Non-vitamin-K-antagonist oral anticoagulants (NOACs) after acute myocardial infarction: a network meta-analysis.
Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The potential of non-vitamin K antagonist oral anticoagulants (NOACs) to prevent ischaemic cardiovascular events is promising, but the evidence remains limited.
To evaluate the efficacy and safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in addition to background antiplatelet therapy, compared with placebo, antiplatelet therapy, or both, after acute myocardial infarction (AMI) in people without an indication for anticoagulation (i.e. atrial fibrillation or venous thromboembolism).
We searched CENTRAL, MEDLINE, Embase, the Conference Proceedings Citation Index - Science, and two clinical trial registers in September 2022 with no language restrictions. We checked the reference lists of included studies for any additional trials.
We searched for randomised controlled trials (RCTs) that evaluated NOACs plus antiplatelet therapy versus placebo, antiplatelet therapy, or both, in people without an indication for anticoagulation after an AMI.
Two review authors independently checked the results of searches to identify relevant studies, assessed each included study, and extracted study data. We conducted random-effects pairwise analyses using Review Manager Web, and network meta-analysis using the R package 'netmeta'. We ranked competing treatments by P scores, which are derived from the P values of all pairwise comparisons and allow ranking of treatments on a continuous 0-to-1 scale.
We identified seven eligible RCTs, including an ongoing trial that we could not include in the analysis. Of the six RCTs involving 33,039 participants, three RCTs compared rivaroxaban with placebo, two RCTs compared apixaban with placebo, and one RCT compared dabigatran with placebo. All participants in the six RCTs received concomitant antiplatelet therapy. The available evidence suggests that rivaroxaban compared with placebo reduces the rate of all-cause mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.69 to 0.98; number needed to treat for an additional beneficial outcome (NNTB) 250; 3 studies, 21,870 participants; high certainty) and probably reduces cardiovascular mortality (RR 0.83, 95% CI 0.69 to 1.01; NNTB 250; 3 studies, 21,870 participants; moderate certainty). There is probably little or no difference between apixaban and placebo in all-cause mortality (RR 1.09, 95% CI 0.88 to 1.35; number needed to treat for an additional harmful outcome (NNTH) 334; 2 studies, 8638 participants; moderate certainty) and cardiovascular mortality (RR 0.99, 95% CI 0.77 to 1.27; number needed to treat not applicable; 2 studies, 8638 participants; moderate certainty). Dabigatran may reduce the rate of all-cause mortality compared with placebo (RR 0.57, 95% CI 0.31 to 1.06; NNTB 63; 1 study, 1861 participants; low certainty). Dabigatran compared with placebo may have little or no effect on cardiovascular mortality, although the point estimate suggests benefit (RR 0.72, 95% CI 0.34 to 1.52; NNTB 143; 1 study, 1861 participants; low certainty). Two of the investigated NOACs were associated with an increased risk of major bleeding compared to placebo: apixaban (RR 2.41, 95% CI 1.44 to 4.06; NNTH 143; 2 studies, 8544 participants; high certainty) and rivaroxaban (RR 3.31, 95% CI 1.12 to 9.77; NNTH 125; 3 studies, 21,870 participants; high certainty). There may be little or no difference between dabigatran and placebo in the risk of major bleeding (RR 1.74, 95% CI 0.22 to 14.12; NNTH 500; 1 study, 1861 participants; low certainty). The results of the network meta-analysis were inconclusive between the different NOACs at all individual doses for all primary outcomes. However, low-certainty evidence suggests that apixaban (combined dose) may be less effective than rivaroxaban and dabigatran for preventing all-cause mortality after AMI in people without an indication for anticoagulation.
Compared with placebo, rivaroxaban reduces all-cause mortality and probably reduces cardiovascular mortality after AMI in people without an indication for anticoagulation. Dabigatran may reduce the rate of all-cause mortality and may have little or no effect on cardiovascular mortality. There is probably no meaningful difference in the rate of all-cause mortality and cardiovascular mortality between apixaban and placebo. Moreover, we found no meaningful benefit in efficacy outcomes for specific therapy doses of any investigated NOACs following AMI in people without an indication for anticoagulation. Evidence from the included studies suggests that rivaroxaban and apixaban increase the risk of major bleeding compared with placebo. There may be little or no difference between dabigatran and placebo in the risk of major bleeding. Network meta-analysis did not show any superiority of one NOAC over another for our prespecified primary outcomes. Although the evidence suggests that NOACs reduce mortality, the effect size or impact is small; moreover, NOACs may increase major bleeding. Head-to-head trials, comparing NOACs against each other, are required to provide more solid evidence.
Al Said S
，Kaier K
，Sumaya W
，Alsaid D
，Duerschmied D
，Storey RF
，Gibson CM
，Westermann D
，Alabed S
... -
《Cochrane Database of Systematic Reviews》
Direct factor Xa inhibitors versus low molecular weight heparins or vitamin K antagonists for prevention of venous thromboembolism in elective primary hip or knee replacement or hip fracture repair.
People undergoing major orthopaedic surgery are at increased risk of postoperative thromboembolic events. Low molecular weight heparins (LMWHs) are recommended for thromboprophylaxis in this population. New oral anticoagulants, including direct factor Xa inhibitors, are recommended as alternatives. They may have more advantages than disadvantages compared to LMWHs and vitamin K antagonists (VKAs, another type of anticoagulant).
To assess the benefits and harms of prophylactic anticoagulation with direct factor Xa inhibitors compared with low molecular weight heparins and vitamin K antagonists in people undergoing major orthopaedic surgery for elective total hip or knee replacement or hip fracture surgery.
We searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, two other databases, and two trial registers to 11 November 2023. We conducted reference checks to identify additional studies.
We included randomised controlled trials (RCTs) comparing the effects of direct factor Xa inhibitors to LMWHs or VKAs in people undergoing major orthopaedic surgery.
We used standard Cochrane methods. Our primary outcomes were all-cause mortality, major venous thromboembolism (VTE), symptomatic VTE, major bleeding, and serious hepatic and non-hepatic adverse events. We evaluated the risk of bias in the included studies using Cochrane's risk of bias 1 tool. We calculated estimates of treatment effects using risk ratios (RR) with 95% confidence intervals (CIs), and used GRADE criteria to assess the certainty of the evidence.
We included 53 RCTs (44,371 participants). Participants' average age was 64 years (range: 18 to 93 years). Only one RCT compared a VKA with direct factor Xa inhibitors. All 53 RCTs compared direct factor Xa inhibitors with LMWHs. Twenty-three studies included participants undergoing total hip replacement; 21 studies, total knee replacement; and three studies included people having hip fracture surgery. The studies' average duration was approximately 42 days (range: two to 720 days). Compared to LMWHs, direct factor Xa inhibitors may have little to no effect on all-cause mortality, but the evidence is very uncertain (RR 0.83, 95% CI 0.52 to 1.31; I2 = 0%; 28 studies, 29,698 participants; very low-certainty evidence). Direct factor Xa inhibitors may make little to no difference to major venous thromboembolic events compared to LMWHs, but the evidence is very uncertain (RR 0.51, 95% CI 0.37 to 0.71; absolute risk difference: 12 fewer major VTE events per 1000 participants, 95% CI 16 fewer to 7 fewer; I2 = 48%; 28 studies, 24,574 participants; very low-certainty evidence). Compared to LMWHs, direct factor Xa inhibitors may reduce symptomatic VTE (RR 0.64, 95% CI 0.50 to 0.83; I2 = 0%; 33 studies, 31,670 participants; low-certainty evidence). The absolute benefit of substituting factor Xa inhibitors for LMWHs may be between two and five fewer symptomatic VTE episodes per 1000 patients. In the meta-analysis with all studies pooled, direct factor Xa inhibitors appeared to make little or no difference to major bleeding compared to LMWHs, but the evidence was very uncertain (RR 1.05, 95% CI 0.86 to 1.30; I2 = 15%; 36 studies, 39,778 participants; very low certainty-evidence). • In a subgroup analysis limited to studies comparing rivaroxaban to LMWHs, people given rivaroxaban may have had more major bleeding events (RR 1.94, 95% CI 1.26 to 2.98; I2 = 0%; 17 studies, 17,630 participants; low-certainty evidence). The absolute risk of substituting rivaroxaban for LMWH may be between one and seven more major bleeding events per 1000 patients. • In a subgroup analysis limited to studies comparing direct factor Xa inhibitors other than rivaroxaban to LMWHs, people given these other direct factor Xa inhibitors may have had fewer major bleeding events, but the evidence was very uncertain (RR 0.80, 95% CI 0.63 to 1.02; absolute risk difference: 3 fewer major bleeding events per 1000 participants, 95% CI 5 fewer to 0 fewer; I2 = 0%; 19 studies, 22,148 participants; very low-certainty evidence). Direct factor Xa inhibitors may make little to no difference in serious hepatic adverse events compared to LMWHs, but the evidence is very uncertain (RR 3.01, 95% CI 0.12 to 73.93; 2 studies, 3169 participants; very low-certainty evidence). Only two studies reported this outcome, with one death in the intervention group due to hepatitis reported in one study, and no events reported in the other study. People given direct factor Xa inhibitors may have a lower risk of serious non-hepatic adverse events than those given LMWHs (RR 0.89, 95% CI 0.81 to 0.97; I2 = 18%; 15 studies, 26,246 participants; low-certainty evidence). The absolute benefit of substituting factor Xa inhibitors for LMWH may be between three and 14 fewer serious non-hepatic adverse events per 1000 patients. Only one study compared a direct factor Xa inhibitor with a VKA. It reported outcome data with imprecise results due to the small number of events. It showed no difference in the effects of the study drugs.
Oral direct factor Xa inhibitors may have little to no effect on all-cause mortality, but the evidence is very uncertain. Oral direct factor Xa inhibitors may slightly reduce symptomatic VTE events when compared with LMWH. They may make little or no difference to major VTE events, but the evidence is very uncertain. In the evaluation of major bleeding, the evidence suggests rivaroxaban results in a slight increase in major bleeding events compared to LMWHs. The remaining oral direct factor Xa inhibitors may have little to no effect on major bleeding, but the evidence is very uncertain. Oral direct factor Xa inhibitors may reduce serious non-hepatic adverse events slightly compared to LMWHs. They may have little to no effect on serious hepatic adverse events, but the evidence is very uncertain. Due to the high rates of missing participants and selective outcome reporting, the effect estimates may be biased.
Salazar CA
，Basilio Flores JE
，Malaga G
，Malasquez GN
，Bernardo R
... -
《Cochrane Database of Systematic Reviews》
Treatment for women with postpartum iron deficiency anaemia.
Postpartum iron deficiency anaemia is caused by antenatal iron deficiency or excessive blood loss at delivery and might affect up to 50% of labouring women in low- and middle-income countries. Effective and safe treatment during early motherhood is important for maternal well-being and newborn care. Treatment options include oral iron supplementation, intravenous iron, erythropoietin, and red blood cell transfusion.
To assess the benefits and harms of the available treatment modalities for women with postpartum iron deficiency anaemia. These include intravenous iron, oral iron supplementation, red blood cell transfusion, and erythropoietin.
A Cochrane Information Specialist searched for all published, unpublished, and ongoing trials, without language or publication status restrictions. We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, LILACS, WHO ICTRP, and ClinicalTrials.gov, together with reference checking, citation searching, and contact with study authors to identify eligible studies. We applied date limits to retrieve new records since the last search on 9 April 2015 until 11 April 2024.
We included published, unpublished, and ongoing randomised controlled trials (RCTs) that compared treatments for postpartum iron deficiency anaemia with placebo, no treatment, or alternative treatments. Cluster-randomised trials were eligible for inclusion. We included RCTs regardless of blinding. Participants were women with postpartum haemoglobin ≤ 12 g/dL, treated within six weeks after childbirth. We excluded non-randomised, quasi-randomised, and cross-over trials.
The critical outcomes of this review were maternal mortality and fatigue. The important outcomes included persistent anaemia symptoms, persistent postpartum anaemia, psychological well-being, infections, compliance with treatment, breastfeeding, length of hospital stay, serious adverse events, anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort/reaction, constipation, gastrointestinal pain, number of red blood cell transfusions, and haemoglobin levels.
We assessed risk of bias in the included studies using the Cochrane RoB 1 tool.
Two review authors independently performed study screening, risk of bias assessment, and data extraction. We contacted trial authors for supplementary data when necessary. We screened all trials for trustworthiness and scientific integrity using the Cochrane Trustworthiness Screening Tool. We conducted meta-analyses using a fixed-effect model whenever feasible to synthesise outcomes. In cases where data were not suitable for meta-analysis, we provided a narrative summary of important findings. We evaluated the overall certainty of the evidence using GRADE.
We included 33 RCTs with a total of 4558 postpartum women. Most trials were at high risk of bias for several risk of bias domains.
Most of the evidence was of low or very low certainty. Imprecision due to few events and risk of bias due to lack of blinding were the most important factors. Intravenous iron versus oral iron supplementation The evidence is very uncertain about the effect of intravenous iron on mortality (risk ratio (RR) 2.95, 95% confidence interval (CI) 0.12 to 71.96; P = 0.51; I² = not applicable; 3 RCTs; 1 event; 572 women; very low-certainty evidence). One woman died of cardiomyopathy, and another developed arrhythmia, both in the groups treated with intravenous iron. Intravenous iron probably results in a slight reduction in fatigue within 8 to 28 days (standardised mean difference -0.25, 95% CI -0.42 to -0.07; P = 0.006; I² = 47%; 2 RCTs; 515 women; moderate-certainty evidence). Breastfeeding was not reported. Oral iron probably increases the risk of constipation compared to intravenous iron (RR 0.12, 95% CI 0.06 to 0.21; P < 0.001; I² = 0%; 10 RCTs; 1798 women; moderate-certainty evidence). The evidence is very uncertain about the effect of intravenous iron on anaphylaxis or hypersensitivity (RR 2.77, 95% CI 0.31 to 24.86; P = 0.36; I² = 0%; 12 RCTs; 2195 women; very low-certainty evidence). Three women treated with intravenous iron experienced anaphylaxis or hypersensitivity. The trials that reported on haemoglobin at 8 to 28 days were too heterogeneous to pool. However, 5 of 6 RCTs favoured intravenous iron, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL (low-certainty evidence). Red blood cell transfusion versus intravenous iron No women died in the only trial that reported on mortality (1 RCT; 7 women; very low-certainty evidence). The evidence is very uncertain about the effect of red blood cell transfusion on fatigue at 8 to 28 days (mean difference (MD) 1.20, 95% CI -2.41 to 4.81; P = 0.51; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence) and breastfeeding more than six weeks postpartum (RR 0.43, 95% CI 0.12 to 1.57; P = 0.20; I² = not applicable; 1 RCT; 13 women; very low-certainty evidence). Constipation and anaphylaxis were not reported. Red blood cell transfusion may result in little to no difference in haemoglobin within 8 to 28 days (MD -1.00, 95% CI -2.02 to 0.02; P = 0.05; I² = not applicable; 1 RCT; 12 women; low-certainty evidence). Intravenous iron and oral iron supplementation versus oral iron supplementation Mortality and breastfeeding were not reported. One trial reported a greater improvement in fatigue in the intravenous and oral iron group, but the effect size could not be calculated (1 RCT; 128 women; very low-certainty evidence). Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone (RR 0.21, 95% CI 0.07 to 0.69; P = 0.01; I² = not applicable; 1 RCT; 128 women; low-certainty evidence). There were no anaphylaxis or hypersensitivity events in the trials (2 RCTs; 168 women; very low-certainty evidence). Intravenous iron and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD 0.00, 95% CI -0.48 to 0.48; P = 1.00; I² = not applicable; 1 RCT; 60 women; low-certainty evidence). Red blood cell transfusion versus no transfusion Mortality, fatigue at day 8 to 28, constipation, anaphylaxis, and haemoglobin were not reported. Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum (RR 0.91, 95% CI 0.78 to 1.07; P = 0.24; I² = not applicable; 1 RCT; 297 women; low-certainty evidence). Oral iron supplementation versus placebo or no treatment Mortality, fatigue, breastfeeding, constipation, anaphylaxis, and haemoglobin were not reported. Two trials reported on gastrointestinal symptoms, but did not report results by study arm.
Intravenous iron probably reduces fatigue slightly in the early postpartum weeks (8 to 28 days) compared to oral iron tablets, but probably results in little to no difference after four weeks. It is very uncertain if intravenous iron has an effect on mortality and anaphylaxis/hypersensitivity. Breastfeeding was not reported. Intravenous iron may increase haemoglobin slightly more than iron tablets, but the data were too heterogeneous to pool. However, changes in haemoglobin levels are a surrogate outcome, and treatment decisions should preferentially be based on patient-relevant outcomes. Iron tablets probably result in a large increase in constipation compared to intravenous iron. The effect of red blood cell transfusion compared to intravenous iron on mortality, fatigue, and breastfeeding is very uncertain. No studies reported on constipation or anaphylaxis/hypersensitivity. Red blood cell transfusion may result in little to no difference in haemoglobin at 8 to 28 days. The effect of intravenous iron and oral iron supplementation on mortality, fatigue, breastfeeding, and anaphylaxis/hypersensitivity is very uncertain or unreported. Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone, and in little to no difference in haemoglobin. The effect of red blood cell transfusion compared to non-transfusion on mortality, fatigue, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. Red blood cell transfusion may result in little to no difference in breastfeeding. The effect of oral iron supplementation on mortality, fatigue, breastfeeding, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported.
This Cochrane review had no dedicated funding.
Protocol and previous versions are available: Protocol (2013) [DOI: 10.1002/14651858.CD010861] Original review (2004) [DOI: 10.1002/14651858.CD004222.pub2] Review update (2015) [DOI: 10.1002/14651858.CD010861.pub2].
Jensen MCH
，Holm C
，Jørgensen KJ
，Schroll JB
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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