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Received Date : 04-Dec-2013 Accepted Date : 07-Feb-2014 Article type
: Original Article - Clinical Haemostasis and Thrombosis
Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: systematic review and meta-analysis. Daniel Caldeira M.D.,*† Cláudio David M.D., *†‡ Ana T. Santos MSc,*† João Costa M.D. PhD,*†§¶ Fausto J. Pinto M.D. PhD,‡ Joaquim J. Ferreira M.D. PhD.*†
* Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
† Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Portugal.
‡ Cardiology Dpt, CCUL, CAML, University of Lisbon, Portugal. § Evidence Based Medicine Centre, Faculty of Medicine, University of Lisbon, Portugal. ¶ Portuguese Collaborating Centre of the Cochrane Iberoamerican Network, Faculty of Medicine, University of Lisbon, Portugal.
Running Title: LMWH and Mechanical Heart Valves.
Corresponding author: Daniel Caldeira, MD This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12544 This article is protected by copyright. All rights reserved.
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Laboratório de Farmacologia Clínica e Terapêutica Faculdade de Medicina da Universidade de Lisboa Av. Prof. Egas Moniz, Lisboa 1649-028, Portugal. E-mail: [email protected] Telef.: (+351) 21 797 34 53 Fax: (+351) 21 781 96 88
Abstract Background: Low molecular weight heparins (LMWH) are not approved for patients with mechanical heart valves (MHV). However, temporary LMWH off-label use in this clinical setting is considered in several guidelines as a valid treatment option. Therefore we reviewed the efficacy and safety of LMWH in patients with MHV.
Methods: MEDLINE and CENTRAL databases were searched from inception to June 2013. Review articles and references also searched. We included experimental and observational studies that compared LMWH with unfractionated heparin (UFH) or Vitamin K Antagonists (VKA). Data was analysed and pooled to estimate odds ratio (OR) with 95% confidence intervals (95%CI) for thromboembolic and major bleeding events. Statistical heterogeneity was evaluated with I2 test.
Results: Nine studies were included: one randomized controlled trial (RCT) and 8 observational studies, with a total of 1042 patients. No differences were found between LMWH and UFH/VKA in the risk of thromboembolic (OR 0.67; 95%CI: 0.27 to 1.68; I2=9%) or major bleeding events (OR 0.66; 95%CI: 0.36 to 1.19; I2=0%).
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Conclusions: The best evidence available might support the temporary use of LMWH as a prophylactic treatment option in patients with MHV. However, conclusions are mostly based from observational data (with large confidence intervals) and an adequately powered RCT is urgently needed in this clinical setting.
Keywords: Heparin, Low-Molecular-Weight; Heart Valve Prosthesis; Heparin; Coumarins; Warfarin.
Introduction Patients with mechanical heart valves (MHV) are at increased risk of thromboembolic events.[1] These patients require lifelong anticoagulant treatment, usually with vitamin K antagonists (VKA) whose efficacy and safety depends on close monitoring of International Normalized Ratio (INR) levels. In some occasions, when the INR level is under the target range (e.g., immediately after valve implantation; patients with a low INR during routine monitoring; or during temporary interruption of oral anticoagulant therapy for invasive procedures), other anticoagulants should be temporarily used. Unfractionated heparin (UFH) have been recommended and used in this context.[2-5] However, low molecular weight heparins (LMWH) have pharmacokinetic and pharmacodynamic properties (such as a more predictable dose-response relationship) that make this class a more attractive option for thromboprophylaxis.[6]
The lack of randomized clinical trials (RCTs), together with some published reports with inconclusive and contradictory findings, raised doubts about the safety and efficacy of LMWH in patients with MHV.[7-11] The European Society of Cardiology Guidelines consider both UFH and LMWH as treatment options for post-surgery in This article is protected by copyright. All rights reserved.3
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patients with MHV and for those undergoing surgical or diagnostic procedures needing bridging anticoagulation. These recommendations were graded “IIa” and were classified as ‘level C’ of evidence, reflecting the uncertainty of the recommendation but still in favor of treatment.[12,13]
In this study, we aimed to review and evaluate the efficacy and safety of LMWH compared to UFH or VKA in patients with MHV.
Methods Eligibility Criteria We included RCTs and observational studies (cohort or case-control studies) comparing LMWH with VKA or UFH in patients with MHV. Studies should report the incidence of thromboembolic events. We considered all patients with implanted MHV irrespective of the prosthesis position and model. LMWH included the following drugs: enoxaparin, dalteparin, parnaparin, reviparin, nadroparin, ardeparin and tinzaparin. Studies without a control group were excluded.
Database and search method MEDLINE and Cochrane Library (CENTRAL) databases were searched in October 2013 for eligible studies. The search strategy is detailed in Supplementary Online. Studies were considered irrespective of publication language. We also evaluated PubMed’s related citations and hand searched for other reviews and studies. References of obtained studies were systematically and comprehensively analyzed.
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Studies and Data Selection Potential studies retrieved from electronic search were screened independently by two authors (DC and ATS), followed by full-text assessment for the inclusion in the systematic review according to the outlined criteria.
Primary outcome was overall incidence of thrombotic and thromboembolic events, defined as any of the following events: valvular thrombosis, stroke, transient ischemic attack and peripheral arterial embolic events. Secondary outcome was overall incidence of major bleeding events, defined as those evolving a critical organ, or requiring transfusion, surgical operation, or prolongation of hospitalization. Overall we accepted each study definition for major bleeding. We extracted detailed data about population, analysed interventions, follow-up and outcomes. Disagreements were resolved by consensus between the authors.
Quality reporting assessment Studies’ reported quality was independently assessed by two authors (DC and ATS). RCTs were evaluated using the Cochrane Collaboration’s Tool, which stratifies qualitatively the risk of bias as high, unclear or low.[14] This tool evaluates the adequacy of randomisation method and allocation concealment, the blinding of participants and personnel, the selectiveness of outcome reporting, the completeness of withdrawals description, and other bias deemed to be relevant. Observational studies were qualitatively assessed with the Newcastle-Ottawa Scale.[15] This instrument has nine different questions for cohort and case-control studies and evaluates three parameters: selection of patients, comparability of study groups and assessment of This article is protected by copyright. All rights reserved.5
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outcomes. For treatment arms comparability, the characteristics considered most important for data adjustment were age, gender, valve position and other prothrombotic conditions, such as atrial fibrillation or deep venous thrombosis.
The quality of reporting was not used a priori as an exclusion criterion.
Data Synthesis Primary and secondary outcomes were summarized as dichotomous data. To estimate the effect of treatment, we choose the relative measure odds ratio (OR), and its 95% confidence interval (95% CI), rather than an absolute measure, to estimate the effect of treatment because they are more applicable to comparisons across studies with different populations and lengths of follow-up.[16] The OR was also chosen in order to include estimates from case-control studies without losing data comparability.
All statistical analyses were performed using the RevMan version 5.2.6 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). This software calculates data from individual studies and derives forest plots for the pooled analysis. Heterogeneity was assessed with the I2 test, which measures the percentage of total variation attributed to inter-study heterogeneity rather than random.[17,18] The inverse of variance method with random effects model was used by default independently of the existence (I2≥50%) or not of substantial heterogeneity between studies’ results because we anticipated to pool data from studies with different designs.[17,18] Publication bias was planned to be assessed through visual inspection of funnel plots asymmetry and Peters’ regression tests.[19,20] The latter evaluates the linearity of effect estimate with sample size.
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Results After searching electronic databases, review articles and references of obtained studies, we were able to include 9 studies (one RCT and eight observational studies) according to our eligibility criteria.[21-29] Supplemental Figure 1 shows the studies’ selection steps and reasons for excluding studies.
Description of studies and risk of bias A total of 1042 MHV patients were evaluated in these 9 studies.[21-29] The only RCT included had focused VKA-treated patients undergoing tooth extraction.[27] There were 68 patients with prosthetic heart valves (31 in LMWH arm vs. 38 in VKA arm), and we confirmed with the authors that all these patients had MHV. There were no thromboembolic or major bleeding events in all study’s patients on either LMWH or non-bridged arms, which includes patients with MHV.
The observational studies were 2 case-control studies,[21,22] and six cohort studies (three of which were prospective cohorts).[23-26,28,29] Four studies evaluated LMWH in pregnant patients with MHV,[23,24,28,29] 2 studies in patients that underwent mechanical valve implantation,[21,22] while the remaining 3 studies evaluated patients undergoing invasive procedures or non-cardiac surgeries.[25-27]
Sample size of included studies varied between 24 and 342 patients. The control group was VKA in 4 studies, UFH in 4 studies (3 with intravenous heparin and 1 with subcutaneous heparin), and both UFH and VKA in one study. Reported mean follow-up varied between 14 days and after delivery period of pregnancy. This article is protected by copyright. All rights reserved.7
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Table 1 and Supplementary Table 1 show the main characteristics and data retrieved from of studies. Adjudicated events for primary outcome and major bleeding definitions used in the studies are described in Supplementary Table 2.
Overall, the methodological/reporting quality was low. The RCT of Bajkin and colleagues was considered to be at high risk for performance, detection and reporting bias.[27] All observational studies are intrinsically prone to high risk of selective reporting bias. Following the Newcastle-Ottawa scale for quality reporting, the most common flaw was the absence of adjustment for confounding factors (including those considered important by the authors). In case-control studies, the cases were not independently validated and controls were all hospital-based. All these aspects increase the risk of bias of the included studies. Supplementary Figure 2 shows the risk of bias figure for all studies.
Effects of interventions Thromboembolic events and major bleeding
Regarding the primary outcome, one study (the RCT) reported zero events in both treatment arms.[27] Thus, only 8 studies contributed for the pooled odds ratio estimate. The risk of thromboembolic events with LMWH was not different compared to UFH or VKA with OR 0.67 (95%CI 0.27-1.68). There was no significant statistical heterogeneity (I2=9%) (Figure 1).
Regarding our secondary outcome, in three studies there were no major bleeding events reported in both arms.[23,24,27] In the pooled analysis of the six included studies,
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LMWH did not increased the risk of major bleeding with OR 0.66 (95%CI 0.36-1.19). No statistical heterogeneity was found among studies (I2=0%) (Figure 1).
Post-hoc subgroup and sensitivity analyses
Although no significant statistical heterogeneity existed in the pooled results from included studies, we performed several subgroup and sensitivity analysis to explore the robustness of the results and to limit clinical heterogeneity. Pooled estimates were calculated according to the type of control group (LMWH vs. UFH and LMWH vs. VKA), indication for LMWH use (pregnancy, post MHV implantation, post procedure/non-cardiac surgery) and study design (prospective and retrospective). A sensitivity analysis was also performed by excluding from the analysis all case-control studies, which are known to be more prone to bias than cohort studies and RCTs. Overall results for both primary and secondary outcomes were consistent across all these analyses, i.e., no differences existed between LMWH and controls (Figure 2).
Three studies have used anti-Xa monitoring in the LMWH arm.[21,28,29] The incidence of thromboembolic events (OR 2.09, 95%CI 0.17-25.85; I2=61%) and major bleeding (OR 0.80, 95%CI 0.26-2.50; I2=0%) was similar to controls.
Analyses using Peto’s Odds Ratio and Risk Difference measures
We further explored the impact of using different effect measurements on pooled estimates, because the events’ rates were low or null in some studies.
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Peto’s odds ratio in circumstances of rare events has been reported to be an adequate and more reliable effect measurement for dichotomous outcomes.[30] Results were similar to those of primary analysis with Peto’s OR 0.62 (95% CI 0.25-1.57; I2=55%). For major bleeding, the Peto´s OR was 0.64 (95% CI 0.34-1.21; I2=0%).
Risk difference (RD) is a measure that can give inconsistent estimates in pooled analyses mainly due to the constrains of different baseline risks when applying results across different groups and clinical settings.[31] However it has the advantage to consider studies with zero events in both arms for meta-analysis estimate.[31,32] The RD between LMWH and UFH/VKA was -1.0% (95%CI: -2.6% to 0.5%; I2=0%) and 0.1% (95%CI: -3.4% to +1.4%; I2=0%) for thromboembolic and major bleeding events, respectively.
Publication bias
The visual inspection of the funnel plot is not conclusive about the absence of publication bias (Supplementary Figure 3). Peters regression test did not found evidence of publication bias (p=0.156).
Discussion
VKA are the oral anticoagulants of choice for patients with MHV and UFH (the only heparin approved for patients with MHV) has been the most commonly used drug for bridging.[2-5] According to the present data, based on 10 studies and 1068 patients, LMWH is effective and safe for temporary use in patients with MHV in terms of thromboembolic risk, compared to the ‘reference’ drugs. Subgroup and sensitivity This article is protected by copyright. All rights reserved.10
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analyses consistently showed no differences between LMWH and the “reference” drugs (VKA/UFH). Compared to other reviews,[11,33] this systematic review had the merit to review all clinical controlled studies and to use a quantitative method to assess benefit and harm of the intervention.
The data here presented is partially based on studies that used LMWH as a bridging agent. In this context, LMWH offer some pharmacological advantages comparing to UFH: lower incidence of thrombocytopenia and osteoporosis, predictable dose-response relationship, decreased of hospital length of stay and reduced costs.[22] However, doseresponse relationship may be less predictable in patients with obesity,[34] renal dysfunction,[35,36] and pregnant women.[33,37]
Concerns have been raised about the thromboembolic risk during the periprocedural period. Impaired hemostasis related to the prothrombotic effect of ‘switching on and off’ of VKA, in addition to other patients thrombotic risk factors (e.g. atrial fibrillation) highlighted the need of a transitory antithrombotic treatment.[38] Nevertheless, Siegal and colleagues showed in a systematic review that periprocedural bridging is associated with bleeding risk increase.[39] Thus, considering the available data, VKA–treated patients receiving periprocedural heparin (UFH or LMWH) bridging appear to be at an increased risk of overall and major bleeding with similar risk of thromboembolic events, compared to nonbridged patients.[39,40] Despite the absence of approval for the use in patients with MHV, LMWH are considered to be a treatment option in guidelines for peri-procedural bridging treatment.[10] These drugs should be given subcutaneously twice a day using body weight-adjusted therapeutic doses and anti-Xa activity monitoring with target levels ranging from 0.5 to 1.0 U/ml.[9] This article is protected by copyright. All rights reserved.11
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After MHV replacement, patients may also require heparin-based anticoagulation in order to avoid thromboembolic events associated to delayed therapeutic effect and early prothrombotic effect of VKA.[41] Steger and colleagues followed a cohort of 256 patients who underwent MHV implantation and were treated with fixed and lower dose of enoxaparin (40 mg, twice daily, subcutaneously).[42] In this study, with a mean follow-up of 38 days, LMWH showed to be safe without prosthesis thrombosis and major bleeding.[42]
Only 3 studies used anti-Xa monitoring to adjust LMWH anticoagulation.[21,28,29] No significant differences were found comparing to UFH or VKA, but the comparison is clearly underpowered. In fact, anti-Xa monitoring may optimize anticoagulation in some patients after surgery not only because of the higher risk of bleeding,[21] particularly those in whom the dosage may be difficult to determine (eg. patients with renal dysfunction or obesity), but also due to the lack of full reversibility of LMWH by protamine, frequently insufficient to arrest bleeding.[6,43]
In pregnant patients, VKA cross the placenta with teratogenic risk in the first trimester and increases the risk of fetal bleeding during the delivery.[33] LMWH does not cross the placenta and is not toxic to the fetus, but pregnant women have increased risk of thromboembolic events, due to pregnancy itself and to lower anti-Xa levels,[44,45] probably related to unstable LMWH clearance and higher volume of distribution.[46,47] Tight monitoring is recommended with target anti-Xa levels of 1.01.2U/ml at 4-6 h after subcutaneous injection and 0.6-0.7 U/ml before the next LMWH dose.[48,49] This article is protected by copyright. All rights reserved.12
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The use of LMWH in MHV patients is associated with a low risk of events similarly to atrial fibrillation patients bridged with LMWH.[50] This safety data was also sustained in case series and in prospective ‘real world’ registries,[41,51-53] but the absence of a control group limits their conclusions.
Limitations
In this systematic review we performed a meta-analysis of the best available evidence (mainly based on observational studies, not patient level data) in order to overcome the scarcity of controlled studies in this area. The use of data from observational studies may raise methodological and interpretational concerns.[54] Clinical decisions based exclusively on this type of evidence should be weighted with caution.[55] Nevertheless, these data are informative and increases the knowledge of the use of LMWH in patients with MHV.
Other limitations should be taken into account in the interpretation of our findings. First, we pooled different studies with different indications, which cumulatively limit our conclusions. Second, we acknowledge that most of the evidence and estimates here shown were derived from observational studies’ data. The only randomized study included, was not considered in most of the quantitative analyses due to the lack of events, which suggests safety despite the underpowered nature of the study. Third, short duration bridging treatment is different from longer substitution of anticoagulants (as occurs in pregnant women with MHV), as VKA residual effect may still be present during the first days, with potential higher risk of hemorrhagic events. This article is protected by copyright. All rights reserved.13
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Should be acknowledged that outcomes were not systematically adjudicated, with the potential for major imprecision in outcome rates and that the definition of major bleeding, was also different among studies (Supplementary Table 2).
In a systematic review of non-randomized studies, the risk of selective reporting bias should be noticed. Furthermore, we included studies based on the absence of events. Nevertheless, these studies did not contributed to the primary analysis of this review. Confounding factors were not considered in individual studies estimates (e.g. possible lack of therapeutic compliance or inadequate anti-Xa levels in some populations; the mechanical valve position and model), neither taken into account in the quantitative analysis. As previously studied, there are two main effects of this limitations in a metaanalysis: a systematic bias overestimating the effect of the studied intervention and an increase of between-study variability in the estimates with high statistical heterogeneity.[56] In opposition to such potential bias, the estimates obtained for LMWH still have a large margin to remain similar to UFH/VKA, and there was no statistical heterogeneity in the meta-analysis results.
Pregnant women belong to a special population that requires special attention in terms of safety. Results here presented are limited by the scarce number of studies and absence of RCTs.
Implications for clinical practice and research
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Temporary use of LWMH appears to be as efficacious and safe as VKA or UFH in terms of thromboembolic and major bleeding risks in patients with MHV. LMWH higher predictability, ease of use and the possibility of administration to outpatients, may decrease length of in-hospital stay and translate into clinical as well as financial benefits.[22] Despite the absence of association of LMWH with increased thromboembolic risk, the data were mainly derived from observational studies. Therefore, an adequately powered multicentre RCT is urgently needed in this clinical setting to definitely establish the true efficacy and safety of LMWH in patients with MHV.
Conclusions LMWH temporary use does not seem to be associated with an increased risk of thromboembolic or major bleeding events compared to UFH or VKA continued use in patients with MHV. The majority of the evidence comes from observational studies with large confidence intervals, highlighting the need of larger and experimental studies to ensure the safety and further evaluate the efficacy.
Funding: None. Acknowledgments: We thank the Portuguese Collaborating Centre of the Cochrane Iberoamerican Network.
Addendum This article is protected by copyright. All rights reserved.15
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D. Caldeira contributed to the concept and design, data acquisition, data analysis, and interpretation of the data; wrote the first draft of the manuscript; critically revised the manuscript; and gave final approval of the submitted manuscript. C. David contributed to the interpretation of the data; wrote the first draft of the manuscript; critically revised the manuscript; and gave final approval of the submitted manuscript. A. T. Santos contributed to data acquisition and data analysis; critically revised the manuscript; and gave final approval of the submitted manuscript. J. Costa contributed to data analysis, and interpretation of the data; critically revised the manuscript; and gave final approval of the submitted manuscript. J. J. Ferreira contributed to interpretation of the data; critically revised the manuscript; and gave final approval of the submitted manuscript. F. J. Pinto contributed to interpretation of data, critically revised the manuscript, and gave final approval of the submitted manuscript.
Daniel Caldeira M.D.,*† Cláudio David M.D., *†‡ Ana T. Santos MSc,*† João Costa M.D. PhD,*†§¶ Fausto J. Pinto M.D. PhD,‡ Joaquim J. Ferreira M.D. PhD.*†
Conflict of Interests Disclosure J. J. Ferreira had speaker and consultant fees with GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, Bial, Merck-Serono, Grunenthal, and Merck Sharp and Dohme. F. J. Pinto had consultant and speaker fees with Astra Zeneca, Bayer and Boehringhrer Ingelheim. All other authors state that they have no conflicts of interest.
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38. Gohlke-Bärwolf C. Valve disease. Anticoagulation in valvular heart disease: New aspects and management during non-cardiac surgery. Heart 2000;84:56757
39. Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving VKA: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation. 2012;126:1630-9.
40. Birnie DH, Healey JS, Wells GA, Verma A, Tang AS, Krahn AD, Simpson CS, Ayala-Paredes F, Coutu B, Leiria TL, Essebag V; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med. 2013;368:2084-93.
41. Meurin P, Tabet JY, Weber H, Renaud N, Ben Driss A. Low-molecular-weight heparin as a bridging anticoagulant early after mechanical heart valve replacement. Circulation. 2006;113:564-9.
42. Steger V, Bail DH, Graf D, Walker T, Rittig K, Ziemer G. A practical approach for bridging anticoagulation after mechanical heart valve replacement. J Heart Valve Dis. 2008;17:335-42.
43. Crowther MA, Berry LR, Monagle PT, Chan AK. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116:178-86. This article is protected by copyright. All rights reserved.24
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44. Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114:409-14.
45. Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004;92:747-51.
46. Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999;181:1113-17.
47. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004;191:1024-29.
48. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:627S-44S.
49. Elkayam U, Bitar F. Valvular heart disease and pregnancy. Part II: Prosthetic valves. J Am Coll Cardiol 2005;46:403-10.
50. Bui HT, Krisnaswami A, Le CU, Chan J, Shenoy BN. Comparison of safety of subcutaneous enoxaparin as outpatient anticoagulation bridging therapy in
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patients with a mechanical heart valve versus patients with nonvalvular atrial fibrillation. Am J Cardiol. 2009;104:1429-33.
51. Douketis JD, Johnson JA, Turpie AG. Low-molecularweight heparin as bridging anticoagulation during interruption of warfarin: Assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med 2004;164:1319–26.
52. Ferreira I, Dos L, Tornos P, Nicolau I, Permanyer-Miralda G, Soler-Soler J. Experience with enoxaparin in patients with mechanical heart valves who must withhold acenocumarol. Heart 2003;89:527–30.
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56. Deeks JJ, Dinnes J, D'Amico R, Sowden AJ, Sakarovitch C, Song F, Petticrew M, Altman DG; International Stroke Trial Collaborative Group; European This article is protected by copyright. All rights reserved.26
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Carotid Surgery Trial Collaborative Group. Evaluating non-randomised intervention studies. Health Technol Assess. 2003;7:1-173.
Table 1 – Main characteristics of included studies.
Study, y Population; and des Mean Age
Valve positio n and type
Interventio ns
LMWH
Obesity; Renal dysfuncti on; Pregnanc y
Atrial fibrillatio n; LV dysfuncti on; Previous TE
Outcomes
Followup
AF: N/R LVD: N/R PTE: N/R
TE events and bleeding
1 mo
AF: N/R LVD: N/R PTE: N/R
Fetal anomalies and losses, TE events and bleeding
During pregna ncy and after deliver y
Randomized controlled trial
Bajkin e 69 patients 2009 treated with VKA requiring RCT; subgrou teeth of patie extraction valvula (without prosthe the need (MHV, for a confirm mucoperios by the teal author) flap raise), with INR 3 mo (83 % patient s)
No anti-Xa monitoring reported LMWH vs. UFH
Periproced ural bridging
172 vs. 73 Subcutane ous LMWH: enoxapari n 1 mg/kg 12/12h (76% patients), dalteparin 100 IU/kg 12/12h (13% patients), and tinzaparin 175 IU/kg per day (4% patients)
Mitral position : 62 vs. 31 Double prosthe sis: 17 vs. 8 BL: 116 vs. 32 (p
Received Date : 04-Dec-2013 Accepted Date : 07-Feb-2014 Article type
: Original Article - Clinical Haemostasis and Thrombosis
Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: systematic review and meta-analysis. Daniel Caldeira M.D.,*† Cláudio David M.D., *†‡ Ana T. Santos MSc,*† João Costa M.D. PhD,*†§¶ Fausto J. Pinto M.D. PhD,‡ Joaquim J. Ferreira M.D. PhD.*†
* Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal.
† Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Portugal.
‡ Cardiology Dpt, CCUL, CAML, University of Lisbon, Portugal. § Evidence Based Medicine Centre, Faculty of Medicine, University of Lisbon, Portugal. ¶ Portuguese Collaborating Centre of the Cochrane Iberoamerican Network, Faculty of Medicine, University of Lisbon, Portugal.
Running Title: LMWH and Mechanical Heart Valves.
Corresponding author: Daniel Caldeira, MD This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12544 This article is protected by copyright. All rights reserved.
Accepted Article
Laboratório de Farmacologia Clínica e Terapêutica Faculdade de Medicina da Universidade de Lisboa Av. Prof. Egas Moniz, Lisboa 1649-028, Portugal. E-mail: [email protected] Telef.: (+351) 21 797 34 53 Fax: (+351) 21 781 96 88
Abstract Background: Low molecular weight heparins (LMWH) are not approved for patients with mechanical heart valves (MHV). However, temporary LMWH off-label use in this clinical setting is considered in several guidelines as a valid treatment option. Therefore we reviewed the efficacy and safety of LMWH in patients with MHV.
Methods: MEDLINE and CENTRAL databases were searched from inception to June 2013. Review articles and references also searched. We included experimental and observational studies that compared LMWH with unfractionated heparin (UFH) or Vitamin K Antagonists (VKA). Data was analysed and pooled to estimate odds ratio (OR) with 95% confidence intervals (95%CI) for thromboembolic and major bleeding events. Statistical heterogeneity was evaluated with I2 test.
Results: Nine studies were included: one randomized controlled trial (RCT) and 8 observational studies, with a total of 1042 patients. No differences were found between LMWH and UFH/VKA in the risk of thromboembolic (OR 0.67; 95%CI: 0.27 to 1.68; I2=9%) or major bleeding events (OR 0.66; 95%CI: 0.36 to 1.19; I2=0%).
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Conclusions: The best evidence available might support the temporary use of LMWH as a prophylactic treatment option in patients with MHV. However, conclusions are mostly based from observational data (with large confidence intervals) and an adequately powered RCT is urgently needed in this clinical setting.
Keywords: Heparin, Low-Molecular-Weight; Heart Valve Prosthesis; Heparin; Coumarins; Warfarin.
Introduction Patients with mechanical heart valves (MHV) are at increased risk of thromboembolic events.[1] These patients require lifelong anticoagulant treatment, usually with vitamin K antagonists (VKA) whose efficacy and safety depends on close monitoring of International Normalized Ratio (INR) levels. In some occasions, when the INR level is under the target range (e.g., immediately after valve implantation; patients with a low INR during routine monitoring; or during temporary interruption of oral anticoagulant therapy for invasive procedures), other anticoagulants should be temporarily used. Unfractionated heparin (UFH) have been recommended and used in this context.[2-5] However, low molecular weight heparins (LMWH) have pharmacokinetic and pharmacodynamic properties (such as a more predictable dose-response relationship) that make this class a more attractive option for thromboprophylaxis.[6]
The lack of randomized clinical trials (RCTs), together with some published reports with inconclusive and contradictory findings, raised doubts about the safety and efficacy of LMWH in patients with MHV.[7-11] The European Society of Cardiology Guidelines consider both UFH and LMWH as treatment options for post-surgery in This article is protected by copyright. All rights reserved.3
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patients with MHV and for those undergoing surgical or diagnostic procedures needing bridging anticoagulation. These recommendations were graded “IIa” and were classified as ‘level C’ of evidence, reflecting the uncertainty of the recommendation but still in favor of treatment.[12,13]
In this study, we aimed to review and evaluate the efficacy and safety of LMWH compared to UFH or VKA in patients with MHV.
Methods Eligibility Criteria We included RCTs and observational studies (cohort or case-control studies) comparing LMWH with VKA or UFH in patients with MHV. Studies should report the incidence of thromboembolic events. We considered all patients with implanted MHV irrespective of the prosthesis position and model. LMWH included the following drugs: enoxaparin, dalteparin, parnaparin, reviparin, nadroparin, ardeparin and tinzaparin. Studies without a control group were excluded.
Database and search method MEDLINE and Cochrane Library (CENTRAL) databases were searched in October 2013 for eligible studies. The search strategy is detailed in Supplementary Online. Studies were considered irrespective of publication language. We also evaluated PubMed’s related citations and hand searched for other reviews and studies. References of obtained studies were systematically and comprehensively analyzed.
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Studies and Data Selection Potential studies retrieved from electronic search were screened independently by two authors (DC and ATS), followed by full-text assessment for the inclusion in the systematic review according to the outlined criteria.
Primary outcome was overall incidence of thrombotic and thromboembolic events, defined as any of the following events: valvular thrombosis, stroke, transient ischemic attack and peripheral arterial embolic events. Secondary outcome was overall incidence of major bleeding events, defined as those evolving a critical organ, or requiring transfusion, surgical operation, or prolongation of hospitalization. Overall we accepted each study definition for major bleeding. We extracted detailed data about population, analysed interventions, follow-up and outcomes. Disagreements were resolved by consensus between the authors.
Quality reporting assessment Studies’ reported quality was independently assessed by two authors (DC and ATS). RCTs were evaluated using the Cochrane Collaboration’s Tool, which stratifies qualitatively the risk of bias as high, unclear or low.[14] This tool evaluates the adequacy of randomisation method and allocation concealment, the blinding of participants and personnel, the selectiveness of outcome reporting, the completeness of withdrawals description, and other bias deemed to be relevant. Observational studies were qualitatively assessed with the Newcastle-Ottawa Scale.[15] This instrument has nine different questions for cohort and case-control studies and evaluates three parameters: selection of patients, comparability of study groups and assessment of This article is protected by copyright. All rights reserved.5
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outcomes. For treatment arms comparability, the characteristics considered most important for data adjustment were age, gender, valve position and other prothrombotic conditions, such as atrial fibrillation or deep venous thrombosis.
The quality of reporting was not used a priori as an exclusion criterion.
Data Synthesis Primary and secondary outcomes were summarized as dichotomous data. To estimate the effect of treatment, we choose the relative measure odds ratio (OR), and its 95% confidence interval (95% CI), rather than an absolute measure, to estimate the effect of treatment because they are more applicable to comparisons across studies with different populations and lengths of follow-up.[16] The OR was also chosen in order to include estimates from case-control studies without losing data comparability.
All statistical analyses were performed using the RevMan version 5.2.6 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). This software calculates data from individual studies and derives forest plots for the pooled analysis. Heterogeneity was assessed with the I2 test, which measures the percentage of total variation attributed to inter-study heterogeneity rather than random.[17,18] The inverse of variance method with random effects model was used by default independently of the existence (I2≥50%) or not of substantial heterogeneity between studies’ results because we anticipated to pool data from studies with different designs.[17,18] Publication bias was planned to be assessed through visual inspection of funnel plots asymmetry and Peters’ regression tests.[19,20] The latter evaluates the linearity of effect estimate with sample size.
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Results After searching electronic databases, review articles and references of obtained studies, we were able to include 9 studies (one RCT and eight observational studies) according to our eligibility criteria.[21-29] Supplemental Figure 1 shows the studies’ selection steps and reasons for excluding studies.
Description of studies and risk of bias A total of 1042 MHV patients were evaluated in these 9 studies.[21-29] The only RCT included had focused VKA-treated patients undergoing tooth extraction.[27] There were 68 patients with prosthetic heart valves (31 in LMWH arm vs. 38 in VKA arm), and we confirmed with the authors that all these patients had MHV. There were no thromboembolic or major bleeding events in all study’s patients on either LMWH or non-bridged arms, which includes patients with MHV.
The observational studies were 2 case-control studies,[21,22] and six cohort studies (three of which were prospective cohorts).[23-26,28,29] Four studies evaluated LMWH in pregnant patients with MHV,[23,24,28,29] 2 studies in patients that underwent mechanical valve implantation,[21,22] while the remaining 3 studies evaluated patients undergoing invasive procedures or non-cardiac surgeries.[25-27]
Sample size of included studies varied between 24 and 342 patients. The control group was VKA in 4 studies, UFH in 4 studies (3 with intravenous heparin and 1 with subcutaneous heparin), and both UFH and VKA in one study. Reported mean follow-up varied between 14 days and after delivery period of pregnancy. This article is protected by copyright. All rights reserved.7
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Table 1 and Supplementary Table 1 show the main characteristics and data retrieved from of studies. Adjudicated events for primary outcome and major bleeding definitions used in the studies are described in Supplementary Table 2.
Overall, the methodological/reporting quality was low. The RCT of Bajkin and colleagues was considered to be at high risk for performance, detection and reporting bias.[27] All observational studies are intrinsically prone to high risk of selective reporting bias. Following the Newcastle-Ottawa scale for quality reporting, the most common flaw was the absence of adjustment for confounding factors (including those considered important by the authors). In case-control studies, the cases were not independently validated and controls were all hospital-based. All these aspects increase the risk of bias of the included studies. Supplementary Figure 2 shows the risk of bias figure for all studies.
Effects of interventions Thromboembolic events and major bleeding
Regarding the primary outcome, one study (the RCT) reported zero events in both treatment arms.[27] Thus, only 8 studies contributed for the pooled odds ratio estimate. The risk of thromboembolic events with LMWH was not different compared to UFH or VKA with OR 0.67 (95%CI 0.27-1.68). There was no significant statistical heterogeneity (I2=9%) (Figure 1).
Regarding our secondary outcome, in three studies there were no major bleeding events reported in both arms.[23,24,27] In the pooled analysis of the six included studies,
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LMWH did not increased the risk of major bleeding with OR 0.66 (95%CI 0.36-1.19). No statistical heterogeneity was found among studies (I2=0%) (Figure 1).
Post-hoc subgroup and sensitivity analyses
Although no significant statistical heterogeneity existed in the pooled results from included studies, we performed several subgroup and sensitivity analysis to explore the robustness of the results and to limit clinical heterogeneity. Pooled estimates were calculated according to the type of control group (LMWH vs. UFH and LMWH vs. VKA), indication for LMWH use (pregnancy, post MHV implantation, post procedure/non-cardiac surgery) and study design (prospective and retrospective). A sensitivity analysis was also performed by excluding from the analysis all case-control studies, which are known to be more prone to bias than cohort studies and RCTs. Overall results for both primary and secondary outcomes were consistent across all these analyses, i.e., no differences existed between LMWH and controls (Figure 2).
Three studies have used anti-Xa monitoring in the LMWH arm.[21,28,29] The incidence of thromboembolic events (OR 2.09, 95%CI 0.17-25.85; I2=61%) and major bleeding (OR 0.80, 95%CI 0.26-2.50; I2=0%) was similar to controls.
Analyses using Peto’s Odds Ratio and Risk Difference measures
We further explored the impact of using different effect measurements on pooled estimates, because the events’ rates were low or null in some studies.
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Peto’s odds ratio in circumstances of rare events has been reported to be an adequate and more reliable effect measurement for dichotomous outcomes.[30] Results were similar to those of primary analysis with Peto’s OR 0.62 (95% CI 0.25-1.57; I2=55%). For major bleeding, the Peto´s OR was 0.64 (95% CI 0.34-1.21; I2=0%).
Risk difference (RD) is a measure that can give inconsistent estimates in pooled analyses mainly due to the constrains of different baseline risks when applying results across different groups and clinical settings.[31] However it has the advantage to consider studies with zero events in both arms for meta-analysis estimate.[31,32] The RD between LMWH and UFH/VKA was -1.0% (95%CI: -2.6% to 0.5%; I2=0%) and 0.1% (95%CI: -3.4% to +1.4%; I2=0%) for thromboembolic and major bleeding events, respectively.
Publication bias
The visual inspection of the funnel plot is not conclusive about the absence of publication bias (Supplementary Figure 3). Peters regression test did not found evidence of publication bias (p=0.156).
Discussion
VKA are the oral anticoagulants of choice for patients with MHV and UFH (the only heparin approved for patients with MHV) has been the most commonly used drug for bridging.[2-5] According to the present data, based on 10 studies and 1068 patients, LMWH is effective and safe for temporary use in patients with MHV in terms of thromboembolic risk, compared to the ‘reference’ drugs. Subgroup and sensitivity This article is protected by copyright. All rights reserved.10
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analyses consistently showed no differences between LMWH and the “reference” drugs (VKA/UFH). Compared to other reviews,[11,33] this systematic review had the merit to review all clinical controlled studies and to use a quantitative method to assess benefit and harm of the intervention.
The data here presented is partially based on studies that used LMWH as a bridging agent. In this context, LMWH offer some pharmacological advantages comparing to UFH: lower incidence of thrombocytopenia and osteoporosis, predictable dose-response relationship, decreased of hospital length of stay and reduced costs.[22] However, doseresponse relationship may be less predictable in patients with obesity,[34] renal dysfunction,[35,36] and pregnant women.[33,37]
Concerns have been raised about the thromboembolic risk during the periprocedural period. Impaired hemostasis related to the prothrombotic effect of ‘switching on and off’ of VKA, in addition to other patients thrombotic risk factors (e.g. atrial fibrillation) highlighted the need of a transitory antithrombotic treatment.[38] Nevertheless, Siegal and colleagues showed in a systematic review that periprocedural bridging is associated with bleeding risk increase.[39] Thus, considering the available data, VKA–treated patients receiving periprocedural heparin (UFH or LMWH) bridging appear to be at an increased risk of overall and major bleeding with similar risk of thromboembolic events, compared to nonbridged patients.[39,40] Despite the absence of approval for the use in patients with MHV, LMWH are considered to be a treatment option in guidelines for peri-procedural bridging treatment.[10] These drugs should be given subcutaneously twice a day using body weight-adjusted therapeutic doses and anti-Xa activity monitoring with target levels ranging from 0.5 to 1.0 U/ml.[9] This article is protected by copyright. All rights reserved.11
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After MHV replacement, patients may also require heparin-based anticoagulation in order to avoid thromboembolic events associated to delayed therapeutic effect and early prothrombotic effect of VKA.[41] Steger and colleagues followed a cohort of 256 patients who underwent MHV implantation and were treated with fixed and lower dose of enoxaparin (40 mg, twice daily, subcutaneously).[42] In this study, with a mean follow-up of 38 days, LMWH showed to be safe without prosthesis thrombosis and major bleeding.[42]
Only 3 studies used anti-Xa monitoring to adjust LMWH anticoagulation.[21,28,29] No significant differences were found comparing to UFH or VKA, but the comparison is clearly underpowered. In fact, anti-Xa monitoring may optimize anticoagulation in some patients after surgery not only because of the higher risk of bleeding,[21] particularly those in whom the dosage may be difficult to determine (eg. patients with renal dysfunction or obesity), but also due to the lack of full reversibility of LMWH by protamine, frequently insufficient to arrest bleeding.[6,43]
In pregnant patients, VKA cross the placenta with teratogenic risk in the first trimester and increases the risk of fetal bleeding during the delivery.[33] LMWH does not cross the placenta and is not toxic to the fetus, but pregnant women have increased risk of thromboembolic events, due to pregnancy itself and to lower anti-Xa levels,[44,45] probably related to unstable LMWH clearance and higher volume of distribution.[46,47] Tight monitoring is recommended with target anti-Xa levels of 1.01.2U/ml at 4-6 h after subcutaneous injection and 0.6-0.7 U/ml before the next LMWH dose.[48,49] This article is protected by copyright. All rights reserved.12
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The use of LMWH in MHV patients is associated with a low risk of events similarly to atrial fibrillation patients bridged with LMWH.[50] This safety data was also sustained in case series and in prospective ‘real world’ registries,[41,51-53] but the absence of a control group limits their conclusions.
Limitations
In this systematic review we performed a meta-analysis of the best available evidence (mainly based on observational studies, not patient level data) in order to overcome the scarcity of controlled studies in this area. The use of data from observational studies may raise methodological and interpretational concerns.[54] Clinical decisions based exclusively on this type of evidence should be weighted with caution.[55] Nevertheless, these data are informative and increases the knowledge of the use of LMWH in patients with MHV.
Other limitations should be taken into account in the interpretation of our findings. First, we pooled different studies with different indications, which cumulatively limit our conclusions. Second, we acknowledge that most of the evidence and estimates here shown were derived from observational studies’ data. The only randomized study included, was not considered in most of the quantitative analyses due to the lack of events, which suggests safety despite the underpowered nature of the study. Third, short duration bridging treatment is different from longer substitution of anticoagulants (as occurs in pregnant women with MHV), as VKA residual effect may still be present during the first days, with potential higher risk of hemorrhagic events. This article is protected by copyright. All rights reserved.13
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Should be acknowledged that outcomes were not systematically adjudicated, with the potential for major imprecision in outcome rates and that the definition of major bleeding, was also different among studies (Supplementary Table 2).
In a systematic review of non-randomized studies, the risk of selective reporting bias should be noticed. Furthermore, we included studies based on the absence of events. Nevertheless, these studies did not contributed to the primary analysis of this review. Confounding factors were not considered in individual studies estimates (e.g. possible lack of therapeutic compliance or inadequate anti-Xa levels in some populations; the mechanical valve position and model), neither taken into account in the quantitative analysis. As previously studied, there are two main effects of this limitations in a metaanalysis: a systematic bias overestimating the effect of the studied intervention and an increase of between-study variability in the estimates with high statistical heterogeneity.[56] In opposition to such potential bias, the estimates obtained for LMWH still have a large margin to remain similar to UFH/VKA, and there was no statistical heterogeneity in the meta-analysis results.
Pregnant women belong to a special population that requires special attention in terms of safety. Results here presented are limited by the scarce number of studies and absence of RCTs.
Implications for clinical practice and research
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Temporary use of LWMH appears to be as efficacious and safe as VKA or UFH in terms of thromboembolic and major bleeding risks in patients with MHV. LMWH higher predictability, ease of use and the possibility of administration to outpatients, may decrease length of in-hospital stay and translate into clinical as well as financial benefits.[22] Despite the absence of association of LMWH with increased thromboembolic risk, the data were mainly derived from observational studies. Therefore, an adequately powered multicentre RCT is urgently needed in this clinical setting to definitely establish the true efficacy and safety of LMWH in patients with MHV.
Conclusions LMWH temporary use does not seem to be associated with an increased risk of thromboembolic or major bleeding events compared to UFH or VKA continued use in patients with MHV. The majority of the evidence comes from observational studies with large confidence intervals, highlighting the need of larger and experimental studies to ensure the safety and further evaluate the efficacy.
Funding: None. Acknowledgments: We thank the Portuguese Collaborating Centre of the Cochrane Iberoamerican Network.
Addendum This article is protected by copyright. All rights reserved.15
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D. Caldeira contributed to the concept and design, data acquisition, data analysis, and interpretation of the data; wrote the first draft of the manuscript; critically revised the manuscript; and gave final approval of the submitted manuscript. C. David contributed to the interpretation of the data; wrote the first draft of the manuscript; critically revised the manuscript; and gave final approval of the submitted manuscript. A. T. Santos contributed to data acquisition and data analysis; critically revised the manuscript; and gave final approval of the submitted manuscript. J. Costa contributed to data analysis, and interpretation of the data; critically revised the manuscript; and gave final approval of the submitted manuscript. J. J. Ferreira contributed to interpretation of the data; critically revised the manuscript; and gave final approval of the submitted manuscript. F. J. Pinto contributed to interpretation of data, critically revised the manuscript, and gave final approval of the submitted manuscript.
Daniel Caldeira M.D.,*† Cláudio David M.D., *†‡ Ana T. Santos MSc,*† João Costa M.D. PhD,*†§¶ Fausto J. Pinto M.D. PhD,‡ Joaquim J. Ferreira M.D. PhD.*†
Conflict of Interests Disclosure J. J. Ferreira had speaker and consultant fees with GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, Bial, Merck-Serono, Grunenthal, and Merck Sharp and Dohme. F. J. Pinto had consultant and speaker fees with Astra Zeneca, Bayer and Boehringhrer Ingelheim. All other authors state that they have no conflicts of interest.
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Table 1 – Main characteristics of included studies.
Study, y Population; and des Mean Age
Valve positio n and type
Interventio ns
LMWH
Obesity; Renal dysfuncti on; Pregnanc y
Atrial fibrillatio n; LV dysfuncti on; Previous TE
Outcomes
Followup
AF: N/R LVD: N/R PTE: N/R
TE events and bleeding
1 mo
AF: N/R LVD: N/R PTE: N/R
Fetal anomalies and losses, TE events and bleeding
During pregna ncy and after deliver y
Randomized controlled trial
Bajkin e 69 patients 2009 treated with VKA requiring RCT; subgrou teeth of patie extraction valvula (without prosthe the need (MHV, for a confirm mucoperios by the teal author) flap raise), with INR 3 mo (83 % patient s)
No anti-Xa monitoring reported LMWH vs. UFH
Periproced ural bridging
172 vs. 73 Subcutane ous LMWH: enoxapari n 1 mg/kg 12/12h (76% patients), dalteparin 100 IU/kg 12/12h (13% patients), and tinzaparin 175 IU/kg per day (4% patients)
Mitral position : 62 vs. 31 Double prosthe sis: 17 vs. 8 BL: 116 vs. 32 (p
