Initial management of suspected acute PE

Management of a patient presenting with symptoms and/or signs compatible with suspicion of acute PE consists of concomitant clinical assessment of the probability of the condition (pre-test probability) and of risk of early death due to PE, if indeed present. These simple assessments, based entirely on clinical history and physical examination, are required to enable the selection of an appropriate diagnostic strategy and optimal management5 (figure 1). Clearly, ECG, blood gases, chest x-ray and routine blood tests are most helpful in the initial differential diagnosis, including acute coronary syndromes, pneumothorax or internal bleeding.

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Figure 1

Initial assessment useful for selecting a management strategy in suspected acute pulmonary embolism (PE).

Significant hypotension and particularly shock are ominous prognostic signs regardless of their cause. In the case of a suspected acute PE, those signs indicate the ‘high risk’ group with expected PE related in-hospital mortality of >15% despite treatment. The diagnostic approach to those patients should be maximally simplified, preferably based on urgent computed tomography (CT) angiography.5

Patients not in shock and with normal systemic blood pressure are considered ‘non-high risk’ for early PE related death. Further diagnostic steps should be selected after assessing their pre-test clinical probability, as it may influence both the negative and positive predictive value of some of the laboratory diagnostic tests.5

Assessment of pulmonary arteries with contrast multidetector CT (MDCT angiography) is currently the core of most diagnostic algorithms.6 However, whenever possible or necessary, CT should be substituted by diagnostic tests which are cheaper, safer or more easily available (eg, at the bedside). Bedside echocardiography is an alternative to CT for haemodynamically unstable ‘high risk’ patients who are not suitable for transport. Lung scintigraphy is useful in patients with contraindications to contrast media (such as renal failure and thyrotoxicosis) or with relative contraindications to irradiation, such as pregnancy. Assessment of pulmonary arteries with magnetic resonance imaging may be also considered in such circumstances. In some clinical situations normal D-dimer values may suffice to justify withholding treatment, while positive venous compression ultrasound alone justifies anticoagulation.5

The terms ‘high/non-high/intermediate/low risk’, which refer to PE related risk of early death, should not be confused with the different levels of ‘probability’ of PE (colloquially sometimes also referred to as ‘risk’)—for example, due to the presence of predisposing factors or suggestive clinical presentation.

Because management strategies for ‘high risk’ and ‘non-high risk’ PE are different, the initial clinical staging is particularly important. Potential problems may be due to a diagnosis of hypotension, defined as systolic blood pressure either <90 mmHg or reduced by ≥40 mmHg compared to usual values.7 The latter might be difficult to establish for individual patients in an emergency setting.

For the patient with suspected ‘high risk’ PE, presenting with shock or hypotension, the suggested diagnostic algorithm is based on expert consensus.5 Diagnostic recommendations in suspected ‘non-high risk’ PE, taking into account the level of clinical (pre-test) probability of PE, have been validated by outcome trials. The Polish ZATPOL registry, which assessed diagnostic strategies in 2015 patients suspected of acute PE reported from 80 hospitals, showed that using non-validated diagnostic criteria resulted in doubling the 30 day all cause mortality (M Kurzyna, 2010, unpublished data).

Patients with suspected acute PE at high risk of early death

Patients with suspected ‘high risk’ PE—that is, presenting with shock or systemic hypotension—should be immediately referred for CT angiography.5 The absence of multiple, large, usually bilateral clots at CT angiography makes PE highly unlikely as a cause of haemodynamic instability, particularly in the absence of an increased ratio of right to left ventricular dimensions. In some of those cases CT may suggest an alternative diagnosis, such as pericardial tamponade, aortic dissection, tension pneumothorax or pneumonia.

If CT angiography is not immediately feasible the patient should be assessed using bedside echocardiography for signs of RV pressure overload and failure, which strongly support a diagnosis of PE. Their absence makes diagnosis of PE as a cause of shock/hypotension highly unlikely and should prompt further diagnostic work-up.5 Echocardio-graphy is also at least as useful as CT angiography for the differential diagnosis of alternative causes of haemodynamic instability. Additional important information may include severe left ventricular dysfunction or collapsed inferior vena cava, suggesting hypovolaemia. Unfortunately RV pressure overload is not specific for acute PE. Bedside compression venous ultrasound or transoesophageal echocardiographic assessment of proximal pulmonary arteries for the presence of thrombi may help in decision making. This is particularly useful if the clinical presentation is not highly suggestive of acute PE or there are important contraindications to thrombolysis. CT angiography should always be reconsidered if the patient has been stabilised in the meantime.

A management algorithm and main recommendations which might be helpful for treating cases with suspected and eventually confirmed ‘high risk’ PE are suggested in figure 2 and table 1.

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Figure 2

Diagnostic algorithm useful for patients with suspected ‘high risk’ PE—that is, presenting with shock or hypotension. Computed tomography (CT) angiography is a first choice test provided it is immediately feasible. Otherwise a search for signs of right ventricular (RV) pressure overload with bedside echocardiography should be undertaken. Bedside compression venous ultrasound (VUS) or transoesophageal echocardiographic (TEE) evidence of, respectively, proximal venous or pulmonary artery thrombi may greatly help in the decision to start aggressive treatment (thrombolysis or embolectomy), which is otherwise difficult to make based on indirect echocardiographic signs alone.

As soon as blood samples are drawn for haemoglobin, platelets and coagulation status, and if bleeding seems unlikely as a cause of haemodynamic instability, intravenous unfractionated heparin (UFH) should be considered and eventually started as a weight adjusted bolus (80 U/kg) followed by weight adjusted (18 U/kg/h) and later activated partial thromboplastin time (APTT) adjusted infusion. One of the potential concerns in this phase of management is a possibility of aortic dissection, with impending cardiac tamponade. Therefore, even a short echocardiographic glimpse of the heart and ascending aorta would be most useful if the CT findings are not yet available.

While specific emergency diagnostic tests are being performed, all efforts should be undertaken to stabilise the patient. Low aortic pressure may be particularly deleterious as it further reduces RV coronary perfusion, already impaired by increased RV systolic intramural pressure. In the presence of congested jugular veins and a dilated inferior vena cava at echocardiography, any rapid intravenous fluid infusions are contraindicated. Instead, catecholamines, including norepinephrine, should be used to keep systolic blood pressure above 90 mmHg, providing a bridge for the patient to specific therapy. Oxygen supply is usually necessary. Mechanical ventilation is rarely needed and should be introduced with the understanding of its potential adverse effect on systemic venous return; therefore positive end-expiratory pressure (PEEP) should be avoided.

Preparations for definitive treatment should still be made while awaiting the results of the diagnostic tests. Potential contraindications to thrombolysis should be analysed. They will be particularly important for treatment selection in patients in whom CT was not possible and in those presenting with hypotension, but not with shock. In patients with confirmed PE and in shock the mortality risk is about 50%, with 80% of deaths occurring within 2.5 h of admission. Therefore, except in the case of an ongoing major bleeding episode or recent intracranial haemorrhage, all contraindications to emergency thrombolysis in this subgroup are considered relative.5 If immediate surgical embolectomy is a feasible alternative option, the risk of additional delay related to ‘time to cardiopulmonary bypass’ should be weighted against bleeding risk due to thrombolysis. If thrombolysis is selected as an initial treatment, cardiac surgery should be on standby as a potential second line treatment option in case of treatment failure. Repeated thrombolytic attempts are less successful than rescue surgical pulmonary embolectomy.8

Short lasting high dose infusions of thrombolytics (usually of 2 h) are preferred over prolonged 12 h regimens. A bolus of 0.6 mg/kg (but ≤50 mg) of recombinant tissue plasminogen activator (rt-PA) over 15 min is the shortest approved regimen, and is particularly useful during resuscitation.9 Of note, thrombolysis is a valid option also in ‘high risk’ PE in pregnancy. Existing evidence collected mostly from streptokinase treated patients suggests an acceptably low risk of fetal complications, mainly due to placental bleeding.

Routine filter insertion is not required before either thrombolytic or surgical treatment. Percutaneous embolectomy/thrombus fragmentation with/without local thrombolysis is still an experimental intervention. It may be considered in the case of serious contraindications to systemic thrombolysis and life threatening PE without the availability of surgical embolectomy.10 Theoretically, percutaneous interventions could be particularly helpful if acute ‘high risk’ PE is found during an attempted percutaneous coronary intervention in a patient initially misdiagnosed as having an acute coronary syndrome. Usually, in such circumstances, rather than moving the patient out of the catheterisation laboratory to perform CT angiography, classical pulmonary angiography is undertaken for diagnostic purposes. This makes proximal pulmonary arterial thrombi immediately accessible for catheter fragmentation or aspiration. This could be a potentially interesting therapeutic option in patients with cannulated femoral arteries who are not the best candidates for thrombolytic treatment. However, no published data exist to allow any formal recommendations.

Patients with suspected acute PE, not at high risk of early death

In general the management of a patient with suspected ‘non-high risk’ PE—that is, without shock and hypotension—is compatible with a concept of ‘guilty unless proved otherwise’. The first diagnostic step is the assessment of the clinical probability of PE. Reliability of its evaluation is similar regardless of whether it is assessed implicitly or based on a score assigned to preselected predisposing factors, symptoms and signs suggesting PE.11 Two such prediction rules—Geneva and Wells—have been prospectively validated and are recommended by current guidelines.

Because of the high risk of subsequent embolic events, heparin treatment should be started immediately in patients with intermediate and high clinical probability who do not have significantly increased bleeding risk while the definitive results of the diagnostic tests are still awaited.

Pre-test clinical probability also determines the role of D-dimer and modifies the positive and particularly negative diagnostic value of the ventilation/perfusion scan (V/Q), single detector CT, and even multidetector CT angiography.

Formal confirmation of PE or deep vein thrombosis (DVT) interrupts the diagnostic process and implies prolonged anticoagulation. On the other hand a patient with suspected PE should always receive specific treatment for PE until the diagnostic tests justify withholding treatment. Such justification is considered sufficient if the expected risk of recurrent venous thromboembolic episodes (VTE) without anticoagulation is ≤3% at 3 months—similar to the risk following negative traditional contrast pulmonary angiography. A number of tests or their combinations may provide such justification.5

A management algorithm which might be helpful for cases of suspected ‘non-high risk’ PE is suggested in figure 3.

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Figure 3

Diagnostic algorithm useful for patients with suspected ‘non-high risk’ pulmonary embolism (PE)—that is, presenting without shock or hypotension. Negative D-dimer results obtained with a high sensitivity test justify withholding treatment despite low or intermediate clinical probability (*intermediate sensitivity tests can still be useful for this purpose but only in low probability patients or those ‘unlikely’ to have PE according to the recently introduced binominal probability scale). Otherwise, computed tomography (CT) angiography is recommended. **While positive compression venous ultrasound (VUS) may obviate the need for CT angiography, its diagnostic yield in the absence of clinical symptoms/signs of DVT is relatively low. ***VUS, ventilation/perfusion scan (V/Q) or pulmonary angiography should be considered to assist in decision making whenever a negative CT result is reported, despite a high clinical probability of acute PE.

Some confusion has been introduced by recent modification of the Wells score. Instead of three levels of pre-test clinical probability (‘low–intermediate–high’), a binominal scale (‘unlikely–likely’) has been suggested. In addition, equal rank was recently assigned to all prediction score elements, apparently without significantly affecting its performance. Most probably it is not the choice of a particular method but the consistency of its use that is of importance. Recent guidelines for the European Society of Cardiology accept existing evidence as sufficient to consider ‘low’ and ‘intermediate’ pre-test probability in the Geneva three-level score of similar consequence for diagnostic pathways to the ‘unlikely’ pre-test probability in the two-level Wells score, as far as CT angiography is concerned. In contrast, a moderately sensitive D-dimer test is acceptable as a rule-out test in PE only in patients with ‘low’ pre-test probability of PE, while high sensitive tests are required both in the case of ‘intermediate’ probability and when PE is considered ‘unlikely’ by the two-level Wells prediction score.

Once PE is confirmed, comprehensive prognostic staging is helpful for optimising clinical management.5 Sub-stratification of patients at ‘non-high risk’ of early PE related death into intermediate and low risk groups is based on risk markers related to the severity of RV involvement due to PE. Risk markers related to RV involvement consist of signs of myocardial necrosis and RV dysfunction. Troponin elevation—assumed to result from RV injury—has been reported as being related to increased risk of adverse outcome in acute PE. Right ventricular dysfunction found at echocardiography, CT angiography, B-type natriuretic peptide/N terminal-proBNP (BNP/NT-proBNP) assessment or at right heart catheterisation was related to complicated clinical course and increased mortality. Unfortunately, for each individual marker the positive predictive value for mortality is low and the optimal cut-off point not well established. A possible additive value of the concomitant presence of signs of myocardial injury and dysfunction is likely, but not fully documented. In any case, a patient with at least one risk factor should be considered as being at ‘intermediate risk’ of early death (3–15% in hospital or 30 days mortality). Since approximately 25% of intermediate risk patients will have a complicated clinical course, they should be considered for close monitoring either by telemetry or in the intensive care unit, to allow early ‘rescue’ therapy.12

Patients without any of the above mentioned risk factors (‘low risk’ group) may be considered for early discharge on anticoagulant treatment, provided the spectrum of non-specific, prognostic markers related to general characteristics and comorbidities of the patient is reassuring.13

The therapeutic approach to patients with ‘non-high risk’ PE—that is, without shock or hypotension—has changed little over the last decade (table 1). There is a long lasting debate over whether some of these patients should be considered for thrombolytic treatment. A large multicentre trial is currently underway to assess the potential superiority of thrombolysis over heparin-alone treatment in patients with PE, RV dysfunction and positive troponin. Efforts to document such superiority before the era of blood biomarkers failed and therefore heparins remain the cornerstone of treatment of the patient with ‘non-high risk’ PE.12 14

Weight adjusted low molecular weight heparins (LMWH) are the first choice treatment for the majority of patients with documented acute PE,15 including those presenting with pulmonary infarction and haemoptysis, which usually resolves over the next few days. Fondaparinux in three fixed doses depending on the body weight (5 mg for patients weighing <50 kg, 7.5 mg for patients weighing 50–100 kg, and 10 mg for patients weighing >100 kg) is a valid alternative,16 particularly in patients with renal insufficiency as it allows non-modified administration down to a glomerular filtration rate (GFR) of 20 ml/kg/min, compared to 30 ml/kg/min for the LMWH. Fondaparinux has a good publication record as far as heparin induced thrombocytopenia is considered, with only a single controversial report linking it to this potentially life threatening complication of heparin treatment. In contrast to LMWH, fondaparinux should not be used in pregnancy due to lack of evidence. LMWH usually do not require monitoring. Exceptions include extremes of body weight, particularly moribund obesity, and the pre-delivery period in pregnancy, when anti-Xa activity assessment may be considered, with uncertain clinical significance. While tinzaparin, enoxaparin, and—for cancer patients—dalteparin have formal labelling for PE, it is common practice to extrapolate existing evidence to other LMWH, with documented efficacy in DVT. This is often due to local/national availability and reimbursement strategy, which locally might be different for different compounds.

UFH started as a weight adjusted intravenous bolus (80 U/kg) followed by 18 U/kg/h and a further APTT adjusted infusion is preferred to LMWH in several clinical circumstances, including unstable and ‘high risk’ PE, significant bleeding risk, and severe renal failure. Starting with an adequately high dose of UFH is a main prerequisite of success. Otherwise, risk of recurrence is significantly increased. Apart from severe antithrombin deficiency, an intravenous daily dose of 30 000 U guarantees effective anticoagulation even in cases without adequate APTT prolongation (defined as >1.5–2.5 control value). Slight overdosing of heparin is probably less harmful than underdosing, particularly in the first 24–48 h of treatment. Switching from intravenous to LMWH is often done but is not advisable, as it may be linked to increased bleeding risk.

Initial treatment with heparins or fondaparinux should be replaced by a vitamin K antagonist (VKA). Newer trends in the treatment of VTE call for starting VKA on the first day of therapy and continuing in parallel with parenteral anticoagulant in therapeutic doses for at least 4 days. The latter can be stopped only after bringing the international normalised ratio (INR) to the target range—that is, 2.0–3.0 for ≥2 consecutive days. However, in acute PE we usually aim at 7–10 days of parenteral anticoagulation, and therefore tend to delay the start of VKA to the third day of initial treatment. In selected patients in whom optimal INR monitoring seems difficult, LMWH may be used for secondary prevention at doses recommended by the manufacturer for such purpose.

Thrombophilia does not require modification of initial treatment, with the exception of significant antithrombin (AT) deficiency. It may result in resistance to UFH manifesting as lack of APTT prolongation. Lack of APTT increase due to AT deficiency can be corrected either by increasing the dose of UFH or—in exceptional cases—by substitution of AT. The effect on LMWH efficacy is less clear, but should be suspected. It is our practice to assess AT antigen and its activity in young patients with VTE, if LMWH is selected for initial treatment.

Secondary prevention and management of long term consequences of PE

Much has been written on the strategy of secondary prevention of VTE. Clearly it should depend on the underlying causes of the thromboembolic event. In patients with a strong and obvious predisposing factor, which could be removed, 3 months of anticoagulation is considered sufficient. Nevertheless, a 3% annual risk of VTE recurrence can still be expected. The decision regarding the duration of secondary prevention, in the case of permanent predisposing factors or ‘idiopathic’ unprovoked PE, is more difficult. The annual incidence of VTE may exceed 10% and does not seem to decrease notably with time elapsed since the index event. Clear recommendations can be made for patients at highest risk: those with a history of previous VTE events, antiphospholipid syndrome or untreatable malignancy. All are candidates for chronic, life long anticoagulation. Patients with cancer require secondary prevention with LMWH instead of VKA, as it seems to improve their survival, at least when given during the first 6 months after an acute VTE event. Some progress has been also made in evaluation of VTE recurrence risk following discontinuation of VTE prevention in patients with idiopathic VTE. An abnormal level of D-dimer assessed 1 month after stopping VKA was highly predictive of a high recurrence rate, which can be successfully abolished by continued treatment.17 Unfortunately, a negative result of a D-dimer test 1 month after a discontinuation attempt does not guarantee safe withholding of secondary prevention. This population of patients is in clear need of additional markers for further risk stratification for VTE recurrence.

An individual's risk of bleeding may also decide about continuing or stopping secondary prevention.18 In fact, chronic anticoagulation is highly efficient in preventing recurrent VTE events, but at a cost of a major bleeding rate of 3–4% within, and up to 5–9% outside, controlled clinical trials. Bleeding complications during the first 3 months of treatment are strong determinants of mortality. Out of 407 patients followed in the RIETE registry who had major bleeding during the study period, 133 (33%) died in the next 30 days—including 75 of bleeding and 12 of recurrent PE.19 Even though most serious bleeding events occur in the first months of anticoagulation, periodical reassessment of indications and contraindications to continued VTE prevention, accounting also for the patient's preferences, is still very important.15 Increasing use of potent antiplatelet therapies following cardiovascular interventions represents a new challenge for prophylactic long term anticoagulation. Venous filters seem to reduce mortality when inserted because of bleeding complications in patients receiving anticoagulants up to 3 months after a VTE episode. In the RIETE registry, insertion of a vena cava filter was the only variable independently associated with a lower incidence of fatal bleeding (odds ratio (OR) 0.10, 95% confidence interval (CI) 0.01 to 0.79) and all cause mortality (OR 0.21, 95% CI 0.07 to 0.63). Stopping anticoagulation was related to increased risk of death (OR 2.31, 95% CI 1.37 to 3.94).

Most survivors do not experience any significant long term consequences of an acute PE event, except for chronic venous insufficiency related to concomitant DVT.1 A small, so far not precisely estimated subgroup (0.1–5%) remain with post-embolic organised thrombi that may increase RV afterload. Pulmonary vascular remodelling in overperfused non-obstructed areas may result in progressive chronic thromboembolic pulmonary hypertension (CTEPH). There is no generally accepted strategy of follow-up of acute PE survivors. This is related to the relatively low incidence of clinically relevant CTEPH developing after acute PE events which were diagnosed early and adequately treated. However, echocardiographic follow-up is certainly advisable in all survivors of acute PE who remain symptomatic or develop exercise limitation due to dyspnoea with time.

In the case of signs suggesting RV pressure overload, comprehensive pulmonary vascular imaging and eventually right heart catheterisation is recommended. This should be performed preferably in a referral centre experienced in differential diagnosis and treatment of chronic pulmonary hypertension. Indeed, differential diagnosis may be difficult due to several common causes of chronic pulmonary hypertension. On the other hand, a diagnosis of CTEPH must be unequivocally confirmed as it should lead in most patients to pulmonary endarterectomy.20 This complex intervention, requiring deep hypothermia and periods of complete circulatory arrest, may restore both pulmonary haemodynamics and life expectancy close to normal. The efficacy of pharmacological treatment targeting the patent pulmonary arterial bed to prevent its remodelling is currently being assessed in randomised clinical trials enrolling patients with inoperable, distally located post-embolic vascular obstructions. Regardless of the operability and surgical result, all CTEPH patients require life-long anticoagulation.