Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level
Mariette J. Agterof, Department of Internal Medicine, University Medical Center Utrecht, Room G 02.228, PO Box 85500, 3508 GA Utrecht, the Netherlands.
Tel.: +31 88 7559662; fax: +31 30 2518328.
Summary. Background: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL−1) NT-proBNP. Methods and results: Hemodynamically stable outpatients with acute PE and NT-proBNP level < 500 pg mL−1 were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of re-admission due to PE or its treatment and the patient’s satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3-month follow-up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow-up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS-A anxiety score did not change significantly between day 0 and day 10. The PSQ-18 showed a high score for satisfaction with home treatment. Conclusion: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL−1) NT-proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. Clinical Trial Registration Information: http://clinicaltrials.gov/ct2/show/NCT00455819.
Treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) comprises subcutaneous injection of low molecular weight heparin (LMWH), followed by a variable period of oral anticoagulation therapy (OAT) . Studies investigating quality of life and cost of health care are in favor of outpatient treatment of patients with DVT and PEs [2,3]. Outpatient treatment of patients with DVT is safe [2,4–6], but out of hospital treatment for patients with acute PE has not been validated prospectively.
The majority of patients with PE have an uncomplicated course  and the need for hospitalization of all patients with PE can be questioned. The implementation of LMWH as a bridging therapy in patients with PE facilitates early discharge. Outpatient treatment for patients with non-massive PE is, however, not widely accepted as no explicit criteria exist for an accurate identification of patients who are suitable candidates for outpatient treatment .
Brain natriuretic peptide (BNP) is a hormone synthesized in cardiomyocytes. Its precursor, proBNP, is formed after splicing of the signal peptide from the pre-pro-hormone. After stimulation of cardiomyocytes, in case of volume expansion and pressure overload, pro-BNP is proteolytically split into the inactive N-terminal-proBNP (NT-proBNP) and the active component BNP . Patients with PE with low BNP [10–14] or NT-proBNP [10,11,15–20] concentrations have a low risk of death or hemodynamic deterioration .
There is increasing interest in NT-proBNP as a parameter for risk assessment in patients with acute PE, especially in the identification of low-risk patients [16,18,20]. In this management study, we investigated the safety of outpatient treatment of hemodynamically stable patients with PE with a low NT-proBNP level at presentation.
Inclusion criteria This is a multicenter, prospective management study involving patients with PE, aged 18 years or older, who presented at the emergency room in one of the five participating centers in the Netherlands between September 2006 and March 2009. The diagnosis of PE had to be confirmed within 24 h after presentation and was based on an intraluminal filling defect on spiral CT or pulmonary angiography, a high probability ventilation-perfusion lung scan, or a non-diagnostic lung scan with a proximal or distal deep venous thrombosis shown by ultrasonography of the legs.
All outpatients with confirmed acute PE were registered by research nurses or doctors within 24 h of admission. The screening was performed on a 24-h basis, 7 days a week. For all patients, we used the first recorded blood pressure, oxygen saturation and pulse rate on admission to the emergency department. Clinical data such as age, gender and medical history (heart failure, malignancy, previous VTE or medically treated chronic obstructive pulmonary disease) were also registered.
Only patients with a NT-proBNP level < 500 pg mL−1, measured before treatment was initiated, were included in the study. Plasma NT-proBNP concentrations were measured with the Elecsys proBNP electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany).
The medical ethical committees of the participating hospitals approved the study protocol. Written informed consent was obtained from all patients. Clinical Trial Registration Information: http://clinicaltrials.gov/ct2/show/NCT00455819
Exclusion criteria We excluded patients with the following criteria: (i) hemodynamic or respiratory instability, defined as one of the following symptoms: collapse, systolic blood pressure < 90 mmHg, pulse rate > 100 beats per minute or the need for oxygen therapy to maintain oxygen saturation > 90%; (ii) illness unrelated to PE for which the patient would require hospitalization for more than 24 h; (iii) pain requiring intravenous analgesia; (iv) need for acute thrombolysis at presentation; (v) active bleeding or known hemorrhagic diathesis; (vi) pregnancy; (vii) in-hospital patients; (viii) likelihood of poor compliance; (ix) no support system at home; and (x) renal insufficiency, defined as a creatinine level > 150 μmoL L−1.
All eligible patients were treated with therapeutic dosages of LMWH subcutaneously once a day as a bridging towards OAT, or with LMWH alone in the case of a malignancy. The first dose of LMWH was given as soon as possible after the diagnosis of PE was established (usually within 3 h of presentation). A nurse educated the patient regarding how to administer LMWH. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. Subsequent INR monitoring after discharge was provided by the Thrombosis Services. This is a Dutch network of regional anticoagulation clinics that carries out INR measuring and establishes the subsequent OAT dosing schedule for out of hospital patients. All participating patients received an information leaflet about the study with instructions about readmission in the case of well-defined symptoms or signs, pointing towards recurrent venous thromboembolism (VTE) or bleeding. A 24-h emergency number was provided. Patients were asked to complete an anxiety and a satisfaction score. The patients were contacted by telephone on days 2 and 4 after inclusion. All patients were seen in the outpatient department on day 10.
The primary objective was the safety of out of hospital treatment of patients with PE with an NT-proBNP < 500 pg mL−1. Because the mean in-hospital stay of patients with PE varies between 6.4 and 10 days [21–24], the main outcome parameter was the mortality rate due to PE or its treatment during the first 10 days of outpatient treatment.
The secondary objectives were to: (i) estimate the incidence of re-admission to hospital due to PE or its treatment during the first 10 days; (ii) investigate the rates of recurrence of VTE and major bleeding during the first 10 days; (iii) assess the patient’s satisfaction and anxiety during the first 10 days of outpatient treatment; and (iv) investigate the mortality rate and the rates of recurrence of VTE and major bleeding during a period of 90 days.
Definition of outcomes
The main objective was the 10-day mortality rate due to PE or its treatment. Fatal outcome was classified as being related to PE, bleeding, cancer or another diagnosis according to the judgment of an independent steering committee.
Information about the cause of death was obtained from autopsy reports, clinical reports or from additional information provided by the patient’s general practitioner. In all cases of death, the outcome events were reviewed and classified by an independent adjudication committee. Deaths were classified by the committee as caused by PE if autopsy confirmed PE, or if an objective test demonstrated PE prior to death, or if PE was most likely as the cause of death.
Recurrent PE was defined as a new intraluminal filling defect on spiral CT or pulmonary angiography with a cut-off of contrast material in a vessel > 2.5 mm in diameter on pulmonary angiography or a new perfusion defect involving at least 75% of a segment, with corresponding normal ventilation or a new non-diagnostic lung scan accompanied by documentation of DVT by ultrasonography of the legs or confirmation of a new PE at autopsy . The objective criterion defining a new DVT was a new, non-compressible venous segment or a substantial increase (> 4 mm) in the diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography of the legs .
Major bleeding was defined as bleeding that: (i) was clinically overt and associated with a decrease of 2.0 g dL−1 (1.24 mmol L−1) or more in the hemoglobin level, (ii) led to the transfusion of two or more units of whole blood or red cells, (iii) occurred in a critical area or organ, or (iv) contributed to death .
Patient’s satisfaction with their out of hospital treatment was evaluated with the Patient Satisfaction Questionnaire PSQ-18 score on day 10 . The PSQ-18 contains 18 items relating to the following seven subscales: general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctor and accessibility and convenience. The minimum score for every item was 0 (not satisfied); the maximum score was five (very satisfied). Items within each subscale were averaged after scoring.
Patient anxiety during the first 10 days of outpatient treatment was evaluated with an anxiety score containing seven questions, which is part of the Hospital Anxiety and Depression Scale (HADS-A); questions with regard to depression were omitted. The anxiety score was scored on the day of admission and on day 10. The minimum score was 0 points; the maximum score was 21 points. A higher score indicates higher distress. The score on day 0 was compared with the score on day 10 to intercept a possible increase of anxiety during outpatient treatment.
Sample size and premature termination of the trial
We considered the outpatient treatment of patients with PE with a normal pro-BNP level as safe if death did not occur in the outpatient group during the first 10 days of therapy. Therefore, this management study had to be stopped if death (related to PE or its therapy) occurred in more than 1% of the included patients. If no patient in the study group of 150 patients died in the first 10 days of therapy, our hypothesis (that outpatient treatment of patients with PE based on a normal pro-BNP level is safe) was confirmed. If one patient died in the outpatient group, the chance of dying would be 0.67% (95% confidence interval, 0–1.9%). By chance, the 1% limit could have been crossed. Therefore, another 150 patients would be recruited. Expanding the population to 300 would result in one death in 300, which is a chance of 0.3% with 95% confidence intervals below 1% (0–0.98%). This study would be stopped definitely if two or more patients in the outpatient group died due to PE or its therapy during the first 10 days of therapy.
This study would also be stopped if there were more than 5% readmissions due to PE or to the treatment, such as hemodynamic instability, recurrence of VTE or major bleeding, in the first 10 days of therapy. An independent steering committee was installed to judge all deaths and readmissions in the outpatient group.
Descriptive statistics were used to describe patient characteristics. The statistical analysis was performed using the Statistical Package for the Social Sciences software (version 16; SPSS, Chicago, IL, USA).
Characteristics of the study population
PE was diagnosed in 351 consecutive patients during the study period (Fig. 1). A total of 68 patients were excluded for: other illness (unrelated to PE) for which hospitalization was required (n = 21), collapse (n = 10), oxygen saturation < 90% (n = 9), systolic blood pressure < 90 mmHg (n = 6), psychiatric co-morbidity (n = 5), asystole (n = 4), severe hemoptysis (n = 1), pregnancy (n = 1), age < 18 years (n = 1), or no support system at home (n = 10) (Fig. 1). A total of 283 patients were eligible. Protocol violation occurred in 26 patients due to an unacceptable delay (> 24 h after admission) in the time needed to inform and include these patients. A total of 25 patients refrained from participation in the study. Eighty (34.5%) of 232 eligible patients had a NT-proBNP level > 500 pg mL−1 and were excluded. Finally, 152 (43.3%) of 351 patients presenting with acute PE at the emergency room were included in this study.
None of the 152 patients were lost to follow-up during the first 3 months. The clinical and laboratory characteristics of these patients are given in Table 1. The mean age of these 152 patients was 53.4 ± 14.3 years (range 20–84) and 51.3% of the patients were female. One hundred and five (69.1%) patients returned home directly from the emergency room without hospitalization and 47 patients (30.9%) were hospitalized for a period of 6–24 h.
Table 1. Baseline characteristics of 152 included patients with acute pulmonary embolism
|Age||53.4 ± 14.3 years|
|Female, n (%)||78 (51.3)|
|Systolic blood pressure||144 ± 21.2 mmHg|
|Pulse rate||82.3 ± 14.9 bpm|
|Oxygen saturation||97.1 ± 1.9% O2|
|Active malignancy, n (%)||20 (13.2)|
|Cardiac failure, n (%)||1 (0.7)|
|COPD, n (%)||8 (5.3)|
|Previous VTE, n (%)||23 (15.1)|
|NT-proBNP||116.8 ± 102.1 pg mL−1|
There were no deaths during the first 10 days in these 152 patients, resulting in a mortality rate as primary outcome parameter of 0%.
Seven (4.6%) patients required renewed hospitalization in the first 10 days after the diagnosis of PE. Four of these seven patients were admitted because of an illness unrelated to PE: one with cellulitis, one with myocardial failure due to severe mitral valve insufficiency, one with pneumonia and one because of fever and neutropenia after chemotherapy. Three patients were admitted because of complaints possibly related to PE: two patients had complaints of anxiety in combination with chest pain and one patient had dyspnoea with an oxygen saturation of 88%. These three patients remained hemodynamically stable and NT-proBNP levels remained low during their in-hospital stay. In two of these three patients (one with anxiety in combination with chest pain and one with hypoxemia) a new CT scan was performed; there were no signs of progression of PE. The two patients, readmitted because of anxiety and pain, stayed in the hospital for 2 and 3 days and the patient readmitted with dyspnoea for 5 days; the primary treatment (LMWH in combination with OAT) was continued and no other anticoagulant therapy was given in these three patients. All three patients had a quick recovery.
There were no recurrences of VTE or major bleedings during the first 10 days of treatment, nor deaths, recurrences of VTE or major bleedings during the 90-day follow-up period.
One hundred and three patients (67.8%) returned the Patient Satisfaction Questionnaire score (PSQ-18) on day 10. The mean (SD) score for satisfaction with out of hospital treatment was 3.80 (0.97); the mean (SD) scores for communication and interpersonal manner were 3.98 (0.89) and 4.07 (0.95), respectively. The mean scores of the total PSQ-18 are given in Table 2.
Table 2. Patient Satisfaction Questionnaire (PSQ-18) score on day 10
|General satisfaction||3.80 ± 0.97|
|Technical quality||3.88 ± 0.98|
|Interpersonal manner||4.07 ± 0.95|
|Communication||3.98 ± 0.89|
|Financial aspects||4.11 ± 0.90|
|Time spent with doctor||3.78 ± 0.94|
|Accessibility and convenience||3.74 ± 0.90|
One hundred and one patients (67.1%) returned the HADS-A anxiety score on both days (day 0 and day 10). There was no difference in the mean score on day 0 as compared with the mean (SD) score on day 10 [4.29 (3.34) vs. 4.31 (3.59); P = 0.968]. In 72 (71.3%) patients, the anxiety score did not decrease or increase by two or more points between day 0 and day 10. In 12 patients, the anxiety score decreased by greater then two points between day 0 and day 10. In 5 of these 12 patients the anxiety score decreased by five or more points. In 17 patients, the anxiety score increased by greater then two points between day 0 and day 10. In 5 of these 17 patients, the anxiety score increased by five or more points.
Outcome of the 80 patients excluded because of a NT-proBNP level > 500 pg mL−1
Eighty (34.5%) of 283 eligible patients had an NT-proBNP level > 500 pg mL−1 and were excluded. The baseline characteristics of these patients are given in Table 3. These patients were older than the 152 patients included in the study (61.2 ± 17.6 vs. 53.4 ± 14.3 years, P = 0.002). The mean oxygen saturation in the patients with an NT-proBNP level > 500 pg mL−1 was lower than the mean oxygen saturation in the included patients (94.8 ± 3.2% vs. 97.1 ± 1.9%, P < 0.001). There were more patients with cardiac failure in the high NT-proBNP group than in the included patients (P = 0.007). No differences were found in gender, blood pressure, pulse rate, rate of active malignancy, chronic pulmonary disease or previous VTE between patients with a high NT-proBNP level and the 152 patients with an NT-proBNP level < 500 pg mL−1.
Table 3. Baseline characteristics of the 80 excluded patients due to NT-proBNP levels > 500 pg mL−1
|Age||61.2 ± 17.6 years|
|Female, n (%)||47 (58.8)|
|Systolic blood pressure||138.4 ± 22.2 mmHg|
|Pulse rate||89.7 ± 16.9 bpm|
|Oxygen saturation||94.8 ± 3.2% O2|
|Active malignancy, n (%)||6 (7.5)|
|Cardiac failure, n (%)||6 (7.5)|
|COPD, N (%)||8 (10)|
|Previous VTE, n (%)||11 (18.8)|
|NT-proBNP||2909.3 ± 4875.4 pg mL−1|
One of the 80 patients underwent thrombolysis on the first day. In another patient an embolectomy occurred on the second day after a collapse. One patient died on day 32 because of cardiac decompensation. No major bleedings or recurrent VTEs occurred during the follow-up period.
This management study is the first prospective study to demonstrate the safety of out of hospital treatment in hemodynamically stable patients with PE with a low risk profile, based on a low NT-proBNP level (< 500 pg mL−1). No serious adverse events (SAE), including death, recurrent VTE or major bleeding, occurred in the first 10 days of outpatient treatment or during the 3-month follow-up period. Forty-three per cent of all patients presenting with PE at the emergency department could be treated in an outpatient setting in our study. Home treatment was considered to be convenient by most patients according to the Patient Satisfaction Questionnaire and the HADS-A anxiety score.
The treatment of PE with LMWH is simple and effective. LMWH has become the drug of choice in bridging towards long-term anticoagulation with coumarins such as warfarin in patients with VTE. Nowadays, the treatment of most patients with DVT occurs on an outpatient base. Nearly 50% of patients with a proximal DVT have evidence of a coexistent PE, often without typical symptoms . Therapy for VTE is no longer a reason for hospitalization. However, most patients with acute PE stay in the hospital for at least 6–10 days [21–24]. Only 4.5% of patients with PE are confronted with serious complications during the first 10 days of treatment . Patients defined as low risk based on the PE severity index have mortality rates below 2% . There is an actual interest in the development of strategies for treatment of a selected group of patients with PE in an outpatient setting. A prerequisite for home treatment is the absence of hemodynamic complications in patients with PE. Several studies pointed towards the role of cardiovascular biomarkers (such as BNP or its derivates and troponin) or plasmin degradation products (such as D-dimer concentration) in the risk stratification of patients with PE, but none of them have implemented these biomarkers in a prospective management model for outpatient treatment.
To our knowledge, this study is the largest prospective study in which patients with PE are treated entirely as outpatients. Six previous prospective studies have also identified subgroups of patients with PE who appeared to be suitable for safe outpatient treatment [30–35]. Exclusion was based only on clinical signs and symptoms. None of these studies used a low NT-proBNP level as an inclusion criterion. Four of these studies treated patients as outpatients [30–33] and in one study patients were treated in an outpatient hotel . Furthermore, the numbers of patients in these studies are rather small, ranging from 36 to 100 patients. Only the study carried out by Davies et al.  had more patients (156 patients). However, in this study patients were allowed to stay for 3 days in the hospital. No PE-related deaths and one death due to a major bleeding were reported in these six studies. The small percentage of recurrent VTE (0–6.2%) or major bleeding (0–3.7%) resembles the low-risk group of patients with PE in these studies.
An intriguing point is whether risk identification in patients with PE can be restricted to clinical signs and symptoms only. An advantage of risk stratification based on clinical symptoms is its simplicity, but its reliability can be questioned. In recent years several studies have shown that, in patients with acute PE, abnormal levels of cardiac biomarkers such as (NT-pro)BNP correlate with right ventricular dysfunction and predict an increased risk of short-term adverse outcome . Patients with PE with low NT-proBNP concentrations have a low risk of adverse clinical outcome [10,11,15–20]. In the study carried out by Bova et al., which included a heterogeneous population, BNP did not suffice as a prognostic marker for in-hospital PE-related adverse events. However, we found a high negative predictive value for NT-proBNP for adverse outcomes. This supports the use of (NT-pro)BNP in the algorithm to identify patients who can be treated without, or with only a short, admission to the hospital .
At the initiation of this study, the cut-off concentrations for NT-proBNP to discriminate between patients at low and at high risk of adverse clinical outcome varied from 500 to 1000 pg mL−1 [15–18]. For safety reasons, we used a cut-off level of < 500 pg mL−1 in our study. Standardization of NT-proBNP assays will be very helpful to determine the optimal cut-off level in the discrimination between high- and low-risk groups and for the interpretation of study results in daily practise.
Our study has some limitations. First, patients were not randomized. Due to the nature of the study with a very low (near zero) a priori chance of hemodynamic complications in patients with a low NT-proBNP, a very large randomized controlled trial is needed. We, therefore, preferred the setting of a management study. Second, it takes several hours for NT-proBNP levels to increase significantly after the onset of acute myocardial stretch . It is possible that a very recent (within hours) onset of PE can be seen with a not yet increased NT-proBNP level. It is important to consider determining a second NT-proBNP level, several hours after admission in patients with a very recent onset of complaints. Third, we recently found that tachycardia is a strong predictor of short-term adverse outcome in patients with PE . For safety reasons, an amendment was written to add pulse rate > 100 bpm to the exclusion criteria. This additional exclusion criterion was applied to the last 38 patients.
In conclusion, our prospective management study has shown that outpatient treatment of a selected group of low-risk patients with non-massive acute PE and an NT-proBNP level < 500 pg mL−1 appears to be safe. Approximately 45% of patients with acute PE are candidates for home treatment. Out of hospital therapy is considered to be convenient by the vast majority of the patients and it can contribute to the reduction of health care costs. The ideal setting to confirm our findings is a randomized controlled trial, for which, however, large numbers of patients are needed.
Conception, design and author’s contribution: M. J. Agterof, R. E. G. Schutgens, D. H. Biesma. Acquisition of data: M. J. Agterof, R. J. Snijder, G. Epping, H. G. Peltenburg, E. F. M. Posthuma, J. A. Hardeman, R. van der Griend, T. Koster. Analysis and interpretation of data: M. J. Agterof, R. E. G. Schutgens, D. H. Biesma. Drafting of the manuscript: M. J. Agterof, R. E. G. Schutgens, D. H. Biesma. Critical revision of the manuscript: R. J. Snijder, G. Epping, H. G. Peltenburg, E. F. M. Posthuma, J. A. Hardeman, R. van der Griend, T. Koster, M. H. Prins. Statistical expertise: M. J. Agterof, M. H. Prins.
Disclosure of Conflict of Interests
The authors declare that they have no conflict of interest.