Acute pulmonary thromboembolism in the Argentine Republic – 20th CONAREC Registry
IGNACIO M. CIGALINI, DARÍO B. IGOLNIKOF, CRISTHIAN E. SCATULARO,
JUAN CC. JAUREGUI, MAICO I. BERNAL, JUAN M. ABOY, SEBASTIÁN GARCÍA ZAMORA, JOSÉ M. BONORINO, JORGE THIERER, EZEQUIEL J. ZAIDEL
En representación del Consejo Argentino de Residentes de Cardiología. E-mail
Recibido 02-DIC-2018 – ACEPTADO después de revisión el 15-ENERO-2019.
There are no conflicts of interest to disclose.
Introduction: Pulmonary embolism (PE) represents the third cause of cardiovascular death. However, there is a lack of information about this entity in our country. Our aim was to describe baseline characteristics, clinical evolution and treatments for patients with acute PE in Argentina. Methods: Prospective multicenter registry which included patients with acute PE hospitalized in centers with cardiology residencies from October 2016 to November 2017. Conventional analysis was performed for descriptive and comparative statistics. A value of p<0.05 was considered significant. Cross audit was performed on 20% of the participating centers. Results: We included 684 consecutive patients from 75 centers with an average age of 63.8 years, 56.7% of them being female. PE was the reason for hospitalization in 70.8% of the cases. The most frequent predisposing factors were obesity, recent hospitalization, transient rest and active cancer. 96.8% received anticoagulation during hospitalization and reperfusion therapy was performed in 13.3% of patients. However, only 49% of patients with hemodynamic instability received any reperfusion therapy. Overall in-hospital mortality was 12.3%, mainly related to PE. Conclusions: PE affects a heterogeneous group of patients with high in-hospital mortality mainly related to PE. We observed a low use of reperfusion therapies in patients with hemodynamic instability.
Pulmonary thromboembolism (PTE) is the third cause of cardiovascular mortality , being responsible for at least 100,000 yearly deaths in the United States  and 300,000 in Europe . Its clinical presentation is variable, and often unspecific, leading to a diagnostic challenge with the risk of underestimating its real incidence , and delaying the onset of specific treatment, which will result in a worse outcome. This situation determines it to be the main cause of preventable in-hospital mortality .
Although there are numerous international registries that have collaborated to define risk factors and its natural history [6,7,8,9], there is scant information in our area about the management of this pathology .
Simultaneously, in spite of advancements and the increasing interest in this pathology, there are still large “grey areas” and controversies, particularly in regard to the treatment in its acute stage. Likewise, we do not have information about the impact generated by the introduction of direct oral anticoagulants (DOACs) in the usual clinical practice.
These factors motivated the Consejo Argentino de Reisdentes de Cardiología to start a new national registry that would help to understand what is the reality of PTE in our country.
MATERIALS AND METHODS
Cross-sectional and observational study that included prospectively patients with acute PTE admitted in centers with cardiology residency, affiliated to CONAREC, regardless of whether this was the cause of admission or it arose as a complication of hospitalization by another cause.
Patients hospitalized in the coronary unit, intensive care unit or general ward were included, over the term of thirteen consecutive months (October 2016 to November 2017), with a follow-up only during hospitalization. There were no diagnosis algorithms or guidelines to manage patients.
The data load was conducted online, in an electronic form for the report of cases, with exclusive access for each center through an individual class. The members of the committee of investigators, expert collaborators, and participating centers along with those in charge are listed in detail in the supplementary material.
Likewise, a cross audit was carried out in 20% of the centers by an independent committee, verifying random variables of the submitted information with the clinical histories of the institutions.
To stratify the risk of death by PTE of patients, a classification was used, suggested by the European Society of Cardiology (ESC) , the Pulmonary Embolism Severity Index (PESI) [12,13], and the simplified PESI (sPESI) . Likewise, the RIETE  and HAS-BLED  scores were used to determine the risk of bleeding. The analysis of the risk scores was performed independently and blindly by the main researcher from the variables that constitute it.
The classification of the Bleeding Academic Research Consortium (BARC)  was considered to define the bleedings.
The study protocol and informed consent were sent to the ethics committee of each center for approval. The study protocol, the different definitions used and the informed consent have been previously published .
The continuous variables were expressed as mean and standard deviation or median and interquartile range (IQR), depending on their distribution. The categorical variables were expressed as numbers and percentages. For comparisons between groups, Student’s t test or Wilcoxon rank-sum test were used, as it corresponded. The comparisons between proportions were made by the Chi-square test or Fisher’s exact test, depending on the frequency of expected values. In all cases, an alpha error of 5% was assumed to establish statistical significance.
For the statistical analysis, the Epi Info 7.2 and STATA 13 softwares were used.
There were 684 consecutive patients included, from 75 centers distributed over 16 states in the country (Figure 1).
Figure 1. Participating centers distributed by provinces
A cross audit was conducted in 15 centers (20%), chosen at random, with 97% of successes in the variables evaluated randomly. All patients were included in the final analysis from the results of the audit.
It was a population with age average of 64 years (±17) and 56.7 of the female gender. 85.5% had medical insurance and the maximum level of education was secondary or more in 79%.
The predisposing factors for PTE were divided according to the ESC recommendations , in those related to the patient (usually permanent) and those related to the context (usually temporary). Between the first, obesity (34%), active cancer (22%) and previous venous thromboembolism (VTE) (18%) stand out; while recent hospitalization (34%), transient rest of more than 72 h (30%) and recent surgery (24%) were the factors most frequently related to this scenario. The rest of the basal characteristics are described in Table 1. Only 2% of patients did not have predisposing factors for VTE.
Table 1. Basal characteristics
Weight (Kgs) ᵻ
Height (m) ᵻ
Level of education *
Incomplete primary school
- Primary school
- Secondary school
- Private/Prepaid health services
- Retired people’s health insurance
Main predisposing factors related to the patient
- Previous VTE Deep venous thrombosis
At times, for a factor or an item in the clinical history, the addition of the different categories considered is higher than 100% due to patients existing with more than one of them // * The maximum level reached is considered fully. Missing data in 232 patients (33.92%). // ‡ INR 2-3 in admission for VKA or with a proper dose of DOACs and LMWH.
Nine percent of patients had indication of anticoagulation. However, the degree of anticoagulation was inappropriate in more than half of cases.
PTE was the reason for admission in 70.8%, while the rest developed PTE during hospitalization by another cause.
In those patients who were admitted by PTE, time since the onset of symptoms until admission was 48 h (IQR 8-168), making a retrospective diagnosis of PTE in 10.4% of cases, after ruling out another diagnostic suspicion.
On the other hand, only 68% of individuals that presented PTE during hospitalization by another cause, presented appropriate antithrombotic prophylaxis.
The main findings in admission and additional tests made are described in Table 2. Dyspnea (85%) was the most frequent manifestation, followed by tachypnea (47%) and tachycardia (37%).
Table 2. Findings in admission and additional tests
- P pulmonale
- Q DII-aVF
Negative T from V1 through V4
Complete right bundle branch block
ST segment depression
QR in V1
‡ positive value according to local lab parameters.
* by arteriography or tomography angiography
Sinus tachycardia (52%) and the S1Q3T3 pattern (20%) were the most frequently found electrocardiographic signs.
Echocardiogram was performed in 625 patients (91%) with dilatation or right ventricular (RV) dysfunction in 41% and 35% of cases, respectively. The median of pulmonary artery systolic pressure (PASP) was 43 mmHg (IQR 35-55).
Likewise, venous Doppler echo was made in lower limbs, in 534 patients, verifying deep venous thrombosis (DVT) in 310 patients.
The most used diagnostic method was multislice computed tomography angiography (81%), followed by ventilation/perfusion scintigraphy (14%) and pulmonary arteriography (8%). Only 52 patients (8%) required two or more specific diagnostic tests.
In admission, 42% presented with anemia and basal creatinine was 0.91 mg/dl (IQR 0.72-1.2). Biomarkers of myocardial injury were evaluated in 83% of patients, particularly with troponin measurement (70%) that was positive in 65% of cases.
The median of the PESI was 83 (IQR 47-112) with 41% of patients in low/very low risk, 26% of intermediate risk and the remaining 33% of high/very high risk (Table 3). On the contrary, when evaluating risk according to the simplified PESI, only 26% were categorized as in low risk (sPESI of 0).
Table 3. Risk stratification and relation to events (in-hospital mortality and bleeding).
- Class I
Intermediate risk (1-4)
High risk (>4 points)
When considering clinical and echocardiographic variables, and lab parameters according to the ESC classification, the patients were stratified as in low risk (24%), low-intermediate risk (34%), intermediate-high risk (26%) and high risk (15%).
On the other hand, when evaluating the risk of bleeding according to the RIETE score, a median of 2.5 points was obtained (IQR 1-3.5) with 12% of patients in high risk. Likewise, a median of HAS-BLED of 1 point (IQR 0-2) was recorded with 9% presenting a value greater or equal to 3 points.
Treatment during admission
In this registry, 75% of patients were treated in the cardiology service, and 78% required admission in a closed unit during the acute episode.
97% of patients received anticoagulation during hospitalization, using most frequently as first therapeutic scheme, low molecular weight heparins (LMWH) (56%) or unfractionated heparins (22%). The remaining 3% did not receive anticoagulation, mainly by absolute (30%) or relative (22%) contraindications.
Vena cava filter was implanted in 43 patients, mainly in a scenario of anticoagulation contraindication (47%) or PTE recurrence while receiving anticoagulation (21%).
Pharmacological reperfusion, endovascular or surgical therapy were performed in 91 patients (13%) with a reperfusion time of 2 days (IQR 1-5). The cases dealt with by cardiology received more reperfusion in comparison to other specialties (16% vs 7%; p<0.01). When evaluating its use, depending on risk stratification, we observe that reperfusion was conducted in 16% of patients in high-intermediate risk and only in 49% of patients in high risk. In 77% of patients in high risk and with no reperfusion, there was no formal contraindication to perform it, with this management being strictly a decision of the attending physician.
The use of systemic lithium was the most used reperfusion strategy (86%), mainly streptokinase (62%). Endovascular revascularization was used in 14 patients, with the techniques implemented being aspiration (57%), fragmentation (50%) and administration of local lithium (36%). Surgical revascularization was performed in a single patient.
The median of admission was 8 days (IQR 5-14). The main complications recorded are described in Table 4, highlighting 15% of renal dysfunction, 12% of concomitant infection and 7% of bleeding.
* The BARC classification was used to define and stratify bleedings. ᵻ Assessed according to the AKIN classification.
There were no differences in the RIETE or HAS-BLED scores, among those that presented major bleeding and those who didn’t (RIETE 2.5 [IQR 1-3.5] vs 2.5 [IQR 1-3.5]; p=ns; HAS-BLED 1 [IQR 0-2]; p=ns).
Overall mortality was 12%, with significant difference according to risk stratification (Table 3). The cause of death was mostly related to PTE (51%), followed by other noncardiovascular causes (30%), cardiovascular causes (16%) and bleeding (4%).
Management upon discharge
Anticoagulation was indicated upon discharge in 96% of patients: 60% vitamin K antagonists (VKA), 21% LMWH and 19% DOACs (Figure 2). One in every 4 patients that were discharged with dicoumarin was not in a range of anticoagulation.
Figure 2. Anticoagulation upon discharge.
The patients receiving DOACs upon discharge were more frequently those attended by cardiologists (21% vs other services 12%; p=0.012), with a better level of education (20% in secondary/university level vs 9% primary/minimum level; p=0.013), private insurance/medical insurance (22% vs 8% of the state/retired people medical insurance; p<0.001) and less severe symptoms (PESI 84.4 ± 26.4 vs 93.7 ± 31.3; p=0.004). DOACs were not indicated in patients that presented major bleeding during admission (0% vs 19% in those without bleeding; p=0.035).
DISCUSSION Data from the largest Argentine PTE registry, as well as one of the largest in the region, are presented. This project was the central axis of an overarching program including training activities and dissemination for cardiology residents and the community in general.
The baseline characteristics of the patients included are consistent with the findings in literature reinforcing the heterogeneity of this pathology by affecting a population with wide age range (16-97 years) and with a variable presentation of predisposing factors.
Although there is a presentation similar in terms of age average, the tendency to a greater compromise in the female gender and the prevalence of the most relevant predisposing factors as active neoplasia, the low number of patients with idiopathic presentation or without a cause (2%) is remarkable in regard to other series: 9% in the Sociedad Argentina de Cardiología registry , 19% in the ICOPER  and up to 42.9% in the MASTER registry . Maybe, the better understanding of the pathophysiology and identification of predisposing factors as years have passed, have enabled a better identification in our population. However, the finding of an inappropriate indication of prophylaxis in patients that presented PTE concomitantly during hospitalization by another cause, still shows that there are key aspects to be improved with the aim of preventing this pathology in our daily clinical practice.
Tomography angiography has settled as the most used diagnostic method, increasing its use in successive registries (37%, 55%, 86% and 81% in EMEPCO , the Brazilian registry , the SAC registry  and CONAREC XX, respectively), replacing ventilation/perfusion scintigraphy. Its higher sensitivity and specificity are probably responsible for a lower need of additional tests: 7.6% of patients required two or more specific studies in comparison to 31.3% shown in the MASTER registry . An increase in the use of arteriography was equally observed as diagnostic method (8%) in comparison to the SAC registry (1%) .
Echocardiogram in PT has become an essential tool due to its wide availability and capacity to stratify risk [11,22], with dilatation and particularly RV dysfunction being independent predictors of mortality . In this registry, mortality in patients with dilatation and/or RV dysfunction was 17% and 7% in those who did not show compromise in it (p<0.001).
The risk stratification suggested by the ESC  was used for the first time in a Latin American registry, which combines clinical parameters with the search for injury or ventricular dysfunction, observing a good correlation with in-hospital mortality according to the different strata. Similar findings were observed with the PESI and sPESI indices; although these deductions should be confirmed with specific analyses that exceed the aims of this paper.
About the treatment, the high rate of anticoagulation in hospitalization, mainly with LMWH corresponds to the transition observed in different publications, pushing the use of unfractionated heparins into the background .
This is one of the only registries to describe the rate of reperfusion according to risk stratification, allowing the identification of a low rate of reperfusion in patients in high risk; in spite of no strict contraindication existing for its use [11,22] due to its proven decrease of mortality [25,26]. The increase in bleeding risk inherent to this practice could be the reason it is underused by attending physicians .
This Registry shows the lack of tools to predict bleedings in patients with PTE, as neither the RIETE nor the HAS-BLED scores could identify patients in higher risk of bleeding in hospitalization. Although the HAS-BLED score was developed to evaluate the risk of bleeding in patients with atrial fibrillation and under anticoagulation treatment, its widespread use in daily practice and recent evidence of its potential application in patients with VTE were the reasons to include it in this registry .
The 12% mortality recorded is comparable to that observed in Latin American registries [20,21]; although remarkably greater to the 7% reported by the SAC registry . The different classification used to stratify the risk of PTE and the lower number of cases incorporated to the mentioned registry, make a direct comparison impossible. However, it seems that the decrease in mortality in patients with PTE observed in some series  does not reflect in our area.
VKA is still the most indicated anticoagulant upon discharge; however, one in every four patients was not within a therapeutic range. The proven safety and efficacy of DOACs in clinical trials [27,28,29] and subsequent meta-analyses  make them an attractive alternative in selected patients. In this regard, by being the first report on the use of DOACs due to PTE in our area, a greater use of this drug is to be expected, replacing VKA in the next few years. For the time being, its use is related to the management by the cardiology service, and a better social status of the patient probably in regard to the higher cost of the treatment.
LIMITATIONS The inclusion of patients admitted in care centers with cardiology residency, members of CONAREC, may not be representative of the general Argentine population, by restricting the participation to academic centers of moderate-to-high complexity. Likewise, no data are provided of patients with PTE of low risk with ambulatory treatment. Similarly, by exclusively enrolling patients with confirmed PTE, there is also a possibility of under-registration of patients with more severe PTE, in whom the diagnostic confirmation was not achieved before death.
Finally, there was no confirmation on the diagnosis of PTE, adopting the interpretations of additional tests performed by the participating institutions. However, a cross audit was made on 20% of the participating centers by an independent committee backing the provided data.
In spite of the limitations expressed, the strength of this Registry is focused on the prospective gathering of data from real practice in a large number of patients with PTE, based on diagnostic tests and clinical practices in a wide sample of institutions in our country.
PTE in Argentina presents as a pathology affecting a heterogeneous group of patients, with high mortality in hospitalization, directly related to PTE in more than half of the cases.
Although the rate of use of anticoagulation management during hospitalization is high, the low use of reperfusion therapies stands out in high risk patients with no contraindications for it.
Also, this Registry is the first report in our country on the use of DOACs for PTE.
This Registry could not have been made without the input by hundreds of residents throughout the country and the professional contribution by Drs. José Bonorino, Jorge Thierer and Ezequiel Zaidel. “When gratitude is so absolute, there is no need for words.”
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