Plain language summary
Heparin to prevent deep vein thrombosis or pulmonary embolism in acutely ill medical patients (excluding those with stroke or myocardial infarction)
Blood clots may form in the veins of patients who are admitted to hospital suffering from an acute medical illness. These types of blood clots are referred to as deep vein thromboses (DVT) and they may break free from the blood vessel wall and travel to the lungs and cause death, at which point they are referred to as a pulmonary embolism (PE). These types of blood clots and their prevention have been thoroughly studied in surgical patients but not as much in non-surgical, medical patients, who make up a greater proportion of hospital patients. Medical patients differ from surgical patients with regard to their health, the progression of clots and the impact that preventative measures can have. The extensive experience from clot prevention studies in surgical patients is therefore not necessarily applicable to non-surgical patients.
Heparin is a blood thinning drug, which has been shown to reduce the occurrence of blood clots in patients after they have had surgery. Heparin exists in two forms, the original unfractionated (UFH) form and a newer form called low molecular weight heparin (LMWH). The aim of the current review is to determine the effectiveness and safety of heparin (UFH or LMWH) to prevent DVTs and PEs in non-surgical, medical patients admitted to hospital, excluding those admitted to hospital with a heart attack or stroke or those requiring admission to an intensive care unit. The outcomes investigated in this review were DVT, PE that did not cause death, PE that resulted in death, combined non-fatal and fatal PE, all-cause death, bleeding complications and thrombocytopaenia, which is a condition that can be caused by heparin and results in decreased platelets in the blood.
This review of 16 trials in 34,369 non-surgical patients who suffered an acute medical illness found that heparin reduced the number of patients suffering DVTs but also increased the risk of bleeding complications when compared to participants that received a placebo or no medication. We had some concerns over how reliable the results were from the unblinded studies, which made up just under half of the studies. Also, most of the studies were lacking explanations of how the allocation of the treatments was performed. The lower risk of PEs (when combining those that caused death and those that did not) with heparin could have been a chance effect. There was no clear evidence of a difference in the rate of death or thrombocytopaenia. The review also found that patients who were given LMWH developed fewer DVTs and fewer bleeding complications compared with those given UFH, leading to the conclusion that LMWH is more effective and carries a lower risk of adverse events in preventing blood clots than with UFH. There was no clear evidence of differences between LMWH and UFH for PE, death or thrombocytopaenia.
L’héparine dans la prévention des thromboses veineuses profondes ou des embolies pulmonaires chez les patients en hospitalisation médicale en phase aiguë (à l'exclusion des AVC et des infarctus du myocarde)
Des caillots sanguins peuvent se former dans les veines de patients qui sont hospitalisés dans un service de médecine pour une maladie aiguë. On parle alors de thrombose veineuse profonde (TVP). Ces caillots peuvent se détacher de la paroi du vaisseau sanguin et se déplacer jusqu'aux poumons, provoquant alors une embolie pulmonaire mortelle. Leur formation et leur prévention ont été largement étudiées chez les patients de chirurgie, mais pas de façon aussi approfondie dans un contexte non chirurgical, qui concerne pourtant une plus grande proportion des patients hospitalisés. Les patients des services de médecine différent des patients de chirurgie en termes d’état de santé, de progression de caillots sanguins et d'impact potentiel des mesures préventives. L’important corpus d'expérience issu des études de prévention des thromboses chez les patients de chirurgie ne leur est donc pas nécessairement applicable.
L'héparine est un médicament qui fluidifie le sang, avec pour effet démontré de réduire la formation de caillots sanguins après une opération chirurgicale. Il existe deux formes d'héparine : la forme d’origine, non fractionnée (HNF), et une nouvelle forme appelée héparine de bas poids moléculaire (HBPM). L'objectif de la présente revue est de déterminer l'efficacité et l'innocuité de l'héparine (HNF ou HBPM) pour prévenir les TVP et les embolies pulmonaires chez les patients hospitalisés dans les services de médecine et n’ayant pas subi d’opération chirurgicale, à l'exclusion de ceux hospitalisés pour un infarctus du myocarde ou un accident vasculaire cérébral (AVC) ou reçus en soins intensifs. Les critères de jugement étudiés dans cette revue étaient les TVP, les embolies pulmonaires non fatales aussi bien que fatales, la mortalité toutes causes confondues, les complications hémorragiques et la thrombopénie (baisse du nombre de plaquettes sanguines, qui peut être causée par l'héparine).
Cette revue de 16 essais, portant sur 34 369 patients souffrant d'une maladie aiguë et hospitalisés dans un service de médecine, a montré que l'héparine réduisait le nombre de cas de TVP, mais augmentait par ailleurs le risque de complications hémorragiques par rapport aux participants ayant reçu un placebo ou sans traitement médicamenteux. La fiabilité des résultats des études ouvertes, qui représentaient un peu moins de la moitié des études, nous a paru sujette à caution. De plus, la plupart des études ne comportaient aucune explication sur la manière dont l'assignation des traitements avait été réalisée. Le risque plus faible d’embolie pulmonaire (combinaison des embolies fatales et non fatales) avec l'héparine pourrait être fortuit. Il n'y avait aucune preuve probante d'une différence dans le taux de décès ou de thrombopénie. La revue a également révélé que les patients qui étaient traités à l'HBPM développaient moins de TVP et moins de complications hémorragiques que ceux recevant de l'HNF, ce qui conduit à la conclusion que l'HBPM est plus efficace et comporte un plus faible risque d'événements indésirables que l’HNF pour la prévention des thromboses. Il n'y avait aucune différence claire entre l'HBPM et l'HNF en ce qui concerne les embolies pulmonaires, les décès ou la thrombopénie.
Notes de traduction
Translated by: French Cochrane Centre
Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�
Description of the condition
Venous thromboembolism (VTE) is a major health problem, the significance and seriousness of which is often not fully appreciated. VTE is one of the most important preventable causes of morbidity and mortality in hospital patients, having an annual incidence of one per 1000 individuals (Dahlback 2008). Most clinicians, whatever their specialty, will experience patients with this condition.
Description of the intervention
During the past 40 years numerous studies have shown that UFH and LMWH are effective and safe for the prevention of VTE in surgical patients (Geerts 2008). This has led to the widespread use of these agents for thromboprophylaxis in surgical patients with a resultant reduction in the incidence of fatal PE (Cohen 1996). During the same period of time, there have been fewer trials investigating the benefits and risks of thromboprophylaxis in medical patients. Most of these studies have concentrated on specific conditions such as myocardial infarction (MI) (Collins 1996) and ischaemic stroke (Gubitz 2004).
How the intervention might work
Thrombosis results from a disturbance in the balance between pro-thrombotic and antithrombotic forces that exist within the blood stream. The pro-thrombotic forces include platelets and the formation of fibrin. There are two phases of normal haemostasis; the first phase is platelet activation and adhesion, and the forming of a 'platelet plug'. In parallel, the second phase results in the activation of a series of procoagulant clotting factors, which generate a burst of thrombin, formation of fibrin and stabilisation of the platelet plug, resulting in a thrombus. When this process becomes unregulated venous thrombosis may occur in any vein in the body, although it usually occurs in the deep veins of the lower limbs. People admitted to hospital with an acute medical illness appear to be particularly at risk of suffering from thrombosis of these lower limb deep veins.
Heparin (UFH and LMWH) binds to a naturally occurring anticoagulant, antithrombin (AT), via a pentasaccharide sequence. The heparin-AT complex inactivates thrombin (factor IIa) as well as coagulation factors Xa, IXa and XIa. As a direct result of inactivating or reducing the generation of thrombin, fibrin formation is inhibited, as is thrombin directed activation of coagulation factors V, VIII and XI. In addition, thrombin mediated platelet activation is attenuated (Garcia 2012). Therefore, heparin affects both the primary and secondary phases of thrombus formation and this is the rationale behind its use as a thromboprophylactic agent.
Why it is important to do this review
Unlike their surgical counterparts, it wasn't until the late 1990s and early part of the 21st century that physicians caring for general medical patients had convincing evidence of the efficacy and safety of thromboprophylaxis for their patients upon which to base prescribing decisions (Geerts 2008). We believe that this has resulted in the underuse of thromboprophylaxis in the medical setting (Alikhan 2001), and this continues to be a problem (Cohen 2008). The under use may in part explain the high incidence rate of fatal PE in this patient group (Alikhan 2004; Sandler 1989). This is an update of a review first published in 2009 (Alikhan 2009).
The aim of this review is to determine the effectiveness and safety of heparin (unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) thromboprophylaxis in acutely ill medical patients admitted to hospital, excluding those admitted to hospital with an acute myocardial infarction or stroke (ischaemic or haemorrhagic) or those requiring admission to an intensive care unit.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials comparing UFH with placebo or no treatment
Randomised controlled trials comparing LMWH with placebo or no treatment
Randomised controlled trials comparing UFH with LMWH
Types of participants
People over the age of 18 years admitted to hospital with an acute medical illness, for example:
*Studies that primarily involve cancer patients not in an acute medical setting are excluded, such as receiving chemotherapy in tandem with thromboprophylaxis. This is the subject of another Cochrane review (Di Nisio 2012).
Studies involving participants with only myocardial infarction or stroke are excluded because the risk of VTE differs in this population, and therefore the need for thromboprophylaxis. Collins 1996 and Geerts 2001 address these patient populations in reference to VTE and thromboprophylaxis.
Types of interventions
Participants randomised to receive UFH, LMWH, placebo or no treatment. Fondaparinux and other pentasaccharide agents were excluded from this review as they are addressed in another Cochrane review that is currently in progress (Song 2011).
Types of outcome measures
Asymptomatic or symptomatic deep vein thrombosis (DVT) of the lower limbs detected by fibrinogen uptake test, ultrasound, venography or plethysmography
Symptomatic non-fatal PE detected by ventilation perfusion scan, computed tomography, pulmonary angiography, or confirmed at autopsy
Major haemorrhage. As it was not possible to obtain a standardised definition of major bleeding, the study author's definition, where given, was used. See Characteristics of included studies for individual study definitions
Minor haemorrhage. As it was not possible to obtain a standardised definition of minor bleeding, the study author's definition, where given, was used. See Characteristics of included studies for individual study definitions
Thrombocytopaenia, as defined by individual study authors
Search methods for identification of studies
There was no restriction on the language of publication.
For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched November 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL and AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).
Searching other resources
In the previous version of this review we consulted with colleagues and investigators as well as the manufacturers of the various LMWH preparations to identify unpublished or missed studies. This was not done for the current version.
Data collection and analysis
Selection of studies
For this update one review author (RA) identified possible trials, and the trial reports were assessed independently by another review author (RB) to confirm eligibility for inclusion in the review. In the previous version of this review study selection was performed by RA and AC.
Data extraction and management
For this update, RA and RB individually extracted the data using the following endpoints: DVT of the lower limbs; symptomatic non-fatal PE; fatal PE; combined symptomatic non-fatal and fatal PE; all-cause mortality; major and minor bleeding (as defined by individual authors); and thrombocytopaenia (reduced numbers of platelets). We recorded all information collected on data extraction forms. We resolved disagreements by discussion. In the previous version of this review data extraction was performed by RA and AC.
Assessment of risk of bias in included studies
The methodological quality of included trials was assessed independently by RA and RB using the 'Risk of bias' tool from The Cochrane Collaboration (Higgins 2011). The following domains were assessed: selection bias (random sequence generation, allocation concealment), performance bias (blinding of participants and personnel, and blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias. The domains were classified as low risk of bias, high risk of bias, or unclear risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Disagreements were resolved by discussion between the two review authors assessing bias.
Measures of treatment effect
We performed statistical analyses according to the statistical guidelines for authors recommended by the Cochrane Peripheral Vascular Diseases Group.
We divided the studies into two groups and analysed them separately:
heparin (UFH or LMWH) prophylaxis versus placebo or no treatment;
LMWH versus UFH.
For each of the two groups we pooled data from each study on DVT, non-fatal PE, fatal PE, combined non-fatal and fatal PE, all-cause mortality, major bleeding, minor bleeding, and thrombocytopaenia in order to arrive at an overall estimate of efficacy and safety of heparin versus no treatment or placebo and LMWH versus UFH. We summarised the results of each trial on an intention-to-treat basis in 2 x 2 tables for each outcome measurement. Where possible, all randomised participants were included, even if the original trial authors excluded them. The results obtained from different methods were similar (risk ratios, Mantel-Haenzel and Peto odds ratios), therefore the meta-analysis was performed using odds ratios (ORs) with 95% confidence intervals (CIs).
Unit of analysis issues
The individual participant was the unit of analysis in all included studies.
Dealing with missing data
Analysis was performed on an intention-to-treat basis, including all participants randomised.
Assessment of heterogeneity
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. We obtained P values comparing the test statistic with a Chi2 distribution. To help readers assess the consistency of results of studies in a meta-analysis, RevMan 5 software includes a method (I2 statistic) that describes the percentage of total variation across studies due to heterogeneity rather than by chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity (Higgins 2003).
Assessment of reporting biases
To detect reporting bias we planned to construct funnel plots for meta-analyses that included at least 10 studies, as funnel plots with less than 10 studies lack the power to distinguish chance from real asymmetry.
An heterogeneity test was performed and we planned to use a random-effects model if the test was positive (I2 > 50%); unless otherwise stated the meta-analysis was performed using a fixed-effect model.
Subgroup analysis and investigation of heterogeneity
Where data were available, subgroup analysis was performed to evaluate outcomes based on medical diagnosis at hospital admission.
Four studies included in the review had a loss of ≥ 20% of the study population between randomisation and evaluation for DVT or PE (CERTAIN 2010; CERTIFY 2010; Fraisse 2000; MEDENOX 1999). Although the majority of the missing participants were accounted for with suitable reasoning, it was still possible these losses could alter the outcome. Sensitivity analysis was performed by removing these studies from the DVT and PE outcomes and evaluating their affect on the meta-analysis.
DVT diagnosis using a fibrinogen uptake test and plethysmography is often less accurate than by ultrasound or venography. In order to establish that the meta-analysis results were not dependent on studies using these low-accuracy tests, sensitivity analysis was conducted by removing three studies using a fibrinogen uptake test or plethysmography to detect DVT (Belch 1981; Dahan 1986; EMSG 1996) and the effect evaluated.
The safety data for the CERTAIN 2010 study was collected after a three month follow-up period, which was different to the other studies that collected the efficacy and safety data during the same study time period. With this additional time allotted for these endpoints it was possible this study unduly altered the meta-analysis, therefore sensitivity analysis was performed by removing this study from the meta-analyses for major and minor bleeding, as well as thrombocytopaenia, and evaluating the effect.
In two studies (Belch 1981; Dahan 1986) major bleeding was not defined, and was only described as 'major bleeding'. In order to determine if these studies with inadequate definitions of major bleeding were not having an overt effect on the meta-analysis they were removed in a sensitivity analysis to evaluate the effect.
Two studies (EMSG 1996; MEDENOX 1999) included a low-dosage (20 mg) of the LMWH enoxaparin. For EMSG 1996 this was the only LMWH dosage, but for MEDENOX 1999 there was also a higher dosage of 40 mg. Sensitivity analysis was performed by removing the 20 mg dosages and the effect was evaluated.
Summary of main results
Heparin resulted in a reduction in DVT and a borderline statistically significant reduction in combined non-fatal and fatal PE when compared with placebo or no treatment. The reduction in VTE risk is comparable to that previously reported in prophylaxis studies of patients following acute myocardial infarction (Collins 1996), acute ischaemic stroke (Gubitz 2004), colorectal surgery (Wille-Jørgensen 2004) and orthopaedic surgery (Collins 1988).
The analysis found no clear difference in all-cause mortality in patients receiving heparin prophylaxis. However, these studies are not powered to show a difference in mortality, which would require over 200,000 patients (assuming an overall 5% mortality, 10% of deaths due to VTE, and a 50% relative risk (RR) reduction in events). Despite this lack of effect on all-cause mortality, there did appear to be a borderline benefit of heparin (UFH and LMWH) on the combined outcome of clinically symptomatic PE and fatal PE.
In the presence of heparin prophylaxis the rate of major haemorrhage (0.64%) was statistically higher than with no prophylaxis (0.36%). LMWH resulted in significantly less major haemorrhage than UFH. This suggests a favourable benefit-risk ratio for LMWH therapy in the prevention of VTE in general medical patients.
In summary, patients hospitalised with an acute medical illness who receive UFH or LMWH thromboprophylaxis have a reduced risk of DVT, however there is an increase in major haemorrhage when compared to those who do not receive chemical thromboprophylaxis. LMWH reduced the odds of DVT compared with UFH as well as reduced the odds of major bleeding, suggesting LMWH has a better efficacy profile and carries a lower risk of adverse events compared with UFH. There are currently insufficient published data to allow analysis of outcomes of interest based on patient medical diagnosis at hospital admission.
Overall completeness and applicability of evidence
The conclusions provided in this analysis have a strong external application as the evidence was generated using 16 good quality studies that were sufficient to address the study outcomes. The 16 studies included 34,369 participants from at least 17 different countries, with the majority of studies being multi-centre, and four being multi-national.
Although this review does not identify heparin as preventing all-cause mortality in patients with an acute medical illness, it does appear to show a benefit in reducing DVT and possibly the combined outcome of symptomatic PE and fatal PE. Therefore, in patients with an acute medical illness heparin appears to reduce the risk of hospital acquired thrombosis (HAT), supporting the current medical practice of increasing awareness and advocating VTE prevention (NICE).
Currently, published studies are lacking outcome data specific to medical diagnosis at hospital admission. These data would help us to understand if certain patients, based on disease, would benefit more or less from thromboprophylaxis or are at a higher or lower risk of bleeding. Understanding these differences would help develop a stronger profile for the use of thromboprophylaxis in acutely ill medical patients.
Patients who develop VTE following an acute medical illness have a more severe presentation and significantly worse outcome than patients who develop VTE following surgery (Monreal 2004). Venous thromboembolic disease in hospitalised medical patients is a preventable occurrence and is associated with unacceptably high levels of morbidity and mortality.
In a report by the House of Commons Health Committee, it was recommended that "VTE and its prevention, including the implementation of, and adherence to guidelines relating to thromboprophylaxis, counselling and risk assessment, be given more prominence in undergraduate medical education, continuing professional development, and other relevant aspects of medical and paramedical training" (Health Committee 2005).
The current 'Prevention of VTE' guidelines presented by the American College of Chest Physicians also stress the importance of all hospitals having formal, written guidelines for thromboprophylaxis and that all patients undergo VTE risk assessment (Kahn 2012).
Current medical practice concerning VTE emphasizes awareness of HAT, with appreciation for the risk of VTE increasing dramatically within the past decade. All patients admitted to hospital with an acute medical illness should be risk assessed and thromboprophylaxis offered to those perceived to be at increased risk of VTE. In fact, patients are actively encouraged to question their admitting physicians as to their individual VTE risk and need for thromboprophylaxis (NICE) in an attempt to reduce the risk of HAT.
Quality of the evidence
Sixteen studies were used to compile evidence, 10 comparing heparin prophylaxis with no treatment or placebo and six which compared LMWH to UFH, with a total of 34,369 participants. For the majority of the outcomes there was general agreement between the studies. Overall quality of the studies was good, with concern for performance bias in the studies that were open label, which made up just under half of the studies. Also, most of the studies were lacking in an explanation of how random sequence generation and allocation concealment were performed, although this is most likely due to the fact that many included studies are older and were not held to as high reporting standards when published.
Potential biases in the review process
All data used were dichotomous, therefore little data manipulation that could introduce bias was required for analysis. However, for the Bergmann 1996 study all-cause mortality data were calculated using provided percentages and were transformed into dichotomous values for the purposes of the meta-analysis.
In order to reduce bias, both the 20 mg and 40 mg enoxaparin groups from MEDENOX 1999 were included in the meta-analysis. To avoid double-counting of participants, the participants and events within the comparison (placebo) group were split evenly between the two treatment groups, rounding down for odd numbers.
While all attempts to include relevant studies were made by the review authors, it is possible pertinent data were overlooked.
Agreements and disagreements with other studies or reviews
Several meta-analysis are available on this topic.
The findings of this review are in keeping with the meta-analysis published by Mismeti et al, which assessed seven trials comparing prophylactic heparin to control and nine trials comparing UFH with LMWH (Mismetti 2000). The meta-analysis found a statistically significant decrease in DVT (RR 0.44; 95% CI 0.29 to 0.64; P < 0.001) and clinical PE (RR 0.48; 95% CI 0.34 to 0.68; P < 0.001) when heparin was compared to control, which are consistent with our review, although Mismeti identified a stronger relationship with PE as our findings for non-fatal and fatal PE were imprecise and possibly due to chance effect. The Mismeti review found no difference in mortality, the same as our review, but they also found no difference in major bleeding, which is inconsistent with our review. No difference was observed in efficacy between UFH and LMWH in the Mismeti review, but our review found a decrease in DVT favouring LMWH. Also, our review found a decrease in major bleeding favouring LMWH, which is consistent with the Mismeti review findings.
The Mismetti review used six of the same studies as we did for the comparison of heparin to control (Belch 1981; Bergmann 1996; Dahan 1986; Fraisse 2000; Gardlund 1996; Ibarra-Perez 1988) and one study which was excluded from our review. For the comparison between UFH and LMWH, the Mismeti study analysed four studies used in our review (EMSG 1996; Forette 1995; PRIME 1996; THE-PRINCE 2003) and five studies that we excluded. While the authors described that they excluded cases of acute ischaemic stroke and acute myocardial infarction some of the studies included patients with acute coronary disease that could not be removed for analysis. Other criteria that warranted exclusion in our review were not upheld in the Mismeti review, such as detection method and inclusion of surgical patients, which led to differences in the profile of the included studies and the minor differences seen in the results.
A meta-analysis by Dentali et al assessed anticoagulant prophylaxis (UFH, LMWH and fondaparinux) to prevent symptomatic VTE in hospitalised medical patients (Dentali 2007). Nine trials were included in this analysis. Anticoagulant prophylaxis was associated with a borderline risk reduction in DVT (RR 0.47; 95% CI 0.22 to 1.00), which is consistent with this review. The Dentali review found a reduction in all PE (RR 0.43; 95% CI 0.26 to 0.71) for the prophylaxis group, but our review found only a borderline decrease in non-fatal and fatal PE. It was also noted in the Dentali review that anticoagulant prophylaxis was associated with a RR 1.32 (95% CI 0.73 to 2.37) for major bleeding, where our review found a statistically significant increase in major bleeding (OR 1.81; 95% CI 1.10 to 2.98; P = 0.02).
The Dentali review considered seven of the same studies that we included in this review for the comparison between anticoagulant prophylaxis and control (Belch 1981; Bergmann 1996; Dahan 1986; Fraisse 2000; Gardlund 1996; MEDENOX 1999; PREVENT 2004) and two studies considered not relevant or excluded from our review. Although study inclusion and exclusion criteria were similar for the Dentali review and this review, the minor differences led to the different study profile and variations in results. A major difference is that the Dentali review included studies that observed effects of fondaparinux, and not solely heparin. Also, one included study did contain participants with a recent myocardial infarction, which excluded it from the current review.
A meta-analysis published in 2009 by Bump et al compared heparin prophylaxis to control in seven studies, and LMWH to UFH in six studies (Bump 2009). Comparing heparin versus control, the authors found a decreased risk of all DVT, with a RR of 0.55 (95% CI 0.36 to 0.83), and all PE, with a RR of 0.70 (95% CI 0.53 to 0.93) in the heparin treatment group, but no difference in mortality between the groups (RR 0.92; 95% CI 0.82 to 1.03). The findings on all DVT and all-cause mortality are consistent with our review, but our review found only a borderline decrease in non-fatal and fatal PE. The Bump review did not find a difference between heparin and control for major bleeding, but in our review we found major bleeding to be significantly increased in the heparin group. For the studies comparing LMWH to UFH there were no statistically significant differences between the two treatment groups for DVT, PE, death or bleeding. The data on PE and death are consistent with our review, but we found a decrease in DVT and major bleeding favouring LMWH.
For the comparison between heparin and control the Bump et al review included six of the same studies as in our review (Belch 1981; Bergmann 1996; Dahan 1986; Gardlund 1996; MEDENOX 1999; PREVENT 2004) with the addition of two studies that we excluded or considered not relevant. Comparing UFH to LMWH the Bump review included three of the same studies as in our review (EMSG 1996; PRIME 1996; THE-PRINCE 2003) with two extra studies which were excluded from our review. Although the Bump review sought to exclude trials predominantly made up of stroke or acute myocardial infarction patients, it did include studies that had some of these types of participants that could not be separated out for statistical purposes. This difference, along with the review being conducted before some of the big trials included in our review were published, has lead to a different profile of included studies and variations in results.
A more recent meta-analysis published by Lederle et al analysed 10 studies that compared prophylaxis with heparin or related agents to no heparin and nine studies comparing LMWH with UFH, all in hospitalised medical patients (Lederle 2011). The review also analysed stroke patients, but this was performed separately and is not considered here. For studies that compared heparin prophylaxis with no heparin, a statistically significant decrease in PE was found in the heparin group with an OR of 0.69 (95% CI 0.52 to 0.90; P = 0.006), but our review found only a borderline statistically significant decrease in non-fatal and fatal PE. In the Lederle review there were no differences found for symptomatic DVT, fatal PE or all-cause mortality. The fatal PE and all-cause mortality results are consistent with our review, but DVTs were found to be statistically decreased in the heparin group compared to the placebo or no treatment group. No difference in major bleeding was observed in the Lederle review (OR 1.49; 95% CI 0.91 to 2.43; P = 0.110), whereas in our review the increase in major bleeding in the heparin arm was statistically significant. No differences were found between LMWH and UFH for efficacy or safety outcomes, but in our review we found a statistically significant decrease in both DVT and major bleeding favouring LMWH.
The Lederle review considered seven of the same studies as in the current review for the comparison between heparin and placebo or no treatment (Belch 1981; Bergmann 1996; Dahan 1986; Fraisse 2000; Gardlund 1996; MEDENOX 1999; PREVENT 2004), with the addition of three studies which were either considered not relevant or excluded from the current review. For the comparison between UFH and LMWH the Lederle review used five of the same studies as in our review (CERTAIN 2010; CERTIFY 2010; EMSG 1996; PRIME 1996; THE-PRINCE 2003), with the addition of four studies that we either considered not relevant or excluded. The Lederle review extended inclusion to studies with common treatments for VTE, and not strictly heparin (which led to the inclusion of a study evaluating fondaparinux), and while studies including only acute myocardial infarction patients were excluded in the Lederle review it did include studies that had some acute coronary syndrome patients, which would have been excluded from our review. Also, the Lederle review was conducted before several newer studies were published that have been included in the current review. These differences can account for the variations in findings regarding both the heparin versus no heparin and UFH versus LMWH comparisons.
The review authors would like to thank the PVD Group editorial base for all their assistance in updating this review.
Last assessed as up-to-date: 12 November 2013.
|19 May 2016||Feedback has been incorporated||Feedback received, the review authors have been invited to respond to the feedback|
Protocol first published: Issue 3, 2002
Review first published: Issue 3, 2009
|12 November 2013||New search has been performed||Searches rerun, three additional studies included and one additional study excluded.|
|12 November 2013||New citation required but conclusions have not changed||Searches rerun, three additional studies included and one additional study excluded, full risk of bias assessments made for all included studies, data errors amended. New author has joined review team.|
|14 February 2011||Amended||Link to anticoagulant feedback added.|
|10 August 2009||Amended||Minor amendment to the text in the 'Background' section.|
|3 April 2009||Amended||Converted to new review format.|
Contributions of authors
RA reviewed identified studies, extracted the data, performed the analyses, and wrote the review.
RB reviewed identified studies, extracted the data and assisted in data analyses and writing of the review.
AC commented on the writing of the review and in previous review versions reviewed identified studies and extracted the data.
Declarations of interest
Dr Alikhan has received travel expenses to attend educational meetings from the following companies marketing parenteral anticoagulants: Aventis, Leo Pharma and Pfizer.
Dr Cohen is a medical consultant and has received consultancy and clinical trial funding from many pharmaceutical companies, including Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Portola, Sanofi-Avenits, Schering Plough, and Takeda. He is an advisor to the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS on the prevention of VTE. He is also an advisor to Lifeblood, the thrombosis charity, and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Dr Cohen is one of the principal investigators of the Medenox (MEDENOX 1999), Prevent (PREVENT 2004) and Exclaim (EXCLAIM) trials.
A member of the PVD editorial base performed data extraction and risk of bias assessment on studies where both Dr Alikhan and Dr Cohen were involved.
Differences between protocol and review
The title of the review has been changed from the previous version. In the original title the term 'general medical patients' was used to describe the study population, but has been changed to 'acutely ill medical patients'. The review authors made this change because 'general medical patients' was thought to be too generic and 'acutely ill medical patients' was a more precise description, and better represents the study population used for the review.
The efficacy outcome 'symptomatic PE' was further defined as 'symptomatic non-fatal PE' and the outcome 'combined clinically symptomatic non-fatal PE and fatal PE' has been added.