Kristian Hellenkamp(1), Anja Kaeberich(2), Johanna Schwung(1), Mareike Lankeit(1,2)
(1)Department of Cardiology and Pulmonology, Heart Center, University of Göttingen, Germany
(2)Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
A 76 year old female patient presented to the emergency unit with cough of two weeks’ duration, chest pain radiating to her back and exertional dyspnoea that had started four days earlier. Apart from a history of deep vein thrombosis and several gynaecological operations, the patient did not have any relevant comorbidities. Her medication included amitriptyline and aspirin.
On admission, the patient presented with a blood pressure of 145/90 mm Hg, a heart rate of 90 beats per minute, a respiration rate of 30 per minute and a resting oxygen saturation of 92% while breathing room air. Electrocardiogram did not reveal abnormal findings. Routine laboratory testing showed mild thrombocytopenia (123,000 /µl) and a slightly reduced glomerular filtration rate (GFR, 59 ml/min/1.73m2). Based on the Wells prediction rule indicating an intermediate probability of pulmonary embolism (PE), D-dimer testing was performed (12.5 mg/l) followed by computed tomography pulmonary angiography (CTPA) showing central bilateral thrombi in the pulmonary arteries (Figure 1A). Additionally, right ventricular (RV) dilatation was detected (Figure 1B) and subsequent transthoracic echocardiography (TTE) confirmed the presence of RV dysfunction (indicated by RV dilatation, paradoxical septal motion and an estimated systolic pulmonary arterial pressure of 46 mm Hg). Moreover, laboratory testing showed elevated plasma concentrations of high-sensitivity troponin T (hsTnT, 65.8 ng/l; reference <14 ng/l ) and N-terminal pro-brain natriuretic peptide (NT-proBNP, 9024 pg/ml; reference <600 pg/ml ).
Since the patient met all inclusion and no exclusion criteria, she was included in the Pulmonary Embolism Thrombolysis (PEITHO) study  and randomized to tenecteplase versus placebo on top of therapeutic anticoagulation using unfractionated heparin. On the second day of hospitalization, the patient developed a right-sided hemiparesis and paraesthesia. Cranial CT revealed intracranial bleeding sized 2.2 x 1.4 cm in the left hemisphere (Figure 1C). The patient recovered with moderate disability (Rankin score, 3 points) and was discharged on day 22 to a rehabilitation clinic. Anticoagulant treatment on discharge consisted of phenprocoumon (target INR, 2.0-3.0).
Figure 1. CT revealing central thrombus in the right pulmonary artery (A), RV dilatation (B) and intracranial bleeding (C)
Contrast-enhanced CT showing a central thrombus in the right pulmonary artery (A) and dilatation of the right atrium and ventricle compared to the left atrium and ventricle (B). (C) Cranial CT revealed intracranial bleeding in the left hemisphere sized 2.2 x 1.4 cm.
Reflecting the absence of relevant comorbidities and stable haemodynamics on admission, the sPESI was calculated post-hoc with 0 in the presented case. However, imaging testing revealed RV dilatation and dysfunction and cardiac biomarkers were elevated. According to the current guidelines of the European Society (ESC) of Cardiology , should this patient be classified as low-, intermediate-low-, or intermediate-high-risk of an adverse outcome?
According to the 2014 ESC guidelines, patients with a sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests (e. g. in situations in which imaging or biomarker results become available before calculation of the clinical prognostic score), should be classified in the intermediate-low-risk category . However, given the combination of i) RV dilatation on diagnostic CTPA, ii) confirmation of RV dysfunction on TTE and iii) elevation of laboratory biomarkers of myocardial ischemia (hsTnT) and dysfunction (NT-proBNP) in the case presented here, this patient might have been classified more appropriately as intermediate-high-risk. A recommendation referring to this combination is missing in the 2014 ESC guidelines and the optimal treatment strategy remains unclear.
According to the 2014 ESC guidelines, patients with acute low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided . Given the evidence of RV dilation and dysfunction on imaging procedures and elevation of cardiac biomarkers in the case presented, is the sPESI “safe enough” to identify low-risk patients and candidates for home treatment?
An sPESI of 0 has been shown to be at least as accurate as imaging parameters and laboratory biomarkers for the identification of patients at low-risk for an adverse outcome [5, 6]. Therefore, routine performance of imaging or laboratory tests is not, at present, considered necessary in patients with a sPESI of 0 . In the “Outpatient versus inpatient Treatment for patients with acute Pulmonary Embolism” (OTPE) study, patients were selected for outpatient treatment based on the original PESI (and a number of further exclusion criteria) . Only one of 171 patients (0.6%) reached the primary outcome (symptomatic recurrent venous thromboembolism [VTE] within 90 days) compared to none of 168 patients treated in hospital. Only one (0.6%) patient in each treatment group died within 90 days, and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days.This study indicates that outpatient care can safely and effectively be used in place of in-patient care in selected low-risk PE patients . Although the performance of the sPESI to identify candidates for home treatment has not been directly tested in a management trial, it has been demonstrated that the sPESI is as reliable and as safe as the original version [5, 6]. Thus, the sPESI is generally considered a very valuable tool to identify low-risk patients in the majority of cases. However, based on the sPESI alone, the normotensive patient presented here would have been presumably falsely classified as low-risk for an adverse course.
Despite remarkable progress and numerous scores and models for risk stratification of non-high-risk PE developed and validated over the past years, and leading to the introduction of a new algorithm for risk assessment by the 2014 ESC guidelines , in individual patients, as in the case presented here, this stepwise algorithm may not be eligible for accurate risk assessment. Thus, are other models or scores available to identify normotensive PE patients at higher risk?
The stepwise algorithm for risk stratification proposed by the 2014 ESC guideline is based on the best available evidence. For example, the prognostic relevance of cardiac biomarkers [2, 8, 9] and RV dysfunction on imaging [10, 11] has been demonstrated in numerous studies and meta-analysis. However, recently developed and validated risk prediction scores such as the Bova  and the FAST  score explicitly aimed to identify intermediate-high risk patients who might benefit from more aggressive treatment regimens such as thrombolysis. These scores are based on combinations of clinical parameters and tests indicating RV dysfunction and were able to identify a subgroup of patients with high rates of 30-day PE-related complications (29.2% for the Bova  and 20.5% for the FAST  score, respectively). Certainly, whether these scores might help in guiding therapeutic decision making requires further investigation and clinical management trials.
Although not unblinded from PEITHO study medication, based on the occurrence of intracranial bleeding in the presented case, the patient presumably received the active treatment. How can bleeding in PE patients treated with thrombolysis - and for patients receiving anticoagulation only - be predicted?
While the patient met all inclusion and no exclusion criteria for the PEITHO study and no contraindications for systemic thrombolysis were present, several potential risk factors for major bleeding could be identified: female sex, age (76 years), mild thrombocytopenia, mild renal insufficiency, and aspirin intake. In the PEITHO study, patients aged =75 years tended to have an increased rate of major extracranial bleeding compared to younger patients, although this effect did not reach statistical significance . Comparably,in the Strategic Reperfusion Early after Myocardial Infarction (STREAM) study, evaluating whether fibrinolysis provides a clinical outcome similar to that achieved with primary percutaneous coronary intervention (PCI) early after acute ST-segment elevation myocardial infarction (STEMI), due to an excess of intracranial haemorrhage in patients =75 years, the study protocol was amended to a dose reduction of tenecteplase in those patients . Unfortunately, reliable and validated tools for the prediction of bleeding risk in patients with acute PE – both for patients receiving thrombolysis and for patients receiving anticoagulation only  – are still missing.Currently available bleeding prediction scores, mainly developed for patients with atrial fibrillation, have insufficient accuracy to predict bleeding in patients with VTE .
In normotensive PE patients, the use of a validated clinical risk prediction score, preferably the PESI or sPESI, should be considered to distinguish between low- and intermediate-risk PE. In patients at intermediate-risk, assessment of the RV with TTE or CT, and of myocardial injury using a laboratory biomarker, should be considered for further risk stratification. Routine performance of imaging or laboratory tests in the presence of a sPESI of 0 is not considered necessary at present as, in these cases, it has not been shown to have therapeutic implications. However, patients with a sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, should be classified in the intermediate-low-risk category.
While the routine use of primary systemic thrombolysis is not recommended in patients not suffering from shock or hypotension, close monitoring is recommended in patients with intermediate-high risk PE to permit early detection of haemodynamic decompensation and timely initiation of “rescue” reperfusion therapy.
The sPESI is generally very reliable in identifying normotensive patients with acute PE and a low-risk of an adverse outcome. However and as presented in this case, the presence of RV dysfunction on diagnostic CTPA should prompt further prognostic assessment and classification into the intermediate-high- versus intermediate-low-risk category, even if the sPESI is 0. Additionally, given the heterogeneity of inclusion and exclusion criteria of studies investigating home treatment in low-risk patients, future trials are needed to optimise patient selection . At the other end of the risk spectrum, in patients with intermediate-high-risk PE, the benefit of (potential) prevention of haemodynamic decompensation needs to be balanced against the increased risk of bleeding when deciding for or against fibrinolysis. Unquestionably, the optimal tools to assess the risk-to-benefit ratio of thrombolytic therapy in normotensive PE patients deserve further investigation.
We thank Prof. Dr. Joachim Lotz, Department of Diagnostic and Interventional Radiology, Georg-August University of Göttingen, Germany and German Centre for Cardiovascular Research (DZHK), partner site Göttingen for the images shown in Figure 1.
The work was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003). The authors are responsible for the contents of this publication.
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