Venous thromboembolism in COPD hospitalized patients
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- Barba, R., Zapatero, A., Marco, J. et al. J Thromb Thrombolysis (2012) 33: 82. doi:10.1007/s11239-011-0646-x
Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for venous thromboembolism (VTE). We analyzed a large Spanish database to determine the incidence of VTE in these patients during hospitalization. A retrospective chart review of cohort of consecutive patients admitted with COPD as the primary reason for discharge in Spain between January 1st 2006 and December 31st 2007 was performed. For each patient, demographic data, risk factors for VTE and the diagnosis of VTE during hospitalization was recorded. We analyzed the clinical data of 313,233 adults with acute exacerbations of COPD admitted to the hospital at any public centre in Spain, in 2006 and 2007. We identify 3,562 new diagnosed VTE events among 270,840 COPD patients hospitalized more than two days (incidence 1.32%). Hospitalized-acquired VTE risk factors were male gender (odds ratio [OR] 1.77; CI95% 1.66–1.90), neoplasic disease (OR 2.93 CI95% 2.69–3.16, systemic arterial disease (OR 1.17 CI95% 1.10–1.36), decubitus ulcer (OR 1.19 CI95% 1.01–1.43), diabetes (OR 0.74 IC95% 0.69–0.81), and atrial fibrillation (OR 0.79 CI95% 0.72–0.87). VTE appears as a major threat to patients admitted for acute exacerbation of COPD, and pharmacologic prophylaxis should be considered in all high risk situations.
KeywordsVenous thrombosisCOPDHospitalized patients
Venous thromboembolic disease (VTE) is an important health-care problem, resulting in significant mortality, morbidity and resource expenditure. It is considerate the most common preventable cause of hospital death [1, 2]. The implementation of thromboprophylaxis strategies provides benefit to patients, and should also help protect their caregivers and hospitals for legal liability . Unfortunately, despite the number of randomized trials demonstrating the benefit of thromboprophylaxis [3–6], low adherence is frequent, and the number of patient with VTE is higher than expected [7–10], specially in medical populations .
A number of reasons may account for this situation: the apparent greater heterogeneity of medical patients compared with surgical patient may limit accurate assessment of the overall burden of VTE in medical patients; identifying individual medical patient at high risk for VTE may seem difficult. Finally many internist overlook prophylaxis for reasons that remain uncertain, and thromboprophylaxis remains under-prescribed in acutely ill medical patients [9, 11, 12].
Largely on the basis of postmortem studies, pulmonary emboli have been implicated as an etiologic factor in the acute and chronic respiratory failure of chronic obstructive pulmonary disease (COPD) . Because of the presence of some concomitant risk factors such as immobilization, bronchial superinfection, patients who are admitted for acute exacerbations of COPD are generally considered to be at moderate-high risk for the development of venous thromboembolism.
The objective of this study was to identify the proportion of patients with acute exacerbation of COPD who experience VTE events during the admission and to characterize the prevalence of previously identified risk factors for VTE. We also tried to estimate the cost and impact of this complication during admission.
Materials and methods
The study included all patients admitted to all acute care hospital of the Public Health Service through an emergency department in Spain between 1st January 2006 and 31st December 2007 with COPD as the primary reason for discharge. All elective admissions and elective transfers were excluded. Hospital discharge data were obtained from the CMBD (basic minimum data set). CMBD contains sociodemographic and clinical data for each documented hospital stay including: gender and age, primary and secondary diagnoses (according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code); primary and secondary procedures; admission and discharge status; length of stay; and hospital characteristics (group 1 less than 150 beds; group 2: 150–200 beds, group 3: 200–500 beds; group 4: 500–1,000 beds; group 5 more than 1,000 beds). For every patient, a diagnosis-related group (DRG) was identified. DRGs are a way of classifying patient hospitalizations by diagnosis and procedure on the assumption that similar costs are expended on patients by using similar resources. The CMBD registry is compulsory for every patient admitted to a hospital of the Spanish National Health Service, a system that cares for more than 90% of the country’s population.
Cases were selected if they were discharged with the diagnosis of COPD (code DRG 88: CHRONIC OBSTRUCTIVE PULMONARY DISEASE, 540: RESPIRATORY INFECTIONS & INFLAMMATIONS WITH MAJOR COMPLICATIONS or 541: RESPIRATORY DISORDERS EXCEPT INFECTIONS, BRONCHITIS, ASTHMA WITH MAJOR COMPLICATIONS; DRG-AP.21 version). The primary diagnosis of COPD was identified using ICD-9-MC codes in the primary diagnosis field: 491.0, 491.1, 491.9, 491.20, 491.21, 491.22, 496, 518.8, 518.81, and 518.9.
The main outcome was a diagnoses of deep vein thrombosis (DVT) or pulmonary embolism (PE) during hospitalization. Patients whose duration of hospital stay was <48 h and patients whose main code diagnosis was DVT or PE were excluded (ICD-9-MC Pulmonary Embolism diagnosis codes: 415.11, 415.19, 451.11, 451.19, ICD-9-CM Deep Vein Thrombosis diagnosis codes: 451.2, 451.81, 451.9, 453.40, 453.41, 453.42, 453.8, 453.9, or DRG code: 128 —Deep vein thrombophlebitis or DRG code: 78 —Pulmonary embolism). Screening for VTE was not performed routinely in these patients.
The Age Adjusted Charlson Co-morbidity Index (CCI) was computed for each patient. This index reflects the number and importance of comorbid diseases, relies on ICD-9-CM categories, and was used to adequately adjust for severity of illness [14, 15].
The following risk factors for VTE were identified using ICD-9-MC codes in any primary or secondary diagnosis field: Cardiac disease ICD-9-MC:398.91, 404*, 402.11, 402.91,428–428.9, Dementia ICD-9-MC: 290–290.9, Cancer ICD-9-MC:140.0–172.9,174.0–195.8, 200–208.9, V10.0–V10.9, Diabetes ICD-9-CM: 250.00–250.99, Chronic renal failure ICD-9-CM: 585–586.99, 582.0–582.9, 583.0–583.7, 588.0–588.9 Obesity ICD-9-CM: 278.00–278.09, Hypertension ICD-9-CM 401.0, 401.1, 401.9, Anaemia ICD-9-CM: 280.00–285.99, Malnutrition ICD-9-CM:260–263.9, Tobacco ICD-9-CM:305.10, Atrial fibrillation ICD-9-CM: 427.3–427.32. The following acute medical illness were considered when they occurred during the index hospitalization, and then only primary diagnoses ICD-9-MC codes were used: Acute Congestive heart failure ICD-9-MC: 398.91, 404*, 402.11, 402.91,428–428.9, Acute renal failure ICD-9-MC: 403.11, 403.91,404.12, 585–586, Acute respiratory failure ICD-9-MC: 518.81–518.84. Acute infectious disease ICD-9-MC: 001–137, 460–466, 487–487.8 and Cerebrovascular disease ICD-9-MC: 430–438. Also the presence of decubitus ulcer ICD-9-MC: 707.0–707.09 was considered. These are based in the ACCP guideline criteria for being at risk for VTE based on medical-illness risk factors .
Differences in the distribution of various demographic and clinical characteristics between patients who presented VTE during hospitalization and those who no were diagnosed were examined. We used the Chi-square test for categorical variables with the Yates correction, and the Fisher’s exact test for dichotomic variables when the expected value of a cell was less than 5, and Student t for quantitative variables. All the univariate analyses were carried out after adjusting for age and gender. The odds-ratios (OR) and 95% Confidence Intervals (CI) were estimated from the regression coefficients. The most clinically relevant variables and those with statistical significance (P < 0.1) in the univariate analyses of every subgroup were introduced in the logistic regression analyses, to determine independent risk factors for developing VTE during hospitalization.
All statistical analyses were carried out with the use of a SPSS Software version 16.
During the study period, there were 313,233 patients’ discharges with acute exacerbation of COPD. Of these, 270,840 (86.5%) met the basic inclusion criteria. On the other hand 42,482 patients (14.5%) were excluded: 6,165 (2.0%) cases because they had a diagnosis of PE or DVT present at admission, 35,902 cases (11.5%) who were discharged before 48 h; and 415 patients (0,13%) who present both conditions at the same time. Median age of patients was 73.92 years (SD, 12.97); 70.3% of the patients were men. The median stay was 10.75 days (SD, 9.18). A CCI ≥ 2 was present in 22.8% of the cases.
VTE during admission (N = 3,562)
No VTE (N = 267,278)
Age (year); SD
Duration of hospital stay (days); SD
Charlson index >2
Admission cost (€) (SD)
Univariate logistic analysis of potential risk factor and acute clinical conditions for VTE in the internal medicine patients
VTE during admission N = 3562 (%)
No VTE N = 267,278 (%)
OR (95% CI)a
Age (>76 years)
Chronic renal failure
Acute respiratory failure
Acute heart failure
Acute renal failure
Independent factor associated to VTE during admission
Chronic renal failure
Despite the availability of proven effective preventative strategies, VTE continues to be a cause of significant death and disability among hospitalized medical patients [16–18]. We examined more than two hundred thousand of consecutive hospitalizations of adult COPD patients in Spain, over a 2-year period, and we have seen than almost one patients out of 100 suffer a VTE during hospitalization. This rate of complication is more than quadruple that the rate demonstrated in the surgical population, based in study which used a similar methodology, where authors observed that 0.24% of hospitalized patients after a surgical procedure suffered a VTE during hospitalization .
COPD patients who presented VTE during hospitalization have a significantly poorer clinical outcome, with a rate of death more than double, and an average cost for hospitalization 25% higher. The incremental cost of these patients is almost 500€ per patient. Cost associated with VTE treatment and diagnoses could contribute to the overall cost of patient care, however this study do not examined the cost of care for each complication.
Our analysis shows that the presence of some risk factors as gender (male), cancer, the presence of decubitus ulcer, or arterial disease are independently associated with higher risk of VTE during admission. VTE is a frequent complication in cancer patients [20, 21]. Although the true rate of VTE in hospitalized cancer patients is virtually unknown, because of the surprising lack of information in most all studies, previous studies have suggested that patients with cancer have up to sixfold increase risk of VTE compare with those without cancer . The most common situations that make cancer patients at higher risk of VTE include immobilization, surgery, chemotherapy and insertion of central venous catheters as well as cancer per se. In our series neoplasic patients have double risk of VTE than patients without this disease.
Atrial fibrilation, chronic renal failure, diabetes mellitus were evidenced as protective factors in the present study. Patients with atrial fibrillation used to be treated with anticoagulants. Chronic renal failure is a known risk factor for thrombosis. A possible explanation for this is that appropriate thromboprophylaxis is better characterized for these patients , and most of the doctors used VTE prophylaxis in these patients .
We found that some conditions were not associated with VTE such as obesity, acute infection or respiratory failure. Obesity was not found to be a risk factor for VTE in previous studies [3, 25]; however other studies the (SIRIUS , a prospective nurses health study  and a prospective Swedish cohort study ) suggested that obesity was linked to VTE. The MEDENOX study  showed that acute infection was in independent risk factor in the generation of venous thrombosis, but in our series the association did not reach the statistical signification (OR 1.02 95% CI 0.94–1.11). Acute respiratory disease was not related with the risk of VTE in our study, in keeping the findings from MEDENOX , which showed that in 1,102 acutely ill, immobilize general medical patients, there was no association between acute respiratory disease and VTE (relative risk 1.26 95% CI 0.85–1.87).
One explanation to the high incidence of VTE in COPD patients could be the underutilization of prophylaxis in these patients. The reasons for this underutilization are difficult to explain , but some authors suggest that the most common reason appears to be a lack of awareness of both the disease and evidence-based guidelines [9, 30, 31]. The complexity of the existing guidelines may also lead to the underused of prophylaxis. A further factor is that many hospitals do not have formal protocols for the prevention of VTE in at-risk medical patients. VTE prophylaxis in the Spanish centres was more common in surgical patients than in medical patients . The ENDORSE  study shows that it is still necessary to extend the VTE prophylaxis beyond the hospitalization period to a significant number of patients (29%) at high risk of VTE, particularly in medical wards.
The limitations of this study should be noted. We relied on administrative data which may have included coding errors. However some studies have shown that data obtained from a large prospective series of consecutive patients in the RIETE registry is very similar to the CMBD database [33, 34]. In addition, our analysis did not account for the presence or absence of previous anticoagulation, prophylaxis during hospitalization or contraindications for anticoagulation, therefore we are not able to determine how many of our patients had an adequate prophylaxis regime. We know that just 60% of patients who met criteria to receive prophylaxis actually received it [7, 9, 31, 35]. We suppose that many of our VTE patients have not received adequate prophylaxis, but the design of our study could not permit us to know this certainly. Thus, the identification of patients with hospital acquired DVT or PE was based on symptoms and there is no information about asymptomatic VTE, some of which might easily manifest it clinically post-discharge and might come in for another hospitalization with an acute DVT which would be excluded from the analysis. So we think that the incidence reported here probably represents the lower threshold of actually hospital acquired DVT/PE.
In summary, the high prevalence of VTE reported in the present study shows that VTE is a common clinical problem in COPD hospitalized patients. Increased awareness of the risk factors in medical wards may improve patient care by encouraging the use of thromboprophylaxis . This may help reduce the risk of long-term complications, and result in better outcomes in these patients. To reduce this problem it is also necessary to design a new set of hospital strategies. The institution of computer-alert programs could have the potential to increase physicians` use of prophylaxis and reduce the rate of VTE among hospitalized patients . The rate of VTE could also be reduced with extended post hospital discharge thromboprophylaxis in high and very high risk patients . Based on the large number of patients affected, our data add strength to the argument that VTE prevention should be high on the list of priorities when health care policies are being formed.
The authors thank the Spanish Minister of Health for the permission to obtain of the data.
Conflicts of interest