Inpatient therapy may be associated with less major bleeding; therefore, if LMWHs are given in the outpatient setting, patients should be rigorously monitored.
Furthermore, LMWHs have been shown to be safe and effective for outpatient therapy. The issue is particularly important when considering cost-effectiveness in patients who require in-hospital anticoagulation therapy, such as those with pulmonary embolism PE or those with deep vein thrombosis DVT who require hospitalization for other reasons. Are there differences in effectiveness and safety among different LMWH preparations? Each citation was reviewed by 2 reviewers independently who assessed them for inclusion based on a predetermined process and set of criteria.
Disagreements were resolved by consensus. Agreement scores were calculated and evaluated at different stages of the process. Revisions in coding definitions and procedures at each stage were made, if needed.
To be included in this meta-analysis, a trial had to meet the following criteria: 1 randomized controlled trial; 2 enroll adult patients with a diagnosis of VTE that was confirmed by the presence of an intraluminal filling defect on contrast venography films, venous noncompressibility on Duplex ultrasonography films taken for acute DVT, the results of a high-probability ventilation-perfusion lung scan, or the presence of an intraluminal filling defect on pulmonary angiography films taken for PE 11 - 13 ; 3 compare intravenous UFH with subcutaneous LMWHs; and 4 evaluate the outcomes of recurrent VTE DVT and PE or PE alone as determined by objective test results and blinded outcome assessment that was confirmed by an independent assessor or adjudication committee, major bleeding, minor bleeding, total mortality, or thrombocytopenia.
A study was excluded if it was not written in English or French, if data could not be extracted, or if there was no patient follow-up beyond the initial administration of heparin therapy. Recurrent DVT involving the calf or more proximal veins had to be diagnosed by a new intraluminal filling defect on venography, a new noncompressible vein segment on ultrasonography, or, if these were inconclusive, a newly abnormal impedance plethysmography test result was considered acceptable.
A study was classified as providing outpatient therapy if some of the patients who were allocated to receive LMWHs were treated as outpatients. Bleeding and thrombocytopenia were classified according to the criteria listed by the authors.
All bleeding events that were not classified as major were considered minor. Methodological quality was assessed using criteria adapted from published sources. Discrepancies were resolved by review of the original study.
A priori, potential secondary analyses were identified; 7 potential secondary analyses were methodological in nature eg, blinded outcome analysis or financial support and 10 were clinical in nature eg, early vs late recurrence of thromboembolism or adjusted-dosage UFH or not. These potential secondary analyses were evaluated for rationale and supportive evidence and then rated independently by 3 clinical experts according to clinical importance and relevance.
Those with the highest rating formed the basis for the 3 subgroup analyses presented. Based on this selection process, the following secondary analyses were performed: 1 once-daily vs twice-daily treatment regimen, 2 inpatient vs outpatient treatment location, and 3 comparisons of individual LMWHs.
The value reported indicates the risk of the outcome while receiving LMWHs as a percentage of the risk of the event while receiving UFH for example, 0. Weighted least squares linear regression was used to determine statistically significant differences between subgroups. The dependent variable was the individual study RR. Weights were the components of variance owing to interstudy variation in effect size as determined using the random effects model. From articles screened, 33 articles were identified as randomized controlled trials comparing LMWHs and UFH and were included for data extraction.
Of these, 20 articles were excluded; the remaining 13 studies 6 , 7 , 24 - 34 were included in this meta-analysis.
Various aspects of methodological quality were evaluated. All studies involved adjustment of treatment with UFH to a specified target-activated partial thromboplastin time range, and all patients received either LMWH or UFH for at least 5 days. The maximum duration of injectable anticoagulant administration was 10 days. The anticoagulant regimens used are presented in Table 1.
Event rates for selected outcomes are provided in Table 2. Analysis of the pooled RR yielded a nonsignificant result of 0. For the outcome of PE alone as a manifestation of recurrence , analysis of the pooled RR yielded a nonsignificant result of 1. Again, none of the individual RRs was statistically significant in the primary studies.
All 13 studies that were included also assessed the incidence of major bleeding. The combined analysis for minor bleeding included 12 of the 13 studies and produced a nonsignificant pooled RR of 1. The analysis of total mortality produced a statistically significant pooled RR of 0. This was based on information that was available from 10 of 13 studies. The pooled analysis yielded a nonsignificant RR of 0.
No statistically significant heterogeneity was found for any of the primary analyses. Three studies were considered to be outpatient therapy trials. Five of 13 studies involved once-daily LMWH administration. The analysis of studies using twice-daily vs once-daily dosing is presented in Table 5 and Figure 3.
Pooled trials administering once-daily LMWH, compared with those administering twice-daily dosing, did not produce a statistically significant difference for any outcomes that were analyzed. Blood Purif ; 7 : — Nephrolgie ; 15 : — Anticoagulacion en hemodialisis con dosis unica de heparina de bajo peso molecular. Rev Med Chile ; : — Longterm effects of low-molecular-weight heparin in hemodialyzed patients. Hellen Nephrol ; 6 : — Oxford University Press is a department of the University of Oxford.
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Subjects and methods. Comparison of low-molecular-weight heparin enoxaparin sodium and standard unfractionated heparin for haemodialysis anticoagulation. David Saltissi , David Saltissi. Oxford Academic. Google Scholar. Colleen Morgan. Justin Westhuyzen. Helen Healy. Select Format Select format. Permissions Icon Permissions. Abstract Background. Table 1. Age, years Open in new tab. Open in new tab Download slide.
Table 2. Frequency of adverse events, during and between dialysis sessions. Clexane a. Titrated Clexane b. Distribution of Clexane doses after dose titration. Table 3. Vascular access clotting times s. Clexane after dose titration. Table 4. J Clin Invest. Clin Nephrol. Scand J Haematol. N Engl J Med. Aus Prescriber. Eur J Clin Invest. Nephrol Dial Transplant. Kidney Int. Nieren- Hochdruckkr. Thromb Haemost. Blood Purif.
Rev Med Chile. Hellen Nephrol. Issue Section:. Many hospitals will lack a fondaparinux-calibrated anti-Xa level assay. This has numerous physiologic effects as shown above e. They are active against both fluid-phase and clot-bound thrombin unlike heparin, which acts only on fluid-phase thrombin. PTT prolongation is generally used to titrate the dose of a direct thrombin inhibitor. INR prolongation is problematic, as this can make it difficult to transition to warfarin.
Assays for clotting factors and fibrinogen may be falsely prolonged causing the lab to register falsely low values. They are not dependent on anti-thrombin III levels Pharmacokinetics are generally more predictable than those of heparin especially bivalirudin, which doesn't bind to plasma proteins.
Bivalirudin's short half-life 25 minutes may make it easier to stop, compared to a heparin infusion with half-life close to 45 minutes. Lack of any reversal agent. This could be problematic for patients with hepatic dysfunction on argatroban — wherein the half-life may be considerable. Bivalirudin has traditionally been used more in the cardiac catheterization laboratory.
Properties of the two agents are compared here: direct thrombin inhibitor pseudo-resistance True resistance doesn't seem to occur with direct thrombin inhibitors because unlike heparin, their pharmacology is more predictable and their efficacy doesn't depend on anti-thrombin III. Pseudo-resistance can occur with both argatroban and bivalirudin Kennedy et al. This is essentially the same as pseudo-heparin resistance discussed above.
This creates a dangerous situation where it falsely appears that the patient is resistant. Ongoing up-titration of the direct thrombin inhibitor in efforts to increase the PTT can cause hemorrhage. Pseudo-resistance may be suspected if: An unusually high dose of direct thrombin inhibitor is required, or if it is impossible to achieve a therapeutic PTT. A baseline reduction in PTT might also support pseudo-resistance. Diagnostic evaluation: In the case of argatroban, drug levels may be checked if this test is available unfortunately, many hospitals may lack this.
Thrombin time may be a better measurement of direct thrombin effect than PTT Beiderlinden et al. If the thrombin time is considerably elevated, this may support a diagnosis of pseudo-resistance. Marked elevation of factor VIII also supports the diagnosis of pseudo-resistance. Management If argatroban levels are available with a rapid turn-around time, then argatroban could be continued with a transition towards monitoring based on argatroban levels rather than PTT.
Unfortunately, this currently isn't an option in most hospitals. An alternative form of anticoagulation is generally needed, one that doesn't rely on PTT for dose titration. In patients with normal hepatic function, coagulation will normalize about hours after stopping the infusion. Argatroban may be used in patients with liver dysfunction, but lower doses should be used and it may be harder to rapidly discontinue anticoagulation. Use caution in patients with hepatic dysfunction e.
Make sure to obtain a baseline PTT before starting the argatroban infusion and possibly a thrombin time as well Beiderlinden et al. The optimal target PTT might be 1.
However, sources disagree about whether to target PTT to the patient's baseline or to the laboratory baseline. Medscape monograph on argatroban. Along with argatroban, it is an intravenous direct thrombin inhibitor.
Given its peptide structure, bivalirudin is partially metabolized by serum proteases. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing interests: The authors have declared that no competing interests exist. In daily clinical practice, low molecular weight heparins LMWH and unfractionated heparin UFH are the most commonly prescribed anticoagulant drugs for the treatment of acute thrombotic conditions, such as venous thromboembolism VTE and acute coronary syndromes ACS. These properties allow the use of LMWH at weight-adjusted doses in most patients, without the need for laboratory monitoring.
On the other hand, although treatment with UFH needs laboratory monitoring with Activated Partial Thromboplastin Time aPTT , because its anticoagulant effect is unpredictable, it has the advantage that bleeding complications can be more easily managed, because UFH has a shorter half-life than LMWH, and can be effectively antagonized by protamine [1].
Minimizing the bleeding risk in patients treated with anticoagulants is of utmost clinical relevance, considering that major bleeding, anemia and blood transfusion are powerful and independent predictors of morbidity and mortality in patients with VTE or ACS on treatment with antithrombotic drugs [5] — [7]. To date, the systematic reviews comparing LMWH and UFH, focused on drug efficacy as primary end point and considered the incidence of bleeding a secondary end point.
This choice could have affected the selection of studies to be included in the analysis, since some studies reporting haemorrhagic events could have been excluded due to the absence of the primary end point considered as inclusion criteria in those meta-analysis. We attempted to identify all relevant published randomized controlled trials RCT that compared fixed-dose subcutaneous LMWH with adjusted-dose intravenous UFH in the initial treatment of thrombotic episodes. The search was completed in May We manually searched the references of retrieved publications to look for additional studies.
No language restrictions were applied. Two investigators EC, AMR independently evaluated the studies for inclusion, and disagreements were resolved by discussion. In order to be included in this systematic review, published studies had to meet the following criteria: 1 study design: randomized controlled trial; 2 intervention: comparison of subcutaneous weight-adjusted, fixed-dose LMWH with adjusted doses based on APTT values intravenous UFH, for the initial treatment of acute thrombotic episodes; 3 availability of outcome data on the incidence of major bleeding.
We accepted the definitions of major bleeding that were chosen in each individual trial. Dose-finding studies were excluded. Studies with no events in both LMWH and UFH arms were included in the descriptive analysis, but excluded from the meta-analysis, because calculation of the odds ratio OR was not feasible.
In order to evaluate the quality of the included studies, we used the study-quality criteria of Jadad, which take into account proper randomization, allocation of patients and blinding [8]. The data extracted for each trial were confirmed by consensus between the reviewers.
The homogeneity of the estimates of OR among studies was evaluated using the chi-square statistic test. Given the known difference of clinical settings of primary studies included in our meta-analysis clinical heterogeneity , random effects analysis was performed for all studies, irrespective of the statistical significance of the heterogeneity chi-square test.
Figure 1 shows the process of study selection. We identified articles from Medline, from Embase, from the Cochrane Library. Of these, studies were duplicates, which were therefore eliminated, leaving articles for consideration.
After the exclusion of irrelevant studies, which were identified by reviewing the titles and abstracts of all retrieved articles, publications remained for analysis. We could not obtain the full publication of 19 studies after searching in the British Library and writing to the authors.
Fifty-four of the remaining 93 articles were subsequently excluded, based on a more detailed evaluation of the full publications Fig. No additional studies were identified by reviewing the references from the original studies and other meta-analyses. One study, which operated a double randomization was considered as two data sets [11]. Thus, 37 studies were included in the descriptive analysis [11] — [47].
In 10 of them, no bleeding events were observed in any treatment group: therefore, 27 studies were included in the meta-analysis [12] — [15] ; [17] — [38] ; [47]. Table 1 describes the characteristics of the included studies.
Thirty-four studies were published in English, one in French and two in Spanish, in journals of Internal Medicine, Cardiology, Hematology, or, less frequently, Angiology and Pneumology. The years of publication ranged between and Nine different types of LMWH were used: the most commonly used one was enoxaparin.
Treatments lasted between 2 and 28 days mean, 8 days. Most studies used the TIMI criteria to define major bleeding [48]. The aim of the majority of the studies was to evaluate combined end-points; less frequently, a single clinical end-point or an instrumental measure were evaluated.
Major bleeding ranged from 0 to The mean incidence of bleeding events were lower in VTE 1. Considering the efficacy end-points, 15 studies showed that LMWH were superior to UFH [12] ; [15] ; [17] — [19] ; [21] — [23] ; [26] ; [27] ; [29] ; [30] ; [36] ; [40] ; [42] , 1 study showed that UFH was superior to LMWH [46] , while the remaining 21 showed that there was no statistically significant difference between the two treatments [11] ; [13] ; [14] ; [16] ; [20] ; [24] ; [25] ; [28] ; [31] — [35] ; [37] — [39] ; [41] ; [43] — [45] ; [47].
Based on the study-quality criteria of Jadad [8] , 3 studies scored 1 point, 17 scored 2 points, 14 scored 3 points, 1 scored 4 points and 2 scored 5 points. Lack of blindness was the most common flaw in the studies with a low Jadad score.
Based on our a priori defined protocol, we excluded dose-finding studies [49] — [52] , which had been included in other revisions.
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