reported that ST-segment elevation, which can indicate anteroseptal acute myocardial infarction, is associated with acute PE on rare occasions.15–17 In the present study, PE patients displayed a higher frequency of complete or incomplete right bundle-branch block, S1Q3T3 pattern, and right axis deviation on ECGs, which are reportedly common in massive or submassive embolism, and usually induced by rapid right ventricular pressure overload, though these ECG changes are nonspecific.18 ECG abnormalities associated with acute PE further obscure the diagnosis.
Plasma D-dimer and cTns are frequently elevated in both PE and ACS.19 Plasma cTns are the preferred markers for the diagnosis of myocardial injury and are found in up to 50% of patients with acute PE.20 In the present study, plasma cTnI increased in 36.4% of PE cases and 54.6% of ACS patients. Plasma D-dimer increased in all PE cases and 40.9% of the ACS patients. The elevated plasma biomarkers, both in PE and ACS, again impeded the diagnosis.
Another reason for the misdiagnosis is the low awareness of PE. Though PE and ACS are all cardiovascular emergencies with high mortality, clinicians are more familiar with ACS than with PE, mainly because the incidence of coronary heart disease far exceeds incidences of PE. The reported overall average age and sex-adjusted annual incidence of PE was 69/100 000,21 and coronary heart disease was 561/100 000,22 acute myocardial infarction was 209/100 000.23 In the present study, all the 22 PE patients were initially suspected to be having ACS not only by the non-cardiovascular doctors, but also by cardiovascular physicians until they were proven to have PE. Therefore, symptoms of dyspnea and chest pain together with ECG abnormalities, with or without increased plasma cTns and D-dimer are frequently diagnosed as ACS rather than PE by clinicians. The misdiagnosis of the 22 cases in the present study suggested the insufficient recognition and knowledge of PE on the part of the physicians.
Though PE and ACS have similar clinical features, PE has its own distinct characteristics suggesting the differentiations of the two diseases. Clinicians should seek clinical clues such as risk factors for VTE, signs of DVT, unexplained dyspnea or hypoxemia, and RV pressure overload on ECGs that will enable them to distinguish the two diseases. Prompt diagnosis of PE heavily relies on clinical suspicion.
Knowledge of risk factors for VTE is essential in the evaluation of the likelihood of PE, which increases with the number of risk factors present. In fact, the initial misdiagnosis of PE in the present study mainly resulted from the neglect of the PE risk factors on physicians, such as recent surgery, bone fracture, immobilization, cancer, or use of oral contraceptives, which are all associated with markedly reduced mobility and/or increased plasma viscidity.11,24 DVT is the most important risk factor for PE and is considered to be a marker for PE. About 79% of patients who present with PE have evidence of DVT in their legs. Patients with DVT should be highly suspected of PE.11 In our study, all the PE patients had risk factors for VTE, they were more likely to have DVT (P <0.01) detected than ACS patients. Being cognizant of DVT may reduce diagnostic mistakes or delays.
Though the two patient-groups had many similar symptoms and signs, the ratio of dyspnea in PE patients was significantly higher than that of ACS patients (90.9% vs. 36.4%, P <0.001). Reissig et al25 reported that dyspnea and tachycardia are the most common symptoms in fatal PE. In several series, dyspnea, tachypnoea, or chest pain were present in more than 90% of patients with PE.26,27 In patients with pre-existing heart failure or pulmonary disease, worsening dyspnea may be the only symptom indicative of PE.7 PE should be considered whenever unexplained dyspnea occurs.
Hypoxemia is one of the most important clinical signs of PE. Patients with acute PE usually have hypoxemia and thus dyspnea was the most common symptom. In the present study, the rate of hypoxemia (81.8% vs. 27.3%) and increased P(A-a)O2 gradient (100% vs. 18.2%) in PE patients were significantly higher than that of ACS patients. Cvitanic28 reported that among PE patients with essentially no prior cardiac or pulmonary disease, 93% had hypoxemia or hypocapnia and 98% had an increased P(A-a)O2 gradient or hypocapnia. A sudden or unexplained change in arterial oxygen saturation should raise suspicion of PE, and a normal P(A-a)O2 gradient and arterial blood pressure of carbon dioxide (PaCO2) >35 mmHg had a sensitivity of only 92% in excluding PE.29
ECG signs of right ventricular strain, such as inversion of T waves in leads V1-V4, a QR pattern in lead V1, the classic S1Q3T3 type, and incomplete or complete right bundle-branch block, as in the present study, are helpful in the diagnosis of PE, particularly when of new onset.30 Such changes are generally associated with the more severe forms of PE and may be found in RV strain of any cause.
Though patients in the present study were treated early with heparin therapy, either low molecular weight or unfractionated, they would theoretically be treated for nonlethal PE. However, PE is considered to be a lifelong disease and chronic secondary prophylaxis is necessary. Without continuing anticoagulation, as many as 50% of PE patients may suffer a recurrent episode within the first 3 months.11,25 Oral anticoagulant (warfarin) is highly effective in preventing recurrent VTE and remains to be long-term treatment for PE,11 but is not standard therapy for ACS. Therefore, the correct diagnosis of PE can substantially change the succeeding therapy and the prognosis of the patients from that of ACS. In the present study, 17 ACS patients received treatment of PTCA and stent implantation, and five received CABG. They were then given long-term antiplatelet therapy of aspirin and clopidogrel or aspirin alone. On the contrary, all PE patients succeeded with long-term anticoagulant therapy of warfarin.
The study was retrospectively performed at a single center and included a small number of patients with acute PE and ACS; therefore, we did not find the differences of the underlying diseases on the attack of the two kinds of diseases, the interpretation of the findings is limited by the small sample size. Prospective studies with larger number of patients are required to improve the diagnosis efficacy of PE by the clinicians.
In conclusion, the study showed that PE can often mimic ACS due to the similar clinical manifestations, which presented a diagnostic challenge for the clinicians. Identification and estimation of the risk factors for VTE and clues of PE are necessary for the timely diagnosis of PE. We emphasized that not only ACS but also PE should be considered when a patient presents with dyspnea, chest pain, or both, together with RV overload on ECGs, even ST-segment elevation in the precordial leads, with or without plasma cTns elevation, especially for those with DVT. Further examinations should be undertaken for accurate diagnosis. Patients who are confirmed as having PE should receive long-term oral anticoagulant therapy.
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