|Year : 2006 | Volume
| Issue : 2 | Page : 87-91
|Top ten articles in venous thromboembolism
Yaseen M Arabi, Abdulaziz Dawood, Ousama Dabbagh
Acting Chairman, Department of Intensive Care, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Yaseen M Arabi
College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, MC 1425,Acting Chairman, Intensive Care Department, King Abdulaziz Medical City P. O. Box 22490, Riyadh - 11426
| Abstract|| |
Emerging literature about venous thromboembolism (VTE) increased our understanding of the risk factors, diagnosis, therapy and prophylaxis of this serious medical condition. In this review, we examine new studies on the incidence and the risk factors for VTE in the critically ill patients, diagnostic approaches to VTE, the relation between VTE and cardiovascular risk and duration of therapy. Also, we will review the new evidence on the use of electronic reminders to improve the adherence to VTE prophylaxis and the risk of heparin-induced thrombocytopenia in patients receiving pharmacologic prophylaxis for VTE.
Keywords: Venous thromboembolism, heparin, prophylaxis
|How to cite this article:|
Arabi YM, Dawood A, Dabbagh O. Top ten articles in venous thromboembolism. Ann Thorac Med 2006;1:87-91
| Incidence and Risk Factors|| |
Cook DM, Crowther M, Meade C, Rabbat L, Griffith D, Schiff W, et al . Crit Care Med 2005;33:1565-71.
Critically ill patients represent a special group with high risk of deep venous thrombosis. In a prospective cohort study by Cook and colleagues from a closed university-affiliated intensive care unit, the investigators evaluated the prevalence, incidence and risk factors for proximal lower extremity deep venous thrombosis among critically ill medical-surgical patients. They enrolled consecutive patients ³ 18 years of age expected to be in intensive care unit for ³ 72 h and excluded patients admitted with trauma orthopedic surgery, pregnancy and life support withdrawal. Bilateral lower extremity compression ultrasound was performed within 48 h of intensive care unit admission, twice weekly and if venous thromboembolism was clinically suspected. Thromboprophylaxis was protocol directed and applied for all patients. Among 261 patients, the prevalence of deep venous thrombosis on ICU admission was 3% and the incidence was 10% over the ICU stay. The authors found four independent risk factors for ICU-acquired DVT: personal or family history of venous thromboembolism (hazard ratio 4.0, 95% confidence interval 1.5-10.3), end-stage renal failure (hazard ratio 3.7, 95% confidence interval 1.2-11.1), platelet transfusion (hazard ratio 3.2, 95% confidence interval 1.2-8.4) and vasopressor use (hazard ratio 2.8, 95% confidence interval 1.1-7.2). The occurrence of DVT was associated with a longer duration of mechanical ventilation ( P =0.03), intensive care unit stay ( P =0.005) and hospitalization ( P <0.001).
This is an important study that looked specifically at this group with high DVT risk. Despite universal prophylaxis, 10% of patients acquired DVT while in ICU. The study confirmed previous observations that personal history and family history are important risk factors for DVT. The study also found that end-stage renal disease was an independent risk factor for DVT. The importance of this risk factor was only recently recognized. In a registry of 77,000 patients with end-stage renal disease, the incidence ratio for PE was 2.1 for dialysis patients without comorbidity and 2.3 for all dialysis compared with the general U.S. population after adjusting for confounding comorbidity. In addition, the study made the novel observation that critically ill patients who received platelet transfusions appear to be at increased risk of DVT. Additionally, the study suggests that vasopressor administration predisposes to DVT, which the authors attributed to adrenergic vasoconstriction of peripheral blood vessels, reduced skin blood flow and decreased absorption of subcutaneous heparin prophylaxis. Strengths of this study include the prospective nature, the enrollment of consecutive eligible patients, 100% compliance with twice-weekly lower extremity ultrasound screening and performance and interpretation of the ultrasounds by experienced ultrasonographers who were blinded to patient characteristics.
Girard P, Sanchez O, Leroyer C, Musset D, Meyer G, Stern JB, et al . Chest 2005;128:1593-600.
Another study of Girard and collegues that determine the prevalence of DVT of lower limb that was diagnosed by compression ultrasonography (CUS) in patients with symptomatic pulmonary embolism (PE) diagnosed with spiral CT pulmonary angiography (CTPA) and to explore the risk factors for positive DVT results and the prognostic significance of such findings. The study was a prospective multicenter study of 1,041 patients with clinically suspected non-severe PE. Among the 290 patients with positive CT findings, who constitute the eligible population for the study, DVT signs or symptoms were present in 90 patients (32%). CUS detected DVT in 169 patients (60.1%), including 127 patients with proximal DVT. Multivariate analysis showed that an age > or = 70 years and the presence of DVT signs or symptoms were independent risk factors for positive CUS results. DVT symptoms and a history of venous thromboembolism were independent risk factors for proximal DVT. The 3-month risk of recurrent thromboembolic event or death was not significantly different among patients with and without DVT (6.5 vs. 2.7%, P =0.15).
This study improves our knowledge on the epidemiology of detectable DVT in patients with suspected PE and may limit the need for further testing because both DVT and PE are subgroup of thromboembolism disease and their treatments are essentially the same. The authors identify risk factors for detectable DVT in patients with PE, which may help define subpopulation with suspected PE, in whom screening for DVT is a frontline investigation, like elderly patients. Also, this study confirms the poor sensitivity of DVT signs and/or symptoms. Finding DVT among patients with confirmed PE was not found to have a significant impact on the risk of recurrence of venous thromboembolism events or death. Lower prevalence of DVT in this study could be explained in part by exclusion of patients with severe PE. Whether the presence the DVT acts as an independent risk factor for fatal PE after discontinuing the treatment in patients with symptomatic PE needs further prospective study.
| Diagnosis|| |
Perrier AP, Roy M, Sanchez O, Le Gal G, Meyer G, Gourdier AL, et al . N Engl J Med 2005;352:1760-8.
A study by Perrier and colleagues evaluated whether the use of D-dimer and multidetector-row CT (MRCT), without lower-limb ultrasonography (LL-US), might exclude PE. A total of 756 patients with clinically suspected PE from ER was included and followed for 3 months. Among the 82 patients with a high clinical probability of PE, multidetector-row CT showed PE in 78. Of the 674 patients without a high probability of PE, 34% had a negative D-dimer assay and an uneventful follow-up; CT showed PE in 109 patients. The 3-month risk of VTE in patients with negative CT and LL-US was 1.7%. The overall 3-month risk of VTE in patients without PE would have been 1.5% if the D-dimer assay and MRCT had been the only tests used to rule out PE and LL-US had not been performed.
First-generation single-detector-row helical CT scanners have 90% specificity but only 70% sensitivity for pulmonary embolism. This technique was subject to limited visualization of subsegmental PE, hence LL-US was recommended as an adjuvant strategy to a negative helical CT to increase the negative predictable value. Recently, MRCT scanners have been introduced and improved visualization of the segmental and subsegmental pulmonary arteries has been achieved, which may obviate the need for LL-US. That is exactly what this study proved, as the improvement of the overall detection rate of VTE by LL-US was marginal in this series (0.9% patients had DVT with negative MRCT). Furthermore, if those who had negative results on MRCT and ELISA plasma D-dimer were left untreated and were followed for 3 months only, 1.5% developed VTE even though LL-US was not used. The result of this diagnostic strategy is as good as pulmonary angiography in many reports. Therefore, forfeiting LL-US if this strategy is used would not be a major problem; in contrast, it may decrease costs, time and effort. We may face a significant challenge with this strategy, which is overdiagnosis, as MRCT may detect more peripheral subsegmental PE that are otherwise not detected by conventional CT. This has been addressed by the investigators, as they indicated that although they could not calculate the false positive rates (as no other gold standard was used), their overall PE rate was 26% as compared to 23% reported in previous reports. Another concern that arises in this study is that 25% of the screened patients were excluded. However; this study offers an alternative and fast approach to ER patients with suspicion of PE.This strategy needs to be validated by further larger studies.
Mathis GW, Blank A, Reissig P, Lechleitner J, Reuss A, Schuler A, et al . Chest 2005;128:1531-8.
An interesting multicenter study by Mathis and colleagues determined the accuracy of thorax ultrasound (TUS) in the diagnosis of PE (TUSPE). A total of 352 patients with suspected PE was examined in seven clinics. In all cases, CT pulmonary angiography (CTPA) was used as the reference method. In the event of discrepant findings, a combination of duplex sonography of the leg veins, echocardiography, ventilation/perfusion scintigraphy and a quantitative enzyme-linked immunosorbent assay or latex d-dimmer or a biopsy/autopsy was performed. Findings: PE was diagnosed in 194 patients. On TUS, 144 patients with PE were diagnosed. PE true-positive, n = 144; PE false positive, n = 8; PE true negative, n = 150; and PE false negative, n = 50. The sensitivity was 74%, specificity was 95%, positive predictive value was 95%, negative predictive value was 75% and accuracy was 84% at a prevalence of 55%. The sensitivity in patients with criterion 1 was 43% and a specificity of 99%. The authors concluded that "TUS is a noninvasive method to diagnose peripheral PE and, in the absence of CTPA, it is a suitable tool to demonstrate a PE at the bedside and in the emergency setting."
This clinical study shows that the chest sonography may achieve importance in the diagnosis of PE with positive predictor value of 95%, but TUS missed PE in 25% of patients. The sonomorphology of inflammatory pulmonary condition and neoplasm should be considered when scanning patients suspected with PE. A majority of ICU patients was excluded for technical reasons. With portable ultrasound systems, the patient can be examined at the bedside. Also, in case of pregnancy, renal failure, contrast allergy, TUS may be an alternative to CT scan with concurrent echocardiography and duplex sonography of veins increase the diagnostic accuracy of sonographic procedures. Further, large multicenter study including critically ill patients to validate these findings may give us more insight result.
Parambil JG, Savci CD, Tazelaar HD, Ryu JH. Chest 2005;127:1178-83.
Pulmonary infarction is usually associated with pulmonary thromboembolism; it can occur with other disorders such as vasculitis, angioinvasive infections, sickle-cell disease, tumor embolism and pulmonary torsion. A cohort retrospective study by Parambil and colleagues identified the causes and presenting features of pulmonary infarctions diagnosed by surgical biopsy in a consecutive series of patients: forty-three encountered at a single institution over a period of 7 years - January 1996 through December 2002; thirty-five patients (81%) had a smoking history; twenty-eight patients (65%) presented with solitary or multiple lung nodules/masses of undetermined etiology. The underlying cause was identifiable in 31 cases (72%), based on a review of clinical, laboratory, radiologic and histopathological data. The two most common causes were pulmonary thromboembolism (18 cases, 42%) and pulmonary infections (5 cases, 12%). Thromboembolic pulmonary infarctions typically presented as solitary or multiple nodules located in the subpleural regions. Other causes included diffuse alveolar damage in two cases (5%); pulmonary torsion in two cases (5%); and one case each of lung cancer, amyloidosis, embolotherapy and catheter embolism. In 12 cases (28%), the underlying cause was not directly identifiable but was probably due to previous pulmonary thromboembolism.
This data provides new insight into the spectrum of causes of pulmonary infarction. Pulmonary infarction usually results from pulmonary thromboembolism; however, one-third of pulmonary infarction in this cohort resulted from a variety of nonthromboembolic causes. The occurrence of pulmonary infarction caused by lung cancer was rare in this cohort. There are potential biases in evaluating the causes of pulmonary infarction, since the diagnosis of pulmonary infarction was based on a surgical lung biopsy. Thromboembolic infarction is probably under-represented when compared to the actual incidence, infection, vasculitis; and other causes of pulmonary infarction usually do not require lung biopsy for diagnosis. This cohort did not include any patient with pulmonary infarction resulting from vasculitis, Swan-Ganz catheter More Details use or sickle cell disease.,
| Complications|| |
Becattini CG, Agnelli P, Prandoni M, Silingardi R, Salvi MR, Taliani R, et al . Eur Heart J 2005;26:77-83.
A study by Becattini and colleagues evaluated the incidence of cardiovascular events in the long-term clinical course of patients with a first episode of PE. A total of 360 patients was prospectively studied and was followed for a median of 38 months: 209 with idiopathic PE (IPE) and 151 with PE associated with transient risk factors (PETRF). Outcomes were cardiovascular events (recurrent VTE, acute MI, stroke, sudden otherwise unexplained death), cardiovascular death and death due to any cause. More cardiovascular events occurred in patients with IPE than those with PETRF (7.5% patient-year vs. 3.1% patient-year; RR 2.0; P =0.006). This was more pronounced with arterial cardiovascular events (3.2 vs. 0.4% patient-year; RR 7.2; P =0.001). IPE was an independent predictor of cardiovascular events after adjusting for age. The study investigators concluded that cardiovascular events are more common in patients with IPE than in patients with PETRF.
This is a very important study that differentiates between two groups of PE: one without risk factors (IPE) and the other with transient risk factors (PETRF) such as trauma. The hypothesis is that those with IPE would be more susceptible to cardiovascular events, i.e., atherosclerosis. Goldhaber has identified that atherosclerosis and IPE share common risk factors such as obesity, smoking and hypertension. The association between PE and atherosclerosis has been studied in a recent report, which found that carotid plaques were more prevalent among those with IPE than those with identifiable risk factors; however, this was a case-control study. This current Italian study was the first to explore this association in a prospective fashion. The interesting finding is that cardiovascular events were the major killers of patients with IPE, which may spark a debate about long-term anticoagulation or other cardiovascular risk modifying agents in this group. Though the percentage of smokers and hyperlipidemic patients was comparable in the two groups, more IPE patients were diabetic (10% vs. 2%; P =0.02), which may be a confounding factor. This was actually addressed by the study since multivariate analysis revealed that IPE was the only independent risk factor for cardiovascular events in this group, taking in to account diabetes, smoking, age and hyperlipidemia. The high incidence of arterial events in patients with IPE is biologically plausible, given the common risk factors for arterial and venous diseases. This study explores wider horizons of long-term follow-up of not only venous complications but also arterial atherosclerotic complications for patients with PE.
| Treatment|| |
Ost D, Tepper J, Mihara H, Lander O, Heinzer R, Fein A. JAMA 2005;294:706-15.
A meta-analysis study evaluated the evidence regarding the duration of anticoagulation therapy for VTE; it quantifies the risks and benefits of extending the duration of anticoagulation in patients with VTE (17). The included studies were randomized controlled trials. Excluded studies were those enrolling only pure populations of high-risk patients. Two independent reviewers assessed each article for inclusion and exclusion criteria. Fifteen of 67 studies were included in the analysis. If patients in the long-term therapy group continued receiving anticoagulation, the risk of recurrent VTE with long- vs. short-term therapy (median duration for long term and short term was 6 months and 1.5 months respectively) was reduced (weighted incidence rate, 0.020 vs. 0.126 events/person-year; P <0.001). If anticoagulation in the long-term therapy group was discontinued, the risk reduction was less pronounced (weighted incidence rate, 0.052 vs. 0.072 events/person-year; P =0.009). The risk of major bleeding with long- vs. short-term therapy was similar ( P =0.21).
This systematic review helps to synthesize and it supplements the existing body of evidence regarding the optimal duration of therapy. The power of these studies to detect a difference was limited by pooling the result of many studies; this meta-analysis suggests that long-term therapy reduces the risk of recurrence. This is consistent with the finding of previous meta-anaylasis. Based on the limited available evidence, it appears that 6 months or more of treatment for patients at higher risk may be warranted. The bleeding risk in absolute and relative terms is very low. This suggests that physicians should focus on risk stratification and that for certain high-risk populations, lifelong anticoagulation may be needed. The harm that is associated with each adverse outcome must be considered; intracranial bleed must be weighted heavily compared to recurrence of VTE of lower limbs. Meta-analysis cannot answer these types of questions but it can provide some of the information necessary to help make good decisions.
| Prophylaxis|| |
Yalamanchili K, Sukhija R, Sinha N, Aronow WS, Maguire GP, Lehrman SG. Am J Ther 2005;12:293-9.
A systematic review of randomized controlled trials by Yalamanchili and colleagues assessed the efficacy of unfractionated heparin versus placebo and versus low-molecular-weight heparin in medical patients. These trials included patients with stroke, myocardial infarction, respiratory failure and infectious diseases. The authors excluded studies with a dose other than 10,000 or 15,000 U s.q. heparin, studies in which pneumatic compression stockings or aspirin was used, studies in which the randomization between the two groups was not clear and studies that included surgical patients. Studies were also excluded if there was no provision for investigation of all the patients in the study for deep venous thrombosis. The outcomes studied were deep vein thrombosis, pulmonary embolism, major bleeding and mortality. They identified five studies eligible for inclusion in the analysis for heparin versus placebo and eight studies for inclusion in the analysis comparing heparin with low-molecular-weight heparins. The analysis found both heparin 5000 U b.i.d. and heparin 5000 U t.i.d. to be effective for prevention of deep vein thrombosis. Heparin 5000 U t.i.d. was more effective than heparin 5000 U b.i.d. Relative risk for DVT was 0.4 (95% confidence interval 0.22-0.73) in studies comparing heparin 5000 U s.q. b.i.d. with placebo. Relative risk for DVT was 0.28 (95% confidence interval 0.21-0.38) in studies comparing heparin 5000 units s.q. t.i.d. with placebo. In studies comparing unfractionated heparin with enoxaparin, relative risk was 1.42 (95% confidence interval 0.99-2.05). Heparin 5000 U s.q. b.i.d. is less efficacious than low-molecular-weight heparins and unfractionated heparin 5000 U s.q. t.i.d. The difference in incidence of bleeding complication could not be assessed accurately in view of the wide confidence intervals.
This systematic review adds to the body of evidence about the efficacy of venous thromboembolism prophylaxis in medical patients. LMWH appears to be more effective, but this review could not answer conclusively whether the benefit of VTE prophylaxis outweighs the increased risk of bleeding. At present, the recommendations of the American College of Chest Physicians (ACCP) represent the most widely acceptable evidence-based guidelines. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy recommends that in hospitalized medical patients with congestive heart failure or severe respiratory disease or patients who are confined to bed and have one or more additional risk factors-including active cancer, previous VTE, sepsis, acute neurologic disease or inflammatory bowel disease-either LDUH (Grade 1A) or LMWH (Grade 1A) should be used.
Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov B, et al . N Engl J Med 2005;352:969-77.
Kucher and colleagues studied the impact of electronic computer alerts on VTE prophylaxis. A total of 2,506 patients was randomized to either intervention (1255) or control (1251) groups. Electronic alerts were sent to the treating team if patients achieved a certain risk score in the intervention group. The primary end point was VTE at 90 days. More patients in the intervention group than in the control group received mechanical prophylaxis (10.0 vs. 1.5%; P <0.001) or pharmacologic prophylaxis (23.6 vs. 13.0%; P <0.001). VTE occurred less in the intervention group than the control group (4.9 vs. 8.2%), which translated in risk reduction by 41% ( P = 0.001).
Despite the extensive data in this area, VTE prophylaxis continues to be underused. Goldhaber keeps surprising us with novel and solid research concepts. As previously identified by many studies, VTE prophylaxis gets frequently missed as the decision is influenced by human discretion. Physicians can easily miss this important aspect due to workload, inexperience and in some instances, misjudgment. Alerting the treating personnel to this aspect by a robust electronic system (that is not subject to human errors) such as the one presented in this study can ensure adherence to the widely accepted guidelines of VTE. This group was not only successful in increasing the use of prophylaxis as proven by many other trials, but it could couple that with a significant and favorable impact on outcome (90-day VTE). Despite these significant findings, many limitations exist, such as other potential confounding factors like physiotherapy and early ambulation, which could have been utilized more in the intervention group and were not accounted for in the study. Diagnostic bias may also be a factor since no diagnostic protocol was applied to this population, opening the way to variable physician-diagnostic behaviors. On a practical note, many hospitals do not have the capabilities to develop such computer programs that depend on integrated complicated systems, so reproducibility is an issue. Nevertheless; this study proves that the outcome can be favorably influenced by simple measures.
| Complications of prophylaxis|| |
Martel NJ, Lee, Wells PS. Blood 2005;106:2710-5.
Heparin-induced thrombocytopenia (HIT) is an uncommon but a serious complication of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). However, there is a paucity of data regarding heparin-induced thrombocytopenia (HIT) in venous thromboembolism prophylaxis studies, particularly for comparing UFH with LMWH a systematic review by Martel and colleagues examined the incidence of HIT in surgical and medical patients receiving thromboprophylaxis with either UFH or LMWH. The review included all randomized and nonrandomized controlled trials comparing prophylaxis with UFH and LMWH and measuring HIT or thrombocytopenia as outcomes. HIT was defined as a decrease in platelets to less than 50% or to less than 100-109/L and positive laboratory HIT assay. Fifteen studies (7,287 patients) were eligible: 2 randomized controlled trials (RCTs) measuring HIT (1,014 patients), 3 prospective studies (1,464 patients) with nonrandomized comparison groups in which HIT was appropriately measured in both groups and 10 RCTs (4,809 patients) measuring thrombocytopenia but not HIT. Three analyses were performed and they favored the use of LMWH: (1) RCTs measuring HIT showed an odds ratio (OR) of 0.10 (95% confidence interval [CI], 0.01-0.2; P -0.03); (2) prospective studies measuring HIT showed an OR of 0.10 (95% CI, 0.03-0.33; P <0.001); (3) all 15 studies measured thrombocytopenia; the OR was 0.47 (95% CI, 0.22-1.02; P - 0.06). The review determined the absolute risk for HIT with LMWH was 0.2% and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery.
This important systematic review shows clearly the difference in HIT incidence with the use of UFH and LMWH in VTE prophylaxis. Because most of the included studies were performed in patients after orthopedic surgery, the advantage of LMWH in non-orthopedic surgery patients in terms of predisposition to HIT cannot be ascertained. In fact, in a recent prospective cohort study (published after this systematic review) of 1,754 consecutive medical patients referred to 17 medical centers, the incidence of HIT was not different between UFH and LMWH. Further studies are needed to evaluate this important issue.
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