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. 2020 Jul 6;15(7):e0235683. doi: 10.1371/journal.pone.0235683

Low venous thromboembolism incidence in high risk medical patients in an Israeli hospital. Can risk assessment be extrapolated to different populations?

Ofir Koren 1,2, Arin Nasser 3, Mazen Elias 2,3, Gilat Avraham 3, Nahum Freidberg 1, Walid Saliba 2,4, Lee H Goldstein 2,5,*
Editor: Raffaele Serra6
PMCID: PMC7337280  PMID: 32628725

Abstract

Background

Guidelines recommend venous thromboembolism (VTE) prophylaxis in hospitalized medical patients with Padua prediction score (PPS) ≥4 points. This recommendation is based on the high risk of symptomatic VTE observed among these patients in the Italian PPS derivation study, and the fivefold risk reduction with VTE-prophylaxis. This study aims to assess the incidence of VTE in high risk medical patients in a medium sized hospital in Israel.

Method

In this retrospective cohort study, data was collected of all medical patients hospitalized between January and June 2014. Patients were classified into low and high risk groups according to their PPS score, and according to whether they received anticoagulant thromboprophylaxis for VTE. Patients were further randomly selected to compare high risk patients that did or did not receive anticoagulant thromboprophylaxis. We further compared VTE incidence in high and low risk patients not treated with thromboprophylaxis. A search was conducted for diagnoses of venous thromboembolism and death during hospitalization and the following 90 days.

Results

568 high risk patients (PPS ≥4 points) were included, 284 treated with prophylactic anticoagulation and 284 not. There were no VTE events in either group. There was no difference in mortality. A total of 642 non anticoagulated patients were randomly selected, 474 low risk and 168 high risk. There were no VTE events in either group.

Conclusions

The risk of VTE appears to be very low in our study, suggesting that among medical patients with PPS ≥4, the risk of VTE may differ dramatically between populations.

Introduction

Venous Thromboembolism (VTE) is defined as deep vein thrombosis (DVT) or pulmonary embolism or both, and is associated with increased mortality and complications such as, post-thrombotic syndrome, increased risk for recurrence of thrombosis and development of pulmonary hypertension [1].

In the past, only surgical patients were considered at risk for developing VTE [2]. Over the past few decades it has become apparent that hospitalized patients have an increased risk of developing VTE [3–8] and VTE prophylaxis confers a strong benefit in a selected high risk group of medical patients [9–15]. The recommendation for prophylaxis has been expanded to patients hospitalized in all wards, and in particular, to those hospitalized in the internal medicine wards (medical patients) [16, 17].

Various risk assessment models (RAMs) have been developed for identifying medical patients at increased risk of VTE. The Padua Prediction Score (PPS) [18], the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) [19] and the Geneva Risk model [20] are three risk assessment models (RAM) that have undergone external validation in cohorts of acutely ill hospitalized medical patients. The Padua Prediction Score incorporates 15 risk factors within 11 items, and is one of the few RAMs which have been validated in medical patients. In the Padua Prediction study VTE event rate at 90 days was 11.0% in high-risk patients (score 4 and above) without thrombo-prophylaxis as compared to 2.2% in high risk patients with thrombo-prophylaxis reflecting a relative risk reduction of 80%.

The 90 day VTE event rate in low-risk patients of whom the majority did not receive thrombo-prophylaxis was 0.3% [18]. In an additional Italian study, the results of the Padua RAM were validated and the risk of VTE in high risk medical patients reduced from 8.3% to 1.5% with appropriate anticoagulation. [21] In 2014 a multicenter validation of the Geneva Risk Score was published. When compared with the Padua Prediction Score, the Geneva score was better at identifying low-risk patients, who are not in need of thrombo-prophylaxis. An interesting finding in the Geneva Score validation study was the relatively low incidence of VTE in medical patients. In this study, which included 1478 patients hospitalized in internal medicine departments in Geneva, the VTE incidence rate, in high risk patients (PPS ≥4) was only 3.5%, whereas in the Padua Score validation studies, the VTE incidence rate was 11% [20] and 8.5% [21]. The IMPROVE RAM was derived from a registry of 15,125 medically-ill patients and includes 11 predictors. Patients at high risk for VTE are designated with a score ≥4.These patients had a VTE risk of 5.7% versus <1% in the low-risk group [19].The IMPROVEDD RAM adds D Dimer to the risk assessment model [22].

According to international guidelines, such as the guidelines of the American College of Chest Physicians (ACCP), prophylactic anticoagulation should be administered to high-risk medical patients using the Padua Score (PPS ≥4) [16]. The American Society of Hematology suggested assessing patients individual VTE risk using either the Padua or the IMPROVE or IMPPROVEDD risk RAMs taking into account the patients bleeding risk.[17] The recommended prophylaxis, among others, is a low molecular weight heparin (LMWH), such as Enoxaparin. In view of the international guidelines, calculating the Padua prediction score has been proclaimed a quality measure, by all the Clalit Health Services hospitals in Israel, our hospital included.

The objective of this study was to examine the incidence of VTE events in our medical patients stratified by the Padua score and examine the benefit of administering LMWH as prophylaxis treatment (Table 1).

Table 1. Padua Prediction Score.

Risk factor Score
Active cancer and/or chemotherapy over the past six months 3
Past VTEx event 3
Reduced mobility over the past three days 3
Hypercoagulability 3
Trauma and/or surgery over the past month 2
Old aged (70 or more) 1
Lung and/or heart failure 1
Acute myocardial infarction and/or acute stroke 1
Acute infection and/or rheumatologic disorder 1
Obesity 1
Active hormonal treatment 1
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XVTE–Venous Thromboembolism.

Material and methods

We conducted a retrospective observational descriptive study in Emek Medical Center, a general, 500 bed teaching hospital in the north east of Israel, belonging to the Clalit Health Services. We collected data from files of patients hospitalized in four internal medicine departments from January 1 2014 to June 30 2014 who met the study inclusion criteria (ages 18 and up with a Padua score recorded) (Table 2).

Table 2. Inclusion and exclusion criteria.

Inclusion Criteria
    1) Hospitalized in Internal Medicine departments Jan-Jun 2014
    2) Age ≥18
    3) Record of Padua Score
Exclusion Criteria
    4) Pregnant women
    5) Patients hospitalized for venous thromboembolism (VTE)
    6) Patients on anticoagulants prior to hospitalization.
    7) Patients discharged from hospital with an anticoagulant of any kind provided it was not prescribed for venous thromboembolism that developed over the course of the hospitalization.
    8) Patients who received full dose anticoagulants during hospitalization
    9) Patients with contraindications for anticoagulant treatment
        a. Platelets< 50,000
        b. Recent acute bleeding
        c. INR > 1.5
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Pregnant women, patients hospitalized for deep vein thrombosis, pulmonary embolism, acute coronary syndrome and other conditions requiring therapeutic dose of anticoagulants were not included in the study. Also not included were patients with contraindications to anticoagulant treatment as severe thrombocytopenia (defined as less than 50,000 platelets), INR above 1.5 and recent severe bleeding.

Thromboprophylaxis was defined as once daily treatment with an Enoxaparin, a low molecular weight heparin, at a dose of 0.5–1 mg/kg throughout the hospitalization for VTE prevention. The Padua score was calculated prospectively and entered in the electronic medical chart by the attending hospital-physicians upon patients arrival to the ward.

In order to compare VTE incidence in high risk patients, treated or not treated with thromboprophylaxis, a computerized random sampling, of 284 patients in each group was performed.

We further compared VTE incidence in high and low risk patients not treated with thromboprophylaxis by random sampling of 168 high risk patients and 474 low risk patients. The primary outcome was defined as symptomatic deep vein thrombosis or pulmonary embolism (Venous Thromboembolism–VTE) during hospitalization and over the course of a further 90 days. The secondary outcome was defined as all-cause mortality over the same time period. Since the hospital is a regional hospital which belongs to Clalit Heath Services and most of the hospitalized patients are insured by Clalit, a computerized scan of the hospital and Clalit Health Services databases was conducted in search of diagnoses of VTE, major bleeding or death. When there wasn't sufficient information regarding outcomes an experienced physician reviewed the medical files, and if need, contacted the patient. In order to detect possible cases of death due to unrecognized pulmonary embolism, cause of death was reviewed in search of unexpected death. Patients who died out of hospital, and the reason of death was unknown were also defined as unexpected death.

Sample size

The sample size was calculated based on the incidence of VTE found in two large studies, the Italian Padua Score validation study, in which an 11% incidence rate was demonstrated, and the Swiss, Geneva Score Validation study which demonstrated an incidence of 3.2%. We estimated a VTE risk of 5% in our patients with PPS ≥4 points. In order to show that in the group that received thromboprophylaxis, the incidence of VTE decreases by approximately 80%, 568 patients were enrolled (284 in each group) in order to achieve power of 80% and alpha of 5% (two tailed test). In order to show that in the group with the low Padua score the VTE incidence is 1%, we would need to recruit 644 patients (at a 1:3 ratio, i.e. 161 patients with a high Padua score and 474 with a low Padua score), in order to achieve power 80% and alpha of 5% (two-tailed test).

Ethics

The study was approved by Emek Medical Center Ethics Committee in accordance with the Helsinki Convention No. EMC-135-14. Informed consent was waived due to the confidentiality of patients data and the methodology of the study.

Statistical analysis

Chi-square test was performed to analyses the association between the study groups and categorical variables. For continuous variables we used the T-test (or alternative the Wilcoxon two-sample test). Categorical variables were presented using frequencies and percent's. Continuous variables were presented using mean ± standard deviation. The statistical analyses were performed using SAS 9.4 software. P-value<0.05 was considered significant.

Results

During the first six months of 2014, there were 6409 hospitalizations in the internal medicine departments (Fig 1). Of 6409 medical patients, 4611 met the study criteria, 1968 high risk and 2643 low risk patients. Among 1968 high risk patients, 874 patients were treated with prophylactic LMWH and 1094 were not. A computerized random sampling, of 284 patients in each group was performed in order to compare VTE incidence in high risk patients, treated or not treated with thromboprophylaxis. We further compared VTE incidence in high and low risk patients not treated with thromboprophylaxis by random sampling of 474 low risk patients and 168 high risk patients.

Fig 1. Study design.

Fig 1

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For the high risk group comparison between thromboprophylaxis /non thromboprophylaxis the average age in both groups was 75 years of age. There was no difference in the basic characteristics of the two groups, including: gender, age, weight and primary admission diagnosis (Table 3).

Table 3. Patients characteristics.

High Risk Patients with/without thromboprophylaxis High versus low risk patients (without thromboprophylaxis)
Patients Characteristics Prophylactic LMWH N = 284 No Prophylactic LMWH N = 284 Padua score≥4 N = 168 Padua score<4 N = 474
Age (average (SD) 75.5(13.3) 74.2(13.6) 75.3±13.6 61.1± 17.5
Gender (male) N (%) 128 (45.10) (140) 49.60 85 (50.6) 281 (59.3)
Weight (kg) (average (SD)) 77.2±17.7 74.5±17.3 74.3± 17.8 78.2± 17.9
Duration of hospitalization (days) (average (SD)) 6.82±5.6 4.9±3.8 5.3 ± 4.8 3.9± 3.2
Padua Score (average (SD), [Median (min,max)]) 5.77(1.68) [5(4,14)] 5.15(1.29) [5(4,11) 5.4(1.56) [5(4,11)] 1.14(1.04) [1(0,3)]
Primary Diagnosis N (%) Infection/sepsis X 111 (39) 102 (36) 24(14) 48 (10)
Cardiovascular^ 40(14) 39 (14) 32 (19) 136(29)
Neurological* 37(13) 31(11) 24 (14) 79 (17)
Pulmonary disease¥ 31 (11) 29 (10) 44 (26) 78(16)
Hemato-oncological disease 11 (4) 20 (7) 9 (5) 10 (2)
Acute renal failure ψ 3(1) 3 (1) 6 (4) 15 (3)
Acute rheumatologic disorder 3 (1) 1 (0) 1 (1) 12 (3)
Other 48 (17) 59 (21) 28(17) 96 (19)
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Average ± standard deviation.

X Infectious and sepsis; pneumonia, urinary tract infection, cellulitis.

^Cardiovascular- congestive heart failure, ischemic heart disease, tachy/bradyarrythmias.

*Neurological and cerebrovascular accident; Transient ischemic attack, syncope, vertigo.

ψ–Calculated with the Cockroft-Gault formula.

¥Pulmonary- asthma, COPD, acute bronchitis, upper respiratory tract infection.

The average Padua score was higher in patients treated with LMWH as opposed to non-treated group (5.77±1.68, 5.15±1.29 [P<0.001]) respectively. No significant correlation was detected between the Padua score and duration of hospitalization (P = 0.1191, with a correlation coefficient of 0.06547). The hospital stay in the treated group was longer than the stay in the non-treated group (6.82±5.6, 4.9±3.8 days respectively [P = 0.0009]). No VTE events were detected during hospitalization and over the course of 90 days in both groups (Table 4).

Table 4. VTE and death within 90 days.

High Risk Patients with/without thromboprophylaxis High versus low risk patients (without thromboprophylaxis)
Prophylactic LMWH N = 284 No Prophylactic LMWH N = 284 P Value Padua score≥4 N = 168 Padua score<4 N = 474 P Value
VTE 0 0 0 0
Death within 90 days 65 (22.9%) 53 (18.7%) 0.21 35 (20.0%) 17(3.6%) <0.001
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Ninety-day all-cause mortality rate was 65/284 (22.9%) in the group treated with prophylactic LMWH, compared to 53/284 (18.7%) in the non-treated group (P = 0.21). No significant difference was detected in the incidence of unexpected deaths between groups. (10/284 (3.52%) in the group that received thromboprophylaxis and 7/284 (2.46%) in the non-treated group. (p = 0.46)

As expected, for the comparison between high and low risk patients (all of whom were not treated by, thromboprophylaxis), the two groups differed in most indices (Table 3). The high risk patients were on average older (75.3±13.6years) compared to (61.1±17.5years) (p<0.001), and with lower weight (74.3±17.8kg) as opposed to (78.2±17.9 kg) (p = 0.01). The groups also differed in terms of primary admission diagnosis and length of hospital stay. The average hospitalization length was 5.3±4.8 days in the high-risk patients compared to 3.9±3.2 in the low risk patients (p = 0.0005). No VTE events occurred in either high or low risk patients during hospitalization or the 90-day post hospitalization follow-up (Table 4). The mortality rate was, as expected, higher in the high risk group 35/168 (20.4%) in comparison to the low risk group 17/474 (3.6%), p<0.001. The odds of mortality was 5.6 folds higher in high risk patients compared to low risk patients (95% CI: 3.1–10.3, P = 0.001). The results were similar after controlling for hemoglobin, length of hospitalization and eGFR; OR = 3.05 (95%CI: 1.58–5.9 (P = 0.001).

No difference was observed in the incidence of unexpected deaths in the low risk in comparison to the high risk group (7/474 (1.46%) and 6/168 (3.57%) respectively (p = 0.11). Likewise, no difference in the incidence of unexpected death was observed in the high risk patients with or without thromboprophylaxis. (10/284 (3.52%) and 7/284 (2.46%) respectively, p = 0.62)

Discussion

No VTE events were detected in our cohort of medical patients, despite some being defined as high risk patients according to the Padua risk score (PPS ≥4) and not treated by thromboprophylaxis. In other words, a Padua score greater than or less than four was not able to predict who would suffer of VTE in our patients who didn’t receive prophylactic anticoagulant treatment.

Our findings suggest a low risk of VTE in our medical patients with PPS≥4 in contrary to the findings of previous studies that showed a high risk of VTE (11%). We additionally found no difference between low and high risk patients, not treated with anticoagulation, nor between high risk patients treated/non treated with thromboprophylaxis.

The 90-day mortality rate in the high-risk patients was twice higher than the low risk patients in this cohort. The Padua score is based on medical history and age, so it stands to reason that the higher the score, the higher the mortality rate. Exploring those cases reveal 8 unexpected death in the high-risk group (8/35, 22.8%) and 4 unexpected deaths in the low-risk group (4/17, 22.5%). This indicate no difference between the high and low risk groups in the incidence of unexpected death.

The discrepancy between the results of our study to those of the original Padua study could be explained if the incidence of VTE in our population of medical patients is lower than the rate described in previous studies. In retrospect, it is possible that a sample size calculated on the basis of a VTE incidence rate of 5% was insufficient, and that the rate of VTE in our population is much lower, and our sample size was not large enough to detect such a small difference. The Italian population of Padua study possibly have a higher thrombosis risk, as is demonstrated in the Geneva study [20], which attempted to validate a newly proposed risk assessment score (the Geneva Score), comparing the Padua and Geneva scores in their study.

The incidence of VTE in high risk patients in the Geneva population was considerably lower than the Padua population (3% versus 11%). These two trials were performed in specific populations (Italian and Swiss). The incidence of symptomatic VTE was considerably lower in major multi-national and multicenter studies, 0.7% in high risk medical patients in the MEDENOX study [23], the landmark trial for the prevention of VTE in medical patients, 0.9% in the PREVENT study [24], and 3% in the ARTEMIS study [25].

A possibly higher prevalence of VTE in the Italian population is further supported by the results of the PESIT Trial, from Padua Italy [26], which demonstrated an unexpectedly high incidence of pulmonary embolism in patients hospitalized for syncope. The incidence of pulmonary embolism was 17.3% in this Italian cohort, previously reported as 1.6% in an Iranian cohort [27], 2.5% in a Belgian cohort [28] and 1% in a Swiss cohort [29].

The lack of VTE cases in our study suggests that the incidence of VTE in our population is even lower than that observed in the Geneva study and therefore it is unclear whether using this score would be helpful to successfully predict the incidence of VTE in our patient population.

Another possible explanation for the difference in VTE incidence could be if the risk assessment which was performed by the attending physician was done inaccurately regarding mobility assessment. Of all the 11 variables in the Padua Score, the only subjective variable, which could possibly be evaluated incorrectly, is the mobility score. This variable contributes 3 points to the score if the patient incapable to walk any further than the toilet and back, and not, as might be erroneously evaluated as a totally bedridden patient. We assume that if the immobility score was performed inaccurately, the patient would have been evaluated with a lower and not higher score. Thus, our high risk patients would have been of a very high risk, making our results even more significant.

Limitations

This was a retrospective study which on one hand presents a disadvantage in design but on the other hand, works to our advantage since there was no need to obtain the patients signed consent to participate in the study as required in the previous studies (Padua and Geneva). Hence, our study included seriously ill patients at high risk of symptomatic VTE and VTE related death in which we would not have been able to obtain signed consent if a prospective design was adopted. This population probably reflects reality more accurately.

Data was collected from a computerized system in a retrospective manner which may underestimate the true incidence of VTE. Clalit Health Services is the largest of the four health funds with around 3.8 million insured members, 54% of the Israeli population. The HMO's computer system constantly updating medical information from all medical services including other health service organizations and therefore the risk of missing vital information is significantly low. Furthermore, when we suspected that vital medical information was incomplete or missing, we contacted the patient directly.

In retrospect, the number of recruits was too low to prove a difference between the groups due to the low VTE incidence revealed in our study, nonetheless, it was high enough to show a very low incidence of VTE, probably even less than 0.5%. Another limitation is that the population sampled was the population for whom a Padua score had been determined. The Padua score is currently implemented on approximately 95% of the patients hospitalized at our center. During the study period (2014), implementation was lower and Padua score was not determined for 1194 patients. It is possible that this fact had an effect on the random sample.

In summary, there was no difference in the incidence of symptomatic VTE in high risk medical patients with a Padua score of 4 and above treated with prophylactic LMWH in comparison to high risk medical patients who were not treated, and there was no difference between high and low risk patients in VTE incidence. The VTE incidence rate was very low. The findings of this study imply that the risk benefit ratio of prophylactic treatment with LMWH based on the Padua score in our patients should be reassessed.

Supporting information

S1 Data

(XLS)

Click here for additional data file. (162KB, xls)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work

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Decision Letter 0

Raffaele Serra

26 May 2020

PONE-D-20-10275

Low Venous Thromboembolism Incidence in High Risk Medical Patients in an Israeli Hospital. Can Risk assessment be extrapolated to different populations?

PLOS ONE

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Comments to the Author

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Reviewer #1: Partly

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: O Koren et al explore in a retrospective cohort study (1) whether the risk of hospital-associated VTE is 80% lower among inpatients with a high Padua score with thromboprophylaxis, compared with those without thromboprophylaxis, and (2) what the comparative VTE risk is in those with a low Padua score and a high Padua score, without thromboprophylaxis. The design is interesting and sound, with random samplings from a 6-month period in 2014 in a teaching hospital in Israel. Given that no VTE case was identified, these planned analyses become somewhat unrelevant. Nevertheless, this challenges the importance of hospital-associated VTE, and therefore indirectly of thromboprophylaxis. These provocative findings require a very strong methodology, and several major comments should be addressed.

Major comments

1. Identification and capture of VTE events

The main limitation of this study is its retrospective design. It is very surprising that there were no in-hospital diagnoses of pulmonary embolism among >700 medical inpatients. Reporting the number of chest CT and leg compression ultrasounds performed in this sample would be very important, given their routine use for in-hospital care.

Also, the capture of VTE events after discharge is not convincing enough. Authors should provide more details on the Clalit Health Services database, and how confident they can be not to have missed VTE events in the retrospective follow-up. Exploring “unexpected” death remains quite vague, especially retrospectively, as fatal PE can occur in patients with co-morbidities and not be recognized.

2. Representativeness of medical inpatients

The authors could provide more characteristics of the participants, such as the individual components of the Padua score. Some characteristics appear different from the Padua or ESTIMATE cohorts the authors cite, such as the low proportion of cancer (4-7%, vs. 20-27%). Overall, I would like to be convinced that included participants were acutely ill medical inpatients, and not rehabilitation or more geriatric inpatients. A sampling-weighted mortality estimated would also be interesting here.

3. Definition of thromboprophylaxis

Could the authors provide the study operational definition for thromboprophylaxis? Was there a minimum duration, was it for specific drugs or doses?

4. Calculation of the Padua score

The authors provide little information on how the score was calculated. Given that its evaluation is part of the inclusion criteria, was it prospectively calculated and entered in the electronic medical chart by in-charge hospital-physicians? If it was retrospectively calculated, there is a potential for misclassification that goes beyond of the immobility item and this should be discussed. What definition of immobility did the authors use?

5. Choice of the Padua score

Why was the Padua score selected for this analysis? Other scores are valid and more simple to implement, such as the Improve score (Spyropoulos, Chest 2011) or the simplified Geneva score (Blondon, JTH 2020).

Minor comments

Did none of the low-risk Padua score inpatients receive thromboprophylaxis?

Was extended thromboprophylaxis used in some participants?

Why did the authors choose a time period in 2014, for a 2020 study?

I do not understand the second sample size calculation “In order to show that in the group with the low Padua score the VTE incidence is 1%, we would

need to recruit 644 patients (at a 1:3 ratio, i.e. 161 patients with a high Padua score and 474 witha low Padua score), in order to achieve power 80% and alpha of 5% (two-tailed test).” Did the author forget to describe the comparison arm here?

Were the 474 and 284 randomly sampled high-risk Padua score without thromboprophylaxis independent, or are there same individuals in both groups?

I don’t understand why the assessment of mobility by the attending physician would change the observed incidence of VTE, given that most participants did not receive thromboprophylaxis anyway.

Table 1: past VTE instead of past deep VTE

Table 2 is improperly labeled as table 1.

Reviewer #2: Great manuscript in general;Fits into the difference the other manuscript the author mention (Geneva Score)

One comment the authors should address: Could a difference with regard to the underlying disease being responsible for the difference within the studies; eg in this analysis there is a really small number of renal disease patients, hematooncological patients.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2020 Jul 6;15(7):e0235683. doi: 10.1371/journal.pone.0235683.r002

Author response to Decision Letter 0

2 Jun 2020

Monday, June 1, 2020

Dear PLOS ONE Editorial Office,

First, I would like to thank the reviewers for their comprehensive and meticulous review and the PLOS ONE journal editors for their decision to reconsider the article for publication.

General comments:

1. The manuscript underwent extensive changes based on reviewer's comments. All changes have been highlighted in the corresponding file and labeled "revised manuscript with track changes". I will address to the specific points of the reviewers in the following paragraph. Additional unmarked version of the article will also be submitted.

2. The financial disclosure was not change

3. The manuscript has been formatted according PLOS ONE style. Tables were incorporated into text; figures were removed within the manuscript file and formatted according PACE digital diagnostics in separate files. Reference has been formatted.

4. Repository Data will be available upon acceptation. I do not have a DOI or website to upload the repository data. I will need your assistance with that.

5. The full name of the ethics committee was included in the Methods section of the manuscript and in the submission form.

6. The Authors’ affiliations were corrected to ensure that each author is linked to an affiliation.

I will address each point of the reviewers.

Reviewer #1:

Major comments

1. Identification and capture of VTE events - The main limitation of this study is its retrospective design. It is very surprising that there were no in-hospital diagnoses of pulmonary embolism among >700 medical inpatients. Reporting the number of chest CT and leg compression ultrasounds performed in this sample would be very important, given their routine use for in-hospital care. Also, the capture of VTE events after discharge is not convincing enough. Authors should provide more details on the Clalit Health Services database, and how confident they can be not to have missed VTE events in the retrospective follow-up. Exploring “unexpected” death remains quite vague, especially retrospectively, as fatal PE can occur in patients with co-morbidities and not be recognized. –

a. “The main limitation of this study is its retrospective design” – We address this in the limitation paragraph. “This was a retrospective study which on one hand presents a disadvantage in design but on the other hand, works to our advantage since there was no need to obtain the patients signed consent to participate in the study as required in the previous studies (Padua and Geneva). Hence, our study included seriously ill patients at high risk of symptomatic VTE and VTE related death in which we would not have been able to obtain signed consent if a prospective design was adopted. This population probably reflects reality more accurately”.

b. “It is very surprising that there were no in-hospital diagnoses of pulmonary embolism among >700 medical inpatients. Reporting the number of chest CT and leg compression ultrasounds performed in this sample would be very important, given their routine use for in-hospital care” – Our study, as opposed to others, didn’t search for asymptomatic VTE. The routine use of VTE diagnosis used in our hospital are Chest CTA for PE and US doppler for Distal DVT when suspected. Alternative modalities such as Transesophageal Echocardiography and Ventilation perfusion scan are used when C/I appear as per guidelines. We cannot provide information regarding patients who seek medical care or complain due to PE or DVT and discharge with a wrong diagnosis. It is unlikely that patients will not seek medical therapy again when PE/DVT was missed.

c. “The capture of VTE events after discharge is not convincing enough. Authors should provide more details on the Clalit Health Services database, and how confident they can be not to have missed VTE events in the retrospective follow-up” We address this issue in the limitation section and updated the paragraph. “Clalit Health Services is the largest of the four health funds with around 3.8 million insured members, 54% of the Israeli population. The HMO's computer system constantly updating medical information from all medical services including other health service organizations and therefore the risk of missing vital information is significantly low. Furthermore, when we suspected that vital medical information was incomplete or missing, we contacted the patient directly”.

d. Exploring “unexpected” death remains quite vague, especially retrospectively, as fatal PE can occur in patients with co-morbidities and not be recognized. – All fatality cases were explored reveal 8 unexpected death in the high-risk group (8/35, 22.8%) and 4 unexpected deaths in the low-risk group (4/17, 22.5%). This indicates no difference between the high and low risk groups in the incidence of unexpected death. The paragraph has been changed accordingly.

2. Representativeness of medical inpatients - The authors could provide more characteristics of the participants, such as the individual components of the Padua score. Some characteristics appear different from the Padua or ESTIMATE cohorts the authors cite, such as the low proportion of cancer (4-7%, vs. 20-27%). Overall, I would like to be convinced that included participants were acutely ill medical inpatients, and not rehabilitation or more geriatric inpatients. A sampling-weighted mortality estimated would also be interesting here. – Data obtained from four internal medicine departments. Geriatric patients were included since they are hospitalizing in internal medicine wards in our medical center. Rehabilitation patients were not included, they hospitalize in different ward. We do not have oncology ward so patients with VTE due to malignancy are hospitalizing in internal medicine wards. The average age was 75y. The proportion of cancer patients in our study, in our opinion, reflect the reality better than cited reports.

3. Definition of thromboprophylaxis - Could the authors provide the study operational definition for thromboprophylaxis? Was there a minimum duration, was it for specific drugs or doses? Thromboprophylaxis was defined as once daily treatment with an Enoxaparin, a low molecular weight heparin, at a dose of 0.5-1 mg/kg throughout the hospitalization for VTE prevention. This sentence was added to the method paragraph.

4. Calculation of the Padua score - The authors provide little information on how the score was calculated. Given that its evaluation is part of the inclusion criteria, was it prospectively calculated and entered in the electronic medical chart by in-charge hospital-physicians? If it was retrospectively calculated, there is a potential for misclassification that goes beyond of the immobility item and this should be discussed. What definition of immobility did the authors use? The Padua score was calculated prospectively and entered in the electronic medical chart by the attending hospital-physicians upon patients arrival to the ward. This sentence was added to the method paragraph.

5. Choice of the Padua score - Why was the Padua score selected for this analysis? Other scores are valid and more simple to implement, such as the Improve score (Spyropoulos, Chest 2011) or the simplified Geneva score (Blondon, JTH 2020). – We agree that all predictive models should be re-asses geographically for cost-benefit, efficiency and safety. We analyzed the Padua model since clalit health service, as with other HMO worldwide, proclaimed this model as quality measure for internal wards

Minor comments

1. Did none of the low-risk Padua score inpatients receive thromboprophylaxis? – Correct

2. Was extended thromboprophylaxis used in some participants? – Thromboprophylaxis defined as VTE treatment throughout the hospitalization and not further.

3. Why did the authors choose a time period in 2014, for a 2020 study? – It was the second year that all of the medical records were computerized, and the Padua score was applied.

4. I do not understand the second sample size calculation “In order to show that in the group with the low Padua score the VTE incidence is 1%, we would need to recruit 644 patients (at a 1:3 ratio, i.e. 161 patients with a high Padua score and 474 with a low Padua score), in order to achieve power 80% and alpha of 5% (two-tailed test).” Did the author forget to describe the comparison arm here? Comparison arm was done in the first sentences of the paragraph comparing the PEP in treated vs non-treated groups. “We estimated a VTE risk of 5% in our patients with PPS ≥4 points. In order to show that in the group that received thromboprophylaxis, the incidence of VTE decreases by approximately 80%, 568 patients were enrolled (284 in each group) in order to achieve power of 80% and alpha of 5% (two tailed test)”. The second analyses were comparing the High vs Low Risk group.

5. Were the 474 and 284 randomly sampled high-risk Padua score without thromboprophylaxis independent, or are there same individuals in both groups? Same individuals in both groups

6. I don’t understand why the assessment of mobility by the attending physician would change the observed incidence of VTE, given that most participants did not receive thromboprophylaxis anyway. – Mobility assessment would contribute 3 points to the Padua score. Incorrect filling of this criteria will result in placing the patient to the wrong risk group which then influence whether the patient will receive or not receive thromboprophylaxis. This may affect the incidence of the primary end points. Therefore, we explained it in the limitation paragraph.

7. Table 1: past VTE instead of past deep VTE – Corrected

8. Table 2 is improperly labeled as table 1. – Corrected

Reviewer #2:

1. Could a difference with regard to the underlying disease being responsible for the difference within the studies; eg in this analysis there is a really small number of renal disease patients, hematooncological patients. – The data in the study were randomly taken from four internal wards and included geriatric patients. The prevalence of co-morbidities among our patients did not differ when we compared it to other periods (we asses it follow reviewer comment) and we believe it faithfully represent our real population. Our patients may differ from other population worldwide, but this is exactly the message we want to convey from our research. Prior implement comprehensive and routinely treatment strategy for all hospitalized patients, the real incidence of VTE should be re-asses based on specific population or geographical areas. Previous studies have demonstrated a marked difference in the incidence of VTE events, some of which are probably explained by differences in the patient population.

Sincerely,

Dr. Koren Ofir

Attachment

Submitted filename: response to reviewers 01.06.2020.docx

Click here for additional data file. (22.3KB, docx)

Decision Letter 1

Raffaele Serra

22 Jun 2020

Low Venous Thromboembolism Incidence in High Risk Medical Patients in an Israeli Hospital. Can Risk assessment be extrapolated to different populations?

PONE-D-20-10275R1

Dear Dr. Koren,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

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amended manuscript is acceptable.

Reviewers' comments:

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Comments to the Author

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Reviewer #2: All comments have been addressed

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: no further comments, all comments addresses in adequate manner and therefore the manuscript should be accepted as it is now

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Reviewer #2: No

Acceptance letter

Raffaele Serra

23 Jun 2020

PONE-D-20-10275R1

Low Venous Thromboembolism Incidence in High Risk Medical Patients in an Israeli Hospital. Can Risk assessment be extrapolated to different populations?

Dear Dr. Koren:

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